antithrombotic therapy for vte disease : antithrombotic ... · e420s antithrombotic therapy for vte...

DOI 10.1378/chest.11-2301 2012;141;e419S-e494SChest

Michael K. Gould, Francesco Dentali, Mark Crowther and Susan R. KahnBounameaux, Samuel Z. Goldhaber, Michael E. Nelson, Philip S. Wells, Clive Kearon, Elie A. Akl, Anthony J. Comerota, Paolo Prandoni, Henri Practice GuidelinesChest Physicians Evidence-Based Clinical Thrombosis, 9th ed: American College ofAntithrombotic Therapy and Prevention of Antithrombotic Therapy for VTE Disease :

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CHEST Supplement

www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e419S

ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Recommendations that remain unchanged are not shaded.

2.1. In patients with acute DVT of the leg treated with vitamin K antagonist (VKA) therapy, we

Background: This article addresses the treatment of VTE disease. Methods: We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence. Results: For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagu-lant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a fi rst proximal DVT or PE that is provoked by surgery or by a nonsurgical tran-sient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsur-gical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivar-oxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superfi cial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C). Conclusion: Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences. CHEST 2012; 141(2)(Suppl):e419S–e494S

Abbreviations: CALISTO 5 Comparison of ARIXTRA in Lower Limb Superfi cial Thrombophlebitis With Placebo; CDT 5 catheter-directed thrombolysis; CTPH 5 chronic thromboembolic pulmonary hypertension; HR 5 hazard ratio; INR 5 international normalized ratio; IVC 5 inferior vena cava; LMWH 5 low-molecular-weight heparin; PE 5 pulmo-nary embolism; PESI 5 Pulmonary Embolism Severity Index; PREPIC 5 Prevention du Risque d’Embolie Pulmonaire par Interruption Cave; PTS 5 postthrombotic (phlebitic) syndrome; RR 5 risk ratio; rt-PA 5 recombinant tissue plasminogen activator; SC 5 subcutaneous; SVT 5 superfi cial vein thrombosis; tPA 5 tissue plasminogen activator; UEDVT 5 upper-extremity DVT; UFH 5 unfractionated heparin; VKA 5 vitamin K antagonist

Antithrombotic Therapy for VTE Disease Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Clive Kearon , MD , PhD ; Elie A. Akl , MD , MPH , PhD ; Anthony J. Comerota , MD ; Paolo Prandoni , MD , PhD ; Henri Bounameaux , MD ; Samuel Z. Goldhaber , MD , FCCP ; Michael E. Nelson , MD , FCCP ; Philip S. Wells , MD ; Michael K. Gould , MD , FCCP ; Francesco Dentali , MD ; Mark Crowther, MD ; and Susan R. Kahn , MD

Summary of Recommendations

Note on Shaded Text: Throughout this guideline, shading is used within the summary of recommenda-tions sections to indicate recommendations that are newly added or have been changed since the publica-tion of Antithrombotic and Thrombolytic Therapy:


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e420S Antithrombotic Therapy for VTE

of diagnostic tests, provided test results are expected within 24 h (Grade 2C) .

2.3.1. In patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension, we suggest serial imaging of the deep veins for 2 weeks over initial antico-agulation (Grade 2C) .

2.3.2. In patients with acute isolated distal DVT of the leg and severe symptoms or risk factors for extension (see text), we suggest initial anti-coagulation over serial imaging of the deep veins (Grade 2C) .

Remarks: Patients at high risk for bleeding are more likely to benefi t from serial imaging. Patients who place a high value on avoiding the inconvenience of repeat imaging and a low value on the inconvenience of treatment and on the potential for bleeding are likely to choose initial anticoagulation over serial imaging.

2.3.3. In patients with acute isolated distal DVT of the leg who are managed with initial anti-coagulation, we recommend using the same approach as for patients with acute proximal DVT (Grade 1B) .

2.3.4. In patients with acute isolated distal DVT of the leg who are managed with serial imaging, we recommend no anticoagulation if the throm-bus does not extend (Grade 1B) ; we suggest anti-coagulation if the thrombus extends but remains confi ned to the distal veins (Grade 2C) ; we rec-ommend anticoagulation if the thrombus extends into the proximal veins (Grade 1B) .

2.4. In patients with acute DVT of the leg, we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anti-coagulation for a minimum of 5 days and until the international normalized ratio (INR) is 2.0 or above for at least 24 h (Grade 1B) .

2.5.1. In patients with acute DVT of the leg, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux) .

Remarks: Local considerations such as cost, availability, and familiarity of use dictate the choice between fondaparinux and LMWH.

LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH .

recommend initial treatment with parenteral anticoagulation (low-molecular-weight heparin [LMWH], fondaparinux, IV unfractionated hep-arin [UFH], or subcutaneous [SC] UFH) over no such initial treatment (Grade 1B) .

2.2.1. In patients with a high clinical suspicion of acute VTE, we suggest treatment with paren-teral anticoagulants compared with no treat-ment while awaiting the results of diagnostic tests (Grade 2C) .

2.2.2. In patients with an intermediate clinical suspicion of acute VTE, we suggest treatment with parenteral anticoagulants compared with no treatment if the results of diagnostic tests are expected to be delayed for more than 4 h (Grade 2C) .

2.2.3. In patients with a low clinical suspicion of acute VTE, we suggest not treating with paren-teral anticoagulants while awaiting the results

Revision accepted August 31, 2011. Affi liations: From the Departments of Medicine and Clinical Epidemiology and Biostatistics (Dr Kearon), Michael De Groote School of Medicine, McMaster University, Hamilton, ON, Can-ada; Departments of Medicine, Family Medicine, and Social and Preventive Medicine (Dr Akl), State University of New York at Buffalo, Buffalo, NY; Department of Surgery (Dr Comerota), Jobst Vascular Center, Toledo, OH; Department of Cardiotho-racic and Vascular Sciences (Dr Prandoni), University of Padua, Padua, Italy; Department of Medical Specialties (Dr Bounameaux), University Hospitals of Geneva, Geneva, Switzerland; Department of Medicine (Dr Goldhaber), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; Department of Medicine (Dr Nelson), Shawnee Mission Medical Center, Shawnee Mission, KS; Department of Medicine (Dr Wells), University of Ottawa, Ottawa, ON, Canada; Departments of Medicine and Preventive Medicine (Dr Gould), Keck School of Medicine, University of Southern California, Los Angeles, CA; Department of Medicine (Dr Dentali), University of Insubria, Varese, Italy; Department of Medicine (Dr Crowther), Michael De Groote School of Med-icine, McMaster University, Hamilton, ON, Canada; and Depart-ments of Medicine and Clinical Epidemiology and Biostatistics (Dr Kahn), McGill University, Montreal, QC, Canada. Funding/Support : The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants were also provided by Bristol-Myers Squibb; Pfi zer, Inc; Canyon Pharmaceuticals; and sanofi -aventis US. Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S. Correspondence to: Elie A. Akl, MD, MPH, PhD, Department of Medicine, State University of New York at Buffalo, ECMC-CC 142, 462 Grider St, Buffalo, NY 14215 ; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http://www.chestpubs.org/site/misc/reprints.xhtml ). DOI: 10.1378/chest.11-2301


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2.13.1. In patients with acute DVT of the leg, we recommend against the use of an inferior vena cava (IVC) fi lter in addition to anticoagulants (Grade 1B) .

2.13.2. In patients with acute proximal DVT of the leg and contraindication to anticoagulation, we recommend the use of an IVC fi lter (Grade 1B) .

2.13.3. In patients with acute proximal DVT of the leg and an IVC fi lter inserted as an alterna-tive to anticoagulation, we suggest a conven-tional course of anticoagulant therapy if their risk of bleeding resolves (Grade 2B) .

Remarks: We do not consider that a permanent IVC fi lter, of itself, is an indication for extended anti-coagulation.

2.14. In patients with acute DVT of the leg, we suggest early ambulation over initial bed rest (Grade 2C) .

Remarks: If edema and pain are severe, ambula-tion may need to be deferred. As per section 4.1, we suggest the use of compression therapy in these patients.

3.0. In patients with acute VTE who are treated with anticoagulant therapy, we recommend long-term therapy (see section 3.1 for recom-mended duration of therapy) over stopping anti-coagulant therapy after about 1 week of initial therapy (Grade 1B) .

3.1.1. In patients with a proximal DVT of the leg provoked by surgery, we recommend treatment with anticoagulation for 3 months over (i) treat-ment of a shorter period (Grade 1B) , (ii) treat-ment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , or (iii) extended therapy (Grade 1B regardless of bleeding risk) .

3.1.2. In patients with a proximal DVT of the leg provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , and (iii) extended therapy if there is a high bleeding risk (Grade 1B) . We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (Grade 2B) .

3.1.3. In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical

2.5.2. In patients with acute DVT of the leg treated with LMWH, we suggest once- over twice-daily administration (Grade 2C) .

Remarks: This recommendation only applies when the approved once-daily regimen uses the same daily dose as the twice-daily regimen (ie, the once-daily injection contains double the dose of each twice-daily injection). It also places value on avoiding an extra injection per day.

2.7. In patients with acute DVT of the leg and whose home circumstances are adequate, we recommend initial treatment at home over treatment in hospital (Grade 1B) .

Remarks: The recommendation is conditional on the adequacy of home circumstances: well-maintained living conditions, strong support from family or friends, phone access, and ability to quickly return to the hospital if there is deterioration. It is also condi-tional on the patient feeling well enough to be treated at home (eg, does not have severe leg symptoms or comorbidity).

2.9. In patients with acute proximal DVT of the leg, we suggest anti coagulant therapy alone over catheter-directed thrombolysis (CDT) (Grade 2C) .

Remarks: Patients who are most likely to benefi t from CDT (see text), who attach a high value to prevention of postthrombotic syndrome (PTS), and a lower value to the initial complexity, cost, and risk of bleeding with CDT, are likely to choose CDT over anticoagu-lation alone.

2.10. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over systemic thrombolysis (Grade 2C) .

Remarks: Patients who are most likely to benefi t from systemic thrombolytic therapy (see text), who do not have access to CDT, and who attach a high value to prevention of PTS, and a lower value to the initial complexity, cost, and risk of bleeding with systemic thrombolytic therapy, are likely to choose systemic thrombolytic therapy over anticoagulation alone.

2.11. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over operative venous thrombectomy (Grade 2C) .

2.12. In patients with acute DVT of the leg who undergo thrombosis removal, we recommend the same intensity and duration of anticoagu-lant therapy as in comparable patients who do not undergo thrombosis removal (Grade 1B) .





Remarks (3.1.3, 3.1.4, 3.1.4.3): Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anti-coagulant therapy; however, it is anticipated that not all patients who are diagnosed with isolated distal DVT will be prescribed anticoagulants (see section 2.3).

In all patients who receive extended anticoagu-lant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually).

3.2. In patients with DVT of the leg who are treated with VKA, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR , 2) or higher (INR 3.0-5.0) range for all treatment durations (Grade 1B) .

3.3.1. In patients with DVT of the leg and no cancer, we suggest VKA therapy over LMWH for long-term therapy (Grade 2C) . For patients with DVT and no cancer who are not treated with VKA therapy, we suggest LMWH over dab-igatran or rivaroxaban for long-term therapy (Grade 2C) .

3.3.2. In patients with DVT of the leg and cancer, we suggest LMWH over VKA therapy (Grade 2B) . In patients with DVT and cancer who are not treated with LMWH, we suggest VKA over dab-igatran or rivaroxaban for long-term therapy (Grade 2B) .

Remarks (3.3.1-3.3.2): Choice of treatment in patients with and without cancer is sensitive to the individual patient’s tolerance for daily injections, need for labo-ratory monitoring, and treatment costs.

LMWH, rivaroxaban, and dabigatran are retained in patients with renal impairment, whereas this is not a concern with VKA.

Treatment of VTE with dabigatran or rivaroxaban, in addition to being less burdensome to patients, may prove to be associated with better clinical outcomes than VKA and LMWH therapy. When these guide-lines were being prepared (October 2011), postmar-keting studies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, we give a weak recommenda-tion in favor of VKA and LMWH therapy over dab-igatran and rivaroxaban, and we have not made any recommendations in favor of one of the new agents over the other.

3.4. In patients with DVT of the leg who receive extended therapy, we suggest treatment with the

transient risk factor (see remark), we suggest treatment with anticoagulation for 3 months over treatment of a shorter period (Grade 2C) and recommend treatment with anticoagulation for 3 months over treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) or extended therapy (Grade 1B regardless of bleeding risk) .

3.1.4. In patients with an unprovoked DVT of the leg (isolated distal [see remark] or proximal), we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B) . After 3 months of treatment, patients with unprovoked DVT of the leg should be evaluated for the risk-benefi t ratio of extended therapy.

3.1.4.1. In patients with a fi rst VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B) .

3.1.4.2. In patients with a fi rst VTE that is an unprovoked proximal DVT of the leg and who have a high bleeding risk, we recommend 3 months of anticoagulant therapy over extended therapy (Grade 1B) .

3.1.4.3. In patients with a fi rst VTE that is an unprovoked isolated distal DVT of the leg (see remark), we suggest 3 months of anticoag-ulant therapy over extended therapy in those with a low or moderate bleeding risk (Grade 2B) and recommend 3 months of anticoagulant treatment in those with a high bleeding risk (Grade 1B) .

3.1.4.4. In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk (Grade 1B), and we sug-gest extended anticoagulant therapy in those with a moderate bleeding risk (Grade 2B) .

3.1.4.5. In patients with a second unprovoked VTE who have a high bleeding risk, we sug-gest 3 months of anticoagulant therapy over extended therapy (Grade 2B) .

3.1.5. In patients with DVT of the leg and active cancer, if the risk of bleeding is not high, we recommend extended anticoagulant therapy over 3 months of therapy (Grade 1B) , and if there is a high bleeding risk, we suggest extended anticoagulant therapy (Grade 2B) .




of diagnostic tests, provided test results are expected within 24 h (Grade 2C) .

5.3. In patients with acute PE, we recommend early initiation of VKA (eg, same day as paren-teral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the INR is 2.0 or above for at least 24 h (Grade 1B) .

5.4.1. In patients with acute PE, we suggest LMWH or fondaparinux over IV UFH (Grade 2C for LMWH; Grade 2B for fondaparinux) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux) .

Remarks: Local considerations such as cost, availability, and familiarity of use dictate the choice between fondaparinux and LMWH.

LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH.

In patients with PE where there is concern about the adequacy of SC absorption or in patients in whom thrombolytic therapy is being considered or planned, initial treatment with IV UFH is preferred to use of SC therapies.

5.4.2. In patients with acute PE treated with LMWH, we suggest once- over twice-daily admin-istration (Grade 2C) .


5.5. In patients with low-risk PE and whose home circumstances are adequate, we suggest early discharge over standard discharge (eg, after fi rst 5 days of treatment) (Grade 2B) .

Remarks: Patients who prefer the security of the hospi-tal to the convenience and comfort of home are likely to choose hospitalization over home treatment.

5.6.1.1. In patients with acute PE associated with hypotension (eg, systolic BP , 90 mm Hg) who do not have a high bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2C) .

5.6.1.2. In most patients with acute PE not asso-ciated with hypotension, we recommend against

same anticoagulant chosen for the fi rst 3 months (Grade 2C) .

3.5. In patients who are incidentally found to have asymptomatic DVT of the leg, we suggest the same initial and long-term anticoagulation as for comparable patients with symptomatic DVT (Grade 2B) .

4.1. In patients with acute symptomatic DVT of the leg, we suggest the use of compression stockings (Grade 2B) .

Remarks: Compression stockings should be worn for 2 years, and we suggest beyond that if patients have developed PTS and fi nd the stockings help ful.

Patients who place a low value on preventing PTS or a high value on avoiding the inconvenience and discomfort of stockings are likely to decline stockings.

4.2.1. In patients with PTS of the leg, we sug-gest a trial of compression stockings (Grade 2C) .

4.2.2. In patients with severe PTS of the leg that is not adequately relieved by compression stock-ings, we suggest a trial of an intermittent com-pression device (Grade 2B) .

4.3. In patients with PTS of the leg, we suggest that venoactive medications (eg, rutosides, defi -brotide, and hidrosmin) not be used (Grade 2C) .

Remarks: Patients who value the possibility of response over the risk of side effects may choose to undertake a therapeutic trial.

5.1. In patients with acute PE, we recommend initial treatment with parenteral anticoagula-tion (LMWH, fondaparinux, IV UFH, or SC UFH) over no such initial treatment (Grade 1B) .

5.2.1. In patients with a high clinical suspicion of acute PE, we suggest treatment with paren-teral anticoagulants compared with no treat-ment while awaiting the results of diagnostic tests (Grade 2C) .

5.2.2. In patients with an intermediate clinical suspicion of acute PE, we suggest treatment with parenteral anticoagulants compared with no treatment if the results of diagnostic tests are expected to be delayed for more than 4 h (Grade 2C) .

5.2.3. In patients with a low clinical suspicion of acute PE, we suggest not treating with paren-teral anticoagulants while awaiting the results





6.1. In patients with PE provoked by surgery, we recommend treatment with anticoagula-tion for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , or (iii) extended therapy (Grade 1B regardless of bleeding risk) .

6.2. In patients with PE provoked by a nonsur-gical transient risk factor, we recommend treat-ment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , and (iii) extended therapy if there is a high bleeding risk (Grade 1B) . We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (Grade 2B) .

6.3. In patients with an unprovoked PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter dura-tion (Grade 1B) . After 3 months of treatment, patients with unprovoked PE should be evaluated for the risk-benefi t ratio of extended therapy.

6.3.1. In patients with a fi rst VTE that is an unprovoked PE and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B) .

6.3.2. In patients with a fi rst VTE that is an unprovoked PE and who have a high bleeding risk, we recommend 3 months of anticoagulant therapy over extended therapy (Grade 1B) .

6.3.3. In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk (Grade 1B) , and we sug-gest extended anticoagulant therapy in those with a moderate bleeding risk (Grade 2B) .

6.3.4. In patients with a second unprovoked VTE who have a high bleeding risk, we sug-gest 3 months of therapy over extended therapy (Grade 2B) .

6.4. In patients with PE and active cancer, if there is a low or moderate bleeding risk, we rec-ommend extended anticoagulant therapy over 3 months of therapy (Grade 1B) , and if there is a high bleeding risk, we suggest extended anti-coagulant therapy (Grade 2B) .

Remarks: In all patients who receive extended anticoag-ulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually).

systemically administered thrombolytic therapy (Grade 1C) .

5.6.1.3. In selected patients with acute PE not associated with hypotension and with a low bleeding risk whose initial clinical presentation, or clinical course after starting anticoagulant therapy, suggests a high risk of developing hypo-tension, we suggest administration of thrombo-lytic therapy (Grade 2C) .

5.6.2.1. In patients with acute PE, when a throm-bolytic agent is used, we suggest short infusion times (eg, a 2-h infusion) over prolonged infu-sion times (eg, a 24-h infusion) (Grade 2C) .

5.6.2.2. In patients with acute PE when a throm-bolytic agent is used, we suggest administration through a peripheral vein over a pulmonary artery catheter (Grade 2C) .

5.7. In patients with acute PE associated with hypotension and who have (i) contraindica-tions to thrombolysis, (ii) failed thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours), if appropriate expertise and resources are available, we suggest catheter-assisted thrombus removal over no such inter-vention (Grade 2C) .

5.8. In patients with acute PE associated with hypotension, we suggest surgical pulmonary embolectomy over no such intervention if they have (i) contraindications to thrombolysis, (ii) failed thrombolysis or catheter-assisted embolectomy, or (iii) shock that is likely to cause death before thrombolysis can take effect (eg, within hours), provided surgical expertise and resources are available (Grade 2C) .

5.9.1. In patients with acute PE who are treated with anticoagulants, we recommend against the use of an IVC fi lter (Grade 1B) .

5.9.2. In patients with acute PE and contraindi-cation to anticoagulation, we recommend the use of an IVC fi lter (Grade 1B) .

5.9.3. In patients with acute PE and an IVC fi l-ter inserted as an alternative to anticoagulation, we suggest a conventional course of anticoagu-lant therapy if their risk of bleeding resolves (Grade 2B) .

Remarks: We do not consider that a permanent IVC fi lter, of itself, is an indication for extended anticoagulation.




8.1.1. In patients with superfi cial vein thrombo-sis (SVT) of the lower limb of at least 5 cm in length, we suggest the use of a prophylactic dose of fondaparinux or LMWH for 45 days over no anticoagulation (Grade 2B) .

Remarks: Patients who place a high value on avoiding the inconvenience or cost of anticoagulation and a low value on avoiding infrequent symptomatic VTE are likely to decline anticoagulation.

8.1.2. In patients with SVT who are treated with anticoagulation, we suggest fondaparinux 2.5 mg daily over a prophylactic dose of LMWH (Grade 2C) .

9.1.1. In patients with acute upper-extremity DVT (UEDVT) that involves the axillary or more proximal veins, we recommend acute treatment with parenteral anticoagulation (LMWH, fonda-parinux, IV UFH, or SC UFH) over no such acute treatment (Grade 1B) .

9.1.2. In patients with acute UEDVT that involves the axillary or more proximal veins, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B) .

9.2.1. In patients with acute UEDVT that involves the axillary or more proximal veins, we sug-gest anticoagulant therapy alone over throm-bolysis (Grade 2C) .

Remarks: Patients who (i) are most likely to benefi t from thrombolysis (see text); (ii) have access to CDT; (iii) attach a high value to prevention of PTS; and (iv) attach a lower value to the initial complexity, cost, and risk of bleeding with thrombolytic therapy are likely to choose thrombolytic therapy over anticoagu-lation alone.

9.2.2. In patients with UEDVT who undergo thrombolysis, we recommend the same inten-sity and duration of anticoagulant therapy as in similar patients who do not undergo thromboly-sis (Grade 1B) .

9.3.1. In most patients with UEDVT that is asso-ciated with a central venous catheter, we sug-gest that the catheter not be removed if it is functional and there is an ongoing need for the catheter (Grade 2C) .

9.3.2. In patients with UEDVT that involves the axillary or more proximal veins, we sug-gest a minimum duration of anticoagulation of 3 months over a shorter period (Grade 2B) .

6.5. In patients with PE who are treated with VKA, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR , 2) or higher (INR 3.0-5.0) range for all treatment durations (Grade 1B) .

6.6. In patients with PE and no cancer, we sug-gest VKA therapy over LMWH for long-term therapy (Grade 2C) . For patients with PE and no cancer who are not treated with VKA therapy, we suggest LMWH over dabigatran or rivaroxa-ban for long-term therapy (Grade 2C) .

6.7. In patients with PE and cancer, we suggest LMWH over VKA therapy (Grade 2B) . In patients with PE and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2C) .

Remarks (6.6-6.7): Choice of treatment in patients with and without cancer is sensitive to the individual patient’s tolerance for daily injections, need for labo-ratory monitoring, and treatment costs.

Treatment of VTE with dabigatran or rivaroxaban, in addition to being less burdensome to patients, may prove to be associated with better clinical outcomes than VKA and LMWH therapy. When these guide-lines were being prepared (October 2011), postmar-keting studies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, we give a weak recommendation in favor of VKA and LMWH therapy over dabigatran and rivaroxaban, and we have not made any recommen-dation in favor of one of the new agents over the other.

6.8. In patients with PE who receive extended therapy, we suggest treatment with the same anticoagulant chosen for the fi rst 3 months (Grade 2C) .

6.9. In patients who are incidentally found to have asymptomatic PE, we suggest the same initial and long-term anticoagulation as for comparable patients with symptomatic PE (Grade 2B) .

7.1.1. In patients with chronic thromboem-bolic pulmonary hypertension (CTPH), we rec-ommend extended anticoagulation over stopping therapy (Grade 1B) .

7.1.2. In selected patients with CTPH, such as those with central disease under the care of an experienced throm boendarterectomy team, we suggest pulmonary thromboendarterectomy over no pulmonary thromboendarterectomy (Grade 2C) .





which are collectively referred to as VTE. We also provide recommendations for patients with (1) post-thrombotic syndrome (PTS), (2) chronic thromboem-bolic pulmonary hypertension (CTPH), (3) incidentally diagnosed (asymptomatic) DVT or PE, (4) acute upper-extremity DVT (UEDVT), (5) superfi cial vein thrombosis (SVT), (6) splanchnic vein thrombosis, and (7) hepatic vein thrombosis.

Table 1 describes the populations, interventions, comparators, and outcomes (ie, PICO elements) for the questions addressed in this article and the design of the studies used to address them. Refer to Garcia et al, 1 Ageno et al, 2 and Holbrook et al 3 in these guidelines for recommendations on the man-agement of parenteral anticoagulation (dosing and monitoring) and oral anticoagulation (dosing and mon itoring). Refer to Bates et al 4 and Monagle et al 5 in these guidelines for recommendations for preg-nancy and neonates and children. The current article builds on previous versions of these guidelines and, most recently, the eighth edition. 6

1.0 Methods

1.1 Presentation as DVT or PE

In addressing DVT, we fi rst review studies that included (1) only patients who presented with symptomatic DVT or (2) patients who presented with DVT or PE (ie, meeting the broader criterion of VTE). For the PE components, we review studies (and sub-groups within studies) that required patients to have presented with symptomatic PE (who may also have had symptoms of DVT). For this reason and because more patients with VTE present with symptoms of DVT alone than with symptoms of PE (including those who also have symptoms of DVT), the DVT section deals with a larger body of evidence than the PE section.

In the evaluation of anticoagulant therapy, there are a number of justifi cations for inclusion of patients who present with DVT and PE in the same study, and for extrapolating evidence obtained in patients with one presentation of VTE (eg, DVT) to the other presentation (eg, PE). First, a majority of patients with symp-tomatic DVT also have PE (symptomatic or asymptomatic), and a majority of those with symptomatic PE also have DVT (symp-tomatic or asymptomatic). 7,8 Second, clinical trials of anticoagu-lant therapy have yielded similar estimates for effi cacy and safety in patients with DVT alone, in those with both DVT and PE, and in those with only PE. Third, the risk of recurrence appears to be similar after PE and after proximal DVT. 7,9 Consequently, the results of all studies of VTE have been considered when formu-lating recommendations for short- and long-term anticoagula-tion of proximal DVT and PE ( Fig 1 ), and these recommendations are essentially the same for proximal DVT or PE.

There are, however, some important differences between patients who present with PE and those who present with DVT that justify separate consideration of some aspects of the treatment of PE. First, the risk of early death (within 1 month) from VTE due to either the initial acute episode or recurrent VTE is much greater after presenting with PE than after DVT 9 ; this difference may justify more aggressive initial treatment of PE (eg, thrombo-lytic therapy, insertion of an inferior vena cava (IVC) fi lter, more intensive anticoagulant therapy) compared with DVT. Second, recurrent episodes of VTE are about three times as likely to be

Remarks: This recommendation also applies if the UEDVT was associated with a central venous cath-eter that was removed shortly after diagnosis.

9.3.3. In patients who have UEDVT that is asso-ciated with a central venous catheter that is removed, we recommend 3 months of antico-agulation over a longer duration of therapy in patients with no cancer (Grade 1B) , and we sug-gest this in patients with cancer (Grade 2C) .

9.3.4. In patients who have UEDVT that is asso-ciated with a central venous catheter that is not removed, we recommend that anticoagulation is continued as long as the central venous cath-eter remains over stopping after 3 months of treatment in patients with cancer (Grade 1C) , and we suggest this in patients with no cancer (Grade 2C) .

9.3.5. In patients who have UEDVT that is not associated with a central venous catheter or with cancer, we recommend 3 months of anticoagula-tion over a longer duration of therapy (Grade 1B) .

9.4. In patients with acute symptomatic UEDVT, we suggest against the use of compression sleeves or venoactive medications (Grade 2C) .

9.5.1. In patients who have PTS of the arm, we suggest a trial of compression bandages or sleeves to reduce symptoms (Grade 2C) .

9.5.2. In patients with PTS of the arm, we sug-gest against treatment with venoactive medica-tions (Grade 2C) .

10.1. In patients with symptomatic splanch-nic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), we recommend anti-coagulation over no anticoagulation (Grade 1B) .

10.2. In patients with incidentally detected splanchnic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), we suggest no anticoagulation over anticoagulation (Grade 2C) .

11.1. In patients with symptomatic hepatic vein thrombosis, we suggest anticoagulation over no anticoagulation (Grade 2C) .

11.2. In patients with incidentally detected hepatic vein thrombosis, we suggest no antico-agulation over anticoagulation (Grade 2C) .

This article provides recommendations for the use of antithrombotic agents as well as the use of

devices or surgical techniques in the treatment of patients with DVT and pulmonary embolism (PE),




Tabl

e 1—

Stru

ctu

red

Cli

nica

l Q

ues

tion

s

Stru

ctur

ed P

ICO

Que

stio

n

Issu

e (I

nfor

mal

Que

stio

n)Po

pula

tion

Inte

rven

tion

Com

para

tors

Out

com

eM

etho

dolo

gy

Patie

nt w

ith a

cute

DV

T o

f the

leg

(2.0

-3.0

)

Initi

al a

ntic

oagu

lant

(2.1

)Pa

tient

s w

ith a

cute

DV

T o

f th

e le

gA

ntic

oagu

latio

nN

o an

ticoa

gula

tion

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts

Whe

ther

to tr

eat w

hile

aw

aitin

g th

e re

sults

of t

he d

iagn

ostic

wor

k-up

(2

.2.1

- 2.2

.3)

Patie

nts

with

sus

pect

ed a

cute

D

VT

of t

he le

g aw

aitin

g th

e re

sults

of d

iagn

ostic

test

s

Ant

icoa

gula

tion

No

antic

oagu

latio

nPE

, maj

or b

leed

ing,

and

m

orta

lity

RC

Ts a

nd

coho

rt

stud

ies

Whe

ther

to tr

eat i

sola

ted

dist

al

thro

mbo

sis

(2.3

.1-2

.3.4

)Pa

tient

with

acu

te is

olat

ed

dist

al D

VT

of t

he le

gA

ntic

oagu

latio

nN

o an

ticoa

gula

tion

DV

T e

xten

sion

, PE

, maj

or

blee

ding

, mor

talit

y,

QO

L, a

nd P

TS

RC

Ts a

nd

coho

rt

stud

ies

Tim

ing

of in

itiat

ion

of V

KA

rel

ativ

e to

the

initi

atio

n of

par

ente

ral

antic

oagu

latio

n (2

.4)

Patie

nts

with

acu

te D

VT

of

the

leg

Ear

ly in

itiat

ion

of V

KA

Del

ayed

initi

atio

n of

VK

AD

VT

ext

ensi

on, P

E, m

ajor

bl

eedi

ng, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts a

nd

coho

rt

stud

ies

Dur

atio

n of

initi

al

antic

oagu

latio

n (2

.4)

Patie

nts

with

acu

te D

VT

of

the

leg

Lon

ger

dura

tion

Shor

ter

dura

tion

DV

T e

xten

sion

, PE

, maj

or

blee

ding

, mor

talit

y,

QO

L, a

nd P

TS

RC

Ts a

nd

coho

rt

stud

ies

Cho

ice

and

rout

e of

initi

al

antic

oagu

lant

(2.5

.1, 2

.5.2

, 2.6

)Pa

tient

s w

ith a

cute

DV

T

of th

e le

gU

FH

IV

or

SQL

MW

H, f

onda

pari

nux,

ri

varo

xaba

nD

VT

ext

ensi

on, P

E, m

ajor

bl

eedi

ng, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts

Sett

ing

of in

itial

an

ticoa

gula

tion

(2.7

)Pa

tient

s w

ith a

cute

DV

T

of th

e le

gIn

-hos

pita

l tre

atm

ent

At-

hom

e tr

eatm

ent

DV

T e

xten

sion,

PE

, maj

or b

leed

ing,

m

orta

lity,

QO

L, a

nd P

TSR

CTs

Rol

e of

thro

mbo

lytic

and

mec

hani

cal

inte

rven

tions

(2.9

-2.1

2)Pa

tient

s w

ith a

cute

pro

xim

al

DV

T o

f the

leg

Cat

hete

r di

rect

ed

thro

mbo

lysi

sN

o ac

tive

thro

mbu

s re

mov

al o

r an

othe

r m

etho

d of

thro

mbu

s re

mov

al

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, PT

S, s

hort

er I

CU

an

d ho

spita

l sta

ys, a

nd

acut

e co

mpl

icat

ions

RC

Ts a

nd

coho

rt

stud

ies

Syst

emic

thro

mbo

lytic

th

erap

yO

pera

tive

veno

us

thro

mbe

ctom

yR

ole

of I

VC

fi lte

rs in

add

ition

to

antic

oagu

latio

n (2

.13.

1)Pa

tient

s w

ith a

cute

DV

T

of th

e le

g st

arte

d on

an

ticoa

gula

tion

IVC

fi lte

rN

o IV

C fi

lter

Rec

urre

nt D

VT

and

PE

, maj

or

blee

ding

, mor

talit

y, Q

OL

, PT

S,

and

com

plic

atio

ns o

f pro

cedu

re

RC

Ts

Rol

e of

IV

C fi

lters

whe

n an

ticoa

gula

tion

is c

ontr

aind

icat

ed

(2.1

3.2)

Patie

nts

with

acu

te D

VT

of

the

leg

and

a co

ntra

indi

catio

n to

ant

icoa

gula

tion

IVC

fi lte

rN

o IV

C fi

lter

Rec

urre

nt D

VT

and

PE

, maj

or

blee

ding

, mor

talit

y, Q

OL

, PT

S,

and

com

plic

atio

ns o

f pro

cedu

re

RC

Ts a

nd

coho

rt

stud

ies

Rol

e of

ant

icoa

gula

tion

in p

atie

nts

who

initi

ally

rec

eive

d an

IV

C

fi lte

r w

hen

cont

rain

dica

tion

to

antic

oagu

latio

n re

solv

es (2

.13.

3)

Patie

nts

with

acu

te D

VT

of t

he

leg

who

initi

ally

rec

eive

d an

IV

C fi

lter,

now

con

trai

ndic

atio

n to

ant

icoa

gula

tion

reso

lved

Ant

icoa

gula

tion

in

addi

tion

to I

VC

fi lte

rN

o an

ticoa

gula

tion

in

addi

tion

to I

VC

fi lte

rR

ecur

rent

DV

T a

nd P

E, m

ajor

bl

eedi

ng, m

orta

lity,

QO

L, P

TS,

an

d co

mpl

icat

ions

of p

roce

dure

RC

Ts a

nd

coho

rt

stud

ies

Rol

e of

ear

ly a

mbu

latio

n (2

.14)

Patie

nts

with

acu

te D

VT

of t

he

leg

star

ted

on a

ntic

oagu

lant

tr

eatm

ent

Ear

ly a

mbu

latio

nIn

itial

bed

res

tR

ecur

rent

DV

T a

nd P

E, m

ajor

bl

eedi

ng, m

orta

lity,

QO

L, P

TS,

an

d co

mpl

icat

ions

of p

roce

dure

RC

Ts a

nd

coho

rt

stud

ies

(Con

tinu

ed)





Stru

ctur

ed P

ICO

Que

stio

n

Issu

e (I

nfor

mal

Que

stio

n)Po

pula

tion

Inte

rven

tion

Com

para

tors

Out

com

eM

etho

dolo

gy

Lon

g-te

rm a

ntic

oagu

latio

n th

erap

y (3

.0)

Patie

nts

with

acu

te V

TE

of

the

leg

Lon

g-te

rm a

ntic

oagu

latio

n th

erap

yN

o lo

ng-t

erm

an

ticoa

gula

tion

ther

apy

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts

Dur

atio

n of

long

-ter

m

antic

oagu

latio

n (3

.1.1

- 3.1

.5)

Patie

nts

with

an

acut

e D

VT

of

the

leg

Lon

ger

dura

tion

Shor

ter

dura

tion

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts

Inte

nsity

of V

KA

(3.2

)Pa

tient

s w

ith a

cute

DV

T

of th

e le

gIN

R 2

-3H

ighe

r or

low

er I

NR

ra

nges

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts

Cho

ice

of lo

ng-t

erm

ant

icoa

gula

nt

(3.3

.1, 3

.3.2

, 3.4

)Pa

tient

s w

ith a

cute

DV

T

of th

e le

g.L

MW

H, d

abig

atra

n,

riva

roxa

ban

VK

AR

ecur

rent

DV

T a

nd P

E,

maj

or b

leed

ing,

mor

talit

y,

QO

L, a

nd P

TS

RC

Ts

Whe

ther

to tr

eat a

n in

cide

ntal

ly

diag

nose

d as

ympt

omat

ic a

cute

D

VT

of t

he le

g (3

.5)

Patie

nts

with

inci

dent

ally

di

agno

sed

asym

ptom

atic

D

VT

of t

he le

g

Ant

icoa

gula

tion

No

antic

oagu

latio

nR

ecur

rent

DV

T a

nd P

E,

maj

or b

leed

ing,

mor

talit

y,

QO

L, a

nd P

TS

RC

Ts

Patie

nts

with

PT

S of

the

leg

Rol

e of

com

pres

sion

sto

ckin

g in

pr

even

ting

PTS

(4.1

)Pa

tient

s w

ith a

cute

DV

T o

f the

le

g st

arte

d on

ant

icoa

gula

nt

trea

tmen

t

Com

pres

sion

sto

ckin

gsN

o co

mpr

essi

on

stoc

king

sQ

OL

, PT

S, a

nd r

ecur

rent

D

VT

RC

Ts

Rol

e of

com

pres

sion

sto

ckin

g in

PT

S (4

.2.1

)Pa

tient

s w

ith P

TS

of th

e le

gC

ompr

essi

on s

tock

ings

No

com

pres

sion

st

ocki

ngs

QO

L, s

ympt

omat

ic r

elie

f, ul

cera

tion

RC

Ts a

nd

coho

rt

stud

ies

Rol

e of

inte

rmitt

ent p

neum

atic

co

mpr

essi

on in

PT

S (4

.2.2

)Pa

tient

s w

ith P

TS

of th

e le

gIn

term

itten

t pne

umat

ic

com

pres

sion

No

inte

rmitt

ent

pneu

mat

ic

com

pres

sion

QO

L, s

ympt

omat

ic r

elie

f, ul

cera

tion

RC

Ts a

nd

coho

rt

stud

ies

Rol

e of

ven

oact

ive

med

icat

ions

in

PTS

(4.3

)Pa

tient

s w

ith P

TS

of th

e le

gVe

noac

tive

med

icat

ions

No

veno

activ

e m

edic

atio

nsQ

OL

, PT

S, a

nd r

ecur

rent

D

VT

RC

Ts a

nd

coho

rt

stud

ies

Patie

nt w

ith a

cute

PE

Initi

al a

ntic

oagu

lant

(5.1

)Pa

tient

s w

ith a

cute

PE

Ant

icoa

gula

tion

No

initi

al

antic

oagu

latio

nR

ecur

rent

DV

T a

nd P

E,

maj

or b

leed

ing,

mor

talit

y,

QO

L, a

nd P

TS

RC

Ts

Whe

ther

to tr

eat w

hile

aw

aitin

g th

e re

sults

of t

he d

iagn

ostic

wor

k-up

(5

.2.1

-5.2

.3)

Patie

nts

with

sus

pect

ed a

cute

PE

aw

aitin

g th

e re

sults

of

the

diag

nost

ic te

sts

Ant

icoa

gula

tion

No

antic

oagu

latio

nR

ecur

rent

DV

T a

nd P

E,

maj

or b

leed

ing,

mor

talit

y,

QO

L, a

nd P

TS

RC

Ts a

nd

coho

rt

stud

ies

Tim

ing

of in

itiat

ion

of V

KA

rel

ativ

e to

the

initi

atio

n of

par

ente

ral

antic

oagu

latio

n (5

.3)

Patie

nts

with

acu

te P

EE

arly

initi

atio

n of

VK

AD

elay

ed in

itiat

ion

of V

KA

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts a

nd

coho

rt

stud

ies

Dur

atio

n of

initi

al

antic

oagu

latio

n (5

.3)

Patie

nts

with

acu

te P

EL

onge

r du

ratio

nSh

orte

r du

ratio

nR

ecur

rent

DV

T a

nd P

E,

maj

or b

leed

ing,

mor

talit

y,

QO

L, a

nd P

TS

RC

Ts a

nd

coho

rt

stud

ies

Tabl

e 1—

Con

tinu

ed

(Con

tinu

ed)




(Con

tinu

ed)

Tabl

e 1—

Con

tinu

ed

Stru

ctur

ed P

ICO

Que

stio

n

Issu

e (I

nfor

mal

Que

stio

n)Po

pula

tion

Inte

rven

tion

Com

para

tors

Out

com

eM

etho

dolo

gy

Cho

ice

and

rout

e of

initi

al

antic

oagu

lant

(5.4

.1, 5

.4.2

)Pa

tient

s w

ith a

cute

DV

T

of th

e le

gU

FH

IV

or

SQL

MW

H, f

onda

pari

nux,

an

d ri

varo

xaba

nR

ecur

rent

DV

T a

nd P

E,

maj

or b

leed

ing,

mor

talit

y,

QO

L, a

nd P

TS

RC

Ts

Sett

ing

of in

itial

an

ticoa

gula

tion

(5.5

)Pa

tient

s w

ith a

cute

PE

In-h

ospi

tal t

reat

men

tA

t-ho

me

trea

tmen

tR

ecur

rent

DV

T a

nd P

E,

maj

or b

leed

ing,

mor

talit

y,

QO

L, a

nd P

TS

RC

Ts

Thr

ombo

lytic

ther

apy

in p

atie

nts

with

acu

te P

E (5

.6.1

.1, 5

.6.1

.2,

5.6.

1.3)

Patie

nts

with

acu

te P

ET

hrom

boly

tic th

erap

yN

o th

rom

boly

tic

ther

apy

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts

Infu

sion

tim

e fo

r th

rom

boly

tic

ther

apy

(5.6

.2.1

)Pa

tient

s w

ith a

cute

PE

re

quir

ing

thro

mbo

lytic

th

erap

y

Lon

ger

infu

sion

tim

eSh

orte

r in

fusi

on ti

me

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts a

nd

coho

rt

stud

ies

Veno

us a

cces

s fo

r th

rom

boly

tic

ther

apy

(5.6

.2.2

)Pa

tient

s w

ith a

cute

PE

re

quir

ing

thro

mbo

lytic

th

erap

y

Peri

pher

al v

ein

Pulm

onar

y ca

thet

erR

ecur

rent

DV

T a

nd P

E,

maj

or b

leed

ing,

mor

talit

y,

QO

L, a

nd P

TS

RC

Ts a

nd

coho

rt

stud

ies

Rol

e of

cat

hete

r-as

sist

ed th

rom

bus

rem

oval

(5.7

)Pa

tient

s w

ith a

cute

PE

Use

of c

athe

ter-

assi

sted

th

rom

bus

rem

oval

No

use

of

cath

eter

-ass

iste

d th

rom

bus

rem

oval

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts a

nd

coho

rt

stud

ies

Rol

e of

sur

gica

l pul

mon

ary

embo

lect

omy

(5.8

)Pa

tient

s w

ith a

cute

PE

Surg

ical

pul

mon

ary

embo

lect

omy

No

surg

ical

pul

mon

ary

embo

lect

omy

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts a

nd

coho

rt

stud

ies

Rol

e of

IV

C fi

lter

in a

dditi

on to

an

ticoa

gula

tion

in p

atie

nts

with

acu

te P

E (5

.9.1

)

Patie

nts

with

acu

te P

E s

tart

ed

on a

ntic

oagu

latio

nIV

C fi

lter

No

IVC

fi lte

rR

ecur

rent

DV

T a

nd P

E,

maj

or b

leed

ing,

mor

talit

y,

QO

L, a

nd P

TS

RC

Ts a

nd

coho

rt

stud

ies

Rol

e of

IV

C fi

lters

whe

n an

ticoa

gula

tion

is c

ontr

aind

icat

ed

(5.9

.2)

Patie

nts

with

acu

te P

E a

nd

a co

ntra

indi

catio

n to

an

ticoa

gula

tion

IVC

fi lte

rN

o IV

C fi

lter

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts a

nd

coho

rt

stud

ies

Rol

e of

ant

icoa

gula

tion

in p

atie

nts

who

initi

ally

rec

eive

d an

IV

C

fi lte

r w

hen

cont

rain

dica

tion

to

antic

oagu

latio

n re

solv

es (5

.9.3

)

Patie

nts

with

acu

te P

E w

ho

initi

ally

rec

eive

d an

IV

C

fi lte

r, no

w c

ontr

aind

icat

ion

to a

ntic

oagu

latio

n re

solv

ed

Ant

icoa

gula

tion

in

addi

tion

to I

VC

fi lte

rN

o an

ticoa

gula

tion

in

addi

tion

to I

VC

fi lte

rR

ecur

rent

DV

T a

nd P

E,

maj

or b

leed

ing,

mor

talit

y,

QO

L, a

nd P

TS

RC

Ts a

nd

coho

rt

stud

ies

Dur

atio

n of

long

-ter

m

antic

oagu

latio

n in

pat

ient

s w

ith

acut

e PE

(6.1

-6.4

)

Patie

nts

with

acu

te P

EL

onge

r du

ratio

nSh

orte

r du

ratio

nR

ecur

rent

DV

T a

nd P

E,

maj

or b

leed

ing,

mor

talit

y,

QO

L, a

nd P

TS

RC

Ts a

nd

coho

rt

stud

ies

Inte

nsity

of V

KA

(6.5

)Pa

tient

s w

ith a

cute

PE

INR

2-3

Hig

her

or lo

wer

IN

R r

ange

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts a

nd

coho

rt

stud

ies

Cho

ice

of lo

ng-t

erm

ant

icoa

gula

nt

(6.6

, 6.7

, 6.8

)Pa

tient

s w

ith a

cute

PE

LM

WH

, dab

igat

ran,

ri

varo

xaba

nV

KA

Rec

urre

nt D

VT

and

PE

, maj

or

blee

ding

, mor

talit

y, Q

OL,

and

PTS

RC

Ts

Whe

ther

to tr

eat a

n in

cide

ntal

ly

diag

nose

d as

ympt

omat

ic a

cute

PE

(6.9

)Pa

tient

s w

ith in

cide

ntal

ly

diag

nose

d as

ympt

omat

ic P

EA

ntic

oagu

latio

nN

o an

ticoa

gula

tion

Rec

urre

nt D

VT

and

PE

, maj

or

blee

ding

, mor

talit

y, Q

OL

, and

PTS

RC

Ts a

nd

coho

rts





Stru

ctur

ed P

ICO

Que

stio

n

Issu

e (I

nfor

mal

Que

stio

n)Po

pula

tion

Inte

rven

tion

Com

para

tors

Out

com

eM

etho

dolo

gy

Patie

nt w

ith C

TPH

Rol

e of

ora

l ant

icoa

gula

tion

in

CT

PH (7

.1.1

)Pa

tient

s w

ith C

TPH

Ora

l ant

icoa

gula

tion

No

oral

ant

icoa

gula

tion

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts a

nd

coho

rt

stud

ies

Rol

e of

pul

mon

ary

thro

mbo

enda

rter

ecto

my

in C

TPH

(7.1

.2)

Patie

nts

with

CT

PHPu

lmon

ary

thro

mbo

enda

rter

ecto

my

No

pulm

onar

y th

rom

boen

dart

erec

tom

yR

ecur

rent

DV

T a

nd P

E,

maj

or b

leed

ing,

mor

talit

y,

QO

L, a

nd P

TS

RC

Ts a

nd

coho

rt

stud

ies

Patie

nt w

ith S

VT

Rol

e of

ant

icoa

gula

tion

in S

VT

(8

.1.1

, 8.1

.2)

Patie

nts

with

SV

TA

ntic

oagu

latio

nN

o an

ticoa

gula

tion

or

othe

r an

ticoa

gula

ntD

VT

and

PE

, maj

or

blee

ding

, mor

talit

y, Q

OL

, sy

mpt

omat

ic r

elie

f, an

d PT

S

RC

Ts a

nd

coho

rt

stud

ies

Patie

nt w

ith a

cute

UE

DV

TA

cute

ant

icoa

gula

tion

(9.1

.1, 9

.1.2

)Pa

tient

s w

ith U

ED

VT

Pare

nter

al a

ntic

oagu

latio

nN

o an

ticoa

gula

tion

Rec

urre

nt D

VT

and

PE

, m

ajor

ble

edin

g, m

orta

lity,

Q

OL

, and

PT

S

RC

Ts a

nd

coho

rt

stud

ies

Rol

e of

thro

mbo

lytic

ther

apy

(9.2

.1, 9

.2.2

)Pa

tient

s w

ith U

ED

VT

Syst

emic

thro

mbo

lytic

th

erap

yN

o sy

stem

ic th

rom

boly

tic

ther

apy

Rec

urre

nt D

VT

and

PE

, maj

or

blee

ding

, mor

talit

y, Q

OL

, PT

S, sh

orte

r IC

U a

nd h

ospi

tal

stay

s, an

d ac

ute

com

plic

atio

ns

RC

Ts a

nd

coho

rt

stud

ies

Whe

ther

indw

ellin

g ce

ntra

l ve

nous

cat

hete

r sh

ould

be

rem

oved

(9.3

.1)

Patie

nts

with

UE

DV

T a

nd

indw

ellin

g ce

ntra

l ven

ous

cath

eter

Rem

oval

of i

ndw

ellin

g ce

ntra

l ven

ous

cath

eter

No

rem

oval

of

indw

ellin

g ce

ntra

l ve

nous

cat

hete

r

Rec

urre

nt D

VT

and

PE

, maj

or

blee

ding

, mor

talit

y, Q

OL

, PT

S, sh

orte

r IC

U a

nd h

ospi

tal

stay

s, an

d ac

ute

com

plic

atio

ns

RC

Ts a

nd

coho

rt

stud

ies

Dur

atio

n of

long

-ter

m

antic

oagu

latio

n (9

.3.2

-9.3

.5)

Patie

nts

with

UE

DV

T a

nd

indw

ellin

g ce

ntra

l ven

ous

cath

eter

Lon

ger

dura

tion

Shor

ter

dura

tion

Rec

urre

nt D

VT

and

PE

, maj

or

blee

ding

, mor

talit

y, Q

OL

, PT

S, sh

orte

r IC

U a

nd h

ospi

tal

stay

s, an

d ac

ute

com

plic

atio

ns

RC

Ts a

nd

coho

rt

stud

ies

Prev

entio

n of

PT

S of

the

arm

(9.4

)Pa

tient

s w

ith U

ED

VT

Com

pres

sion

sle

eves

or

ven

oact

ive

med

icat

ions

No

com

pres

sion

sle

eves

or

ven

oact

ive

med

icat

ions

QO

L, P

TS,

and

re

curr

ent D

VT

RC

Ts a

nd

coho

rt

stud

ies

Trea

tmen

t of P

TS

of th

e ar

m

(9.5

.1, 9

.5.2

)Pa

tient

s w

ith P

TS

of

the

arm

Com

pres

sion

sle

eves

or

ven

oact

ive

med

icat

ions

No

com

pres

sion

sle

eves

or

ven

oact

ive

med

icat

ions

QO

L, s

ympt

omat

ic r

elie

f, an

d ul

cera

tion

RC

Ts a

nd

coho

rt

stud

ies

Patie

nt w

ith th

rom

bosi

s in

unu

sual

site

sR

ole

of a

ntic

oagu

latio

n in

spl

anch

nic

vein

thro

mbo

sis

(10.

1, 1

0.2)

Patie

nts

with

spl

anch

nic

vein

thro

mbo

sis

Ant

icoa

gula

tion

No

antic

oagu

latio

nM

orta

lity,

bow

el is

chem

ia,

maj

or b

leed

ing,

QO

L,

and

sym

ptom

atic

rel

ief

RC

Ts a

nd

coho

rt

stud

ies

Rol

e of

ant

icoa

gula

tion

in h

epat

ic

vein

thro

mbo

sis

(11.

1, 1

1.2)

Patie

nts

with

hep

atic

ve

in th

rom

bosi

sA

ntic

oagu

latio

nN

o an

ticoa

gula

tion

Mor

talit

y, li

ver

failu

re, P

E,

maj

or b

leed

ing,

QO

L,

and

sym

ptom

atic

rel

ief

RC

Ts a

nd

coho

rt

stud

ies

CT

PH 5

chro

nic

thro

mbo

embo

lic p

ulm

onar

y hy

pert

ensi

on;

INR

5 in

tern

atio

nal

norm

aliz

ed r

atio

; IV

C 5

infe

rior

ven

a ca

va;

LM

WH

5 lo

w-m

olec

ular

-wei

ght

hepa

rin,

PE

5 p

ulm

onar

y em

bolis

m;

PIC

O 5

pop

ulat

ion,

inte

rven

tion,

com

para

tor,

outc

ome;

PT

S 5

pos

tthr

ombo

tic s

yndr

ome,

QO

L 5

qua

lity

of li

fe; R

CT

5 ra

ndom

ized

con

trol

led

tria

l; SV

T 5

supe

rfi c

ial v

ein

thro

mbo

sis;

UE

DV

T 5

upp

er-

extr

emity

DV

T; U

FH

5 u

nfra

ctio

nate

d he

pari

n, V

KA

5 vi

tam

in K

ant

agon

ist.

Tabl

e 1—

Con

tinu

ed




Figure 1. Phases of anticoagulation. LMWH 5 low-molecular-weight heparin.

and preferences for the most part were obtained from ratings that all panelists for these guidelines provided in response to standardized descriptions of different outcomes and treatments, supplemented with the fi ndings of a systematic review of the literature on this topic. 15 However, we also took into account that values and preferences vary markedly among individual patients and that often there is appreciable uncertainty about the average patient values we used.

On average, we assumed that patients attach equal value (or dislike [disutility]) to nonfatal thromboembolic and major bleeding events. Concern that the panelist rating exercise that attached a similar disutility to vitamin K antagonist (VKA) therapy (frequent blood testing and telephone or clinic visits, attention to changes in other medications) and long-term low-molecular-weight-heparin (LMWH) therapy (daily subcutaneous [SC] injection, injection site bruising or nodules) may have been misguided led us to request a review of this issue at the fi nal meeting of all panelists. Our judgment that, on average, patients would prefer VKA therapy to long-term LMWH therapy was confi rmed at that meeting.

1.4 Infl uence of Bleeding Risk and Cost

Usually, we did not assess how an individual patient’s risk of bleeding would infl uence each recommendation because (1) we considered that most recommendations would be unlikely to change based on differences in risk of bleeding (eg, anticoagula-tion vs no anticoagulation for acute VTE, comparison of anticoag-ulant regimens), (2) there are few data assessing outcomes in patients with different risks of bleeding, and (3) there is a lack of well-validated tools for stratifying risk of bleeding in patients with VTE. However, for a small number of the recommendations in which the risk of bleeding is very infl uential (eg, use of extended-duration anticoagulation), we stratifi ed recommendations based on this risk ( Table 2 ). Unless otherwise stated, the cost (eg, to the patient, a third-party payer, or society) associated with different treatments did not infl uence our recommendations. In most situ-ations of uncertain benefi t of a treatment, particularly if it was potentially harmful, we took the position of primum non nocere (fi rst do no harm) and made a weak recommendation against the treatment.

2.0 Treatment of Acute DVT

2.1 Initial Anticoagulation of Acute DVT of the Leg

The fi rst and only randomized trial that compared anticoagulant therapy with no anticoagulant therapy in patients with symptomatic DVT or PE was pub-lished in 1960 by Barritt and Jordan. 50 Trial results suggested that 1.5 days of heparin and 14 days of

PE after an initial PE than after an initial DVT (ie, about 60% after a PE vs 20% after a DVT) 7,9,10 ; this difference may justify more aggressive, or more prolonged, long-term therapy. Third, the long-term sequelae of PE are cardiorespiratory impairment, especially due to pulmonary hypertension, rather than PTS of the legs or arms. These differences are most important for recommen-dations about the use of thrombus removal procedures (eg, thrombo-lytic therapy) in patients who present with DVT and PE.

1.2 Outcomes Assessed

The outcomes important to patients we considered for most rec-ommendations are recurrent VTE, major bleeding, and all-cause mortality. These outcomes are categorized in two different ways in the evidence profi les. Whenever data were available, fatal epi-sodes of recurrent VTE and bleeding were included in the mor-tality outcome, and nonfatal episodes of recurrent VTE and bleeding were reported separately in their own categories to avoid reporting an outcome more than once in an evidence profi le. However, many original reports and published meta-analyses did not report fatal and nonfatal events separately. In this situa-tion, we have reported the outcome categories of mortality, recur-rent VTE, and major bleeding, with fatal episodes of VTE and bleeding included in both mortality and two specifi c outcomes (ie, fatal episodes of VTE and bleeding are included in two out-comes of the evidence profi le).

With both ways of reporting outcomes, we tried to specifi cally identify deaths from recurrent VTEs and major bleeds. As part of the assessment of the benefi ts and harms of a therapy, we gener-ally assume that � 5% of recurrent episodes of VTE are fatal 11,12 and that � 10% of major bleeds are fatal, 12-14 and if we deviated from these estimates, we noted the reasons for so doing. We did not consider surrogate outcomes (eg, vein patency) when there were adequate data addressing the corresponding outcome of importance to patients (eg, PTS).

When developing evidence profi les, we tried to obtain the baseline risk of outcomes (eg, risk of recurrent VTE or major bleeding) from observational studies because these estimates are most likely to refl ect real-life incidence. In many cases, however, we used data from randomized trials because observational data were lacking or were of low quality. Methodologic issues specifi c to duration of anticoagulation are addressed in the section 3.1 under the subsection on general consideration in weighing the benefi ts and risks of different durations of anticoagulant therapy.

1.3 Patient Values and Preferences

In developing our recommendations, we took into account average patient values for each outcome and preferences for different types of antithrombotic therapy. As described in MacLean et al 15 and Guyatt et al 16 in these guidelines, these values





“S” before the number denote supplementary tables not contained in the body of the article and avail-able instead in an online data supplement. See the “Acknowledgments” for more information.) The need for an initial course of heparin is also supported by the observation that there are high rates of recur-rent VTE during 3 months of follow-up in patients

VKA therapy markedly reduced recurrent PE (0/16 vs 10/19) and appeared to reduce mortality (1/16 vs 5/19) in patients with acute PE. In the early 1990s, a single randomized trial established the need for an initial course of heparin in addition to VKA as com-pared with starting treatment with VKA therapy alone 51 ( Table 3 , Table S1). (Tables that contain an

Table 2—[Section 2.3, 3] Risk Factors for Bleeding With Anticoagulant Therapy and Estimated Risk of Major Bleeding in Low-, Moderate-, and High-Risk Categories

Risk Factorsa

Age . 65 y17-25

Age . 75 y17-21,23,25-34

Previous bleeding18,24,25,30,33-36

Cancer20,24,30,37

Metastatic cancer36.38,

Renal failure18,24,25,28,30,33

Liver failure19,21,27,28

Thrombocytopenia27,36

Previous stroke18,25,27,39

Diabetes18,19,28,32,34

Anemia18,21,27,30,34

Antiplatelet therapy19,27,28,34,40

Poor anticoagulant control22,28,35

Comorbidity and reduced functional capacity24,28,36

Recent surgery21,41,b

Frequent falls27

Alcohol abuse24,25,27,34

Estimated Absolute Risk of Major Bleeding, %Categorization of Risk of Bleedingc Low Riskd (0 Risk Factors) Moderate Riskd (1 Risk Factor) High Riskd (� 2 Risk Factors) Anticoagulation 0-3 moe

Baseline risk (%) 0.6 1.2 4.8 Increased risk (%) 1.0 2.0 8.0 Total risk (%) 1.6e 3.2 12.8f

Anticoagulation after fi rst 3 mog

Baseline risk (%/y) 0.3h 0.6 � 2.5 Increased risk (%/y) 0.5 1.0 � 4.0 Total risk (%/y) 0.8i 1.6i � 6.5

See Table 1 legend for expansion of abbreviations.aThe increase in bleeding associated with a risk factor will vary with (1) severity of the risk factor (eg, location and extent of metastatic disease, platelet count), (2) temporal relationships (eg, interval from surgery or a previous bleeding episode),29 and (3) how effectively a previous cause of bleeding was corrected (eg, upper-GI bleeding).bImportant for parenteral anticoagulation (eg, fi rst 10 d) but less important for long-term or extended anticoagulation.cAlthough there is evidence that risk of bleeding increases with the prevalence of risk factors,20,21,25,27,30,33,34,36,42,43 this categorization scheme has not been validated. Furthermore, a single risk factor, when severe, will result in a high risk of bleeding (eg, major surgery within the past 2 d, severe thrombocytopenia).dCompared with low-risk patients, moderate-risk patients are assumed to have a twofold risk and high-risk patients an eightfold risk of major bleeding.18,20,21,27,28,30,36,44

eThe 1.6% corresponds to the average of major bleeding with initial UFH or LMWH therapy followed by VKA therapy (Table S6 Evidence Profi le: LMWH vs IV UFH for initial anticoagulation of acute VTE). We estimated baseline risk by assuming a 2.6 relative risk of major bleeding with anticoagulation (footnote g in this table).fConsistent with frequency of major bleeding observed by Hull et al41 in high-risk patients.gWe estimate that anticoagulation is associated with a 2.6-fold increase in major bleeding based on comparison of extended anticoagulation with no extended anticoagulation (Table S27 Evidence Profi le: extended anticoagulation vs no extended anticoagulation for different groups of patients with VTE and without cancer). The relative risk of major bleeding during the fi rst 3 mo of therapy may be greater that during extended VKA therapy because (1) the intensity of anticoagulation with initial parenteral therapy may be greater than with VKA therapy; (2) anticoagulant control will be less stable during the fi rst 3 mo; and (3) predispositions to anticoagulant-induced bleeding may be uncovered during the fi rst 3 mo of therapy.22,30,35 However, studies of patients with acute coronary syndromes do not suggest a � 2.6 relative risk of major bleeding with parenteral anticoagulation (eg, UFH or LMWH) compared with control.45,46

hOur estimated baseline risk of major bleeding for low-risk patients (and adjusted up for moderate- and high-risk groups as per footnote d in this table).iConsistent with frequency of major bleeding during prospective studies of extended anticoagulation for VTE22,44,47,48,49 (and Table S27 Evidence Profi le: extended anticoagulation vs no extended anticoagulation for different groups of patients with VTE and without cancer and Table S24).




account that starting anticoagulant therapy in patients who ultimately have DVT excluded is costly and is a burden to patients and the health-care system. Poor cardiopulmonary reserve may also encourage the use of anticoagulant therapy while awaiting diagnostic testing. If clinicians choose to administer anticoagu-lant therapy and diagnostic testing will be completed within 12 h, we suggest using a 12-h over a 24-h dose of LMWH. VKA therapy usually should not be started before VTE has been confi rmed.

Recommendations

2.2.1. In patients with a high clinical suspicion of acute VTE, we suggest treatment with paren-teral anticoagulants compared with no treat-ment while awaiting the results of diagnostic tests (Grade 2C) .

2.2.2. In patients with an intermediate clinical suspicion of acute VTE, we suggest treatment with parenteral anticoagulants compared with no treat-ment if the results of diagnostic tests are expected to be delayed for more than 4 h (Grade 2C) .

2.2.3. In patients with a low clinical suspicion of acute VTE, we suggest not treating with paren-teral anticoagulants while awaiting the results of diagnostic tests, provided test results are expected within 24 h (Grade 2C) .

2.3 Whether and How to Prescribe Anticoagulants to Patients With Isolated Distal DVT

Whether to Look for Isolated Distal DVT and When to Prescribe Anticoagulants if Distal DVT Is Found:

with acute VTE treated with suboptimal heparin therapy. 1,3,52,53 We discuss whether isolated distal (calf) DVT should be sought and if isolated distal DVT is diagnosed, whether and how it should be treated in section 2.3.

Recommendation

2.1. In patients with acute DVT of the leg treated with VKA therapy, we recommend initial treat-ment with parenteral anticoagulation (LMWH, fondaparinux, IV unfractionated heparin [UFH], or SC UFH) over no such initial treatment (Grade 1B) .

2.2 Whether to Treat With Parenteral Anticoagulation While Awaiting the Results of Diagnostic Work-up for VTE

We identifi ed no trial addressing this question. The decision regarding treatment while awaiting test results requires balancing (1) minimizing thrombotic complications in patients with VTE and (2) avoiding bleeding in those without VTE. Our recommenda-tions are based on two principles. First, the higher the clinical suspicion for VTE (use of validated predic-tion models for probability of having DVT 54 or PE 55,56 can usefully inform this assessment, 57 the shorter the acceptable interval without treatment until results of diagnostic testing become available. Second, the higher the risk of bleeding, the longer the acceptable interval without treatment until results are available.

Our recommendations assume that patients do not have major risk factors for bleeding, such as recent surgery. The recommendations also take into

Table 3—[Section 2.1] Summary of Findings: Parenteral Anticoagulation vs No Parenteral Anticoagulation in Acute VTEa, 51

OutcomesNo. of Participants

(Studies), Follow-upQuality of the

Evidence (GRADE)Relative Effect

(95% CI)

Anticipated absolute effects

Risk With No Parenteral Anticoagulation

Risk Difference With Parenteral Anticoagulation (95% CI)

Mortality 120 (1 study), 6 mo Moderateb,c due to imprecision

RR 0.5 (0.05-5.37)

33 per 1,000 16 fewer per 1,000 (from 31 fewer to 144 more)

VTE symptomatic extension or recurrence

120 (1 study), 6 mo Moderateb,d due to imprecision

RR 0.33 (0.11-0.98)

200 per 1,000 134 fewer per 1,000 (from 4 fewer to 178 fewer)

Major bleeding 120 (1 study), 6 mo Moderateb,c due to imprecision

RR 0.67 (0.12-3.85)


The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. GRADE 5 Grades of Recommendations, Assessment, Development, and Evaluation; RR 5 risk ratio.aBoth groups treated with acenocoumarol.bStudy described as double blinded; outcome adjudicators blinded. None of the study participants were lost to follow-up. Intention-to-treat analysis. Study was stopped early for benefi t.cCI includes values suggesting no effect as well as values suggesting either appreciable benefi t or appreciable harm.dLow number of events caused by the early stoppage of the trial.





the risk for thrombus extension (the greater the risk, the stronger the indication for anticoagula-tion), we suggest either (1) anticoagulation or (2) withholding of anticoagulation while performing sur-veillance ultrasound examinations to detect thrombus extension. We consider the following to be risk fac-tors for extension: positive D -dimer, thrombosis that is extensive or close to the proximal veins (eg, . 5 cm in length, involves multiple veins, . 7 mm in max-imum diameter), no reversible provoking factor for DVT, active cancer, history of VTE, and inpatient status. 7,60,63,64 Thrombosis that is confi ned to the mus-cular veins has a lower risk of extension than true iso-lated distal DVT. 63,65 We anticipate that isolated distal DVT detected using a selective approach to whole-leg ultrasound often will satisfy criteria for initial anti-coagulation, whereas distal DVT detected by routine whole-leg ultrasound often will not. A high risk for bleeding ( Table 2 ) favors ultrasound surveillance over initial anticoagulation, and the decision to use sur-veillance or initial anticoagulation is expected to be sensitive to patient preferences. The evidence sup-porting recommendations to prescribe anticoagu-lants for isolated calf DVT is low quality because it is not based on direct comparisons of the two man-agement strategies, and the ability to predict exten-sion of distal DVT is limited.

How to Treat With Anticoagulants: A single con-trolled trial of 51 patients with symptomatic isolated distal DVT, all of whom were initially treated with heparin, found that 3 months of VKA therapy pre-vented DVT extension and recurrent VTE (29% vs 0%, P , .01). 66 The evidence in support of parenteral anti-coagulation and VKA ther apy for isolated distal DVT, which includes indirect evidence from patients with acute proximal DVT and PE that is presented else-where in this article, is of moderate quality (there is high-quality evidence that anticoagulation is effec-tive, but uncertainty that benefi ts outweigh risks). There have not been evaluations of alternatives to full-dose anticoagulation of symptomatic isolated dis-tal DVT, and it is possible that less-aggressive anti-coagulant strategies may be adequate. Duration of anticoagulation for isolated distal DVT is discussed in section 3.1.

Recommendations

2.3.1. In patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension (see text), we suggest serial imaging of the deep veins for 2 weeks over ini-tial anticoagulation (Grade 2C) .

2.3.2. In patients with acute isolated distal DVT of the leg and severe symptoms or risk factors

Whether patients with isolated distal DVT (DVT of the calf [peroneal, posterior tibial, anterior tibial veins] without involvement of the popliteal or more proximal veins) are identifi ed depends on how suspected DVT is investigated. 57 If all patients with suspected DVT have ultrasound examination of the calf veins (whole-leg ultrasound), isolated distal DVT accounts for about one-half of all DVT diagnosed. 58 If a diagnostic approach is used that does not include ultrasound examination of the calf veins or that only performs ultrasound examination of the calf veins in selected patients, isolated distal DVT is rarely diagnosed. 59

The primary goal of diagnostic testing for DVT is to identify patients who will benefi t from anticoagulant therapy. This does not mean that all symptomatic DVT need to be identifi ed. Isolated distal DVT do not need to be sought and treated provided that (1) there is strong evidence that the patient does not have a distal DVT that will extend into the proximal veins (ie, the patient is unlikely to have a distal DVT, and if a distal DVT is present, it is unlikely to extend); (2) if this crite-rion is not satisfi ed, a follow-up proximal ultrasound is done after 1 week to detect distal DVT that has extended into the proximal veins, in which case antico-agulant therapy is started; and (3) the patient does not have severe symptoms that would require anticoagu-lant therapy if the symptoms were due to a distal DVT.

Diagnostic approaches to suspected DVT that do not examine the calf veins (eg, use of a combination of clinical assessment, D-dimer testing, single and serial proximal vein ultrasound examination to man-age patients) or only examine the calf veins in selected patients (eg, those who cannot have DVT excluded using the previously noted tests) have been proven safe and are presented in Bates et al 57 in these guide-lines. If the calf veins are imaged (usually with ultra-sound) and isolated distal DVT is diagnosed, there are two management options: (1) treat patients with anticoagulant therapy or (2) do not treat patients with anticoagulant therapy unless extension of the DVT is detected on a follow-up ultrasound examination (eg, after 1 and 2 weeks or sooner if there is concern [there is no widely accepted protocol for surveil-lance ultrasound testing]). 60 Natural history studies suggest that when left untreated, � 15% of symptom-atic distal DVT will extend into the proximal veins and that if extension does not occur within 2 weeks, it is unlikely to occur subsequently. 7,60-62 The risk of extension of isolated distal DVT will vary among patients (see later discussion).

As noted in Bates et al, 57 these guidelines favor diagnostic approaches to suspected DVT other than routine whole-leg ultrasound. If isolated dis-tal DVT is diagnosed, depending on the severity of patient symptoms (the more severe the symptoms, the stronger the indication for anticoagulation) and




2.5 Choice of Initial Anticoagulant Regimen in Patients With Proximal DVT

Initial anticoagulant regimens vary according to the drug, the route of administration, and whether dose is adjusted in response to laboratory tests of coagulation. Six options are available for the initial treatment of DVT: (1) SC LMWH without moni-toring, (2) IV UFH with monitoring, (3) SC UFH given based on weight initially, with monitoring, (4) SC UFH given based on weight initially, without monitoring, (5) SC fondaparinux given without monitoring, and (6) rivaroxaban given orally. We considered the SC UFH options as a single category because results were similar in studies that used SC UFH with and with-out laboratory monitoring ( Table 5 , Tables S3-S5). Rivaroxaban is used in the acute treatment of VTE without initial parenteral therapy; studies of its use for the acute treatment of VTE are reviewed under long-term treatment of DVT (section 3.1) and PE (section 6) of this article. Recommendations for dosing and monitoring of IV UFH, SC UFH, and SC LMWH are addressed in Garcia et al 1 and Holbrook et al 3 in these guidelines. Because LMWH, fondaparinux, and rivaroxaban have substantial renal excretion, these agents should be avoided (eg, use UFH instead) or should be used with coagulation monitoring (test selection is specifi c to each agent and requires expert interpretation) in patients with marked renal impair-ment (eg, estimated creatinine clearance , 30 mL/min [in a 70-year-old weighing 70 kg, a creatinine clear-ance of 30 mL/min corresponds to a serum creati-nine of about 200 m mol/L (2.3 mg/dL) in a man and 175 m mol/L (2.0 mg/dL) in a woman] http://www.nephron.com/cgi-bin/CGSIdefault.cgi).

LMWH Compared With IV UFH for the Initial Treatment of DVT: A number of meta-analyses 72-75 have summarized the trials addressing this question. The evidence suggests that LMWH is associated with decreased mortality, lower recurrence of VTE, and decreased incidence of major bleeding compared with IV UFH ( Table 6 , Table S6). However, the qual-ity of supporting evidence is low due to a high risk of bias in the primary studies, and evidence of publica-tion bias in favor of LMWH. LMWH has the advan-tage over IV UFH that it is much easier to administer (which makes outpatient treatment feasible) and that it has a lower potential for heparin-induced thrombocytopenia, 69 but the disadvantage is that it accumulates in patients with renal failure.

SC UFH Compared With LMWH for the Initial Treatment of DVT: Four randomized trials have compared SC UFH with SC LMWH ( Table 6 , Tables S3-S5). 70,71,76,77 This evidence suggests that SC UFH is associated with a similar frequency of

for extension (see text), we suggest initial anti-coagulation over serial imaging of the deep veins (Grade 2C) .

Remarks: Patients at high risk for bleeding are more likely to benefi t from serial imaging. Patients who place a high value on avoiding the inconvenience of repeat imaging and a low value on the inconve-nience of treatment and on the potential for bleeding are likely to choose initial anticoagulation over serial imaging.

Recommendations

2.3.3. In patients with acute isolated distal DVT of the leg who are managed with initial anti-coagulation, we recommend using the same approach as for patients with acute proximal DVT (Grade 1B) .

2.3.4. In patients with acute isolated distal DVT of the leg who are managed with serial imaging, we recommend no anticoagulation if the thrombus does not extend (Grade 1B) ; we suggest anticoagulation if the thrombus extends but remains confi ned to the distal veins (Grade 2C) ; we recommend anticoagulation if the thrombus extends into the proximal veins (Grade 1B) .

2.4 Timing of Initiation of VKA and Associated Duration of Parenteral Anticoagulant Therapy

Until � 20 years ago, initiation of VKA therapy was delayed until patients had received about 5 days of heparin therapy, which resulted in patients remain-ing in the hospital until they had received � 10 days of heparin. Three randomized trials 41,67,68 provided moderate-quality evidence that early initiation of VKA, with shortening of heparin therapy to � 5 days, is as effective as delayed initiation of VKA with about a 10-day course of heparin ( Table 4 , Table S2). Short-ening the duration of initial heparin therapy from about 10 to 5 days is expected to have the added advan-tage of reducing the risk of heparin-induced throm-bocytopenia. 69 If the international normalized ratio (INR) exceeds the therapeutic range (ie, INR . 3.0) prematurely, it is acceptable to stop parenteral therapy before the patient has received 5 days of treatment.

Recommendation

2.4. In patients with acute DVT of the leg, we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral antico-agulation for a minimum of 5 days and until the INR is 2.0 or above for at least 24 h (Grade 1B) .


http://www.nephron.com/cgi-bin/CGSIdefault.cgi


http://www.nephron.com/cgi-bin/CGSIdefault.cgi



equivalence of fondaparinux to LMWH for the treat-ment of acute VTE.

Fondaparinux Compared With IV UFH for the Ini-tial Treatment of DVT: In the absence of direct evi-dence in patients with DVT, indirect evidence in patients with acute PE (section 5.4) suggests that fondaparinux is equivalent to IV UFH. 79 As noted previously, we judge that fondaparinux and LMWH are equivalent; fondaparinux also shares the advan-tages that LMWH has over IV UFH and the disad-vantage that it is renally excreted (section 2.5). The quality of the evidence regarding the comparison of fondaparinux and UFH is moderate as, although there is some indirectness, it is minor.

Fondaparinux Compared With SC UFH for the Initial Treatment of DVT: There is no direct evidence for this comparison in any patient population. Our recommendation is based on our assessment that

mortality, recurrent VTE, and major bleeding as LMWH. However, the quality of the evidence is mod erate because of imprecision. LMWH has the disadvantage of a higher cost but is more conve-nient to use (LMWH can be administered once daily [see later discussion]), is more widely available for use in outpatients, has a lower potential for heparin-induced thrombocytopenia, 69 and there is much more experience with its use than with SC UFH.

Fondaparinux Compared With LMWH for the Initial Treatment of DVT: The Matisse-DVT trial 78 compared fondaparinux with LMWH for short-term treatment of DVT ( Table 7 , Table S7). This study sug-gests that fondaparinux is associated with a similar frequency of mortality, recurrent VTE, and major bleeding as LMWH. However, the quality of the evidence from this study was moderate because of imprecision. Evidence that fondaparinux is effective for the treatment of PE 79 (section 5.4) supports the

Table 4—[Recommendation 2.4] Summary of Findings: Early Warfarin (and Shorter Duration Heparin) vs Delayed Warfarin (and Longer Duration Heparin) for Acute VTEa-d,41,67,68


(Studies), Follow-up

Quality of the Evidence (GRADE)

Relative Effect (95%

CI)

Anticipated Absolute Effects

Risk With Delayed Warfarin Initiation (and Longer

Duration Heparin)

Risk Difference With Early Warfarin Initiation (and Shorter Duration

Heparin) (95% CI)

Mortality 688 (3 studies), 3 moe Moderatef,g due to imprecision

RR 0.9 (0.41-1.95)

24 per 1,000h 2 fewer per 1,000 (from 14 fewer to 23 more)

Recurrent VTE 688 (3 studies), 3 moe Moderatef,g due to imprecision

RR 0.83 (0.4-1.74)


Major bleeding 688 (3 studies), 3 moi Highf,j,k RR 1.48 (0.68-3.23)

16 per 1,000h 14 more per 1,000 (from 9 fewer to 66 more)

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aMost patients had proximal DVT, some had isolated distal DVT, most DVT were symptomatic (asymptomatic DVT included in Hull et al41), and few had PE (only included in Gallus et al67).bThe early initiation of VKA was associated with a fewer number of days of heparin therapy (4.1 vs 9.5 in Gallus et al67; 5 vs 10 in Hull et al41) and a fewer number of days of hospital stay (9.1 vs 13.0 in Gallus et al; 11.7 vs 14.7 in Hull et al; 11.9 vs 16.0 in Leroyer et al68).cVKA therapy started within 1 day of starting heparin therapy (UFH in two studies and LMWH in one study).dVKA therapy delayed for 4 to 10 d.eOutcome assessment was at hospital discharge in the study by Gallus et al67 (although there was also extended follow-up) and 3 mo in the studies by Hull et al41 and Leroyer et al.68

fPatients and investigators were not blinded in two studies (Gallus et al67 and Leroyer et al68) and were blinded in one study (Hull et al41). Concealment was not clearly described but was probable in the three studies. Primary outcome appears to have been assessed after a shorter duration of follow-up in the shorter treatment arm of one study because of earlier discharge from hospital, and 20% of subjects in this study were excluded from the fi nal analysis postrandomization (Gallus et al).gThe 95% CI on relative effect includes both clinically important benefi t and clinically important harm.hEvent rate corresponds to the median event rate in the included studies.iBleeding was assessed early (in hospital or in the fi rst 10 d) in two studies (Gallus et al67 and Hull et al41) and at 3 mo in one study (Leroyer et al68).jIt is unclear whether bleeding was assessed at 10 d in all subjects or just while heparin was being administered, which could yield a biased estimate in favor of short-duration therapy in one study (Hull et al41).kBecause the shorter duration of heparin therapy is very unlikely to increase bleeding, the wide 95% CIs around the relative effect of shorter therapy on risk of bleeding is not a major concern.




Table 6—[Section 2.5.1] Summary of Findings: LMWH vs IV UFH for Initial Anticoagulation of Acute VTE74

OutcomesNo. of Participants (Studies),

Follow-upQuality of the Evidence

(GRADE)Relative Effect

(95% CI)


Risk With IV UFHRisk Difference With

LMWH (95% CI)

All-cause mortality

7,908 (17 studies), 3 mo Lowa,b due to risk of bias, publication bias

RR 0.79 (0.66-0.95) 46 per 1,000c 10 fewer per 1,000 (from 2 fewer to 16 fewer)

Recurrent VTE 7,976 (17 studies), 3 mo Lowa,b due to risk of bias, publication bias

RR 0.72 (0.58-0.89) 55 per 1,000c 15 fewer per ,1000 (from 6 fewer to 23 fewer)

Major bleeding 6,910 (20 studies), 3 mo Lowa,b,d due to risk of bias, publication bias

RR 0.67 (0.45-1) 15 per 1,000c 5 fewer per 1,000 (from 8 fewer to 0 more)

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aOf the 20 trials, allocation was concealed in nine and was unclear whether concealed in the remaining 11. In 18 trials, outcome assessors were blinded. Seven trials did not have any postrandomization exclusions or losses to follow-up. Ten trials reported the number of participants lost to follow-up, which ranged from 1.0% to 12.7%. One trial did not report the drop-outs.bInverted funnel plot very suggestive of publication bias. Many of the included studies are of small size, and all were funded by industry.cEvent rate corresponds to the median event rate in the included studies.dCI includes values suggesting signifi cant benefi t and no effect.

fi ve of these studies 83-87 that had unconfounded com-parisons. This evidence suggests that LMWH once daily and twice daily are associated with similar mor-tality, recurrent VTE, and major bleeding. However, the quality of the evidence is low because of impre-cision and inconsistency. The sixth study that used a lower total daily dose of LMWH with once-daily compared with twice-daily administration (enox-aparin 1.5 mg/kg once daily vs 1.0 mg/kg bid; enox-aparin 2 mg/kg once daily is not used) suggested that outcomes might be inferior with this once-daily regimen. 85

fondaparinux and LMWH are equivalent and that fondaparinux shares the advantages that LMWH has over SC UFH (section 2.5). This recommendation does not take into account difference in purchase cost between SC UFH and fondaparinux and is based on low-quality evidence.

Once- vs Twice-Daily Administration of LMWH for Initial Treatment of DVT: Two meta-analyses 80,81 summarized six studies comparing once-daily and twice-daily administrations of the same LMWH. 82-87 Table 8 and Table S8 summarize the fi ndings of

Table 5—[Section 2.5.1] Summary of Findings: LMWH vs SC UFH for Initial Anticoagulation of Acute VTE70,71,76,77




(95% CI)


Risk With SC UFHRisk Difference With

LMWH (95% CI)

All-cause mortality

1,566 (3 studies), 3 mo Moderatea,b due to imprecision

RR 1.1 (0.68-1.76) 33 per 1,000c 3 more per 1,000 (from 11 fewer to 25 more)

Recurrent VTE 1,563 (3 studies), 3 mo Moderatea,b due to imprecision

RR 0.87 (0.52-1.45) 42 per 1,000c 5 fewer per 1,000 (from 20 fewer to 19 more)

Major bleeding 1,634 (4 studies), 3 mo Moderatea,b due to imprecision

RR 1.27 (0.56-2.9) 16 per 1,000c 4 more per 1,000 (from 7 fewer to 30 more)

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. SC 5 subcutaneous. See Table 1 and 3 legends for expansion of abbreviations.aIn the two largest trials (Prandoni et al,70 Kearon et al;71 87% of patients), allocation was concealed, outcome adjudicators and data analysts were concealed, analysis was intention to treat, and there were no losses to follow-up.bPrecision judged from the perspective of whether SC heparin is noninferior to LMWH. The total number of events and the total number of participants were relatively low.cEvent rate corresponds to the median event rate in the included studies.





Remarks: Local considerations such as cost, avail-ability, and familiarity of use dictate the choice between fondaparinux and LMWH. LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH.

Recommendations

2.5.1. In patients with acute DVT of the leg, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux) .

Table 7—[Section 2.5.1] Summary of Findings: Fondaparinux vs LMWH for Initial Anticoagulation of Acute DVTa-c,78




(95% CI)


Risk With LMWHRisk Difference With

Fondaparinux (95% CI)

Mortality 2,205 (1 study), 3 mo Moderated,e due to imprecision

RR 1.25 (0.8-1.97) 30 per 1,000 7 more per 1,000 (from 6 fewer to 29 more)

Recurrent VTE 2,205 (1 study), 3 mo Moderated,e due to imprecision

RR 0.96 (0.64-1.45) 41 per 1,000f 2 fewer per 1,000 (from 15 fewer to 18 more)

Major bleeding 2,205 (1 study), 3 mo Moderated,e due to imprecision

RR 0.93 (0.43-2.03) 12 per 1,000g 1 fewer per 1,000 (from 7 fewer to 12 more)

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aAll patients had acute symptomatic DVT.bFondaparinux 7.5 mg (5.0 mg in patients weighing , 50 kg and 10.0 mg in patients weighing . 100 kg) SC once daily for at least 5 d and until VKAs induced an INR . 2.0.cEnoxaparin 1 mg/kg of body weight SC bid for at least 5 d and until VKAs induced an INR . 2.0.dAllocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Analysis excluded 0.6% of randomized patients. Not stopped early for benefi t.eCI includes values suggesting no effect and values suggesting either benefi t or harm; relatively low number of events.fFive fatal VTE in fondaparinux group and fi ve fatal VTE in LMWH group.g Twelve patients in the fondaparinux group and 13 in the LMWH group had a major bleeding event during the initial period (7 d). Of these, two in the fondaparinux group and none in the LMWH group were fatal.

Table 8—[Section 2.5.2] Summary of Findings: LMWH Once vs Twice Daily for Initial Anticoagulation of Acute VTEa,b,81


(Studies), Follow-upQuality of the Evidence


(95% CI)


Risk With Twice Daily

Risk Difference With LMWH Once Daily (95% CI)

Mortality 1,261 (3 studies), 3 mo Lowc-e due to inconsistency and imprecision


VTE recurrence 1,261 (3 studies), 3 mo Lowc,e,f due to inconsistency and imprecision

RR 0.86 (0.52-1.42) 49 per 1,000 7 fewer per 1,000 (from 24 fewer to 21 more)

Major bleeding 1,522 (5 studies), 10 d Moderatec,e due to imprecision


The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aOf the fi ve included studies, one included patients with PE and DVT and four included only patients with DVT. All studies addressed the initial management of VTE.bThe fi ve included studies used four brands of LMWH (enoxaparin, tinzaparin, dalteparin, and nadroparin). In Merli et al,85 enoxaparin 1 mg/kg bid was compared with 1.5 mg/kg once daily. Holmström et al84 adjusted the dose to anti-Xa levels, which resulted in different daily doses after a number of days. In the remaining studies, the dose of the once-daily administration was double the dose of the twice-daily administration (equal total daily dose).cAll included studies concealed allocation. Two studies had a double-blind design, and two others were single blind. One study did not mention blinding. Intention to treat likely used in all studies. Participants were lost to follow-up in only two studies (0.3% and 2.2%).dI2 5 37%; point effect estimate in favor of twice-daily dose in Merli et al85 and in favor of once-daily dose in Charbonnier et al.83

eImprecision judged relative to no difference.fI2 5 65%; point effect estimate in favor of twice-daily dose in Merli et al85 and in favor of once-daily dose in Charbonnier.83




conditional on the patient feeling well enough to be treated at home (eg, does not have severe leg symp-toms or comorbidity).

2.8 Treatment Strategies of Thrombus Removal for Acute DVT

Treatments that actively remove thrombus in patients with acute DVT have the potential to reduce acute symptoms and the risk of developing PTS. Patients with DVT that involves the iliac and common femoral veins are at highest risk for PTS and, therefore, are the subset with the greatest potential to benefi t from thrombus removal strategies. 102 Thrombus removal strategies are indicated in patients with the very rare complication of impending venous gangrene despite optimal anticoagulant therapy; such patients are not the focus of the following sections. A recent trial that randomized 183 patients with proximal DVT to per-cutaneous endovascular intervention or to anticoagu-lant therapy alone reported reduced acute symptoms, hospital stay, recurrent VTE, and PTS at 6 months in the thrombus removal group. 103 This trial, which had a high potential for bias (randomization not described, no blinding), is not considered further because it was not possible to determine outcomes in patients treated with mechanical thrombectomy alone and in those treated with thrombolytic therapy.

2.9 Catheter-Directed Thrombolysis for Acute DVT

The rationale for catheter-directed thrombolysis (CDT) is that compared with systemic thromboly-sis, it will achieve lysis of thrombus more rapidly and with lower doses of thrombolytic therapy, thereby reducing serious bleeding. The addition of mechan-ical thrombus fragmentation (collectively referred to as pharmacomechanical thrombolysis) with or with-out aspiration can further reduce the dose of throm-bolytic therapy and shorten the procedure. 104

One randomized trial of CDT has been com-pleted, 105 and a second has reported short-term outcomes (but not the development of PTS). 106,107 Table 10 and Table S10 present the combined fi nd-ings from these studies (see also Tables S11 and S12). This evidence suggests that CDT may reduce PTS and improve quality of life without being associated with an unacceptable increase in bleeding. However, the quality of evidence is low for mortality, recur-rent VTE, and major bleeding because of very serious imprecision, and is low for PTS because of indirect-ness (ie, use of surrogate outcome [PTS has yet to be measured directly during follow-up]).

In addition to the two randomized trials, 105,106 fi ndings of observational studies suggest that CDT improves venous patency and preserves venous valve function (Tables S11 and S12). Use of CDT, however, requires

2.5.2. In patients with acute DVT of the leg treated with LMWH, we suggest once- over twice-daily administration (Grade 2C) .


2.6 Initial Treatment With Rivaroxaban vs Parenteral Therapy

One trial directly compared short- and long-term rivaroxaban (without initial parenteral anticoagula-tion) with parenteral anticoagulation (LMWH) and VKA in patients with acute DVT. 88 The fi ndings of this study and associated recommendations are pre-sented in section 3.3.

2.7 At-Home vs In-Hospital Initial Treatment of DVT

One trial of 201 patients directly compared outpa-tient and inpatient administration of the same initial anticoagulant regimen (three LMWH preparations were used); there were few recurrent VTE and major bleeds in each group. 89 A number of trials 90-94 have compared LMWH administered at home (without hospital admis-sion or after early discharge) in a substantial proportion of patients, with IV UFH administered in the hospital ( Table 9 , Table S9). This evidence suggests that home treatment is not associated with an increase in mortality, recurrent VTE, or major bleeding and may be asso-ciated with improved outcomes. However, the quality of the evidence is moderate because of indirectness (patients were not explicitly randomized to home therapy in most studies) and imprecision.

Health economic evaluations that have assessed initial treatment of DVT at home, although they have weaknesses (eg, industry funded, not derived from trials in which LMWH was used both in the hospital and at home, short time horizon (ie, � 3 months), and limited use of sensitivity analyses), all conclude that home treatment is cost-saving (about US $500-$2,500 per patient). 95-101

Recommendation

2.7. In patients with acute DVT of the leg and whose home circumstances are adequate, we rec-ommend initial treatment at home over treat-ment in hospital (Grade 1B) .

Remarks: The recommendation is conditional on the adequacy of the following home circumstances: well-maintained living conditions, strong support from family or friends, phone access, and ability to quickly return to hospital if there is deterioration. It is also





assess the benefi t or risk of inserting an IVC fi lter in patients who have CDT performed (recommended by manufacturer with some endovascular devices and techniques, whereas not with others). Percutaneous mechanical venous thrombectomy without concomi-tant thrombolysis has not been evaluated in random-ized trials, and its use is discouraged because small retrospective studies suggest that it often fails to remove much of the thrombus 115,116 and is associated with a high risk of PE. 117,118

Recommendation

2.9. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over CDT (Grade 2C) .

substantial resources and expertise. Patients who are most likely to benefi t from CDT have iliofemoral DVT, symptoms for , 14 days, good functional status, life expectancy of � 1 year, and a low risk of bleeding ( Table 11 ). Because the balance of risks and benefi ts with CDT is uncertain, anticoagulant therapy alone is an acceptable alternative to CDT in all patients with acute DVT who do not have impending venous gangrene.

There is no single standardized approach to per-forming CDT or pharmacomechanical thrombolysis. If these interventions are performed, the technique used will vary with local resources and expertise. If CDT has been successful but there are residual lesions in the common femoral or more proximal veins, balloon angioplasty and stenting often are used to relieve obstruction. There are inadequate data to

Table 9—[Section 2.7] Summary of Findings: Home Treatment vs Hospital Treatment of Acute DVTa-d,442



Evidence(GRADE)Relative Effect

(95% CI)


Risk With Hospital Treatment

Risk Difference With Home Treatment (95% CI)

Mortality 1,708 (6 studies), 3 mo

Lowc-f due to indirectness and imprecision


Recurrent VTE 1,708 (6 studies), 3 mo

Moderatec-e due to indirectness RR 0.61 (0.42-0.9) 74 per 1,000 29 fewer per 1,000 (from 7 fewer to 43 fewer)

Major bleeding 1,708 (6 studies), 3 mo

Moderatec-e,g due to indirectness RR 0.67 (0.33-1.36) 21 per 1,000 7 fewer per 1,000 (from 14 fewer to 8 more)

QOL 0 (3 studiesh), 3 mo

Lowi-k due to indirectness and imprecision

Not estimable … h

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aStudies included in the systematic review should have recruited patients whose home circumstances were adequate.bAll studies included patients with lower-extremity DVT and excluded patients with suspected or confi rmed PE. Studies also excluded patients who were pregnant.cFour studies had partial hospital treatment of many in the home arm: Koopman et al92 (mean hospital stay, 2.7 in home arm vs 8.1 d in hospital arm), Levine et al93 (2.1 vs 6.5 d), Boccalon et al89 (1 vs 9.6 d), and Ramacciotti et al94 (3 vs 7 d). In Daskalopoulos et al,91 there was no hospital stay at all in the home group. Chong et al90 did not report duration of hospital stay.dOnly one study (Boccalon et al89) used LMWH in both treatment arms. Remaining studies used UFH in the inpatient arm and LMWH in the outpatient arm.eOut of six studies, allocation was clearly concealed in three (unclear in remaining three), outcome adjudicators were blinded in the two largest studies (unclear in remaining four), loss to follow-up was signifi cant in only one small study, intention-to-treat analysis was conducted in four (unclear in remaining two), and no study was stopped early for benefi t. Overall, the judgment was that these limitations would not warrant downgrading of quality; it has already been downgraded by at least one level based on other factors.fThe CI includes values suggesting benefi t and harm.gJudged as precise based on the narrow CI around absolute effect.hBäckman et al95 reported evaluation of health-related QOL using the EQ-5D. They found no differences in mean QOL scores or in the proportion of patients showing improvement in self-rated health state. Koopman et al92 evaluated health-related QOL using the Medical Outcome Study Short Form-20 and an adapted version of the Rotterdam Symptom Checklist. The changes over time were similar in both groups, except that the patients receiving LMWH had better scores for physical activity (P 5 .002) and social functioning (P 5 .001) at the end of the initial treatment. The authors did not report enough data to assess precision and clinical signifi cance of results. O’Brien et al96 assessed changes in QOL using the Medical Outcome Study Short Form-36 in 300 patients participating in Levine et al.93 They found that the change in scores from baseline to day 7 was not signifi cantly different between the treatment groups for seven of the eight domains. The one exception was the domain of social functioning, where a greater improvement was observed for the outpatient group.iPotential inconsistency as Bäckman et al95 showed no effect, whereas Koopman et al92 and O’Brien et al96 showed potential benefi t.jTwo of the three studies had partial hospital treatment of many in the home arm: Koopman et al92 (mean hospital stay, 2.7 in home arm vs 8.1 d in hospital arm) and Levine et al93 (2.1 vs 6.5 d).kNot able to evaluate, but imprecision is possible. Taken together with the potential inconsistency, we downgraded the quality of evidence by one level.




bleeding, and PTS ( Table 12 , Table S15). This evi-dence suggests that systemic thrombolysis has the potential to reduce PTS at the expense of an increase in major bleeding. However, the overall quality of this evidence is low because of imprecision and risk of bias.

There have been no direct comparisons of different thrombolytic agents; however, prolonged infusions of streptokinase that were used predominantly in the earlier studies appear to be associated with higher bleeding rates than other regimens. No random-ized trial has compared systemic thrombolysis with CDT, but a single-center, retrospective study 127 sug-gested that systemic thrombolysis achieves less

Remarks: Patients who are most likely to benefi t from CDT (see text) and attach a high value to prevention of PTS and a lower value to the initial complexity, cost, and risk of bleeding with CDT are likely to choose CDT over anticoagulation alone.

2.10 Systemic Thrombolytic Therapy for Acute DVT

Many trials of systemic thrombolysis for the treat-ment of DVT assessed early lysis, often reported bleeding, but rarely reported recurrent VTE or development of PTS (Table S13 and S14). 119-137 A meta-analysis 138 summarized the fi ndings of trials that assessed mortality, recurrent VTE, major

Table 10—[Section 2.9] Summary of Findings: CDT vs No CDT for Extensive Acute DVT of the Lega,b,105,106




(95% CI)


Risk With No CDT

Risk Difference With CDT (95% CI)

Mortality 153 (2 studies), 3 mo Lowc,d due to imprecision

RR 0.14 (0.01-2.71) 39 per 1,000e 34 fewer per 1,000 (from 39 fewer to 67 more)

Nonfatal recurrent VTE 153 (1 study), 3 mo Lowc,d due to imprecision

RR 0.35 (0-8.09) 48 per 1,000f 31 fewer per 1,000 (from 48 fewer to 340 more)

Nonfatal major bleeding 153 (2 studies), 7 d Lowc,d due to imprecision

RR 2.00 (0.19-19.46) 29 per 1,0006,7 29 more per 1,000 (from 23 fewer to 535 more)

PTS (complete lysis on venography [Elsharawy et al73]; patency on ultrasound and air plethysmography [Enden et al74])

138 (2 studies), 2 y Moderatec,g due to indirectness

RR 0.46 (0-0.79) 588 per 1,000h 318 fewer per 1,000 (from 123 fewer to 588 fewer)i

QOL (SF-12, HUI Mark version 2/3 questionnaires)

98 (1 studyj), 16 mo Lowk,l See footnotem

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. HUI 5 Health Utilities Index; SF-12 5 Medical Outcomes Survey Short Form-12; VETO 5 Venous Thrombosis Outcomes. See Table 1 and 3 legends for expansion of other abbreviations.aIn selected patients with extensive acute proximal DVT (eg, iliofemoral DVT, symptoms for , 14 d, good functional status, life expectancy � 1 y) who have a low risk of bleeding.bAll patients prescribed anticoagulants per protocol, but the intervention group receives CDT in addition to anticoagulation.cAllocation was concealed in Enden et al106 but unclear in Elsharawy et al.105 Outcome assessor blinded in both studies. Follow-up rates were 87% in Enden et al and 100% in Elsharawy et al. Neither of the studies was stopped early for benefi t.dCI includes values suggesting both benefi t and harm.eThree control patients died of cancer.fBaseline risks for nonfatal recurrent VTE and for major bleeding derived from Douketis et al.108

gSurrogate outcome: absence of patency at 6 mo in Enden et al106 study; absence of complete lysis at 6 mo in Elsharawy et al105 study.hThis estimate is based on the fi ndings of the VETO study.102 This probably underestimates PTS baseline risk given that overall, 52% of patients reported the current use of compression stockings during study follow-up.iSevere PTS: assuming the same RR of 0.46 and a baseline risk of 13.8%,102 the absolute reduction is 75 fewer severe PTS per 1,000 (from 29 fewer to 138 fewer) over 2 y.jCamerota et al.109

kParticipation rate was 65%.lRecall was used to measure QOL prior to the thrombotic event; we did not consider these measurements.mAt the initial follow-up (mean, 16 mo), patients treated with CDT reported a trend toward a higher mental summary scale (P 5 .087) and improved HUI (P 5 .078). They reported better overall role physical functioning (P 5 .046), less stigma (P 5 .033), less health distress (P 5 .022), and fewer overall symptoms (P 5 .006) compared with patients who were treated with anticoagulation alone.





lysis (31% vs 50%) and less preservation of valve function (13% vs 44%) (Tables S13 and S14), and the higher doses of thrombolytic agent used with

sys temic thrombolysis are expected to be associ-ated with a higher risk of nonprocedure-related bleeding.

We believe that systemic thrombolysis should be considered only in patients who meet all of the following criteria: iliofemoral DVT, symptoms for , 14 days, good functional status, life expec-tancy of � 1 year, and low risk of bleeding ( Table 11 ). Based on low-quality evidence of greater effective-ness and less bleeding, if resources and expertise are available to perform CDT, we consider it the preferable approach. Because the balance of risks and benefi ts with systemic thrombolysis is uncertain, and particularly because of concerns about major bleeding, anticoagulant therapy alone is an accept-able alternative to systemic thrombolysis in all patients with acute DVT who do not have impending venous gangrene.

Recommendation

2.10. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over systemic thrombolysis (Grade 2C) .

Remarks: Patients who are most likely to benefi t from systemic thrombolytic therapy (see text), who do not have access to CDT, and who attach a high value to prevention of PTS and a lower value to the initial complexity, cost, and risk of bleeding with systemic thrombolytic therapy are likely to choose systemic thrombolytic therapy over anticoagulation alone.

2.11 Operative Venous Thrombectomy for Acute DVT

Operative venous thrombectomy, with contempo-rary operative techniques 140 and more effective anti-coagulant regimens, appears to achieve improved outcomes compared with earlier reports. 141,142 A single small randomized trial with extended follow-up com-pared iliofemoral venous thrombectomy with a tem-porary arteriovenous fi stula plus anticoagulation with anticoagulation alone. 143-145 Results at 6 months, 5 years, and 10 years suggested improved iliac vein patency, less leg swelling, and fewer leg ulcers with throm-bectomy ( Table 13 , Tables S16-S18). 143-145 Evidence from this trial is of low quality because of impreci-sion and risk of bias.

We believe that operative venous thrombec-tomy should be considered only if all of the following criteria are met: iliofemoral DVT, symp-toms for , 7 days (criterion used in the single randomized trial), good functional status, life expec-tancy of � 1 year, and both resources and expertise are available. Based on low-quality evidence of greater effectiveness and less bleeding, we consider

Table 11—[Section 2.9, 2.10, 5.6, 9.2] Risk Factors for Bleeding With and Contraindications to Use of Thrombolytic Therapy (Both Systemic and Locally

Administered)

Major contraindicationsa

Structural intracranial disease Previous intracranial hemorrhage Ischemic stroke within 3 mo Active bleeding Recent brain or spinal surgery Recent head trauma with fracture or brain injury Bleeding diathesisRelative contraindicationsb

Systolic BP . 180 mm Hg Diastolic BP . 110 mm Hg Recent bleeding (nonintracranial) Recent surgery Recent invasive procedure Ischemic stroke more that 3 mo previously Anticoagulation (eg, VKA therapy) Traumatic cardiopulmonary resuscitation Pericarditis or pericardial fl uid Diabetic retinopathy Pregnancy Age . 75 y Low body weight (eg, , 60 kg) Female sex Black race

Among 32,000 Medicare patients (� 65 y) with myocardial infarc-tion who were treated with thrombolytic therapy, the following fac-tors were independently associated with intracranial hemorrhage: age � 75 y (OR, 1.6), black race (OR, 1.6), female sex (OR, 1.4), previous stroke (OR, 1.5), systolic BP � 160 mm Hg (OR, 1.8), women weighing � 65 kg or men weighing � 80 kg (OR, 1.5), and INR . 4 (OR, 2.2).110 The rate of intracranial hemorrhage increased from 0.7% with none or one of these risk factors to 4.1% with fi ve or more of these risk factors. Among 32,000 patients with myocardial infarction who were treated with thrombolytic therapy in fi ve clini-cal trials, the following factors were independently associated with moderate or severe bleeding: older age (OR, 1.04 per year), black race (OR, 1.4), female sex (OR, 1.5), hypertension (OR, 1.2), and lower weight (OR, 0.99/kg).111 We estimated that systemic thrombolytic therapy is associated with a relative risk of major bleeding of 3.5 within 35 d (RR, �7 for intracranial bleeding); about three-fourths of the excess of major bleeds with thrombolytic therapy occur in the fi rst 24 h.112 See Table 1 legend for expansion of abbreviations.aThe presence of major contraindications usually precludes use of thrombolytic therapy and, consequently, these factors have not been well studied as risk factors for bleeding associated with thrombolytic therapy. The factors listed in this table are consistent with other recommendations for the use of thrombolytic therapy in patients with PE.72,259,260,454 104,111,113,114

bRisk factors for bleeding during anticoagulant therapy noted in Table 10 that are not included in this table are also likely to be relative contraindications to thrombolytic therapy. The increase in bleeding associated with a risk factor will vary with (1) severity of the risk factor (eg, extent of trauma or recent surgery) and (2) temporal relationships (eg, interval from surgery or a previous bleeding episode believed to decrease markedly after �2 wk). Risk factors for bleeding at critical sites (eg, intracranial, intraocular) or noncompressible sites are stronger contraindications for thrombolytic therapy.




method of thrombus removal (including systemic thrombolysis). Mechanical components of these procedures are associated with a high early risk of early recurrent thrombosis, and thrombus removal is not known to alter the long-term risk of recurrent VTE. We used evidence from patients with DVT who did not have thrombus removal to guide anti-coagulant decisions in those who had thrombus removal. This evidence is rated down to moderate quality because of its indirectness in this patient population.

Recommendation

2.12. In patients with acute DVT of the leg who undergo thrombosis removal, we recommend

CDT preferable to the operative venous thrombec-tomy approach.

Recommendation

2.11. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over operative venous thrombectomy (Grade 2C) .

2.12 Anticoagulation in Patients Who Have Had Any Method of Thrombus Removal Performed

There are no randomized trials or observational studies that have compared different anticoagulant regimens or durations of therapy in patients with acute proximal DVT of the leg who have had any

Table 12—[Section 2.10] Summary of Findings: Systemic Lysis vs No Systemic Lysis for Extensive Acute DVT of the Leg138


(Studies), Follow-upQuality of the Evidence


(95% CI)


Risk With No Systemic Lysis

Risk Difference With Systemic Lysis (95% CI)

Mortality 688 (5 studies), 3 moa Lowb-e due to imprecision RR 0.86 (0.27-2.68) 21 per 1,000 3 fewer per 1,000 (from 16 fewer to 36 more)

Nonfatal recurrent VTE

687 (3 studies), 3 mof Lowd,e,g due to imprecision RR 1.28 (0.25-6.68) 48 per 1,000h 13 more per 1,000 (from 36 fewer to 273 more)

Nonfatal major bleeding

688 (10 studies), 3 mof Moderatec,d,i due to imprecision

RR 1.84 (0.94-3.59) 29 per 1,000h,j 24 more per 1,000 (from 2 fewer to 75 more)

PTS 678 (2 studies), 2 yk Lowd,e,l,m due to risk of bias and imprecision

RR 0.71 (0.49-1.04) 588 per 1,000n 171 fewer per 1,000 (from 300 fewer to 24 more)o

QOL not measured

… … … … …

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1, 3, and 10 legends for expansion of abbreviations.aRange of follow-up in included studies, 1 to 72 mo.bAllocation was concealed in three of fi ve studies. Follow-up inadequate in one of fi ve studies (Common et al139). Excluding this study from the analysis does not change the effect estimate. All studies had blinded outcome assessors. None of the studies used a placebo control.cThe population of one study (Schulman et al131) comprised patients with calf vein thrombosis.dInterventions varied across studies with regard to agent (eg, tissue plasminogen activator, streptokinase, urokinase), dose, use of the pedal vein administration, duration of treatment, and concomitant drugs (eg, steroids). However, we did not downgrade for indirectness given that there was no standard regimen and all analyses showed no heterogeneity in results.eCI included both no effect and a potentially signifi cant effect.fRange of follow-up in included studies, 1 to 30 d.gAllocation was concealed in two of three studies. Follow-up adequate in all studies. All studies had blinded outcome assessors. None of the studies used a placebo control.hBaseline risks for nonfatal recurrent VTE and for major bleeding derived from Douketis et al.108

iAllocation was concealed in seven of 10 studies. Follow-up inadequate in one of 10 studies (Common et al139). Excluding this study from the analysis does not affect the effect estimate. All studies had blinded outcome assessors. Two studies used placebo (Turpie et al135 and Verhaeghe et al136).jOnly 4% of all major bleeding events were intracranial bleeds.kRange of follow-up in included studies, 1 to 6 y.lAllocation was concealed in two of two studies. Follow-up adequate in both studies. Both studies had blinded outcome assessors. Neither study used placebo control.mNo use of a standardized validated tool reported.nThis estimate is based on the fi ndings of the VETO study.102 This probably underestimates PTS baseline risk, given that overall, 52% of patients reported the current use of compression stockings during study follow-up.oSevere PTS: Assuming the same RR of 0.71 and a baseline risk of 13.8%,102 the absolute reduction is 40 fewer severe PTS per 1,000 (from 70 fewer to 6 more) over 2 y.





bleeding), we assume that the relative risk of out-comes will be the same as in patients who received anticoagulant therapy in the Prevention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) study. However, their absolute rate of symptomatic PE and recurrent DVT will be higher compared with the PREPIC participants who were prescribed antico-agulants. A comprehensive review of mostly retrospec-tive case series of IVC fi lter insertions (6,500 patients in 89 reports) suggested that venous thrombosis at the site of fi lter insertion occurs in � 10% of patients and that fi lters can be placed above the renal veins and in the superior vena cava if necessary. 150 A prospec-tive observational study also suggested that symp-tomatic VTE and asymptomatic fi lter thrombosis are common, 151 and a systematic review suggested that the prevalence of PTS may be increased 152 in patients with permanent IVC fi lters. A small single-center randomized trial suggested a higher complication rate with the Trapease compared with the Green-fi eld permanent fi lter. 153

the same intensity and duration of anticoagu-lant therapy as in similar patients who do not undergo thrombosis removal (Grade 1B) .

2.13 Vena Caval Filters for the Initial Treatment of DVT

No randomized trial or prospective observational study has evaluated IVC fi lters as sole therapy (ie, without concurrent anticoagulation) in patients with DVT. A single, large, randomized controlled trial evaluated permanent IVC fi lter insertion as an adjunct to anticoagulant therapy in patients with acute DVT who were considered to be at high risk for PE ( Table 14 , Table S19). The fi ndings at 2 years 146 and 8 years 149 of follow-up, suggest that IVC fi lters increase the risk of recurrent DVT, reduce the risk of PE, do not alter the combined frequency of DVT and PE (ie, recurrent VTE), do not increase the risk of PTS, and do not alter mortality.

In assessing the role of an IVC fi lter in patients who cannot receive anticoagulant therapy (eg, actively

Table 13—[Section 2.11] Summary of Findings: Surgical Thrombectomy vs No Surgical Thrombectomy for Extensive Acute DVT of the Lega,144




(95% CI)


Risk With No Surgical Thrombectomy

Risk Difference With Surgical Thrombectomy (95% CI)

Mortality not reported

… … … … …

Nonfatal recurrent VTE

51 (1 study), 3 mo Lowb,c due to risk of bias and imprecision

RR 0.37 (0.02-8.75)

48 per 1,000d,e 30 fewer per 1,000 (from 47 fewer to 372 more)

Nonfatal major bleeding

51 (1 study), 3 mo Lowb,c due to risk of bias and imprecision

Not estimable (no events)

… -

PTS 51 (1 study), 2 y Lowf,g due to risk of bias and imprecision

RR 0.63 (0.44-0.9)h

588 per 1,000i 218 fewer per 1,000 (from 59 fewer to 329 fewer)j

QOL not measured

… … … … …

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1, 3 and 10 legends for expansion of abbreviations.aThe study included patients with DVT with symptoms of leg swelling not exceeding 7 d and a proximal extension of the thrombus above the inguinal ligament but not into the vena cava.bNot clear whether allocation was concealed. No blinding reported. Not clear whether analysis was intention to treat. Follow-up rate was 88% at 6 mo. Study not stopped early for benefi t.cCI includes values suggesting either harm or benefi t.dBaseline risks for nonfatal recurrent VTE derived from Douketis et al.108

eOne event was a symptomatic PE.fIn addition to other study limitations, this outcome was assessed by those who did the surgery and anticoagulation. No standardized tool was used. One surgical patient had an amputation secondary to venous gangrene and was not counted in the PTS assessment.gFew number of events. This warrants rating down the quality of evidence by a second level when considered along with study limitations.hThe RR is based on the 6-mo data.iThis estimate is based on the fi ndings of the VETO study.102 This probably underestimates PTS baseline risk, given that overall, 52% of patients reported the current use of compression stockings during study follow-up.jSevere PTS: assuming the same RR of 0.63 and a baseline risk of 13.8% over 2 y,102 the absolute reduction is 51 fewer severe PTS per 1,000 (from 14 fewer to 77 fewer) over 2 y.




be treated for the same length of time as if the same patient had not had an IVC fi lter inserted (see section 3.1). The duration of anticoagulation, therefore, will vary according to whether the DVT was provoked by a temporary risk factor, was unprovoked, or was asso-ciated with cancer, and may be infl uenced by the patient’s ongoing risk of bleeding and preferences.

Our recommendation to treat patients with an IVC fi lter with anticoagulants when contraindications to anticoagulation resolve is weaker than for anticoagu-lation of most patients with VTE because the risks of bleeding may remain elevated, and the patient’s risk of recurrence is expected to be lower if the acute episode of thrombosis occurred remotely. The evidence for IVC fi lter use in patients with acute proximal DVT who cannot be treated with anticoagulation is mod-erate because of serious imprecision and indirectness (ie, extrapolated from the PREPIC study in which

If an IVC fi lter is indicated in a patient with acute DVT or PE because anticoagulant therapy is temporarily contraindicated (eg, active bleeding), there is the option of inserting a retrievable fi lter and removing it when it is safe to start anticoagu-lant therapy. However, most retrievable fi lters are not removed; retrievable fi lters that are not removed may have a higher long-term complication rate than permanent fi lters, and there currently is no good evidence that retrievable IVC fi lters improve patient outcomes. 104,147,154,155

Insertion of an IVC fi lter does not eliminate the risk of PE and increases the risk of DVT ( Table 14 , Table S19). Consequently, we suggest that patients who have an IVC fi lter inserted should receive a con-ventional course of anticoagulation (eg, parenteral and long-term anticoagulation) if the contraindica-tion to anticoagulation resolves. Such patients should

Table 14—[Section 2.13] Summary of Findings: Vena Cava Filter vs No Vena Cava Filter for Acute Proximal DVT of the Leg Treated With Anticoagulationa,b,146,443




(95% CI)


Risk With No vena cava Filters

Risk Difference With Vena cava Filters (95% CI)

Mortality 400 (1 study), 8 y Moderatec,d due to imprecision

RR 0.95 (0.78-1.16)e


Symptomatic PE 304 (1 study), 8 y Moderatec,f due to imprecision

RR 0.41 (0.2-0.86)g


Recurrent DVT 310 (1 study), 8 y Moderatec,f due to imprecision

RR 1.3 (0.93-1.82)h

273 per 1,000 82 more per 1,000 (from 19 fewer to 224 more)

Major bleeding 337 (1 study), 8 y Moderatec,d due to imprecision

RR 0.83 (0.52-1.34)i


PTS 308 (1 study), 8 y Lowd,j due to risk of bias and imprecision

RR 0.87 (0.66-1.13)


Complications 379 (1 study), 2 y Moderatef due to imprecision

… … k

QOL not reported … … … … …

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. PREPIC 5 Prevention du Risque d’Embolie Pulmonaire par Interruption Cave. See Table 1 and 3 legends for expansion of other abbreviations.aAnticoagulation consisted of LMWH or UFH initially (according to a 2 3 2 factorial design) followed by oral anticoagulation for at least 3 mo.bFour types of permanent vena cava fi lters were used: Vena Tech LGM (B. Braun Melsugen AG), titanium Greenfi eld (Boston Scientifi c Corporation), Cardial (C.R. Bard, Inc), and Bird’s Nest (Cook Group Incorporated).cAllocation was concealed. Data collectors and outcome adjudicators were blinded. Intention-to-treat analysis. Data missing for 4% at 2 y and 1% at 8 y. Enrollment was stopped at 400 instead of targeted 800 because of slow recruitment.dCI includes both negligible effect and appreciable benefi t or appreciable harm.eRR, 1.0 (95% CI, 0.29-3.4) at 12 d; RR, 1.08 (95% CI, 0.73-1.58) at 2 y.fSmall number of events.gRR. 0.23 (95% CI, 0.05-1.05) at 12 d (both symptomatic and asymptomatic PE). RR, 0.54 (0.21-1.41) at 2 y (symptomatic PE).hRR, 1.78 (95% CI, 1.09-2.94) at 2 y.iRR, 1.5 (95% CI, 0.54-4.14) at 12 d. RR, 0.74 (95% CI, 0.41-1.36) at 2 y.jNo standardized validated tool used to measure PTS.kNo complications directly related to the fi lter or its insertion reported in the PREPIC trial.146 Mismetti et al147 (prospective study) reported an incidence of 3.2% (excluding fi lter tilting and puncture site hematoma) among 220 patients receiving a retrievable vena cava fi lter for secondary prevention of VTE, whereas Athanasoulis et al148 (retrospective study) reported an incidence of 0.3% for major complications among 1,731 patients receiving vena cava fi lters predominantly for secondary prevention of VTE.





2.14 Early Ambulation of Patients With Acute DVT

Treatment of acute DVT with bed rest and antico-agulation (originally IV UFH) has given way to early mobilization with anticoagulation (often administered SC). Two meta-analyses 156,157 summarized evidence from four relevant trials ( Table 15 , Tables S20-S22). This evidence is of low quality because of risk of bias and imprecision. We suggest early ambulation (eg, with-out a period of bed rest) when feasible because of its potential to decrease PTS and improve quality of life.

Recommendation

2.14. In patients with acute DVT of the leg, we suggest early ambulation over initial bed rest (Grade 2C) .

Remarks: If edema and pain are severe, ambulation may need to be deferred. As per section 4.1, we rec-ommend the use of compression therapy in these patients.

patients were routinely treated with anticoagulants; this indirectness, however, is minor).

Recommendations

2.13.1. In patients with acute DVT of the leg, we recommend against the use of an IVC fi lter in addition to anticoagulants (Grade 1B) .

2.13.2. In patients with acute proximal DVT of the leg and contraindication to anticoagulation, we recommend the use of an IVC fi lter (Grade 1B) .

2.13.3. In patients with acute proximal DVT of the leg and an IVC fi lter inserted as an alterna-tive to anticoagulation, we suggest a conventional course of anticoagulant therapy if their risk of bleeding resolves (Grade 2B) .

Remarks: We do not consider that a permanent IVC fi lter, of itself, is an indication for extended anticoagulation.

Table 15—[Section 2.14] Summary of Findings: Early Ambulation vs Delayed Ambulation for Acute DVT of the Lega,b,273,309,310,314,315




(95% CI)


Risk With Delayed Ambulation

Risk Difference With Early Ambulation (95% CI)

Mortality 385 (4 studies), 3 moc Lowd,e due to risk of bias, imprecision

RR 1.3 (0.23-7.55)


PE (symptomatic or asymptomatic)

385 (4 studies), 4-12 d Lowd-g due to risk of bias, imprecision

RR 1.16 (0.66-2.05)


QOL questionnaire in chronic limb venous insuffi ciency (CIVIQ)

53 (1 study), 2 y Lowh,i due to risk of bias, indirectness

See footnotej

PTS Villata-Prandoni scores (value, . 5)

37 (1 study), 2 y Lowe,h due to risk of bias, imprecision

RR 0.66 (0.42-1.03)


The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. CIVIQ 5 ChronIc Venous Insuffi ciency Questionnaire. See Table 1 and 3 legends for expansion of other abbreviations.aTwo of four eligible studies excluded patients with symptomatic PE; in the third study, 24% of participants had symptomatic PE at baseline. It was not clear whether the fourth study excluded patients with symptomatic PE.bIn two of four eligible trials, all patients received early compression therapy (bandages or stockings). In the two other trials, only patients randomized to early ambulation received early compression therapy.cThree studies reporting acute-phase mortality reported no deaths.dConcealment of allocation was reported in one of four studies; blinding of outcome assessors was reported in two of four studies; intention-to-treat analysis reported in two of four studies. Follow-up was 97% to 100%. In two of four trials, only patients randomized to early ambulation received early compression therapy (bandages or stockings). In the other two trials, all patients received early compression therapy.eCI includes both values of clinically signifi cant benefi t and values of clinically signifi cant harms.fPE assessed as both symptomatic and asymptomatic PE.gFunnel plot reported as not asymmetrical by Aissaoui et al.156

hConcealment of allocation was not reported; outcome assessors were not blinded for this outcome. Seventy percent follow-up rate; compression stockings used on patients with early mobilization but not in patients with delayed mobilization.iNo explanation was provided.jPsychologic and overall somatic QOL did not differ signifi cantly between the treatment groups, whereas DVT-related items, especially those refl ecting the ease of locomotion, showed signifi cantly greater improvement with compression than with bed rest (P , .001 for bandages, P , .05 for stockings).




continued until (1) the reduction of recurrent VTE no longer clearly outweighs the increase in bleeding or (2) it is patient preference (which may be infl uenced by fi nancial burden) to stop treatment, even if the reduc-tion in VTE would outweigh the increase in bleeding.

Increase in Risk of Recurrent VTE After Stopping Therapy— Current evidence suggests that the risk of recurrence after stopping therapy is largely deter-mined by two factors: (1) whether the acute episode of VTE has been effectively treated (duration of therapy) and (2) the patient’s intrinsic risk of having a new episode of VTE (individual risk of recurrence).

Duration of therapy: The primary goal of trials that compare different time-limited durations of antico-agulation is to identify the shortest duration of therapy that results in a posttreatment risk of recurrence that is as low as can be achieved. The fi ndings of these trials generally are not sensitive to differences in indi-vidual patient risk of bleeding.

Individual risk of recurrence: Primary factors for estimating risk of recurrence: Presence of a reversible provoking risk factor, 47,159,160,162-168,169,170 unprovoked VTE, 47,159,160,162-168,169,170 and presence of active cancer 9,47,165,166 are the most important factors that infl uence risk of recurrent VTE after stopping VKA. Among patients with VTE provoked by a reversible factor, the risk of recurrence is much lower if the provoking factor was recent surgery com-pared with a nonsurgical trigger (eg, estrogen therapy, pregnancy, leg injury, fl ight of . 8 h). 162,171 In patients with proximal DVT and PE, the estimated cumula-tive risk of recurrent VTE after stopping anticoagu-lant therapy of each of these categories is as follows: VTE provoked by surgery, 1% after 1 year and 3% after 5 years; VTE provoked by a nonsurgical revers-ible risk factor, 5% after 1 year and 15% after 5 years; and unprovoked VTE, 10% recurrence after 1 year and 30% after 5 years.

There are sparse data addressing the risk of recur-rent VTE after stopping therapy in patients with cancer because treatment is rarely stopped in these patients because of a high risk for recurrence. 38,47,165,166,172 A reasonable estimate for this risk, expressed as an annualized rate, may be 15%. However, the risk of recurrence is expected to vary according to whether the cancer is metastatic, being treated with chemo-therapy, or rapidly progressing. 38,165 The high mortality in patients with VTE and cancer (40% at 6 months in one large study 173 ) precludes estimating the cumu-lative risk of recurrence after long-term follow-up. We categorize patients with VTE according to these primary individual risk factors for recurrence when we make recommendations for duration of anticoag-ulant therapy.

Secondary factors for estimating risk of recurrence: Additional factors that infl uence the risk of recurrence

3.0 Long-term Anticoagulation of Acute DVT of the Leg

In this review, the term long-term treatment refers to treatments (eg, VKA therapy, LMWH, dabigatran) that are continued after initial therapy (eg, parenteral anticoagulation, thrombolytic therapy) ( Fig 1 ). In addition, we consider treatment with rivaroxaban, which is used without initial parenteral therapy. Long-term therapy has two goals: (1) to complete treat-ment of the acute episode of VTE and (2) to prevent new episodes of VTE that are not directly related to the acute event. During the early phase of long-term treatment (ie, fi rst 3 months), treatment of the acute episode of VTE predominates. During the late phase of long-term treatment (ie, after the fi rst 3 months), prevention of new episodes of VTE predominates. We use the term extended anticoagulation to refer to anticoagulation that is continued beyond 3 months without a scheduled stop date. However, regular (eg, yearly) reassessments are needed to assess whether a patient’s risk of bleeding increased or the patient’s preferences changed.

Three lines of evidence from randomized trials sup-port the need for long-term anticoagulant treatment of DVT (ie, after 5-10 days of initial heparin therapy): (1) a randomized controlled trial of long-term anti-coagulant therapy in 51 patients with symptomatic calf-vein thrombosis that documented a 25% rate of symptomatic extension of thrombosis within 3 months in the control group, 66 (2) a randomized trial com-paring long-term SC low-dose UFH (5,000 units bid) with VKA therapy in patients with proximal DVT that found that low-dose UFH was ineffective and resulted in a high rate of recurrent VTE (47% within 3 months), 158 and (3) randomized trials in which reduced durations of treatment of 4 or 6 weeks resulted in important increases in recurrent VTE compared with conventional durations of treat-ment of 3 or 6 months (section 3.1). 159-161 This evi-dence is of moderate quality because of imprecision and indirectness.

Recommendation

3.0. In patients with acute VTE who are treated with anticoagulant therapy, we recommend long-term therapy (see section 3.1 for recommended duration of therapy) over stopping anticoag-ulant therapy after 1 week of initial therapy (Grade 1B) .

3.1 Duration of Long-term Anticoagulant Therapy

Weighing the Benefi ts and Risks of Different Dura-tions of Anticoagulant Therapy: General Consider-ations: Anticoagulant therapy for VTE should be





VKA therapy targeted to an INR of 2.5 was the anti-coagulant regimen in all comparisons.

Short vs Intermediate Durations of Therapy—Five trials have evaluated shortening the duration of oral anticoagulant therapy from 3 or 6 months to 4 or 6 weeks in patients with mostly fi rst episodes of VTE ( Table 16 , Tables S23-S25). 159,160,167,169 This evidence, which is high quality, indicates that with the shorter duration of therapy, the absolute decrease in bleeding was small compared with the absolute increase in recurrent VTE. Patients with isolated distal DVT provoked by a major transient risk factor have a very low risk of recurrence after anticoagulant therapy is stopped ( � 1% per year 170 ). It is uncertain whether this risk is lowered by treating for 3 months compared with 4 or 6 weeks (hazard ratio [HR] for 4 or 6 weeks vs � 3 months at 2 years after stopping therapy, 0.36; 95% CI, 0.09-1.54 170 ). For this reason, we make a weaker recommendation for 3 months compared with a shorter duration of therapy in patients with isolated distal DVT that was provoked by a reversible risk factor. The evidence supporting this weaker rec-ommendation is rated down to low quality because of serious imprecision and because it is a post hoc observation.

Different Intermediate Durations of Therapy (6 or 12 months vs 3 months)—We considered trials that randomized patients with VTE to 3 months vs to 6 or 12 months of treatment to determine, when using a time-limited duration of therapy, whether there was any benefi t to treating for . 3 months. Five reports, which included six randomized comparisons, con-tributed to this analysis ( Table 17 , Tables S24-S26). 167,194,203-205 These studies found that 6 or 12 months of therapy did not convincingly lower risk of recurrence but increased major bleeding about 2.5-fold. In a meta-analysis of individual patient data from randomized trials, during the 2 years after stop-ping anticoagulant therapy, treatment of 3 months compared with � 6 months was associated with an HR of 1.19 (95% CI, 0.86-1.65) in all patients and an HR of 1.39 (95% CI, 0.96-2.01) in patients with unprovoked DVT or PE. 170 Therefore, although anti-coagulants are very effective at preventing recurrence while patients are receiving therapy, when anticoagu-lants are stopped, there is a similar risk of recurrence whether patients have been treated for 3 months or longer. 170 This evidence is of moderate quality because of serious imprecision.

As an alternative to comparing two time-limited durations of anticoagulant therapy, the AESOPUS (Ultrasound Findings to Adjust the Duration of Anti-coagulation) trial compared a predefi ned duration of therapy with a fl exible duration of therapy that depended on whether there was residual thrombo-sis during follow-up in patients with a fi rst proximal

strongly enough to modify some recommendations about duration of therapy include (1) whether DVT was confi ned to the distal veins (isolated distal [or calf] DVT), which is estimated to be associated with about one-half of the risk of recurrence of proximal DVT and PE, 10,164,167,169,170 and (2) whether the VTE was a second or subsequent episode of VTE, which is estimated to be associated with about a 50% higher risk of recurrence compared with a fi rst VTE. 9,173,175

Additional factors for estimating risk of recur-rence: Other factors predict risk of recurrence, but not strongly or consistently enough to infl uence rec-ommendations on duration of therapy once the pri-mary and secondary factors noted previously have been considered. These factors, which have mostly been evaluated in patients with unprovoked VTE, include negative D -dimer testing 1 month after withdrawal of VKA (risk ratio [RR], � 0.4), 48,176-181 antiphospholipid antibody (RR, � 2), 182-185 heredi-tary thrombophilia (RR, � 1.5), 162,163,174,177,180-182,185-190 male vs female sex (RR, � 1.6), 191,192 Asian ethnicity (RR, � 0.8), 193 and residual thrombosis in the prox-imal veins (RR, � 1.5). 149,182,185,194-198 Combinations of factors have the potential to be more important predictions of recurrence risk than single factors (eg, low risk of recurrence in women with unpro-voked proximal DVT or PE who have a negative D -dimer test before 185 or 1 month after 180,199 stop-ping anticoagulant therapy). PTS may be a risk factor for recurrent VTE, 183,185,200 and recurrent ipsilateral DVT is a risk factor for development of PTS. 201,202 Both associations may contribute to a decision to use extended therapy in a patient with established PTS.

Increase in Risk of Bleeding While Remaining on Anticoagulant Therapy— Although the decision to treat patients with different time-limited durations of anticoagulant therapy generally are insensitive to an individual’s risk of bleeding, the decision to use extended anticoagulation, particularly in patients with an unprovoked proximal DVT or PE, is sensitive to risk of bleeding. There is no validated prediction tool to stratify the risk of major bleeding during extended anticoagulant therapy specifi cally in patients with VTE, but this risk appears to increase with the prevalence of the factors noted in Table 2 . This table also provides our estimate of the absolute risk of bleeding without anticoagulation (baseline risk), the increase with anticoagulation, and the sum of these two risks (ie, risk of bleeding on therapy).

Comparisons of Time-Limited Durations of Therapy: Randomized trials have compared either a short (eg, 4 or 6 weeks) with an intermediate (eg, 3 or 6 months) duration of therapy, or two intermediate durations of therapy, (eg, 3 months vs 6 or 12 months).




bleeding. The quality of evidence for the reduction in recurrent VTE with extended therapy is high but is rated down to moderate for bleeding and mortality because of imprecision.

Weighing the Benefi ts and Risks of Extended VKA Therapy— The decision to extend anticoagulation therapy beyond 3 months is sensitive to both baseline risks of recurrent VTE and major bleeding. We did not identify a validated prediction tool for either outcome that takes into account all relevant risk fac-tors. As an alternative, for patients without cancer, we chose to stratify our recommendations according to four primary risk groups for recurrent VTE (sec-tion 3.1) and three risk groups for major bleeding (section 3.1) ( Table 2 ). This approach resulted in a total of 12 combinations of risk profi les. Table 19 shows the estimated total (and fatal) number of recurrent episodes of VTE prevented and the number of major bleeds caused by 5 years of extended therapy for each of the 12 combinations. In the absence of robust trial data for mortality for recurrent VTE and

Table 16—[Section 3.1.1-3.1.4] Summary of Findings: Four or Six Weeks vs Three or Six Months as Minimum Duration of Anticoagulation for VTEa,b,16,159,167,169,195




(95% CI)


Risk With Control

Risk Difference With 4 or 6 wk vs 3 or 6 mo Months of Anticoagulation (95% CI)

Recurrent VTE 2,185 (5 studiesc), 1-2 yd Highe-g RR 1.83 (1.39-2.42)

64 per 1,000 53 more per 1,000 (from 25 more to 91 more)

Major bleeding 2,185 (5 studies), 1-2 y Highf RR 0.54 (0.22-1.32)


Mortality 2,098 (5 studies), 1-2 y Highe,f,h RR 0.97 (0.68-1.38)


The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confidence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aPopulations varied among studies: fi rst provoked isolated distal DVT, proximal DVT, or PE provoked in Kearon et al195; fi rst isolated distal DVT in Pinede et al167; fi rst isolated distal DVT, proximal DVT, or PE in Schulman et al169; proximal DVT (21% had cancer) in Levine et al159; DVT or PE (29% not objectively confi rmed) in British Thoracic Society.160

bShort vs longer duration of anticoagulation was 6 wk vs 6 mo for Schulman et al169, 6 wk vs 3 mo for Pinede et al,167 and 4 wk vs 3 mo for the other three studies.cTiming of randomization relative to the start of treatment varied across studies: Pinede et al,167 Schulman et al,169 and British Thoracic Society160 randomized at diagnosis, and Kearon et al195 and Levine et al159 randomized to stop or to continue treatment for 2 mo more after the initial 4 wk of treatment.dFollow-up was for �1 y in all studied except for Schulman et al169 in which it was 2 y.eGenerally, study design was strong. No study stopped early for benefi t; two stopped early because of slow recruitment (Kearon et al,195 Pinede et al167). In one study (British Thoracic Society160), 44 randomized patients were excluded centrally as they did not satisfy eligibility criteria. Patients and caregivers were blinded in two studies (Kearon et al, Levine et al159). Adjudicators of outcomes were blinded in all but one study (British Thoracic Society). All studies appear to have used effective randomization concealment, intention-to-treat analysis, and a low unexplained drop-out frequency.fNo heterogeneity with I2 5 0%.gNo imprecision for overall estimates. However, for the subgroup of patients with isolated distal DVT, who are known to have a very low risk of recurrence, there is imprecision and the possibility that the shorter duration of anticoagulation is adequate and not associated with a clinically important higher risk of recurrence.hDifferences in mortality are expected to be mediated by differences in recurrent VTE and bleeding.

DVT 206 (Tables S24 and S25). Its fi ndings suggest that the latter approach may be helpful for tailoring the duration of therapy.

Extended vs Time-Limited Anticoagulant Therapy: Five trials compared extended anticoagulation with VKA therapy (target INR 2.0-2.85, 161 2.0-3.0, 48,182,207 and 1.5-2.0 174 ) with stopping VKA therapy at 3 or 6 months in patients who were judged to have a high risk of recurrence ( Table 18 , Table S24, S25, and S27). The results indicate that randomization to indefi nite treatment with conventional-intensity VKA (target INR 2.5) reduces recurrent VTE by about 90% (RR for the four studies, 0.12; 95% CI, 0.05-0.25 48,161,182,207 ), and randomization to low-intensity therapy (target INR 1.75) reduces VTE by 64% (95% CI for HR, 23%-81%), 174 with about one-half of recurrent VTE in the active treatment groups in these studies occurring in patients who had prematurely stopped VKA therapy. Extended anticoagulant therapy was associated with about a 2.6-fold increase in major





others fi nd it a major burden that greatly erodes their sense of well-being. 210

The presence of additional risk factors for VTE recurrence (section 3.1), the patient’s relative value for the different outcome of interest (recurrence of VTE, major bleeding, PTS), and the patient’s per-ceived burden of anticoagulant therapy may infl uence decisions about the use of extended anticoagulant therapy in patient groups for which we provide a weak recommendation but are unlikely to infl uence this decision in patients groups for which we provide a strong recommendation. 16 Similarly, the costs of therapy and how those costs are paid (eg, patient, third party) are more likely to infl uence treatment decisions when there is a weak recommendation (Grade 2) in favor of extended therapy.

Patients With VTE and Cancer: As previously noted (section 3.1), because they have a high risk of recur-rence, patients with active cancer (eg, treated within the past 6 months, persistent or progressive) should benefi t from extended anticoagulant therapy unless they have a very high risk of bleeding. The quality of the evidence supporting this recommendation is moderate because of indirectness (the relative effects of anticoagulation are based, in part, on evidence

bleeding, we assumed that 3.6% of recurrent VTE and 11.3% of major bleeds will be fatal. 12

We make (1) a strong recommendation for extended therapy when it is associated with a reduction in VTE that is substantially more frequent than the increase in major bleeding and with a mortality advantage, (2) a weak recommendation for extended therapy when it is associated with a reduction in VTE that is more frequent than the increase in major bleeding but the magnitude of this difference and the suggested mortality advantage are more modest, (3) a weak recommendation against extended therapy when extended therapy is associated with a reduc-tion in VTE that is less frequent than the increase in major bleeding and no mortality advantage exists, and (4) a strong recommendation against extended therapy when extended therapy is associated with a reduction in VTE that is less frequent than the increase in major bleeding and a mortality disadvan-tage may exist. We assume that on average, extended anticoagulation with VKA therapy is a modest burden to patients. 15 However, this differs markedly among patients; some do not fi nd anticoagulant therapy a burden and have an enhanced feeling of well-being because they feel protected from recurrence, whereas

Table 17—[Section 3.1.1-3.1.4] Summary of Findings: Six or Twelve Months vs Three Months as Minimum Duration of Anticoagulation for VTEa,b,167,203,204




(95% CI)


Risk With 3 moRisk Difference With 6 or

12 mo (95% CI)

Recurrent VTE 2,061 (6 studies), 1-3 y Moderatec-e due to imprecision

RR 0.89 (0.69-1.14)


Major bleeding 2,061 (6 studies), 1-3 y Highf RR 2.49 (1.2-5.16)


Mortalityg 1,331 (5 studies), 1-3 y Moderated due to imprecision

RR 1.3 (0.81-2.08)


The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of other abbreviations.aStudy populations varied across studies: Pinede et al167 enrolled provoked and unprovoked proximal DVT and PE; Campbell et al203 enrolled provoked and unprovoked isolated distal DVT, proximal DVT, and PE; Agnelli et al194 had separate randomizations for provoked PE (3 vs 6 mo) and unprovoked (3 vs 12 mo); and Agnelli et al204 enrolled unprovoked proximal DVT.bTiming of randomization relative to the start of treatment and length of treatment in the non-3 mo group varied across studies: Pinede et al167 and Campbell et al203 randomized at diagnosis; and Agnelli et al194,204 randomized after the initial 3 mo of treatment to stop or continued treatment. The longer duration of treatment was 6 mo in Agnelli et al194 (provoked PE) and 12 mo in Agnelli et al204 and Agnelli et al194 (unprovoked PE).cGenerally, study design was strong. No study stopped early for benefi t; two stopped early because of slow recruitment (Campbell et al,203 Pinede et al167) and one because of lack of benefi t (Agnelli et al204). In one study (Campbell et al), 20% of VTE outcomes were not objectively confi rmed. Patients and caregivers were not blinded in any study. Adjudicators of outcomes were blinded in all but one study (Campbell et al). All studies used effective randomization concealment, intention-to-treat analysis, and a low unexplained drop-out frequency.dCIs include both values suggesting no effect and values suggesting either benefi t or harm.eLow number of events and a total number of participants , 2,000.fOne study may have confi ned the assessment of bleeding to when subjects were receiving anticoagulant therapy, which could have infl ated the increase in bleeding associated with the longer duration of therapy (Campbell et al203).gDifferences in mortality are expected to be mediated by differences in recurrent VTE and bleeding.




Table 18—[Section 3.1.1-3.1.4] Summary of Findings: Extended Anticoagulation vs No Extended Anticoagulation for Different Groups of Patients with VTE and Without Cancera,b,48,161,182,207



Quality of the Evidence


(95% CI)


Risk With No Extended Duration

Oral Anticoagulation

Risk Difference With Extended Duration Oral Anticoagulation (95% CI)

Mortality 1,184 (4 studies), 10-36 mo

Moderatec-e due to imprecision


Recurrent VTE at 1 y

1,184 (4 studies), 10-36 mo

High RR 0.12 (0.09-0.38) First VTE provoked by surgeryf-j


First proximal DVT or PE provoked nonsurgical/fi rst unprovoked distal DVTf-j


First unprovoked VTEf-j


Second unprovoked VTEf-j


Major bleeding at 1 y

1,184 (4 studies), 10-36 mo

Moderate due to imprecision

RR 2.63 (1.02-6.76) Lowk,l (see Table 2)3 per 1,000 5 more per 1,000 (from

0 more to 15 more)Moderatek,l (see Table 2)


Highk,l (see Table 2)25 per 1,000 40 more per 1,000 (from

3 more to 122 more)Recurrent VTE

at 5 y1,184 (4 studies),

10-36 moHigh RR 0.12 (0.09-0.38) First VTE provoked by surgeryf-j


First proximal DVT or PE provoked nonsurgical/fi rst unprovoked distal DVTf-j


First unprovoked VTEf-j


Second unprovoked VTEf-j


Major bleeding at 5 y

1,184 (4 studies), 10-36 mo

Moderate due to imprecision

RR 2.63 (1.02-6.76) Lowk,l (see Table 2)15 per 1,000 24 more per 1,000 (from

2 more to 73 more)Moderatek,l (see Table 2)


Highk,l (see Table 2)125 per 1,000 199 more per 1,000

(from 17 more to 609 more)

(Continued)





from patients without cancer). Presence of factors associated with a lower risk of recurrence that may support stopping anticoagulant therapy, particularly if the risk of bleeding was high, include the following: (1) VTE was associated with a superimposed revers-ible risk factor (eg, recent surgery, chemotherapy), (2) the cancer has responded to treatment, (3) the cancer has not metastasized, and (4) the VTE was an isolated distal DVT.

Follow-up of Patients on Extended Therapy: Patients who are treated with extended anticoagulant therapy should be reviewed regularly (eg, annually) to ensure that (1) they have not developed contraindications to extended therapy, (2) their preferences have not changed (eg, anticoagulation has become an exces-sive burden), (3) they can benefi t from improved ways





(95% CI)


Risk With No Extended Duration

Oral Anticoagulation

Risk Difference With Extended Duration Oral Anticoagulation (95% CI)

Burden of anticoagulation not reported

… … … Warfarin: daily medication, dietary and activity restrictions, frequent blood testing/monitoring, increased hospital/clinic visitsm

…

PTS not reported … … … n …

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. PREVENT 5 Prevention of Recurrent Venous Thromboembolism. See Table 1 and 3 legends for expansion of other abbreviations.aStudies vary in follow-up duration (10 mo to 3 y) and in duration of time-limited VKA (3-6 mo).bWe excluded PREVENT trial because target INR was 1.75 (low intensity), which has been shown in an RCT44 to be less effective than a target of 2.5.cI2 5 0%.dCI includes both values suggesting no effect and values suggesting either appreciable harms or appreciable benefi t.eSmall number of events. Decision to rate down also takes into account that two studies were stopped early for benefi t.fAnnual risk of VTE recurrence after discontinuing oral anticoagulation therapy in patients with fi rst VTE provoked by surgery: 1% (Iorio et al171); we assumed a 0.5% yearly risk thereafter (3% over 5 y).gAnnual risk in patients with fi rst VTE provoked by nonsurgical factor: �5% the fi rst year (Iorio et al171); we assumed a 2.5% yearly thereafter (15% over 5 y).hAnnual risk in patients with fi rst episode of unprovoked VTE: 9.3% over 1 y in Rodger et al185; 11.0% over 1 y, 19.6% over 3 y, and 29.1% over 5 y in Prandoni et al.208 We assumed a risk of 10% the fi rst year after discontinuation and 5% yearly thereafter (30% over 5 y).iAnnual risk in patients with second episode of unprovoked VTE: we assumed an RR of 1.5 compared with a fi rst episode of unprovoked VTE: 15% the fi rst year after discontinuation, 7.5% yearly thereafter (45% over 5 y).jCase fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% (Carrier et al12).kAnnual risk of major bleeding is based on three risk levels: low, intermediate, and high. The corresponding 0.3%, 0.6%, and 1.2% risks are estimates based on control arms of included studies (see Table 2).lCase fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al12) (no data available for after discontinuing oral anticoagulation therapy).mBurden of anticoagulation: endured by all patients who continue extended-duration anticoagulation (100%) and applies to patients who stop anticoagulation (no extended duration anticoagulation) who subsequently experienced a recurrent VTE (5%/10%/15% at 1 y; 15%/30%/45% at 5 y).nPTS: baseline risk over 2 y of 58.8% for PTS and 13.8% for severe PTS (Kahn et al102). There was a threefold (Prandoni et al202) to 10-fold (van Dongen et al209) increase in PTS with recurrent VTE in the ipsilateral leg.

Table 18—Continued

of selecting a patient for extended therapy if these have become available, and (4) they are being treated with the anticoagulant regimen that best suits them.

LMWH for Extended Therapy: We identifi ed no direct evidence for LMWH compared with (1) VKA, (2) other anticoagulant strategies, or (3) control for the extended phase of anticoagulation in patients who were treated with a standardized initial long-term anticoagulant regimen. Based on indirect evidence from comparisons of LMWH with VKA therapy during the initial 3 or 6 months of long-term therapy, we judged LMWH to be at least as effective in terms of recurrent VTE and as safe in terms of major bleeding ( Table 20 , Table S28). The potential for drug-induced osteoporosis, however, may be greater with extended therapy LMWH than with VKA therapy. 1




Table 19—[Section 3.1.1-3.1.4] Estimated Absolute Difference in Recurrent VTE and Major Bleeding Events (Including Fatal Events) With 5 Years of vs No Extended Anticoagulation

Outcomes After 5 y of Treatment

Risk of Bleeding

Low Intermediate Higha

First VTE provoked by surgery

Recurrent VTE reduction per 1,000

↓ 26 (19-27) (1 fatal)b ↓ 26 (19-27) (1 fatal)b ↓ 26 (19-27) (1 fatal)b

Major bleeding increase per 1,000

↑ 24 (2-73) (3 fatal)b ↑ 49 (1-173) (5 fatal)b ↑ 98 (1-346) (11 fatal)b

First VTE provoked by a nonsurgical factor/fi rst unprovoked distal DVT


↓ 132 (93-137) (5 fatal)c ↓ 132 (93-137) (5 fatal)c ↓ 132 (93-137) (5 fatal)b


↑ 24 (2-73) (3 fatal)c ↑ 49 (1-173) (5 fatal)c ↑ 98 (1-346) (11 fatal)b

First unprovoked proximal DVT or PE


↓ 264 (186-273) (10 fatal)d ↓ 264 (186-273) (10 fatal)d ↓ 264(186-273) (10 fatal)b


↑ 24 (2-73) (3 fatal)d ↑ 49 (1-173) (5 fatal)d ↑ 98 (1-346) (11 fatal)b

second unprovoked VTE Recurrent VTE reduction per 1,000

↓ 396 (279-409) (14 fatal)e ↓ 396 (279-409) (14 fatal)d ↓ 396 (279-409) (14 fatal)c


↑ 24 (2-73) (3 fatal)e ↑ 49 (1-173) (5 fatal)d ↑ 98 (1-346) (11 fatal)c

Recommendations:Risk of dying in patients with a recurrent VTE or a major bleed:• Case fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% (Carrier et al12).• Case fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al12) (no data available for after discontinuing oral

anticoagulation therapy).Annual risks of recurrent VTE after discontinuation of anticoagulation:• First VTE provoked by surgery: 1% (Iorio et al171); we assumed a 0.5% yearly risk thereafter (3% over 5 y).• First episode of VTE provoked by nonsurgical factor: �5% the fi rst year (Iorio et al171); we assumed a 2.5% yearly thereafter (15% over 5 y)• First episode of unprovoked VTE: 9.3% over 1 y (Rodger et al185); 11.0% over 1 y, 19.6% over 3 y, 29.1% over 5 y (Prandoni et al208). We assumed

a risk of 10% the fi rst year after discontinuation and 5% yearly thereafter (30% over 5 y).• Second episode of unprovoked VTE: we assumed that this infl icts 1.5 the risk of recurrent VTE relative to fi rst episode of unprovoked VTE: 15%

the fi rst year after discontinuation, 7.5% yearly thereafter (45% over 5 y).Relative risk reduction with extended anticoagulant therapy:• 82% based on Table 18Annual risks of major bleeding in patients not on anticoagulant therapy:• Low risk, 0.3%/y; intermediate risk 0.6%/y; high risk, 2.4%/y (Table 2).Relative risk of major bleeding with extended anticoagulant therapy:• 2.6 based on Table 18.Criteria used to decide on direction and strengths of recommendations:• Criterion for a strong recommendation against whenever the estimated number of fatal bleeding events exceeded the estimated number of fatal

recurrent VTE prevented.• Criterion to go from a strong recommendation against to weak recommendation against: difference between the lower boundary of increased

major bleeding and upper boundary of reduction in recurrent VTE , 2% (risk over 5 y averaged per year).• Criterion to go from a weak recommendation against to a weak recommendation in favor of: difference between point estimate of reduction of recurrent

VTE and point estimate for increase in major bleeding is . 2% (risk over 5 y averaged per year) (2% to account for the burden and cost of VKA).• Criterion to go from a weak recommendation for to strong recommendation for: difference between the lower boundary of reduction in VTE and

upper boundary of increased major bleeding . 4% (risk over 5 y averaged per year).Another way of interpreting the direction and strength of recommendation based on the number of deaths (related to either bleeding or recurrent VTE) is as follows:• A strong recommendation against: extended anticoagulation is estimated to be associated with an increase in deaths.• A weak recommendation against: extended anticoagulation is estimated to be associated with from no effect on deaths to only a very small

reduction in deaths (0-4/1,000 prevented over 5 y or , 0.5%/patient-y).• A weak recommendation for: extended anticoagulation is estimated to be associated with a small reduction in deaths (5 to 9/1,000 prevented over

5 y or 0.5%-0.9%/patient-y).• A strong recommendation for: extended anticoagulation is estimated to be associated with a large reduction in deaths (. 10/1,000 prevented over

5 y or . 1%/patient-y).aWith an eightfold risk of bleeding in the high-risk group compared with the low-risk group, a strong recommendation against extended anticoagulation for a second unprovoked VTE is justifi ed. The high-risk group, however, includes patients who have a risk of bleeding that is less than this estimate (eg, patients aged . 75 y without additional risk factors for bleeding [Table 2]) and, therefore, may benefi t from extended anticoagulant therapy. For this reason, we provide a weak rather than a strong recommendation against extended anticoagulation for patients with a second unprovoked VTE in the high-bleeding-risk group.bStrong againstcWeak againstdWeak in favoreStrong in favor





Rivaroxaban for Extended Therapy: Use of rivar-oxaban compared with initial parenteral therapy followed by VKA therapy for the short- and long-term treatment of DVT is reviewed in section 3.3 ( Table 21 , Table S29). In the current section, we con-sider rivaroxaban compared with no anticoagulation in patients with proximal DVT or PE who have com-pleted 6 or 12 months of anticoagulant therapy, which has been evaluated in a single study ( Table 22 , Table S30). 127 This study found that rivaroxaban markedly reduced recurrent VTE at the expense of a modest absolute increase in major bleeding. The evi-dence from this one study is of moderate quality because of serious imprecision.

Dabigatran for Extended Therapy: There are no completed studies that have compared dabigatran with no anticoagulation for extended treatment of VTE.

Choice of Anticoagulant Regimen for Extended Therapy: This question is addressed in section 3.3.

Recommendations

3.1.1. In patients with a proximal DVT of the leg provoked by surgery, we recommend treatment with anticoagulation for 3 months over: (i) treat-ment of a shorter period (Grade 1B) , (ii) treat-ment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , or (iii) extended therapy (Grade 1B regardless of risk of bleeding) .

3.1.2. In patients with a proximal DVT of the leg provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , and (iii) extended therapy if there is a high bleeding risk ( Table 2 ) (Grade 1B) . We suggest treatment with anticoagulation for 3 months over extended ther apy if there is a low or mod-erate bleeding risk ( Table 2 ) (Grade 2B) .

3.1.3. In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor (see remark), we suggest treatment with anticoagulation for 3 months over treatment of a shorter period (Grade 2C) and recommend treatment with anticoagulation for 3 months over treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) or extended therapy (Grade 1B regardless of bleeding risk) .

3.1.4. In patients with an unprovoked DVT of the leg (isolated distal [see remark] or prox-imal), we recommend treatment with anticoagu-

lation for at least 3 months over treatment of a shorter duration (Grade 1B). After 3 months of treatment, patients with unprovoked DVT of the leg should be evaluated for the risk-benefi t ratio of extended therapy.

3.1.4.1. In patients with a fi rst VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk ( Table 2 ), we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B) .

3.1.4.2. In patients with a fi rst VTE that is an unprovoked proximal DVT of the leg and who have a high bleeding risk ( Table 2 ), we recom-mend 3 months of anticoagulant therapy over extended therapy (Grade 1B) .

3.1.4.3. In patients with a fi rst VTE that is an unprovoked isolated distal DVT of the leg (see remark), we suggest 3 months of anticoagulant therapy over extended therapy in those with a low bleeding risk ( Table 2 ) (Grade 2B) , and recommend 3 months of anticoagulant treat-ment in those with a moderate or high bleeding risk ( Table 2 ) (Grade 1B) .

3.1.4.4. In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk ( Table 2 ) (Grade 1B) , and we suggest extended anticoagulant therapy in those with a moderate bleeding risk ( Table 2 ) (Grade 2B) .

3.1.4.5. In patients with a second unprovoked VTE who have a high bleeding risk ( Table 2 ), we suggest 3 months of anticoagulant therapy over extended therapy (Grade 2B) .

3.1.5. In patients with DVT of the leg and active cancer, if the risk of bleeding is not high ( Table 2 ), we recommend extended anti-coagulant therapy over 3 months of therapy (Grade 1B) , and if there is a high bleeding risk ( Table 2 ), we suggest extended anticoagulant therapy (Grade 2B) .

Remarks (3.1.3, 3.1.4, 3.1.4.3): Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anti-coagulant therapy; however, it is anticipated that not all patients who are given a diagnosis of isolated distal DVT will be prescribed anticoagulants (see section 2.3). In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually).




Table 20—[Section 3.3] Summary of Findings: LMWH vs VKA for Long-term Treatment of VTEa-c,173,211,213,223,224,226-228

Outcomes

No. of Participants



Relative Effect (95% CI)


Risk With VKARisk Difference With

LMWH (95% CI)

Death 2,496 (7 studies), 6 mo

Moderated,e due to imprecision

RR 0.96 (0.81-1.13)


Recurrent VTE 2,727 (8 studies), 6 mo

Moderatef due to risk of bias

RR 0.62 (0.46-0.84)

No cancerg


Nonmetastatic cancerg


Metastatic cancerg


Major bleeding 2,737 (8 studies), 6 mo

Moderateh,i due to imprecision

RR 0.81 (0.55-1.2)

No cancer or nonmetastatic cancerj


Metastatic cancerj


Burden of anticoagulation

… Highk … Warfarin: daily medication, dietary restrictions, frequent blood testing/monitoring, increased hospital/clinic visits

LMWH: daily injection, no dietary restrictions, no frequent blood testing/monitoring

PTS (self-reported leg symptoms and signs)

100 (1 study), 2 y Lowl,m due to risk of bias, indirectness

RR 0.85 (0.77-0.94)

200 per 1,000n 30 fewer per 1,000 (from 12 fewer to 46 fewer)

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aTwo of these studies enrolled only patients without cancer, three enrolled only patients with cancer, and three enrolled both patients with and without cancer (separate data provided for patients with cancer and without cancer in one study).bLimited to LMWH regimens that used � 50% of the acute treatment dose during the extended phase of treatment.cThe initial parenteral anticoagulation was similar in both arms for all except one study (Hull et al211) in which patients randomized to LMWH initially received the same LWMH, whereas patients randomized to VKA received initially UFH.dOne study did not report deaths, which is unusual and could refl ect selective reporting of outcomes.eCI includes both no effect and harm with LMWH.fNone of the studies were blinded, whereas the diagnosis of recurrent VTE has a subjective component and there could be a lower threshold for diagnosis of recurrent VTE in VKA-treated patients because switching the treatment of such patients to LMWH is widely practiced. At the same time, there is reluctance to diagnose recurrent VTE in patients who are already taking LMWH because there is no attractive alternative treatment option.gRisk of recurrent VTE: low corresponds to patients without cancer (3% estimate taken from recent large RCTs of acute treatment), intermediate corresponds to patients with local or recently resected cancer (based on average rate across the six studies in this analysis and appears to be consistent with Prandoni et al38 [particularly if low risk is increased to 4%]), and high corresponds to patients with locally advanced or distant metastatic cancer (Prandoni et al).hNo study was blinded; diagnosis of major bleeding has a subjective component.iThe 95% CIs for the RR for major bleeding includes a potentially clinically important increase or decrease with LMWH and may vary with the dose of LMWH used during the extended phase of therapy.jRisk of bleeding: low corresponds to patients without risk factor for bleeding (ie, age . 75 y, cancer, metastatic disease; chronic renal or hepatic failure; platelet count , 80,0000; requirement for antiplatelet therapy; history of bleeding without a reversible cause) (Table 2). Based on Prandoni et al38 and Beyth et al212 and adjusted to a 6-mo time frame.kHull et al213 reported no signifi cant difference in QOL but suggested greater satisfaction with LMWH over VKA (questionnaire did not directly assess the burden of injections).lPatients and investigators not blinded. Self-reported leg symptoms and signs after 3 mo of treatment.mThe association between leg symptoms and signs at 3 mo and long-term PTS is uncertain.nBaseline risk assumes that patients all wear pressure stockings. Control event rate comes from observational studies in a review by Kahn et al,214 adjusted to a 2-y time frame.





3.2 Intensity of Anticoagulant Effect

Ageno et al 2 and Holbrook et al 3 in these guidelines present evidence for the optimal intensity of VKA therapy (ie, target INR) during the long-term (eg, fi rst 3 months of treatment) and extended phases of treatment of VTE.

Recommendation

3.2. In patients with DVT of the leg who are treated with VKA, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR , 2) or higher (INR 3.0-5.0) range for all treatment durations (Grade 1B) .

3.3 Choice of Anticoagulant Regimen for Long-term Therapy

VKA therapy has been the standard method of anticoagulant therapy for VTE. Adjusted-dose SC UFH is an effective alternative to VKA therapy, but it has never been popular because it requires initial

laboratory monitoring and twice-daily injection and is associated with osteoporosis. 215,216 SC LMWH has advantages over SC UFH in that it does not require laboratory monitoring, is less likely to cause osteoporosis, 216 and can be given once a day. For these reasons, LMWH has been used for the long-term treatment of VTE. The synthetic pentasaccha-ride, fondaparinux, has not been evaluated or widely used for long-term treatment of VTE. Idraparinux, a long-acting pentasaccharide, is effective for the long-term treatment of VTE, 217 but it is not being marketed because of concerns about bleeding given its prolonged duration of action (once weekly injec-tion) and lack of reversibility. The direct antithrombin dabigatran and the direct factor Xa inhibitors apixa-ban and rivaroxaban have been evaluated for treat-ment of VTE and are now available in many countries. In this section, we compare VKA therapy (target INR 2.5), LMWH, dabigatran, and rivaroxaban for the long-term treatment of VTE (ie, fi rst 3 months and extended therapy).

Table 21—[Section 3.3] Summary of Findings: Rivaroxaban vs LMWH and VKA Therapy for Acute and Long-term Treatment of VTEa-c,88

Outcomes

No. of Participants




(95% CI)


Risk With LMWH and VKA Therapy

Risk Difference With Rivaroxaban (95% CI)

Mortality 3,449 (1 study), 6-12 mod

Moderatee,f due to imprecision

HR 0.67 (0.44-1.02)


Recurrent VTE 3,449 (1 study), 6-12 mod

Moderatee,g due to imprecision

HR 0.68 (0.44-1.04)


Major bleeding 3,429 (1 study), 6-12 mod

Moderatee,g due to imprecision

HR 0.68 (0.34-1.38)i

11 per 1,000j 4 fewer per 1,000 (from 7 fewer to 4 more)


… … … Warfarin: daily medication, dietary restrictions, frequent blood testing/monitoring, increased hospital/clinic visits

Rivaroxaban: daily medication, no dietary restrictions, no frequent blood testing/monitoring

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. HR 5 hazard ratio. See Table 1 and 3 legends for expansion of other abbreviations.aIncluded patients had acute, symptomatic, and objectively verifi ed proximal DVT of the legs (unprovoked, 62%; cancer, 6%; previous, VTE 19%).bRivaroxaban 15 mg bid for 3 wk and then 20 mg/d for a total of 3 (12%), 6 (63%), or 12 (25%) mo.cEnoxaparin 1 mg/kg bid for �8 d and then VKA therapy targeted to an INR of 2.5 for 3, 6, or 12 mo.dFollow-up was prespecifi ed to be 3 (12%), 6 (63%), or 12 (25%) mo.eAllocation was concealed. Patients, providers, and data collectors were not blinded, but outcome adjudicators were blinded. Intention-to-treat analysis; 1.0% were loss to follow-up. Not stopped early for benefi t.fCI includes values suggesting benefi t or no effect; relatively low number of events.gCI includes values suggesting benefi t and harm.hOne defi nite or possible fatal VTE in the rivaroxaban group and one in the LMWH/VKA group.iCalculated from reported data.jBleeds contributing to death: one in the rivaroxaban group and fi ve in the warfarin group.




LMWH vs VKA Therapy for the Long-term Treat-ment of DVT: Two meta-analyses compared LMWH in widely differing doses with VKAs. 218,219 In an analysis by Iorio and colleagues, 218 which included seven studies 168,221-225 and a total of 1,379 patients, among study differences of mean daily dose of LMWH, little effect on the effi cacy of LMWH compared with VKA therapy was found, but the dose of LMWH appeared to infl uence the risk of major bleeding (OR, � 0.2 with � 4,000 International Units/d to � 0.7 with 12,000 International Units/d, relative to the VKA groups; P 5 .03 for dose-dependent interac-tion). Because prophylactic doses of LMWH are rarely used as an alternative to VKA therapy in patients with VTE, we restricted our analysis to eight studies that used � 50% of the full therapeutic dose of LMWH for long-term treatment of VTE ( Table 20 , Table S28). 173,211,213,223,224,226-228 This evidence suggests that compared with VKA therapy, LMWH is associated with a reduction of recurrent VTE and a similar frequency of major bleeding and mor-tality. The quality of this evidence is moderate because of potential for bias in the assessment of recurrent VTE (nonblinded outcome assessment) and serious imprecision for major bleeding and mortality.

Cancer vs No Cancer— There are differences between patients with and without cancer with VTE that may infl uence response to anticoagulant ther-apies. These include about a 10-fold higher risk of dying and a threefold higher risk of recurrent VTE and major bleeding during the fi rst 3 or 6 months of treatment 38 ; different mechanisms of thrombosis that may be associated with a poor response to VKA ther-apy 229 ; use of cancer chemotherapy that is associated with thrombocytopenia, vomiting, and anorexia and may have other interactions with VKA therapy; and the need for invasive therapeutic interventions (eg, drainage procedures) that require reversal of antico-agulation. Many of these factors make LMWH more attractive and VKA therapy less attractive in patients with VTE and cancer and suggest that cancer may alter the response of VTE to LMWH vs VKA therapy (ie, presence of an interaction).

Among the eight studies included in Table 20 and Table S28, separate data are provided for 1,114 patients with cancer and 660 patients with-out cancer. Subgroup analyses suggest the possi-bility that the response to LMWH vs VKA therapy may differ between patients with cancer and with-out cancer (recurrent VTE: RR, 0.52 with cancer

Table 22—[Section 3.3] Summary of Findings: Rivaroxaban vs Placebo for Extended Anticoagulation of VTEa,b,88




(95% CI)


Risk With PlaceboRisk Difference With Rivaroxaban (95% CI)

Mortality 1,196 (1 study), 6 or 12 moc


RR 0.49 (0.04-5.4)f


Recurrent VTE 1,196 (1 study), 6 or 12 moc

Highd HR 0.18 (0.09-0.39)

71 per 1,000g 58 fewer per 1,000 (from 43 fewer to 64 fewer)

Major bleeding 1,188 (1 study), 6 or 12 mo

Moderated,h due to imprecision

RR 4.9 (0.58-42)f

i 7 more per 1,000 (from 3 more to 16 more)


… Rivaroxaban: daily medication

PTS not reported … … … … j

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1, 3, and 21 legends for expansion of abbreviations.aIncluded patients had acute, symptomatic, and objectively verifi ed proximal DVT of the legs or PE (unprovoked, 73%; cancer, 5%; previous VTE, 19%).bRivaroxaban 20 mg/d for 6 or 12 mo after initial long-term therapy.cFollow-up was prespecifi ed to be 6 (60%) or 12 (40%) mo.dAllocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Intention-to-treat analysis; 0.2% were loss to follow-up. Not stopped early for benefi t.eCI includes values suggesting benefi t or no effect; relatively low number of events.fCalculated from reported data with addition of one event to each event rate because event rate was 0 in the control group.gOne defi nite or possible fatal VTE in the rivaroxaban group and one in the LMWH/VKA group.hCI includes values suggesting benefi t and harm.iBleeds contributing to death: none in the rivaroxaban group and none in the warfarin group.jPTS: baseline risk over 2 y of 58.8% for PTS and 13.8% for severe PTS (Kahn et al102). There is threefold (Prandoni et al202) to 10-fold (van Dongen et al209) increase in PTS with recurrent VTE in the ipsilateral leg.





[95% CI, 0.36-0.76] vs 0.99 without cancer [95% CI, 0.46-2.13]); major bleeding: RR, 0.92 with cancer [95% CI, 0.59-1.44] vs 0.43 without cancer [95% CI, 0.16-1.17]); mortality: RR, 0.93 with cancer [95% CI, 0.79-1.09] vs 1.85 without cancer [95% CI, 0.59-5.77]). However, none of these differences is sta-tistically signifi cant, making it less likely that there is a true difference in response to LMWH vs VKA in the two patient populations. For this reason, we have applied the same relative effects for LMWH vs VKA in patients with and without cancer. The baseline risks of events, however, are clearly different in the two populations.

Patient Preferences— As discussed in the Methods section, the ultimate judgment of the entire Anti-thrombotic Therapy and Prevention of Thrombo-sis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (AT9) panel is that most patients prefer VKA therapy over LMWH therapy. The higher purchase cost of LMWH compared with VKA therapy is an additional barrier to the long-term use of LMWH.

Quality of Evidence and Strength of Recommen-dations— Evidence for the comparison of long-term LMWH vs VKA therapy in patients without cancer is of low quality. The subgroup effect discussed previ-ously was not suffi ciently convincing to allow us to generate an effect estimate specifi cally for patients without cancer, but still reduced our confi dence that the overall effect estimate applies to the noncancer subgroup that contributed a minority of data. Consid-erations favoring use of VKA over LMWH in patients without cancer include (1) the evidence of benefi t with LMWH is of low quality, (2) the estimated abso-lute reductions in recurrent VTE events with LMWH compared with VKA therapy is small, (3) the high cost of LMWH, and (4) our assessment that LMWH is a greater burden to patients than VKA therapy. Considerations favoring use of LMWH over warfarin in patients with cancer include (1) a large absolute reduction in recurrent VTE with LMWH over VKA therapy and (2) that LMWH is better suited to the care of patients with cancer than is VKA therapy. Among patients with VTE and cancer, the advan-tages of LMWH over VKA therapy are expected to be greatest in patients (1) with metastatic disease, (2) being treated with aggressive chemotherapy, (3) presenting with extensive VTE, (4) with liver dysfunction, (5) with poor or unstable nutritional status, and (6) who wish to avoid laboratory moni-toring of coagulation.

Dabigatran vs VKA Therapy for the Long-term Treatment of DVT: One completed study has directly compared dabigatran and VKA for the fi rst 6 months of treatment of VTE ( Table 23 , Table S31 ). 343 Like

patients treated with VKA therapy, patients treated with dabigatran initially received parenteral therapy (usually IV UFH or LMWH). This study suggests that treatment with dabigatran or VKA therapy is associated with a similar frequency of recurrent VTE, major bleeding, and death. This evidence is of mod-erate quality because of serious imprecision for each outcome and lack of long-term safety data for dab-igatran in this patient population. Because the study included few patients with cancer, we were unable to assess whether its fi ndings apply equally to patients with and without cancer. In the absence of evidence of such an interaction, however, we have not further rated down the quality of evidence for patients with VTE and cancer.

Rivaroxaban vs VKA Therapy for the Long-term Treatment of DVT: A single study has directly com-pared rivaroxaban (without initial parenteral antico-agulation) with parenteral anticoagulation and VKA in patients with acute DVT ( Table 21 , Table S29). 88 Results suggested that treatment with rivaroxaban and VKA therapy are associated with a similar fre-quency of recurrent VTE, major bleeding, and death. This evidence is of moderate quality because of serious imprecision for each outcome. Because the study included few patients with cancer, we were unable to assess whether its fi ndings apply equally to patients with and without cancer. In the absence of evidence of such an interaction, however, we have not further rated down the quality of evidence for patients with VTE and cancer.

Comparisons Among LMWH, Dabigatran, and Rivaroxaban for the Long-term Treatment of DVT: There are no direct comparisons of these three agents for the long-term treatment of VTE. Recommendations about the use of one of these agents over the other are based on indirect comparisons, and the evidence is low quality.

Recommendations

3.3.1. In patients with DVT of the leg and no cancer, we suggest VKA therapy over LMWH for long-term therapy (Grade 2C) . For patients with DVT and no cancer who are not treated with VKA therapy, we suggest LMWH over dab-igatran or rivaroxaban for long-term therapy (Grade 2C) .

3.3.2. In patients with DVT of the leg and cancer, we suggest LMWH over VKA therapy (Grade 2B) . In patients with DVT and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2B) .




Remarks (3.3.1-3.3.2): Choice of treatment in patients with and without cancer is sensitive to individual patient’s tolerance for daily injections, need for labo-ratory monitoring, and treatment costs. LMWH, rivar-oxaban, and dabigatran are retained in patients with renal impairment, whereas this is not a concern with VKA. Treatment of VTE with dabigatran or rivaroxa-ban, in addition to being less burdensome to patients, may prove to be associated with better clinical out-comes than VKA and LMWH therapy. When these guidelines were being prepared (October 2011), postmarketing studies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, we give a weak rec-ommendation in favor of VKA and LMWH therapy over dabigatran and rivaroxaban, and we have not made any recommendations in favor of one of the new agents over the other.

3.4 Choice of Anticoagulant Regimen for Extended Therapy

Other than a comparison of low-intensity (target INR 1.75) with conventional-intensity VKA therapy 44 (Table S24 and S25), there are no completed stud ies that have compared different anticoagulant agents or regimens for extended therapy after a standard-ized initial period (eg, � 3 months) of anticoagulation in either patients without or with cancer. Because a

decision about using extended therapy occurs after an initial period of anticoagulation (eg, 3 months) and because the relative effi cacy and safety of anticoagulant regimens are expected to be similar during the early and extended phases of therapy, we anticipate that most patients will continue to use their initial antico-agulant regimen for extended therapy. Possible rea-sons for switching from LMWH to VKA therapy include the following: cancer becomes less active, chemotherapy is completed, patient tires of SC injec-tions, development of renal impairment causes con-cern about accumulation of LMWH (also applies to rivaroxaban and dabigatran), and LMWH costs become prohibitive . Reasons for switching from VKA therapy to LMWH could include diffi culty with INR control and need for repeated invasive proce-dures. New anticoagulant therapies may expand indi-cations for extended anticoagulant therapy because they are less burdensome than VKA or LMWH therapy and because they may be associated with improved clinical outcomes (ie, more effective or safer).

Recommendation

3.4. In patients with DVT of the leg who choose extended therapy, we suggest treatment with the same anticoagulant chosen for the fi rst 3 months (Grade 2C) .

Table 23—[Section 3.3] Summary of Findings: Dabigatran vs VKA Therapy for Long-term Treatment of VTEa-c,343





(95% CI)


Risk With WarfarinRisk Difference With Dabigatran (95% CI)

Mortality 2,539 (1 study), 6 mo


HR 0.98 (0.53-1.79)


Recurrent VTE 2,539 (1 study), 6 mo


HR 1.01 (0.65-1.84)

19 per 1,000f 0 more per 1,000 (from 7 fewer to 16 more)

Major bleeding 2,539 (1 study), 6 mo


HR 0.82 (0.45-1.48)

19 per 1,000g 3 fewer per 1,000 (from 10 fewer to 9 more)


… … … Warfarin: daily medication, dietary restrictions, frequent blood testing/monitoring, increased hospital/clinic visits

Dabigatran: daily medication, no dietary restrictions, no frequent blood testing/monitoring

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1, 3, and 21 legends for expansion of abbreviations.aIncluded patients had acute, symptomatic, and objectively verifi ed proximal DVT of the legs or PE.bDabigatran 150 mg bid taken orally for 6 mo after an initial treatment with LMWH or IV UFH.cWarfarin adjusted to achieve an INR of 2.0 to 3.0 for 6 mo after an initial treatment with LMWH or IV UFH.dAllocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Modifi ed intention-to-treat analysis; 1.1% loss to follow-up. Not stopped early for benefi t.eCI includes values suggesting no effect and values suggesting either benefi t or harm; relatively low number of events.fOne fatal VTE in dabigatran group and three fatal VTE in warfarin group.gOne fatal major bleeding in dabigatran group and one fatal major bleeding in warfarin group.





3.5 Treatment of Asymptomatic DVT of the Leg

Rather than screen postoperative patients for the presence of asymptomatic DVT, clinicians should prescribe primary prophylaxis for VTE to surgical patients. 230,231 If imaging studies performed for other reasons (eg, CT scanning for staging of cancer) inci-dentally detect asymptomatic proximal DVT, the high frequency of false-positive results in patients without a prior suspicion of DVT dictates caution in assuming that a DVT is truly present. Reasons for a high rate of false-positive results include (1) the imaging tech-nique may not have been optimal for the diagnosis of DVT, (2) incidentally diagnosed DVT often is seen in the pelvis where DVT is harder to image (eg, unable to be assessed with compression ultrasound), and (3) the prevalence of DVT in asymptomatic patients is much lower than in symptomatic patients. Conse-quently, when there is evidence of incidental DVT, additional diagnostic testing (eg, ultrasound) to con-fi rm the presence of DVT may be necessary. Because many cases of asymptomatic VTE are detected as PE, see also section 6.9 of this article for recommenda-tions on the management of this condition.

No randomized trials have evaluated anticoagu-lant therapy in patients with incidental VTE; there-fore, evidence is of moderate quality because of indirectness. Moreover, benefi ts of anticoagulant therapy may be less than in symptomatic patients because asymptomatic DVT may be chronic or less extensive and because the prevalence of false-positive results will be higher than in patients who were sus-pected of having DVT.

Factors that justify a more-aggressive approach to anticoagulation in patients with incidentally diagnosed DVT include certainty of diagnosis, extensive throm-bosis that appears to be acute (eg, not present on a previous imaging study), progression of thrombosis on a follow-up imaging study, ongoing risk factors for VTE (eg, cancer), and a low risk of bleeding. A less-aggressive approach to anticoagulation could include (1) withholding of anticoagulation with surveillance to detect DVT extension or (2) limiting anticoagulant therapy to 3 months in patients with continuing risk factors for VTE (eg, cancer). Many patients have left the hospital by the time incidental DVT is reported. If it would be diffi cult for patients to return the same day, it is often reasonable to defer further assessment and anticoagulant therapy until the next day.

Recommendation

3.5. In patients who are incidentally found to have asymptomatic DVT of the leg, we suggest the same initial and long-term anticoagulation as for comparable patients with symptomatic DVT (Grade 2B) .

4.0 PTS of the Leg

PTS is a cluster of leg symptoms and signs attribut-able to previous DVT. PTS occurs in about one-third of patients after acute DVT and up to two-thirds who have had an iliofemoral DVT. 102,232 The initial treat-ment of acute DVT, particularly with the use of thrombus removal strategies, may infl uence the risk of developing PTS (section 2.8). The most prominent symptoms are chronic dependent swelling and pain, discomfort on walking, and skin discoloration. The severity of symptoms may vary over time, and the most severe manifestation is a venous ulcer of the lower leg. In this section, we address prevention of PTS fi rst and then its treatment. Unlike the last edition of these guidelines, 6 we do not address treatment of leg ulcers associated with venous insuffi ciency.

4.1 Compression Stockings and Bandages to Prevent PTS

Five randomized trials evaluated compression stock-ings used at various times after diagnosis of acute DVT for the prevention of PTS (Tables S32 and S33). 201,202,233-235 Two of these trials 163,164 randomized patients soon after diagnosis of a fi rst episode of symptomatic proximal DVT to prolonged use of stockings (30-40 mm Hg pressure at the ankles) or no stockings and otherwise treated patients the same way ( Table 24 , Table S34). These trials suggest that compression stockings started within 2 weeks of DVT and continued for 2 years reduce PTS by about 50% and do not alter the frequency of recurrent VTE. Patients with proximal DVT and a previous DVT in the same leg and who have marked symptoms are expected to gain the most benefi t from compression stockings. 102,201,202 The evidence is of moderate quality because the assessment of PTS, which includes a large subjective component, was not blinded, and the estimate for recurrent VTE was imprecise.

Compression stockings applying an ankle pressure of 30 to 40 mm Hg and a lower pressure higher up the leg (ie, graduated pressure) should be started as soon as feasible after starting anticoagulant therapy. Bandages may be used to provide initial compressive therapy because it may not be possible to fi t compres-sion stockings immediately and if stockings can be worn, a rapid decrease in leg swelling will require them to be refi tted. The fi ndings from a randomized trial of 69 patients suggest that immediate compression ban-daging improves acute symptoms but does not reduce PTS at 1 year (RR, 0.9; 95% CI, 0.4-1.8). 236 Patients or their caregivers need to be able to apply and remove stockings for their use to be feasible. Alternative approaches to the use of stockings, such as routinely wearing stockings after acute DVT but stopping them if there are no symptoms of PTS after 6 months 235,237 or




quality of the evidence is low because of imprecision and risk of bias. There is anecdotal evidence that compression therapy is of benefi t in many patients with PTS, and the potential benefi t of a trial of com-pression stockings in individual patients is likely to outweigh its harm and cost. We suggest below-knee stockings in most patients, but thigh-length stockings may be preferable in those with marked thigh swelling.

Two small crossover randomized trials have evalu-ated the treatment of severe PTS with intermittent compression devices 239,240 ( Table 26 , Table S36). Both studies suggested benefi t from intermittent compres-sion therapy. The quality of the evidence, however, is moderate because of imprecision. The goal of inter-mittent compression therapy is to reduce PTS symp-toms rather than to alter the natural history of its development. These devices can be used with or without compression stockings, depending on patient preference. Leg swelling and associated symptoms (eg, heaviness, tightness) are more likely to respond to compression stockings or intermittent compres-sion devices than are other symptoms.

only wearing stockings if there is persistent leg swell-ing, have not been adequately evaluated.

Recommendation

4.1. In patients with acute symptomatic DVT of the leg, we suggest the use of compression stockings (Grade 2B) .

Remarks : Compression stockings should be worn for 2 years, and we suggest beyond that if patients have developed PTS and fi nd the stockings helpful. Patients who place a low value on preventing PTS or a high value on avoiding the inconvenience and dis-comfort of stockings are likely to decline stockings.

4.2 Physical Treatment of PTS

Treatment of PTS with compression stockings has only been evaluated in two small trials 233, 238 ( Table 25 , Tables S35 and S37) (all patients received rutosides in one study 238 ). These studies did not fi nd compression stockings to be of benefi t. However, the

Table 24—[Section 4.1] Summary of Findings: Elastic Compression Stockings vs No Elastic Compression Stockings to Prevent PTS of the Lega,b,451




(95% CI)


Risk With No Elastic Compression Stockings

Risk Difference With Elastic Compression Stockings (95% CI)

PTS 421 (2 studies), 2 y Moderatec due to risk of bias

RR 0.46 (0.34-0.63)d

479 per 1,000e,f 259 fewer per 1,000 (from 177 fewer to 316 fewer)g

Recurrent VTE

374 (2 studies), 5 y Moderateh,i due to imprecision

RR 1.01 (0.61-1.67)d

210 per 1,000j 2 more per 1,000 (from 82 fewer to 141 more)

QOL not reported

… … k …

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1, 3 and 10 legends for expansion of abbreviations.aPrandoni et al202 excluded patients with recurrent ipsilateral DVT, preexisting leg ulcers, or signs of chronic venous insuffi ciency, bilateral thrombosis, a short life expectancy or a contraindication for use of stockings (eg, advanced-stage peripheral arterial insuffi ciency). Brandjes et al201 excluded patients with short life expectancy, paralysis of the leg, bilateral thrombosis, leg ulcers, or extensive varicosis.bBrandjes201 used graded elastic compression stockings (40 mm Hg of pressure at the ankle, 36 mm Hg at the lower calf, and 21 mm Hg at the upper calf); stockings were applied 2 to 3 wk after the fi rst episode of proximal DVT. Prandoni et al202 used fl at-knitted stockings (30 to 40 mm Hg of pressure at the ankle); stockings were started at hospital discharge, an average of 1 wk after admission. In both studies, stockings were used for 2 y.cPatients were not blinded to the treatment assignment, and outcomes were partly based on subjective report of symptoms.dThe effect estimate shown here results from a meta-analysis (Mantel-Haenszel fi xed-effects model) of the two relevant trials. A fi xed-effects model was chosen because of the small number of studies available.eThis estimate is based on the fi ndings of the VETO study.70 This probably underestimates PTS baseline risk given that overall, 52% of patients reported the current use of compression stockings during study follow-up.fIn Prandoni et al,202 most events occurred during the fi rst 6 mo. The cumulative incidence of the PTS in the control group was 40% after 6 mo, 47% after 1 y, and 49% after 2 y.gSevere PTS: assuming the same RR of 0.46 and a baseline risk of 8.1% over 2 y, the absolute reduction is 44 fewer severe PTS per 1,000 (from 30 fewer to 53 fewer) over 2 y.hWe did not rate down the quality of evidence for recurrent VTE for the lack of blinding because this a more objective outcome than PTS.iCI includes both negligible effect and appreciable benefi t or appreciable harm.jThis estimate is the mean of two estimates derived from two studies: 12.4% probable/defi nite VTE (Heit et al165) and 29.1% confi rmed VTE (Prandoni et al208).kThis is an important outcome that should be considered in future studies.





sion. Furthermore, rutosides may be associated with important side effects.

Recommendation

4.3. In patients with PTS of the leg, we suggest that venoactive medications (eg, rutosides, defi -brotide, and hidrosmin) not be used (Grade 2C) .

Remarks: Patients who value the possibility of response over the risk of side effects may choose to undertake a therapeutic trial

5.0 Initial Treatment of Acute PE

As we noted in Methods (section 1.1), recommenda-tions for management of patients with PE, particu-larly those addressing anticoagulant therapy and IVC fi lter insertion, are based on studies that enrolled patients with only DVT , patients with both DVT and PE, and patients with only symptoms of PE. The following sections emphasize studies that enrolled only patients with symptoms of PE (who could also have symptoms of DVT), emphasize differences in

Recommendations

4.2.1. In patients with PTS of the leg, we sug-gest a trial of compression stockings (Grade 2C) .

4.2.2. In patients with severe PTS of the leg that is not adequately relieved by compres-sion stockings, we suggest a trial of an inter-mittent compression device (Grade 2B) .

4.3 Pharmacologic Treatment of PTS

Hydroxyrutosides, a class of fl avonoid drug pro-duced from plant glycosides, may reduce capillary permeability, reduce infl ammation, improve lym-phatic function, and promote ulcer healing in patients with chronic venous insuffi ciency. 6,241,242 Two studies compared treatment of PTS (without ulceration) with rutosides vs control 238,243 (all patients wore compres-sion stockings in one study 238 ), and one study com-pared rutosides with hidrosmina 244 (Table S37). The two controlled studies suggest that rutosides do not reduce most symptoms of PTS, although they may reduce ankle swelling ( Table 27 ). This evidence is of low quality because of inconsistency and impreci-

Table 25—[Section 4.2.1] Summary of Findings: Compression Stockings vs No Compression Stockings for Patients With PTSa-c,233,238




(95% CI)


Risk With No Compression Stockings

Risk Difference With Compression Stockings

(95% CI)

Symptomatic relief treatment successg

115 (2 studies), 12 to 26 mo

Lowd-f due to risk of bias and imprecision

RR 0.96 (0.70-1.31)


QOL not reported … Not estimableRecurrent VTE not

reported… Not estimable

Ulcerationh not reported

… Not estimableh

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. CLOTS1 5 Clots in Legs or Stocking After Stroke. See Table 1 and 3 legends for expansion of other abbreviations.aGinsberg et al233 included patients with PTS 1 y after chronic, typical proximal DVT. Frulla et al238 included patients with clinical symptoms and signs suggestive of PTS.bGinsberg et al233: Graduated compression stockings (30-40 mm Hg, calf or thigh length, depending on symptoms). Patients were encouraged to wear stockings as much as possible during waking hours. Frulla et al238: below-knee graded elastic compression stockings (ECS) (30-40 mm Hg at the ankle). Patients in both study arms received hydroxyethylrutosides (HR) (we considered the ECS 1 HR vs HR comparison).cGinsberg et al233: placebo stockings (calf or thigh length, depending on symptoms).dGinsberg et al233: Adequacy of sequence generation and allocation concealment were unclear; patients and outcome assessors were adequately blinded; unclear whether analysis followed the intention-to-treat principle; unclear whether follow-up was complete. Frulla et al238: outcome assessors were blinded; follow-up was complete; intention-to-treat principle was adhered to, but sequence generation and allocation concealment were unclear, and patients were not blinded.eVery small number of patientsfPublication bias was not detected but not ruled out given that we identifi ed only one small study partially supported by industry (provision of graduated compression stockings).gGinsberg et al233 reported treatment failure (defi ned a priori based on any of fi ve clinical criteria, including symptoms and ulcer development). Treatment success refers to the absence of treatment failure. Frulla et al238 used the Villalta scale.hIndirect evidence from the CLOTS1 trial suggests that compression stockings is associated with an RR of 4 for skin complications.




the management of patients who present with PE compared with DVT, and make recommendations for the management of patients with PE. We do not repeat evidence that was presented in the corre-sponding section that addresses treatment of DVT; instead, the reader is directed to those sections of the article and to the related tables. We do not comment in the text on the quality of the evidence that under-lies treatment recommendations for PE unless the quality of this evidence differs from that for patients who present with DVT.

5.1 Initial Anticoagulation for Acute PE

See section 2.1, Table 3 , and Table S1.

Recommendation

5.1. In patients with acute PE, we recommend initial treatment with parenteral anticoagula-tion (LMWH, fondaparinux, IV UFH, or SC UFH) over no such initial treatment (Grade 1B) .

5.2 Whether to Treat With Parenteral Anticoagulation While Awaiting the Results of Diagnostic Work-up for PE

See section 2.2. For the purpose of implement-ing this recommendation, validated prediction rules help with estimation of clinical probability of having PE. 55,56

Table 26—[Section 4.2.2] Summary of Findings: Intermittent Compression Device vs No Intermittent Compression Device for Patients With Severe PTSa-c,233,240

Outcomes

No. of Participants (Studies), Follow-up


(GRADE)

Relative Effect (95%

CI)


Risk With No Intermittent

Compression Device

Risk Difference With Intermittent Compression

Device (95% CI)

Symptomatic relief: symptom score includes scoring of pain, swelling, and limitation of activity on a scale of 10-70

82 (2 studiesd), 8 wk

Moderatee-i due to imprecision

The mean symptomatic relief in the control groups was 0

The mean symptomatic relief in the intervention groups was 0.41 SDs higher (0.02 lower to 0.85 higher)

QOL: VEINES-QOL scale of 0-100.

0 (1 studyd,j), 8 wk

Moderateg-i,k,l due to imprecision

The mean QOL in the control groups was 50.2

The mean QOL in the intervention groups was 2.3 higher (1.04 lower to 5.64 higher)

Recurrent VTEm not reported … Not estimablem

Ulcerationn not reported … Not estimablen

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. VEINES 5 Venous Insuffi ciency Epidemiological and Economic Study. See Table 1, 3, and 25 legends for expansion of other abbreviations.aPatients with previous DVT with symptoms of severe PTS.bIntervention group: Ginsberg et al239: Extremity pump used bid for 20 min each session; 50 mm Hg (therapeutic pressure) for 1 mo. O’Donnell et al240: Venowave lower-limb venous return assist device to wear for most of the day for 8 wk.cControl group: Ginsberg et al239: Extremity pump used bid for 20 min each session; 15 mm Hg (placebo pressure) for 1 mo. O’Donnell et al240: Venowave lower-limb venous return assist device with no connection between motor and planar sheet for 8 wk.dCrossover RCTs.eIn both studies, sequence generation was adequate; patients were blinded, analysis adhered to intention-to-treat principle, and there were no missing outcome data. In Ginsberg et al239 (but not O’Donnell et al240), outcome assessors were not blinded, and it was not clear whether allocation was concealed.fI2 5 0%.gSome concerns with indirectness, given relatively short follow-up (8 wk).hVery small number of patients. CI includes both values suggesting no effect and values suggesting a benefi cial effect.iPublication bias not detected but not ruled out given that we identifi ed only two small studies, with one (Ginsberg et al239) partially supported by industry (provision of devices).jO’Donnell et al et al.240

kSequence generation was adequate; patients were blinded, analysis adhered to intention-to-treat principle, and there were no missing outcome data. However, outcome assessors were not blinded, and it was not clear whether allocation was concealed.lPublication bias was not detected but not ruled out given that we identifi ed only a small study.mO’Donnell et al240 indicated no cases of recurrent VTE by the end of this study but judged the follow-up period to be short.nO’Donnell et al240 indicated that one patient in the control group developed a venous ulceration. Three other participants developed nonserious skin-related side effects. Indirect evidence from the CLOTS1 suggests that compression stockings are associated with an RR of 4 for skin complications. Common side effects attributed to Venowave were heat sensation, skin irritation, and increased sweating.





Recommendations

5.2.1. In patients with a high clinical suspicion of acute PE, we suggest treatment with paren-teral anticoagulants compared with no treat-ment while awaiting the results of diagnostic tests (Grade 2C) .

5.2.2. In patients with an intermediate clinical suspicion of acute PE, we suggest treatment with parenteral anticoagulants compared with no treatment if the results of diagnostic tests are expected to be delayed for more than 4 h (Grade 2C) .

5.2.3. In patients with a low clinical suspicion of acute PE, we suggest not treating with parenteral anticoagulants while awaiting the results of diagnostic tests provided that test results are expected within 24 h (Grade 2C) .

5.3 Timing of Initiation of VKA and Associated Duration of Parenteral Anticoagulant Therapy

See section 2.4, Table 4 , and Table S2.

Recommendation

5.3. In patients with acute PE, we recommend early initiation of VKA (eg, same day as paren-teral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the INR is 2.0 or above for at least 24 h (Grade 1B) .

5.4 Choice of Initial Parenteral Anticoagulant Regimen in Patients With PE

See section 2.5.

LMWH Compared With IV UFH for the Initial Treatment of PE: See section 2.5 and Table 6 . Con-sistent with fi ndings in patients with DVT, LMWH has been found to be as effective and safe as IV UFH in studies that included both patients with PE and DVT or only in patients with PE ( Table 6 ). A meta-analysis of 12 studies 85,146,245-254 that included a total of 1,951 patients with either submassive symp-tomatic PE or asymptomatic PE in conjunction with symptomatic DVT failed to demonstrate or

Table 27—[Section 4.3] Summary of Findings: Venoactive Medication vs No Venoactive Medication for Patients With PTSa,b,202,238

Outcomes

No. of Participants (Studies), Follow-up



(95% CI)


Risk With No Venoactive Medication

Risk Difference With Venoactive

Medication (95% CI)

Symptomatic relief: PTS score (Villalta scale) , 5 or decreased by 30% at 12 mo compared with baseline in Frulla et al238; improved tiredness of the leg at 8 wk in de Jongste et al243,c

163 (2 studies) Lowd-g due to inconsistency, imprecision


QOL not reported … Not estimableRecurrent VTE not reported … Not estimableUlceration not reported … Not estimableSide effects 203 (2 studies) Moderated,f-h due

to imprecisionRR 2.04 (0.76-5.51) 61 per 1,000 63 more per 1,000

(from 15 fewer to 275 more)

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aPatients with PTS and history of DVT in PTS leg.bIncluded studies that assessed rutosides.cInvestigators assessed other symptoms (pain, heaviness, swelling feeling, restless legs, and cramps) but did not report a composite score. The symptom we chose to report showed the most benefi t; the effect estimates for the other symptoms ranged from 0.8 to 1.4, and none were statistically signifi cant.dIn both studies, sequence generation and allocation concealment were unclear. Both studies blinded outcome assessors and had complete follow-up. Although de Jongste et al243 blinded patients, the authors did not adhere to the intention-to-treat principle and did not use a validated scale to measure symptomatic relief. Although Frulla et al238 adhered to the intention-to-treat principle, the author did not blind patients.eI2 5 77%.fSmall number of patients. CI included both values suggesting harms and values suggesting benefi ts.gPublication bias was not detected but not ruled out given that we identifi ed only two small studies, and it unclear whether they were funded by industry.hI2 5 7%.




exclude a benefi cial or detrimental effect of LMWH on recurrent VTE (OR, 0.63; 95% CI, 0.33-1.18), major bleeding (OR, 0.67; 95% CI, 0.36-1.27), and all-cause mortality (OR, 1.20; 95% CI, 0.59-2.45). 255

SC UFH Compared With SC LMWH for the Ini-tial Treatment of PE: See section 2.5, Table 5 , and Tables S3 through S5.

Fondaparinux Compared With IV UFH for the Ini-tial Treatment of PE: The Matisse-PE trial compared fondaparinux with IV UFH for acute treatment of PE 79 ( Table 28 , Table S38). This study suggested that fondaparinux is associated with a similar frequency of mortality, recurrent VTE, and major bleeding as LMWH. The quality of this evidence is moderate because of imprecision. In making recommendations, we also considered evidence that fondaparinux is equiv-alent to LMWH for the treatment of DVT (see sec-tion 2.5, Table 7 , and Table S38) and that fondaparinux shares the advantages that LMWH has over IV UFH.

Fondaparinux Compared With LMWH for the Ini-tial Treatment of PE: In the absence of direct evi-dence in patients with PE, indirect evidence in patients with acute DVT (see section 2.5, Table 7 , and Table S7) suggests that fondaparinux is equiva-lent to LMWH.

Fondaparinux Compared With SC UFH for the Initial Treatment of PE: There is no direct evidence

for this comparison. In making recommendations, we considered that fondaparinux and LMWH are equiv-alent and that fondaparinux shares the advantages that LMWH has over IV UFH. We did not take into account the lower purchase cost of SC UFH com-pared with fondaparinux.

Once- vs Twice-Daily Administration of LMWH for Initial Treatment of PE: See section 2.5, Table 8 , and Table S8. Patients who presented with PE were included in only one of the fi ve studies with an unconfounded comparison of once- and twice-daily LMWH 85 and in one additional large study that com-pared once-daily LMWH therapy with IV UFH in patients who presented with PE. 252

Recommendations

5.4.1. In patients with acute PE, we suggest LMWH or fondaparinux over IV UFH (Grade 2C for LMWH; Grade 2B for fondaparinux) , and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux) .

Remarks: Local considerations such as cost, avail-ability, and familiarity of use dictate the choice between fondaparinux and LMWH. LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH. In patients with PE where there is concern about the adequacy of SC absorption or in patients in whom

Table 28—[Section 5.4] Summary of Findings: Fondaparinux vs IV UFH for Initial Anticoagulation of Acute PEa-c,79




Relative Effect (95% CI)


Risk With UFHRisk Difference With

Fondaparinux (95% CI)

Mortality 2,213 (1 study), 3 mo Moderated,e due to imprecision


Recurrent VTE 2,213 (1 study), 3 mo Moderated,e due to imprecision

RR 0.75 (0.51-1.12) 50 per 1,000f 13 fewer per 1,000 (from 25 fewer to 6 more)

Major bleeding 2,213 (1 study), 3 mo Moderated,e due to imprecision

RR 0.85 (0.49-1.49) 23 per 1,000g 4 fewer per 1,000 (from 12 fewer to 11 more)

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aAll patients had acute, symptomatic, hemodynamically stable PE.bFondaparinux (5.0, 7.5, or 10.0 mg in patients weighing , 50, 50 to 100, or . 100 kg, respectively) SC once daily given for at least 5 days and until the use of VKAs resulted in an INR . 2.0.cUFH continuous IV infusion (ratio of the activated partial thromboplastin time to a control value of 1.5-2.5) given for at least 5 days and until the use of VKAs resulted in an INR . 2.0.dAllocation was concealed. Patients, providers, and data collectors were not blinded. Outcome adjudicators were blinded; 0.6% of randomized patients were lost to follow-up. Not stopped early for benefi t.eCI includes values suggesting no effect and values suggesting either benefi t or harm; relatively low number of events.fSixteen fatal VTE in fondaparinux group and 15 fatal VTE in UFH group.gFourteen patients in the fondaparinux group and 12 patients in the LMWH group had a major bleeding event during the initial period (6-7 d). Of these, one in the fondaparinux group and one in the UFH group were fatal.





thrombolytic therapy is being considered or planned, initial treatment with IV UFH is preferred to use of SC therapies.

5.4.2. In patients with acute PE treated with LMWH, we suggest once- over twice-daily admin-istration (Grade 2C) .

Remarks: This recommendation only applies when the approved once-daily regimen uses the same daily dose as the twice-daily regimen (ie, the once-daily injec-tion contains double the dose of each twice-daily injection). It also places value on avoiding an extra injection per day.

5.5 Early vs Standard Discharge of Patients With Acute PE

Consistent with our discussion of outpatient treat-ment of acute DVT (section 2.7), LMWH has made it feasible to treat acute PE at home either without admission to the hospital (ie, discharge from the emergency department) or with admission and early discharge. However, because acute PE is associated with much higher short-term mortality than acute DVT, the safety of treating PE at home is uncertain. Consequently, PE is treated at home much less often than DVT, and the proportion of outpatients with PE that clinical centers treat at home varies from almost none to about 50%.

Two studies randomized patients with acute PE and a low risk of complications to receive LMWH either (1) in the hospital for only 3 days vs entirely in the hospital 256 or (2) entirely out of the hospital (dis-charged within 24 h) vs at least partly in hospital 257 ( Table 29 , Table S39). This evidence suggests that treating appropriately selected patients with acute PE at home does not increase recurrent VTE, bleeding, or mortality.

There are a number of prediction rules for identi-fying patients with acute PE who have a low risk of serious complications and may be suitable for treat-ment at home. 258-263 Of these, the PE Severity Index (PESI) is best validated 261,262,264-266 and was used to select patients for home treatment in the larger of the previously noted clinical trials ( Table 29 , Table S39). Patients with acute PE who meet the following criteria appear to be suitable for treatment out of the hospital: (1) Clinically stable with good car-diopulmonary reserve (eg, PESI score of , 85 257 or simplifi ed PESI score of 0, 262 including none of hypoxia, systolic BP , 100, recent bleeding, severe chest pain, platelet count , 70,000/mm 3 , PE while on anticoagulant therapy, and severe liver or renal disease) 257 , (2) good social support with ready access to medical care, and (3) expected to be compliant with follow-up. Patients also need to feel well enough

to be treated at home (eg, absence of severe symp-toms or comorbidity).

Consistent with the fi ndings of these two trials, a systematic review of 11 observational studies (seven prospective, four retrospective; 928 patients) 267 and four more recent observational studies (two retro-spective with 584 patients 268,269 ; two prospective with 449 patients 270,271 ) reported a very low frequency of complications in low-risk patients with acute PE who were initially treated partially or entirely at home. About one-third to one-half of outpatients with acute PE appear to be in this low-risk group. 272 The evidence from the randomized trials is of moderate quality (rated down for serious imprecision), with additional supportive fi ndings from the observational studies.

Recommendation

5.5. In patients with low-risk PE and whose home circumstances are adequate, we suggest early discharge over standard discharge (eg, after the fi rst 5 days of treatment) (Grade 2 B) .

Remarks: Patients who prefer the security of the hos-pital to the convenience and comfort of home are likely to choose hospitalization over home treatment.

5.6 Systemic Thrombolytic Therapy for PE

5.6.1 Systemic Thrombolytic Therapy vs Anticoag-ulation Alone for PE: Randomized trials have estab-lished that, at 24 h, thrombolytic therapy improves (1) pulmonary artery hemodynamic measurements (eg, mean pulmonary artery pressure improvement, 4.4 mm Hg; 95% CI, 2 4.6-4.2 mm Hg), (2) arterio-venous oxygen (difference of 2 0.3 [ 2 0.4 to 2 0.2] ), (3) pulmonary perfusion (50% early improvement in perfusion scan, OR, 3.8; 95% CI, 0.9-15.7), and (4) echo-cardiographic assessment (OR for improved right ventricular wall movement, 3.1; 95% CI, 1.5-6.3). 273 Thrombolytic therapy, however, does not appear to reduce the extent of residual thrombosis. It is uncer-tain whether the benefi ts of more-rapid resolution of PE outweigh the risk of increased bleeding associ-ated with thrombolytic therapy. In patients with PE, severity of presentation is expected to depend on the extent of embolism (ie, degree of pulmonary artery obstruction) and the presence and severity of chronic cardiopulmonary impairment. 104,274,275 Patients with the most severe presentations who have the highest risk of dying from an acute PE have the most to gain from thrombolysis.

Prognosis in Patients With Acute PE— Of patients who are diagnosed with PE and start treatment, � 5% die of the initial PE or another PE within the next 7 days. 9,104,276-279 However, although the risk of dying of PE differs markedly among patients, no validated




risk prediction tool is available. Risk of dying of PE is estimated to be � 70% if cardiopulmonary arrest occurs ( � 1% of patients at presentation), 30% if there is shock requiring inotropic support ( � 5% of patients), and � 2% in patients who are not hypotensive. 104,276-278,280,281 In the presence of normal systemic arterial pressure, prognosis can also differ, depending on (1) clinical evaluation, 276 (2) cardiac biomarkers such as troponin or brain natriuretic peptide, 279,282-291 and (3) assessment of right ventric-ular size and function. 279,280,283,285,290-295

Clinical evaluation involves assessment of general appearance, BP, heart rate, respiratory rate, temper-ature, pulse oximetry, and signs of right ventricular dysfunction (eg, distended jugular veins, tricuspid regurgitation, accentuated P 2 ). 104 Clues on the ECG include right bundle branch block, S 1 Q 3 T 3 , and T-wave inversion in leads V 1 through V 4 . 296 Elevation of cardiac troponins indicates right ventricular micro-infarction, and echocardiography may show right ven-tricular hypokinesis; both are risk factors for early mortality and are associated with a worse outcome when they occur together. 238,241-245,250 Right ventricular enlargement on the CT pulmonary angiogram, defi ned as a right ventricular diameter � 90% than the left ventricular diameter may also be an independent risk factor for death and nonfatal complications. 279,291,293,295,297

Risk of Bleeding With Thrombolytic Therapy— We have not identifi ed any validated risk predic-

tion tool for bleeding with thrombolytic therapy in patients with PE. However, we assume that the assessment of bleeding risk with thrombolytic ther-apy is similar in patients with PE and with acute ST-segment elevation myocardial infarction. 104,110-113,298,299 Table 11 lists risk factors for bleeding with thrombolytic therapy, categorized as major and relative contra-indications.

Trials Evaluating Thrombolytic Therapy in Patients With Acute PE— The fi ndings of 13 randomized trials that compared thrombolytic therapy to antico-agulant therapy alone in patients with acute PE are summarized in Table 30 and Tables S40 through S42. 300-313 A number of meta-analyses of these studies have been performed. 104,273,315,315 This evidence sug-gests that thrombolysis may be associated with a reduc-tion in mortality and recurrent PE and is associated with an increase in major bleeding, as has been estab-lished in patients with myocardial infarction. 112 The quality of evidence regarding mortality and recurrent PE is low because of risk of bias, serious imprecision, and suspected publication bias. A previous meta-analysis that categorized studies as either including, or not including, patients with cardiopulmonary com-promise, suggested that thrombolytic therapy reduced the composite outcome of death and recurrent PE in studies that included the sickest patients. 315 However, we found that the data available from these studies are not suffi ciently detailed to enable a subgroup

Table 29—[Section 5.5] Summary of Findings: Early Discharge vs Standard Discharge in the Treatment of Acute PEa,b,256,257




(95% CI)


Risk With Standard Discharge

Risk Difference With Early Discharge (95% CI)

Mortality 471 (2 studies), 3 mo Moderatec,d due to imprecision


Nonfatal recurrent PE 471 (2 studies), 3 mo Moderatec,d due to imprecision


Major bleeding 471 (2 studies), 3 mo Moderatec,d due to imprecision


QOL not reported … … … … …PTS not reported … … … … …

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aThe two RCTs included only patients with low risk: risk classes I or II on the Pulmonary Embolism Severity Index in Aujesky et al216; low risk on clinical prediction rule by Uresandi et al.258

bMean length of hospital stay: 3.4 (SD 1.1) vs 9.3 (SD 5.7) d in Otero et al256 and 0.5 (SD 1.0) vs 3.9 (SD 3.1) d in Aujesky et al257; low risk on clinical prediction rule by Uresandi et al258 in Otero et al.cOtero et al256: allocation concealed; no patients lost to follow-up; intention-to-treat analysis; no blinding of outcome assessors reported; study stopped early because the rate of short-term mortality was unexpectedly high in the early discharge group (2 [2.8%] vs 0 [0%]). Aujesky et al257: unclear whether allocation was concealed; three (1%) patients had missing outcome data; intention-to-treat analysis; blinding of outcome adjudicators; no early stoppage.dCI includes both values suggesting no effect and values suggesting appreciable harm or appreciable benefi t.





analysis evaluating outcomes in patients with hemo-dynamic compromise or other markers of heightened risk of death (eg, right ventricular dysfunction).

Balancing Benefi ts and Harms of Thrombolytic Therapy— In patients who present with PE and hypotension (eg, systolic pressure BP , 90 mm Hg or a documented drop in systolic BP . 40 mm Hg with evidence of poor perfusion), especially if they have a low risk of bleeding, even modest effi cacy of throm-bolytic therapy is likely to reduce deaths from PE more than it would increase fatal bleeds and nonfatal intracranial bleeds ( Table 30 , Tables S40-S42). The ultimate judgment of the entire AT9 panel was to issue a weak recommendation for patients with PE and hypotension given the uncertainty of the benefi t. In most patients with PE, given the certain risks of bleeding and less-certain benefi ts, thrombolysis is likely to be harmful. Selected patients without hypo-tension may benefi t from thrombolysis because their initial clinical presentation or clinical course after starting anticoagulant therapy suggest that they are at high risk of dying.

There is no explicit clinical prediction rule that identifi es this subgroup of patients. We suggest that such patients are identifi ed predominantly by clinical evidence of instability (eg, a decrease in systolic BP that still remains . 90 mm Hg, tachycardia, elevated jugular venous pressure, clinical evidence of poor tissue perfusion, hypoxemia) and failure to improve on anticoagulant therapy. As noted previously, labo-ratory (eg, troponin, brain natriuretic peptide), ECG, echocardiography, and CT evidence of right ventric-ular dysfunction or enlargement, can supplement the clinical evaluation of instability; however, they are not suffi ciently predictive to serve as indications for thrombolytic therapy on their own, 289 and we do not recommend that they are routinely measured.

Recommendations

5.6.1.1. In patients with acute PE associated with hypotension (eg, systolic BP , 90 mm Hg) who do not have a high risk of bleeding, we sug-gest systemically administered thrombolytic therapy over no such therapy (Grade 2C) .

5.6.1.2. In most patients with acute PE not asso-ciated with hypotension, we recommend against systemically administered thrombolytic therapy (Grade 1C) .

5.6.1.3. In selected patients with acute PE not associated with hypotension and with a low risk of bleeding whose initial clinical presentation or clinical course after starting anticoagulant therapy suggests a high risk of developing hypo-

tension, we suggest administration of thrombo-lytic therapy (Grade 2C) .

5.6.2 Systemic Thrombolytic Therapy Regimen for PE: Twelve randomized trials (total of 938 patients) have compared the rate of thrombus resolution achieved with various IV thrombolytic regimens. 316-327 These regimens included urokinase given over 2 h 319,326 or 12 h 316,321,326 ; streptokinase given over 2 h, 12 h, 320 or 24 h 316 ; and recombinant tPA (rt-PA) given over 15 min 317,322,325 or 2 h, 317-325,327 reteplase in two boluses 30 min apart, 325 and desmoteplase in three different doses as a bolus 323 .

An additional study compared IV with pulmonary artery catheter administration of rt-PA (50 mg over 2 h). 328 The results of studies that compared different approaches to thrombolysis in patients with PE (noted previously) suggest that (1) prolonged infusions of thrombolytic agents (eg, � 12 h) are associated with higher rates of bleeding 316,318 ; (2) 2-h infu-sions achieve more rapid clot lysis than 12- or 24-h infusions 318,320,321 ; (3) when a high-concentration 2-h infusion of thrombolysis is administered, there is no clear difference in the effi cacy or safety of rt-PA vs streptokinase 327 ; (4) bolus rt-PA regimens (eg, � 50 mg in � 15 min) appears to be as effective and safe as a 2-h infusion of 100 mg of rt-PA 313,317,322,325 ; and (5) infusion of rt-PA directly into a pulmonary artery as opposed to a peripheral vein does not accelerate thrombolysis but does cause more frequent bleeding at the catheter insertion site (there was no attempt to infuse rt-PA directly into or to mechanically dis-rupt the thrombus in this study from 1988). 328 When a lytic agent is appropriate for PE, current evidence supports that thrombolytic therapy should be infused into a peripheral vein over � 2 h. At a dose of 100 mg over 2 h, rt-PA is currently the most widely used and evaluated regimen. In patients with imminent or actual cardiac arrest, bolus infusion of thrombolytic therapy is indicated.

The quality of evidence for comparisons of systemic thrombolytic agents and regimens (eg, different doses or durations of infusion) is low based on very serious imprecision and risk of bias. In addition, there is substantial potential for publication bias. Based on this evidence, we provide only weak rec-ommendations for all comparisons of thrombolytic agents and regimens in the short-term treatment of PE.

Recommendations

5.6.2.1. In patients with acute PE, when a throm-bolytic agent is used, we suggest short infusion times (eg, a 2-h infusion) over prolonged infu-sion times (eg, a 24-h infusion) (Grade 2C) .




5.6.2.2. In patients with acute PE, when a throm-bolytic agent is used, we suggest administration through a peripheral vein over a pulmonary artery catheter (Grade 2C) .

5.6.3 Initial Anticoagulant Therapy in Patients Treated With Thrombolytic Therapy: Trials that evaluated thrombolysis for PE used IV UFH in

conjunction with thrombolytic therapy ( Table 30 , Tables S40-S42), and no randomized trials have com-pared different regimens of IV UFH in this setting. IV UFH should be given in full therapeutic doses 1,3 before thrombolytic therapy is administered, and it is acceptable to either continue or suspend the UFH infusion during administration of thrombo-lytic therapy (these two practices have never been

Table 30—[Section 5.6.1] Summary of Findings: Systemic Thrombolytic Therapy vs Anticoagulation Alone in Patients With Acute PEa-d,273,309,310,314,315




(95% CI)


Risk With No Systemically Administered

Thrombolytic Therapy

Risk Difference With Systemically Administered

Thrombolytic Therapy (95% CI)

Mortality 847 (12 studies), 30 d

Lowe-h due to risk of bias and imprecision

RR 0.7 (0.37-1.31)

Lowi,j


Highi,j


Recurrent PE 801 (9 studies), 30 d

Lowe-h due to risk of bias and imprecision

RR 0.7 (0.4-1.21)


Major bleeding 847 (12 studies), 10 d

Moderatee,f,h,k due to risk of bias and imprecision

RR 1.63 (1-2.68)l

Lowm

1 per 1,000 1 more per 1000 (from 0 more to 2 more)

Highm


The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aOne study included exclusively patients with hemodynamic compromise (shock), six excluded them, whereas the rest either included a number of such patients or did not specify related eligibility criteria. Of studies not restricted to patients with hemodynamic compromise (n 5 11), only three were clearly restricted to patients with right ventricular dysfunction; the rest either did not specify related eligibility criteria or included both patients with and without right ventricular dysfunction. As a result, it was not possible to perform reliable categorization of studies to conduct subgroup analyses based on the presence or absence of right ventricular dysfunction or hemodynamic compromise.bStudies included patients at low risk for bleeding.cIncluded studies that used different thrombolytic agents with varying doses and durations of administration; no statistical heterogeneity was noted.dThrombolysis was in addition to anticoagulation (most of the studies used heparin followed by warfarin; three studies used warfarin only).eReport of methodologic quality was poor in most studies. Of the 12 eligible studies, allocation was concealed in fi ve, three were single blind (outcome assessor), six were double blind, and three were not blinded. Most studies did not report on missing outcome data. None of the studies were stopped early for benefi t. For the increase in bleeding with thrombolytic therapy, quality of evidence is increased from low to moderate because there is high quality evidence of this association in patients with myocardial infarction and the indirectness of this evidence to patients with PE is minor.fI2 5 0%.gCI includes values suggesting both benefi t and no effect or harm; small number of events.hInverted funnel plots suggestive of possible publication bias in favor of thrombolytics.iRecurrent PE stratifi cation based on the simplifi ed Pulmonary Embolism Severity Index validated in the RIETE (RegistroInformatizado de la Enfermedad Tromboembólica) cohort.262

jSome studies suggested that the baseline risk of mortality in patients with hemodynamic instability is as high as 30%.274 In that case, the absolute number of deaths associated with thrombolytics would be 90 fewer per 1,000 (from 189 fewer to 93 more).kCI includes values suggesting both harm and no effect; small number of events.lMajor bleeding risk stratifi cation derived from the RIETE cohort.30 The median risk of bleeding over the fi rst 10 d reported in the eligible trials was 3.1%. In that case, the absolute number of major bleeding events with thrombolysis would be 20 more per 1,000 (from 0 more to 52 more).mIndirect evidence from studies of thrombolysis for myocardial infarction and acute stroke provide more precise estimates of increase major bleeding with thrombolytics use.





compared). During a 2-h infusion of 100 mg of tPA, US regulatory bodies recommend suspension of IV UFH, whereas IV UFH is continued during the tPA infusion in many other countries. US authorities rec-ommend checking the activated partial thrombo-plastin time immediately after completion of the tPA infusion and, provided that the activated antithrombin time is not . 80 s, restarting IV UFH without a bolus at the same infusion rate as before tPA was started.

5.7 Catheter-Based Thrombus Removal for the Initial Treatment of PE

Interventional catheterization techniques for mas-sive PE include mechanical fragmentation of throm-bus with a standard pulmonary artery catheter, clot pulverization with a rotating basket catheter, percu-taneous rheolytic thrombectomy, or pigtail rotational catheter embolectomy. 329-336 Pharmacologic throm-bolysis and mechanical interventions are usually combined unless bleeding risk is high. Catheter embolectomy does not result in extraction of intact pulmonary arterial thrombus; instead, clot fragments are suctioned through the catheter or displaced dis-tally with modest angiographic improvement.

No randomized trials have evaluated interventional catheterization techniques for PE. Most observation studies are retrospective series of , 30 patients. 334 Consequently, evidence for the use of interventional catheter techniques in patients with acute PE is of low quality, and our recommendations are weak. Catheter selection, catheter deployment, and adjunc-tive thrombolytic regimen should be based on local expertise and resources.

Recommendation

5.7. In patients with acute PE associated with hypotension and who have (i) contraindications to thrombolysis, (ii) failed thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours), if appropriate expertise and resources are avail-able, we suggest catheter-assisted thrombus removal over no such intervention (Grade 2C) .

5.8 Surgical Embolectomy for the Initial Treatment of PE

Emergency surgical embolectomy with cardio-pulmonary bypass is another management strategy for acute PE associated with hypotension. 337-340 This operation is also suited for patients with acute PE who require surgical excision of a right atrial thrombus, paradoxical arterial embolism, or clo-sure of a patent foramen ovale. Surgical embolec-tomy also can be performed to rescue patients in

whom thrombolysis has been unsuccessful. The procedure is best performed on a warm, beating heart, without aortic cross-clamping, cardioplegia, or fi brillatory arrest.

No randomized trials or prospective observational studies have evaluated surgical embolectomy in patients with acute PE. Consequently, evidence related to surgical embolectomy in patients with acute PE is of low quality, and our recommendations are weak.

Recommendation

5.8. In patients with acute PE associated with hypotension, we suggest surgical pulmonary embolectomy over no such intervention if they have (i) contraindications to thrombolysis, (ii) failed thrombolysis or catheter-assisted embolectomy, or (iii) shock that is likely to cause death before thrombolysis can take effect (eg, within hours), provided surgical expertise and resources are available (Grade 2C) .

5.9. Vena Caval Filters for the Initial Treatment of PE

As previously noted in section 2.13, IVC fi lters can be used instead of initial anticoagulant therapy in patients with acute PE if there is an unacceptable risk of bleeding or as an adjunct to anticoagulation. As in DVT, no randomized trials or prospective cohort studies have evaluated IVC fi lters as sole therapy for acute PE (ie, without concurrent antico-agulation). As described in section 2.13, the PREPIC study, which evaluated IVC fi lters as an adjunct to anticoagulation in 400 high-risk patients with prox-imal DVT, showed that fi lters reduced PE, increased DVT, and did not change overall frequency of VTE (DVT and PE combined) or mortality 146,149 ( Table 14 ; Table S19).

The PREPIC study included 145 (36%) patients with symptomatic PE and 52 (13%) patients with asymptomatic PE at enrollment. If a patient has an acute PE and a short-term contraindication to anticoagulation, provided there is no proximal DVT on ultrasound, it is reasonable not to insert an IVC fi lter immediately; serial ultrasound examina-tions can be performed to ensure that the patient remains free of proximal DVT while anticoagulation is withheld.

There is uncertainty about the risk and benefi ts of inserting IVC fi lters as an adjunct to anticoagulant and thrombolytic therapy in patients with PE and hypotension. Among patients with hemodynamic compromise in the International Cooperative Pulmo-nary Embolism Registry, insertion of an IVC fi lter was associated with a reduction of early recurrent PE and death. 280 Consequently, our recommendation




against insertion of an IVC fi lter in patients with acute PE who are treated with anticoagulants may not apply to this select subgroup of patients.

Recommendations

5.9.1. In patients with acute PE who are treated with anticoagulants, we recommend against the use of an IVC fi lter (Grade 1B) .

5.9.2. In patients with acute PE and contraindi-cation to anticoagulation, we recommend the use of an IVC fi lter (Grade 1B) .

5.9.3. In patients with acute PE and an IVC fi l-ter inserted as an alternative to anticoagulation, we suggest a conventional course of anticoagu-lant therapy if their risk of bleeding resolves (Grade 2B) .

Remarks: We do not consider that a permanent IVC fi lter of itself is an indication for extended anticoagulation.

6.0 Long-term Treatment of PE

In the following sections, we emphasize studies that were performed exclusively in patients with PE and patients with PE who were enrolled in other studies. For the reasons noted in section 1.1, we make the same recommendations for long-term treatment of PE as for DVT and rate the quality of the under-lying evidence as the same (see corresponding sec-tions for treatment of DVT).

VKA for the Long-term Treatment of PE: There has been only one evaluation of duration of VKA therapy exclusively in patients with PE. After 3 months of initial treatment, patients with PE pro-voked by a temporary risk factor were randomized to stop or to receive 3 more months of therapy, and those with unprovoked PE were randomized to stop or to receive 6 more months of therapy (WODIT PE [Warfarin Optimal Duration Italian Trial in patients with Pulmonary Embolism]) (Table S24 and S25). 194 Consistent with studies that included patients who presented with DVT, extended VKA therapy was effective while treatment was being received. How-ever, extending the duration of treatment beyond 3 months did not lower the rates of recurrence that were observed when anticoagulants were subsequently stopped.

LMWH for the Long-term Treatment of PE: Two small studies from the same investigator group have compared long-term LMWH (enoxaparin 1 mg/kg SC bid for � 14 days followed by 1.5 mg/kg SC daily)

with long-term VKA exclusively in patients who pre-sented with PE. 341,342 The two studies combined found a similar frequency of recurrent VTE (enoxaparin, 4/60; VKA, 1/40) and major bleeding (enoxaparin, 1/60; VKA, 2/40) with the two treatments. 341 Of the 12 other studies that compared LMWH with VKA therapy for long-term treatment of VTE (see section 3.3), only two 173,227 included patients with PE. In these two studies, all patients had cancer, and 295 had PE (36% of all enrolled patients; some PE may have been asymptomatic in one study 227 ); subgroup analyses were not reported for the patients with PE.

Dabigatran for the Long-term Treatment of PE: In the one completed study that compared dabigatran with VKA therapy after initial parenteral therapy ( Table 23 , Table S31), 786 (31%) patients had symp-tomatic PE at enrollment. 343 Subgroup analysis did not suggest that patients with symptomatic PE have a different response to dabigatran vs VKA therapy in terms of either recurrent VTE or bleeding.

Rivaroxaban for the Long-term Treatment of PE: In the Einstein Extension study that compared rivar-oxaban with placebo after an initial period of long-term anticoagulation ( Table 22 , Table S30), 454 (38%) patients had symptomatic PE at enrollment. 88 Sub-group analysis did not suggest that patients with symptomatic PE had a different response to rivaroxa-ban vs VKA therapy in terms of either recurrent VTE or bleeding.

Recommendations

6.1. In patients with PE provoked by surgery, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , or (iii) extended therapy (Grade 1B regardless of bleeding risk) .

6.2. In patients with PE provoked by a nonsur-gical transient risk factor, we recommend treat-ment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , and (iii) extended therapy if there is a high bleeding risk ( Table 2 ) (Grade 1B) . We suggest treatment with antico-agulation for 3 months over extended therapy if there is a low or moderate bleeding risk ( Table 2 ) (Grade 2B) .

6.3. In patients with an unprovoked PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter





duration (Grade 1B) . After 3 months of treat-ment, patients with unprovoked PE should be evaluated for the risk-benefi t ratio of extended therapy.

6.3.1. In patients with a fi rst VTE that is an unprovoked PE and who have a low or moderate bleeding risk ( Table 2 ), we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B) .

6.3.2. In patients with a fi rst VTE that is an unprovoked PE and who have a high bleeding risk, we recommend 3 months of anticoagulant therapy over extended therapy (Grade 1B) .

6.3.3. In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk ( Table 2 ) (Grade 1B) , and we suggest extended anticoagulant therapy in those with a moderate bleeding risk ( Table 2 ) (Grade 2B) .

6.3.4. In patients with a second unprovoked VTE who have a high bleeding risk ( Table 2 ), we suggest 3 months of therapy over extended therapy (Grade 2B) .

6.4. In patients with PE and active cancer, if the risk of bleeding is not high ( Table 2 ), we rec-ommend extended anticoagulant therapy over 3 months of therapy (Grade 1B) , and if there is a high bleeding risk ( Table 2 ), we suggest extended anticoagulant therapy (Grade 2B) .

Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treat-ment should be reassessed at periodic intervals (eg, annually).

6.5. In patients with PE who are treated with VKA, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR , 2) or higher (INR 3.0-5.0) range for all treatment durations (Grade 1B) .

6.6. In patients with PE and no cancer, we suggest VKA therapy over LMWH for long-term therapy (Grade 2C) . For patients with PE and no cancer who are not treated with VKA therapy, we suggest LMWH over dabigatran or rivaroxaban for long-term therapy (Grade 2C) .

6.7. In patients with PE and cancer, we suggest LMWH over VKA therapy (Grade 2B) . In patients with PE and cancer who are not treated with

LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2C) .

Remarks (6.6-6.7): Choice of treatment in patients with and without cancer is sensitive to individual patient tolerance for daily injections, need for labora-tory monitoring, and treatment costs. Treatment of VTE with dabigatran or rivaroxaban, in addition to being less burdensome to patients, may prove to be associated with better clinical outcomes that VKA and LMWH therapy. When these guidelines were being prepared (October 2011), postmarketing stud-ies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, we give a weak recommendation in favor of VKA and LMWH therapy over dabigatran and rivaroxaban, and we have not made any recommen-dations in favor of one of the new agents over the other.

6.8. In patients with PE who receive extended therapy, we suggest treatment with the same anticoagulant chosen for the fi rst 3 months (Grade 2C) .

6.9 Treatment of Asymptomatic PE

Diagnosis of asymptomatic PE occurs in � 1% of outpatients and � 4% of inpatients who have contrast-enhanced CT scans, with a majority being in patients with known malignancy. 40,344-355 When PE is diagnosed unexpectedly in patients with cancer, in retrospect, the clinical history may reveal symptoms that were aggravated by the PE (eg, an increase in fatigue). 345 About one-half of such incidental PE involve the lobar or more central pulmonary arteries, whereas the other one-half are more distal. 40,353

When there is evidence of an asymptomatic PE, the fi rst priority is to review the CT scans to deter-mine whether the fi ndings are convincing for acute PE. Other recent CT scans may be available for com-parison, or the current scan may also reveal DVT in the central deep veins (eg, subclavian vein, IVC, iliac vein). If there is any uncertainty about the pres-ence of an acute PE, additional diagnostic testing is required (eg, ultrasonography of the deep veins, dedicated CT pulmonary angiography, D -dimer).

Consistent with recommendations for the treat-ment of asymptomatic DVT (section 3.5) in patients in whom clinicians are convinced that an asymptom-atic PE has occurred, based on moderate-quality evidence, we suggest the same initial and long-term anticoagulation as for similar patients with symp-tomatic PE. The indication for anticoagulation is most compelling when the presence of PE is unequivocal, PE involves the lobar and more central




pulmonary arteries, PE is a new fi nding on CT, ultrasound reveals proximal DVT, there are ongoing risk factors for VTE such as active cancer, and the patient is not at high risk for bleeding ( Table 2 ). Many patients have left the hospital by the time an incidental PE is reported. If PE is less extensive and it would be diffi cult for patients to return the same day, it often is reasonable to defer further assessment and anticoagulant therapy until the next day.

Recommendation

6.9. In patients who are incidentally found to have asymptomatic PE, we suggest the same ini-tial and long-term anticoagulation as for similar patients with symptomatic PE (Grade 2B) .

7.0 Chronic Thromboembolic Pulmonary Hypertension

Prospective studies suggest that CTPH occurs in � 3% of patients who are treated for PE. 104,354-358 About one-third of patients have a history of VTE, whereas two-thirds have had single or recurrent epi-sodes of PE that were not diagnosed and may have been asymptomatic. 359 Patients with CTPH are likely to have a high risk of recurrent VTE because they have had previous VTE and have cardiopulmonary impairment. Recurrent VTE may be fatal more often in patients with severe cardiopulmonary impairment than in those without such impairment . After PE ini-tiates CTPH, pulmonary vascular remodeling may cause severe pulmonary hypertension out of propor-tion with pulmonary vascular thrombosis. 104,359,360

7.1 Pulmonary Thromboendarterectomy, Anticoagulant Therapy, and Vena Caval Filter for the Treatment of CTPH

Primary therapy for CTPH is pulmonary throm-boendarterectomy, which, if successful, can reduce or cure pulmonary hypertension and associated symp-toms. 104,359-367 The operation is lengthy and complex, requiring a median sternotomy, cardio pulmonary bypass, deep hypothermia with periods of circu-latory arrest, and exploration of both pulmonary arteries. At the most experienced centers, mortality is � 5%. 104,360,363,365-367 Management often includes inser-tion of a permanent IVC fi lter before or during pul-monary endarterectomy and indefi nite anticoagulant therapy. 359,361,363,365 Patients with CTPH who are not candidates for pulmonary endarterectomy because of comorbid disease or surgically inaccessible lesions may be candidates for vasodilator therapy, balloon pulmonary angioplasty, or lung transplantation and may benefi t from referral to a center with expertise in pulmonary hypertension. 359,363-365,368-370

There are no randomized trials of CTPH therapy and, overall, evidence is low quality. There is, how-ever, high-quality indirect evidence that anticoagu-lant therapy is very effective at preventing recurrent VTE in other patient populations (see section 3.1; Table 18 ; and Tables S24, S25, and S27). Conse-quently, the evidence supporting long-term antico-agulation in patients with CTPH is of moderate quality (rated down for indirectness). Features that are expected to be associated with greater benefi t with pulmonary thromboendarterectomy include younger age, central disease, progressive clinical deteriora-tion, and access to an expert multidisciplinary throm-boendarterectomy team.

Recommendations

7.1.1. In patients with CTPH, we recommend extended anticoagulation over stopping therapy (Grade 1B) .

7.1.2. In selected patients with CTPH, such as those with central disease under the care of an experienced thromboendarterectomy team, we suggest pulmonary thromboendarterectomy over no pulmonary thromboendarterectomy (Grade 2C) .

8.0 Superficial Vein Thrombosis

SVT has been less well studied than DVT but is estimated to occur more often. 371,372 It usually affects the lower limbs; often involves a varicose vein; is associated with chronic venous insuffi ciency, malig-nancy, thrombophilia, pregnancy or estrogen therapy, obesity, sclerotherapy, long-distance travel, and a his-tory of VTE; or may be unprovoked. 371-373 The long saphenous vein is involved in about two-thirds of lower-limb SVT. 374

Although traditionally considered a benign disease, a number of studies indicate that the consequences of SVT may be more serious. 371,372 A prospective study of 844 patients with acute SVT of � 5 cm found that at initial presentation, � 4% of patients had symp-tomatic PE, and routine ultrasound detected prox-imal DVT in 10% and distal DVT in an additional 13% of patients. 374 In patients without VTE at presen-tation, despite 90% being treated with anticoagulant therapy (therapeutic doses in two-thirds, prophylac-tic doses in one-third, median duration of 11 days), 3.1% developed symptomatic VTE (0.5% PE, 1.2% proximal DVT, 1.4% distal DVT), 1.9% had recur-rent SVT (different location), and 3.3% had an exten-sion of SVT (same location) at 3 months. Male sex, history of VTE, cancer, and absence of varicose veins each was associated with about a doubling of the risk of VTE during follow-up.





is low because there is no direct comparison in patients with SVT. Factors that favor the use of anticoagulant therapy in patients with SVT (see Recommendation 8.1.1) include: extensive SVT; involvement above the knee, particularly if close to the saphenofemoral junction; severe symptoms; involvement of the greater saphenous vein; history of VTE or SVT; active cancer; and recent surgery. An economic evaluation found that treatment of SVT with fondaparinux was not cost-effective; it cost $500,000 per quality-adjusted life year gained com-pared with no treatment. 383

Graduated compression stockings often are used in patients with SVT (eg, 83% of patients in the CALI-STO study). Oral nonsteroidal antiinfl ammatory agents may be used to alleviate symptoms if patients are not treated with anticoagulants. Topical nonste-roidal antiinfl ammatory agents may reduce symptoms and can be used with anticoagulant therapy. Sur-gical therapy, with ligation of the saphenofemoral junction or stripping of thrombosed superfi cial veins appears to be associated with higher rates of VTE than treatment with anticoagulants. 380,384,385 Anticoag-ulant therapy generally is not used to treat SVT that occurs in association with an IV infusion (ie, infusion thrombophlebitis).

Recommendations

8.1.1. In patients with SVT of the lower limb of at least 5 cm in length, we suggest the use of a prophylactic dose of fondaparinux or LMWH for 45 days over no anticoagulation (Grade 2B) .

Remarks: Patients who place a high value on avoid-ing the inconvenience or cost of anticoagulation and a low value on avoiding infrequent symptomatic VTE are likely to decline anticoagulation.

8.1.2. In patients with SVT who are treated with anticoagulation, we suggest fondaparinux 2.5 mg daily over a prophylactic dose of LMWH (Grade 2C) .

9.0 Acute Upper-Extremity DVT

About 5% to 10% of VTE involve the upper extre m-ities. 386-390 UEDVT includes two etiologic groups: primary (unprovoked with or without thrombophilia, effort-related and thoracic outlet syndrome) and sec-ondary (provoked by central venous catheters, pace-makers, or cancer). Secondary UEDVT accounts for � 75% of cases. 386,388,389,391-394

UEDVT involves the subclavian, axillary, or bra-chial veins and may include extension to the bra-chiocephalic vein, superior vena cava, or the internal

Given the high prevalence of concomitant prox-imal DVT in patients with SVT and the need to treat such patients with higher doses of anticoagulant therapy (ie, therapeutic doses), patients with SVT above the knee should have ultrasonography to exclude proximal DVT. Ultrasound can also help with the diagnosis of SVT if the clinical presentation is uncertain. With greater appreciation of the serious-ness of SVT, investigators have evaluated anticoagu-lant therapy, often in prophylactic or intermediate doses, as a way to reduce acute symptoms, extension, recurrence, and progression to VTE ( Table 31 , Tables S43-S45). 375

8.1 Treatment of SVT

Most studies that have evaluated anticoagulant therapy for SVT have been small (eg, � 100 patients per treatment group), with additional methodologic weaknesses 376-381 (Tables S44, S45). Although these studies suggest that prophylactic-dose LMWH, inter-mediate-dose UFH or LMWH, warfarin therapy, and oral nonsteroidal antiinfl ammatory agents are benefi -cial in patients with SVT, the supporting evidence is of low quality. The recently published Comparison of ARIXTRA™ in lower LImb Superfi cial Thrombo-phlebitis with placebo (CALISTO) study, which com-pared fondaparinux (2.5 mg/d for 45 days) with placebo in 3,000 patients with SVT ( � 5 cm in length), has helped to clarify the role of anticoagulants for the treatment of SVT ( Table 31 , Table S43), and the nat-ural history of this condition. 382

CALISTO found that fondaparinux is very effec-tive at reducing VTE, recurrent SVT, extension of SVT, and the need for venous surgery, and is associ-ated with little bleeding. In the placebo group, throm-botic complications occurred more often if SVT involved the greater saphenous vein (92% of patients in the control group), extended to within 10 cm from the saphenofemoral junction (9% of patients), and involved veins above the knee (46% of patients) and if VTE (7% of patients) or SVT (12% of patients) had occurred previously. 382 Age, sex, and presence of var-icose veins were not convincingly associated with the frequency of thrombotic complications, and there were too few patients with cancer in CALISTO to assess that association.

The evidence is moderate quality. We have inter-preted the fi ndings of the CALISTO study as evi-dence for anticoagulation in general and assume that prophylactic doses of LMWH and fondaparinux have similar antithrombotic effi cacy and safety. Because it is direct and more extensive, the evidence in support of fondaparinux is higher quality than the evidence in support of LMWH. Quality of the evi-dence for comparison of fondaparinux with LMWH




jugular vein. Clinical manifestations include acute and chronic arm pain, swelling, discoloration, and dilated collateral veins over the arm, neck, or chest. UEDVT may lead to complications, including symp-tomatic PE ( � 5% of patients 387-389,393,395 ), recurrent UEDVT ( � 8% at 5 years of follow-up 389,390,395 ), and PTS of the arm ( � 20% of patients). 386,387,395,396 In the absence of a central venous catheter, the dominant arm is more often affected. 387 Complications of UEDVT are expected to occur much more often and to be more severe when UEDVT involves the axillary or more-proximal veins than if thrombosis is confi ned to the brachial vein. In general, when we refer to UEDVT, we are referring to thrombosis that involves the axillary or more-proximal veins.

The most frequent risk factor for UEDVT is a cen-tral venous catheter. 386,388,397,398 If UEDVT occurs in association with a central venous catheter and the catheter is no longer required, it should be removed. There are no data to guide whether catheter removal should be preceded by an initial period of anticoagu-lation, and we do not have a preference for imme-diate or deferred removal. If UEDVT occurs in association with a central venous catheter and there is a continuing need for the catheter, the catheter need

not be removed. If the catheter is not functioning and cannot be made to function (even after a period of systemic anticoagulation), it should be removed .

As with treatment of leg DVT and PE, treatment of UEDVT may be divided into acute (eg, parenteral anticoagulants, thrombolytic therapy) and long-term phases (eg, anticoagulation, treatment of upper-extremity PTS). Because no randomized trials have evaluated treatment of UEDVT, recommendations are based on indirect evidence from studies performed in patients with leg DVT, observational studies (gen-erally small), and understanding of the natural his-tory of UEDVT. Therefore, quality of evidence is, at best, moderate.

9.1 Acute Anticoagulation for UEDVT

No randomized controlled studies have evaluated acute anticoagulation for initial treatment of UEDVT. Several small prospective cohort studies have reported low rates of recurrent DVT, PE, and major bleeding when UEDVT was treated similarly to leg DVT (Tables S46 and S47). 395,399-401 Anticoagulant therapy is used to treat UEDVT because (1) UEDVT causes acute symptoms, can cause PE (including fatal

Table 31—[Section 8.1] Summary of Findings: Fondaparinux vs Placebo for Acute SVTa-c,382




(95% CI)


Risk With No Fondaparinux

Risk Difference With Fondaparinux (95% CI)

Mortality 3,002 (1 study), 3 mo Moderated-g due to imprecision

RR 1.99 (0.18-21.87) 4 per 1,000h 4 more per 1,000 (from 3 fewer to 83 more)

VTE 3,002 (1 study), 3 mo Highd RR 0.18 (0.06-0.53) 33 per 1,000h 27 fewer per 1,000 (from 16 fewer to 31 fewer)

SVT recurrence 3,002 (1 study), 3 mo Highd RR 0.31 (0.14-0.68) 19 per 1,000h 13 fewer per 1,000 (from 6 fewer to 16 fewer)

Major bleeding 2,987(1 study), 47 d Moderated,e,i due to imprecision

RR 0.99 (0.06-15.86)e 1 per 1,000 0 fewer per 1,000 (from 1 fewer to 10 more)

QOL not measured … … … … …

The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aPatients with infusion-related SVT were excluded from CALISTO (Comparison of ARIXTRA in lower Limb Superfi cial Thrombophlebitis with Placebo).bFondaparinux 2.5 mg for 45 d.cPatients in the two treatment groups benefi ted from close clinical monitoring with adequate diagnostic procedures in the event of new or persistent symptoms.dAllocation concealed. Outcome adjudicators, steering committee, patients, providers, and data collectors blinded. Follow-up rate was 98%. Intention-to-treat analysis for effi cacy outcomes. Not stopped early for benefi t.eCI includes values suggesting large benefi t and values suggesting large harm.fWe rated down by only one level because of the low event rate and large sample size.gSmall number of events.hBaseline risk derived from a large prospective cohort study.374

iThe upper limit of the CI for absolute effect (10 more bleeds) is not low enough to suggest a clear balance of benefi ts vs harms.





episodes), and is associated with PTS; (2) observa-tional studies support its use; and (3) there is strong evidence for benefi t in patients with leg DVT.

Uncertainty exists about the need to prescribe antico-agulants to patients with thrombosis confi ned to the brachial vein. Acceptable alternatives to full-dose anti-coagulation in such patients include clinical or ultra-sound surveillance to detect extension of UEDVT while withholding anticoagulation, or treatment with prophylactic-dose anticoagulation, or treatment with therapeutic doses of anticoagulation for , 3 months. We favor anticoagulation if isolated brachial vein thrombosis is symptomatic, associated with a central venous catheter that will remain in place, or associ-ated with cancer in the absence of a central venous catheter. A high risk of bleeding argues against full-dose anticoagulation.

Recommendations

9.1.1. In patients with acute UEDVT that involves the axillary or more proximal veins, we recommend acute treatment with paren-teral anticoagulation (LMWH, fondaparinux, IV UFH, or SC UFH) over no such acute treat-ment (Grade 1B) .

9.1.2. In patients with acute UEDVT that involves the axillary or more proximal veins, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B) .

9.2 Thrombolytic Therapy for the Initial Treatment of UEDVT

No randomized controlled studies have evaluated thrombolytic therapy compared with anticoagula-tion alone in patients with UEDVT. A number of retrospective and small prospective observational studies have evaluated streptokinase, urokinase, or rt-PA administered with varying doses, methods of administration (IV, catheter directed), and infu-sion durations. 402-409 Three of these studies included nonrandomized control groups who received antico-agulation alone. 402,407,408 In some studies, a few patients also had venous angioplasty 405 or surgical decom-pression 402,405,408 (Tables S48 and S49).

These studies suggest that thrombolysis can improve early and late venous patency but is associ-ated with increased bleeding. However, it is not known whether thrombolytic therapy reduces PTS of the arm or recurrent VTE. PTS of the arm appears to be a less common complication of thrombosis than PTS of the leg. 386-388,393,395,410 We believe that throm-bolysis should be considered only in patients who meet all of the following criteria: severe symptoms, thrombus involving most of the subclavian vein and

the axillary vein, symptoms for , 14 days, good func-tional status, life expectancy of � 1 year, and low risk for bleeding ( Table 11 ). If thrombolysis is used, in order to reduce the dose of thrombolytic therapy and the associated risk of bleeding, we encourage cath-eter-based therapy over systemic thrombolysis. In addition, because the balance of risks and benefi ts with all forms of thrombolytic therapy is uncertain, anticoagulant therapy alone is acceptable initial ther-apy in all patients with UEDVT. There is no evidence to suggest that thrombolysis reduces the risk of recur-rent VTE.

Resection of the fi rst rib has been advocated when UEDVT is believed to have been due to entrapment of the subclavian vein as it passes between the clav-icle and the fi rst rib. 6,386,411-421 Insertion of a fi lter in the superior vena cava has also been used in patients with acute UEDVT who cannot be given anticoagu-lants. Complications, however, may be more than with IVC fi lters. 389,413,422 The evidence in support of these procedures is of low quality, and because there is the potential to cause harm, their use should be confi ned to exceptional circumstances in specialized centers.

Recommendations

9.2.1. In patients with acute UEDVT that involves the axillary or more proximal veins, we suggest anticoagulant therapy alone over throm-bolysis (Grade 2C) .

Remarks: Patients who (i) are most likely to benefi t from thrombolysis (see text); (ii) have access to CDT; (iii) attach a high value to prevention of PTS; and (iv) attach a lower value to the initial complexity, cost, and risk of bleeding with thrombolytic therapy are likely to choose thrombolytic therapy over anticoagu-lation alone.

9.2.2. In patients with UEDVT who undergo thrombolysis, we recommend the same inten-sity and duration of anticoagulant therapy as in similar patients who do not undergo thromboly-sis (Grade 1B) .

9.3 Long-term Anticoagulation for UEDVT

No randomized studies have evaluated duration or intensity of long-term anticoagulation in patients with UEDVT. In prospective observational studies, patients with UEDVT generally were treated with VKA (target INR 2.5) for periods of 3 to 6 months. 393,399-

401,423 Rates of recurrent VTE and PTS varied (Tables S50 and S51), but as previously noted, these rates generally were lower than those observed in patients with leg DVT.




The factors that infl uence long-term anticoagu-lation in patients with leg DVT (section 3.1) are relevant to long-term treatment of UEDVT. Some differences between UEDVT and leg DVT are wor-thy of emphasis, especially that UEDVT often is asso-ciated with a central venous catheter that may or may not be removed (section 9.0). The most important continuing risk factors for UEDVT are (1) the pres-ence of a central venous catheter in the same arm and (2) active cancer in patients with UEDVT not associ-ated with a central venous catheter.

Another important distinction between UEDVT and leg DVT relates to long-term anticoagulation in patients with unprovoked thrombosis. Because the risk of recurrent VTE is substantially lower in patients with UEDVT compared with in those with proximal leg DVT, 387,388,393,395 we discourage extended anticoag-ulant therapy (ie, beyond 3 months) in patients with an unprovoked UEDVT.

No data are available for the long-term use of LMWH monotherapy or newer anticoagulants for the long-term treatment of UEDVT. We make the same recommendations for choice of initial, long-term, and extended anticoagulant regimens for UEDVT as for leg DVT (recommendations 3.1.1, 3.1.2, and 3.1.4) and note that the supporting evidence for these weak recommendations is further weakened in this population because of indirectness.

Recommendations

9.3.1. In most patients with UEDVT that is asso-ciated with a central venous catheter, we sug-gest that the catheter not be removed if it is functional and there is an ongoing need for the catheter (Grade 2C) .

9.3.2. In patients with UEDVT that involves the axillary or more proximal veins, we suggest a minimum duration of anticoagulation of 3 months over a shorter period (Grade 2B) .

Remarks: This recommendation also applies if the UEDVT is associated with a central venous catheter that was removed shortly after diagnosis.

9.3.3. In patients who have UEDVT that is asso-ciated with a central venous catheter that is removed, we recommend 3 months of antico-agulation over a longer duration of therapy in patients with no cancer (Grade 1B) , and we sug-gest this in patients with cancer (Grade 2C) .

9.3.4. In patients who have UEDVT that is asso-ciated with a central venous catheter that is not removed, we recommend that anticoagulation is continued as long as the central venous cath-

eter remains over stopping after 3 months of treatment in patients with cancer (Grade 1C) , and we suggest this in patients with no cancer (Grade 2C) .

9.3.5. In patients who have UEDVT that is not associated with a central venous catheter or with cancer, we recommend 3 months of anti-coagulation over a longer duration of therapy (Grade 1B) .

9.4 Prevention of PTS of the Arm

PTS of the arm occurs in � 20% of patients after treatment for UEDVT 38,395,396 and can be a disabl-ing condition that adversely affects quality of life, particularly if the dominant arm is involved. 410,424 No randomized trials have evaluated compression bandages, compression sleeves, or venoactive drugs to prevent PTS after UEDVT. We have not con-sidered indirect evidence from the legs for use of compression therapy to prevent PTS of the arms because (1) the pathophysiology of PTS is believed to be different in the arms than in the legs (less dependent venous hypertension), (2) arm sleeves are more diffi cult to fi t than stockings, and (3) PTS occurs less often after UEDVT than after leg DVT.

Recommendation

9.4. In patients with acute symptomatic UEDVT, we suggest against the use of compression sleeves or venoactive medications (Grade 2C) .

9.5 Treatment of PTS of the Arm

Symptoms of PTS of the arm include swelling, heaviness, and limb fatigue with exertion. 395,410 No randomized trials have evaluated compression ban-dages, compression sleeves (as are used for lym-phedema), or venoactive drugs to treat PTS after UEDVT. We considered anecdotal evidence that compression therapy benefi ts some patients with PTS of the arm and that the benefi ts of a trial of compres-sion therapy will outweigh its harms and costs. There is no evidence that venoactive drugs are of benefi t in PTS of the arm.

Recommendations

9.5.1. In patients who have PTS of the arm, we suggest a trial of compression bandages or sleeves to reduce symptoms (Grade 2C) .

9.5.2. In patients with PTS of the arm, we sug-gest against treatment with venoactive medica-tions (Grade 2C) .





10.0 Splanchnic Vein Thrombosis

Thrombosis in the portal venous system, which includes the superior mesenteric, inferior mesen-teric, splenic, and portal veins, is collectively termed splanchnic vein thrombosis . Depending on the location and extent of thrombosis, how rapidly thrombosis develops, speed and extent of thrombus recannula-tion, presence of collateral portal venous drainage, and adequacy of arterial inflow, splanchnic vein thrombosis may result in bowel or splenic infarction and chronic portal hypertension. 425-430 Acute and chronic splanchnic vein thrombosis may be symp-tomatic, but many episodes are detected incidentally in imaging studies performed for other indications, such as assessing response to surgical or medical therapy in patients with cancer. 348,429 Limited under-standing of the natural history of both symptomatic and incidentally detected splanchnic vein thrombosis in patients who are not treated with anticoagulants (ie, frequency of bowel infarction, development of portal hypertension, recurrence), a paucity of data from prospective cohort studies, 428,431 and a lack of randomized trials of standardized anticoagulant therapy for splanchnic vein thrombosis result in uncertainty about the role of anticoagulation for this condition. Increased risk of bleeding associated with esophageal varices (secondary to portal hypertension), thrombo-cytopenia (secondary to hypersplenism), and the pres-ence of cirrhosis and malignancy (which predispose to splanchnic vein thrombosis) add to this uncertainty.

A number of retrospective, 425,429,430 and two pro-spective, 428,431 studies suggested that bowel ischemia is uncommon in patients with symptomatic splanchnic vein thrombosis who are treated with anticoagulants ( � 2% 428 ), that recurrent venous thrombosis (both involving the splanchnic and nonsplanchnic veins) is common without anticoagulation or after stopping anticoagulation ( � 5% per year 425,429,430 ), and that anti-coagulation is effective at preventing progression and recurrent thrombosis, 425,428-431 although it is asso-ciated with an increased (particularly GI), but usually acceptable, frequency of bleeding. 428-431 Effi cacy of anticoagulant therapy in other forms of symptom-atic venous thrombosis also provides indirect evi-dence for anticoagulation of patients with symptomatic splanchnic vein thrombosis and, supported by the previously noted observational studies, this evidence is of moderate quality. We are not aware of studies of treated or untreated asymptomatic splanchnic vein thrombosis.

Factors that may encourage anticoagulant therapy in patients with incidental splanchnic vein thrombo-sis include extensive thrombosis that appears to be acute (eg, not present on a previous imaging study, presence of an intraluminal fi lling defect, lack of cav-

ernous transformation), progression of thrombosis on a follow-up imaging study, and ongoing cancer che-motherapy. Esophageal varices secondary to acute portal vein thrombosis are not necessarily a contrain-dication to anticoagulant therapy because such treat-ment may improve the portal hypertension. LMWH may be preferred over VKA if there is active malig-nancy, liver disease, or thrombocytopenia. 431 The pres-ence of a reversible provoking factor for splanchnic vein thrombosis, such as intraabdominal sepsis or recent surgery, supports stopping anticoagulant therapy after 3 months. Absence of a reversible risk factor (eg, “unprovoked” thrombosis or presence of a per-sistent risk factor, such as myeloproliferative disease) and a low risk of bleeding support extended anticoag-ulant therapy.

Recommendations

10.1. In patients with symptomatic splanchnic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), we recommend anti-coagulation over no anticoagulation (Grade 1B) .

10.2. In patients with incidentally detected splanchnic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), we suggest no anticoagulation over anticoagulation (Grade 2C) .

11.0 Hepatic Vein Thrombosis

Hepatic vein thrombosis, particularly Budd-Chiari syndrome with occlusion of the main hepatic vein, can result in impairment of liver function and an associated coagulopathy. 432,433 Because there is limited understanding of the natural history of this condition and a paucity of prospective studies that have evalu-ated anticoagulant therapy, the role of anticoagulant therapy is uncertain. 432

In a prospective registry of 163 patients with Budd-Chiari syndrome of variable extent, of whom 86% were treated with anticoagulation, one-half of patients did not require invasive interventions (ie, transjugu-lar intrahepatic portosystemic shunting in 34% of all patients, surgical portosystemic shunting in 2% of patients, liver transplantation in 12% of patients), and survival was 82% after 2 years. 432 In an earlier retro-spective study of 237 patients with Budd-Chiari syn-drome performed when use of surgical portosystemic shunting was common (49% of patients), use of anti-coagulant therapy (72% of patients) had no apparent effect on survival (RR, 1.05; 95% CI, 0.62-1.76).

Factors that encourage anticoagulant therapy in patients with incidental hepatic vein thrombosis include extensive thrombosis that appears to be acute (eg, not present on a previous imaging study, pres-ence of an intraluminal fi lling defect), progression




of thrombosis on a follow-up imaging study, and ongoing cancer chemotherapy. Coagulopathy due to liver dysfunction caused by hepatic vein thrombosis is not a contraindication to anticoagulant therapy because anticoagulants may improve hepatic func-tion. LMWH usually will be preferred to VKA therapy when there is hepatic dysfunction and if there is active malignancy. Presence of a reversible provoking factor for hepatic vein thrombosis, such as oral con-traceptive therapy, encourages a time-limited course of therapy. Absence of a reversible risk factor encour-ages the use of extended therapy. Treatment of hepatic vein obstruction is complex and best under-taken by a multidisciplinary team.

Recommendations

11.1. In patients with symptomatic hepatic vein thrombosis, we suggest anticoagulation over no anticoagulation (Grade 2C) .

11.2. In patients with incidentally detected hepatic vein thrombosis, we suggest no antico-agulation over anticoagulation (Grade 2C) .

12.0 Future Research

Several questions in the treatment of VTE need to be answered. Current evidence relating to these questions is of moderate or low quality. We list the questions roughly as they arise in this article rather than in order of importance. We do not present the rationale for each question because this is addressed in the corresponding sections of the article. We have confi ned ourselves to the primary question (eg, Should patients with proximal DVT be treated with antico-agulant therapy alone, or should they be treated with pharmacomechanical CDT?); however, once the primary question is answered, we anticipate that secondary questions will need to be addressed (eg, Which patients with proximal DVT should, or should not, be treated with CDT?) . We are pleased to note that many of the these questions are being addressed in ongoing trials.

• Should patients with an isolated distal DVT rou-tinely be treated with anticoagulant therapy, or should they have serial testing to determine whether the DVT is extending and only be treated if extension is detected?

• Should patients with proximal DVT be treated with anticoagulant therapy alone, or should they be treated with pharmacomechanical CDT?

• Which patients with unprovoked proximal DVT or PE or cancer-associated VTE should stop anticoagulant therapy at 3 months, and which should remain on extended anticoagulant therapy?

• Which patients with unprovoked VTE or cancer-associated VTE have an unacceptable risk of bleeding if they remain on extended anticoagu-lant therapy?

• How should risk of recurrent VTE if anticoagu-lant therapy is stopped be balanced against risk of bleeding is anticoagulant therapy is continued?

• What is the preferred anticoagulant regimen for the short- and long-term treatment of VTE in patients with and without cancer?

• Should patients receiving an incidental diagno-sis of asymptomatic VTE routinely be treated with anticoagulant therapy, or should they have serial testing to determine whether they have evolving DVT and only be treated if this is detected?

• Should patients with symptomatic DVT rou-tinely wear graduated compression stockings from the time of diagnosis, or should stockings be used selectively (eg, in selected patients, in patients whose symptoms do not rapidly resolve)?

• Should patients with PE that causes right ven-tricular dysfunction be treated with anticoagu-lant therapy alone, or should they be treated with thrombolytic therapy?

• If patients have catheter-associated UEDVT and the catheter is removed, should they be treated with anticoagulant therapy or can they be treated without anticoagulant therapy?

• Can UEDVT be treated with less-intense or a shorter duration of anticoagulant therapy than leg DVT?

Acknowledgments Author contributions: As Topic Editor, Dr Akl oversaw the development of this article, including the data analysis and subse-quent development of the recommendations contained herein. Dr Kearon: served as Deputy Editor . Dr Akl: served as Topic Editor. Dr Comerota: served as a panelist. Dr Prandoni: served as a panelist. Dr Bounameaux: served as a panelist. Dr Goldhaber: served as a panelist. Dr Nelson: served as a frontline clinician. Dr Wells: served as a panelist. Dr Gould: served as a resource consultant. Dr Dentali: served as a panelist. Dr Crowther: served as a panelist. Dr Kahn: served as a panelist. Financial/nonfi nancial disclosures: The authors of this guide-line provided detailed confl ict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e419S/suppl/DC1. In summary, the authors have reported to CHEST the following confl icts of interest: Dr Kearon is a consultant to Boehringer Ingelheim and has received peer-reviewed funding for studies in the treatment of VTE. Dr Bounameaux has received grant monies and honoraria for consultancy or lec-tures from Bayer Schering Pharma AG; Daiichi-Sankyo Co, Ltd; Sanofi -Aventis LLC; Pfi zer Inc; Bristol-Myers Squibb; Servier; and Canonpharma Production Ltd. Dr Goldhaber has received funds from Eisai Co, Ltd; EKOS Corporation; Sanofi -Aventis LLC;


http://chestjournal.chestpubs.org/content/141/2_suppl/e419S/suppl/DC1





and Johnson & Johnson. He serves as a consultant for Boeh-ringer Ingelheim GmbH; Bristol-Myers Squibb; Daiichi San-kyo Co, Ltd; Eisai Co, Ltd; EKOS Corporation; Medscape; Merck & Co, Inc; Portola Pharmaceuticals, Inc; and Sanofi -Aventis LLC. Dr Wells has received peer-reviewed and investigator-initiated industry research funding for projects related to venous thrombo-sis treatment. He has received honoraria for industry-sponsored (Bayer, Boehringer-Ingelheim, Pfi zer, BioMerieux, sanofi -aventis) talks pertaining to venous thrombosis and has attended advisory boards for Bayer, Boehringer-Ingelheim, Pfi zer and Bristol-Myers-Squibb. Dr Crowther has served on various advisory boards, has assisted in the preparation of educational materials, has sat on data safety management boards, and his institution has received research funds from the following companies: Leo Pharma A/S, Pfi zer Inc, Boerhinger Ingelheim GmbH, Bayer Healthcare Pharmaceuticals, Octapharm AG, CSL Behring, and Artisan Pharma. Personal total compensation for these activities over the past 3 years totals less than US $10,000. Dr Kahn has received peer-reviewed and investigator-initiated industry research funding for projects related to venous thrombosis and postthrombotic syndrome pre-vention and treatment. She has received honoraria for industry-sponsored talks pertaining to venous thrombosis. Dr Akl is a member of and prominent contributor to the GRADE Working Group. Dr Comerota discloses that he is a consultant to and speaker for Covidien, Inc. Drs Prandoni, Nelson, Gould, and Dentali have reported that no potential confl icts of interest exist with any companies/organizations whose products or services may be dis-cussed in this article . Role of sponsors: The sponsors played no role in the develop-ment of these guidelines. Sponsoring organizations cannot recom-mend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Sci-ence Policy Committee are blinded to the funding sources. Fur-ther details on the Confl ict of Interest Policy are available online at http://chestnet.org . Other contributions: We acknowledge the contributions of the writing groups of previous editions of this guideline and thank Gordon H. Guyatt , MD, FCCP, for his comments and suggestions and Aman Rajpal, MD, for his help with reviewing the proofs. Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clin-ical Pharmacy, the American Society of Health-System Pharma-cists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis. Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e419S/suppl/DC1.

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451 . Kolbach DN , Sandbrink MW , Neumann HA , Prins MH . Compression therapy for treating stage I and II (Widmer) post-thrombotic syndrome . Cochrane Database Syst Rev . 2003 ; ( 4 ): CD004177 .



Online Data SupplementCHEST

1 © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http :// www . chestpubs . org / site / misc / reprints . xhtml ). DOI: 10.1378/chest.11-2301

Antithrombotic Therapy for VTE Disease

Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Clive Kearon, MD, PhD; Elie A. Akl, MD, MPH, PhD; Anthony J. Comerota, MD; Paolo Prandoni, MD; Henri Bounameaux, MD; Samuel Z. Goldhaber, MD, FCCP; Michael Nelson, MD, FCCP; Philip Wells, MD; Michael K. Gould, MD, MS, FCCP; Francesco Dentali, MD; Mark Crowther, MD; and Susan R. Kahn, MD




2© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301

Tabl

e S1

—[S

ecti

on 2

.1]

Evi

denc

e P

rofi l

e: P

aren

tera

l A

ntic

oagu

lati

on v

s N

o P

aren

tera

l A

ntic

oagu

lati

on i

n A

cute

VT

E a

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

B

ias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nPu

blic

atio

n B

ias

Ove

rall

Qua

lity

of E

vide

nce

With

No

Pare

nter

al

Ant

icoa

gula

tion

With

Par

ente

ral

Ant

icoa

gula

tion

Rel

ativ

e E

ffec

t (9

5% C

I)

Ris

k W

ith N

o Pa

rent

eral

A

ntic

oagu

latio

n

Ris

k D

iffer

ence

W

ith P

aren

tera

l A

ntic

oagu

latio

n (9

5% C

I)

Mor

talit

y (im

port

ant o

utco

me)

120

(1 s

tudy

), 6

mo

No

seri

ous

risk

of b

ias b

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s c U

ndet

ecte

dM

oder

ate b,

c du

e to

im

prec

isio

n

2/60

(3.3

)1/

60 (1

.7)

RR

0.5

(0

.05-

5.37

)33

per

1,0

0016

few

er

per

1,00

0 (f

rom

31

few

er

to 1

44 m

ore)

Rec

urre

nt V

TE

(cri

tical

out

com

e; a

sses

sed

with

sym

ptom

atic

ext

ensi

on o

r re

curr

ence

)

120

(1 s

tudy

), 6

mo

No

seri

ous

risk

of b

ias b

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s d U

ndet

ecte

dM

oder

ate b,

d du

e to

im

prec

isio

n

12/6

0 (2

0)4/

60 (6

.7)

RR

0.3

3 (0

.11-

0.98

)20

0 pe

r 1,

000

134

few

er

per

1,00

0 (f

rom

4 fe

wer

to

178

few

er)

Maj

or b

leed

ing

(cri

tical

out

com

e)

120

(1 s

tudy

), 6

mo

No

seri

ous

risk

of b

ias b

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s c U

ndet

ecte

dM

oder

ate b,

c du

e to

im

prec

isio

n

3/60

(5)

2/60

(3.3

)R

R 0

.67

(0.1

2-3.

85)

50 p

er 1

,000

16 fe

wer

pe

r 1,

000

(fro

m 4

4 fe

wer

to

142

mor

e)

Bib

liogr

aphy

: Bra

ndje

s et

al. 1 R

R 5

risk

rat

io.

a Bot

h gr

oups

trea

ted

with

ace

noco

umar

ol.

b Stu

dy d

escr

ibed

as

doub

le b

linde

d; o

utco

me

adju

dica

tors

blin

ded.

Non

e of

the

stud

y pa

rtic

ipan

ts w

ere

lost

to fo

llow

-up.

Int

entio

n-to

-tre

at a

naly

sis.

Stu

dy w

as s

topp

ed e

arly

for

bene

fi t.

c CI

incl

udes

val

ues

sugg

estin

g no

eff

ect a

s w

ell a

s va

lues

sug

gest

ing

eith

er a

ppre

ciab

le b

enefi

t or

app

reci

able

har

m.

d Low

num

ber

of e

vent

s ca

used

by

the

earl

y st

oppa

ge o

f the

tria

l.





Tabl

e S2

—[S

ecti

on 2

.4]

Evi

denc

e P

rofi l

e: E

arly

War

fari

n (a

nd S

hort

er D

ura

tion

Hep

arin

) vs

Del

ayed

War

fari

n (a

nd L

onge

r D

ura

tion

Hep

arin

) fo

r A

cute

VT

E a-d

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Stud

y E

vent

Rat

es (%

)

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

s

Ove

rall

Qua

lity

of

Evi

denc

e

With

Del

ayed

W

arfa

rin

Initi

atio

n (a

nd L

onge

r D

urat

ion

Hep

arin

)

With

Ear

ly

War

fari

n In

itiat

ion

(and

Sho

rter

D

urat

ion

Hep

arin

)

Ris

k W

ith

Del

ayed

W

arfa

rin

Initi

atio

n (a

nd

Lon

ger D

urat

ion

Hep

arin

)

Ris

k D

iffer

ence

W

ith E

arly

W

arfa

rin

Initi

atio

n (a

nd S

hort

er

Dur

atio

n H

epar

in)

(95%

CI)

Mor

talit

y (im

port

ant o

utco

me e )

688

(3 s

tudi

es),

3 m

o f N

o se

riou

s ri

sk

of b

ias g

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s h U

ndet

ecte

dM

oder

ate g,

h du

e to

im

prec

isio

n

13/3

38 (3

.8)

12/3

50 (3

.4)

RR

0.9

(0

.41-

1.95

)24

per

1,0

00 i

2 fe

wer

pe

r 1,

000

(fro

m 1

4 fe

wer

to

23

mor

e)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

688

(3 s

tudi

es),

3 m

o f N

o se

riou

s ri

sk

of b

ias g

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s h U

ndet

ecte

dM

oder

ate g,

h du

e to

im

prec

isio

n

14/3

38 (4

.1)

12/3

50 (3

.4)

RR

0.8

3 (0

.4-1

.74)

47 p

er 1

,000

i 8

few

er

per

1,00

0 (f

rom

28

few

er

to 3

5 m

ore)

Maj

or b

leed

ing

(cri

tical

out

com

e)

688

(3 s

tudi

es),

3 m

o j N

o se

riou

s ri

sk

of b

ias g,

k N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

No

seri

ous

impr

ecis

ion l

Und

etec

ted

Hig

h g,k,

l 10

/338

(3.0

)15

/350

(4.3

)R

R 1

.48

(0.6

8-3.

23)

16 p

er 1

,000

i 14

mor

e pe

r 1,

000

(fro

m 9

few

er

to 6

6 m

ore)

Bib

liogr

aphy

: Gal

lus

et a

l, 2 H

ull e

t al

, 3 L

eroy

er e

t al

. 4 E

xclu

ded

Moh

iudd

in e

t al

5 be

caus

e 34

% o

f su

bjec

ts h

ad m

ural

thr

ombu

s ra

ther

tha

n V

TE

, in

addi

tion

to

maj

or m

etho

dolo

gic

limit

atio

ns).

LM

WH

5 lo

w-m

olec

ular

-wei

ght h

epar

in; P

E 5

pul

mon

ary

embo

lism

; UF

H 5

unf

ract

iona

ted

hepa

rin;

VK

A 5

vita

min

K a

ntag

onis

t. Se

e Ta

ble

S1 le

gend

for

expa

nsio

n of

oth

er a

bbre

viat

ion.

a V

KA

ther

apy

star

ted

with

in 1

day

of s

tart

ing

hepa

rin

ther

apy

(UF

H in

two

stud

ies

and

LM

WH

in o

ne s

tudy

). b V

KA

ther

apy

dela

yed

for

4 to

10

d.

c Mos

t pat

ient

s ha

d pr

oxim

al D

VT,

som

e ha

d is

olat

ed d

ista

l DV

T; m

ost D

VT

wer

e sy

mpt

omat

ic (a

sym

ptom

atic

DV

T in

clud

ed in

Hul

l et a

l), a

nd fe

w h

ad P

E (o

nly

incl

uded

in G

allu

s et

al).

d T

he e

arly

initi

atio

n of

VK

A w

as a

ssoc

iate

d w

ith a

low

er n

umbe

r of

day

s of

hep

arin

ther

apy

(4.1

vs

9.5

in G

allu

s et

al;

5 vs

10

in H

ull e

t al)

and

a lo

wer

num

ber

of d

ays

of h

ospi

tal s

tay

(9.1

vs

13.0

in G

allu

s;

11.7

vs

14.7

in H

ull;

11.9

vs

16.0

in L

eroy

er e

t al).

e D

iffer

ence

s in

dea

th, i

ndep

ende

ntly

of d

iffer

ence

s in

rec

urre

nt V

TE

and

maj

or b

leed

ing,

is u

nlik

ely.

f O

utco

me

asse

ssm

ent w

as a

t hos

pita

l dis

char

ge in

the

stud

y by

Gal

lus

et a

l (al

thou

gh th

ere

was

als

o ex

tend

ed fo

llow

-up)

and

3 m

o in

the

stud

ies

by H

ull e

t al a

nd L

eroy

er e

t al.

g Pat

ient

s an

d in

vest

igat

ors

wer

e no

t blin

ded

in tw

o st

udie

s (G

allu

s et

al a

nd L

eroy

er e

t al)

and

wer

e bl

inde

d in

one

stu

dy (H

ull e

t al)

. Con

ceal

men

t was

not

cle

arly

des

crib

ed b

ut w

as p

roba

ble

in th

e th

ree

stud

ies.

Pri

mar

y ou

tcom

e ap

pear

s to

hav

e be

en a

sses

sed

afte

r a

shor

ter

dura

tion

of f

ollo

w-u

p in

the

sho

rter

tre

atm

ent

arm

of

one

stud

y be

caus

e of

ear

lier

disc

harg

e fr

om t

he h

ospi

tal,

and

20%

of

subj

ects

in th

is s

tudy

wer

e ex

clud

ed fr

om th

e fi n

al a

naly

sis

post

rand

omiz

atio

n (G

allu

s).

h The

95%

CI

on r

elat

ive

effe

ct in

clud

es b

oth

clin

ical

ly im

port

ant b

enefi

t an

d cl

inic

ally

impo

rtan

t har

m.

i Eve

nt r

ate

corr

espo

nds

to th

e m

edia

n ev

ent r

ate

in th

e in

clud

ed s

tudi

es.

j Ble

edin

g w

as a

sses

sed

earl

y (in

hos

pita

l or

in th

e fi r

st 1

0 d)

in tw

o st

udie

s (G

allu

s et

al,

Hul

l et a

l) an

d at

3 m

o in

one

stu

dy (L

eroy

er e

t al).

k I

t is u

ncle

ar w

heth

er b

leed

ing

was

ass

esse

d at

10

d in

all

subj

ects

or j

ust w

hile

hep

arin

was

bei

ng a

dmin

iste

red,

whi

ch c

ould

yie

ld a

bia

sed

estim

ate

in fa

vor o

f sho

rt-d

urat

ion

ther

apy

in o

ne st

udy

(Hul

l et a

l).

l Bec

ause

the

shor

ter

dura

tion

of h

epar

in th

erap

y is

ver

y un

likel

y to

incr

ease

ble

edin

g, th

e w

ide

95%

CIs

aro

und

the

rela

tive

effe

ct o

f sho

rter

ther

apy

on r

isk

of b

leed

ing

is n

ot a

maj

or c

once

rn.





Tabl

e S3

—[S

ecti

on 2

.5.1

] E

vide

nce

Pro

fi le:

LM

WH

vs

SC U

FH

for

Ini

tial

Ant

icoa

gula

tion

of

Acu

te V

TE

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

eW

ith S

C U

FH

With

LM

WH

Rel

ativ

e E

ffec

t (9

5% C

I)R

isk

With

SC

U

FH

Ris

k D

iffer

ence

W

ith L

MW

H

(95%

CI)

Mor

talit

y (im

port

ant o

utco

me)

1,56

6 (3

stu

dies

), 3

mo

No

seri

ous

risk

of b

ias a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s b U

ndet

ecte

dM

oder

ate a,

b du

e to

im

prec

isio

n

31/7

80 (4

)34

/786

(4.3

)R

R 1

.1

(0.6

8-1.

76)

33 p

er 1

,000

c 3

mor

e pe

r 1,

000

(fro

m 1

1 fe

wer

to

25

mor

e)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

1,56

3 (3

stu

dies

), 3

mo

No

seri

ous

risk

of b

ias a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s b U

ndet

ecte

dM

oder

ate a,

b du

e to

im

prec

isio

n

31/7

77 (4

)26

/786

(3.3

)R

R 0

.87

(0.5

2-1.

45)

42 p

er 1

,000

c 5

few

er

per

1,00

0 (f

rom

20

few

er

to 1

9 m

ore)

Maj

or b

leed

ing

(cri

tical

out

com

e)

1,63

4 (4

stu

dies

), 3

mo

No

seri

ous

risk

of b

ias a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s b U

ndet

ecte

dM

oder

ate b,

c du

e to

im

prec

isio

n

15/8

15 (1

.8)

19/8

19 (2

.3)

RR

1.2

7 (0

.56-

2.9)

16 p

er 1

,000

c 4

mor

e pe

r 1,

000

(fro

m 7

few

er

to 3

0 m

ore)

Bib

liogr

aphy

: Lop

aciu

k et

al, 21

Fai

vre

et a

l, 2 Pra

ndon

i et a

l, 23 K

earo

n et

al. 24

SC

5 su

bcut

aneo

us. S

ee T

able

S1

and

S2 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a In

the

two

larg

est t

rial

s (P

rand

oni e

t al a

nd K

earo

n et

al,

87%

of p

atie

nts)

, allo

catio

n w

as c

once

aled

, out

com

e ad

judi

cato

rs a

nd d

ata

anal

ysts

wer

e co

ncea

led,

ana

lysi

s w

as in

tent

ion

to tr

eat,

and

ther

e w

ere

no lo

sses

to fo

llow

-up.

b P

reci

sion

judg

ed fr

om th

e pe

rspe

ctiv

e of

whe

ther

SC

hep

arin

is n

onin

feri

or to

LM

WH

. The

tota

l num

ber

of e

vent

s an

d th

e to

tal n

umbe

r of

par

ticip

ants

are

rel

ativ

ely

low

. c E

vent

rat

e co

rres

pond

s to

the

med

ian

even

t rat

e in

the

incl

uded

stu

dies

.





Tabl

e S4

—[S

ecti

on 2

.5.1

] L

MW

H v

s SC

UF

H f

or I

niti

al A

ntic

oagu

lati

on o

f A

cute

VT

E: C

lini

cal

Des

crip

tion

and

Res

ult

s

Aut

hor/

Year

(Acr

onym

)In

terv

entio

nsPa

tient

s A

naly

zed a

Rec

urre

nt D

VT

or

PEM

ajor

Ble

edin

gTo

tal M

orta

lity

Com

men

ts

Lop

aciu

k et

al 21

/199

2U

FH

5,0

00 u

nits

IV

follo

wed

by

250

uni

ts/k

g SC

bid

in

itial

ly a

nd a

djus

ted

to

aPT

T fo

r 10

d

72/7

51/

72 (1

.4%

)1/

72 (1

.4%

)3/

72 (4

.2%

)Po

pula

tion:

Fem

oral

DV

T in

81

% a

nd p

oplit

eal o

r m

ore

dist

al D

VT

in 1

9%. P

rim

ary

outc

ome

was

rep

eat

veno

grap

hy.

F

raxi

pari

ne 9

7 In

tern

atio

nal

Uni

ts/k

g SC

bid

for

10 d

74/7

40/

74 R

R 3

.1 (0

.1-7

.5)

0/74

RR

3.1

(0.1

-7.5

)0/

74R

R 7

.2 (0

.4-1

37)

Fai

vree

t al 22

/198

8U

FH

5,0

00 u

nits

IV

follo

wed

by

250

uni

ts/k

g SC

bid

and

adj

uste

d to

aP

TT

for

10 d

29/3

51/

353/

351/

35Po

pula

tion:

DV

T (p

ropo

rtio

n of

pro

xim

al a

nd d

ista

l not

re

port

ed).

Prim

ary

outc

ome

was

rep

eat v

enog

raph

y.

C

Y222

2,0

00 I

nter

natio

nal

Uni

ts I

V fo

llow

ed b

y 15

0 In

tern

atio

nal U

nits

/kg

SC b

id fo

r 10

d

30/3

31/

33 R

R 0

.9 (0

.1-1

4.5)

0/33

RR

6.6

(0.3

-123

)0/

33 R

R 2

.8 (0

.1-6

7)

Pran

doni

et a

l 23 /2

004

(Gal

ilei)

UF

H I

V ( ,

50

kg: 4

,000

uni

ts;

50-7

0 kg

: 5,0

00 u

nits

; .

70

kg: 6

,000

uni

ts)

follo

wed

by

SC b

id d

oses

(in

itial

ly ,

50

kg: 1

2,50

0 un

its;

50-7

0 kg

: 15,

000

units

; .

70

kg: 1

7,50

0 un

its)

adju

sted

to a

PTT

fo

r �

6.5

d

360/

360

15/3

60 (4

.2%

)5/

360

(1.4

%)

12/3

60 (3

.3%

)Po

pula

tion:

Pro

xim

al D

VT

in

65%

, dis

tal D

VT

in 1

8%,

and

PE in

17%

.

N

adro

parin

85

Inte

rnat

iona

l U

nits

/kg

SC b

id fo

r � 6.

5 d

360/

360

14/3

60 (3

.9%

) RR

1.1

(0

.5-2

.2)

7/36

0 (1

.9%

) RR

0.7

(0

.2-2

.2)

12/3

60 (3

.3%

) RR

1.0

(0.5

-2.2

)

Kea

ron

et a

l 24 /2

006

(FID

O)

UF

H 3

33 u

nits

/kg

SC

follo

wed

by

250

units

/kg

SC b

id (n

o ad

just

men

t)

for

6.3

d

345/

355

13/3

45 (3

.8%

)6/

348

(1.7

%)

18/3

48 (5

.2%

)Po

pula

tion:

Pro

xim

al D

VT

in

77%

, asy

mpt

omat

ic o

r di

stal

D

VT

in 4

%, a

nd P

E in

19%

. Se

vent

y pe

rcen

t of p

atie

nts

wer

e tr

eate

d en

tirel

y as

an

outp

atie

nt (7

6% o

f DV

T

and

39%

of P

E) P

ostr

an-

dom

izat

ion

excl

usio

ns in

10

pat

ient

s re

ceiv

ing

UF

H

and

one

patie

nt r

ecei

ving

L

MW

H.

D

alte

pari

n (n

5 2

61)

or e

noxa

pari

n (n

5 9

1)

100

Inte

rnat

iona

l Uni

ts/k

g SC

bid

for

7.1

d

352/

353

12/3

52 (3

.4%

) RR

1.1

(0

.5-2

.3)

12/3

52 (3

.4%

) RR

0.5

(0

.2-1

.3)

22/3

52 (6

.3%

) RR

0.8

(0.4

-1.5

)

aPT

T 5

activ

ated

pro

thro

mbi

n tim

e; F

IDO

5 F

ixed

Dos

e H

epar

in. S

ee T

able

S1

and

S2 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a Fol

low

-up

was

for

3 m

o ex

cept

for

the

stud

y by

Fai

vre

et a

l 22 in

whi

ch it

was

10

d.





Tabl

e S5

—[S

ecti

on 2

.5.1

] L

MW

H v

s SC

UF

H f

or I

niti

al A

ntic

oagu

lati

on o

f A

cute

VT

E: M

etho

dolo

gic

Qu

alit

y

Aut

hor/

Year

(Acr

onym

)In

terv

entio

nsSt

udy

Des

ign

Ran

dom

izat

ion

Con

ceal

edB

lindi

ngL

oss

to F

ollo

w-u

pA

naly

sis

Com

men

ts

Lop

aciu

k et

al 21

/199

2U

FH

5,0

00 u

nits

IV

follo

wed

by

250

units

/kg

SC b

id in

itial

ly a

nd

adju

sted

to a

PTT

for

10 d

RC

TPY

Patie

nts:

CN

Car

egiv

ers:

CN

Adj

udic

ator

s: C

ND

ata

Ana

lyst

s: P

N

Not

des

crib

edIT

T

F

raxi

pari

ne 9

7 In

tern

atio

nal

units

/kg

SC b

id fo

r 10

d

Fai

vre

et a

l 22 /1

988

UF

H 5

,000

uni

ts I

V fo

llow

ed b

y 25

0 un

its/k

g SC

bid

and

ad

just

ed to

aPT

T fo

r 10

d

RC

TPN

Patie

nts:

PN

Car

egiv

ers:

PN

Adj

udic

ator

s: P

ND

ata

Ana

lyst

s: P

N

Thr

ee o

f CY2

22 g

roup

and

six

of

UF

H g

roup

who

did

not

ha

ve r

epea

t ven

ogra

phy

are

assu

med

to h

ave

com

plet

ed

clin

ical

follo

w-u

p

ITT

CY2

22 2

,000

Int

erna

tiona

l Uni

ts

IV fo

llow

ed b

y 15

0 In

tern

atio

nal

Uni

ts/k

g SC

bid

for

10 d

Pran

doni

et a

l 23 /2

004

(Gal

ilei)

UF

H I

V ( ,

50

kg: 4

,000

uni

ts;

50-7

0 kg

: 5,0

00 u

nits

; . 7

0 kg

: 6,

000

units

) fol

low

ed b

y SC

bid

do

ses

(initi

ally

, 5

0 kg

: 12,

500

units

; 50-

70 k

g: 1

5,00

0 un

its;

. 7

0 kg

: 17,

500

units

) adj

uste

d to

aPT

T fo

r �

6.5

d

RC

TC

YPa

tient

s: C

NC

areg

iver

s: C

NA

djud

icat

ors:

CY

Dat

a A

naly

sts:

PY

Nil

ITT

Nad

ropa

rin

85 I

nter

natio

nal

Uni

ts/k

g SC

bid

for

� 6

.5 d

Kea

ron

et a

l 24 /2

006

(FID

O)

UF

H 3

33 u

nits

/kg

SC fo

llow

ed

by 2

50 u

nits

/kg

SC b

id (n

o ad

just

men

t) fo

r 6.

3 d

RC

TC

YPa

tient

s: C

NC

areg

iver

s: C

NA

djud

icat

ors:

CY

Dat

a A

naly

sts:

PY

Nil

ITT

Post

rand

omiz

atio

n ex

clus

ions

fr

om th

e ef

fi cac

y an

alys

is

wer

e 10

(2.8

%) f

or th

e U

FH

an

d on

e (0

.2%

) for

the

LM

WH

gro

up.

Dal

tepa

rin

(n 5

261

) or

enox

apar

in

(n 5

91)

100

Int

erna

tiona

l U

nits

/kg

SC b

id fo

r 7.

1 d

CN

5 ce

rtai

nly

no;

CY

5 ce

rtai

nly

yes;

IT

T 5

inte

ntio

n to

tre

at;

PN 5

pro

babl

y no

; PY

5 p

roba

bly

yes;

RC

T 5

rand

omiz

ed c

ontr

olle

d tr

ial.

See

Tabl

e S1

, S2

, an

d S4

leg

ends

for

exp

ansi

on o

f ot

her

abbr

evia

tions

.





Tabl

e S6

—[S

ecti

on 2

.5.1

] E

vide

nce

Pro

fi le:

LM

WH

vs

IV U

FH

for

Ini

tial

Ant

icoa

gula

tion

of

Acu

te V

TE

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

B

ias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nPu

blic

atio

n B

ias

Ove

rall

Qua

lity

of

Evi

denc

eW

ith I

V U

FH

With

LM

WH

Rel

ativ

e E

ffec

t (9

5% C

I)R

isk

With

IV

U

FH

Risk

Diff

eren

ce W

ith

LM

WH

(95%

CI)

Mor

talit

y (im

port

ant o

utco

me)

7,90

8 (1

7 st

udie

s),

3 m

o

Seri

ous a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssN

o se

riou

s im

prec

isio

nR

epor

ting

bias

st

rong

ly

susp

ecte

d b

Low

a,b d

ue to

ri

sk o

f bia

s,

publ

icat

ion

bias

232/

3,78

9 (6

.1)

187/

4,11

9 (4

.5)

RR

0.7

9 (0

.66-

0.95

)46

per

1,0

00 c

10 fe

wer

per

1,0

00

(fro

m 2

few

er to

16

few

er)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

7,97

6 (1

7 st

udie

s),

3 m

o

Seri

ous a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssN

o se

riou

s im

prec

isio

nR

epor

ting

bias

st

rong

ly

susp

ecte

d b

Low

a,b d

ue to

ri

sk o

f bia

s,

publ

icat

ion

bias

208/

3,86

9 (5

.4)

151/

4,10

7 (3

.7)

RR

0.7

2 (0

.58-

0.89

)55

per

1,0

00 c

15 fe

wer

per

1,0

00

(fro

m 6

few

er to

23

few

er)

Maj

or b

leed

ing

(cri

tical

out

com

e)

6,91

0 (2

0 st

udie

s),

3 m

o

Seri

ous a

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssN

o se

riou

s im

prec

isio

n d R

epor

ting

bias

st

rong

ly

susp

ecte

d b

Low

a,b,

d due

to

risk

of b

ias,

pu

blic

atio

n bi

as

69/3

,517

(2)

41/3

,393

(1.2

)R

R 0

.67

(0.4

5-1)

15 p

er 1

,000

c 5

few

er p

er 1

,000

(f

rom

8 fe

wer

to 0

m

ore)

Bib

liogr

aphy

: van

Don

gen

et a

l. 6 Inc

lude

d st

udie

s. 7,

20 S

ee T

able

S1

and

S2 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a O

f the

20

tria

ls, a

lloca

tion

was

con

ceal

ed in

nin

e an

d w

as u

ncle

ar w

heth

er c

once

aled

in th

e re

mai

ning

11.

Eig

htee

n tr

ials

had

blin

ded

outc

ome

asse

ssor

s. S

even

tria

ls d

id n

ot h

ave

any

post

rand

omiz

atio

n ex

clus

ions

or

loss

es to

follo

w-u

p. T

en tr

ials

rep

orte

d th

e nu

mbe

r of

par

ticip

ants

lost

to fo

llow

-up,

whi

ch r

ange

d fr

om 1

.0%

to 1

2.7%

. One

tria

l did

not

rep

ort t

he d

rop-

outs

. b I

nver

ted

funn

el p

lot v

ery

sugg

estiv

e of

pub

licat

ion

bias

. Man

y of

the

incl

uded

stu

dies

are

of s

mal

l siz

e, a

nd a

ll ar

e fu

nded

by

indu

stry

. c E

vent

rat

e co

rres

pond

s to

the

med

ian

even

t rat

e in

the

incl

uded

stu

dies

. d C

I in

terv

al in

clud

es v

alue

s su

gges

ting

sign

ifi ca

nt b

enefi

t an

d no

eff

ect.





Tabl

e S7

—[S

ecti

on 2

.5.1

] E

vide

nce

Pro

fi le:

Fon

dapa

rinu

x vs

LM

WH

for

Ini

tial

Ant

icoa

gula

tion

of

Acu

te D

VT

a-c

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

eW

ith L

MW

HW

ith

Fon

dapa

rinu

xR

elat

ive

Eff

ect

(95%

CI)

Ris

k W

ith

LM

WH

Ris

k D

iffer

ence

W

ith F

onda

pari

nux

(95%

CI)

Mor

talit

y (im

port

ant o

utco

me)

2,20

5 (1

stu

dy),

3 m

oN

o se

riou

s ri

sk

of b

ias d

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s e U

ndet

ecte

dM

oder

ate d,

e due

to

impr

ecis

ion

33/1

,107

(3.0

)41

/1,0

98 (3

.7)

RR

1.2

5 (0

.8-1

.97)

30 p

er 1

,000

7 m

ore

per

1,00

0 (f

rom

6 fe

wer

to

29 m

ore)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

2,20

5 (1

stu

dy),

3 m

oN

o se

riou

s ri

sk

of b

ias d

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s e U

ndet

ecte

dM

oder

ate d,

e due

to

impr

ecis

ion

45/1

,107

(4.1

) f 43

/1,0

98 (3

.9) f

RR

0.9

6 (0

.64-

1.45

)41

per

1,0

00 f

2 fe

wer

per

1,0

00

(fro

m 1

5 fe

wer

to

18

mor

e)

Maj

or b

leed

ing

(cri

tical

out

com

e)

2,20

5 (1

stu

dy),

3 m

oN

o se

riou

s ri

sk

of b

ias d

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s e U

ndet

ecte

dM

oder

ate d,

e due

to

impr

ecis

ion

13/1

,107

(1.2

) g 12

/1,0

98 (1

.1) g

RR

0.9

3 (0

.43-

2.03

)12

per

1,0

00 g

1 fe

wer

per

1,0

00

(fro

m 7

few

er to

12

mor

e)

Bib

liogr

aphy

: Bül

ler

et a

l. 25 I

NR

5 in

tern

atio

nal n

orm

aliz

ed r

atio

. See

Tab

le S

1 an

d S2

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

. a F

onda

pari

nux

7.5

mg

(5.0

mg

in p

atie

nts

wei

ghin

g ,

50

kg a

nd 1

0.0

mg

in p

atie

nts

wei

ghin

g .

100

kg)

SC

onc

e da

ily fo

r at

leas

t 5 d

and

unt

il V

KA

s in

duce

d an

IN

R .

2.0

. E

noxa

pari

n 1

mg/

kg o

f bod

y w

eigh

t SC

bid

for

at le

ast 5

d a

nd u

ntil

VK

As

indu

ced

an I

NR

. 2

.0.

c All

patie

nts

had

acut

e sy

mpt

omat

ic D

VT.

d A

lloca

tion

was

con

ceal

ed. P

atie

nts,

pro

vide

rs, d

ata

colle

ctor

s, a

nd o

utco

me

adju

dica

tors

wer

e bl

inde

d. A

naly

sis

excl

uded

0.6

% o

f ran

dom

ized

pat

ient

s. N

ot s

topp

ed e

arly

for

bene

fi t.

e CI

incl

udes

val

ues

sugg

estin

g no

eff

ect a

nd v

alue

s su

gges

ting

eith

er b

enefi

t or

har

m; r

elat

ivel

y lo

w n

umbe

r of

eve

nts.

f F

ive

fata

l VT

E in

fond

apar

inux

gro

up a

nd fi

ve fa

tal V

TE

in L

MW

H g

roup

. g T

wel

ve p

atie

nts

in th

e fo

ndap

arin

ux g

roup

and

13

in th

e L

MW

H g

roup

had

a m

ajor

ble

edin

g du

ring

the

initi

al p

erio

d (7

d).

Of t

hese

, tw

o in

the

fond

apar

inux

gro

up a

nd n

one

in th

e L

MW

H g

roup

wer

e fa

tal.





Tabl

e S8

—[S

ecti

on 2

.5.2

] E

vide

nce

Pro

fi le:

LM

WH

Onc

e vs

Tw

ice

Dai

ly f

or I

niti

al A

ntic

oagu

lati

on o

f A

cute

VT

E a,b

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

eW

ith B

idW

ith L

MW

H

Onc

eR

elat

ive

Eff

ect

(95%

CI)

Ris

k W

ith B

id

Ris

k D

iffer

ence

W

ith L

MW

H

Onc

e (9

5% C

I)

Mor

talit

y (im

port

ant o

utco

me)

1,26

1 (3

stu

dies

), 3

mo

No

seri

ous

risk

of

bia

s c Se

riou

s d N

o se

riou

s in

dire

ctne

ssSe

riou

s e U

ndet

ecte

dL

ow c-

e due

to

inco

nsis

tenc

y,

impr

ecis

ion

20/6

47 (3

.1)

20/6

14 (3

.3)

RR

1.0

5 (0

.57-

1.94

)31

per

1,0

002

mor

e pe

r 1,

000

(fro

m 1

3 fe

wer

to

29

mor

e)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

1,26

1 (3

stu

dies

), 3

mo

No

seri

ous

risk

of

bia

s c Se

riou

s f N

o se

riou

s in

dire

ctne

ssSe

riou

s e U

ndet

ecte

dL

ow c,

e,f d

ue to

in

cons

iste

ncy,

im

prec

isio

n

32/6

47 (4

.9)

26/6

14 (4

.2)

RR

0.8

6 (0

.52-

1.42

)49

per

1,0

007

few

er p

er 1

,000

(f

rom

24

few

er

to 2

1 m

ore)

Maj

or b

leed

ing

(cri

tical

out

com

e)

1,52

2 (5

stu

dies

), 10

dN

o se

riou

s ri

sk

of b

ias c

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s e U

ndet

ecte

dM

oder

ate c,

e due

to

impr

ecis

ion

9/77

2 (1

.2)

10/7

50 (1

.3)

RR

1.1

3 (0

.48-

2.66

)12

per

1,0

002

mor

e pe

r 1,

000

(fro

m 6

few

er to

20

mor

e)

Bib

liogr

aphy

: van

Don

gen

et a

l. 26 S

ee T

able

S1,

S2,

and

S5

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

. a T

he fi

ve in

clud

ed s

tudi

es u

sed

four

bra

nds

of L

MW

H (e

noxa

pari

n, ti

nzap

arin

, dal

tepa

rin,

and

nad

ropa

rin)

. In

Mer

li et

al,

enox

apar

in 1

mg/

kg b

id w

as c

ompa

red

with

1.5

mg/

kg o

nce

daily

. Hol

mst

röm

27 e

t al

adju

sted

the

dose

to a

nti-X

a le

vels

, whi

ch r

esul

ted

in d

iffer

ent d

aily

dos

es a

fter

a n

umbe

r of

day

s. I

n th

e re

mai

ning

stu

dies

, the

dos

e of

the

once

-dai

ly a

dmin

istr

atio

n w

as d

oubl

e th

e do

se o

f the

twic

e-da

ily

adm

inis

trat

ion

(equ

al to

tal d

aily

dos

e).

b Of t

he fi

ve in

clud

ed s

tudi

es, o

ne in

clud

ed p

atie

nts

with

PE

and

DV

T, a

nd fo

ur in

clud

ed o

nly

patie

nts

with

DV

T. A

ll st

udie

s ad

dres

sed

the

initi

al m

anag

emen

t of V

TE

. c A

ll in

clud

ed s

tudi

es c

once

aled

allo

catio

n. T

wo

stud

ies

had

a do

uble

-blin

d de

sign

, and

two

othe

rs w

ere

sing

le b

lind.

One

stu

dy d

id n

ot m

entio

n bl

indi

ng. I

TT

like

ly u

sed

in a

ll st

udie

s. P

artic

ipan

ts w

ere

lost

to

follo

w-u

p in

onl

y tw

o st

udie

s (0

.3%

and

2.2

%).

d I 2 5

37%

; poi

nt e

ffec

t est

imat

e in

favo

r of

bid

dos

e in

Mer

li et

al 16

and

in fa

vor

of o

nce-

daily

dos

e in

Cha

rbon

nier

et a

l. 28

e Im

prec

isio

n ju

dged

rel

ativ

e to

no

diff

eren

ce.

f I 2 5

65%

; poi

nt e

ffec

t est

imat

e in

favo

r of

bid

dos

e in

Mer

li et

al 16

and

in fa

vor

of o

nce-

daily

dos

e in

Cha

rbon

nier

et a

l. 28





Tabl

e S9

—[S

ecti

on 2

.7]

Evi

denc

e P

rofi l

e: H

ome

Tre

atm

ent

vs H

ospi

tal

Tre

atm

ent

of A

cute

DV

T a-d

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

eW

ith H

ospi

tal

Trea

tmen

tW

ith H

ome

Trea

tmen

t

Rel

ativ

e E

ffec

t (9

5% C

I)

Ris

k W

ith H

ospi

tal

Trea

tmen

t

Ris

k D

iffer

ence

W

ith H

ome

Trea

tmen

t (95

% C

I)

Mor

talit

y (im

port

ant o

utco

me)

1,70

8 (6

stu

dies

), 3

mo

No

seri

ous

risk

of

bia

s e N

o se

riou

s in

cons

iste

ncy

Seri

ous a,

b Se

riou

s f U

ndet

ecte

dL

ow a,

b,e,

f due

to

indi

rect

ness

, im

prec

isio

n

39/8

51 (4

.6)

28/8

57 (3

.3)

RR

0.7

2 (0

.45-

1.15

)46

per

1,0

0013

few

er p

er 1

,000

(f

rom

25

few

er to

7

mor

e)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

1,70

8 (6

stu

dies

), 3

mo

No

seri

ous

risk

of

bia

s e N

o se

riou

s in

cons

iste

ncy

Seri

ous a,

b N

o se

riou

s im

prec

isio

nU

ndet

ecte

dM

oder

ate a,

b,e d

ue

to in

dire

ctne

ss63

/851

(7.4

)39

/857

(4.6

)R

R 0

.61

(0.4

2-0.

9)74

per

1,0

0029

few

er p

er 1

,000

(f

rom

7 fe

wer

to

43 fe

wer

)

Maj

or b

leed

ing

(cri

tical

out

com

e)

1,70

8 (6

stu

dies

), 3

mo

No

seri

ous

risk

of

bia

s e N

o se

riou

s in

cons

iste

ncy

Seri

ous a,

b Se

riou

sfU

ndet

ecte

dM

oder

ate a,

b,e,

g du

e to

in

dire

ctne

ss

18/8

51 (2

.1)

12/8

57 (1

.4)

RR

0.6

7 (0

.33-

1.36

)21

per

1,0

007

few

er p

er 1

,000

(f

rom

14

few

er to

8

mor

e)

Qua

lity

of li

fe (i

mpo

rtan

t out

com

e)

0 (3

stu

dies

h ),

3 m

oN

o se

riou

s ri

sk

of b

ias

No

seri

ous

inco

nsis

tenc

y i Se

riou

s j Se

riou

skU

ndet

ecte

dL

ow i-k

due

to

indi

rect

ness

, im

prec

isio

n

……

Not

poo

led

See

com

men

th-k

See

com

men

th-k

Bib

liogr

aphy

: Oth

ieno

et a

l 29 ; i

nclu

ded

stud

ies.

13,1

4,30

-33 Q

ualit

y of

life

. 13,3

4,35

See

Tab

le S

1 an

d S2

for

expa

nsio

n of

abb

revi

atio

ns.

a Fou

r stu

dies

had

par

tial h

ospi

tal t

reat

men

t of m

any

in th

e ho

me

arm

: Koo

pman

et a

l (m

ean

hosp

ital s

tay

2.7

in h

ome

arm

vs 8

.1 d

in h

ospi

tal a

rm),

Lev

ine

et a

l (2.

1 vs

6.5

d),

Boc

calo

n et

al (

1 vs

9.6

d),

and

Ram

acci

otti

et a

l (3

vs 7

d).

In D

aska

lopo

ulos

et a

l, th

ere

was

no

hosp

ital s

tay

at a

ll in

the

hom

e gr

oup.

Cho

ng e

t al d

id n

ot r

epor

t dur

atio

n of

hos

pita

l sta

y.

b Onl

y on

e st

udy

(Boc

calo

n et

al)

used

LM

WH

in b

oth

trea

tmen

t arm

s. R

emai

ning

stu

dies

use

d U

FH

in th

e in

patie

nt a

rm a

nd L

MW

H in

the

outp

atie

nt a

rm.

c Stu

dies

incl

uded

in th

e sy

stem

atic

rev

iew

sho

uld

have

rec

ruite

d pa

tient

s w

hose

hom

e ci

rcum

stan

ces

wer

e ad

equa

te.

d All

stud

ies

incl

uded

pat

ient

s w

ith lo

wer

-ext

rem

ity D

VT

and

exc

lude

d pa

tient

s w

ith s

uspe

cted

or

confi

rm

ed P

E. S

tudi

es a

lso

excl

uded

pat

ient

s w

ho w

ere

preg

nant

. e O

ut o

f six

stu

dies

, allo

catio

n w

as c

lear

ly c

once

aled

in th

ree

(unc

lear

in r

emai

ning

thre

e). O

utco

me

adju

dica

tors

wer

e bl

inde

d in

the

two

larg

est s

tudi

es (u

ncle

ar in

rem

aini

ng).

Fou

r re

port

ed lo

ss to

follo

w-u

p (w

as s

igni

fi can

t in

onl

y a

smal

l stu

dy).

ITT

ana

lysi

s w

as c

ondu

cted

in f

our

(unc

lear

in r

emai

ning

tw

o). N

o st

udy

was

sto

pped

ear

ly f

or b

enefi

t. O

vera

ll, t

he ju

dgm

ent

was

tha

t th

ese

limita

tions

wou

ld n

ot

war

rant

dow

ngra

ding

of q

ualit

y be

caus

e it

has

alre

ady

been

dow

ngra

ded

by a

t lea

st o

ne le

vel b

ased

on

othe

r fa

ctor

s.

f The

CI

incl

udes

bot

h va

lues

sug

gest

ing

bene

fi t a

nd h

arm

. g J

udge

d as

pre

cise

bas

ed o

n th

e na

rrow

CI

arou

nd a

bsol

ute

effe

ct.

h Bäc

kman

et

al 34

rep

orte

d ev

alua

tion

of h

ealth

-rel

ated

qua

lity

of li

fe u

sing

the

EQ

-5D

. The

y fo

und

no d

iffer

ence

s in

mea

n qu

ality

-of-

life

scor

es o

r in

the

pro

port

ion

of p

atie

nts

show

ing

impr

ovem

ent

in

self-

rate

d he

alth

sta

te. K

oopm

an e

t al e

valu

ated

hea

lth-r

elat

ed q

ualit

y of

life

usi

ng th

e M

edic

al O

utco

me

Stud

y Sh

ort F

orm

-20

and

an a

dapt

ed v

ersi

on o

f the

Rot

terd

am S

ympt

om C

heck

list.

The

cha

nges

ov

er ti

me

wer

e si

mila

r in

bot

h gr

oups

exc

ept t

hat t

he p

atie

nts

rece

ivin

g L

MW

H h

ad b

ette

r sc

ores

for

phys

ical

act

ivity

( P

5 .0

02)

and

soci

al fu

nctio

ning

( P

5 .0

01)

at th

e en

d of

the

initi

al tr

eatm

ent.

The

au

thor

s di

d no

t rep

ort e

noug

h da

ta to

ass

ess

prec

isio

n an

d cl

inic

al s

igni

fi can

ce o

f res

ults

. O’B

rien

et a

l 35 a

sses

sed

chan

ges

in q

ualit

y of

life

usi

ng th

e M

edic

al O

utco

me

Stud

y Sh

ort F

orm

-36

in 3

00 p

atie

nts

part

icip

atin

g in

Lev

ine

et a

l. 14 T

hey

foun

d th

at, t

he c

hang

e in

sco

res

from

bas

elin

e to

day

7 w

as n

ot s

igni

fi can

tly d

iffer

ent b

etw

een

the

trea

tmen

t gro

ups

for

seve

n of

the

eigh

t dom

ains

. The

one

exc

eptio

n w

as th

e do

mai

n of

soc

ial f

unct

ioni

ng, w

here

a g

reat

er im

prov

emen

t was

obs

erve

d fo

r th

e ou

tpat

ient

gro

up.

i Pot

entia

l inc

onsi

sten

cy a

s B

äckm

an e

t al 34

sho

wed

no

effe

ct, w

here

as K

oopm

an e

t al 13

and

O’B

rien

et a

l 35 s

how

ed p

oten

tial b

enefi

t.

j Tw

o of

the

thre

e st

udie

s ha

d pa

rtia

l hos

pita

l tre

atm

ent o

f man

y in

the

hom

e ar

m: K

oopm

an e

t al 13

(mea

n ho

spita

l sta

y 2.

7 in

hom

e ar

m v

s 8.

1 d

in h

ospi

tal a

rm) a

nd L

evin

e et

al (

2.1

vs 6

.5 d

). k N

ot a

ble

to e

valu

ate

but i

mpr

ecis

ion

is p

ossi

ble.

Tak

en to

geth

er w

ith th

e po

tent

ial i

ncon

sist

ency

, we

dow

ngra

ded

the

qual

ity o

f evi

denc

e by

one

leve

l.




Tabl

e S1

0 —[S

ecti

on 2

.9]

Evi

denc

e P

rofi l

e: C

athe

ter-

Dir

ecte

d T

hrom

bol

ysis

vs

No

Cat

hete

r-D

irec

ted

Thr

omb

olys

is f

or E

xten

sive

Acu

te D

VT

of

the

Leg

ab

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Cat

hete

r-D

irec

ted

Thr

ombo

lysis

With

Cat

hete

r-D

irec

ted

Thr

ombo

lysi

sR

elat

ive

Eff

ect

(95%

CI)

Ris

k W

ith N

o C

athe

ter-

Dir

ecte

d T

hrom

boly

sis

Ris

k D

iffer

ence

W

ith C

athe

ter-

Dir

ecte

d T

hrom

boly

sis

(95%

CI)

Mor

talit

y (im

port

ant o

utco

me)

153

(2 s

tudi

es),

3 m

oN

o se

riou

s ri

sk

of b

ias c

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssVe

ry s

erio

us d

Und

etec

ted

Low

c,d d

ue to

im

prec

isio

n3/

76 (3

.9) e

0/77

(0)

RR

0.1

4

(0.0

1-2.

71)

39 p

er 1

,000

e 34

few

er p

er 1

,000

(f

rom

39

few

er to

67

mor

e)

Non

fata

l rec

urre

nt V

TE

(cri

tical

out

com

e)

153

(1 s

tudy

), 3

mo

No

seri

ous

risk

of

bia

s c N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Very

ser

ious

d U

ndet

ecte

dL

ow c,

d due

to

impr

ecis

ion

1/76

(1.3

)0/

77 (0

)R

R 0

.35

(0

-8.0

9)48

per

1,0

00 f

31 fe

wer

per

1,0

00

(fro

m 4

8 fe

wer

to

340

mor

e)

Non

fata

l maj

or b

leed

ing

(cri

tical

out

com

e)

153

(2 s

tudi

es),

7 d

No

seri

ous

risk

of

bia

s c N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Very

ser

ious

d U

ndet

ecte

dL

ow c,

d due

to

impr

ecis

ion

0/76

(0)

1/77

(1.3

) g R

R 2

.00

(0

.19-

19.4

6)29

per

1,0

00 f,h

29

mor

e pe

r 1,

000

(fro

m 2

3 fe

wer

to

535

mor

e)

Post

thro

mbo

tic s

yndr

ome

(cri

tical

out

com

e; a

sses

sed

with

: com

plet

e ly

sis

on v

enog

raph

y (E

lsha

raw

y et

al);

pat

ency

on

ultr

asou

nd a

nd a

ir p

leth

ysm

ogra

phy

(End

en e

t al))

138

(2 s

tudi

es),

2 y

No

seri

ous

risk

of

bia

s c N

o se

riou

s in

cons

iste

ncy

Seri

ous i

No

seri

ous

impr

ecis

ion

Und

etec

ted

Mod

erat

e c,i d

ue

to in

dire

ctne

ss49

/70

(70)

23/6

8 (3

3.8)

RR

0.4

6

(0-0

.79)

588

per

1,00

0 j 31

8 fe

wer

per

1,0

00

(fro

m 1

23 fe

wer

to

588

few

er) k

(Con

tinu

ed)




Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Cat

hete

r-D

irec

ted

Thr

ombo

lysis

With

Cat

hete

r-D

irec

ted

Thr

ombo

lysi

sR

elat

ive

Eff

ect

(95%

CI)

Ris

k W

ith N

o C

athe

ter-

Dir

ecte

d T

hrom

boly

sis

Ris

k D

iffer

ence

W

ith C

athe

ter-

Dir

ecte

d T

hrom

boly

sis

(95%

CI)

Qua

lity

of li

fe (i

mpo

rtan

t out

com

e; m

easu

red

with

the

Med

ical

Out

com

e Su

rvey

Sho

rt F

orm

-12,

Hea

lth U

tiliti

es I

ndex

MA

RK

ver

sion

2/3

que

stio

nnai

res;

bet

ter

indi

cate

d by

low

er v

alue

s)

98 (1

stu

dy l ),

16

mo

No

seri

ous

risk

of

bia

s m,n

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssN

o se

riou

s im

prec

isio

nU

ndet

ecte

dL

ow m

,n

3068

...Se

e fo

otno

te o

Bib

liogr

aphy

: Els

hara

wy

et a

l, 36 E

nden

et a

l, 37 C

omer

ota

et a

l. 38 C

DT

5 ca

thet

er-d

irec

ted

thro

mbo

lysi

s; P

TS

5 p

ostt

hrom

botic

syn

drom

e. S

ee T

able

S1

lege

nd fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a All

patie

nts

wer

e an

ticoa

gula

ted

per

prot

ocol

, but

the

inte

rven

tion

grou

p re

ceiv

ed C

DT

in a

dditi

on to

ant

icoa

gula

tion.

b I

n se

lect

ed p

atie

nts

with

ext

ensi

ve a

cute

pro

xim

al D

VT

(eg,

ilio

fem

oral

DV

T, s

ympt

oms

for

, 1

4 d,

goo

d fu

nctio

nal s

tatu

s, li

fe e

xpec

tanc

y �

1 y

) who

hav

e a

low

ris

k of

ble

edin

g .

c Allo

catio

n w

as c

once

aled

in E

nden

et

al a

nd u

ncle

ar in

Els

hara

wy

et a

l. O

utco

me

asse

ssor

blin

ded

in b

oth

stud

ies.

Fol

low

-up

rate

s w

ere

87%

in E

nden

et

al a

nd 1

00%

in E

lsha

raw

y et

al.

Non

e of

the

st

udie

s w

as s

topp

ed e

arly

for

bene

fi t.

d CI

incl

udes

val

ues

sugg

estin

g bo

th b

enefi

t an

d ha

rm.

e Thr

ee c

ontr

ol p

atie

nts

died

of c

ance

r. f B

asel

ine

risk

s fo

r no

nfat

al r

ecur

rent

VT

E a

nd fo

r m

ajor

ble

edin

g de

rive

d fr

om D

ouke

tis e

t al. 39

g I

n th

e E

nden

et a

l stu

dy, o

ne p

atie

nt h

ad “

dura

ble

and

part

ial i

mpa

irm

ent o

f sen

sibi

lity

of th

e fo

ot”

imm

edia

tely

aft

er r

ecei

ving

CD

T, a

nd n

ine

patie

nts

had

min

or b

leed

ing

com

plic

atio

ns.

h Mos

t of b

leed

ing

even

ts o

ccur

dur

ing

the

fi rst

7 d

. i S

urro

gate

out

com

e: a

bsen

ce o

f pat

ency

at 6

mo

in E

nden

et a

l stu

dy; a

bsen

ce o

f com

plet

e ly

sis

at 6

mo

in E

lsha

raw

y et

al s

tudy

. j T

his

estim

ate

is b

ased

on

the

fi ndi

ngs

of th

e V

ET

O (V

enou

s T

hrom

bosi

s O

utco

mes

) stu

dy. 40

Thi

s pr

obab

ly u

nder

estim

ates

PT

S ba

selin

e ri

sk g

iven

that

ove

rall,

52%

of p

atie

nts

repo

rted

the

curr

ent u

se o

f co

mpr

essi

on s

tock

ings

dur

ing

stud

y fo

llow

-up.

k S

ever

e PT

S: a

ssum

ing

the

sam

e R

R o

f 0.4

6 an

d a

base

line

risk

of 1

3.8%

, the

abs

olut

e re

duct

ion

is 7

5 fe

wer

sev

ere

PTS

per

1,00

0 (f

rom

29

few

er to

138

few

er) o

ver

2 y.

l C

amer

ota

et a

l. 38

m P

artic

ipat

ion

rate

was

65%

. n R

ecal

l was

use

d to

mea

sure

qua

lity

of li

fe p

rior

to th

e th

rom

botic

eve

nt; w

e di

d no

t con

side

r th

ese

mea

sure

men

ts.

o At t

he in

itial

follo

w-u

p (m

ean,

16

mo)

, pat

ient

s tre

ated

with

CD

T re

port

ed a

tren

d to

war

d a

high

er m

enta

l sum

mar

y sc

ale

( P 5

.087

) and

impr

oved

Hea

lth U

tiliti

es In

dex

( P 5

.078

). T

hey

repo

rted

bet

ter o

vera

ll ro

le p

hysi

cal f

unct

ioni

ng ( P

5 .0

46),

less

stig

ma

( P 5

.033

), le

ss h

ealth

dis

tres

s ( P

5 .0

22),

and

few

er o

vera

ll sy

mpt

oms (

P 5

.006

) com

pare

d w

ith p

atie

nts w

ho w

ere

trea

ted

with

ant

icoa

gula

tion

alon

e.

Tabl

e S1

0—C

onti

nued




Tabl

e S1

1 —[S

ecti

on 2

.9]

CD

T v

s N

o C

DT

for

Ext

ensi

ve A

cute

DV

T o

f th

e L

eg: C

lini

cal

Des

crip

tion

and

Res

ult

s (A

ll R

ando

miz

ed T

rial

s an

d P

rosp

ecti

ve

Ob

serv

atio

nal

Stu

dies

of

at L

east

20

Pat

ient

s)

Aut

hor/

Year

Type

of P

ublic

atio

nPa

rtic

ipan

tsIn

terv

entio

nsO

utco

mes

Fol

low

-up

Res

ults

Sem

ba e

t al 41

/199

4Pr

ospe

ctiv

e re

gist

ry21

pat

ient

s (2

7 lim

bs) w

ith

iliof

emor

al D

VT

� 1

4 d

(20)

or

. 1

4 d

(7) d

urat

ion

4.9

mill

ion

units

uro

kina

se

(mea

n) in

fuse

d ov

er 3

0 h

(mea

n),

follo

wed

by

hepa

rin

and

then

w

arfa

rin

for

8-12

wk

Adj

unct

ive

ther

apy:

lim

bs w

ith

resi

dual

ste

nose

s .

50%

rec

eive

d an

giop

last

y (2

) or

sten

ting

(14)

Clo

t lys

is,

com

plic

atio

ns3

mo

Sign

ifi ca

nt ly

sis:

18/

25 a (

72%

) Pa

rtia

l lys

is: 5

/25

(20%

) N

o ly

sis:

2/2

5 (8

%)

Com

plic

atio

ns: 1

sm

all h

emat

oma

at p

unct

ure

site

, no

inte

rven

tion/

tran

sfus

ion

Verh

aegh

e et

al 42

/199

7Pr

ospe

ctiv

e st

udy

24 p

atie

nts

with

ilio

fem

oral

D

VT

� 1

4 d

(16)

or

. 1

4 d

(8) d

urat

ion

3 m

g/h

rt-P

A (m

ean

86 m

g) in

fuse

d w

ith 1

,000

U/h

IV

hep

arin

, fo

llow

ed b

y he

pari

n, a

djus

ted

to A

PTT

Adj

unct

ive

ther

apy:

hyd

rody

nam

ic

thro

mbe

ctom

y (3

) and

ste

nts

(9)

Clo

t lys

is, b

leed

ing

13 m

o (m

ean)

Sign

ifi ca

nt ly

sis:

19/

24 (7

9%)

Part

ial l

ysis

: 5/2

4 (2

1%)

Ble

edin

g: 6

/24

(25%

) Pa

tenc

y:

3

mo:

84%

1

y: 7

8%

Bja

rnas

on e

t al 43

/199

7Pr

ospe

ctiv

e re

gist

ry77

pat

ient

s (8

7 lim

bs) w

ith

iliof

emor

al D

VT

� 1

4 d

(69)

or

. 1

4 d

(18)

dur

atio

n

2,00

0-2,

500

units

/kg

per

h ur

okin

ase

infu

sed

for

75 h

(mea

n)

with

5,0

00 I

nter

natio

nal U

nits

bol

us

hepa

rin

plus

infu

sion

ad

just

ed to

aPT

TA

djun

ctiv

e th

erap

y: a

ngio

plas

ty

(52

limbs

), st

ent (

38),

AVF

(15)

, su

rgic

al th

rom

bect

omy

(13)

, m

echa

nica

l thr

ombe

ctom

y (4

), su

rgic

al b

ypas

s (3

)

Clo

t lys

is, P

E,

blee

ding

1 y

Ear

ly r

esul

ts:

Si

gnifi

cant

lysi

s: 6

9/87

(79%

)

Il

iac

(63%

)

F

emor

al (4

0%)

N

o ly

sis:

18/

87 (2

1%)

PE

: 1 (1

%)

B

leed

ing:

maj

or, 5

/77

(6%

);

m

inor

, 11/

77 (1

4%)

Pate

ncy

at 1

y:

Il

iac:

63%

F

emor

al, 4

0%

(Con

tinu

ed)




Tabl

e S1

1—C

onti

nued

Aut

hor/

Year

Type

of P

ublic

atio

nPa

rtic

ipan

tsIn

terv

entio

nsO

utco

mes

Fol

low

-up

Res

ults

Mew

isse

n et

al 44

/199

9 (N

atio

nal M

ultic

ente

r R

egis

try)

Pros

pect

ive

mul

ticen

ter

regi

stry

287

patie

nts

(312

infu

sion

s)

with

low

er li

mb

DV

T �

10

d (1

88) o

r .

10

d (9

9) d

urat

ion

7.8

mill

ion

units

uro

kina

se

(mea

n) in

fuse

d fo

r 53

.4 h

(m

ean)

in 2

97 li

mbs

In 6

lim

bs, o

nly

syst

emic

infu

sion

(n

o C

DT

)A

djun

ctiv

e th

erap

y: s

tent

s (1

04),

syst

emic

infu

sion

(54)

Clo

t lys

is, P

E,

blee

ding

, dea

th1

yE

arly

res

ults

:

50%

-100

% ly

sis:

258

/312

(83%

) ,

50%

lysi

s: 5

4/31

2 (1

7%)

PE: 6

/473

b (1%

) B

leed

ing:

54/

473 b (

11%

) D

eath

: 2/4

73 b (

, 1

%)

Pate

ncy

at 1

y:

Il

iac:

64%

F

emor

al: 4

7%

Abu

Rah

ma

et a

l 45 /2

001

Pros

pect

ive

stud

y51

pat

ient

s (5

1 lim

bs) w

ith

iliof

emor

al D

VT

giv

en c

hoic

e be

twee

n co

nven

tiona

l the

rapy

(h

epar

in 1

war

fari

n) o

rlys

is

1 a

ngio

/ste

nt (i

f nee

ded)

. L

ysis

off

ered

onl

y to

pat

ient

s w

ith D

VT

� 1

4 d

dura

tion

and

no c

ontr

aind

icat

ions

Ant

icoa

gula

tion:

33

patie

nts

give

n 1,

000-

2000

uni

ts/h

hep

arin

in

fusi

on fo

r 5-

7 d.

Clo

t lys

is, P

E,

blee

ding

Ant

icoa

g: 6

mo

Ant

icoa

gula

tion:

30-d

sig

nifi c

ant l

ysis

: 1/3

3 (3

%)

6-m

o pa

tenc

y: 8

/33

(24%

) B

leed

ing:

2/3

3 (6

%)

PE: 2

/33

(6%

)

C

DT:

18

patie

nts

give

n lo

adin

g do

se 4

,500

uni

ts u

roki

nase

fo

llow

ed b

y 4,

500

units

/kg

per

h fo

r 24-

48 h

or 4

-8-m

g bo

lus o

f rt-

PA fo

llow

ed b

y 2-

4-m

g/h

infu

sion

CD

T: 6

mo?

CD

T:

30

-d si

gnifi

cant

lysi

s: 15

/18

(83%

)6-

mo

pate

ncy:

15/

18 (8

3%)

Ble

edin

g: 2

/18

(11%

)

A

djun

ctiv

e th

erap

y: p

atie

nts

with

re

sidu

al s

teno

sis

. 5

0% r

ecei

ved

sten

ts (1

0)

Els

hara

wy

et a

l 36 /2

002)

R

CT,

sin

gle

cent

er35

pat

ient

s w

ith D

VT

, 1

0 d

dura

tion

rand

omiz

ed to

C

DT

or

antic

oagu

latio

n al

one

CD

T: 1

8 pa

tient

s re

ceiv

ed �

1

mill

ion

units

SK

pul

se-s

pray

for

1 h,

follo

wed

by

100,

000

units

/h S

K in

fusi

on u

ntil

com

-pl

ete

lysi

s, n

o ch

ange

in 1

2 h,

or

com

plic

atio

nA

djun

ctiv

e th

erap

y:

angi

opla

sty/

sten

t (1)

Clo

t lys

is, P

E,

blee

ding

1 w

k an

d 6

mo

CD

T, 1

wk

C

ompl

ete

lysi

s: 1

1/18

(61%

) N

o ly

sis:

0 (0

%)

PE: 0

Ble

edin

g: 0

A

ntic

oagu

latio

n, 1

wk:

Com

plet

e ly

sis:

0/1

7 (0

%)

No

lysi

s: 1

7/17

(100

%)

PE: 1

/17

(6%

) B

leed

ing:

0

(Con

tinu

ed)




Aut

hor/

Year

Type

of P

ublic

atio

nPa

rtic

ipan

tsIn

terv

entio

nsO

utco

mes

Fol

low

-up

Res

ults

A

ntic

oagu

latio

n: 1

7 pa

tient

s re

ceiv

ed 5

,000

uni

ts h

epar

in

bolu

s, fo

llow

ed b

y he

pari

n ad

just

ed to

aPT

T

CD

T, 6

mo

Com

plet

e ly

sis:

13/

18 (7

2%)

No

lysi

s: 0

(0%

) A

ntic

oagu

latio

n, 6

mo

Sign

ifi ca

nt ly

sis:

2/17

(12%

) N

o ly

sis:

7/1

7 (4

1%)

End

en e

t al 37

/200

9 (C

aVen

T)

RC

T, m

ultic

ente

rIl

iofe

mor

al D

VT

, 2

1 d

dura

tion

CD

T: tP

A 0

.01

mg/

kg p

er h

, m

axim

um o

f 20

mg/

24 h

for

4 d.

Tr

eate

d in

four

ref

erra

l cen

ters

Clo

t lys

is, P

E,

blee

ding

(PT

S at

24

mo

pend

ing)

1 w

k an

d 6

mo

CD

T, 1

wk

�

50%

lysi

s: 4

4/50

(68%

) PE

: 0

Maj

or b

leed

ing:

1/5

0

Ant

icoa

gula

tion

alon

e: u

sual

pr

actic

e, a

dmin

iste

red

loca

llyA

ntic

oagu

latio

n, 1

wk:

Lys

is n

ot a

sses

sed

PE: 0

M

ajor

ble

edin

g: 0

(p

unct

ure

site

ner

ve d

amag

e: 0

)

CD

T, 6

mo

Il

iofe

mor

al p

aten

cy:

32/5

0 (6

4%)

Ant

icoa

gula

tion,

6 m

o

Ilio

fem

oral

pat

ency

: 19

/53

(36%

)

Ear

ly p

rosp

ectiv

e ob

serv

atio

nal s

tudi

es w

ith ,

20

patie

nts

and

retr

ospe

ctiv

e st

udie

s ar

e de

scri

bed

in T

able

3 o

f th

e ei

ghth

edi

tion

of t

hese

gui

delin

es. 46

AV

F 5

arte

riov

enou

s fi s

tula

; CaV

enT

5 C

athe

ter-

Dir

ecte

d Ve

nous

Thr

ombo

lysi

s in

Acu

te I

liofe

mor

al V

ein

Thr

ombo

sis;

rt-

PA 5

reco

mbi

nant

tiss

ue p

lasm

inog

en a

ctiv

ator

; SK

5 st

rept

okin

ase.

See

Tab

le S

2, S

4, S

5, a

nd S

10 le

gend

s fo

r ex

pans

ion

of o

ther

ab

brev

iatio

ns.

a Tw

enty

-fi ve

of 2

7 lim

bs tr

eate

d w

ith C

DT;

two

coul

d no

t be

cros

sed

with

the

guid

ewir

e.

b Cal

cula

ted

from

tota

l num

ber

of p

atie

nts

in V

enou

s R

egis

try.

Tabl

e S1

1—C

onti

nued




Table S12 —[Section 2.9] CDT vs No CDT for Extensive Acute DVT of the Leg: Methodologic Quality

Author/Year Randomization Allocation Concealment Blinding Loss to follow-up

Semba et al 41 /1994 N/A N/A N/A N/A

Verhaeghe et al 42 /1997 N/A N/A N/A N/A

Bjarnason et al 43 /1997 N/A N/A N/A N/A

Mewissen et al 44 /1999 N/A N/A N/A N/A

AbuRahma et al 45 /2001 N/A N/A N/A N/A

Elsharawy et al 36 /2002 Computer-designated cards

PN N for patients, caregivers, and probably data analysts. Y for vascular imaging

0

Enden et al 37 /2009 Computer-designated cards

Y No for patients and caregivers. Yes for vascular imaging.

One loss to follow-up (CDT), fi ve

withdrawals, fi ve postrandomization

exclusions

N 5 no; N/A 5 not applicable; Y 5 yes. See Table S10 legend for expansion of other abbreviation.




Tabl

e S1

3 —[S

ecti

on 2

.10]

Sys

tem

ic L

ysis

vs

No

Syst

emic

Lys

is f

or E

xten

sive

Acu

te D

VT

of

the

Leg

: Cli

nica

l D

escr

ipti

on a

nd R

esu

lts

(Ran

dom

ized

Tri

als

Tha

t C

ompa

red

Syst

emic

Thr

omb

olyt

ic T

hera

py W

ith

No

Thr

omb

olyt

ic T

hera

py)

Aut

hor/

Year

Type

of

Publ

icat

ion

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Bro

wse

et a

l 52 /1

968

R

CT,

sin

gle

cent

er10

pat

ient

s w

ith

low

er-e

xtre

mity

D

VT

con

fi rm

ed

by p

hleb

ogra

phy

Lys

is: 6

00,0

00 u

nits

SK

plu

s 10

0 m

g hy

droc

ortis

one

for

fi rst

hou

r, th

en

cont

inue

d ev

ery

6 h

for

3 d

(5 p

atie

nts)

Ant

icoa

gula

tion:

4-6

hou

rly

dose

s of

hep

arin

5,

000

units

for

48 h

fo

llow

ed b

y w

arfa

rin

(5 p

atie

nts)

Clo

t lys

is, P

E,

blee

ding

7-10

dT

hrom

boly

sis:

C

ompl

ete

clot

lysi

s: 3

/5 (6

0%)

Part

ial l

ysis

: 1/5

(20%

) N

o ly

sis:

1 (2

0%)

PE: 0

B

leed

ing:

0

Ant

icoa

gula

tion:

C

ompl

ete

clot

lysi

s: 0

/5

Part

ial l

ysis

: 0/5

N

o ly

sis:

5/5

(100

%))

PE

: 0

Ble

edin

g: 0

Rob

erts

on e

t al 53

/196

8

RC

T, s

ingl

e ce

nter

16 p

atie

nts

with

D

VT

Thr

ombo

lysi

s: S

K 2

00,0

00

units

ove

r 90

min

, the

n 10

0,00

0 un

its a

s m

aint

enan

ce d

ose

for

22.5

h; h

epar

in 5

00 m

g gi

ven

duri

ng 2

4 h,

plu

s pr

edni

sone

(8 p

atie

nts)

Ant

icoa

gula

tion:

Hep

arin

pl

us p

redn

ison

e (8

pat

ient

s)

Clo

t lys

is,

blee

ding

7 d

Thr

ombo

lysi

s:

Sign

ifi ca

nt ly

sis:

5/8

(63%

) Pa

rtia

l lys

is: 2

/8 (2

5%)

No

lysi

s: 1

/8 (1

2%)

Ble

edin

g: M

ajor

: 2/8

(25%

) M

inor

: 2/8

(25%

) A

ntic

oagu

latio

n:

Sign

ifi ca

nt ly

sis:

1/8

(12%

) Pa

rtia

l lys

is: 2

/8 (2

5%)

No

lysi

s: 5

/8 (6

3%)

Ble

edin

g: M

ajor

: 1/8

(12%

) M

inor

: 1/8

(12%

)

Kak

kar

et a

l 54 /1

969

RC

T, s

ingl

e ce

nter

30 p

atie

nts

with

D

VT

of ,

4 d

Thr

ombo

lysi

s: S

K 5

00,0

00 u

nits

IV

ove

r 30

min

; 900

,000

uni

ts

ever

y 6

h 3

5 d

(1

0 pa

tient

s)

Clo

t lys

is, P

E,

blee

ding

, dea

th6-

12 m

oT

hrom

boly

sis:

C

ompl

ete

clot

lysi

s: 6

/9 (6

7%)

Part

ial l

ysis

: 1/9

(11%

) N

o ly

sis:

2/9

(22%

) PE

: 0

Ble

edin

g: 4

/10

(40%

) D

eath

: 2/9

(22%

) N

ote:

(1 p

atie

nt e

xclu

ded

from

trea

tmen

t)

(Con

tinu

ed)




Tabl

e S1

3—C

onti

nued

Aut

hor/

Year

Type

of

Publ

icat

ion

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

A

rvin

: Arv

in lo

adin

g do

se

80 u

nits

IV

ove

r 6

h;

80 u

nits

ove

r 15

min

; 40

-80

units

eve

ry

6 h

3 5

d (1

0 pa

tient

s)A

ntic

oagu

latio

n: H

epar

in

10,0

00 u

nits

IV

ove

r 5

min

, the

n 10

,000

-15,

000

units

eve

ry 6

h 3

5 d

(1

0 pa

tient

s)

Arv

in:

Com

plet

e ly

sis:

1/1

0 (1

0%)

Part

ial l

ysis

: 3/1

0 (3

0%)

No

lysi

s: 6

/10

(60%

) PE

: 0

Ble

edin

g: 0

D

eath

: 0

Ant

icoa

gula

tion:

C

ompl

ete

clot

lysi

s: 2

/9 (2

2%)

Part

ial l

ysis

: 2/9

(22%

) N

o ly

sis:

5/9

(55%

) PE

: 1/1

0 D

eath

: 2/9

(22%

) B

leed

ing:

2/9

(22%

) N

ote:

(1 p

atie

nt e

xclu

ded

from

trea

tmen

t)

Tsap

ogas

et a

l 55 /1

973

R

CT,

sin

gle

cent

er34

pat

ient

s w

ith

DV

T o

f , 5

dT

hrom

boly

sis:

titr

ated

in

itial

dos

e of

SK

IV,

th

en S

K 1

00,0

00 u

nits

/h

mai

ntai

ned

and

adju

sted

up

to 7

2 h

IV h

epar

in fo

r 1

wk

6-12

h p

ost S

K

(19

patie

nts)

Ant

icoa

gula

tion:

Hep

arin

IV

in

to a

ffec

ted

limb,

7,0

00 u

nits

bo

lus

then

1,5

00 u

nits

/h

adju

sted

; con

tinue

d fo

r 7

d (1

5)

Clo

t lys

is, P

E,

blee

ding

7 d

Thr

ombo

lysi

s:

Com

plet

e/pa

rtia

l lys

is: 1

0/19

(53%

) N

o ly

sis:

9/1

9 (4

7%)

PE: 0

M

inor

ble

edin

g: 3

(16%

) A

ntic

oagu

latio

n:

Com

plet

e/pa

rtia

l lys

is: 1

/15

(7%

) N

o ly

sis:

14/

15 (9

3%)

PE: 1

/15

(7%

) B

leed

ing:

0

Duc

kert

et a

l 56 /1

975

Pr

ospe

ctiv

e st

udy

134

patie

nts

with

acu

te

or s

ubac

ute

DV

TT

hrom

boly

sis:

initi

al d

ose

SK c

alcu

late

d ac

cord

ing

to to

lera

nce

inje

cted

ove

r 15

-30

min

; mai

nten

ance

do

se a

t 30

mL

/h w

as

two-

thir

ds o

f fi r

st d

ose

(92

patie

nts)

Ant

icoa

gula

tion:

5,0

00 u

nits

he

pari

n fo

r in

itial

dos

e fo

llow

ed b

y 25

,000

uni

ts/2

4 h

infu

sion

(42

patie

nts)

.

Clo

t lys

is, P

E,

blee

ding

� 7

dT

hrom

boly

sis:

Si

gnifi

cant

lysi

s: 3

9/92

(42%

) Pa

rtia

l lys

is: 2

3/92

(25%

) N

o ly

sis:

30/

92 (3

3%)

PE: 7

(8%

) M

ajor

ble

edin

g: 5

8 (6

2%)

Min

or b

leed

ing:

24

(26%

) s

Ant

icoa

gula

tion:

Si

gnifi

cant

lysi

s: 0

/42

(0%

) Pa

rtia

l lys

is: 4

/42

(10%

) N

o ly

sis:

38/

42 (9

0%)

PE: 5

/42

(12%

) M

ajor

ble

edin

g: 2

/42

(5%

) M

inor

ble

edin

g: 4

/42

(10%

) (C

onti

nued

)




Aut

hor/

Year

Type

of

Publ

icat

ion

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Port

er e

t al 57

/197

5

RC

T, s

ingl

e ce

nter

50 p

atie

nts

with

D

VT

, 1

4 d

dura

tion

Thr

ombo

lysi

s: S

K 2

50,0

00 u

nits

IV

ov

er 3

0 m

in, t

hen

100,

000

units

/h ti

trat

ed

for

72 h

follo

wed

by

IV h

epar

in ti

trat

ed o

ver

7 d

(23

patie

nts)

Ant

icoa

gula

tion:

IV

hep

arin

15

0 un

its/k

g lo

adin

g do

se

then

titr

ated

for

10 d

(2

6 pa

tient

s)

Clo

t lys

is, P

E,

blee

ding

, de

ath

due

to

trea

tmen

t

10 d

Thr

ombo

lysi

s C

ompl

ete

lysi

s: 6

/23

(26%

) Pa

rtia

l lys

is: 1

5/23

(65%

) N

o ly

sis:

2/2

3 (9

%)

PE: 0

B

leed

ing:

4/2

3 (1

7%)

Dea

th: 1

(4%

) A

ntic

oagu

latio

n:

Com

plet

e ly

sis:

1/2

6 (4

%)

Part

ial l

ysis

: 20/

26 (7

7%)

No

lysi

s: 5

/26

(19%

) PE

: 0

Ble

edin

g: 1

/26

(4%

) D

eath

: 0

Mar

der

et a

l 58 /1

977

RC

T, s

ingl

e ce

nter

24 p

atie

nts

with

D

VT

Thr

ombo

lysi

s: in

itial

dos

e of

25

0,00

0 un

its S

K fo

r 20

min

, fol

low

ed b

y 10

0,00

0 un

its/h

for

72 h

(12

patie

nts)

Ant

icoa

gula

tion:

initi

al d

ose

hepa

rin

150

units

/kg

IV,

follo

wed

by

titra

ted

infu

sion

for

72 h

Cot

reat

men

t: 10

0 m

g bo

lus

hydr

ocor

tison

e pr

ior

to tr

eatm

ent

Clo

t lys

is,

deat

h du

e to

tr

eatm

ent

5 d

Thr

ombo

lysi

s:

Sign

ifi ca

nt ly

sis:

5/1

2 (4

2%)

Part

ial l

ysis

: 2/1

2 (1

6%)

No

lysi

s: 5

/12

(42%

) D

eath

: 1/1

2 (8

%)

Ant

icoa

gula

tion:

Si

gnifi

cant

lysi

s: 0

/12

(0%

) Pa

rtia

l lys

is: 3

/12

(25%

) N

o ly

sis:

9/1

2 (7

5%)

Dea

th: 0

Arn

esen

et a

l 59 /1

978

R

CT,

sin

gle

cent

er42

pat

ient

s w

ith

prox

imal

DV

T

of ,

5 d

.

Thr

ombo

lysi

s: lo

adin

g do

se

of S

K 2

50,0

00 u

nits

IV,

th

en 1

00,0

00 I

nter

natio

nal

Uni

ts/h

IV

for

72-9

6 h

(21

patie

nts)

Ant

icoa

gula

tion:

hep

arin

15

,000

Int

erna

tiona

l Uni

ts

IV b

olus

, the

n to

tal o

f 30

,000

Int

erna

tiona

l Uni

ts

IV in

fusi

on fo

r 72

-90

h (2

1 pa

tient

s)

Clo

t lys

is, P

E,

blee

ding

21 d

-6 y

Thr

ombo

lysi

s:

Sign

ifi ca

nt ly

sis:

15/

21 (7

1%)

No

lysi

s: 6

/21

(29%

) PE

: 1/2

1 (5

%)

Ble

edin

g: 2

/21

(9%

) A

ntic

oagu

latio

n:

Sign

ifi ca

nt ly

sis:

5/2

1 (2

4%)

No

lysi

s: 1

6/21

(76%

) PE

: 0

Ble

edin

g: 2

/21

(9%

)

Tabl

e S1

3—C

onti

nued

(Con

tinu

ed)




Aut

hor/

Year

Type

of

Publ

icat

ion

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Elli

ot e

t al 60

/197

9

RC

T, s

ingl

e ce

nter

51 p

atie

nts

with

cl

inic

al h

isto

ry

of D

VT

of ,

8 d

Thr

ombo

lysi

s: lo

adin

g do

se

of S

K 6

00,0

00 u

nits

infu

sed

over

30

min

, fol

low

ed b

y 10

0,00

0/h

for

3 d;

hep

arin

fo

r 4

d fo

llow

ing

SK

(26

patie

nts)

Ant

icoa

gula

tion:

hep

arin

10

,000

uni

ts I

V in

itial

ly,

follo

wed

by

10,0

00 u

nits

IV

dai

ly fo

r a

6-h

infu

sion

to

mai

ntai

n cl

ottin

g tim

e of

2.5

-3 ti

mes

nor

mal

for

7 d

(25

patie

nts)

Imm

edia

te:

clot

lysi

s,

PE, b

leed

ing

Lon

g te

rm:

sym

ptom

free

Imm

edia

te: 5

dL

ong

term

: 19

mo

(mea

n)

Imm

edia

te:

Thr

ombo

lysi

s:

Sign

ifi ca

nt ly

sis:

17/2

6 (6

5%)

Part

ial l

ysis

: 1/2

6 (4

%)

No

lysi

s: 8

/26

(31%

) PE

: 0

Ble

edin

g: 2

(8%

) A

ntic

oagu

latio

n:

Sign

ifi ca

nt ly

sis:

0/2

5 (0

%)

Part

ial l

ysis

: 0/2

5 (0

%)

No

lysi

s: 2

5/25

(100

%)

PE: 0

B

leed

ing:

2/2

1 (9

%)

Lon

g te

rm:

Thr

ombo

lysi

s:

Sym

ptom

-fre

e: 1

2/20

a (60

%)

Trea

tmen

t 2

Sym

ptom

-fre

e: 2

/21 b (

9%)

Wat

z et

al 61

/197

9

Pros

pect

ive

stud

y35

pat

ient

s w

ith

DV

TT

hrom

boly

sis:

initi

al d

ose

of

SK 2

50,0

00 u

nits

in 3

0 m

in,

follo

wed

by

mai

nten

ance

10

0,00

0 un

its/h

(18

patie

nts)

Ant

icoa

gula

tion:

hep

arin

45

,000

uni

ts d

aily

with

w

arfa

rin

(17)

Clo

t lys

is, P

E,

blee

ding

1-2

mo

Thr

ombo

lysi

s:

Sign

ifi ca

nt ly

sis:

8/1

8 (4

4%)

Part

ial l

ysis

: 4/1

8 (2

2%)

No

lysi

s: 6

/18

(34%

) PE

: 1/1

8 (5

%)

Min

or b

leed

ing:

3/1

8 (1

2%)

Ant

icoa

gula

tion:

Si

gnifi

cant

lysi

s: 1

/17

(6%

) Pa

rtia

l lys

is: 5

/17

(29%

) N

o ly

sis:

11/

17 (6

5%)

PE: 1

/17

(6%

) M

inor

ble

edin

g: 2

/17

(12%

)

Tabl

e S1

3—C

onti

nued

(Con

tinu

ed)




Aut

hor/

Year

Type

of

Publ

icat

ion

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Kiil

et a

l 62 /1

981

R

CT,

sin

gle

cent

er20

pat

ient

s w

ith

DV

T o

f , 7

2 h

Thr

ombo

lysi

s: u

roki

nase

20

0,00

0 un

its I

V fo

r 24

h;

afte

r 18

h, h

epar

in lo

adin

g do

se o

f 15,

000

units

, the

n 40

,000

uni

ts/d

for

5 d

(11

patie

nts)

Ant

icoa

gula

tion:

hep

arin

40

,000

uni

ts/d

ay 4

for

6 d

(9 p

atie

nts)

Clo

t lys

is, P

E,

blee

ding

2 w

kT

hrom

boly

sis:

Pa

rtia

l lys

is: 1

/11

(9%

) N

o ly

sis:

10/

11 (9

1%)

PE: 0

B

leed

ing:

3/1

1 (2

7%)

Ant

icoa

gula

tion:

Pa

rtia

l lys

is: 1

/8 (1

2%)

No

lysi

s: 7

/8 (8

8%)

PE: 0

B

leed

ing:

3/9

(33%

) N

ote:

1 p

atie

nt e

xclu

ded

from

gro

up

Arn

esen

et a

l 63 /1

982

F

ollo

w-u

p to

RC

T o

f A

rnes

en

(197

8)

35/4

2 pa

tient

s fr

om

RC

TPh

lebo

grap

hy a

nd c

linic

al

exam

inat

ion

by b

linde

d ev

alua

tors

Nor

mal

legs

, PT

S sy

mpt

oms

6.5

yT

hrom

boly

sis:

N

orm

al le

gs: 1

3/17

(77%

) PT

S sy

mpt

oms

(mod

erat

e): 4

/17

(24%

) A

ntic

oagu

latio

n:

Nor

mal

legs

: 6/1

8 (3

3%)

PTS

sym

ptom

s (m

oder

ate)

: 9/1

8 (5

0%)

Schu

lman

et a

l 49 /1

986

R

CT,

sin

gle

cent

er36

pat

ient

s w

ith c

alf

DV

T o

f , 7

dT

hrom

boly

sis:

SK

50,

000

Inte

rnat

iona

l Uni

ts I

V

over

15

min

, the

n 10

0,00

0 In

tern

atio

nal U

nits

ove

r 12

h fo

r up

to 7

d, t

itrat

ed;

give

n w

ith h

epar

in 5

,000

In

tern

atio

nal U

nits

IV

ove

r 12

h (1

7 pa

tient

s)A

ntic

oagu

latio

n: h

epar

in

5,00

0 In

tern

atio

nal U

nits

IV

for

15 m

in th

en 3

0,00

0 In

tern

atio

nal U

nits

/d,

titra

ted

over

7 d

(1

9 pa

tient

s)

Clo

t lys

is,

blee

ding

, PE

5 y

Thr

ombo

lysi

s:

Com

plet

e ly

sis:

7/1

7 (4

1%)

Ble

edin

g:3/

17 (1

8%)

PE: 0

A

ntic

oagu

latio

n:

Com

plet

e ly

sis:

2/1

9 (1

0%)

Ble

edin

g: 1

/19

(5%

) PE

: 0

Verh

aegh

e et

al 51

/198

9Pr

ospe

ctiv

e co

hort

stu

dy

(A) a

nd m

ultic

ente

r R

TC

(B)

32 p

atie

nts

with

D

VT

of ,

10

dSt

udy

A: o

pen-

labe

l stu

dy

with

rt-

PA 1

00 m

g ov

er

IV 8

h (d

ay 1

), 50

mg

rt-P

A

over

8 h

(day

2);

10%

dos

e as

bol

us (1

1 pa

tient

s)

Clo

t lys

is,

blee

ding

72 h

Not

e: A

utho

rs a

ssig

ned

vein

s a

rela

tive

valu

e re

fl ect

ing

degr

ee o

f thr

ombo

sis

(max

imum

, 40

units

: com

plet

e th

rom

bosi

s). T

he u

nit s

core

s re

fl ect

the

redu

ctio

n in

thro

mbo

sis

post

lysi

s.

Tabl

e S1

3—C

onti

nued

(Con

tinu

ed)




Aut

hor/

Year

Type

of

Publ

icat

ion

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

St

udy

B: r

t-PA

100

mg:

IV

of

100

mL

con

tain

ing

rt-P

A

100

mg

infu

sed

over

8 h

(d

ay 1

), IV

of 1

00 m

L

cont

aini

ng 5

0 m

g rt

-PA

in

fuse

d ov

er 8

h (d

ay 2

); 10

% d

ose

as b

olus

(8

pat

ient

s)rt

-PA

50

mg:

IV

of 1

00 m

L

cont

aini

ng r

t-PA

50

mg

infu

sed

over

8 h

on

both

da

ys 1

and

2; 1

0% d

ose

as b

olus

(6 p

atie

nts)

Plac

ebo:

IV

of 1

00 m

L

cont

aini

ng p

lace

bo in

fuse

d ov

er 8

h o

n bo

th d

ays

1 an

d 2

(7 p

atie

nts)

Co-

trea

tmen

t: he

pari

n 5,

000

units

IV

bol

us th

en c

ontin

uous

in

fusi

on 1

,000

uni

ts/h

fo

r up

to 7

2 h

Stud

y A

C

hang

e in

uni

t sco

re: 2

3.2

St

udy

B

rt-P

A 1

00 m

g:

Cha

nge

in u

nit s

core

: 2 2

4.3

Ble

edin

g: 6

rt

-PA

50

mg:

C

hang

e in

uni

t sco

re: 2

34.

3 B

leed

ing:

3

Plac

ebo:

C

hang

e in

uni

t sco

re: 2

2.8

B

leed

ing:

0

Gol

dhab

er e

t al 64

/199

0R

CT,

m

ultic

ente

r64

pat

ient

s (6

5 ra

ndom

izat

ions

) w

ith D

VT

of ,

14

d

rt-P

A: r

t-PA

0.0

5 m

g/kg

per

h

IV fo

r 24

h, t

hen

hepa

rin

100

units

/kg

bolu

s, th

en

1,00

0 un

its/h

, adj

uste

d (3

6 pa

tient

s)rt

-PA

1 h

epar

in: r

t-PA

as

in g

roup

1 p

lus

hepa

rin

conc

omita

ntly

(17

patie

nts)

Ant

icoa

gula

tion:

hep

arin

10

0 un

its/k

g bo

lus,

then

1,

000

units

/h (1

2 pa

tient

s)

Clo

t lys

is,

blee

ding

36 h

rt-P

A:

Com

plet

e ly

sis:

2/3

2 (6

%)

Part

ial l

ysis

: 18/

32 (5

7%)

No

lysi

s: 1

2/32

(38%

) B

leed

ing:

1/3

2 (3

%)

rt-P

A 1

hep

arin

: C

ompl

ete

lysi

s: 1

/17

(6%

) Pa

rtia

l lys

is: 8

/17

(48%

) N

o ly

sis:

8/17

(48%

) B

leed

ing:

0

Ant

icoa

gula

tion:

Pa

rtia

l lys

is: 2

/11

(18%

) N

o ly

sis:

9/1

1 (8

9%)

Ble

edin

g: 0

N

ote:

5/6

5 ve

nogr

ams

not a

naly

zed

Tabl

e S1

3—C

onti

nued

(Con

tinu

ed)




(Con

tinu

ed)

Aut

hor/

Year

Type

of

Publ

icat

ion

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Turp

ie e

t al 50

/199

0R

CT,

m

ultic

ente

r83

pat

ient

s w

ith

DV

T o

f , 7

dPh

ase

1: L

ysis

1 h

epar

in:

two-

chai

n rt

-PA

0.5

mg/

kg

IV fo

r 4

h (1

2 pa

tient

s)

Clo

t lys

is,

blee

ding

24-4

8 h

Phas

e 1:

L

ysis

1 h

epar

in:

� 5

0% ly

sis:

7/1

2 (5

8%)

, 5

0% ly

sis:

2/1

2 (1

7%)

No

lysi

s: 3

/12

(25%

) B

leed

ing:

4/1

2 (3

3%)

Pl

aceb

o 1

hep

arin

(1

2 pa

tient

s)Pl

aceb

o 1

hep

arin

: ,

50%

lysi

s: 2

/12

(17%

) N

o ly

sis:

10/

12 (8

3%)

Ble

edin

g: 1

/12

(8%

)

Ph

ase

2: L

ysis

1 h

epar

in:

one-

chai

n rt

-PA

0.5

mg/

kg

IV fo

r 8

h an

d re

peat

ed

in 2

4 h

(29

patie

nts)

Phas

e 2:

L

ysis

1 h

epar

in:

� 5

0% ly

sis:

6/2

9 (2

1%)

, 5

0% ly

sis:

7/2

9 (2

4%)

No

lysi

s: 1

5/29

(52%

) B

leed

ing:

1/2

9 (3

%)

Pl

aceb

o 1

hep

arin

(30

pts)

Plac

ebo

1 h

epar

in

� 5

0% ly

sis:

2/3

0 (7

%)

, 5

0 ly

sis:

5/30

(17%

) N

o ly

sis:

23/

30 (7

7%)

Ble

edin

g: 1

/30

(3%

)

C

otre

atm

ent:

hepa

rin

5,00

0-un

it IV

bol

us th

en

30,0

00 u

nits

/24

h,

adju

sted

for

7-10

d

Schw

eize

r et

al 65

/199

8R

CT,

sin

gle

cent

er69

pat

ient

s w

ith

DV

T o

f , 7

drt

-PA

20

mg

IV in

to p

edal

ve

in 4

h/d

for

7 d;

hep

arin

IV

giv

en c

onco

mita

ntly

; w

arfa

rin

day

7-12

mo

Uro

kina

se 1

00,0

00

Inte

rnat

iona

l Uni

ts/h

r IV

into

ped

al v

ein

cont

inuo

usly

7 d

; hep

arin

IV

7 d

; pla

smin

ogen

m

onito

red;

war

fari

n da

y 7-

12 m

o

7 d:

clo

t lys

is,

blee

ding

1 y:

PT

S sy

mpt

oms

7 d

and

1 y

rt-P

A:

Com

plet

e ly

sis:

6/2

2 (2

7%)

Ble

edin

g: 1

/22

(5%

) PT

S sy

mpt

oms:

14/

22 (6

4%)

Uro

kina

se:

Com

plet

e ly

sis:

11/

22 (5

0%)

Ble

edin

g: 1

/22

(5%

) PT

S sy

mpt

oms:

9/2

2 (4

1%)

Tabl

e S1

3—C

onti

nued




Aut

hor/

Year

Type

of

Publ

icat

ion

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

A

ntic

oagu

latio

n: h

epar

in I

V

adju

sted

for

7 d;

war

fari

n da

y 1-

12 m

o

Ant

icoa

gula

tion:

C

ompl

ete

lysi

s: 0

B

leed

ing:

0 P

TS

Sym

ptom

s: 1

5/22

(68%

)

Schw

eize

r et

al 66

/200

0R

CT,

m

ultic

ente

r25

0 pa

tient

s w

ith

DV

T o

f , 9

drt

-PA

: loc

oreg

iona

l rt-

PA

20 m

g/da

y fo

r 4

h th

roug

h pe

dal v

ein

for

4-7

d;

IV h

epar

in g

iven

si

mul

tane

ousl

y at

1,0

00

Inte

rnat

iona

l Uni

ts/h

, adj

uste

d

Clo

t lys

is,

blee

ding

, m

orta

lity

1 y

rt-P

A:

Com

plet

e ly

sis:

10/

50 (2

0%)

� 5

0% ly

sis:

7/5

0 (1

4%)

, 5

0% ly

sis:

16/

50 (3

2%)

No

lysi

s: 1

3/50

(26%

) B

leed

ing:

2/5

0 (4

%)

U

roki

nase

: loc

oreg

iona

l ur

okin

ase

100,

000

Inte

rnat

iona

l Uni

ts in

fuse

d co

ntin

uous

ly; fi

bri

noge

n an

d pl

asm

inog

en m

onito

red;

IV

hep

arin

giv

en c

onco

mita

ntly

Uro

kina

se:

Com

plet

e ly

sis:

10/

50 (2

0%)

� 5

0% ly

sis:

9/5

0 (1

8%)

, 5

0% ly

sis:

17/

50 (3

4%)

No

lysi

s: 1

1/50

(22%

) B

leed

ing:

1/5

0 (2

%)

Sy

stem

ic S

K: 3

mill

ion

units

/d

for

6 h

with

hep

arin

for

up to

7

d. P

rem

edic

atio

ns:

hydr

ocor

tison

e 10

0 m

g,

rani

tidin

e 50

mg,

cl

emas

tine

2 m

g

Syst

emic

SK

: C

ompl

ete

lysi

s: 2

0/50

(40%

) �

50%

lysi

s: 7

/50

(14%

) ,

50%

lysi

s: 1

3/50

(26%

) N

o ly

sis:

8/5

0 (1

6%)

Ble

edin

g: 5

/50

(10%

) PE

: 5/5

0 (1

0%)

Sy

stem

ic u

roki

nase

: 5 m

illio

n In

tern

atio

nal U

nits

/d fo

r 4

h up

to 7

d; I

V h

epar

in g

iven

co

ncom

itant

ly

Syst

emic

uro

kina

se:

Com

plet

e ly

sis:

17/

50 (3

4%)

� 5

0% ly

sis:

10/5

0 (2

0%)

, 5

0% ly

sis:

13/

50 (2

6%)

No

lysi

s: 8

/50

(16%

) B

leed

ing:

4/5

0 (8

%)

PE: 4

/50

(8%

)

Ant

icoa

gula

tion:

hep

arin

IV,

ad

just

ed.

C

otre

atm

ent:

bed

rest

, co

mpr

essi

on b

anda

ges,

co

mpr

essi

on th

erap

y,

war

fari

n fo

r 12

mo

See

Tabl

e S1

, S2,

and

S11

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Fou

r de

aths

, oth

er c

ause

s, tw

o lo

st to

follo

w-u

p.

b Fou

r de

aths

, tw

o PE

s, tw

o ot

her

caus

es.

Tabl

e S1

3—C

onti

nued




Table S14 —[Section 2.10] Systemic Lysis vs No Systemic Lysis for Extensive Acute DVT of the Leg: Methods

Author/Year Randomization Allocation concealment Blinding Loss to follow-up

Browse et al 52 /1968 N/A N/A N/A 0

Robertson et al 53 /1968 Patients given consecutive code numbers and divided into equal groups of 2—not truly randomized

Labels on SK and heparin coded

Y, data assessors; unclear for patients, caregivers, analysts

0

Kakkar et al 54 /1969 Sequential sealed envelope Adequate Y, patients No, caregivers, assessors, analysts

0

Tsapogas et al 55 /1973 Sealed envelope Adequate Not blinded 0

Duckert et al 56 /1975 N/A N/A N/A N/A

Porter et al 57 /1975 Assigned at random to one of two groups

N/A N/A N/A

Marder et al 58 /1977 Assigned at random to one of two groups. Five-day follow-up venograms were not performed in 3 of the SK patients, so an additional 3 patients were added to SK group in nonrandomized fashion.

Unclear Not blinded 23

Arnesen et al 59 /1978 Assigned at random to either group by sealed envelope

Adequate Y, radiologic assessors No, patients, caregivers, analysts

0

Elliot et al 60 /1979 Assigned at random to one of two groups

Unclear Y, assessors N, patients, caregivers, analysts

N/A

Watz et al 61 /1979 N/A N/A N/A N/A

Kiil et al 62 /1981 Assigned at random to either group

Unclear Y, assessors, analysts N, patients, caregivers

0

Arnesen et al 63 /1982 N/A N/A Evaluator blinded 7

Schulman et al 49 /1986 Assigned at random to either group by sealed envelope

Adequate Single blind 0

Verhaeghe et al 51 /1989 Assigned at random to one of three groups

Unclear Y, patients, assessors N, caregivers, analysts

0

Goldhaber et al 64 /1990 Assigned at random to one of three groups through sealed envelope

2:2:1 allocation scheme

Not blinded 0

Turpie et al 50 /1990 Assigned at random to one of two groups in each phase of study

Unclear Y, patients, assessors N, caregivers, analysts

37

Schweizer et al 65 /1998 Assigned at random to one of three groups

Adequate Y, assessors N, patients, caregivers, analysts

1

Schweizer et al 66 /2000 Assigned at random to one of fi ve groups

Unclear Single blind—not sure who 12

Y 5 yes. See Table S5 and S12 legends for expansion of other abbreviations.




Tabl

e S1

5 —[S

ecti

on 2

.10]

Evi

denc

e P

rofi l

e: S

yste

mic

Lys

is v

s N

o Sy

stem

ic L

ysis

for

Ext

ensi

ve A

cute

DV

T o

f th

e L

eg

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

eW

ith N

o Sy

stem

ic L

ysis

With

Sy

stem

ic

Lys

isR

elat

ive

Eff

ect

(95%

CI)

Ris

k W

ith

No

Syst

emic

L

ysis

Ris

k D

iffer

ence

W

ith S

yste

mic

L

ysis

(95%

CI)

Mor

talit

y (im

port

ant o

utco

me)

688

(5 s

tudi

es),

3 m

o a N

o se

riou

s ri

sk

of b

ias b

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ss c,

d Ve

ry s

erio

us e

Und

etec

ted

Low

b-e d

ue to

im

prec

isio

n5/

233

(2.1

)4/

455

(0.9

)R

R 0

.86

(0.2

7-2.

68)

21 p

er 1

,000

3 fe

wer

per

1,

000

(fro

m

16 fe

wer

to

36 m

ore)

Non

fata

l rec

urre

nt V

TE

(cri

tical

out

com

e)

687

(3 s

tudi

es),

3 m

o f N

o se

riou

s ri

sk

of b

ias g

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ss d

Very

ser

ious

e U

ndet

ecte

dL

ow d,

e,g d

ue to

im

prec

isio

n2/

233

(0.9

)10

/454

(2.2

)R

R 1

.28

(0.2

5-6.

68)

48 p

er 1

,000

h 13

mor

e pe

r 1,

000

(fro

m

36 fe

wer

to

273

mor

e)

Non

fata

l maj

or b

leed

ing

(cri

tical

out

com

e)

688

(10

stud

ies)

, 3

mo f

No

seri

ous

risk

of

bia

s i N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

c,d

Seri

ous

Und

etec

ted

Mod

erat

e c,d,

i due

to

impr

ecis

ion

10/2

34 (4

.3)

38/4

54 (8

.4)

RR

1.8

4 (0

.94-

3.59

)29

per

1,0

00 h,

j 24

mor

e pe

r 1,

000

(fro

m

2 fe

wer

to 7

5 m

ore)

(C

onti

nued

)




Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

eW

ith N

o Sy

stem

ic L

ysis

With

Sy

stem

ic

Lys

isR

elat

ive

Eff

ect

(95%

CI)

Ris

k W

ith

No

Syst

emic

L

ysis

Ris

k D

iffer

ence

W

ith S

yste

mic

L

ysis

(95%

CI)

Post

thro

mbo

tic s

yndr

ome

(cri

tical

out

com

e)

678

(2 s

tudi

es),

2 y k

Seri

ous l,m

N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

d3 Se

riou

s e4

Und

etec

ted

Low

d,e,

l,m d

ue to

ri

sk o

f bia

s,

impr

ecis

ion

24/2

30 (1

0.4)

27/4

48 (6

)R

R 0

.71

(0.4

9-1.

04)

588

per

1,00

0 n 171

few

er p

er

1,00

0 (f

rom

30

0 fe

wer

to

24 m

ore)

o

Qua

lity

of li

fe n

ot m

easu

red

……

……

……

……

…-

……

Bib

liogr

aphy

: Wat

son

et a

l. 47 W

e ex

clud

ed E

lsha

raw

y et

al 36

fro

m t

he a

naly

sis

beca

use

it us

ed c

athe

ter

dire

cted

thr

ombo

lysi

s. 36

We

iden

tifi e

d no

stu

dies

pub

lishe

d si

nce

the

sear

ch d

ate

of t

he s

yste

mat

ic

revi

ew. S

ee T

able

S1,

S10

, and

S11

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Ran

ge o

f fol

low

-up

in in

clud

ed s

tudi

es, 1

to 7

2 m

o.

b Allo

catio

n co

ncea

led

in t

hree

of

fi ve

stud

ies.

Fol

low

-up

inad

equa

te in

one

of

fi ve

(Com

mon

et

al 48

). E

xclu

ding

thi

s st

udy

from

the

ana

lysi

s do

es n

ot c

hang

e th

e ef

fect

est

imat

e. A

ll st

udie

s ha

d bl

inde

d ou

tcom

e as

sess

ors.

Non

e of

the

stud

ies

used

a p

lace

bo c

ontr

ol.

c The

pop

ulat

ion

of o

ne s

tudy

(Sch

ulm

an e

t al 49

) con

sist

ed o

f pat

ient

s w

ith c

alf v

ein

thro

mbo

sis.

d I

nter

vent

ions

var

ied

acro

ss s

tudi

es w

ith r

egar

d to

age

nt (e

g, tP

A, S

K, u

roki

nase

), do

se, u

se o

f the

ped

al v

ein

adm

inis

trat

ion,

dur

atio

n of

trea

tmen

t, an

d co

ncom

itant

dru

gs (e

g, s

tero

ids)

. How

ever

, we

did

not d

owng

rade

for

indi

rect

ness

giv

en th

at th

ere

is n

o st

anda

rd r

egim

en, a

nd a

ll an

alys

es s

how

ed n

o he

tero

gene

ity in

res

ults

. e C

I in

clud

ed b

oth

no e

ffec

t and

a p

oten

tially

sig

nifi c

ant e

ffec

t. f R

ange

of f

ollo

w-u

p in

incl

uded

stu

dies

, 1 to

30

d.

g Allo

catio

n co

ncea

led

in tw

o of

thre

e st

udie

s. F

ollo

w-u

p ad

equa

te in

all

stud

ies.

All

stud

ies

had

blin

ded

outc

ome

asse

ssor

s. N

one

of th

e st

udie

s us

ed a

pla

cebo

con

trol

. h B

asel

ine

risk

s fo

r no

nfat

al r

ecur

rent

VT

E a

nd f

or m

ajor

ble

edin

g de

rive

d fr

om D

ouke

tis e

t al

. 39i A

lloca

tion

conc

eale

d in

sev

en o

f 10

stu

dies

. Fol

low

-up

inad

equa

te in

one

10

stud

ies

(Com

mon

et

al 48

). E

xclu

ding

this

stu

dy fr

om th

e an

alys

is d

oes

not a

ffec

t the

eff

ect e

stim

ate.

All

stud

ies

had

blin

ded

outc

ome

asse

ssor

s. T

wo

stud

ies

used

pla

cebo

(Tur

pie

et a

l; 50

Verh

aegh

e et

al 51

). j O

nly

4% o

f all

maj

or b

leed

ing

even

ts w

ere

intr

acra

nial

ble

eds.

k R

ange

of f

ollo

w-u

p in

incl

uded

stu

dies

: 1 to

6 y

. l A

lloca

tion

conc

eale

d in

two

of tw

o st

udie

s. F

ollo

w-u

p ad

equa

te in

all

stud

ies.

All

stud

ies

had

blin

ded

outc

ome

asse

ssor

s. N

one

of th

e st

udie

s us

ed p

lace

bo c

ontr

ol.

m N

o us

e of

a s

tand

ardi

zed

valid

ated

tool

rep

orte

d.

n Thi

s es

timat

e is

bas

ed o

n th

e fi n

ding

s of

the

VE

TO

(Ven

ous

Thr

ombo

sis

Out

com

es) s

tudy

. 40 T

his

prob

ably

und

eres

timat

es P

TS

base

line

risk

giv

en th

at o

vera

ll, 5

2% o

f pat

ient

s re

port

ed th

e cu

rren

t use

of

com

pres

sion

sto

ckin

gs d

urin

g st

udy

follo

w-u

p.

o Sev

ere

PTS:

ass

umin

g th

e sa

me

RR

of 0

.71

and

a ba

selin

e ri

sk o

f 13.

8%, 40

the

abso

lute

red

uctio

n is

40

few

er s

ever

e PT

S pe

r 1,

000

(fro

m 7

0 fe

wer

to 6

mor

e) o

ver

2 y.

Tabl

e S1

5—C

onti

nued




Tabl

e S1

6 —[2

.11]

Evi

denc

e P

rofi l

e: S

urg

ical

Thr

omb

ecto

my

Vs

No

Surg

ical

Thr

omb

ecto

my

for

Ext

ensi

ve A

cute

DV

T o

f th

e L

eg a

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Surg

ical

T

hrom

bect

omy

With

Sur

gica

l T

hrom

bect

omy

Rel

ativ

e E

ffec

t (9

5% C

I)

Ris

k W

ith

No

Surg

ical

T

hrom

bect

omy

Ris

k D

iffer

ence

W

ith S

urgi

cal

Thr

ombe

ctom

y (9

5% C

I)

Mor

talit

y no

t rep

orte

d

……

……

……

...…

……

......

Non

fata

l rec

urre

nt V

TE

(cri

tical

out

com

e)

51 (1

stu

dy),

3 m

oSe

riou

s b N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

c Ve

ry s

erio

us c

Und

etec

ted

Low

b,c d

ue to

ri

sk o

f bia

s,

impr

ecis

ion

1/27

(3.7

) d 0/

24 (0

)R

R 0

.37

(0.0

2-8.

75)

48 p

er 1

,000

d,e

30 fe

wer

per

1,

000

(fro

m

47 fe

wer

to

372

mor

e)

Non

fata

l maj

or b

leed

ing

(cri

tical

out

com

e)

51 (1

stu

dy),

3 m

oSe

riou

s b N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Very

ser

ious

c U

ndet

ecte

dSe

e co

mm

ent

0/27

(0)

0/24

(0) f

Not

est

imab

leSe

e co

mm

ent

…

PTS

(cri

tical

out

com

e)

51 (1

stu

dy),

2 y

Seri

ous g

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s h U

ndet

ecte

dL

ow g,

h due

to

risk

of b

ias,

im

prec

isio

n

25/2

7 (9

2.6)

14/2

4 (5

8.3)

RR

0.6

3 (0

.44-

0.9)

i 58

8 pe

r 1,

000 j

218

few

er p

er

1,00

0 (f

rom

59

few

er to

32

9 fe

wer

) k

Qua

lity

of li

fe n

ot m

easu

red

……

……

……

……

…-

……

Bib

liogr

aphy

: Pla

te e

t al. 67

See

Tab

le S

1, S

5, a

nd S

10 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a T

he s

tudy

incl

uded

pat

ient

s w

ith D

VT

with

sym

ptom

s of

leg

swel

ling

not e

xcee

ding

7 d

and

a p

roxi

mal

ext

ensi

on o

f the

thro

mbu

s ab

ove

the

ingu

inal

liga

men

t, bu

t not

into

the

vena

cav

a.

b Not

cle

ar w

heth

er a

lloca

tion

was

con

ceal

ed. N

o bl

indi

ng r

epor

ted.

Not

cle

ar w

heth

er a

naly

sis

was

IT

T. F

ollo

w-u

p ra

te 8

8% a

t 6 m

o. S

tudy

not

sto

pped

ear

ly fo

r be

nefi t

. c C

I in

clud

es v

alue

s su

gges

ting

eith

er h

arm

or

bene

fi t.

d One

eve

nt, w

hich

was

a s

ympt

omat

ic P

E.

e Bas

elin

e ri

sks

for

nonf

atal

rec

urre

nt V

TE

der

ived

from

Dou

ketis

et a

l. 39

f No

seve

re b

leed

ing

com

plic

atio

ns w

ere

reco

rded

in e

ither

gro

up. T

hree

pat

ient

s in

thro

mbe

ctom

y gr

oup

deve

lope

d lo

cal w

ound

hem

atom

a.

g In

addi

tion

to o

ther

stu

dy li

mita

tions

, thi

s ou

tcom

e w

as a

sses

sed

by th

ose

who

did

the

surg

ery

and

antic

oagu

latio

n. N

o st

anda

rdiz

ed to

ol w

as u

sed.

One

sur

gica

l pat

ient

had

an

ampu

tatio

n se

cond

ary

to

veno

us g

angr

ene

and

was

not

cou

nted

in th

e PT

S as

sess

men

t. h F

ew n

umbe

r of

eve

nts.

Thi

s w

arra

nts

ratin

g do

wn

the

qual

ity o

f evi

denc

e by

a s

econ

d le

vel w

hen

cons

ider

ed a

long

with

stu

dy li

mita

tions

. i T

he R

R is

bas

ed o

n th

e 6-

mo

data

. j T

his

estim

ate

is b

ased

on

the

fi ndi

ngs

of th

e V

ET

O (V

enou

s T

hrom

bosi

s O

utco

mes

stu

dy. 40

Thi

s pr

obab

ly u

nder

estim

ates

PT

S ba

selin

e ri

sk g

iven

that

ove

rall,

52%

of p

atie

nts

repo

rted

the

curr

ent u

se o

f co

mpr

essi

on s

tock

ings

dur

ing

stud

y fo

llow

-up.

k S

ever

e PT

S: a

ssum

ing

the

sam

e R

R o

f 0.6

3 an

d a

base

line

risk

of 1

3.8%

ove

r 2

y, 40

the

abso

lute

red

uctio

n is

51

few

er s

ever

e PT

S pe

r 1,

000

(fro

m 1

4 fe

wer

to 7

7 fe

wer

) ove

r 2

y.




Tabl

e S1

7 —[S

ecti

on 2

.11]

Su

rgic

al T

hrom

bec

tom

y vs

No

Surg

ical

Thr

omb

ecto

my

for

Ext

ensi

ve A

cute

DV

T o

f th

e L

eg: C

lini

cal

Des

crip

tion

and

Res

ult

s (A

ll R

ando

miz

ed T

rial

s an

d P

rosp

ecti

ve O

bse

rvat

iona

l St

udi

es o

f at

Lea

st 2

0 P

atie

nts)

Aut

hor/

Year

Type

of P

ublic

atio

nPa

rtic

ipan

tsIn

terv

entio

nsO

utco

mes

Fol

low

-up

Res

ults

Plat

e et

al 67

/198

4R

CT,

mul

ticen

ter

58 p

atie

nts

with

acu

te

iliof

emor

al v

enou

s th

rom

bosi

s

Med

ical

: 5,0

00-u

nit b

olus

hep

arin

fo

llow

ed b

y 50

0 un

its/k

g pe

r 24

h a

djus

ted

to a

PTT,

and

ora

l an

ticoa

gula

tion

(31

patie

nts)

PTS

sequ

elae

: ilio

fem

oral

pa

tenc

y, v

alve

com

pete

nce

6 m

oM

edic

al:

PTS

sequ

elae

: 25/

27 (9

3%)

Ilio

fem

oral

pat

ency

: 9/2

6 (3

5%)

Valv

e co

mpe

tenc

e: 7

/27

(26%

) (P

E in

1 p

atie

nt)

Su

rgic

al: o

pera

tive

veno

us th

rom

-be

ctom

y w

ith te

mpo

rary

AV

F

plus

ant

icoa

gula

tion

as a

bove

(2

7 pa

tient

s)

Surg

ical

: PT

S se

quel

ae: 1

4/24

(58%

, P ,

.005

) Il

iofe

mor

al p

aten

cy: 1

6/21

(76%

, P ,

.025

) Va

lve

com

pete

nce:

13/

23, (

52%

P ,

.05)

(ven

ous

gang

rene

in 1

pat

ient

)

Ein

arss

on e

t al 68

/198

6Pr

ospe

ctiv

e re

gist

ry70

pat

ient

s (7

1 le

gs) w

ith

iliof

emor

al D

VT

(age

of

clot

mea

n, 3

d)

Ilio

fem

oral

ven

ous

thro

mbe

ctom

y w

ith te

mpo

rary

AV

F c

lose

d at

6-8

wk,

hep

arin

pre

oper

ativ

ely

and

post

oper

ativ

ely

plus

w

arfa

rin

post

oper

ativ

ely

Veno

us p

aten

cy, h

emat

oma,

AV

F p

aten

cy, P

E, w

ound

in

fect

ion

56 d

(mea

n)Pa

tent

ilia

c ve

in: 8

8%

Hem

atom

a: 1

1%

AVF

pat

ency

: 86%

PE

: 4%

W

ound

infe

ctio

n: 2

6%:

Ein

arss

on e

t al 69

/198

657

pat

ient

s (5

8 lim

bs) w

ith

prio

r op

erat

ive

veno

us

thro

mbe

ctom

y an

d AV

F

clos

ed a

t 6-8

wk

for

iliof

emor

al D

VT

Clin

ical

PT

S, v

enog

raph

y,

veno

us p

ress

ure,

ve

nous

ple

thys

mog

raph

y,

foot

vol

umet

ry

Veno

us in

suffi

cien

cy:

Goo

d, fa

ir, p

oor

9-10

mo

Veno

us in

suffi

cien

cy:

Goo

d: 7

5%

Fai

r: 2

0%

Poor

: 5%

Ve

nogr

aphy

(vei

n se

gmen

t):

Nor

mal

, pos

tthr

ombo

tic,

occl

uded

Veno

grap

hy (i

liofe

mor

al):

Nor

mal

: 61%

Po

stth

rom

botic

: 23%

O

cclu

ded:

39%

Veno

us p

ress

ure:

Nor

mal

, ab

norm

alIV

pre

ssur

e:

Nor

mal

: 82%

A

bnor

mal

: 18%

Plet

hysm

ogra

phy:

Nor

mal

, ab

norm

alPl

ethy

smog

raph

y:

Nor

mal

: 29%

A

bnor

mal

: 71%

Foo

t vol

umet

ry: N

orm

al,

abno

rmal

Foo

t vol

umet

ry:

Nor

mal

: 29%

A

bnor

mal

: 71%

Plat

e et

al 70

/199

0F

ive-

year

follo

w-

up to

RC

T (P

late

, 19

8467

)

41/5

8 pa

tient

s (2

2 m

edic

al,

19 s

urgi

cal)

avai

labl

e fo

r ev

alua

tion

at 5

y

Prio

r tr

eatm

ent:

Med

ical

: an

ticoa

gula

tion

alon

e vs

Su

rgic

al: o

pera

tive

veno

us

thro

mbe

ctom

y pl

us

antic

oagu

latio

n

PTS

sequ

elae

, ilia

c pa

tenc

y,

veno

us p

ress

ure

5 y

Med

ical

: PT

S se

quel

ae: 6

/22

(27%

) Il

iac

pate

ncy:

11/

22 (5

0%)

Veno

us p

ress

ure:

60

mm

Hg

(mea

n)

(Con

tinu

ed)




Aut

hor/

Year

Type

of P

ublic

atio

nPa

rtic

ipan

tsIn

terv

entio

nsO

utco

mes

Fol

low

-up

Res

ults

Su

rgic

al:

PTS

sequ

elae

: 2/1

9 (1

1%)

Ilia

c pa

tenc

y: 1

5/19

(78%

) Ve

nous

pre

ssur

e: 4

3 m

m H

g (m

ean,

P ,

.05)

Neg

lén

et a

l 71 /1

991

Pros

pect

ive

regi

stry

48 p

atie

nts

with

ilio

fem

oral

D

VT

of 1

-14

dO

pera

tive

veno

us th

rom

bect

omy

with

tem

pora

ry A

VF

(c

lose

d 6-

12 w

k po

stop

erat

ive)

Pate

ncy,

PE

, clin

ical

sy

mpt

oms,

nor

mal

ph

otop

leth

ysm

ogra

phy,

su

cces

sful

AV

F c

losu

re

24 m

o (m

ean)

Pate

ncy:

Il

iofe

mor

al: 8

8%

Popl

iteal

: 94%

PE

: 16%

sym

ptom

atic

, 31%

asym

ptom

atic

Sym

ptom

-fre

e: 8

1%

Nor

mal

pho

topl

ethy

smog

raph

y

(no

refl u

x): 5

6% A

VF

clo

sure

su

cces

s ra

te: 8

7%

A

djun

ctiv

e th

erap

y: tr

ansv

enou

s pe

rcut

aneo

us d

ilata

tion

of

seve

re il

iac

sten

osis

(3 p

atie

nts)

Plat

e et

al 72

/199

7Te

n-ye

ar fo

llow

-up

to R

CT

(Pla

te,

1984

[10]

and

19

90 [2

0])

30/5

8 pa

tient

s (1

7 fr

om

med

ical

arm

, 13

from

su

rgic

al a

rm) a

vaila

ble

for

eval

uatio

n

Prio

r tr

eatm

ent M

edic

al:

antic

oagu

latio

n al

one

vs S

urgi

cal:

oper

ativ

e ve

nous

thro

mbe

ctom

y pl

us a

ntic

oagu

latio

n

PTS

sequ

elae

, ilia

c pa

tenc

y,

veno

us p

ress

ure

10 y

Med

ical

: PT

S se

quel

ae: 1

5/17

(88%

) Il

iac

pate

ncy:

7/1

7 (4

1%)

Veno

us p

ress

ure:

63

mm

Hg

(mea

n)

Su

rgic

al:

PTS

sequ

elae

: 7/1

3 (5

4%)

Ilia

c pa

tenc

y: 1

0/12

(83%

) Ve

nous

pre

ssur

e: 5

5 m

m H

g (m

ean)

Ear

ly p

rosp

ectiv

e ob

serv

atio

nal s

tudi

es w

ith ,

20

patie

nts

and

retr

ospe

ctiv

e st

udie

s ar

e de

scri

bed

in T

able

5 o

f th

e ei

ghth

edi

tion

of t

hese

gui

delin

es. 46

See

Tab

le S

1, S

2, S

4, S

10, a

nd S

11 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

.

Tabl

e S1

7—C

onti

nued




Table S18 —[Section 2.11 ] Surgical Thrombectomy vs No Surgical Thrombectomy for Extensive Acute DVT of the Leg: Methodologic Quality

Author/Year Randomization Allocation Concealment Blinding Loss to Follow-up

Plate et al 67 /1984 ND PN N, patients, caregivers, assessors, and data analysts

7

Einarsson et al 68 /1986 N/A N/A N/A N/A

Einarsson et al 69 /1986 N/A N/A N/A N/A

Plate et al 70 /1990 N/A N/A N/A 17

Neglén et al 71 /1991 N/A N/A N/A N/A

Plate et al 72 /1997 N/A N/A N/A 28

See Table S5 and S12 legends for expansion of abbreviations.




Tabl

e S1

9 —[S

ecti

on 2

.13]

Evi

denc

e P

rofi l

e: V

ena

Cav

a F

ilte

r vs

No

Ven

a C

ava

Fil

ter

for

Acu

te P

roxi

mal

DV

T o

f th

e L

eg T

reat

ed W

ith

Ant

icoa

gula

tion

a,b

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Vena

Cav

a F

ilter

sW

ith V

ena

Cav

a F

ilter

s

Rel

ativ

e E

ffec

t (9

5% C

I)

Ris

k W

ith N

o Ve

na C

ava

Filt

ers

Ris

k D

iffer

ence

W

ith V

ena

Cav

a F

ilter

s (9

5% C

I)

Mor

talit

y (im

port

ant o

utco

me)

400

(1 s

tudy

), 8

yN

o se

riou

s ri

sk

of b

ias c

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s d U

ndet

ecte

dM

oder

ate c,

d due

to

impr

ecis

ion

103/

200

(51.

5)98

/200

(49.

0)R

R 0

.95

(0.7

8-1.

16) e

515

per

1,00

026

few

er p

er 1

,000

(f

rom

113

few

er

to 8

2 m

ore)

Sym

ptom

atic

PE

(cri

tical

out

com

e)

304

(1 s

tudy

), 8

yN

o se

riou

s ri

sk

of b

ias c

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s f U

ndet

ecte

dM

oder

ate c,

f due

to

impr

ecis

ion

24/1

59 (1

5.1)

9/14

5 (6

.2)

RR

0.4

1 (0

.2-0

.86)

g 15

1 pe

r 1,

000

89 fe

wer

per

1,0

00

(fro

m 2

1 fe

wer

to

121

few

er)

Rec

urre

nt D

VT

(im

port

ant o

utco

me)

310

(1 s

tudy

), 8

yN

o se

riou

s ri

sk

of b

ias c

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s f U

ndet

ecte

dM

oder

ate c,

f due

to

impr

ecis

ion

41/1

50 (2

7.3)

57/1

60 (3

5.6)

RR

1.3

(0

.93-

1.82

) h 27

3 pe

r 1,

000

82 m

ore

per

1,00

0 (f

rom

19

few

er

to 2

24 m

ore)

Maj

or b

leed

ing

(impo

rtan

t out

com

e)

337

(1 s

tudy

), 8

yN

o se

riou

s ri

sk

of b

ias c

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s d U

ndet

ecte

dM

oder

ate c,

d due

to

impr

ecis

ion

31/1

68 (1

8.5)

26/1

69 (1

5.4)

RR

0.8

3 (0

.52-

1.34

) i 18

5 pe

r 1,

000

31 fe

wer

per

1,0

00

(fro

m 8

9 fe

wer

to

63

mor

e)

(Con

tinu

ed)




Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Vena

Cav

a F

ilter

sW

ith V

ena

Cav

a F

ilter

s

Rel

ativ

e E

ffec

t (9

5% C

I)

Ris

k W

ith N

o Ve

na C

ava

Filt

ers

Ris

k D

iffer

ence

W

ith V

ena

Cav

a F

ilter

s (9

5% C

I)

PTS

(impo

rtan

t out

com

e)

308

(1 s

tudy

), 8

ySe

riou

s j N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous d

Und

etec

ted

Low

d,j d

ue to

ri

sk o

f bia

s,

impr

ecis

ion

107/

153

(69.

9)10

9/15

5 (7

0.3)

RR

0.8

7 (0

.66-

1.13

)69

9 pe

r 1,

000

91 fe

wer

per

1,0

00

(fro

m 2

38 fe

wer

to

91

mor

e)

Com

plic

atio

ns (i

mpo

rtan

t out

com

e)

379

(1 s

tudy

), 2

yN

o se

riou

s ri

sk

of b

ias

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s f U

ndet

ecte

dM

oder

ate f d

ue to

im

prec

isio

n0/

186

(0)

0/19

3 (0

)…

……

k

Qua

lity

of li

fe n

ot r

epor

ted

……

……

……

……

…-

……

Bib

liogr

aphy

: Dec

ousu

s et

al, 8 T

he P

RE

PIC

Inv

estig

ator

s. 73

See

Tab

le S

1, S

2, S

5, a

nd S

10 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a F

our

type

s of

per

man

ent

vena

cav

a fi l

ters

wer

e us

ed: V

ena

Tech

LG

M (

B. B

raun

Mel

suge

n A

G),

titan

ium

Gre

enfi e

ld (

Bos

ton

Scie

ntifi

c C

orpo

ratio

n), C

ardi

al (

C.R

. Bar

d, I

nc),

and

Bir

d’s

Nes

t (C

ook

Gro

up I

ncor

pora

ted)

. b A

ntic

oagu

latio

n co

nsis

ted

of L

MW

H o

r U

FH

initi

ally

(acc

ordi

ng to

a 2

3 2

fact

oria

l des

ign)

follo

wed

by

oral

ant

icoa

gula

tion

for

at le

ast 3

mo.

c A

lloca

tion

conc

eale

d. D

ata

colle

ctor

s an

d ou

tcom

e ad

judi

cato

rs b

linde

d. I

TT

ana

lysi

s. D

ata

mis

sing

for

4%

at

2 y

and

1% a

t 8

y. E

nrol

lmen

t w

as s

topp

ed a

t 40

0 in

stea

d of

tar

gete

d 80

0 du

e to

slo

w

recr

uitm

ent.

d CI

incl

udes

bot

h ne

glig

ible

eff

ect a

nd a

ppre

ciab

le b

enefi

t or

app

reci

able

har

m.

e RR

, 1.0

(95%

CI,

0.2

9-3.

4) a

t 12

d; R

R, 1

.08

(95%

CI,

0.7

3-1.

58) a

t 2 y

. f S

mal

l num

ber

of e

vent

s.

g RR

, 0.2

3 (9

5% C

I, 0

.05-

1.05

) at 1

2 d

(bot

h sy

mpt

omat

ic a

nd a

sym

ptom

atic

PE

). R

R, 0

.54

(95%

CI,

0.2

1-1.

41) a

t 2 y

(sym

ptom

atic

PE

) h R

R, 1

.78

(95%

CI,

1.0

9-2.

94) a

t 2 y

. i R

R, 1

.5 (9

5% C

I, 0

.54-

4.14

) at 1

2 d.

RR

, 0.7

4 (9

5% C

I, 0

.41-

1.36

) at 2

y.

j No

stan

dard

ized

val

idat

ed to

ol u

sed

to m

easu

re P

TS.

k N

o co

mpl

icat

ions

dir

ectly

rel

ated

to

the

fi lte

r or

its

inse

rtio

n re

port

ed in

the

PR

EPI

C (

Prev

entio

n du

Ris

que

d’E

mbo

lie P

ulm

onai

re p

ar I

nter

rupt

ion

Cav

e) t

rial

. 8 M

ism

etti

et a

l 74 (

pros

pect

ive

stud

y)

repo

rted

an

inci

denc

e of

3.2

% (

excl

udin

g fi l

ter

tilt

ing

and

punc

ture

sit

e he

mat

oma)

am

ong

220

pati

ents

rec

eivi

ng r

etri

evab

le v

ena

cava

fi lt

er f

or s

econ

dary

pre

vent

ion

of V

TE

, w

here

as w

hile

A

than

asou

lis e

t al 75

(ret

rosp

ectiv

e st

udy)

rep

orte

d an

inci

denc

e of

0.3

% fo

r m

ajor

com

plic

atio

ns a

mon

g 1,

731

patie

nts

rece

ivin

g ve

na c

ava

fi lte

rs p

redo

min

antly

for

seco

ndar

y pr

even

tion

of V

TE

.

Tabl

e 19

—C

onti

nued




Tabl

e S2

0 —[S

ecti

on 2

.14]

Evi

denc

e P

rofi l

e: E

arly

Am

bu

lati

on v

s D

elay

ed A

mb

ula

tion

for

Acu

te D

VT

of

the

Leg

a,b

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

B

ias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nPu

blic

atio

n B

ias

Ove

rall

Qua

lity

of E

vide

nce

With

Del

ayed

A

mbu

latio

nW

ith E

arly

A

mbu

latio

n

Rel

ativ

e E

ffec

t (9

5% C

I)

Ris

k W

ith

Del

ayed

A

mbu

latio

n

Ris

k D

iffer

ence

W

ith E

arly

A

mbu

latio

n (9

5% C

I)

Mor

talit

y (im

port

ant o

utco

me)

385

(4 s

tudi

es),

3 m

o c Se

riou

s d N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Very

se

riou

s e U

ndet

ecte

dL

ow d,

e due

to

risk

of b

ias,

im

prec

isio

n

2/18

6 (1

.1)

3/19

9 (1

.5)

RR

1.3

(0.2

3-7.

55)

11 p

er 1

,000

3 m

ore

per

1,00

0 (f

rom

8

few

er to

70

mor

e)

PE (c

ritic

al o

utco

me;

ass

esse

d w

ith s

ympt

omat

ic o

r as

ympt

omat

ic P

E)

385

(4 s

tudi

es),

4-12

dSe

riou

s d N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

f Se

riou

s e U

ndet

ecte

d g L

ow d-

g due

to

risk

of b

ias,

im

prec

isio

n

22/1

86 (1

1.8)

27/1

99 (1

3.6)

RR

1.1

6 (0

.66-

2.05

)11

8 pe

r 1,

000

19 m

ore

per

1,00

0 (f

rom

40

few

er to

124

mor

e)

Qua

lity

of li

fe (i

mpo

rtan

t out

com

e; m

easu

red

with

qua

lity

of li

fe q

uest

ionn

aire

in c

hron

ic li

mb

veno

us in

suffi

cien

cy [C

IVIQ

]; be

tter

indi

cate

d by

low

er v

alue

s)

53 (1

stu

dy ),

2 y

Seri

ous h

No

seri

ous

inco

nsis

tenc

ySe

riou

s i N

o se

riou

s im

prec

isio

nU

ndet

ecte

dL

ow h,

i due

to

risk

of b

ias,

in

dire

ctne

ss

1736

-Se

e fo

otno

te j

PTS

(impo

rtan

t out

com

e; a

sses

sed

with

Vill

ata-

Pran

doni

sco

re [v

alue

. 5

])

37 (1

stu

dy) 2

ySe

riou

s h N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous e

Und

etec

ted

Low

e,h d

ue to

ri

sk o

f bia

s,

impr

ecis

ion

9/11

(81.

8)14

/26

(53.

8)R

R 0

.66

(0.4

2-1.

03)

Mod

erat

e

400

per

1,00

013

6 fe

wer

per

1,0

00 (f

rom

23

2 fe

wer

to 1

2 m

ore)

Bib

liogr

aphy

: Kah

n et

al, 76

Ais

saou

i et a

l. 77 I

nclu

ded

stud

ies.

78-8

2 See

Tab

le S

1, S

2, S

5, a

nd S

10 le

gend

s ex

pans

ion

of o

ther

abb

revi

atio

ns.

a In

two

of f

our

elig

ible

tri

als,

all

patie

nts

rece

ived

ear

ly c

ompr

essi

on t

hera

py (

band

ages

or

stoc

king

s). I

n th

e tw

o ot

her

tria

ls, o

nly

patie

nts

rand

omiz

ed t

o ea

rly

ambu

latio

n re

ceiv

ed e

arly

com

pres

sion

th

erap

y.

b Tw

o of

four

elig

ible

stu

dies

exc

lude

d pa

tient

s w

ith s

ympt

omat

ic P

E; i

n th

e th

ird

stud

y, 2

4% o

f par

ticip

ants

had

sym

ptom

atic

PE

at b

asel

ine.

It w

as n

ot c

lear

whe

ther

the

four

th s

tudy

exc

lude

d pa

tient

s w

ith s

ympt

omat

ic P

E.

c Thr

ee s

tudi

es r

epor

ting

acut

e ph

ase

mor

talit

y re

port

ed n

o de

aths

. d C

once

alm

ent o

f allo

cati

on re

port

ed in

one

of f

our s

tudi

es; b

lindi

ng o

f out

com

e as

sess

ors r

epor

ted

in tw

o of

four

stud

ies;

IT

T a

naly

sis r

epor

ted

in tw

o of

four

stud

ies.

Fol

low

-up

97%

-100

%. I

n tw

o of

fo

ur tr

ials

, onl

y pa

tient

s ra

ndom

ized

to e

arly

am

bula

tion

rece

ived

ear

ly c

ompr

essi

on th

erap

y (b

anda

ges

or s

tock

ings

). In

the

two

othe

r tr

ials

, all

patie

nts

rece

ived

ear

ly c

ompr

essi

on th

erap

y.

e CI

incl

udes

bot

h va

lues

of c

linic

ally

sig

nifi c

ant b

enefi

t an

d va

lues

of c

linic

ally

sig

nifi c

ant h

arm

s.

f PE

ass

esse

d as

bot

h sy

mpt

omat

ic a

nd a

sym

ptom

atic

PE

. g F

unne

l plo

t rep

orte

d as

not

asy

mm

etri

cal b

y A

issa

oui e

t al. 77

h C

once

alm

ent o

f allo

catio

n no

t rep

orte

d, o

utco

me

asse

ssor

s no

t blin

ded

for

this

out

com

e; 7

0% fo

llow

-up

rate

; com

pres

sion

sto

ckin

gs u

sed

on p

atie

nts

with

ear

ly m

obili

zatio

n bu

t in

patie

nts

with

del

ayed

m

obili

zatio

n.

iNo

expl

anat

ion

was

pro

vide

d.

j Psy

chol

ogic

and

ove

rall

som

atic

qua

lity

of li

fe d

id n

ot d

iffer

sig

nifi c

antly

bet

wee

n th

e tr

eatm

ent g

roup

s, w

here

as D

VT-

rela

ted

item

s, e

spec

ially

thos

e re

fl ect

ing

the

ease

of l

ocom

otio

n, s

how

ed s

igni

fi can

tly

grea

ter

impr

ovem

ent w

ith c

ompr

essi

on th

an w

ith b

ed r

est (

P ,

.001

for

band

ages

, P ,

.05

for

stoc

king

s).




Tabl

e S2

1 —[S

ecti

on 2

.14]

Ear

ly A

mb

ula

tion

vs

Del

ayed

Am

bu

lati

on f

or A

cute

DV

T o

f th

e L

eg: C

lini

cal

Des

crip

tion

and

Res

ult

s

Aut

hor/

Year

Type

of

Publ

icat

ion

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Sche

llong

et a

l 82 /1

999

RC

T, s

ingl

e ce

nter

126

patie

nts

with

ac

ute

prox

imal

D

VT

Am

bula

tion:

leg

elev

atio

n un

til

day

2, th

en a

mbu

latio

n an

d co

mpr

essi

on (6

4 pa

tient

s)

PE b

y /

sca

n10

dA

mbu

latio

n: P

E: 1

0/59

(17%

)

B

ed r

est f

or 8

d w

ith le

g el

evat

ion

and

com

pres

sion

(6

2 pa

tient

s)

Bed

Res

t: PE

: 14/

63 (2

2%)

Part

sch

et a

l 81 /2

000

RC

T,

mul

ticen

ter

45 p

atie

nts

with

pr

oxim

al D

VT

,

14

d du

ratio

n

Am

bula

tion

1 b

anda

ges:

in

elas

tic U

nna

boot

ba

ndag

es p

lus

wal

king

ex

erci

ses

(15

patie

nts)

Wal

king

dis

tanc

e, p

ain

leve

ls, l

eg c

ircu

mfe

renc

e,

clin

ical

sco

res,

PE

, sid

e ef

fect

s

9 d

Sum

mar

y re

sults

bet

wee

n gr

oups

: Wal

king

dis

tanc

e, p

ain,

le

g ci

rcum

fere

nce

and

clin

ical

sco

res

sign

ifi ca

ntly

impr

oved

in

gro

ups

A a

nd B

com

pare

d w

ith g

roup

C

A

mbu

latio

n 1

sto

ckin

gs:

elas

tic c

ompr

essi

on

stoc

king

s pl

us w

alki

ng

exer

cise

s (1

5 pa

tient

s)

PE, g

roup

A: 2

/15

(13%

) PE

, gro

up B

: 1/1

5 (7

%)

PE, g

roup

C: 1

/15

(7%

)

B

ed r

est,

no c

ompr

essi

on,

LM

WH

(15

patie

nts)

Asc

hwan

den

et a

l 78 /2

001

RC

T, s

ingl

e ce

nter

129

patie

nts

with

ac

ute

DV

TA

mbu

latio

n �

4 h

/d fo

r 4

d un

der

supe

rvis

ion,

LM

WH

(6

9 pa

tient

s)

New

PE

bet

wee

n ba

selin

e an

d da

y 4

by

/ s

can

3 m

oA

mbu

latio

n: P

E: 1

0/69

(14%

)

B

ed r

est f

or 4

d (6

0 pa

tient

s)B

ed r

est:

PE: 6

/60

(10%

)

Not

e: n

ew P

Es

wer

e as

ympt

omat

ic; 1

2/16

pat

ient

s ha

d ba

selin

e PE

s

Part

sch

et a

l 83 /2

001

Pros

pect

ive

stud

y1,

289

patie

nts

with

ac

ute

DV

TA

ll tr

eate

d w

ith L

MW

H,

com

pres

sion

, and

im

med

iate

am

bula

tion

PE o

n /

sca

n at

ad

mis

sion

and

aft

er

10 d

of t

reat

men

t,

10 d

PE a

t adm

issi

on: 6

29/1

,270

(50%

) PE

at 1

0 d:

77/

1,25

6 (6

1%)

Not

e: in

itial

lung

sca

ns w

ere

perf

orm

ed in

1,2

70/1

,289

pat

ient

s;

follo

w-u

p sc

ans

wer

e pe

rfor

med

in 1

,256

/1,2

89 p

atie

nts

Blä

ttle

r et

al 79

/200

3R

CT

53 p

atie

nts

with

pr

oxim

al D

VT

Am

bula

tion

1 b

anda

ges:

fi r

m in

elas

tic b

anda

ges,

am

bula

tion

(18

patie

nts)

Am

bula

tion

1 s

tock

ings

: el

astic

com

pres

sion

st

ocki

ngs,

am

bula

tion

(18

patie

nts)

Wal

king

dis

tanc

e,

wel

l-bei

ng, a

nd

DV

T-re

late

d qu

ality

of

life,

leg

pain

by

visu

al

anal

og s

cale

, ede

ma,

cl

inic

al s

core

s, th

rom

bus

prog

ress

ion

9 d

Wel

l-bei

ng/q

ualit

y of

life

: Im

prov

ed w

ith s

tock

ings

( P ,

.05)

, ba

ndag

es ( P

, .0

1)

Leg

pai

n: D

ecre

ased

fast

er d

urin

g fi r

st 4

d w

/ ban

dage

s an

d st

ocki

ngs

vs b

ed r

est (

P ,

.01)

; nea

r ab

senc

e of

pai

n at

9 d

ach

ieve

d w

ith b

anda

ges

only

(Con

tinu

ed)




Aut

hor/

Year

Type

of

Publ

icat

ion

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

B

ed r

est o

nly

(17

patie

nts)

Ede

ma:

Mar

ked

redu

ctio

n in

leg

size

with

ban

dage

s an

d st

ocki

ngs

vs b

ed r

est (

P ,

.001

)

Clin

ical

sco

res:

Im

prov

ed w

ith b

anda

ges

and

stoc

king

s vs

bed

re

st ( P

, .0

01)

T

hrom

bus

prog

ress

ion:

Im

prov

ed w

ith b

anda

ges

and

stoc

king

s vs

bed

res

t ( P

, .0

1)

PE

: No

diff

eren

ce b

etw

een

grou

ps

Part

sch

et a

l 84 /2

004

2-y

follo

w-u

p to

RC

T (7

7)37

pat

ient

s fo

llow

ed u

p 2

y po

st-R

CT

Ant

icoa

gula

tion

and

bed

rest

vs

antic

oagu

latio

n an

d am

bula

tion

with

com

pres

sion

ba

ndag

es o

r st

ocki

ngs

PTS

asse

ssm

ent

(Vill

alta

-Pra

ndon

i sca

le)

2 y

PTS

scor

es: A

mbu

lato

ry g

roup

(mea

n sc

ore,

5.1

) had

impr

oved

ou

tcom

e vs

bed

res

t gro

up (m

ean

scor

e, 8

.2; P

, .0

1)

Pa

in a

sses

smen

t by

visu

al

anal

og s

cale

and

mod

ifi ed

L

owen

berg

test

Pain

: Low

er p

ain

leve

ls in

mob

ile g

roup

vs

bed

rest

(ns)

T

hrom

bus

regr

essi

onT

hrom

bus

exte

nsio

n: N

o di

ffer

ence

in th

rom

bus

regr

essi

on o

f th

rom

bus

rem

nant

s be

twee

n gr

oups

Truj

illo-

Sant

os e

t al 85

/200

5

Pros

pect

ive

stud

y2,

650

patie

nts

with

ac

ute

DV

T

(2,0

38 [7

7%])

or

PE (6

12 [2

3%])

DV

T g

roup

, bed

res

t or

ambu

latio

n: 1

,050

(52%

) pa

tient

s re

ceiv

ed b

ed r

est,

and

988

(48%

) am

bula

ted.

A

ll re

ceiv

ed L

MW

H.

PE g

roup

, bed

res

t or

ambu

latio

n: 3

85 (6

3%)

patie

nts

rece

ived

bed

res

t, an

d 22

7 (3

7%) a

mbu

late

d.

All

rece

ived

LM

WH

.

Sym

ptom

atic

, con

fi rm

ed

PE d

urin

g fi r

st 1

5 d

of

ther

apy

3 m

oD

VT

gro

up, b

ed r

est:

PE: 7

/105

0 (0

.7%

) D

VT

gro

up, a

mbu

late

: PE

: 4/9

88 (0

.4%

) PE

gro

up, b

ed r

est:

PE: 2

/385

(0.5

%)

PE g

roup

, am

bula

te: P

E: 2

/227

(0.9

%)

Jüng

er e

t al 80

/200

6R

CT,

mul

ticen

ter

open

des

ign

stra

tifi e

d by

age

103

patie

nts

with

pr

oxim

al D

VT

Bed

res

t: 50

pat

ient

s re

ceiv

ed

5 d

of s

tric

t bed

res

t, L

MW

H, c

ompr

essi

on

band

ages

.

PE, p

rogr

essi

on o

f or

new

th

rom

bosi

s, in

fect

ion

or

seri

ous

adve

rse

even

t

5 d

New

PE

bed

res

t: 8/

50 (1

6%) a

mbu

latio

n: 2

/52

(4%

)

A

mbu

latio

n: 5

2 pa

tient

s am

bula

ted

for

5 d,

LM

WH

, co

mpr

essi

on b

anda

ges

Prim

ary

targ

et v

aria

ble:

Bed

res

t: 14

/50

(28%

) A

mbu

latio

n: 7

/52

(13%

)

ns 5

not

sig

nifi c

ant;

/ 5

vent

ilatio

n/pe

rfus

ion.

See

Tab

le S

2, S

5, a

nd S

10 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

Tabl

e S2

1—C

onti

nued




Table S22 —[Section 2.14] Early Ambulation vs Delayed Ambulation for Acute DVT of the Leg: Methodologic Quality

Author/Year RandomizationAllocation

Concealment Blinding Loss to Follow-up

Schellong et al 82 /1999 Patients randomized to 1 of 2 study groups Unclear Y, assessors N, patients, caregivers, analysts

4

Partsch et al 81 /2000 Patients randomized to 1 of 3 study groups by sealed envelope

Unclear Y, assessors N, patients, caregivers, analysts

0

Aschwanden et al 78 /2001 Patients randomized to 1 of 2 study groups Sealed envelope Not blinded 5

Partsch et al 83 /200 N/A N/A N/A N/A

Blättler et al 79 /2003 Patients randomized to 1 of 3 study groups by sealed envelope

Not specifi ed Y, assessors N, patients, caregivers, analysts

0

Partsch et al 84 /2004 N/A N/A N/A 21

Trujillo-Santos et al 85 /2005 N/A N/A N/A N/A

Jünger et al 80 /2006 Patients randomized to 1 of 2 study groups by sealed envelope

Unclear Y, analysts N, patients, caregivers, assessors





Tabl

e S2

3 —[S

ecti

ons

3.1.

1-3.

1.4]

Evi

denc

e P

rofi l

e: F

our

or S

ix W

eeks

vs

Thr

ee o

r Si

x M

onth

s as

Min

imu

m D

ura

tion

of

Ant

icoa

gula

tion

for

VT

E a,b

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

up

Ris

k of

B

ias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nPu

blic

atio

n B

ias

Ove

rall

qual

ity o

f E

vide

nce

With

Con

trol

With

4 o

r 6

wk

vs 3

or

6 m

o of

A

ntic

oagu

latio

n

Rel

ativ

e E

ffec

t (9

5% C

I)R

isk

With

C

ontr

ol

Ris

k D

iffer

ence

With

4

or 6

wk

vs 3

or

6 m

o of

A

ntic

oagu

latio

n (9

5% C

I)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

2,18

5 (5

stu

dies

c ),

1-2

y d N

o se

riou

s ri

sk o

f bia

s e N

o se

riou

s in

cons

iste

ncy f

No

seri

ous

indi

rect

ness

No

seri

ous

impr

ecis

ion g

Und

etec

ted

Hig

h e-g

70/1

,090

(6.4

)12

7/1,

095

(11.

6)R

R 1

.83

(1.3

9-2.

42)

64 p

er 1

,000

53 m

ore

per

1,00

0 (f

rom

25

mor

e to

91

mor

e)

Maj

or b

leed

ing

(cri

tical

out

com

e)

2,18

5 (5

stu

dies

), 1-

2 yd

No

seri

ous

risk

of

bia

sN

o se

riou

s in

cons

iste

ncy f

No

seri

ous

indi

rect

ness

No

seri

ous

impr

ecis

ion

Und

etec

ted

Hig

h f 13

/1,0

90 (1

.2)

7/1,

095

(0.6

)R

R 0

.54

(0.2

2-1.

32)

12 p

er 1

,000

5 fe

wer

per

1,0

00 (f

rom

9

few

er to

4 m

ore)

Mor

talit

y (im

port

ant o

utco

me)

2,09

8 (5

stu

dies

), 1-

2 yd

No

seri

ous

risk

of

bia

s e N

o se

riou

s in

cons

iste

ncy f

No

seri

ous

indi

rect

ness

No

seri

ous

impr

ecis

ion h

Und

etec

ted

Hig

h e,f,h

55

/998

(5.5

)57

/1,1

00 (5

.2)

RR

0.9

7 (0

.68-

1.38

)55

per

1,0

002

few

er p

er 1

,000

(fro

m

18 fe

wer

to 2

1 m

ore)

Bib

liogr

aphy

: Kea

ron

et a

l, 86 P

ined

e et

al, 87

Sch

ulm

an e

t al, 88

Lev

ine

et a

l, 89 B

ritis

h T

hora

cic

Soci

ety.

90 S

ee T

able

S1,

S5,

and

S2

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Sho

rt v

s lo

nger

dur

atio

n of

ant

icoa

gula

tion

was

6 w

k vs

6 m

o fo

r Sc

hulm

an e

t al,

6 w

k vs

3 m

o fo

r Pi

nede

et a

l, an

d 4

wk

vs 3

mo

for

the

othe

r th

ree

stud

ies.

b P

opul

atio

ns v

arie

d am

ong

stud

ies:

fi rs

t pro

voke

d is

olat

ed d

ista

l DV

T, p

roxi

mal

DV

T o

r PE

pro

voke

d in

Kea

ron

et a

l; fi r

st is

olat

ed d

ista

l DV

T in

Pin

ede

et a

l; fi r

st is

olat

ed d

ista

l DV

T, p

roxi

mal

DV

T, o

r PE

in

Sch

ulm

an e

t al;

prox

imal

DV

T (2

1% h

ad c

ance

r) in

Lev

ine

et a

l; an

d D

VT

or

PE (2

9% n

ot o

bjec

tivel

y co

nfi r

med

) in

Bri

tish

Tho

raci

c So

ciet

y.

c Tim

ing

of ra

ndom

izat

ion

rela

tive

to th

e st

art o

f tre

atm

ent v

arie

d ac

ross

stud

ies:

Pin

ede

et a

l, Sc

hulm

an e

t al,

and

Bri

tish

Tho

raci

c So

ciet

y ra

ndom

ized

at d

iagn

osis

; Kea

ron

et a

l and

Lev

ine

et a

l ran

dom

ized

to

sto

p or

to c

ontin

ue tr

eatm

ent o

f 2 m

ore

mon

ths

afte

r th

e in

itial

4 w

k of

trea

tmen

t. e G

ener

ally

, stu

dy d

esig

n w

as s

tron

g. N

o st

udy

stop

ped

earl

y fo

r be

nefi t

; tw

o st

oppe

d ea

rly

beca

use

of s

low

rec

ruitm

ent (

Kea

ron

et a

l, Pi

nede

et a

l). I

n on

e st

udy

(Bri

tish

Tho

raci

c So

ciet

y), 4

4 ra

ndom

ized

pa

tient

s w

ere

excl

uded

cen

tral

ly a

s th

ey d

id n

ot s

atis

fy e

ligib

ility

cri

teri

a. P

atie

nts

and

care

give

rs w

ere

blin

ded

in tw

o st

udie

s (K

earo

n et

al,

Lev

ine

et a

l). A

djud

icat

ors

of o

utco

mes

wer

e bl

inde

d in

all

but

one

stud

y (B

ritis

h T

hora

cic

Soci

ety)

. All

stud

ies

appe

ared

to h

ave

used

eff

ectiv

e ra

ndom

izat

ion

conc

ealm

ent,

ITT

ana

lysi

s, a

nd a

ppea

rs to

hav

e a

low

une

xpla

ined

dro

p-ou

t fre

quen

cy.

f No

hete

roge

neity

with

I 2 5

0%

. g N

o im

prec

isio

n fo

r ov

eral

l est

imat

es. H

owev

er, f

or th

e su

bgro

up o

f pat

ient

s w

ith is

olat

ed d

ista

l DV

T, w

ho a

re k

now

n to

hav

e a

very

low

ris

k of

rec

urre

nce,

ther

e is

impr

ecis

ion

and

the

poss

ibili

ty th

at th

e sh

orte

r du

ratio

n of

ant

icoa

gula

tion

is a

dequ

ate

and

not a

ssoc

iate

d w

ith a

clin

ical

ly im

port

ant h

ighe

r ri

sk o

f rec

urre

nce.

d F

ollo

w-u

p w

as fo

r �

1 y

in a

ll st

udie

d ex

cept

for

Schu

lman

et a

l in

whi

ch it

was

2 y

. h D

iffer

ence

s in

mor

talit

y ar

e ex

pect

ed to

be

med

iate

d by

diff

eren

ces

in r

ecur

rent

VT

E a

nd b

leed

ing.




Tabl

e S2

4 —[S

ecti

ons

3.1.

1-3.

1.4]

Com

pari

son

of D

ura

tion

s of

Ant

icoa

gula

nt T

hera

py f

or D

VT

and

PE

: Cli

nica

l D

escr

ipti

on a

nd R

esu

lts

Aut

hor/

Year

(Acr

onym

)In

terv

entio

nN

o. P

atie

nts

Ana

lyze

dL

engt

h F

ollo

w-u

pR

ecur

rent

DV

T o

r PE

Maj

or B

leed

ing

Tota

l Mor

talit

yC

omm

ents

Shor

t (4

or 6

wk)

vs

inte

rmed

iate

(3 o

r 6

mo)

dur

atio

ns o

f ant

icoa

gula

tion

Kea

ron

et a

l 86 /2

004

(SO

FAST

)V

KA

sto

pped

(pla

cebo

)84

/84

11 m

o5/

84 (6

%)

0/84

0/84

Popu

latio

n: fi

rst D

VT

or

PE.

Trea

ted

for

1 m

o. V

TE

was

as

ympt

omat

ic in

9%

and

isol

ated

ca

lf D

VT

in 1

8%. O

ne V

TE

oc

curr

ed w

hile

on

war

fari

n.

V

KA

(IN

R 2

.0-3

.0)

For

2 m

ore

mo.

81/8

111

mo

3/81

(4%

) RR

0.6

(0

.1-2

.5)

0/81

RR

1.0

(0

.0-5

1.6)

1/81

(1%

) RR

3.1

(0

.1-7

4.4)

Pine

de e

t al 87

/200

1 (D

OTA

VK

)V

KA

(IN

R 2

.0-3

.0)

for

1.5

mo

105/

105

15 m

o2/

105

(2%

)1/

105

(1%

)N

ot s

peci

fi ed

Popu

latio

n: fi

rst i

sola

ted

calf

DV

T.

V

KA

(IN

R 2

.0-3

.0)

for

3 m

o92

/92

3/92

RR

1.7

(0

.3-1

0.0)

3/92

RR

3.4

(0.4

-33.

4)

Schu

lman

et a

l 88 /1

995

(DU

RA

C 1

)V

KA

(IN

R 2

.0-2

.85)

fo

r 1.

5 m

o44

3/44

32

y80

/443

(18%

)1/

443

22/4

43 (5

%)

Fir

st V

TE

: DV

T (d

ista

l or

prox

imal

) or

PE

. Onl

y as

ked

abou

t ble

edin

g w

hile

on

VK

As.

VK

A (I

NR

2.0

-2.8

5)

for

6 m

o45

4/45

443

/454

(9%

) RR

0.5

(0

.4, 0

.7)

5/45

4 (1

%)

RR

4.9

(0.6

-41.

6)17

/454

(4%

) RR

(0

.7-1

.4)

Lev

ine

et a

l 89 /1

995

VK

A s

topp

ed (p

lace

bo)

105/

107

9 m

o12

/105

(11%

)0/

105

9/10

5 (9

%)

Prox

imal

DV

T (fi

rst

epi

sode

in

91%

). C

ance

r in

21%

.

VK

A (I

NR

2.0

-3.0

) fo

r 2

mor

e m

o.10

9/11

37/

109

(6%

) RR

0.6

(0

.2-1

.4)

1/10

9 (1

%) R

R 2

.9

(0.1

-70.

2) (w

ithin

2

mo

of r

ando

miz

atio

n)

9/10

9 (8

%) R

R 1

.0

(0.4

-2.5

)

Bri

tish

Tho

raci

c So

ciet

y et

al 90

/199

2V

KA

(IN

R 2

.0-3

.0)

For

1 m

o35

8/35

81

y28

/358

(11%

)5/

358

(1%

)26

/358

(7%

)Po

pula

tion:

DV

T o

r PE

; onl

y 71

%

obje

ctiv

ely

diag

nose

d; p

ropo

rtio

n w

ith a

pre

viou

s V

TE

not

kno

wn.

VK

A (I

NR

2.0

-3.0

) fo

r 3

mo

354/

354

1 y

14/3

54 (4

%) R

R

0.5

(0.3

-0.9

)

4/35

4 (1

%)

RR

0.8

(0.2

-3.0

)28

/354

(8) R

R 1

.1

(0.6

-1.8

)A

ll bl

eeds

wer

e on

VK

A. O

nly

1 re

curr

ent V

TE

am

ong

116

patie

nts

with

pos

tope

rativ

e V

TE

. (C

onti

nued

)




Aut

hor/

Year

(Acr

onym

)In

terv

entio

nN

o. P

atie

nts

Ana

lyze

dL

engt

h F

ollo

w-u

pR

ecur

rent

DV

T o

r PE

Maj

or B

leed

ing

Tota

l Mor

talit

yC

omm

ents

Diff

eren

t int

erm

edia

te d

urat

ions

(6 o

r 12

mo

vs 3

mo)

of a

ntic

oagu

latio

n

Cam

pbel

l et a

l 91 /2

007

VK

A (I

NR

2.0

.0-3

.5)

for

3 m

o36

9/39

61

y31

/369

(8%

)0/

369

(dur

ing

3 m

o.

trea

tmen

t)15

/369

(4%

)Po

pula

tion:

DV

T o

r PE

; pro

port

ion

with

cal

f DV

T n

ot k

now

n. O

nly

blee

ding

dur

ing

trea

tmen

t is

repo

rted

; 20%

of V

TE

out

com

es

wer

e no

t obj

ectiv

ely

veri

fi ed.

VK

A (I

NR

2.0

-3.5

) fo

r 6

mo

380/

414

1 y

29/3

80 (8

%) R

R0.

9 (0

.6-1

.5)

8/38

0 (2

%) (

duri

ng 6

mo.

tr

eatm

ent)

RR

16.

5 (1

.0-2

85)

19/3

69 (5

%) R

R 1

.3

(0.6

-2.5

)

Agn

elli

et a

l 92 /2

003

(WO

DIT

PE

)V

KA

sto

pped

91/9

12.

6 y

(mea

n)11

/91

(12%

)1/

91 (1

%)

7/91

(8%

)Po

pula

tion:

fi rs

t unp

rovo

ked

PE.

Trea

ted

for

� 3

mo.

Am

ong

the

4 gr

oups

, onl

y 1

recu

rren

t VT

E

whi

le o

n V

KA

.

VK

A (I

NR

2.0

-3.0

) fo

r 9

mor

e m

o90

/90

2.9

y (m

ean)

11/9

0 (1

2%) R

R 1

.0

(0.5

-2.2

)2/

90 (2

%) R

R 2

.0

(0.5

-21.

9)8/

90 (9

%) R

R 1

.16

(0.4

-3.0

)

V

KA

sto

pped

70/7

02.

8 y

(mea

n)7/

70 (1

0%)

0/70

(0%

)0/

70 (0

%)

Popu

latio

n: fi

rst p

rovo

ked

PE.

Trea

ted

for

� 3

mo

(see

abo

ve)

V

KA

(IN

R 2

.0-3

.0)

for

3 m

ore

mo

75/7

52.

9 y

(mea

n)4/

75 (5

%) R

R 0

.5

(0.2

-1.7

)1/

75 (1

%) R

R 1

.9

(0.1

-56)

4/75

(5%

) RR

8.4

(0

.5-1

53)

Agn

elli

et a

l 93 /2

001

(WO

DIT

DV

T)

VK

A s

topp

ed13

3/13

33.

2 y

(mea

n)21

/133

(16%

)2/

133

(2%

)7/

133

(5%

)Po

pula

tion:

fi rs

t unp

rovo

ked

prox

-im

al D

VT

trea

ted

for

3 m

o. O

ne

patie

nt h

ad r

ecur

rent

VT

E o

n V

KA

. Ble

edin

g in

the

inte

rven

-tio

n gr

oup

was

whi

le o

n V

KA

.

VK

A (I

NR

2.0

-3.0

) fo

r 9

mo

134/

134

3.1

y (m

ean)

21/1

34 (1

6%) R

R 1

.0

(0.6

-1.7

)4/

134

(3%

) RR

2.0

(0

.4-1

0.7)

7/13

4 (5

%) R

R 1

.0

(0.4

-2.8

)

Pine

de e

t al 87

/200

1 (D

OTA

VK

)V

KA

(IN

R 2

.0-3

.0)

for

3 m

o27

0/27

015

mo

21/2

70 (8

%)

5/27

0 (2

%)

Not

spe

cifi e

dPo

pula

tion:

fi rs

t pro

xim

al D

VT

or

PE. R

ecur

rent

VT

E o

ccur

red

afte

r V

KA

in 2

6/28

of t

he s

hort

du

ratio

n gr

oups

and

21/

27 o

f the

lo

ng d

urat

ion

grou

ps.

V

KA

(IN

R 1

.0-3

.0)

for

6 m

o26

9/26

923

/269

(9%

) RR

1.1

(0

.6-1

.9)

7/26

9 (3

%))

RR

1.4

(0

.4-4

.4)

Sira

gusa

et a

l 94 /2

008

(DA

CU

S)V

KA

sto

pped

92/9

21.

8 y

27/9

2 (2

9%)

1/92

(1%

)N

ot s

peci

fi ed

(tot

al o

f 3 n

on-

VT

E/b

leed

dea

ths)

Popu

latio

n: fi

rst p

roxi

mal

DV

T

(pro

voke

d, 2

4%; u

npro

voke

d,

76%

) tre

ated

for

3 m

o an

d re

sidu

al D

VT

on

base

line

ultr

asou

nd

Tabl

e S2

4—C

onti

nued

(Con

tinu

ed)




Aut

hor/

Year

(Acr

onym

)In

terv

entio

nN

o. P

atie

nts

Ana

lyze

dL

engt

h F

ollo

w-u

pR

ecur

rent

DV

T o

r PE

Maj

or B

leed

ing

Tota

l Mor

talit

yC

omm

ents

Inde

fi nite

vs

inte

rmed

iate

dur

atio

ns o

f ant

icoa

gula

tion

(IN

R �

2.0

-3.0

)

Pala

reti

et a

l 95 /2

006

(PR

OL

ON

G)

Rem

ain

off (

stop

) VK

A10

3/10

51.

4 y

(mea

n)18

/120

(15%

)0/

103

1/10

3 (1

%)

Popu

latio

n: fi

rst u

npro

voke

d pr

ox-

imal

DV

T o

r PE

. Tre

ated

for

� 3

m

o. V

KA

sto

pped

and

D-d

imer

po

sitiv

e 1

mo

late

r. E

ight

con

trol

pa

tient

. Res

tart

ed V

KA

, som

e af

ter

supe

rfi c

ial p

hleb

itis.

One

re

curr

ent V

TE

in V

KA

gro

up

afte

r V

KA

sto

pped

.

Res

tart

inde

fi nite

VK

A

(IN

R 2

.0-3

.0) (

not

blin

ded)

120/

122

(max

imum

, 1.

5 y)

2/10

3 (2

%) R

R 0

.1

(0.0

-0.4

)1/

120

(1%

) RR

2.6

(0

.1-6

2.6)

1/12

0 (1

%) R

R 0

.9

(0.1

-13.

6)

Kea

ron

et a

l 96 /1

999

(LA

FIT

)V

KA

sto

pped

(pla

cebo

)83

/83

10 m

o (m

ean)

17/8

3 (2

0%)

0/83

3/83

(4%

)Po

pula

tion:

fi rs

t unp

rovo

ked

prox

imal

DV

T o

r PE

(5%

had

pr

evio

us p

rovo

ked

VT

E).

The

re

curr

ent V

TE

in th

e V

KA

pa

tient

was

aft

er s

topp

ing

VK

A.

V

KA

(IN

R 2

.0-3

.0) f

or 2

m

ore

year

s79

/79

(max

imum

, 2 y

)1/

79 (1

%) R

R 0

.1

(0.0

-0.5

)3/

79 (4

%) R

R 7

.4 (0

.4-1

40)

1/79

(1%

) RR

0.3

(0

.0-3

.3)

Schu

lman

et a

l 97 /1

997

(DU

RA

C 2

)V

KA

(IN

R 2

.0-2

.85)

for

6 m

o11

1/11

14

y23

/111

(2%

)3/

111

(3%

)16

/111

(14%

)Se

cond

VT

E: D

VT

(dis

tal o

r pr

ox-

imal

) or

PE. A

ll re

curr

ent V

TE

in

the

inde

fi nite

VK

A g

roup

wer

e af

ter

stop

ping

VK

As.

Ble

edin

g du

ring

the

fi rst

6 m

o of

VK

A in

1

of 6

mo

grou

p an

d 6

of in

defi n

ite

grou

p (o

nly

aske

d ab

out b

leed

ing

whi

le o

n V

KA

s).

V

KA

(IN

R 2

.0-2

.85)

in

defi n

itely

116/

116

3/11

6 (3

%) R

R 0

.1

(0.0

-0.4

)10

/116

(9%

) RR

3.2

(0

.9-1

1.3)

10/1

16 (9

%) R

R 0

.6

(0.3

-1.3

)

Far

raj e

t al 98

/200

4V

KA

(IN

R 2

.0-3

.0) f

or

6 m

o32

/36

3 y

7/32

(22%

)2/

32 (6

%)

0/32

In to

tal:

2 V

TE

aft

er 2

4 m

o (2

4 m

o gr

oup)

; 1 V

TE

on

ther

apy

(24

mo

grou

p)

V

KA

(IN

R 2

.0-2

.85)

for

24 m

o32

/36

3/32

(3%

) RR

0.4

(0

.1-1

.5)

2/32

(6%

) RR

1.0

(0

.2-6

.7)

0/32

Tabl

e S2

4—C

onti

nued

(Con

tinu

ed)




Aut

hor/

Year

(Acr

onym

)In

terv

entio

nN

o. P

atie

nts

Ana

lyze

dL

engt

h F

ollo

w-u

pR

ecur

rent

DV

T o

r PE

Maj

or B

leed

ing

Tota

l Mor

talit

yC

omm

ents

Fix

ed v

s fl e

xibl

e du

ratio

n, d

epen

ding

on

pres

ence

of r

esid

ual t

hrom

bosi

s on

follo

w-u

p ul

tras

ound

(IN

R 2

.0-3

.0)

Pran

doni

et a

l 99 /2

009

(AE

SOPU

S)V

KA

sto

pped

if p

rovo

ked

and

3 m

ore

mon

ths

if un

prov

oked

268/

268

33 m

o46

/268

(17%

)2/

268

(1%

)11

/268

(4%

)Po

pula

tion:

fi rs

t pro

voke

d (4

3%)

or u

npro

voke

d (5

7%) p

roxi

mal

D

VT

trea

ted

for

3 m

o. O

ne V

TE

in

eac

h gr

oup

whi

le o

n V

KA

s.

The

fl ex

ible

gro

up w

as tr

eate

d fo

r a

mea

n of

4 m

o (p

rovo

ked)

and

5

mo

(unp

rovo

ked)

long

er.

St

oppe

d if

no r

esid

ual v

ein

thro

mbo

sis

and

until

re

solv

ed o

r 9

mor

e m

o if

prov

oked

or

21 m

ore

mo

if un

prov

oked

270/

270

32/2

70 (1

2%) R

R 0

.7

(0.4

-1.1

)4/

270/

255

(1%

) R

R 2

.0 (0

.4-1

0.8)

4/25

5 (6

%) R

R 1

.5

(0.7

-3.2

)

Inde

fi nite

vs

inte

rmed

iate

dur

atio

ns o

f ant

icoa

gula

tion

(IN

R �

1.5

-2.0

, aft

er in

itial

IN

R 2

.0-3

.0 in

bot

h gr

oups

)

Rid

ker

et a

l 100 /2

003

(PR

EV

EN

T)

VK

A s

topp

ed o

r no

t re

star

ted

(pla

cebo

)25

3/25

32.

1 y

(mea

n)37

/253

(15%

)2/

253

(1%

)8/

253

(3%

)Po

pula

tion:

unp

rovo

ked

DV

T

(dis

tal o

r pr

oxim

al) o

r PE

(fi r

st

epis

ode

in 3

8%).

Eig

ht r

ecur

rent

V

TE

in th

e V

KA

gro

up a

fter

st

oppi

ng V

KA

s.

V

KA

IN

R 1

.5-2

.025

5/25

5(m

axim

um,

4.3

y)14

/255

(5%

) RR

0.4

(0

.2-0

.7)

5/25

5 (2

%) R

R 2

.5

(0.5

-12.

7)4/

255

(2%

) R

R 0

.5 (0

.1-1

.6)

Low

inte

nsity

(IN

R 1

.5-1

.9) v

s co

nven

tiona

l int

ensi

ty (I

NR

2.0

-3.0

)

Kea

ron

et a

l 101 /2

003

(EL

ATE

)V

KA

IN

R 1

.5-1

.936

9/36

92.

4 y

(mea

n)16

/369

(4%

)9/

369

(2%

)16

/369

(4%

)Po

pula

tion:

unp

rovo

ked

prox

imal

D

VT

or

PE (fi

rst

epi

sode

in

31%

). Tr

eate

d fo

r �

3 m

o. V

KA

(I

NR

2.0

-3.0

) (m

ean

12 m

o). F

ive

recu

rren

t VT

E in

IN

R 1

.5-1

.9

and

thre

e in

the

INR

2.0

-3.0

gr

oup

afte

r st

oppi

ng V

KA

s.

V

KA

IN

R 2

.0-3

.0

(blin

ded)

369/

369

6/36

9 (2

%)R

R 0

.4

(0.1

-0.9

)8/

369

(2%

) RR

0.9

(0

.3-2

.3)

8/36

9 (2

%) R

R 0

.5

(0.2

-1.2

)

AE

SOPU

S 5

Ultr

asou

nd F

indi

ngs

to A

djus

t the

Dur

atio

n of

Ant

icoa

gula

tion;

DA

CU

S 5

Dur

atio

n of

Ant

icoa

gula

tion

base

d on

Com

pres

sion

Ultr

aSon

ogra

phy;

DO

TAV

K 5

Dur

ée O

ptim

ale

du T

raite

men

t A

ntiV

itam

ines

K; D

UR

AC

5 D

urat

ion

of A

ntic

oagu

latio

n; E

LAT

E 5

Ant

icoa

gula

tion

for

Thr

ombo

-Em

bolis

m; L

AF

IT 5

Lon

g-te

rm A

ntic

oagu

latio

n fo

r a

Fir

st e

piso

de o

f Idi

opat

hic

veno

us T

hrom

boem

-bo

lism

; PR

EV

EN

T 5

Pre

vent

ion

of R

ecur

rent

Ven

ous

Thr

ombo

embo

lism

; SO

FAST

5 F

irst

Acu

te S

econ

dary

Thr

ombo

sis;

WO

DIT

DV

T 5

War

fari

n O

ptim

al D

urat

ion

Ital

ian

Tria

l in

patie

nts

with

DV

T;

WO

DIT

PE

5 W

arfa

rin

Opt

imal

Dur

atio

n It

alia

n Tr

ial i

n pa

tient

s w

ith P

ulm

onar

y E

mbo

lism

. See

Tab

le S

1, S

2, a

nd S

7 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

Tabl

e S2

4—C

onti

nued




(Con

tinu

ed)

Tabl

e S2

5 —[S

ecti

ons

3.1.

1-3.

1.4]

Com

pari

son

of D

ura

tion

s of

Ant

icoa

gula

nt T

hera

py f

or D

VT

and

PE

: Met

hodo

logi

c Q

ual

ity

Aut

hor/

Year

(Acr

onym

)In

terv

entio

nSt

udy

Des

ign

Ran

dom

izat

ion

Con

ceal

edB

lindi

ngL

oss

to F

ollo

w-u

pA

naly

sis

Com

men

ts

Kea

ron

et a

l 86 /2

004

(SO

FAST

)

VK

A s

topp

ed (p

lace

bo)

VK

A (I

NR

2.0

-3.0

)

for

2 m

ore

mo

RC

TC

YPa

tient

s: C

Y C

areg

iver

s: C

Y A

djud

icat

ions

: CY

Dat

a A

naly

sts:

CY

Plac

ebo:

0/8

4V

KA

: 0/8

1IT

TSt

oppe

d ea

rly

beca

use

of s

low

re

crui

tmen

t.

Pine

de e

t al 87

/200

1 (D

OT

AV

K)

VK

A (I

NR

2.0

-3.0

)

for

1.5

and

3 m

oV

KA

(IN

R 1

.0-3

.0) f

or

3

and

6 m

o

RC

TC

YPa

tient

s: C

N

Car

egiv

ers:

CN

A

djud

icat

ions

: CY

Dat

a A

naly

sts:

PN

Not

spe

cifi e

dPr

obab

ly lo

w o

r ni

lIT

TSt

oppe

d ea

rly

beca

use

of s

low

re

crui

tmen

t. Pa

tient

with

draw

als:

4

in s

hort

- and

16

in lo

ng-d

urat

ion

grou

ps. T

otal

of 2

2 pa

tient

s dr

oppe

d ou

t.

Schu

lman

et a

l 88 /1

995

(DU

RA

C 1

)V

KA

(IN

R2.

0-2.

85)

fo

r 1.

5 m

oV

KA

(IN

R 2

.0-2

.85)

for

6 m

o

RC

TC

YPa

tient

s: C

N

Car

egiv

ers:

CN

A

djud

icat

ions

: VT

E, C

Y O

ther

: PN

D

ata

Ana

lyst

s: P

N

Tota

l of 4

4 pa

tient

s

drop

ped

out d

urin

g fo

llow

-up

but p

artia

l fo

llow

-up

achi

eved

ITT

Fiv

e pa

tient

wer

e ex

clud

ed b

ecau

se

prot

ein

C fo

und

afte

r ra

ndom

izat

ion.

Lev

ine

et a

l 89 /1

995

VK

A s

topp

ed (p

lace

bo)

VK

A (I

NR

2.0

-3.0

)

for

2 m

ore

mo.

RC

TC

YPa

tient

s: C

Y C

areg

iver

s: C

Y A

djud

icat

ions

: VT

E, C

Y D

ata

Ana

lyst

s: P

N

Plac

ebo:

1/1

05

VK

A: 6

/109

(d

id n

ot c

ompl

ete

11

-mo

follo

w-u

p)

ITT

Two

plac

ebo

and

4 w

arfa

rin

patie

nts

with

drew

con

sent

sho

rtly

aft

er

rand

omiz

atio

n.

Bri

tish

Tho

raci

c So

ciet

y et

al 90

/199

2V

KA

(IN

R 2

.0-3

.0) F

or 1

mo

VK

A

(IN

R 2

.0-3

.0) f

or 3

mo

RC

TC

YPa

tient

s: C

N

Car

egiv

ers:

CN

A

djud

icat

ions

: CN

D

ata

Ana

lyst

s: P

N

No

VK

A: 2

7/35

4 V

KA

: 30/

358

ITT

For

ty-f

our

rand

omiz

ed p

atie

nts

excl

uded

cen

tral

ly a

s di

d no

t sat

isfy

en

try

crite

ria.

Cam

pbel

l et a

ll 91 /2

007

VK

A (I

NR

2.0

.0-3

.5) f

or 3

mo

VK

A (I

NR

2.0

-3.5

) for

6 m

oR

CT

CY

Patie

nts:

CN

C

areg

iver

s: C

N

Adj

udic

atio

ns: C

N

Dat

a A

naly

sts:

PN

3- m

o V

KA

: 6/3

69

6- m

o V

KA

: 4/3

80IT

TSi

xty-

one

rand

omiz

ed p

atie

nts

excl

uded

cen

tral

ly a

s di

d no

t sat

isfy

en

try

crite

ria.

Sto

pped

ear

ly b

ecau

se

of lo

w r

ecru

itmen

t.

Agn

elli

et a

l 92 /2

003

(WO

DIT

PE

)V

KA

sto

pped

VK

A (I

NR

2.0

-3.0

)

for

9 m

ore

mo.

RC

TC

YPa

tient

s: C

N

Car

egiv

ers:

CN

A

djud

icat

ions

: CY

Dat

a A

naly

sts:

PN

Not

spe

cifi e

d Pr

obab

ly lo

w o

r ni

lIT

TTw

o pa

tient

s in

the

cont

rol g

roup

s an

d 2

patie

nts

in th

e in

terv

entio

n gr

oups

cr

osse

d ov

er. F

ive

patie

nts

in th

e in

tend

ed g

roup

did

not

sto

p V

KA

. F

our

patie

nts

in th

e co

ntro

l gro

ups

rest

arte

d V

KA

s.

Agn

elli

et a

l 93 /2

001

(WO

DIT

DV

T)

VK

A s

topp

edV

KA

(IN

R 2

.0-3

.0) f

or 9

mo

RC

TC

YPa

tient

s: C

N

Car

egiv

ers:

CN

A

djud

icat

ions

: CY

Dat

a A

naly

sts:

PN

Not

spe

cifi e

d Pr

obab

ly lo

w o

r ni

lIT

TTr

ial s

topp

ed e

arly

for

lack

of a

dequ

ate

bene

fi t. F

our

patie

nts

in th

e in

terv

entio

n an

d 2

patie

nts

in th

e co

ntro

l gro

up c

ross

ed o

ver.




Tabl

e S2

5—C

onti

nued

Aut

hor/

Year

(Acr

onym

)In

terv

entio

nSt

udy

Des

ign

Ran

dom

izat

ion

Con

ceal

edB

lindi

ngL

oss

to F

ollo

w-u

pA

naly

sis

Com

men

ts

Sira

gusa

et a

l 94 /2

008

(DA

CU

S)V

KA

sto

pped

V

KA

(IN

R 1

.0-3

.0)

fo

r 9

mo.

RC

TPY

Patie

nts:

CN

C

areg

iver

s: C

N

Adj

udic

atio

ns: P

Y D

ata

Ana

lyst

s: P

N

Non

eIT

TN

ot k

now

n w

heth

er th

e m

any

post

enro

llmen

t exc

lusi

ons

wer

e po

stra

ndom

izat

ion.

Tri

al s

topp

ed

earl

y be

caus

e re

curr

ent V

TE

was

hi

gher

than

exp

ecte

d.

Pala

reti

et a

l 95 /2

006

(PR

OL

ON

G)

Rem

ain

off (

stop

) VK

AR

esta

rt in

defi n

itely

VK

A

(IN

R 2

.0-3

.0) (

not b

linde

d)

RC

TC

YPa

tient

s: C

N

Car

egiv

ers:

CN

A

djud

icat

ions

: CY

Dat

a A

naly

sts:

PN

No

VK

A: ,

3/1

05

VK

A: 0

/122

ITT

Fou

r pa

tient

s ex

clud

ed b

ecau

se

lupu

s an

ticoa

gula

nt fo

und

afte

r ra

ndom

izat

ion.

Kea

ron

et a

l 96 /1

999

(LA

FIT

)V

KA

sto

pped

(pla

cebo

)V

KA

(IN

R 2

.0-3

.0) f

or 2

mor

e y

RC

TC

YPa

tient

s: C

Y C

areg

iver

s: C

Y A

djud

icat

ions

: CY

Dat

a A

naly

sts:

CY

Non

eIT

TTr

ial s

topp

ed e

arly

bec

ause

of o

vera

ll be

nefi t

. Aft

er r

ecur

rent

VT

E,

patie

nts

wer

e no

t fol

low

ed. r

esul

ting

in s

hort

er fo

llow

-up

and

pote

ntia

l for

un

dere

stim

atio

n of

ble

edin

g in

the

no-V

KA

gro

up.

Schu

lman

et a

l 97 /1

997

(DU

RA

C 2

)V

KA

(IN

R 2

.0-2

.85)

for

6 m

oV

KA

(IN

R 2

.0-2

.85)

inde

fi nite

lyR

CT

CY

Patie

nts:

CN

C

areg

iver

s: C

N

Adj

udic

atio

ns: V

TE

, CY

Oth

er, P

N

Dat

a A

naly

sts:

PN

Tota

l of 1

4 pa

tient

s

drop

ped

out d

urin

g fo

llow

-up,

but

pa

rtia

l fol

low

-up

achi

eved

ITT

Act

ual m

ean

dura

tion

of V

KA

was

7.

7 m

o in

6-m

o gr

oup

and

42.7

mo

in in

defi n

ite (4

8 m

o) g

roup

.

Pran

doni

et a

l 99 /2

009

(AE

SOPU

S)V

KA

sto

pped

if p

rovo

ked

and

3

mor

e m

o if

unpr

ovok

edR

CT

CY

Patie

nts:

CN

C

areg

iver

s: C

N

Adj

udic

atio

ns: V

TE

, CY

Dat

a A

naly

sts:

PY

4 su

bjec

ts in

eac

h gr

oup

ITT

St

oppe

d if

no r

esid

ual v

ein

th

rom

bosi

s an

d un

til

reso

lved

or

9 m

ore

mo

if pr

ovok

ed o

r 21

mor

e m

o if

unpr

ovok

ed

Rid

ker

et a

l 100 /2

003

(PR

EV

EN

T)

VK

A s

topp

ed o

r no

t

rest

arte

d (p

lace

bo)

VK

A I

NR

1.5

-2.0

RC

TC

YPa

tient

s: C

Y C

areg

iver

s: C

Y A

djud

icat

ions

: CY

Dat

a A

naly

sts:

CY

Not

spe

cifi e

dIT

TTr

ial s

topp

ed e

arly

bec

ause

of o

vera

ll be

nefi t

. Num

ber

of c

ross

over

s no

t de

scri

bed.

Pr

obab

ly lo

w o

r ni

l

Far

raj e

t al 98

/200

4

VK

A (I

NR

2.0

-3.0

) for

6 m

o V

KA

(IN

R 2

.0-2

.85)

for

24 m

oR

CT

PYPa

tient

s: C

N

Car

egiv

ers:

CN

D

ata

Col

lect

ors:

PN

. A

djud

icat

ors:

PN

D

ata

Ana

lyst

s: P

N

0/32

ITT

Fou

r po

stra

ndom

izat

ion

excl

usio

ns

for

each

gro

up b

ecau

se o

f poo

r co

mpl

ianc

e.

0/32

(see

com

men

ts)

Kea

ron

et a

l 101 /2

003

(EL

ATE

)V

KA

IN

R 1

.5-1

.9 V

KA

IN

R 2

.0-3

.0 (b

linde

d)R

CT

CY

Patie

nts:

CY

Car

egiv

ers:

CY

Adj

udic

atio

ns: C

Y D

ata

Ana

lyst

s: C

Y

INR

1.5

-1.9

: � 1

/369

IN

R

1.5-

1.9:

� 1

/369

ITT

Cro

ssov

er to

IN

R 2

.0-3

.0 in

21

patie

nts

See

Tabl

e S1

, S2,

S7,

and

S24

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.




Tabl

e S2

6 —[S

ecti

ons

3.1.

1-3.

1.4]

Evi

denc

e P

rofi l

e: S

ix o

r Tw

elve

Mon

ths

vs T

hree

Mon

ths

as M

inim

um

Du

rati

on o

f A

ntic

oagu

lati

on f

or V

TE

a,b

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

s

Ove

rall

Qua

lity

of E

vide

nce

With

3 m

oW

ith 6

or

12 m

oR

isk

With

3

mo

Ris

k D

iffer

ence

W

ith 6

or

12 m

o (9

5% C

I)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

2,06

1 (6

stu

dies

), 1-

3 y

No

seri

ous

risk

of b

ias c

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s d,e

Und

etec

ted

Mod

erat

e d-e

due

to

impr

ecis

ion

118/

1,02

5 (1

1.5)

105/

1,03

6 (1

0.1)

RR

0.8

9 (0

.69-

1.14

)11

5 pe

r 1,

000

13 fe

wer

per

1,0

00

(fro

m 3

6 fe

wer

to

16

mor

e)

Maj

or b

leed

ing

(cri

tical

out

com

e)

2,06

1 (6

stu

dies

), 1-

3 y

No

seri

ous

risk

of b

ias f

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssN

o se

riou

s im

prec

isio

nU

ndet

ecte

dH

igh f

9/1,

025

(0.9

)24

/1,0

36 (2

.3)

RR

2.4

9 (1

.2-5

.16)

9 pe

r 1,

000

13 m

ore

per

1,00

0 (f

rom

2 m

ore

to

37 m

ore)

Mor

talit

y (im

port

ant o

utco

me g )

1,33

1 (5

stu

dies

), 1-

3 y

No

seri

ous

risk

of b

ias

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s d U

ndet

ecte

dM

oder

ate d

due

to

impr

ecis

ion

29/6

63 (4

.4)

38/6

68 (5

.7)

RR

1.3

(0

.81-

2.08

)44

per

1,0

0013

mor

e pe

r 1,

000

(fro

m 8

few

er to

47

mor

e)

Bib

liogr

aphy

: Pin

ede

et a

l, 87 C

ampb

ell e

t al, 91

Agn

elli

et a

l, 93 A

gnel

li et

al, 92

Sir

agus

a. 94

See

Tab

le S

1, S

2, a

nd S

5 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a T

imin

g of

ran

dom

izat

ion

rela

tive

to th

e st

art o

f tre

atm

ent a

nd le

ngth

of t

reat

men

t in

the

non-

3-m

o gr

oup

vari

ed a

cros

s st

udie

s: P

ined

e et

al a

nd C

ampb

ell e

t al r

ando

miz

ed a

t dia

gnos

is, a

nd A

gnel

li et

al

rand

omiz

ed a

fter

the

initi

al 3

mo

of tr

eatm

ent t

o st

op, o

r con

tinue

, tre

atm

ent.

The

long

er d

urat

ion

of tr

eatm

ent w

as 6

mo

in P

ined

e, C

ampb

ell,

and

Agn

elli

et a

l (20

03) (

prov

oked

PE

), an

d 12

mo

in A

gnel

li (2

001)

and

Agn

elli

(200

3) (u

npro

voke

d PE

). b S

tudy

pop

ulat

ions

var

ied

acro

ss s

tudi

es: P

ined

e et

al e

nrol

led

prov

oked

and

unp

rovo

ked

prox

imal

DV

T a

nd P

E; C

ampb

ell e

t al e

nrol

led

prov

oked

and

unp

rovo

ked

isol

ated

dis

tal D

VT,

pro

xim

al D

VT

and

PE

; Agn

elli

et a

l (20

03) h

ad s

epar

ate

rand

omiz

atio

ns fo

r pr

ovok

ed P

E (3

vs

6 m

o) a

nd u

npro

voke

d (3

vs

12 m

o); a

nd A

gnel

li et

al (

2001

) enr

olle

d un

prov

oked

pro

xim

al D

VT.

c G

ener

ally

, stu

dy d

esig

n w

as s

tron

g. N

o st

udy

stop

ped

earl

y fo

r be

nefi t

; tw

o st

oppe

d ea

rly

beca

use

of s

low

rec

ruitm

ent (

Cam

pbel

l et a

l, Pi

nede

et a

l), a

nd o

ne s

topp

ed b

ecau

se o

f lac

k of

ben

efi t

(Agn

elli

et a

l [20

01])

. In

one

stud

y (C

ampb

ell),

20%

of V

TE

out

com

es w

ere

not o

bjec

tivel

y co

nfi r

med

. Pat

ient

s an

d ca

regi

vers

wer

e no

t blin

ded

in a

ny s

tudy

. Adj

udic

ator

s of

out

com

es w

ere

blin

ded

in a

ll bu

t one

st

udy

(Cam

pbel

l). A

ll st

udie

s us

ed e

ffec

tive

rand

omiz

atio

n co

ncea

lmen

t and

IT

T a

naly

sis

and

appe

ar to

hav

e a

low

une

xpla

ined

dro

p-ou

t fre

quen

cy.

d CIs

incl

ude

both

val

ues

sugg

estin

g no

eff

ect a

nd v

alue

s su

gges

ting

eith

er b

enefi

t or

har

m.

e Low

num

ber

of e

vent

s an

d a

tota

l num

ber

of p

artic

ipan

ts ,

2,0

00.

f One

stu

dy m

ay h

ave

confi

ned

the

asse

ssm

ent o

f ble

edin

g to

whe

n su

bjec

ts w

ere

rece

ivin

g an

ticoa

gula

nt th

erap

y, w

hich

cou

ld h

ave

infl a

ted

the

incr

ease

in b

leed

ing

asso

ciat

ed w

ith th

e lo

nger

dur

atio

n of

th

erap

y (C

ampb

ell e

t al).

g D

iffer

ence

s in

mor

talit

y ar

e ex

pect

ed to

be

med

iate

d by

diff

eren

ces

in r

ecur

rent

VT

E a

nd b

leed

ing.




Tabl

e S2

7 —[S

ecti

ons

3.1.

1-3.

1.4]

Ext

ende

d A

ntic

oagu

lati

on v

s N

o E

xten

ded

Ant

icoa

gula

tion

for

Dif

fere

nt G

rou

ps o

f P

atie

nts

Wit

h V

TE

and

Wit

hou

t C

ance

r a,b

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Ext

ende

d A

ntic

oagu

latio

nW

ith E

xten

ded

Ant

icoa

gula

tion

Rel

ativ

e E

ffec

t (9

5% C

I)

Ris

k W

ith

No

Ext

ende

d A

ntic

oagu

latio

n

Ris

k D

iffer

ence

W

ith E

xten

ded

Ant

icoa

gula

tion

(95%

CI)

Mor

talit

y (im

port

ant o

utco

me)

1,18

4 (4

st

udie

s),

10-3

6 m

o

No

seri

ous

risk

of b

ias

No

seri

ous

inco

nsis

tenc

y c N

o se

riou

s in

dire

ctne

ssSe

riou

s d,e

Und

etec

ted

Mod

erat

e c-e

due

to

impr

ecis

ion

38/5

99 (6

.3)

16/5

85 (2

.7)

RR

0.5

7 (0

.31-

1.03

)63

per

1,0

0027

few

er p

er 1

,000

(fro

m

44 fe

wer

to 2

mor

e)

Rec

urre

nt V

TE

at 1

y (c

ritic

al o

utco

me)

1,18

4 (4

st

udie

s),

10-3

6 m

o

No

seri

ous

risk

of b

ias

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssN

o se

riou

s im

prec

isio

nU

ndet

ecte

dH

igh

102/

599

(17)

21/5

85 (3

.6)

RR

0.1

2 (0

.09-

0.38

)F

irst

VT

E p

rovo

ked

by s

urge

ry f-

j

10 p

er 1

,000

10 p

er 1

,000

F

irst

VT

E p

rovo

ked

nons

urgi

cal/fi

rst

un

prov

oked

dis

tal D

VT

f-j

50

per

1,0

0044

few

er p

er 1

,000

(fro

m

31 fe

wer

to 4

5 fe

wer

)

F

irst

unp

rovo

ked

VT

E f-

j

10

0 pe

r 1,

000

88 fe

wer

per

1,0

00 (f

rom

62

few

er to

91

few

er)

Se

cond

unp

rovo

ked

VT

E f-

j

15

0 pe

r 1,

000

132

few

er p

er 1

,000

(f

rom

93

few

er to

13

7 fe

wer

)

Maj

or b

leed

ing

at 1

y (c

ritic

al o

utco

me)

1,18

4 (4

st

udie

s),

10-3

6 m

o

No

seri

ous

risk

of b

ias

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

sU

ndet

ecte

dM

oder

ate

due

to

impr

ecis

ion

7/59

9 (1

.2%

)21

/585

(3.6

%)

RR

2.6

3 (1

.02-

6.76

)L

ow r

isk

of b

leed

ing k,

l

3 pe

r 1,

000

5 m

ore

per

1,00

0 (f

rom

0

mor

e to

17

mor

e)

M

oder

ate

risk

of b

leed

ing k,

l

6

per

1,00

010

mor

e pe

r 1,

000

(fro

m

0 m

ore

to 3

5 m

ore)

H

igh

risk

of b

leed

ing k,

l

12

per

1,0

0020

mor

e pe

r 1,

000

(fro

m

0 m

ore

to 6

9 m

ore)

(C

onti

nued

)




Tabl

e S2

7—C

onti

nued

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Ext

ende

d A

ntic

oagu

latio

nW

ith E

xten

ded

Ant

icoa

gula

tion

Rel

ativ

e E

ffec

t (9

5% C

I)

Ris

k W

ith

No

Ext

ende

d A

ntic

oagu

latio

n

Ris

k D

iffer

ence

W

ith E

xten

ded

Ant

icoa

gula

tion

(95%

CI)

Rec

urre

nt V

TE

at 5

y (c

ritic

al o

utco

me)

1,18

4 (4

st

udie

s),

10-3

6 m

o

No

seri

ous

risk

of b

ias

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssN

o se

riou

s im

prec

isio

nU

ndet

ecte

dH

igh

102/

599

(17%

)21

/585

(3.6

%)

RR

0.1

2 (0

.09-

0.38

)F

irst

VT

E p

rovo

ked

by s

urge

ry f-

j

30 p

er 1

,000

26 fe

wer

per

1,0

00 (f

rom

19

few

er to

27

few

er)

F

irst

VT

E p

rovo

ked

nons

urgi

cal/fi

rst

un

prov

oked

dis

tal D

VT

f-j

15

0 pe

r 1,

000

132

few

er p

er 1

,000

(f

rom

93

few

er to

13

7 fe

wer

)

F

irst

unp

rovo

ked

VT

E f-

j

30

0 pe

r 1,

000

264

few

er p

er 1

,000

(f

rom

186

few

er to

27

3 fe

wer

)

Se

cond

unp

rovo

ked

VT

E f-

j

45

0 pe

r 1,

000

396

few

er p

er 1

,000

(f

rom

279

few

er to

40

9 fe

wer

)

Maj

or b

leed

ing

at 5

y (c

ritic

al o

utco

me)

1,18

4 (4

st

udie

s),

10-3

6 m

o

No

seri

ous

risk

of b

ias

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

sU

ndet

ecte

dM

oder

ate

due

to

impr

ecis

ion

7/59

9 (1

.2%

)21

/585

(3.6

%)

RR

2.6

3 (1

.02-

6.77

)L

ow r

isk

of b

leed

ing k,

l

15 p

er 1

,000

24 m

ore

per

1,00

0 (f

rom

0

mor

e to

87

mor

e)

M

oder

ate

risk

of b

leed

ing k,

l

30

per

1,0

0049

mor

e pe

r 1,

000

(fro

m

1 m

ore

to 1

73 m

ore)

H

igh

risk

of b

leed

ing k,

l

60

per

1,0

0098

mor

e pe

r 1,

000

(fro

m

1 m

ore

to 3

46 m

ore)

Bur

den

of a

ntic

oagu

latio

n no

t rep

orte

d

(Con

tinu

ed)




Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Ext

ende

d A

ntic

oagu

latio

nW

ith E

xten

ded

Ant

icoa

gula

tion

Rel

ativ

e E

ffec

t (9

5% C

I)

Ris

k W

ith

No

Ext

ende

d A

ntic

oagu

latio

n

Ris

k D

iffer

ence

W

ith E

xten

ded

Ant

icoa

gula

tion

(95%

CI)

……

……

……

……

……

See

com

men

t m

See

com

men

t m

PTS

not r

epor

ted

……

……

……

……

……

See

com

men

t n Se

e co

mm

ent n

Bib

liogr

aphy

: Sch

ulm

an e

t al (

DU

RA

C 2

), 97 K

earo

n et

al (

LA

FIT

), 96 F

arra

j, 98 P

alar

eti (

PRO

LO

NG

). 95 S

ee T

able

S1,

S2,

S7,

and

S10

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Stu

dies

var

y in

follo

w-u

p du

ratio

n (1

0 m

o to

3 y

) and

in d

urat

ion

of ti

me-

limite

d V

KA

(3 to

6 m

o).

b We

excl

uded

Rid

ker

et a

l (PR

EV

EN

T) 10

0 bec

ause

targ

et I

NR

was

1.7

5 (lo

w in

tens

ity),

whi

ch h

as b

een

show

n in

an

RC

T to

be

less

eff

ectiv

e th

an a

targ

et o

f 2.5

. c I

2 5 0

%.

d CI

incl

udes

bot

h va

lues

sug

gest

ing

no e

ffec

t and

val

ues

sugg

estin

g ei

ther

app

reci

able

har

ms

or a

ppre

ciab

le b

enefi

t.

e Sm

all n

umbe

r of

eve

nts.

Dec

isio

n to

rat

e do

wn

also

take

s in

to a

ccou

nt th

at tw

o st

udie

s w

ere

stop

ped

earl

y fo

r be

nefi t

. f A

nnua

l ris

k of

VT

E re

curr

ence

aft

er d

isco

ntin

uing

ora

l ant

icoa

gula

tion

ther

apy

in p

atie

nts w

ith fi

rst V

TE

pro

voke

d by

surg

ery:

1%

(Ior

io A

, Kea

ron

C, F

ilipp

ucci

E, e

t al.

Ris

k of

recu

rren

ce a

fter

a fi

rst e

piso

de

of sy

mpt

omat

ic v

enou

s thr

ombo

embo

lism

pro

voke

d by

a tr

ansi

ent r

isk

fact

or: a

syst

emat

ic re

view

. Arc

h In

tern

Med

. 201

0;17

0(19

):171

0-17

16);

we

assu

med

a 0

.5%

yea

rly

risk

ther

eaft

er (3

% o

ver 5

y).

g Ann

ual r

isk

in p

atie

nts

with

fi rs

t VT

E p

rovo

ked

by n

on s

urgi

cal f

acto

r: a

bout

5%

the

fi rst

yea

r (I

orio

et a

l); w

e as

sum

ed 2

.5%

yea

rly

ther

eaft

er (1

5% o

ver

5 y)

. h A

nnua

l ris

k in

pat

ient

s with

fi rs

t epi

sode

of u

npro

voke

d V

TE

: 9.3

% o

ver 1

y in

Rod

ger M

A, K

ahn

SR, W

ells

PS,

et a

l. Id

entif

ying

unp

rovo

ked

thro

mbo

embo

lism

pat

ient

s at l

ow ri

sk fo

r rec

urre

nce

who

can

di

scon

tinue

ant

icoa

gula

nt th

erap

y. C

MA

J. 2

008;

179(

5):4

17-4

26; 1

1.0%

ove

r 1

y, 1

9.6%

ove

r 3

y, a

nd 2

9.1%

ove

r 5

y in

Pra

ndon

i et a

l (20

07).

We

assu

med

a r

isk

of 1

0% th

e fi r

st y

ear

afte

r di

scon

tinua

tion

and

5% y

earl

y th

erea

fter

(30%

ove

r 5

y).

i Ann

ual r

isk

in p

atie

nts w

ith se

cond

epi

sode

of u

npro

voke

d V

TE

: we

assu

med

an

RR

of 1

.5 c

ompa

red

with

a fi

rst e

piso

de o

f unp

rovo

ked

VT

E: 1

5% th

e fi r

st y

ear a

fter

dis

cont

inua

tion,

7.5

% y

earl

y th

erea

fter

(4

5% o

ver

5 y)

. j C

ase

fata

lity

rate

of r

ecur

rent

VT

E a

fter

dis

cont

inui

ng o

ral a

ntic

oagu

latio

n th

erap

y: 3

.6%

(Car

rier

201

0).

k Ann

ual r

isk

of m

ajor

ble

edin

g is

bas

ed o

n th

ree

risk

leve

ls: l

ow, i

nter

med

iate

, and

hig

h. T

he c

orre

spon

ding

0.3

%, 0

.6%

, and

1.2

% ri

sks a

re e

stim

ates

bas

ed o

n co

ntro

l arm

s of i

nclu

ded

stud

ies (

see

Tabl

e 3 )

. l C

ase

fata

lity

rate

of m

ajor

ble

edin

g du

ring

initi

al o

ral a

ntic

oagu

latio

n th

erap

y: 1

1.3%

(Car

rier

et a

l) (n

o da

ta a

vaila

ble

for

afte

r di

scon

tinui

ng o

ral a

ntic

oagu

latio

n th

erap

y).

m B

urde

n of

ant

icoa

gula

tion:

end

ured

by

all p

atie

nts

who

con

tinue

ext

ende

d-du

ratio

n an

ticoa

gula

tion

(100

%)

and

appl

ies

to p

atie

nts

who

sto

p an

ticoa

gula

tion

(no

exte

nded

-dur

atio

n an

ticoa

gula

tion)

who

su

bseq

uent

ly e

xper

ienc

e a

recu

rren

t VT

E (5

%, 1

0%, 1

5% a

t 1 y

; 15%

, 30%

, 45%

at 5

y).

n Bas

elin

e ri

sk o

ver

2 y

of 5

8.8%

for

PT

S an

d 13

.8%

for

sev

ere

PTS

(VE

TO

[Ve

nous

Thr

ombo

sis

Out

com

es s

tudy

]; A

nn I

nter

n M

ed. 2

008)

and

thr

eefo

ld (

Pran

doni

. Ann

Int

ern

Med

. 200

4) t

o 10

-fol

d (V

an D

onge

n. J

Thr

omb

Hae

mos

t. 20

05) i

ncre

ase

in P

TS .

Tabl

e S2

7—C

onti

nued




(Con

tinu

ed)

Tabl

e S2

8 —[S

ecti

on 3

.3]

Evi

denc

e P

rofi l

e: L

MW

H v

s V

KA

for

Lon

g-te

rm T

reat

men

t of

VT

E a-c

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

eW

ith V

KA

With

LM

WH

Rel

ativ

e E

ffec

t (9

5% C

I)R

isk

With

V

KA

Ris

k D

iffer

ence

W

ith L

MW

H

(95%

CI)

Mor

talit

y (im

port

ant o

utco

me)

2,49

6 (7

stu

dies

), 6

mo

No

seri

ous

risk

of b

ias d

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s e U

ndet

ecte

dM

oder

ate d,

e due

to

impr

ecis

ion

202/

1,23

1 (1

6.4)

204/

1,26

5 (1

6.1)

RR

0.9

6 (0

.81-

1.13

)16

4 pe

r 1,

000

7 fe

wer

per

1,0

00

(fro

m 3

1 fe

wer

to

21

mor

e)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

2,72

7 (8

stu

dies

), 6

mo

Seri

ous f

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssN

o se

riou

s im

prec

isio

nU

ndet

ecte

dM

oder

ate f d

ue

to r

isk

of b

ias

105/

1,34

9 (7

.8)

67/1

,378

(4.9

)R

R 0

.62

(0.4

6-0.

84)

No

canc

er g

30 p

er 1

,000

11 fe

wer

per

1,0

00

(fro

m 5

few

er

to 1

6 fe

wer

)

N

onm

etas

tatic

can

cer g

80

per

1,0

0030

few

er p

er 1

,000

(f

rom

13

few

er

to 4

3 fe

wer

)

M

etas

tatic

can

cer g

20

0 pe

r 1,

000

76 fe

wer

per

1,0

00

(fro

m 3

2 fe

wer

to

108

few

er)

Maj

or b

leed

ing

(cri

tical

out

com

e)

2,73

7 (8

stu

dies

), 6

mo

No

seri

ous

risk

of b

ias h

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s i U

ndet

ecte

dM

oder

ate h,

i due

to

impr

ecis

ion

53/1

,351

(3.9

%)

45/1

,386

(3.2

%)

RR

0.8

1 (0

.55-

1.2)

No

canc

er o

r no

nmet

asta

tic

canc

er j

20 p

er 1

,000

4 fe

wer

per

1,0

00

(fro

m 9

few

er

to 4

mor

e)

M

etas

tatic

can

cer j

80

per

1,0

0015

few

er p

er 1

,000

(f

rom

36

few

er

to 1

6 m

ore)




Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

eW

ith V

KA

With

LM

WH

Rel

ativ

e E

ffec

t (9

5% C

I)R

isk

With

V

KA

Ris

k D

iffer

ence

W

ith L

MW

H

(95%

CI)

Bur

den

of a

ntic

oagu

latio

n (im

port

ant o

utco

me)

k

…N

o se

riou

s lim

itatio

nsN

o se

riou

s lim

itatio

nsN

o se

riou

s lim

itatio

nsN

o se

riou

s lim

itatio

nsN

ot a

pplic

able

Hig

hW

arfa

rin:

dai

ly

med

icat

ion,

die

tary

in

tera

ctio

ns,

freq

uent

blo

od

test

ing/

mon

itori

ng,

incr

ease

d ho

spita

l/cl

inic

vis

its

LM

WH

: dai

ly

inje

ctio

n,

no d

ieta

ry

inte

ract

ions

, no

freq

uent

bl

ood

test

ing/

mon

itori

ng

……

PTS

(impo

rtan

t out

com

e; a

sses

sed

with

sel

f-re

port

ed le

g sy

mpt

oms

and

sign

s)

100 (1

stu

dy),

2 y

Seri

ous l

No

seri

ous

inco

nsis

tenc

ySe

riou

s m

No

seri

ous

impr

ecis

ion

Und

etec

ted

Low

l,m d

ue to

ri

sk o

f bia

s,

indi

rect

ness

31/4

4 (7

0.5%

)34

/56

(60.

7%)

RR

0.8

5 (0

.77-

0.94

)M

oder

ate n

200

per

1,00

030

few

er p

er 1

,000

(f

rom

12

few

er

to 4

6 fe

wer

)

Bib

liogr

aphy

: Inc

lude

d st

udie

s: D

eitc

her

et a

l, 102 H

ull e

t al, 10

3 Hul

l et a

l, 104 L

ee e

t al, 10

5 Lop

aciu

k et

al, 10

6 Lop

ez-B

eret

et a

l, 107 M

eyer

G e

t al, 10

8 Rom

era

et a

l 109 T

wo

of th

ese

stud

ies

enro

lled

only

pat

ient

s w

ithou

t can

cer, 10

4,10

7 3 e

nrol

led

only

pat

ient

s w

ith c

ance

r 108,

102,

105 ,

and

3 en

rolle

d bo

th p

atie

nts

with

and

with

out c

ance

r 103,

106,

109 (

sepa

rate

dat

a pr

ovid

ed fo

r ca

ncer

and

non

-can

cer

patie

nts

in o

ne s

tudy

103,

110 )

. E

xclu

ded

stud

ies

(less

than

50%

of t

hera

peut

ic d

ose

LM

WH

dur

ing

exte

nded

pha

se):

Pini

et a

l, 111 D

as e

t al, 11

2 Gon

zale

z-F

ajar

do e

t al, 11

3 Vei

ga e

t al, 11

4 Kak

kar

et a

l, 115 (

Ces

aron

e 20

03 C

irc

abst

ract

). PT

S da

ta fr

om: H

ull e

t al. 10

4 See

Tab

le S

1, S

2, S

5, a

nd S

10 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a L

imite

d to

LM

WH

reg

imen

s th

at u

sed

� 5

0% o

f the

acu

te tr

eatm

ent d

ose

duri

ng th

e ex

tend

ed p

hase

of t

reat

men

t. b T

he in

itial

par

ente

ral a

ntic

oagu

latio

n w

as s

imila

r in

bot

h ar

ms

for

all e

xcep

t on

e st

udy

(Hul

l et

al [

2007

]) in

whi

ch p

atie

nts

rand

omiz

ed t

o L

MW

H r

ecei

ved

initi

ally

the

sam

e LW

MH

, whe

reas

pat

ient

s ra

ndom

ized

to V

KA

rec

eive

d in

itial

ly U

FH

. c T

wo

of th

ese

stud

ies

enro

lled

only

pat

ient

s w

ithou

t can

cer,

thre

e en

rolle

d on

ly p

atie

nts

with

can

cer,

and

thre

e en

rolle

d bo

th p

atie

nts

with

and

with

out c

ance

r (s

epar

ate

data

pro

vide

d fo

r ca

ncer

and

non

-ca

ncer

pat

ient

s in

one

stu

dy).

d One

stu

dy d

id n

ot r

epor

t dea

ths,

whi

ch is

unu

sual

and

cou

ld r

efl e

ct s

elec

tive

repo

rtin

g of

out

com

es.

e CI

incl

udes

bot

h no

eff

ect a

nd h

arm

with

LM

WH

. f N

one

of th

e st

udie

s wer

e bl

inde

d, a

lthou

gh th

e di

agno

sis o

f rec

urre

nt V

TE

has

a su

bjec

tive

com

pone

nt a

nd th

ere

coul

d be

a lo

wer

thre

shol

d fo

r dia

gnos

is o

f rec

urre

nt V

TE

in V

KA

-tre

ated

pat

ient

s bec

ause

sw

itchi

ng th

e tr

eatm

ent o

f suc

h pa

tient

s to

LM

WH

is w

idel

y pr

actic

ed. A

t the

sam

e tim

e, th

ere

is re

luct

ance

to d

iagn

ose

recu

rren

t VT

E in

pat

ient

s who

are

alr

eady

on

LM

WH

bec

ause

ther

e is

no

attr

activ

e al

tern

ativ

e tr

eatm

ent o

ptio

n.

g Ris

k of

rec

urre

nt V

TE

: low

cor

resp

onds

to

patie

nts

with

out

canc

er (

3% e

stim

ate

take

n fr

om r

ecen

t la

rge

RC

Ts o

f ac

ute

trea

tmen

t), i

nter

med

iate

cor

resp

onds

to

patie

nts

with

loca

l or

rece

ntly

res

ecte

d ca

ncer

(bas

ed o

n av

erag

e ra

te a

cros

s th

e si

x st

udie

s in

this

ana

lysi

s an

d ap

pear

s to

be

cons

iste

nt w

ith P

rand

oni e

t al [

part

icul

arly

if lo

w r

isk

is in

crea

sed

to 4

%])

, and

hig

h to

pat

ient

s w

ith lo

cally

adv

ance

d or

di

stan

t met

asta

tic c

ance

r (P

rand

oni e

t al 11

6 ).

h No

stud

y w

as b

linde

d; d

iagn

osis

of m

ajor

ble

edin

g ha

s a

subj

ectiv

e co

mpo

nent

. i T

he 9

5% C

Is fo

r the

RR

for m

ajor

ble

edin

g in

clud

es a

pot

entia

lly c

linic

ally

impo

rtan

t inc

reas

e or

dec

reas

e w

ith L

MW

H a

nd m

ay v

ary

with

the

dose

of L

MW

H u

sed

duri

ng th

e ex

tend

ed p

hase

of t

hera

py.

j Ris

k of

ble

edin

g: lo

w c

orre

spon

ds to

pat

ient

s w

ithou

t ris

k fa

ctor

for

blee

ding

(ie,

. 7

5 y,

can

cer,

met

asta

tic d

isea

se; c

hron

ic r

enal

or

hepa

tic fa

ilure

; pla

tele

t cou

nt ,

800

,000

; req

uire

s an

tipla

tele

t the

rapy

; hi

stor

y of

ble

edin

g w

ithou

t a r

ever

sibl

e ca

use)

(Tab

le 2

) (ba

sed

on P

rand

oni e

t al 11

6 and

Bey

th e

t al, 11

7 adj

uste

d to

a 6

-mo

time

fram

e).

k Hul

l et a

l rep

orte

d no

sig

nifi c

ant d

iffer

ence

in q

ualit

y of

life

but

sug

gest

ed g

reat

er s

atis

fact

ion

with

LM

WH

ove

r V

KA

(que

stio

nnai

re d

id n

ot d

irec

tly a

sses

s th

e bu

rden

of i

njec

tions

). l P

atie

nts

and

inve

stig

ator

s no

t blin

ded.

Sel

f-re

port

ed le

g sy

mpt

oms

and

sign

s af

ter

3 m

o of

trea

tmen

t. m T

he a

ssoc

iatio

n be

twee

n le

g sy

mpt

oms

and

sign

s at

3 m

o an

d lo

ng-t

erm

PT

S is

unc

erta

in.

n Bas

elin

e ri

sk a

ssum

es th

at p

atie

nts

all w

ear

pres

sure

sto

ckin

gs. C

ontr

ol e

vent

rat

e co

mes

from

obs

erva

tiona

l stu

dies

in r

evie

w b

y K

ahn

et a

l, 118 a

djus

ted

to 2

-y ti

me

fram

e.

Tabl

e S2

8—C

onti

nued




Tabl

e S2

9 —[S

ecti

on 3

.3]

Evi

denc

e P

rofi l

e: R

ivar

oxab

an v

s L

MW

H a

nd V

KA

The

rapy

for

Sho

rt-

and

Lon

g-te

rm T

reat

men

t of

VT

E a-c

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es)

Fol

low

up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

LM

WH

an

d V

KA

T

hera

pyW

ith

Riv

arox

aban

Ris

k W

ith

LM

WH

and

V

KA

The

rapy

Ris

k D

iffer

ence

W

ith R

ivar

oxab

an

(95%

CI)

Dea

th (i

mpo

rtan

t out

com

e)

3,44

9 (1

stu

dy),

6-12

mo d

No

seri

ous

risk

of b

ias e

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s f U

ndet

ecte

dM

oder

ate e,

f du

e to

im

prec

isio

n

49/1

,718

(2.9

)38

/1,7

31 (2

.2)

HR

0.6

7 (0

.44-

1.02

)29

per

1,0

009

few

er p

er 1

,000

(f

rom

16

few

er

to 1

mor

e)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

3,44

9 (1

stu

dy),

6-12

mo d

No

seri

ous

risk

of b

ias e

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s g U

ndet

ecte

dM

oder

ate e,

g du

e to

im

prec

isio

n

51/1

,718

(3) h

36/1

,731

(2.1

) h H

R 0

.68

(0.4

4-1.

04)

30 p

er 1

,000

h 9

few

er p

er 1

,000

(f

rom

17

few

er

to 1

mor

e)

Maj

or b

leed

ing

(cri

tical

out

com

e)

3,42

9 (1

stu

dy),

6-12

mo d

No

seri

ous

risk

of b

ias e

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s g U

ndet

ecte

dM

oder

ate e,

g du

e to

im

prec

isio

n

19/1

,711

(1.1

) i 13

/1,7

18 (0

.8) i

HR

0.6

8 (0

.34-

1.38

) j 11

per

1,0

00 i

4 fe

wer

per

1,0

00

(fro

m 7

few

er

to 4

mor

e)

Bur

den

of a

ntic

oagu

latio

n (im

port

ant o

utco

me)

not

rep

orte

d

……

……

……

…W

arfa

rin:

dai

ly

med

icat

ion,

di

etar

y in

tera

ctio

ns,

freq

uent

blo

od

test

ing/

mon

itori

ng,

incr

ease

d ho

spita

l/cl

inic

vis

its

Riv

aorx

aban

: dai

ly

med

icat

ion,

no

die

tary

in

tera

ctio

ns,

no fr

eque

nt

bloo

d te

stin

g/m

onito

ring

……

…

Bib

liogr

aphy

: Ein

stei

n D

VT.

119 H

R 5

haz

ard

ratio

. See

Tab

le S

1, S

2, S

5, a

nd S

7 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a Riv

arox

aban

15

mg

bid

for

3 w

k an

d th

en 2

0 m

g/d

for

a to

tal o

f 3 (1

2%),

6 (6

3%),

or 1

2 (2

5%) m

onth

s.

b Eno

xapa

rin

1 m

g/kg

bid

for

� 8

d a

nd th

en V

KA

ther

apy

targ

eted

to I

NR

2.5

for

3, 6

, or

12 m

o.

c Inc

lude

d pa

tient

s ha

d ac

ute,

sym

ptom

atic

, obj

ectiv

ely

veri

fi ed

prox

imal

DV

T o

f the

legs

(unp

rovo

ked,

62%

; can

cer,

6%; p

revi

ous

VT

E, 1

9%).

d Fol

low

-up

was

pre

spec

ifi ed

to b

e 3

mo

(12%

), 6

mo

(63%

), or

12

mo

(25%

). e A

lloca

tion

was

con

ceal

ed. P

atie

nts,

pro

vide

rs, a

nd d

ata

colle

ctor

s w

ere

not b

linde

d, b

ut o

utco

me

adju

dica

tors

wer

e bl

inde

d. I

TT

ana

lysi

s; 1

.0%

loss

to fo

llow

-up.

Not

sto

pped

ear

ly fo

r be

nefi t

. f C

I in

clud

es v

alue

s su

gges

ting

bene

fi t o

r no

eff

ect;

rela

tivel

y lo

w n

umbe

r of

eve

nts.

g C

I in

clud

es v

alue

s su

gges

ting

bene

fi t a

nd h

arm

. h O

ne d

efi n

ite o

r po

ssib

le fa

tal V

TE

in r

ivar

oxab

an g

roup

and

one

in L

MW

H/V

KA

gro

up.

i Ble

eds

cont

ribu

ting

to d

eath

: one

in th

e ri

varo

xaba

n gr

oup

and

fi ve

in th

e w

arfa

rin

grou

p.

j Cal

cula

ted

from

rep

orte

d da

ta.




Tabl

e S3

0 —[S

ecti

on 3

.3]

Evi

denc

e P

rofi l

e: R

ivar

oxab

an v

s P

lace

bo

for

Ext

ende

d A

ntic

oagu

lati

on o

f V

TE

a,b

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

eW

ith P

lace

boW

ith

Riv

arox

aban

Ris

k W

ith

Plac

ebo

Ris

k D

iffer

ence

W

ith R

ivar

oxab

an

(95%

CI)

Mor

talit

y (im

port

ant o

utco

me)

1,19

6 (1

stu

dy),

6 or

12

mo c

No

seri

ous

risk

of b

ias d

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s e U

ndet

ecte

dM

oder

ate d,

e du

e to

im

prec

isio

n

2/59

4 (0

.34)

1/60

2 (0

.17)

RR

0.4

9 (0

.04-

5.4)

f 3

per

1,00

02

few

er p

er 1

,000

(f

rom

3 fe

wer

to

15

mor

e)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

1,19

6 (1

stu

dy),

6 or

12

mo c

No

seri

ous

risk

of b

ias d

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssN

o se

riou

s im

prec

isio

nU

ndet

ecte

dH

igh d

42/5

94 (7

.1) g

8/60

2 (1

.3) g

HR

0.1

8 (0

.09-

0.39

)71

per

1,0

00 g

58 fe

wer

pe

r 1,

000

(fro

m 4

3 fe

wer

to

64

few

er)

Maj

or b

leed

ing

(cri

tical

out

com

e)

1,18

8 (1

stu

dy),

6 or

12

mo

No

seri

ous

risk

of b

ias d

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s h U

ndet

ecte

dM

oder

ate d,

h du

e to

im

prec

isio

n

0/59

0 (0

) i 4/

598

(0.7

) i R

R 4

.9

(0.5

8-42

) f i

7 m

ore

per

1,00

0 (f

rom

3 m

ore

to 1

6 m

ore)

Bur

den

of a

ntic

oagu

latio

n (im

port

ant o

utco

me)

not

rep

orte

d

……

……

……

……

Riv

arox

aban

: dai

ly

med

icat

ion,

no

die

tary

in

tera

ctio

ns,

no fr

eque

nt

bloo

d te

stin

g/m

onito

ring

……

PTS

(impo

rtan

t out

com

e) n

ot r

epor

ted

……

……

……

……

……

… j

Bib

liogr

aphy

: Ein

stei

n D

VT.

119 S

ee T

able

S1,

S2,

S5,

S10

, and

S29

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Riv

arox

aban

20

mg/

d fo

r 6

or 1

2 m

o af

ter

initi

al lo

ng-t

erm

ther

apy.

b I

nclu

ded

patie

nts

had

acut

e, s

ympt

omat

ic, o

bjec

tivel

y ve

rifi e

d pr

oxim

al D

VT

of t

he le

gs o

r PE

(unp

rovo

ked,

73%

; can

cer,

5%; p

revi

ous

VT

E, 1

9%).

c Fol

low

-up

was

pre

spec

ifi ed

to b

e 6

mo

(60%

) or

12 m

o (4

0%).

d Allo

catio

n w

as c

once

aled

. Pat

ient

s, p

rovi

ders

, dat

a co

llect

ors,

and

out

com

e ad

judi

cato

rs w

ere

blin

ded.

IT

T a

naly

sis;

0.2

% lo

ss to

follo

w-u

p. N

ot s

topp

ed e

arly

for

bene

fi t.

e CI

incl

udes

val

ues

sugg

estin

g be

nefi t

or

no e

ffec

t; re

lativ

ely

low

num

ber

of e

vent

s.

f Cal

cula

ted

from

rep

orte

d da

ta w

ith a

dditi

on o

f one

eve

nt to

eac

h ev

ent r

ate

as e

vent

rat

e 0

in c

ontr

ol g

roup

. g O

ne d

efi n

ite o

r po

ssib

le fa

tal V

TE

in r

ivar

oxab

an g

roup

and

one

in L

MW

H/V

KA

gro

up.

h CI

incl

udes

val

ues

sugg

estin

g be

nefi t

and

har

m.

i Ble

eds

cont

ribu

ting

to d

eath

: non

e in

the

riva

roxa

ban

grou

p an

d no

ne in

the

war

fari

n gr

oup.

j P

TS:

bas

elin

e ris

k ov

er 2

y o

f 58.

8% fo

r PT

S an

d 13

.8%

for s

ever

e PT

S (K

ahn

et a

l 40 ).

The

re is

thre

efol

d (P

rand

oni e

t al 12

0 ) to

10-

fold

(van

Don

gen

et a

l 121 )

incr

ease

in P

TS

with

recu

rren

t VT

E in

the

ipsil

ater

al le

g.




Tabl

e S3

1 —[S

ecti

on 3

.3]

Dab

igat

ran

vs V

KA

The

rapy

for

Lon

g-te

rm T

reat

men

t of

VT

E a-c

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

eW

ith W

arfa

rin

With

D

abig

atra

n

Ris

k W

ith

War

fari

nR

isk

Diff

eren

ce

With

Dab

igat

ran

(95%

CI)

Dea

th (i

mpo

rtan

t out

com

e)

2,53

9 (1

stu

dy),

6 m

oN

o se

riou

s ri

sk o

f bia

s d N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous e

Und

etec

ted

Mod

erat

e d,e

due

to

impr

ecis

ion

21/1

,265

(1.7

)21

/1,2

74 (1

.6)

HR

0.9

8 (0

.53-

1.79

)17

per

1,0

000

few

er p

er 1

,000

(f

rom

8 fe

wer

to

13

mor

e)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

2,53

9 (1

stu

dy),

6 m

oN

o se

riou

s ri

sk o

f bia

s d N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous e

Und

etec

ted

Mod

erat

e d,e

due

to

impr

ecis

ion

24/1

,265

(1.9

) f 30

/1,2

74 (2

.4) f

HR

1.0

1 (0

.65-

1.84

)19

per

1,0

00 f

0 m

ore

per

1,00

0 (f

rom

7 fe

wer

to

16

mor

e)

Maj

or b

leed

ing

(cri

tical

out

com

e)

2,53

9 (1

stu

dy),

6 m

oN

o se

riou

s ri

sk o

f bia

s d N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous e

Und

etec

ted

Mod

erat

e d,e

due

to

impr

ecis

ion

24/1

,265

(1.9

) g 20

/1,2

74 (1

.6) g

HR

0.8

2 (0

.45-

1.48

)19

per

1,0

00 g

3 fe

wer

per

1,0

00

(fro

m 1

0 fe

wer

to

9 m

ore)

Bur

den

of a

ntic

oagu

latio

n (im

port

ant o

utco

me)

not

rep

orte

d

……

……

……

…W

arfa

rin:

dai

ly

med

icat

ion,

di

etar

y re

stri

ctio

ns,

freq

uent

blo

od

test

ing/

mon

itori

ng,

incr

ease

d ho

spita

l/cl

inic

vis

its

Dab

igat

ran:

dai

ly

med

icat

ion,

N

o di

etar

y re

stri

ctio

ns,

no fr

eque

nt

bloo

d te

stin

g/m

onito

ring

……

…

Bib

liogr

aphy

: Sch

ulm

an e

t al. 12

2 See

Tab

le S

2, S

5, a

nd S

29 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a D

abig

atra

n 15

0 m

g bi

d ta

ken

oral

ly fo

r 6

mo

afte

r an

initi

al tr

eatm

ent w

ith L

MW

H o

r IV

UF

H.

b War

fari

n ad

just

ed to

ach

ieve

an

INR

of 2

.0 to

3.0

for

6 m

o af

ter

an in

itial

trea

tmen

t with

LM

WH

or

IV U

FH

. c I

nclu

ded

patie

nts

had

acut

e, s

ympt

omat

ic, o

bjec

tivel

y ve

rifi e

d pr

oxim

al D

VT

of t

he le

gs o

r PE

. d A

lloca

tion

was

con

ceal

ed. P

atie

nts,

pro

vide

rs, d

ata

colle

ctor

s, a

nd o

utco

me

adju

dica

tors

wer

e bl

inde

d. M

odifi

ed I

TT

ana

lysi

s; 1

.1%

loss

to fo

llow

-up.

Not

sto

pped

ear

ly fo

r be

nefi t

. e C

I in

clud

es v

alue

s su

gges

ting

no e

ffec

t and

val

ues

sugg

estin

g ei

ther

ben

efi t

or h

arm

; rel

ativ

ely

low

num

ber

of e

vent

s.

f One

fata

l VT

E in

dab

igat

ran

grou

p an

d th

ree

fata

l VT

Es

in w

arfa

rin

grou

p.

g One

fata

l maj

or b

leed

ing

even

t in

dabi

gatr

an g

roup

and

one

fata

l maj

or b

leed

ing

even

t in

war

fari

n gr

oup.




Tabl

e S3

2 —[S

ecti

on 4

.1]

Ela

stic

Sto

ckin

g fo

r P

reve

ntio

n of

PT

S: C

lini

cal

Des

crip

tion

and

Res

ult

s

Aut

hor/

Year

Type

of

Publ

icat

ion

Part

icip

ants

Inte

rven

tions

Out

com

esF

ollo

w-u

pR

esul

ts

Bra

ndje

s et

al 12

7 /199

7R

CT

194

patie

nts

with

fi rs

t sym

ptom

atic

pr

oxim

al D

VT

Com

pres

sion

sto

ckin

gs:

belo

w-k

nee

cust

omiz

ed

elas

tic c

ompr

essi

on

stoc

king

s w

ith a

nkle

pr

essu

re 3

0-40

mm

Hg

(96

patie

nts)

Cum

ulat

ive

inci

denc

e of

mild

to m

oder

ate

and

seve

re P

TS

3 an

d 6

mo,

th

en e

very

6 m

o to

a m

edia

n of

76

mo

Com

pres

sion

sto

ckin

gs:

Mild

-mod

erat

e PT

S: 2

0%

(RR

, 0.4

2; 9

5% C

I 0.

27-0

.66;

P

, .0

01) S

ever

e PT

S: 1

1%

(RR

, 0.4

9; 9

5% C

I, 0

.25-

0.95

; P

, .0

01)

C

ontr

ol g

roup

: no

inte

rven

tion

(98

patie

nts)

Con

trol

gro

up: M

ild-m

oder

ate

PTS:

47%

Sev

ere

PTS:

23%

Gin

sber

g et

al 12

4 /200

1R

CT

47 a

sym

ptom

atic

pat

ient

s w

ith v

alvu

lar

inco

mpe

tenc

e 1

y po

st-D

VT

Com

pres

sion

sto

ckin

gs:

belo

w-k

nee

elas

tic

com

pres

sion

sto

ckin

gs

20-3

0 m

m H

g (2

4 pa

tient

s)

PTS

sym

ptom

s57

mo

(mea

n)C

ompr

essi

on s

tock

ings

: PT

S sy

mpt

oms:

0%

Pl

aceb

o: p

lace

bo s

tock

ing

(23

patie

nts)

Plac

ebo:

PT

S sy

mpt

oms:

4%

Pran

doni

et a

l 120 /2

004

RC

T18

0 pa

tient

s w

ith fi

rst

epis

ode

of s

ympt

omat

ic,

acut

e pr

oxim

al D

VT

Com

pres

sion

sto

ckin

gs:

belo

w-k

nee

elas

tic

com

pres

sion

sto

ckin

gs

30-4

0 m

m H

g (9

0 pa

tient

s)

Cum

ulat

ive

inci

denc

e of

mild

to m

oder

ate

and

seve

re P

TS

3-5

yC

ompr

essi

on s

tock

ings

: PT

S sy

mpt

oms:

25%

(C

I, 1

5.6%

-33.

4%)

C

ontr

ol g

roup

: no

inte

rven

tion

(90

patie

nts)

Con

trol

gro

up: P

TS

sym

ptom

s:

49%

(CI,

38.

7%-5

9.4%

)

Part

sch

et a

l 84 /2

004

2-y

follo

w-u

p to

RC

T37

sym

ptom

atic

pat

ient

s w

ith a

cute

DV

T fo

llow

ed

long

term

All

antic

oagu

late

d w

ith

LM

WH

follo

wed

by

oral

ant

icoa

gula

tion

Ove

rall

leg

pain

2

yL

eg p

ain:

No

diff

eren

ce

betw

een

grou

ps

In

elas

tic b

anda

ges

1 e

arly

am

bula

tion

(13

patie

nts)

Leg

cir

cum

fere

nce

Cal

f cir

cum

fere

nce:

N

o di

ffer

ence

bet

wee

n gr

oups

E

last

ic s

tock

ings

(3

0 m

m H

g)

1 e

arly

am

bula

tion

(13

patie

nts)

PTS

scor

e (V

illal

ta-P

rand

oni)

PTS

scor

e: S

igni

fi can

tly

bett

er o

utco

me

with

am

bula

tion

and

band

agin

g or

sto

ckin

gs c

ompa

red

with

be

d re

st ( P

, .0

1)

B

ed r

est f

or 9

d,

no c

ompr

essi

on

(11

patie

nts)

Ash

wan

den

et a

l 130 /2

008

RC

T, s

ingl

e ce

nter

169

fi rst

or

recu

rren

t pr

oxim

al D

VT

with

out

PTS

afte

r 6

mo

of

com

pres

sion

sto

ckin

gs

Com

pres

sion

sto

ckin

gs:

belo

w-k

nee,

26

-36

mm

Hg

(84

patie

nts)

PTS

shin

cha

nges

( � C

4 on

C

EA

P)0-

7 y

(mea

n, 3

y)

PTS

com

pres

sion

st

ocki

ngs:

13%

C

ontr

ol g

roup

: sto

pped

st

ocki

ngs

(85

patie

nts)

Con

trol

gro

up: 2

0% H

R:

0.8

(95

% C

I, 0

.3-1

.3)

See

Tabl

e S1

, S2,

S5,

S10

, and

S29

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

.




Table S33 —[Section 4.1] Elastic Stocking for Prevention of PTS: Methodologic Quality


Brandjes et al 127 /1997 Y Y (sealed envelopes) Patients: N Caregivers: N Assessors: Y Data analysis: PY

Intervention group: 4 lost to follow-up, 19 died

Control group: 2 lost to follow-up, 18 died

Ginsberg et al 124 /2001 Y Probably, but not specifi ed

Patients: Y Caregivers: Y Assessors: Y data analysis: PY

Intervention: lost to follow-up not reported, 3 died

Control group: lost to follow-up not reported

Prandoni et al 120 /2004 Y Y Patients: N caregivers: N Assessors: Y Data analysis: PY

Intervention: 2 lost to follow-up, 6 died

Control group: 13 lost to follow-up

Ashwanden et al 130 /2008 Y Y Patients: N Caregivers: N Assessors: N Data analysis: N

Intervention: 19 (described)

Control group: 13 (described)

See Table S5 legend for expansion of abbreviations.




Tabl

e S3

4 —[S

ecti

on 4

.1]

Evi

denc

e P

rofi l

e: E

last

ic C

ompr

essi

on S

tock

ings

vs

No

Ela

stic

Com

pres

sion

Sto

ckin

gs T

o P

reve

nt P

TS

of t

he L

eg a,b

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Stud

y E

vent

Rat

es (%

)

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Ela

stic

C

ompr

essi

on

Stoc

king

s

With

Ela

stic

C

ompr

essi

on

Stoc

king

s

Ris

k W

ith

No

Ela

stic

C

ompr

essi

on

Stoc

king

s

Ris

k D

iffer

ence

With

E

last

ic C

ompr

essi

on

Stoc

king

s (9

5% C

I)

PTS

(cri

tical

out

com

e; a

sses

sed

with

Vill

alta

Sco

re)

421

(2 s

tudi

es),

2 y

Seri

ous c

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssN

o se

riou

s im

prec

isio

nU

ndet

ecte

dM

oder

ate c

due

to

risk

of b

ias

91/2

11 (4

3.1)

d 41

/210

(19.

5)R

R 0

.46

(0.3

4-0.

63) e

479

per

1,00

0 d,f

259

few

er p

er 1

,000

(f

rom

177

few

er

to 3

16 fe

wer

) g

Rec

urre

nt V

TE

(cri

tical

out

com

e)

374

(2 s

tudi

es),

5 y

No

seri

ous

risk

of b

ias h

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s i U

ndet

ecte

dM

oder

ate h,

i du

e to

im

prec

isio

n

26/1

88 (1

3.8)

26/1

86 (1

4)R

R 1

.01

(0.6

1-1.

67) e

210

per

1,00

0 j 2

mor

e pe

r 1,

000

(fro

m 8

2 fe

wer

to

141

mor

e)

Qua

lity

of li

fe (i

mpo

rtan

t out

com

e)

0 (0

k )…

……

See

com

men

t k …

Bib

liogr

aphy

: Kol

bach

et a

l. 123 W

e ex

clud

ed G

insb

erg

et a

l 124 a

nd B

elca

ro e

t al 12

5 bec

ause

they

res

pect

ivel

y ra

ndom

ized

pat

ient

s 7

and

12 m

o af

ter

thei

r D

VT

rat

her

than

at t

he ti

me

of th

e ac

ute

DV

T. W

e al

so e

xclu

ded

Arp

aia

et a

l 126 b

ecau

se th

ey r

ando

miz

ed p

atie

nts

to r

ecei

ve s

tock

ings

at t

he ti

me

of d

iagn

osis

of D

VT

vs

2 w

k la

ter. 12

6 See

Tab

le S

1 an

d S5

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Bra

ndje

s 127 u

sed

grad

ed e

last

ic c

ompr

essi

on s

tock

ings

(40

mm

Hg

of p

ress

ure

at th

e an

kle,

36

mm

Hg

at th

e lo

wer

cal

f, an

d 21

mm

Hg

at th

e up

per

calf)

; sto

ckin

gs w

ere

appl

ied

2 to

3 w

k af

ter

the

fi rst

ep

isod

e of

pro

xim

al D

VT.

Pra

ndon

i 120 u

sed

fl at-

knitt

ed s

tock

ings

(30

-40

mm

Hg

of p

ress

ure

at th

e an

kle)

; sto

ckin

gs w

ere

star

ted

at h

ospi

tal d

isch

arge

an

aver

age

of 1

wk

afte

r ad

mis

sion

. In

both

stu

dies

, st

ocki

ngs

wer

e us

ed fo

r 2

y.

b Pra

ndon

i 120 e

xclu

ded

patie

nts w

ith re

curr

ent i

psila

tera

l DV

T, p

reex

istin

g le

g ul

cers

, or s

igns

of C

VI,

bila

tera

l thr

ombo

sis,

a sh

ort l

ife e

xpec

tanc

y, o

r a c

ontr

aind

icat

ion

for u

se o

f sto

ckin

gs (e

g, a

dvan

ced-

stag

e pe

riph

eral

art

eria

l ins

uffi c

ienc

y). B

rand

jes

et a

l exc

lude

d pa

tient

s w

ith s

hort

life

, par

alys

is o

f the

leg,

bila

tera

l thr

ombo

sis,

leg

ulce

rs, o

r ex

tens

ive

vari

cosi

s.

c Pat

ient

s w

ere

not b

linde

d to

the

trea

tmen

t ass

ignm

ent,

and

outc

omes

wer

e pa

rtly

bas

ed o

n su

bjec

tive

repo

rt o

f sym

ptom

s.

d In

Pran

doni

, 120 m

ost e

vent

s oc

curr

ed d

urin

g th

e fi r

st 6

mo:

the

cum

ulat

ive

inci

denc

e of

PT

S in

the

cont

rol g

roup

was

40%

aft

er 6

mo,

47%

aft

er 1

y, a

nd 4

9% a

fter

2 y

. e T

he e

ffect

est

imat

e sh

own

here

resu

lts fr

om a

met

a-an

alys

is (M

ante

l-Hae

nsze

l fi x

ed-e

ffect

s mod

el) o

f the

two

rele

vant

tria

ls. A

fi xe

d-ef

fect

s mod

el w

as c

hose

n be

caus

e of

the

smal

l num

ber o

f stu

dies

ava

ilabl

e.

f Thi

s es

timat

e is

bas

ed o

n th

e fi n

ding

s of

the

VE

TO

(Ven

ous

Thr

ombo

sis

Out

com

es) s

tudy

. 40 T

his

prob

ably

und

eres

timat

es th

e PT

S ba

selin

e ri

sk g

iven

that

ove

rall,

52%

of p

atie

nts

repo

rted

the

curr

ent u

se

of c

ompr

essi

on s

tock

ings

dur

ing

stud

y fo

llow

-up.

g S

ever

e PT

S: a

ssum

ing

the

sam

e R

R o

f 0.4

6 an

d a

base

line

risk

of 8

.1%

ove

r 2

y, th

e ab

solu

te r

educ

tion

is 4

4 fe

wer

sev

ere

PTS

per

1,00

0 (f

rom

30

few

er to

53

few

er) o

ver

2 y.

h W

e di

d no

t rat

e do

wn

the

qual

ity o

f evi

denc

e fo

r re

curr

ent V

TE

for

the

lack

of b

lindi

ng b

ecau

se th

is a

mor

e ob

ject

ive

outc

ome

than

PT

S.

i CI

incl

udes

bot

h ne

glig

ible

eff

ect a

nd a

ppre

ciab

le b

enefi

t or

app

reci

able

har

m.

j Thi

s es

timat

e is

the

mea

n of

two

estim

ates

der

ived

from

two

stud

ies:

12.

4% p

roba

ble/

defi n

ite V

TE

(Hei

t 128 )

and

29.

1% c

onfi r

med

VT

E (P

rand

oni 12

9 ).

k Thi

s is

an

impo

rtan

t out

com

e th

at s

houl

d be

con

side

red

in fu

ture

stu

dies

.




Tabl

e S3

5 —[S

ecti

on 4

.2.1

] E

vide

nce

Pro

fi le:

Com

pres

sion

Sto

ckin

gs v

s N

o C

ompr

essi

on S

tock

ings

for

Pat

ient

s W

ith

PT

S a-c

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Stud

y E

vent

Rat

es (%

)

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Com

pres

sion

St

ocki

ngs

With

Com

pres

sion

St

ocki

ngs

Ris

k W

ith N

o C

ompr

essi

on

Stoc

king

s

Ris

k D

iffer

ence

W

ith C

ompr

essi

on

Stoc

king

s (9

5% C

I)

Sym

ptom

atic

rel

ief (

criti

cal o

utco

me;

ass

esse

d w

ith tr

eatm

ent s

ucce

ss d )

115

(2 s

tudi

es),

12-2

6 m

oSe

riou

s e N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous f

Und

etec

ted g

Low

e-g d

ue to

ri

sk o

f bia

s,

impr

ecis

ion

33/5

7 (5

7.9)

32/5

8 (5

5.2)

RR

0.9

6 (0

.70-

1.31

)57

9 pe

r 1,

000

23 fe

wer

per

1,0

00

(fro

m 1

74 fe

wer

to

179

mor

e)

Qua

lity

of li

fe n

ot r

epor

ted

……

……

……

...…

……

......

Rec

urre

nt V

TE

not

rep

orte

d

……

……

……

...…

……

......

Ulc

erat

ion

not r

epor

ted h

……

……

……

...…

……

......

Bib

liogr

aphy

: Gin

sber

g 20

01 12

4 ; F

rulla

. 200

5 131 S

ee T

able

S1,

S2,

S5,

and

S10

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Gin

sber

g et

al:

grad

uate

d co

mpr

essi

on st

ocki

ngs,

30-

40 m

m H

g (c

alf o

r thi

gh le

ngth

, dep

endi

ng o

n sy

mpt

oms)

. Pat

ient

s wer

e en

cour

aged

to w

ear s

tock

ings

as m

uch

as p

ossi

ble

duri

ng w

akin

g ho

urs.

Fru

lla

(200

5): b

elow

-kne

e gr

aded

ela

stic

com

pres

sion

sto

ckin

gs (E

CS)

(30-

40 m

m H

g at

the

ankl

e). P

atie

nts

in b

oth

arm

s of

the

stud

y re

ceiv

ed h

ydro

xyet

hylr

utos

ides

(HR

) (w

e co

nsid

ered

the

EC

S 1

HR

vs

HR

co

mpa

riso

n).

b Gin

sber

g et

al:

plac

ebo

stoc

king

s (c

alf o

r th

igh

leng

th, d

epen

ding

on

sym

ptom

s).

c Gin

sber

g et

al i

nclu

ded

patie

nts

with

PT

S 1

y af

ter

chro

nic,

typi

cal p

roxi

mal

DV

T. F

rulla

(200

5) in

clud

ed p

atie

nts

with

clin

ical

sym

ptom

s an

d si

gns

sugg

estiv

e of

PT

S.

d Gin

sber

g et

al r

epor

ted

trea

tmen

t fai

lure

(defi

ned

a p

rior

i bas

ed o

n an

y of

fi ve

clin

ical

cri

teri

a, in

clud

ing

sym

ptom

s an

d ul

cer

deve

lopm

ent)

. Tre

atm

ent s

ucce

ss r

efer

s to

the

abse

nce

of tr

eatm

ent f

ailu

re.

Fru

lla u

sed

the

Vill

alta

sca

le.

e Gin

sber

g et

al:

Ade

quac

y of

seq

uenc

e ge

nera

tion

and

allo

catio

n co

ncea

lmen

t wer

e un

clea

r; p

atie

nts

and

outc

ome

asse

ssor

s w

ere

adeq

uate

ly b

linde

d; u

ncle

ar w

heth

er a

naly

sis

follo

wed

the

ITT

pri

ncip

le;

uncl

ear

whe

ther

follo

w-u

p w

as c

ompl

ete.

Fru

lla (2

005)

: out

com

e as

sess

ors

wer

e bl

inde

d; fo

llow

-up

was

com

plet

e. I

TT

pri

ncip

le w

as a

dher

ed to

, but

seq

uenc

e ge

nera

tion

and

allo

catio

n co

ncea

lmen

t wer

e un

clea

r, an

d pa

tient

s w

ere

not b

linde

d.

f Ver

y sm

all n

umbe

r of

pat

ient

s.

g Pub

licat

ion

bias

not

det

ecte

d bu

t not

rul

ed o

ut g

iven

that

we

iden

tifi e

d on

ly o

ne s

mal

l stu

dy p

artia

lly s

uppo

rted

by

indu

stry

(pro

visi

on o

f gra

duat

ed c

ompr

essi

on s

tock

ings

). h I

ndir

ect e

vide

nce

from

the

CL

OT

S1 (C

lots

in L

egs

Or

sToc

king

s af

ter

Stro

ke) t

rial

sug

gest

s th

at c

ompr

essi

on s

tock

ings

is a

ssoc

iate

d w

ith a

n R

R o

f 4 fo

r sk

in c

ompl

icat

ions

. i A

bsen

ce o

f ulc

er in

clud

ed in

the

trea

tmen

t suc

cess

out

com

e in

Gin

sber

g et

al.




Tabl

e S3

6 —[S

ecti

on 4

.2.2

] E

vide

nce

Pro

fi le:

Int

erm

itte

nt C

ompr

essi

on D

evic

e vs

No

Inte

rmit

tent

Com

pres

sion

Dev

ice

for

Pat

ient

s W

ith

Seve

re P

TS a

-c

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Stud

y E

vent

Rat

es (%

)

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Inte

rmitt

ent

Com

pres

sion

D

evic

e

With

Int

erm

itten

t C

ompr

essi

on

Dev

ice

Ris

k W

ith N

o In

term

itten

t C

ompr

essi

on

Dev

ice

Ris

k D

iffer

ence

W

ith I

nter

mitt

ent

Com

pres

sion

D

evic

e (9

5% C

I)

Sym

ptom

atic

rel

ief (

criti

cal o

utco

me;

mea

sure

d w

ith s

ympt

om s

core

(inc

lude

s sc

orin

g of

pai

n, s

wel

ling,

and

lim

itatio

n of

act

ivity

); ra

nge

of s

core

s, 1

0-70

; bet

ter

indi

cate

d by

hig

her

valu

es)

82 (2

stu

dies

d ),

8 w

kN

o se

riou

s ri

sk o

f bia

s e N

o se

riou

s in

cons

iste

ncy f

No

seri

ous

indi

rect

ness

g Se

riou

s h U

ndet

ecte

d i M

oder

ate e-

i du

e to

im

prec

isio

n

41 d

41 d

…T

he m

ean

sym

ptom

atic

re

lief i

n th

e co

ntro

l gro

ups

was

0

The

mea

n sy

mpt

omat

ic

relie

f in

the

inte

rven

tion

grou

ps

was

0.4

1 SD

s hi

gher

(0.0

2 lo

wer

to

0.8

5 hi

gher

)

Qua

lity

of li

fe (c

ritic

al o

utco

me;

mea

sure

d w

ith V

EIN

ES-

QO

L; r

ange

of s

core

s, 0

-100

; bet

ter

indi

cate

d by

hig

her

valu

es)

0 (1

stu

dy d,

j ),

8 w

kN

o se

riou

s ri

sk o

f bia

s k N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

g Se

riou

s h U

ndet

ecte

d i,l M

oder

ate f-

h,k,

l du

e to

im

prec

isio

n

…0

…T

he m

ean

qual

ity

of li

fe in

the

cont

rol g

roup

s w

as 5

0.2

The

mea

n qu

ality

of l

ife in

the

inte

rven

tion

grou

ps

was

2.3

hig

her

(1.0

4 lo

wer

to

5.64

hig

her)

(C

onti

nued

)




Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

Stud

y E

vent

Rat

es (%

)

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Inte

rmitt

ent

Com

pres

sion

D

evic

e

With

Int

erm

itten

t C

ompr

essi

on

Dev

ice

Ris

k W

ith N

o In

term

itten

t C

ompr

essi

on

Dev

ice

Ris

k D

iffer

ence

W

ith I

nter

mitt

ent

Com

pres

sion

D

evic

e (9

5% C

I)

Rec

urre

nt V

TE

not

rep

orte

d m

……

……

……

...…

……

......

Ulc

erat

ion

not r

epor

ted n

……

……

……

...…

……

......

Bib

liogr

aphy

: Gin

sber

g 19

99, 13

2 O’D

onne

ll, 2

008.

133 S

ee T

able

S1,

S5,

and

S10

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

. a G

insb

erg

et a

l: E

xtre

mity

pum

p us

ed b

id fo

r 20

min

eac

h se

ssio

n; 5

0 m

m H

g (t

hera

peut

ic p

ress

ure)

for

1 m

o. O

’Don

nell

et a

l: Ve

now

ave

low

er-li

mb

veno

us r

etur

n as

sist

dev

ice

to w

ear

for

mos

t of t

he d

ay

for

8 w

k.

b Gin

sber

g et

al:

Ext

rem

ity p

ump

used

bid

for

20 m

in e

ach

sess

ion;

15

mm

Hg

(pla

cebo

pre

ssur

e) fo

r 1

mo.

O’D

onne

ll et

al:

Veno

wav

e lo

wer

-lim

b ve

nous

ret

urn

assi

st d

evic

e w

ith n

o co

nnec

tion

betw

een

mot

or a

nd p

lana

r sh

eet f

or 8

wk.

c P

atie

nts

with

pre

viou

s D

VT

with

sym

ptom

s of

sev

ere

PTS.

d C

ross

over

RC

Ts.

e In

both

stu

dies

, seq

uenc

e ge

nera

tion

was

ade

quat

e; p

atie

nts

wer

e bl

inde

d. A

naly

sis

adhe

red

to I

TT

pri

ncip

le, a

nd th

ere

wer

e no

mis

sing

out

com

e da

ta. I

n G

insb

erg

et a

l (bu

t not

in O

’Don

nell

et a

l), o

ut-

com

e as

sess

ors

wer

e no

t blin

ded,

and

it w

as n

ot c

lear

whe

ther

allo

catio

n w

as c

once

aled

. f I 2 5

0%

. g S

ome

conc

erns

with

indi

rect

enes

s gi

ven

rela

tivel

y sh

ort f

ollo

w-u

p (8

wk)

. h V

ery

smal

l num

ber

of p

atie

nts.

CI

incl

udes

bot

h va

lues

sug

gest

ing

no e

ffec

t and

val

ues

sugg

estin

g a

bene

fi cia

l eff

ect.

i Pub

licat

ion

bias

not

det

ecte

d bu

t not

rul

ed o

ut g

iven

that

we

iden

tifi e

d on

ly tw

o sm

all s

tudi

es w

ith o

ne (G

insb

erg

et a

l) pa

rtia

lly s

uppo

rted

by

indu

stry

(pro

visi

on o

f dev

ices

). j O

’Don

nell

et a

l. k S

eque

nce

gene

ratio

n w

as a

dequ

ate;

pat

ient

s w

ere

blin

ded;

ana

lysi

s ad

here

d to

IT

T p

rinc

iple

; and

ther

e w

ere

no m

issi

ng o

utco

me

data

. How

ever

, out

com

e as

sess

ors

wer

e no

t blin

ded,

and

it w

as n

ot c

lear

w

heth

er a

lloca

tion

was

con

ceal

ed.

l Pub

licat

ion

bias

not

det

ecte

d bu

t not

rul

ed o

ut g

iven

that

we

iden

tifi e

d on

ly o

ne s

mal

l stu

dy.

m O

’Don

nell

et a

l ind

icat

ed n

o ca

ses

of r

ecur

rent

VT

E b

y th

e en

d of

this

stu

dy b

ut ju

dged

the

follo

w-u

p pe

riod

to b

e sh

ort.

n O’D

onne

ll et

al i

ndic

ated

that

one

pat

ient

in th

e co

ntro

l gro

up d

evel

oped

a v

enou

s ulc

erat

ion.

Thr

ee o

ther

par

ticip

ants

dev

elop

ed n

onse

riou

s ski

n-re

late

d si

de e

ffec

ts. I

ndir

ect e

vide

nce

from

the

CL

OT

S1

(Clo

ts in

Leg

s O

r sT

ocki

ngs

afte

r St

roke

) tr

ial s

ugge

sts

that

com

pres

sion

sto

ckin

gs a

re a

ssoc

iate

d w

ith a

n R

R o

f 4 fo

r sk

in c

ompl

icat

ions

: Com

mon

sid

e ef

fect

s ar

e at

trib

uted

to V

enow

ave

wer

e he

at s

en-

satio

n, s

kin

irri

tatio

n, a

nd in

crea

sed

swea

ting.

Tabl

e S3

6—C

onti

nued




Tabl

e S3

7 —[S

ecti

on 4

.3]

Evi

denc

e P

rofi l

e: V

enoa

ctiv

e M

edic

atio

n vs

No

Ven

oact

ive

Med

icat

ion

for

Pat

ient

s W

ith

PT

S a,b

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Rel

ativ

e E

ffec

t (9

5% C

I)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Veno

activ

e M

edic

atio

nW

ith V

enoa

ctiv

e M

edic

atio

n

Ris

k W

ith N

o Ve

noac

tive

Med

icat

ion

Ris

k D

iffer

ence

With

Ve

noac

tive

Med

icat

ion

(95%

CI)

Sym

ptom

atic

relie

f (cr

itica

l out

com

e; a

sses

sed

with

PT

S sc

ore

(Vill

alta

scal

e) ,

5 or

dec

reas

ed b

y 30

% a

t 12

mo

com

pare

d w

ith b

asel

ine

in F

rulla

et a

l ; im

prov

ed ti

redn

ess o

f the

leg

at 8

wk

in d

e Jo

ngst

e et

al c )

163

(2 s

tudi

es )

No

seri

ous

risk

of b

ias d

Seri

ous e

No

seri

ous

indi

rect

ness

Seri

ous f

Und

etec

ted g

Low

d-g d

ue to

in

cons

iste

ncy,

im

prec

isio

n

39/8

2 (4

7.6)

44/8

1 (5

4.3)

RR

1.1

4 (0

.85-

1.52

)47

6 pe

r 1,

000

67 m

ore

per

1,00

0 (f

rom

71

few

er to

24

7 m

ore)

Qua

lity

of li

fe n

ot r

epor

ted

……

……

……

...

……

…...

...

Rec

urre

nt V

TE

not

rep

orte

d

……

……

……

...…

……

......

Ulc

erat

ion

not r

epor

ted

……

……

……

...…

……

......

Side

eff

ects

(cri

tical

out

com

e)

203

(2 s

tudi

es)

No

seri

ous

risk

of b

ias d

No

seri

ous

inco

nsis

tenc

y h N

o se

riou

s in

dire

ctne

ssSe

riou

s f U

ndet

ecte

d g M

oder

ate d,

f-h

due

to

impr

ecis

ion

5/82

(6.1

%)

13/1

21 (1

0.7%

)R

R 2

.04

(0.7

6-5.

51)

61 p

er 1

,000

63 m

ore

per

1,00

0 (f

rom

15

few

er to

27

5 m

ore)

Bib

liogr

aphy

: Fru

lla 2

005 13

1 de

Jong

ste

1989

. 134 S

ee T

able

S1,

S5,

and

S10

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Inc

lude

d st

udie

s as

sess

ed r

utos

ides

; we

excl

uded

Mon

real

et a

l 135 b

ecau

se it

com

pare

d tw

o ve

noac

tive

med

icat

ions

. b P

atie

nts

with

PT

S an

d hi

stor

y of

DV

T in

PT

S le

g.

c Inv

estig

ator

s ass

esse

d ot

her s

ympt

oms (

pain

, hea

vine

ss, s

wel

ling

feel

ing,

rest

less

legs

, and

cra

mps

) but

did

not

repo

rt a

com

posi

te sc

ore.

The

sym

ptom

we

chos

e to

repo

rt sh

owed

the

mos

t ben

efi t;

the

effe

ct

estim

ates

for

the

othe

r sy

mpt

oms

rang

ed fr

om 0

.8 to

1.4

, and

non

e w

as s

tatis

tical

ly s

igni

fi can

t. d I

n bo

th st

udie

s, se

quen

ce g

ener

atio

n an

d al

loca

tion

conc

ealm

ent w

ere

uncl

ear.

Bot

h st

udie

s blin

ded

outc

ome

asse

ssor

s and

had

com

plet

e fo

llow

-up.

Alth

ough

de

Jong

ste

et a

l blin

ded

patie

nts,

they

did

not

ad

here

to th

e IT

T p

rinc

iple

and

did

not

use

a v

alid

ated

sca

le to

mea

sure

sym

ptom

atic

rel

ief.

Alth

ough

Fru

lla (2

005)

adh

ered

to th

e IT

T p

rinc

iple

, it d

id n

ot b

lind

patie

nts.

e I

2 5 7

7%.

f Sm

all n

umbe

r of

pat

ient

s. C

I in

clud

ing

both

val

ues

sugg

estin

g ha

rms

and

valu

es s

ugge

stin

g be

nefi t

s.

g Pub

licat

ion

bias

not

det

ecte

d bu

t not

rul

ed o

ut g

iven

that

we

iden

tifi e

d on

ly tw

o sm

all s

tudi

es, a

nd it

was

unc

lear

whe

ther

they

wer

e fu

nded

by

indu

stry

. h I

2 5 7

%.




Tabl

e S3

8 —[S

ecti

on 5

.4]

Evi

denc

e P

rofi l

e: F

onda

pari

nux

vs I

V U

FH

for

Ini

tial

Ant

icoa

gula

tion

of

Acu

te P

E a-c

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

eW

ith U

FH

With

F

onda

parin

uxR

elat

ive

Eff

ect

(95%

CI)

Ris

k W

ith

UF

H

Ris

k D

iffer

ence

With

F

onda

pari

nux

(95%

CI)

Mor

talit

y (im

port

ant o

utco

me)

2,21

3 (1

stu

dy),

3 m

oN

o se

riou

s ri

sk

of b

ias d

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s e U

ndet

ecte

dM

oder

ate d,

e due

to

impr

ecis

ion

48/1

,110

(4.3

)57

/1,1

03 (5

.2)

RR

1.2

0 (0

.82-

1.74

)43

per

1,0

009

mor

e pe

r 1,

000

(fro

m 8

few

er to

32

mor

e)

Rec

urre

nt V

TE

(cri

tical

out

com

e)

2,21

3 (1

stu

dy),

3 m

oN

o se

riou

s ri

sk

of b

ias d

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s e U

ndet

ecte

dM

oder

ate d,

e due

to

impr

ecis

ion

56/1

,110

(5.0

) f 42

/1,1

03 (3

.8) f

RR

0.7

5 (0

.51-

1.12

)50

per

1,0

00 f

13 fe

wer

per

1,0

00

(fro

m 2

5 fe

wer

to

6 m

ore)

Maj

or b

leed

ing

(cri

tical

out

com

e)

2,21

3 (1

stu

dy),

3 m

oN

o se

riou

s ri

sk

of b

ias d

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s e U

ndet

ecte

dM

oder

ate d,

e due

to

impr

ecis

ion

26/1

,110

(2.3

) g 22

/1,1

03 (2

.0) g

RR

0.8

5 (0

.49-

1.49

)23

per

1,0

00 g

4 fe

wer

per

1,0

00

(fro

m 1

2 fe

wer

to

11 m

ore)

Bib

liogr

aphy

: Bül

ler

et a

l. 136 S

ee T

able

S1,

S2,

S4,

and

S7

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Fon

dapa

rinu

x (5

.0, 7

.5, o

r 10

.0 m

g in

pat

ient

s w

eigh

ing

, 5

0, 5

0 to

100

, or

> 10

0 kg

, res

pect

ivel

y) S

C o

nce

daily

giv

en fo

r at

leas

t 5 d

ays

and

until

the

use

of V

KA

s re

sulte

d in

an

INR

. 2

.0.

b UF

H c

ontin

uous

IV

infu

sion

(rat

io o

f the

aPT

T to

a c

ontr

ol v

alue

, 1.5

-2.5

) giv

en fo

r at

leas

t 5 d

ays

and

until

the

use

of V

KA

s re

sulte

d in

an

INR

. 2

.0.

c All

patie

nts

had

acut

e sy

mpt

omat

ic h

emod

ynam

ical

ly s

tabl

e PE

. d A

lloca

tion

was

con

ceal

ed. P

atie

nts,

pro

vide

rs, a

nd d

ata

colle

ctor

s no

t blin

ded.

Out

com

e ad

judi

cato

rs w

ere

blin

ded;

0.6

% o

f ran

dom

ized

pat

ient

s w

ere

lost

to fo

llow

-up.

Not

sto

pped

ear

ly fo

r be

nefi t

. e C

I in

clud

es v

alue

s su

gges

ting

no e

ffec

t and

val

ues

sugg

estin

g ei

ther

ben

efi t

or h

arm

; rel

ativ

ely

low

num

ber

of e

vent

s.

f Six

teen

fata

l VT

E in

fond

apar

inux

gro

up a

nd 1

5 fa

tal V

TE

in U

FH

gro

up.

g Fou

rtee

n pa

tient

s in

the

fond

apar

inux

gro

up a

nd 1

2 in

the

LM

WH

gro

up h

ad a

maj

or b

leed

ing

durin

g th

e in

itial

per

iod

(6-7

d).

Of t

hese

, one

in th

e fo

ndap

arin

ux g

roup

and

one

in th

e U

FH

gro

up w

ere

fata

l.




Tabl

e S3

9 —[S

ecti

on 5

.5]

Evi

denc

e P

rofi l

e: E

arly

Dis

char

ge v

s St

anda

rd D

isch

arge

in

the

Tre

atm

ent

of A

cute

PE

a,b

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

s

Ove

rall

Qua

lity

of

Evi

denc

eW

ith S

tand

ard

Dis

char

geW

ith E

arly

D

isch

arge

Rel

ativ

e E

ffec

t (9

5% C

I)

Ris

k W

ith

Stan

dard

D

isch

arge

Ris

k D

iffer

ence

W

ith E

arly

Dis

char

ge

(95%

CI)

Mor

talit

y (c

ritic

al o

utco

me)

471

(2 s

tudi

es),

3 m

oSe

riou

s c N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous d

Und

etec

ted

Mod

erat

e c,d d

ue

to im

prec

isio

n6/

228

(2.6

)4/

243

(1.6

)R

R 0

.58

(0.1

7-1.

97)

26 p

er 1

,000

11 fe

wer

per

1,0

00

(fro

m 2

2 fe

wer

to

26

mor

e)

Non

fata

l rec

urre

nt P

E (c

ritic

al o

utco

me)

471

(2 s

tudi

es),

3 m

oSe

riou

s c N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous d

Und

etec

ted

Mod

erat

e c,d d

ue

to im

prec

isio

n2/

228

(0.9

)3/

243

(1.2

)R

R 1

.23

(0.2

5-6.

03)

9 pe

r 1,

000

2 m

ore

per

1,00

0 (f

rom

7 fe

wer

to

44

mor

e)

Maj

or b

leed

ing

(cri

tical

out

com

e)

471

(2 s

tudi

es),

3 m

oSe

riou

s c N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous d

Und

etec

ted

Mod

erat

e c,d d

ue

to im

prec

isio

n1/

228

(0.4

)4/

243

(1.6

)R

R 2

.74

(0.4

5-16

.71)

4 pe

r 1,

000

8 m

ore

per

1,00

0 (f

rom

2 fe

wer

to

69

mor

e)

Qua

lity

of li

fe n

ot r

epor

ted

……

……

……

……

……

…

Bib

liogr

aphy

: Ote

ro e

t al, 13

7 Auj

esky

et a

l. 138 S

ee T

able

S1,

S2,

and

S5

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Mea

n le

ngth

of h

ospi

tal s

tay:

3.4

(SD

1.1

) vs

9.3

(SD

5.7

) in

Ote

ro e

t al a

nd 0

.5 (S

D 1

.0) v

s 3.

9 (S

D 3

.1) i

n A

ujes

ky e

t al.

b The

two

RC

Ts in

clud

ed o

nly

patie

nts

with

low

ris

k: r

isk

clas

ses

I or

II

on th

e Pu

lmon

ary

Em

bolis

m S

ever

ity I

ndex

in A

ujes

ky e

t al 13

9 ; lo

w r

isk

on c

linic

al p

redi

ctio

n ru

le b

y U

resa

ndi e

t al 14

0 in

Ote

ro e

t al.

c Ote

ro e

t al:

allo

catio

n co

ncea

led,

no

patie

nts

lost

to fo

llow

-up,

IT

T a

naly

sis,

no

blin

ding

of o

utco

me

asse

ssor

s re

port

ed, s

tudy

sto

pped

ear

ly b

ecau

se th

e ra

te o

f sho

rt-t

erm

mor

talit

y w

as u

nexp

ecte

dly

high

in

the

earl

y di

scha

rge

grou

p (2

[2.

8%]

vs 0

[0%

]). A

ujes

ky e

t al:

uncl

ear

whe

ther

allo

catio

n w

as c

once

aled

, thr

ee (

1%)

patie

nts

had

mis

sing

out

com

e da

ta, I

TT

ana

lysi

s, o

utco

me

adju

dica

tors

blin

ded,

no

earl

y st

oppa

ge.

d CI

incl

udes

bot

h va

lues

sug

gest

ing

no e

ffec

t and

val

ues

sugg

estin

g ap

prec

iabl

e ha

rm o

r ap

prec

iabl

e be

nefi t

.




Tabl

e S4

0 —[S

ecti

on 5

.6.1

] E

vide

nce

Pro

fi le:

Sys

tem

ic T

hrom

bol

ytic

The

rapy

vs

Ant

icoa

gula

tion

Alo

ne i

n P

atie

nts

Wit

h A

cute

PE

a-d

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Syst

emic

ally

A

dmin

iste

red

Thr

ombo

lytic

T

hera

py

With

Sys

tem

ical

ly

Adm

inis

tere

d T

hrom

boly

tic

The

rapy

Rel

ativ

e E

ffec

t (9

5% C

I)

Ris

k W

ith N

o Sy

stem

ical

ly

Adm

inis

tere

d T

hrom

boly

tic

The

rapy

Ris

k D

iffer

ence

W

ith S

yste

mic

ally

A

dmin

iste

red

Thr

ombo

lytic

T

hera

py (9

5% C

I)

Mor

talit

y (c

ritic

al o

utco

me)

847

(12

stud

ies)

, 30

dSe

riou

s e N

o se

riou

s in

cons

iste

ncy f

No

seri

ous

indi

rect

ness

Seri

ous g

Und

etec

ted h

Low

e-h d

ue

to r

isk

of

bias

and

im

prec

isio

n

26/4

23 (6

.1)

15/4

24 (3

.5)

RR

0.7

(0

.37-

1.31

)L

ow i,j

11 p

er 1

,000

3 fe

wer

per

1,0

00

(fro

m 7

few

er to

3

mor

e)

H

igh i,j

89

per

1,0

0027

few

er p

er 1

,000

(f

rom

56

few

er

to 2

8 m

ore)

Rec

urre

nt P

E (i

mpo

rtan

t out

com

e)

801

(9 s

tudi

es),

30 d

Seri

ous e

No

seri

ous

inco

nsis

tenc

y f N

o se

riou

s in

dire

ctne

ssSe

riou

s g U

ndet

ecte

d h L

ow e-

h due

to

ris

k of

bi

as a

nd

impr

ecis

ion

30/4

04 (7

.4)

18/3

97 (4

.5)

RR

0.7

(0

.4-1

.21)

57 p

er 1

,000

17 fe

wer

per

1,0

00

(fro

m 3

4 fe

wer

to

12

mor

e)

Maj

or b

leed

ing

(cri

tical

out

com

e)

847

(12

stud

ies)

, 10

dSe

riou

s e N

o se

riou

s in

cons

iste

ncy f

No

seri

ous

indi

rect

ness

Seri

ous k

Und

etec

ted h

Mod

erat

e e,f,h

,k

due

to r

isk

of b

ias

and

impr

ecis

ion

24/4

23 (5

.7)

38/4

24 (9

)R

R 1

.63

(1-2

.68)

l L

ow m

1 pe

r 1,

000

1 m

ore

per

1,00

0 (f

rom

0 m

ore

to

2 m

ore)

(C

onti

nued

)




Tabl

e S4

0—C

onti

nued

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

e

With

No

Syst

emic

ally

A

dmin

iste

red

Thr

ombo

lytic

T

hera

py

With

Sys

tem

ical

ly

Adm

inis

tere

d T

hrom

boly

tic

The

rapy

Rel

ativ

e E

ffec

t (9

5% C

I)

Ris

k W

ith N

o Sy

stem

ical

ly

Adm

inis

tere

d T

hrom

boly

tic

The

rapy

Ris

k D

iffer

ence

W

ith S

yste

mic

ally

A

dmin

iste

red

Thr

ombo

lytic

T

hera

py (9

5% C

I)

H

igh m

62

per

1,0

0039

mor

e pe

r 1,

000

(fro

m 0

mor

e to

10

4 m

ore)

Bib

liogr

aphy

: Nin

e ea

rlie

r stu

dies

141-

149 e

xtra

cted

from

thre

e sy

stem

atic

revi

ews (

Don

g et

al, 15

0 Wan

et a

l, 151 A

gnel

li et

al 15

2 ) a

nd tw

o re

cent

ly p

ublis

hed

stud

ies (

Bec

attin

i C e

t al, 15

3 Fas

sulo

et a

l 154 )

. See

Tab

le

S1 a

nd S

2 le

gend

s fo

r ex

pans

ion

of a

bbre

viat

ions

. a I

nclu

ded

stud

ies

used

diff

eren

t thr

ombo

lytic

age

nts

with

var

ying

dos

es a

nd d

urat

ions

of a

dmin

istr

atio

n; n

o st

atis

tical

het

erog

enei

ty w

as n

oted

. b T

hrom

boly

sis

was

in a

dditi

on to

ant

icoa

gula

tion

(mos

t of t

he s

tudi

es u

sed

hepa

rin

follo

wed

by

war

fari

n; th

ree

stud

ies

used

war

fari

n on

ly).

c One

stud

y in

clud

ed e

xclu

sive

ly p

atie

nts w

ith h

emod

ynam

ic c

ompr

omis

e (s

hock

); si

x ex

clud

ed th

em, w

here

as th

e re

st e

ither

incl

uded

a n

umbe

r of s

uch

patie

nts o

r did

not

spec

ify re

late

d el

igib

ility

. cri

teri

a.

Of s

tudi

es n

ot re

stri

cted

to p

atie

nts w

ith h

emod

ynam

ic c

ompr

omis

e (n

5 1

1), o

nly

thre

e w

ere

clea

rly

rest

rict

ed to

pat

ient

s with

righ

t ven

tric

ular

dys

func

tion;

the

rest

eith

er d

id n

ot sp

ecify

rela

ted

elig

ibili

ty

crite

ria

or in

clud

ed b

oth

patie

nts

with

and

with

out r

ight

ven

tric

ular

dys

func

tion.

As

a re

sult,

it w

as n

ot p

ossi

ble

to p

erfo

rm r

elia

ble

cate

gori

zatio

n of

stu

dies

to c

ondu

ct s

ubgr

oup

anal

yses

bas

ed o

n th

e pr

es-

ence

or

abse

nce

of r

ight

ven

tric

ular

dys

func

tion

or h

emod

ynam

ic c

ompr

omis

e.

d Stu

dies

incl

uded

pat

ient

s at

low

ris

k of

ble

edin

g.

e Rep

ort o

f met

hodo

logi

c qu

ality

was

poo

r in

mos

t stu

dies

. Of t

he 1

2 el

igib

le s

tudi

es, a

lloca

tion

was

con

ceal

ed in

fi ve

, thr

ee w

ere

sing

le b

linde

d (o

utco

me

asse

ssor

), si

x w

ere

doub

le b

linde

d, a

nd th

ree

wer

e no

t blin

ded.

Mos

t stu

dies

did

not

rep

ort o

n m

issi

ng o

utco

me

data

. Non

e of

the

stud

ies

was

sto

pped

ear

ly fo

r be

nefi t

. For

the

incr

ease

in b

leed

ing

with

thro

mbo

lytic

ther

apy,

qua

lity

of e

vide

nce

is in

crea

sed

from

low

to m

oder

ate

beca

use

ther

e is

hig

h qu

ality

evi

denc

e of

this

ass

ocia

tion

in p

atie

nts

with

myo

card

ial i

nfar

ctio

n an

d th

e in

dire

ctne

ss o

f thi

s ev

iden

ce to

pat

ient

s w

ith P

E is

min

or.

f I 2 5 0

%.

g CI

incl

udes

val

ues

sugg

estin

g bo

th b

enefi

t an

d no

eff

ect o

r ha

rm; s

mal

l num

ber

of e

vent

s.

h Inv

erte

d fu

nnel

plo

ts s

ugge

sted

pos

sibl

e pu

blic

atio

n bi

as in

favo

r of

thro

mbo

lytic

s.

i Rec

urre

nt P

E s

trat

ifi ca

tion

base

d on

the

sim

plifi

ed P

ulm

onar

y E

mbo

lism

Sev

erity

Ind

ex v

alid

ated

in th

e R

IET

E (R

egis

tro

Info

rmat

izad

o de

la E

nfer

med

ad T

rom

boem

bólic

a) c

ohor

t. 155

j Som

e st

udie

s su

gges

t th

at t

he b

asel

ine

risk

of

mor

talit

y in

pat

ient

s w

ith h

emod

ynam

ic in

stab

ility

is h

igh

as 3

0% (

Woo

d et

al).

156 I

n th

at c

ase,

the

abs

olut

e nu

mbe

r of

dea

th a

ssoc

iate

d w

ith t

hrom

boly

tics

wou

ld b

e 90

few

er p

er 1

,000

(fro

m 1

89 fe

wer

to 9

3 m

ore)

. k C

I in

clud

es v

alue

s su

gges

ting

both

har

m a

nd n

o ef

fect

; sm

all n

umbe

r of

eve

nts.

l In

dire

ct e

vide

nce

from

stu

dies

of t

hrom

boly

sis

for

myo

card

ial i

nfar

ctio

n an

d ac

ute

stro

ke p

rovi

de m

ore-

prec

ise

estim

ates

of i

ncre

ase

maj

or b

leed

ing

with

thro

mbo

lytic

s us

e.

m M

ajor

ble

edin

g ri

sk st

ratifi

cat

ion

deri

ved

from

the

RIE

TE

coh

ort. 15

7 The

med

ian

risk

of b

leed

ing

over

the

fi rst

10

d re

port

ed in

the

elig

ible

tria

ls w

as 3

.1%

. In

that

cas

e, th

e ab

solu

te n

umbe

r of m

ajor

ble

eds

with

thro

mbo

lysi

s w

ould

be

20 p

er 1

,000

(fro

m 0

mor

e to

52

mor

e).




Tabl

e S4

1 —[S

ecti

on 5

.6.1

] Sy

stem

ic T

hrom

bol

ytic

The

rapy

vs

Ant

icoa

gula

tion

Alo

ne i

n P

atie

nts

Wit

h A

cute

PE

: Cli

nica

l D

escr

ipti

on a

nd R

esu

lts

Aut

hor/

Year

Inte

rven

tions

No.

Pat

ient

s A

naly

zed

Len

gth

of

Fol

low

-up

Rec

urre

nt D

VT

and

PE

(%) R

R (9

5% C

I)M

ajor

Ble

edin

g (%

) R

R (9

5% C

I)To

tal M

orta

lity

(%)

RR

(95%

CI)

Com

men

ts

SK 1

hep

arin

vs

hepa

rin

Tibb

utt e

t al 14

8 /197

4SK

600

,000

uni

ts

intr

apul

mon

ary

follo

wed

by

100

,000

uni

ts fo

r 72

h

SK: 1

1/13

(84.

6%)

72 h

SK: 0

/11

SL: 1

/11

(9.1

%)

SK: 0

/11

All

hydr

ocor

tison

e 10

0 m

g an

d at

60

h of

trea

tmen

t war

farin

in

itial

dos

e 25

mg

for 6

mo.

H

epar

in 5

,000

uni

ts

intr

apul

mon

ary

follo

wed

by

2,50

0 un

its fo

r 72

h

Hep

arin

: 12/

17

(70.

6%)

Hep

arin

: 0/1

2H

epar

in: 1

/12

(8.3

%)

RR

0.9

2 (0

.06-

12.9

5)H

epar

in: 0

/12

Seve

n pa

tient

s w

ho fa

iled

to

com

plet

e th

e tr

eatm

ent

regi

men

wer

e ex

clud

ed

from

the

anal

ysis

.

Pa

tient

s re

port

ing

maj

or

blee

ding

req

uire

d a

bloo

d tr

ansf

usio

n.

So

me

6-m

o fo

llow

-up

data

av

aila

ble

Ly

et a

l 146 /1

978

SK 2

50,0

00 u

nits

follo

wed

by

100

,000

uni

ts/h

for

72 h

SK: 1

4/14

10 d

SK: 1

/14

(7.1

%)

SK: 4

/14

(28.

6%)

SK: 1

/14

(7.1

%)

Prim

ary

outc

ome

was

ang

io-

grap

hic

repe

rfus

ion.

H

epar

in 1

5,00

0 un

its

follo

wed

by

1,25

0 un

its/h

fo

r 7

d

Hep

arin

: 11/

11H

epar

in: 2

/11

(18.

2%)

RR

2.5

5 (0

.26-

24.5

6)H

epar

in: 2

/11

(18.

2%)

RR

0.6

4 (0

.14-

2.86

)H

epar

in: 2

/11

(18.

2%)

RR

2.5

5 (0

.26-

24.5

6)F

ive

of th

e 25

pat

ient

s re

ceiv

ed n

onra

ndom

ized

th

erap

y. U

ncer

tain

if

deat

hs w

ere

in p

atie

nts

who

wer

e ra

ndom

ized

or

not r

ando

miz

ed.

Dot

ter

et a

l 143 /1

979

SK 2

50,0

00 u

nits

follo

wed

by

100,

000

units

/h fo

r 18

-72

hSK

: 15/

15In

hos

pita

lSK

: 0/1

5SK

: 3/1

5 (2

0.0%

)SK

: 1/1

5 (6

.7%

)A

ll: w

arfa

rin/

VK

A.

Prim

ary

outc

ome

was

an

giog

raph

ic r

eper

fusi

on

(not

cle

arly

sta

ted)

.

Hep

arin

1,5

00 u

nits

per

kg

for

2-7

dH

epar

in: 1

6/16

Hep

arin

: 1/1

6 (6

.3%

) R

R 2

.82

(0.1

2-64

.39)

Hep

arin

: 4/1

6 (2

5.0%

) R

R 1

.25

(0.3

3-4.

68)

Hep

arin

: 2/1

6 (1

2.5%

) R

R 1

.88

(0.1

9-18

.60)

Jerj

es-S

anch

ez

et a

l 145 /1

995

SK 1

,500

,000

uni

ts o

ver

1 h

follo

wed

by

a bo

lus

of

hepa

rin

10,0

00 u

nits

1

cons

tant

infu

sion

of 1

,000

un

its/h

SK: 4

/4In

hos

pita

lSK

: 0/4

(0%

)SK

: 0/4

(0%

)SK

: 0/4

(0%

)Pr

imar

y ou

tcom

e no

t sta

ted.

Tr

ial s

topp

ed e

arly

for

bene

fi t. A

ll pa

tient

s ha

d ca

rdio

geni

c sh

ock

at r

ando

miz

atio

n.

Hep

arin

-tre

ated

pat

ient

s ap

pear

to h

ave

faile

d he

pari

n th

erap

y be

fore

ra

ndom

izat

ion,

whe

reas

th

e SK

pat

ient

s ha

d no

t.

H

epar

in 1

0,00

0 un

its

follo

wed

by

1,00

0 un

its/h

Hep

arin

: 4/4

Hep

arin

: 4/4

(100

%)

RR

9.0

0 (0

.64-

126.

85)

Hep

arin

: 0/4

(0%

)H

epar

in: 4

/4 (1

00%

) R

R 9

.00

(0.6

4-12

6.85

)

(Con

tinu

ed)




(Con

tinu

ed)

Aut

hor/

Year

Inte

rven

tions

No.

Pat

ient

s A

naly

zed

Len

gth

of

Fol

low

-up

Rec

urre

nt D

VT

and

PE

(%) R

R (9

5% C

I)M

ajor

Ble

edin

g (%

) R

R (9

5% C

I)To

tal M

orta

lity

(%)

RR

(95%

CI)

Com

men

ts

Uro

kina

se v

s he

pari

n

UPE

T S

tudy

Gro

up

et a

l 141 /1

970

Uro

kina

se: i

nfus

ion

of 2

,000

C

TA u

nits

/lb fo

llow

ed b

y 2,

000

CTA

uni

ts/lb

per

h

Hep

arin

: inf

usio

n of

75

uni

ts/lb

follo

wed

by

10 u

nits

/lb p

er h

Uro

kina

se 8

2/82

Hep

arin

: 78/

78

2 w

kU

roki

nase

: 12/

82

(14.

6%)

Hep

arin

: 15/

78 (1

9.2%

) R

R 1

.31

(0.6

6-2.

63)

Uro

kina

se: 3

7/82

(4

5.1%

)

Hep

arin

: 21/

78 (2

6.9%

) R

R 0

.60

(0.3

9-0.

92)

Uro

kina

se: 6

/82

(7.3

%)

Hep

arin

: 7/7

8 (8

.9%

) R

R 1

.23

(0.4

3-3.

49)

All:

hep

arin

for

a m

inim

um

of 5

d.

The

maj

or b

leed

ing

repo

rted

in

clud

es m

oder

ate

1

seve

re b

leed

ing.

A

ngio

grap

hic

follo

w-u

p da

ta

avai

labl

e up

to 1

2 m

o.

Mar

ini e

t al 14

7 /198

8H

igh

dose

: uro

kina

se

3,30

0,00

0 un

its o

ver

12 h

Hig

h-do

se

urok

inas

e: 1

0/10

7 d

Hig

h-do

se u

roki

nase

: 0/

10H

igh-

dose

uro

kina

se:

0/10

Hig

h-do

se u

roki

nase

: 0/

10Pr

imar

y ou

tcom

e w

as lu

ng

scan

per

fusi

on.

L

ow d

ose:

uro

kina

se 8

00,0

00

units

ove

r 12

h d

aily

for

3 d

Low

-dos

e ur

okin

ase:

10/

10L

ow-d

ose

urok

inas

e:

0/10

Low

-dos

e ur

okin

ase:

0/

10L

ow-d

ose

urok

inas

e:

0/10

Thr

ombo

lysi

s ar

ms

did

not

rece

ive

hepa

rin.

Hep

arin

30,

000

units

/d fo

r 7

d fo

llow

ed b

y O

AC

Hep

arin

: 10/

10H

epar

in: 0

/10

Hep

arin

: 0/1

0H

epar

in: 0

/10

All

patie

nts:

OA

Cs

cont

inue

d fo

r 1

y.

rt-P

A (a

ltepl

ase)

1 h

epar

in v

s he

pari

n

Dal

la-V

olta

et a

l 142 /1

992

rt-P

A 1

0 m

g fo

llow

ed b

y 90

mg

over

2 h

rt-P

A a

ltepl

ase:

20

/20

30 d

rt-P

A a

ltepl

ase:

1/2

0 (5

.0%

)rt

-PA

alte

plas

e: 3

/20

(15.

0%)

rt-P

A a

ltepl

ase:

2/2

0 (1

0.0%

)Pr

imar

y ou

tcom

e w

as

angi

ogra

phic

rep

erfu

sion

.

Hep

arin

10,

000

units

follo

wed

by

1,7

50 u

nits

/h fo

r 7-

10 d

Hep

arin

: 16/

16H

epar

in: 0

/16

RR

2.4

3 (0

.11-

55.8

9)H

epar

in: 2

/16

(12.

5%)

RR

1.2

0 (0

.23-

6.34

)H

epar

in: 0

/16

RR

4.0

5 (0

.21-

78.7

6)

Gol

dhab

er e

t al 15

8 /199

3rt

-PA

alte

plas

e 10

0 m

g ov

er

2 h

follo

wed

by

hepa

rin

1,00

0 un

its/h

rt-P

A: 4

6/46

In h

ospi

tal

14-2

1 d

rt-P

A: 0

/46

rt-P

A: 3

/46

(6.5

%)

rt-P

A: 0

/46

Prim

ary

outc

ome

was

ec

hoca

rdio

grap

hic

righ

t ve

ntri

cula

r fu

nctio

n.

H

epar

in 5

,000

uni

ts fo

llow

ed

by 1

,000

uni

ts/h

Hep

arin

: 55/

55H

epar

in: 5

/55

(9.1

%)

RR

0.1

1 (0

.01-

1.91

)H

epar

in: 1

/55

(1.8

%) R

R 3

.59

(0.3

9-33

.33)

Hep

arin

: 2/5

5 (3

.6%

) R

R 0

.24

(0.0

1-4.

84)

Kon

stan

tinid

es

et a

l 159 /2

002

Alte

plas

e 10

0 m

g fo

llow

ed

by a

ltepl

ase

90 m

g ov

er

2 h

1 h

epar

in 1

,000

un

its/h

Alte

plas

e: 1

18/1

1830

dA

ltepl

ase:

4/1

18 (3

.4%

)A

ltepl

ase:

1/1

18

(0.8

%)

Alte

plas

e: 4

/118

(3.4

%)

Prim

ary

outc

ome

was

dea

th

or n

eed

for

esca

latio

n of

th

erap

y (la

ter

deci

sion

co

uld

be m

ade

afte

r un

blin

ding

).

Hep

arin

5,0

00 u

nits

follo

wed

by

1,0

00 u

nits

/h 1

pla

cebo

Hep

arin

1 p

lace

bo:

138/

138

Hep

arin

1 p

lace

bo:

4/13

8 (2

.9%

) R

R 1

.17

(0.3

0-4.

57)

Hep

arin

1 p

lace

bo:

5/13

8 (3

.6%

) R

R 0

.23

(0.0

3-1.

97)

Hep

arin

1 p

lace

bo:

3/13

8 (2

.2%

) R

R 1

.56

(0.3

6-6.

83)

Tabl

e S4

1—C

onti

nued




Aut

hor/

Year

Inte

rven

tions

No.

Pat

ient

s A

naly

zed

Len

gth

of

Fol

low

-up

Rec

urre

nt D

VT

and

PE

(%) R

R (9

5% C

I)M

ajor

Ble

edin

g (%

) R

R (9

5% C

I)To

tal M

orta

lity

(%)

RR

(95%

CI)

Com

men

ts

Lev

ine

et a

l 160 /1

990

rt-P

A 0

.6m

g/kg

ove

r 2

min

rt-P

A: 3

3/33

10 d

rt-P

A: 0

/33

rt-P

A: 0

/33

rt-P

A: 1

/33

(3.0

%)

Prim

ary

outc

ome

was

lung

sc

an r

eper

fusi

on

Pl

aceb

o pl

us h

epar

in

5,00

0 un

its fo

llow

ed

by 3

0,00

0/d

Plac

ebo:

25/

25Pl

aceb

o: 0

/25

Plac

ebo:

0/2

5Pl

aceb

o: 0

/25

RR

2.2

9 (0

.10-

54.0

6)

PIO

PED

In

vest

igat

ors 14

4 /199

0rt

-PA

40-

80 m

g at

1 m

g/m

inrt

-PA

: 9/9

7 d

rt-P

A: 0

/9rt

-PA

: 1/9

(11.

1%)

rt-P

A: 0

/9Pr

imar

y ou

tcom

e no

t sta

ted

(ser

ial a

ngio

grap

hic

and

lung

sca

ns w

ere

asse

ssed

).

Plac

ebo

1 h

epar

in

(dos

es d

eter

min

ed

by p

hysi

cian

)

Plac

ebo:

4/4

Plac

ebo:

0/4

Plac

ebo:

0/4

RR

1.5

0 (0

.07-

30.5

9)Pl

aceb

o: 0

/4H

epar

in d

oses

det

erm

ined

by

att

endi

ng p

hysi

cian

in

both

gro

ups

O

ne d

eath

occ

urre

d 19

d

afte

r tr

eatm

ent

Fas

ullo

et a

l 154 /2

011

Alte

plas

e 10

0 m

g ov

er 2

hA

ltepl

ase:

37/

3710

dA

ltepl

ase:

0/3

7A

ltepl

ase:

2/3

7 (5

.4%

)A

ltepl

ase:

0/3

7A

ll ha

d ri

ght v

entr

icul

ar

dysf

unct

ion.

Pri

mar

y ou

tcom

e w

as

echo

card

iogr

aphi

c ch

ange

s.

Pl

aceb

o 1

hep

arin

5,

000

units

fo

llow

ed b

y 1,

000

units

/h

Plac

ebo:

35/

35Pl

aceb

o: 3

/35

(8.5

%)

Plac

ebo:

1/3

5 (2

.9%

)Pl

aceb

o: 5

/35

(14.

2%)

Thr

ee r

ecur

rent

PE

wer

e fa

tal.

One

add

ition

al fa

tal

and

nonf

atal

PE

in

hepa

rin

arm

by

180

d.

N

o fa

tal o

r in

trac

rani

al

blee

ds.

Tene

ctap

lase

1 h

epar

in v

s he

pari

n

Bec

attin

i et a

l 153 /2

010

Tene

ctap

lase

: � 2

mg/

kg

bolu

sTe

nect

apla

se: 2

8/28

30 d

Tene

ctap

lase

: 2/2

8Te

nect

apla

se: 2

/28

Tene

ctap

lase

: 0/2

8A

ll ha

d ri

ght v

entr

icul

ar

dysf

unct

ion.

Pri

mar

y ou

tcom

e w

as

echo

card

iogr

aphi

c ch

ange

s.

Pl

aceb

o 1

hep

arin

(8

0 In

tern

atio

nal U

nits

/kg

and

18 I

nter

natio

nal

Uni

ts/k

g pe

r h)

Plac

ebo:

32/

32Pl

aceb

o: 1

/32

Plac

ebo:

1/3

2Pl

aceb

o: 1

/32

No

fata

l PE

or

maj

or

blee

ding

; one

intr

acra

nial

bl

eed

(ten

ecta

plas

e).

CTA

5 C

omm

ittee

on

Thr

ombo

lytic

Age

nts;

OA

C 5

ora

l ant

icoa

gula

nt; P

IOPE

D 5

Pro

spec

tive

Inve

stig

atio

n of

Pul

mon

ary

Em

bolis

m D

iagn

osis

; UPE

T 5

Uro

kina

se P

ulm

onar

y E

mbo

lism

Tri

al. S

ee T

able

S1

, S2,

and

S11

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

.

Tabl

e S4

1—C

onti

nued




Tabl

e S4

2 —[S

ecti

on 5

.6.1

] Sy

stem

ic T

hrom

bol

ytic

The

rapy

vs

Ant

icoa

gula

tion

Alo

ne i

n P

atie

nts

Wit

h A

cute

PE

: Met

hodo

logi

c Q

ual

ity

Aut

hor/

Year

Inte

rven

tion

Stud

y D

esig

nR

ando

miz

e C

once

aled

Blin

ding

Los

t to

Fol

low

-up

Ana

lysi

sC

omm

ents

SK 1

hep

arin

vs

hepa

rin

Tibb

utt e

t al 14

8 /197

4SK

600

,000

uni

ts in

trap

ulm

onar

y fo

llow

ed b

y 10

0,00

0 un

its fo

r 72

hR

CT

PYPa

tient

s: P

Y C

areg

iver

s: P

N

Dat

a C

olle

ctor

s: P

N

Adj

udic

ator

s: P

N

Dat

a A

naly

sts:

PN

SK: 0

/11

(0%

)Pe

r pr

otoc

olA

ll hy

droc

ortis

one

100

mg

and

at 6

0 h

of tr

eatm

ent,

war

fari

n in

itial

dos

e 25

mg

for

6 m

o.

H

epar

in 5

,000

uni

ts in

trap

ulm

onar

y fo

llow

ed b

y 2,

500

units

for

72 h

Hep

arin

: 0/1

2 (0

%)

Seve

n pa

tient

s w

ho fa

iled

to

com

plet

e th

e tr

eatm

ent

regi

men

wer

e ex

clud

ed

from

the

anal

ysis

.

Lye

t al 14

6 /197

8SK

250

,000

uni

ts fo

llow

ed b

y 10

0,00

0 un

its/h

for

72 h

RC

TC

YPa

tient

s: P

Y C

areg

iver

s: P

N

Dat

a C

olle

ctor

s: P

N

Adj

udic

ator

s: P

N

Dat

a A

naly

sts:

PN

SK: 0

/14

(0%

)A

s tr

eate

d In

clud

ed 5

non

rand

omiz

ed

patie

nts,

and

unc

erta

in if

de

aths

occ

urre

d in

thos

e w

ho w

ere

rand

omiz

ed o

r no

t ran

dom

ized

.

H

epar

in 1

5,00

0 U

follo

wed

by

1250

U/h

for

7day

sH

epar

in: 0

/11

(0%

)

Dot

ter

et a

l 143 /1

979

SK 2

50,0

00 u

nits

follo

wed

by

100,

000

units

/h fo

r 18

-72

hR

CT

PYPa

tient

s: P

Y C

areg

iver

s: P

N

Dat

a C

olle

ctor

s: P

N

Adj

udic

ator

s: P

N

Dat

a A

naly

sts:

PN

SK p

lus

hepa

rin:

0/1

5 (0

%)

ITT

H

epar

in 1

,500

uni

ts p

er k

g fo

r 2-

7 d

Hep

arin

: 0/1

6 (0

%)

Jerj

es-S

anch

ez e

t al 14

5 /199

5SK

1,5

00,0

00 u

nits

ove

r 1

h fo

llow

ed

by a

bol

us o

f hep

arin

10,

000

units

1

con

stan

t inf

usio

n of

1,

000

units

/h

RC

TC

YPa

tient

s: P

Y C

areg

iver

s: P

N

Dat

a C

olle

ctor

s: P

N

Adj

udic

ator

s: P

N

Dat

a A

naly

sts:

PN

SK 1

hep

arin

: 0/4

(0%

)IT

T

H

epar

in 1

0,00

0 un

its fo

llow

ed

by 1

,000

uni

ts/h

Hep

arin

: 0/4

(0%

)

Uro

kina

se v

s he

pari

n

UPE

T S

tudy

G

roup

141,

149 /1

970

Uro

kina

se: i

nfus

ion

of 2

,000

C

TA u

nits

/lb fo

llow

ed b

y 2,

000

CTA

uni

ts/lb

per

h H

epar

in:

infu

sion

of 7

5 un

its/lb

follo

wed

by

10

units

/lb p

er h

RC

TC

YPa

tient

s: C

Y C

areg

iver

s: C

N

Dat

a C

olle

ctor

s: C

Y A

djud

icat

ors:

CY

Dat

a A

naly

sts:

CY

Uro

kina

se: 0

/82

(0%

) H

epar

in: 0

/78

(0%

)

As

trea

ted

(Con

tinu

ed)




Mar

ini e

t al 14

7 /198

8H

igh

dose

: uro

kina

se 3

,300

,000

uni

ts

over

12

hR

CT

PYPa

tient

s: P

N

Car

egiv

ers:

CN

D

ata

Col

lect

ors:

PN

A

djud

icat

ors:

PN

D

ata

Ana

lyst

s: P

N

Hig

h-do

se u

roki

nase

: 0/

10 (0

%)

ITT

L

ow d

ose:

uro

kina

se 8

00,0

00 u

nits

ov

er 1

2 h

daily

for

3 d

Low

-dos

e ur

okin

ase:

0/

10 (0

%)

H

epar

in 3

0,00

0 un

its/d

for

7 d

follo

wed

by

OA

CH

epar

in: 0

/10

(0%

)

rt-P

A (a

ltepl

ase)

1 h

epar

in v

s he

pari

n

Dal

la-V

olta

et a

l 142 /1

992

rt-P

A (a

ltepl

ase)

10

mg

follo

wed

by

90

mg

over

2 h

RC

TPY

Patie

nts:

PN

C

areg

iver

s: C

N

Dat

a C

olle

ctor

s: P

N

Adj

udic

ator

s: P

N

Dat

a A

naly

sts:

PN

rt-P

A: 0

/20

(0%

)IT

T

H

epar

in 1

0,00

0 un

its fo

llow

ed

by 1

,750

uni

ts/h

for

7-10

dH

epar

in: 0

/16

(0%

)

Gol

dhab

er e

t al 15

8 /199

3rt

-PA

100

mg

over

2 h

follo

wed

by

hep

arin

1,0

00 u

nits

/hR

CT

CY

Patie

nts:

PN

C

areg

iver

s: C

N

Dat

a C

olle

ctor

s: P

N

Adj

udic

ator

s: P

N

Dat

a A

naly

sts:

PN

rt-P

A: 0

/46

(0%

)IT

T

H

epar

in 5

,000

uni

ts fo

llow

ed b

y 1,

000

units

/hH

epar

in: 0

/55

(0%

)

Kon

stan

tinid

es e

t al 15

9 /200

2rt

-PA

(alte

plas

e) 1

00 m

g fo

llow

ed

by a

ltepl

ase

90 m

g ov

er

2 h

1 h

epar

in 1

,000

uni

ts/h

RC

TC

YPa

tient

s: P

Y C

areg

iver

s: C

N

Dat

a C

olle

ctor

s: P

Y A

djud

icat

ors:

PN

D

ata

Ana

lyst

s: P

Y

rt-P

A: 0

/118

(0%

)IT

TA

ll: U

FH

5,0

00 u

nits

.

H

epar

in 5

,000

uni

ts fo

llow

ed

by 1

,000

uni

ts/h

UF

H: 0

/138

(0%

)

Lev

ine

et a

l 160 /1

990

rt-P

A 0

.6 m

g/kg

ove

r 2

min

RC

TPY

Patie

nts:

CY

Car

egiv

ers:

CY

Dat

a C

olle

ctor

s: C

Y A

djud

icat

ors:

CY

Dat

a A

naly

sts:

CY

rt-P

A: 0

/33(

0%)

ITT

All:

UF

H in

itial

bol

us o

f 5,

000

units

follo

wed

by

cont

inuo

us in

fusi

on a

t st

artin

g do

se o

f 30,

000

for

the

fi rst

24

h.

Pl

aceb

o 1

hep

arin

5,0

00 u

nits

fo

llow

ed b

y 30

,000

/dH

epar

in: 0

/25(

0%)

(Con

tinu

ed)

Aut

hor/

Year

Inte

rven

tion

Stud

y D

esig

nR

ando

miz

e C

once

aled

Blin

ding

Los

t to

Fol

low

-up

Ana

lysi

sC

omm

ents

Tabl

e S4

2—C

onti

nued




PIO

PED

In

vest

igat

ors 14

4 /199

0rt

-PA

40-

80m

g at

1 m

g/m

inR

CT

PYPa

tient

s: C

Y C

areg

iver

s: C

Y D

ata

Col

lect

ors:

PY

Adj

udic

ator

s: P

Y D

ata

Ana

lyst

s: P

Y

rt-P

A: 0

/9(0

%)

ITT

All:

hep

arin

dos

es d

eter

min

ed

by a

tten

ding

phy

sici

an.

Pl

aceb

o pl

us h

epar

in (d

oses

de

term

ined

by

phys

icia

n)H

epar

in: 0

/4(0

%)

Fas

ullo

et a

l 154 /2

011

Alte

plas

e 10

0 m

g ov

er 2

hR

CT

CY

Patie

nts:

CY

Car

egiv

ers:

CY

Dat

a C

olle

ctor

s: P

Y A

djud

icat

ors:

CY

Dat

a A

naly

sts:

PY

rt-P

A: 0

/37

ITT

Prim

ary

outc

ome

was

ec

hoca

rdio

grap

hic

chan

ges.

Pl

aceb

o 1

hep

arin

5,0

00 u

nits

fo

llow

ed b

y 1,

000

units

/hH

epar

in: 0

/35

rt-P

A (a

ltepl

ase)

1 h

epar

in v

s he

pari

n

Bec

attin

i et a

l 153 /2

010

Tene

ctap

lase

: � 2

mg/

kg b

olus

RC

TC

YPa

tient

s: C

Y C

areg

iver

s: C

Y D

ata

Col

lect

ors:

CY

Adj

udic

ator

s: C

Y D

ata

Ana

lyst

s: P

Y

Tene

ctap

lase

: 0/2

8(0%

)IT

TPr

imar

y ou

tcom

e w

as

echo

card

iogr

aphi

c ch

ange

s.

Pl

aceb

o 1

hep

arin

(80

Inte

rnat

iona

l U

nits

/kg

and

18 I

nter

natio

nal

Uni

ts/k

g pe

r h)

Hep

arin

: 0/3

0(0%

)

See

Tabl

e S1

, S2,

S5,

S11

, and

S41

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

.

Aut

hor/

Year

Inte

rven

tion

Stud

y D

esig

nR

ando

miz

e C

once

aled

Blin

ding

Los

t to

Fol

low

-up

Ana

lysi

sC

omm

ents

Tabl

e S4

2—C

onti

nued




Tabl

e S4

3 —[S

ecti

on 8

.1]

Evi

denc

e P

rofi l

e: F

onda

pari

nux

vs P

lace

bo

for

Acu

te S

VT

a-c

Qua

lity

Ass

essm

ent

Sum

mar

y of

Fin

ding

s

St

udy

Eve

nt R

ates

(%)

Ant

icip

ated

Abs

olut

e E

ffec

ts

Part

icip

ants

(S

tudi

es),

Fol

low

-up

Ris

k of

Bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Publ

icat

ion

Bia

sO

vera

ll Q

ualit

y of

Evi

denc

eW

ith N

o F

onda

pari

nux

With

F

onda

parin

uxR

elat

ive

Eff

ect

(95%

CI)

Ris

k W

ith N

o F

onda

parin

ux

Ris

k D

iffer

ence

W

ith F

onda

parin

ux

(95%

CI)

Mor

talit

y (im

port

ant o

utco

me)

3,00

2 (1

stu

dy),

3 m

oN

o se

riou

s ri

sk o

f bia

s d N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous e,

f U

ndet

ecte

dM

oder

ate d-

g due

to

impr

ecis

ion

1/1,

500

(0.1

)2/

1,50

2 (0

.1)

RR

1.9

9 (0

.18-

21.8

7)4

per

1,00

0 h 4

mor

e pe

r 1,

000

(fro

m 3

few

er

to 8

3 m

ore)

VT

E (c

ritic

al o

utco

me)

3,00

2 (1

stu

dy),

3 m

oN

o se

riou

s ri

sk o

f bia

s d N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

No

seri

ous

impr

ecis

ion

Und

etec

ted

Hig

h d 22

/1,5

00 (1

.5)

4/1,

502

(0.3

)R

R 0

.18

(0.0

6-0.

53)

33 p

er 1

,000

h 27

few

er p

er

1,00

0 (f

rom

16

few

er to

31

few

er)

SVT

rec

urre

nce

(impo

rtan

t out

com

e)

3,00

2 (1

stu

dy),

3 m

oN

o se

riou

s ri

sk o

f bia

s d N

o se

riou

s in

cons

iste

ncy

No

seri

ous

indi

rect

ness

Seri

ous f,g

U

ndet

ecte

dH

igh d d

ue to

im

prec

isio

n26

/1,5

00 (1

.7)

8/1,

502

(0.5

)R

R 0

.31

(0.1

4-0.

68)

19 p

er 1

,000

h 13

few

er p

er

1,00

0 (f

rom

6

few

er to

16

few

er)

Maj

or b

leed

ing

(cri

tical

out

com

e)

2,98

7 (1

stu

dy),

47 d

No

seri

ous

risk

of b

ias d

No

seri

ous

inco

nsis

tenc

yN

o se

riou

s in

dire

ctne

ssSe

riou

s e,i

Und

etec

ted

Mod

erat

e d,e,

i due

to

impr

ecis

ion

1/1,

488

(0.1

)1/

1,49

9 (0

.1)

RR

0.9

9 (0

.06-

15.8

6) e

1 pe

r 1,

000

0 fe

wer

per

1,0

00

(fro

m 1

few

er

to 1

0 m

ore)

Qua

lity

of li

fe n

ot m

easu

red

……

……

……

……

……

…

Bib

liogr

aphy

: CA

LIS

TO

stu

dy b

y D

ecou

sus

et a

l. 161 C

AL

IST

O 5

Com

pari

son

of A

RIX

TR

A™

in lo

wer

LIm

b Su

perfi

cia

l Thr

ombo

phle

bitis

with

pla

cebo

; SV

T 5

supe

rfi c

ial v

ein

thro

mbo

sis.

See

Tab

le S

1 an

d S5

lege

nds

for

expa

nsio

n of

oth

er a

bbre

viat

ions

. a F

onda

pari

nux

2.5

mg

for

45 d

. b P

atie

nts

in th

e tw

o tr

eatm

ent g

roup

s be

nefi t

ed fr

om c

lose

clin

ical

mon

itori

ng w

ith a

dequ

ate

diag

nost

ic p

roce

dure

s in

the

even

t of n

ew a

nd p

ersi

sten

t sym

ptom

s.

c Pat

ient

s w

ith in

fusi

on-r

elat

ed S

VT

wer

e ex

clud

ed if

from

CA

LIS

TO

. d A

lloca

tion

conc

eale

d. O

utco

me

adju

dica

tors

, st

eeri

ng c

omm

ittee

, pa

tient

s, p

rovi

ders

, an

d da

ta c

olle

ctor

s bl

inde

d. F

ollo

w-u

p ra

te w

as 9

8%.

ITT

ana

lysi

s fo

r ef

fi cac

y ou

tcom

es.

Not

sto

pped

ear

ly f

or

bene

fi t.

e CI

incl

udes

val

ues

sugg

estin

g la

rge

bene

fi t a

nd v

alue

s su

gges

ting

larg

e ha

rm.

f We

rate

d do

wn

by o

nly

one

leve

l bec

ause

the

low

eve

nt r

ate

and

larg

e sa

mpl

e si

ze.

g Sm

all n

umbe

r of

eve

nts.

h B

asel

ine

risk

der

ived

from

a la

rge

pros

pect

ive

coho

rt s

tudy

. 162

i The

upp

er li

mit

of th

e C

I fo

r ab

solu

te e

ffec

t (10

mor

e bl

eeds

) is

not l

ow e

noug

h to

sug

gest

a c

lear

bal

ance

of b

enefi

ts v

s ha

rms.




(Con

tinu

ed)

Tabl

e S4

4 —[S

ecti

on 8

.1]

Supe

rfi c

ial

Vei

n T

hrom

bos

is T

reat

men

t: C

lini

cal

Des

crip

tion

and

Res

ult

s (R

ando

miz

ed T

rial

s C

ompa

ring

Tre

atm

ents

)

Aut

hor/

Year

Type

of

Publ

icat

ion a

Part

icip

ants

Inte

rven

tion b

Out

com

es c

Fol

low

-up

Res

ults

STE

NO

X S

tudy

163

Gro

up/2

003

Para

llel R

CT,

m

ultic

ente

r43

6 pa

tient

s w

ith

ultr

asou

nd-c

onfi r

med

ac

ute

sym

ptom

atic

SV

T ( �

5 c

m le

ngth

) of

the

low

er e

xtre

mity

Eno

xapa

rin

40 m

g SC

dai

lyE

noxa

pari

n 1.

5 m

g/kg

SC

dai

lyTe

noxi

cam

, 20

mg

po d

aily

Plac

ebo

once

dai

lyA

ll gi

ven

for

8-12

dA

ll pa

tient

s pr

escr

ibed

ela

stic

ba

ndag

es o

r co

mpr

essi

on

stoc

king

s fo

r at

leas

t 15

d

Day

12

(end

of t

reat

men

t):

Scre

enin

g ul

tras

ound

or

sym

ptom

atic

rec

urre

nce:

VT

E

SVT

rec

urre

nce/

exte

nsio

n to

sa

phen

ofem

oral

junc

tion

3-m

o V

TE

SV

T r

ecur

renc

e/ex

tens

ion

Maj

or b

leed

ing

Dea

th

3 m

oV

TE

day

12:

Pla

cebo

: 4/1

12 (3

.6%

) (PE

0)

Eno

xapa

rin

40 m

g: 1

/110

(0.9

%) (

PE 0

); R

R 0

.25

(95%

CI,

0.0

3-2.

24)

Eno

xapa

rin

1.5

mg/

kg: 1

/106

(0.9

%)

(PE

0);

RR

0.2

6 (9

5% C

I, 0

.03-

2.33

) Te

noxi

cam

: 2/9

9 (2

.0%

) (PE

1);

RR

0.5

7 (9

5% C

I, 0

.11-

3.02

) P

5 n

s fo

r al

l com

pari

sons

of a

ctiv

e tr

eatm

ent v

s pl

aceb

o SV

T r

ecur

renc

e/ex

tens

ion

day

12:

Plac

ebo:

33/

112

(29.

5%)

Eno

xapa

rin

40 m

g: 9

/110

(8.3

%);

RR

0.2

8 (9

5% C

I, 0

.14-

0.55

) E

noxa

pari

n 1.

5 m

g/kg

: 6/1

06 (5

.7%

); R

R 0

.19

(95%

CI,

0.0

8-0.

44)

Teno

xica

m: 1

3/99

(13.

1%);

RR

0.4

5 (9

5% C

I, 0

.25-

0.80

) V

TE

3 m

o:

Plac

ebo:

5/1

12 (4

.5%

) (PE

0)

Eno

xapa

rin

40 m

g: 6

/110

(5.7

%);

(PE

2);

RR

1.2

2 (9

5% C

I, 0

.38-

3.89

) E

noxa

pari

n 1.

5mg/

kg: 4

/106

(3.9

%)

(PE

0);

RR

0.8

5 (9

5% C

I, 0

.23-

3.06

) Te

noxi

cam

: 4/9

9 (4

.3%

) (PE

1);

RR

0.9

1 (9

5% C

I, 0

.25-

3.28

) P

5 n

s fo

r al

l com

pari

sons

of a

ctiv

e tr

eatm

ent v

s pl

aceb

o SV

T r

ecur

renc

e/ex

tens

ion

3 m

o: P

lace

bo:

37/1

12 (3

3.0%

) E

noxa

pari

n 40

mg:

16/

110

(14.

5%);

RR

0.4

4 (9

5% C

I, 0

.26-

0.74

)




Aut

hor/

Year

Type

of

Publ

icat

ion a

Part

icip

ants

Inte

rven

tion b

Out

com

es c

Fol

low

-up

Res

ults

E

noxa

pari

n 1.

5 m

g/kg

: 16/

106

(15.

1%);

RR

0.4

6 (9

5% C

I, 0

.27-

0.77

)

Te

noxi

cam

: 15/

99 (1

5.2%

); R

R 0

.46

(95%

CI,

0.2

7-0.

78)

M

ajor

ble

edin

g: 0

Dea

th: 0

Tito

n et

al 16

4 /19

94Pa

ralle

l RC

T,

mul

ticen

ter

117

patie

nts

with

ul

tras

ound

-con

fi rm

ed

SVT

of t

he lo

wer

ex

trem

ities

Nad

ropa

rin

fi xed

dos

e, 6

,150

an

ti-X

a In

tern

atio

nal

Uni

ts d

aily

Ech

ocar

diog

raph

ic e

xten

sion

of

thro

mbu

s at

day

7 a

nd a

t 8 w

k8

wk

Day

7 e

xten

sion

of t

hrom

bus:

Fix

ed-d

ose

nadr

opar

in: 1

/38

(2.6

%)

N

adro

pari

n 31

.5 a

nti-X

a In

tern

atio

nal U

nits

/kg

SC d

aily

Cha

nges

in s

ympt

oms

and

clin

ical

si

gns

(war

mth

, fl u

shin

g, e

dem

a,

pain

on

palp

atio

n)

Wei

ght-

base

d na

drop

arin

: 2/4

0 (5

%);

RR

1.9

0 (9

5% C

I, 0

.18-

20.1

)

N

apro

xen

500

mg

po d

aily

DV

TN

apro

xen:

1/3

9 (2

.6%

); R

R 0

.97

(95%

CI,

0.0

6-15

.02)

Trea

tmen

ts g

iven

for

6 d

PE P

5 n

s

All

patie

nts

wor

e co

mpr

essi

on

stoc

king

s fo

r 7

dM

ajor

ble

edin

g8-

wk

exte

nsio

n of

thro

mbu

s or

new

SV

T:

Fix

ed-d

ose

nadr

opar

in: 2

/36

(5.6

%)

W

eigh

t-ba

sed

nadr

opar

in: 0

/40

(0%

); R

R 0

.18

(95%

CI,

0.0

1-3.

64)

N

apro

xen:

0/3

9 (0

%);

RR

(95%

CI)

0.

19 (0

.01-

3.73

)

No

DV

T, P

E, o

r m

ajor

ble

edin

g in

any

gro

up

In

tens

ity o

f sym

ptom

s/si

gns:

Ove

rall

impr

ovem

ent i

n sc

ore

from

day

0 to

day

7:

Fix

ed-d

ose

nadr

opar

in: 7

9.1%

impr

oved

Wei

ght-

base

d na

drop

arin

: 63.

0% im

prov

ed

N

apro

xen:

46.

4% im

prov

ed

P �

.01

in fa

vor

of n

adro

pari

n vs

nap

roxe

n;

this

diff

eren

ce w

as m

aint

aine

d at

8 w

k

Pran

doni

for

Vesa

lio

Inve

stig

ator

s G

roup

165 /2

005

Para

llel R

CT,

m

ultic

ente

r16

4 pa

tient

s w

ith

ultr

asou

nd-c

onfi r

med

ac

ute

SVT

of t

he

grea

ter

saph

enou

s ve

in

Hig

h-do

se w

eigh

t-ad

just

ed

nadr

opar

in (1

90 a

nti-X

a In

tern

atio

nal U

nits

/kg

for

10 d

follo

wed

by

95 a

nti-X

a In

tern

atio

nal U

nits

/kg

for

20 d

)

Com

posi

te o

utco

me

of

asym

ptom

atic

or

sym

ptom

atic

SV

T e

xten

sion

, asy

mpt

omat

ic

or s

ympt

omat

ic D

VT,

sy

mpt

omat

ic P

E a

t 3 m

o

3 m

o3

mo

follo

w-u

p:

Tabl

e S4

4—C

onti

nued

(Con

tinu

ed)




Aut

hor/

Year

Type

of

Publ

icat

ion a

Part

icip

ants

Inte

rven

tion b

Out

com

es c

Fol

low

-up

Res

ults

Im

prov

emen

t in

clin

ical

sy

mpt

oms

and

sign

s at

1 m

o

L

ow-d

ose

nadr

opar

in

(2,8

50 a

nti-X

a In

tern

atio

nal

Uni

ts fo

r 30

d)

Maj

or b

leed

ing

SVT

Hig

h do

se: 2

/83

(2.4

%) (

1 oc

curr

ed

whi

le o

n tr

eatm

ent)

Low

dos

e: 5

/81

(6.2

%)

(all

occu

rred

whi

le o

n tr

eatm

ent)

RR

2.5

6 (9

5% C

I, 0

.51-

12.8

3)

D

eath

No

plac

ebo

grou

p N

SAID

S an

d as

piri

n us

e di

scou

rage

dV

TE

Hig

h do

se: 4

/83

(4.8

%)

(3 s

ympt

omat

ic e

vent

s; 1

[PE

] occ

urre

d w

hile

on

trea

tmen

t)

Low

dos

e: 2

/81

(2.5

%) (

both

sy

mpt

omat

ic D

VT

) RR

0.5

1 (9

5% C

I,

0.10

-2.7

2)

R

ate

of im

prov

emen

t in

clin

ical

sy

mpt

oms

and

sign

s si

mila

r bo

th g

roup

s M

ajor

ble

edin

g: 0

D

eath

: 0

Mar

chio

ri e

t al 16

6 /200

2Pa

ralle

l RC

T,

sing

le c

ente

r60

pat

ient

s w

ith

ultr

asou

nd-c

onfi r

med

fi r

st a

cute

SV

T o

f gr

eate

r sa

phen

ous

vein

Low

-dos

e U

FH

(5,0

00

Inte

rnat

iona

l Uni

ts b

id

SC fo

r 4

wk)

VT

E6

mo

VT

E d

urin

g tr

eatm

ent p

erio

d: L

ow d

ose:

4/

30 (1

3.3%

) (3

asym

ptom

atic

DV

T, 1

PE

) E

xten

sion

/Rec

urre

nce

of th

rom

bosi

s

Hig

h-do

se U

FH

(12,

500

Inte

rnat

iona

l Uni

ts fo

r 1

wk

then

10,

000

Inte

rnat

iona

l U

nits

for

3 w

k)

Maj

or b

leed

ing

Hig

h do

se: 0

/30

(0%

); R

R 0

.11

(95%

CI,

0.0

1-1.

98; P

5 n

s)

HIT

D

eath

Ext

ensi

on/r

ecur

renc

e SV

T d

urin

g tr

eatm

ent p

erio

d:

Low

dos

e: 7

/30

(23.

3%)

Hig

h do

se: 3

/30

(10%

); R

R 0

.40

(95%

CI,

0.1

1-1.

40; P

5 n

s)

Use

of c

onco

mita

nt s

yste

mic

or

loca

l ant

iinfl a

mm

ator

y dr

ugs

perm

itted

but

use

no

t des

crib

ed

Ove

rall

VT

E d

urin

g fo

llow

-up

peri

od:

Low

dos

e: 6

/30

(20%

) H

igh

dose

: 1/3

0 (3

.3%

); R

R 0

.17

(95%

CI,

0.0

2-1.

30; P

5 n

s)

O

vera

ll ex

tens

ion/

recu

rren

ce S

VT

dur

ing

follo

w-u

p pe

riod

: Low

dos

e: 1

1/30

(36.

7%)

Hig

h do

se: 8

/30

(26.

7%);

RR

0.7

3 (9

5% C

I, 0

.34,

1.5

5; P

5 n

s)

Tabl

e S4

4—C

onti

nued

(Con

tinu

ed)




Aut

hor/

Year

Type

of

Publ

icat

ion a

Part

icip

ants

Inte

rven

tion b

Out

com

es c

Fol

low

-up

Res

ults

N

o m

ajor

ble

edin

g, H

IT, o

r de

ath

in

any

grou

p

Bel

caro

et a

l 167 /1

999

Para

llel R

CT,

m

ultic

ente

r56

2 pa

tient

s w

ith

ultr

asou

nd-c

onfi r

med

SV

T a

nd la

rge

vari

cose

vei

ns o

r ve

nous

inco

mpe

tenc

e

A. E

last

ic c

ompr

essi

on s

tock

ings

al

one

Ext

ensi

on o

f SV

T a

t 3 m

o6

mo

Ext

ensi

on o

f thr

ombu

s at

3 m

o:

A: 3

2/78

(41%

) B: 1

1/78

(14.

1%);

RR

0.3

4 (9

5% C

I, 0

.19-

0.63

) C: 0

/70;

R

R 0

.02

(95%

CI,

0.0

0-0.

27) D

: 4/7

1 (5

.6%

); R

R 0

.14

(95%

CI,

0.0

5-0.

37)

E: 4

/76

(5.2

%);

RR

0.1

3 (9

5% C

I,

0.05

-0.3

5) F

: 5/7

1 (7

.0%

); R

R 0

.17

(95%

CI,

0.0

7-0.

42)

Ext

ensi

on o

f SV

T a

t 6 m

o

B. E

last

ic c

ompr

essi

on s

tock

ings

an

d si

mpl

e fl u

sh li

gatio

nN

ew D

VT

at 3

mo

C

. Ela

stic

com

pres

sion

sto

ckin

gs

and

com

plet

e st

ripp

ing

and

perf

orat

or li

gatio

n

P ,

.05

for

grou

ps C

, D, E

, F v

s A

or

B

D

. Ela

stic

com

pres

sion

sto

ckin

gs

and

low

-dos

e SC

hep

arin

Ext

ensi

on a

t 6 m

o: A

: 13/

78 (1

6.7%

) B

: 6/7

8 (7

.7%

); R

R 0

.46

(95%

CI,

0.

18-1

.15)

C: 1

/70

(1.4

%);

RR

0.0

9 (9

5% C

I, 0

.01-

0.64

) D: 2

/71

(2.8

%);

RR

0.1

7 (9

5% C

I, 0

.04-

0.72

) E: 1

/76

(1.3

%);

RR

0.0

8 (9

5% C

I, 0

.01-

0.59

) F

: 5/7

1 (7

%);

RR

0.4

2 (9

5% C

I, 0

.16-

1.13

)

E. E

last

ic c

ompr

essi

on s

tock

ings

an

d L

MW

HF.

Ela

stic

com

pres

sion

sto

ckin

gs

and

VK

A

D

oses

and

dur

atio

n of

an

ticoa

gula

nts

not s

peci

fi ed

P

not s

tate

d

N

ew D

VT

at 3

mo:

A: 6

/78

(7.7

%)

B: 2

/78

(2.5

%);

RR

0.3

3 (9

5% C

I,

0.07

-1.6

0) C

: 2/7

0 (2

.8%

); R

R 0

.37

(95%

CI,

0.0

8-1.

78) D

: 0/7

1 (0

%);

RR

0.0

8 (9

5% C

I, 0

.0-1

.47)

E: 0

/76

(0%

); R

R 0

.08

(95%

CI,

0.0

-1.3

8) F

: 0/7

1 (0

%);

RR

0.0

8 (9

5% C

I, 0

.0-1

.47)

P

5 n

s

Loz

ano

et a

l 168 /2

003

Para

llel R

CT,

si

ngle

cen

ter

60 p

atie

nts

with

ul

tras

ound

-con

fi rm

ed

abov

e-kn

ee in

tern

al

saph

enou

s SV

T

Saph

enof

emor

al d

isco

nnec

tion

unde

r lo

cal a

nest

hesi

a w

ith

shor

t-te

rm u

se o

f a

com

pres

sion

ban

dage

Rec

urre

nce/

exte

nsio

n of

SV

T6

mo

Rec

urre

nt S

VT

Sur

gica

l gro

up: 1

/30

(3.3

%)

Eno

xapa

rin

grou

p: 3

/30

(10%

); R

R 3

.0 (9

5% C

I, 0

.33-

27.2

4)

VT

E

C

ompl

icat

ions

of s

urge

ry

Tabl

e S4

4—C

onti

nued

(Con

tinu

ed)




Aut

hor/

Year

Type

of

Publ

icat

ion a

Part

icip

ants

Inte

rven

tion b

Out

com

es c

Fol

low

-up

Res

ults

O

utpa

tient

eno

xapa

rin

1 m

g/kg

bi

d fo

r 1

wk

then

onc

e da

ily

for

3 w

k

VT

E S

urgi

cal g

roup

: 2/3

0 (6

.7%

) (bo

th

sym

ptom

atic

PE

) Eno

xapa

rin

grou

p:

0/30

(0%

); R

R 0

.20

(95%

CI,

0.0

1-4.

0)

Maj

or b

leed

ing

Dea

th

No

plac

ebo/

cont

rol g

roup

Wou

nd in

fect

ions

: Sur

gica

l gro

up:

2/30

(6.7

%)

Cos

ts

All

patie

nts

wer

e in

stru

cted

to

wea

r el

astic

com

pres

sion

st

ocki

ngs

and

used

ac

etam

inop

hen

for

pain

Maj

or b

leed

ing:

0

D

eath

: 0

C

ost o

f tre

atm

ent:

Surg

ical

gro

up: $

1,4

00/

patie

nt; m

ean,

1.6

d in

hos

pita

l E

noxa

pari

n gr

oup:

$ 3

00/p

atie

nt;

0 d

in h

ospi

tal

Sulli

van

et a

l 169 /2

001

Syst

emat

ic r

evie

w

of 6

stu

dies

(in

clud

es B

elca

ro

(14

patie

nts)

and

5

smal

l cas

e se

ries

)

Patie

nts

with

obj

ectiv

ely

confi

rm

ed a

bove

-kne

e SV

T

Lig

atio

n of

gre

ater

sap

heno

us

vein

at s

aphe

nofe

mor

al

junc

tion

with

or

with

out

vein

str

ippi

ng (n

5 2

46)

SVT

pro

gres

sion

Surg

ical

gr

oup:

4-

6 m

o

SVT

pro

gres

sion

: Sur

gica

l gro

up:

18/1

48 (1

2%) M

edic

al g

roup

: 10/

71 (1

4%);

RR

1.1

6 (9

5% C

I, 0

.56-

2.38

) D

VT:

Sur

gica

l gro

up: 7

/204

(3.4

%) M

edic

al

grou

p: 2

/88

(2.2

%) R

R 0

.66

(95%

CI,

0.

14-3

.13)

PE

: Sur

gica

l gro

up: 2

/98

(2.0

%) M

edic

al

grou

p: 0

/17

(0%

); R

R 1

.10

(95%

CI,

0.

06-2

1.98

) Su

rgic

al c

ompl

icat

ions

: 6/7

8 (7

.7%

) (h

emat

oma,

ser

oma,

infe

ctio

n)

Ble

edin

g co

mpl

icat

ions

: 0/1

7 (0

%)

DV

T

PEM

edic

al

grou

p: 6

d

to 1

4 m

o

A

ntic

oagu

latio

n (I

V h

epar

in

follo

wed

by

VK

A fo

r 6

wks

-6 m

o) (n

5 8

8)Su

rgic

al c

ompl

icat

ions

Ble

edin

g co

mpl

icat

ions

Tabl

e S4

4—C

onti

nued

(Con

tinu

ed)




Aut

hor/

Year

Type

of

Publ

icat

ion a

Part

icip

ants

Inte

rven

tion b

Out

com

es c

Fol

low

-up

Res

ults

Gór

ski e

t al 17

0 /200

5Pa

ralle

l RC

T,

mul

ticen

ter

46 p

atie

nts

with

ul

tras

ound

-con

fi rm

ed

SVT

Topi

cal l

ipos

omal

hep

arin

sp

ray

gel (

4 sp

rays

of

458

Inte

rnat

iona

l Uni

ts ti

d)

Pain

by

visu

al a

nalo

g sc

ale

(0-1

0)21

dD

ata

extr

apol

ated

from

gra

phs

and

fi gur

es

in a

rtic

le b

y re

view

er

A

rea

of e

ryth

ema

Eno

xapa

rin

40 m

g SC

onc

e da

ilySu

bjec

tive

effi c

acy

asse

ssm

ent

by in

vest

igat

or a

nd p

atie

ntPa

in b

y vi

sual

ana

log

scal

e, d

ay 2

1: T

opic

al

hepa

rin:

0 L

MW

H: 0

Trea

tmen

t giv

en fo

r 7-

14 d

Dup

lex

asse

ssm

ent f

or th

rom

bus

regr

essi

on d

ay 2

1Im

prov

emen

t not

ed a

t eac

h tim

e po

int;

no p

ain

at 2

1 d,

no

sign

ifi ca

nt d

iffer

ence

be

twee

n gr

oups

DV

TA

rea

of e

ryth

ema:

Im

prov

emen

t not

ed a

t ea

ch ti

me

poin

t; no

ery

them

a at

21

d,

no s

igni

fi can

t diff

eren

ce b

etw

een

grou

ps

A

dver

se e

vent

s

D

eath

Subj

ectiv

e ef

fi cac

y as

sess

men

t: M

ajor

ity o

f pa

tient

s ( .

75%

) rep

orte

d go

od o

r ve

ry

good

trea

tmen

t effi

cacy

, no

sign

ifi ca

nt

diff

eren

ce b

etw

een

grou

ps

T

hrom

bus

regr

essi

on: T

opic

al h

epar

in:

10/2

1 (4

7.6%

) LM

WH

: 9/2

3 (3

9.1%

); R

R 0

.82

(95%

CI,

0.4

2-1.

62)

D

VT:

Top

ical

hep

arin

: 3/2

1 (1

4.3%

) LM

WH

: 1/

23 (4

.3%

); R

R 0

.30

(95%

CI,

0.0

3-2.

70)

A

dver

se e

vent

s: A

llerg

ic r

eact

ion

in 1

pat

ient

in

eno

xapa

rin

grou

p

Dea

th: 0

And

reoz

zi

et a

l 171 /1

996

Para

llel R

CT,

m

ultic

ente

r56

pat

ient

s w

ith S

VT

of

the

low

er li

mbs

A: D

erm

atan

sul

fate

100

mg

SC o

nce

daily

Pain

30 d

Dat

a ex

trap

olat

ed fr

om g

raph

s an

d fi g

ures

in

artic

le b

y re

view

er

In

crea

se in

func

tiona

l abi

lity

B: D

erm

atan

sul

fate

100

mg

SC b

idL

ocal

ede

ma

Res

olut

ion

of p

ain,

day

30:

Gro

up A

: 47

% G

roup

B: 8

3% G

roup

C: 7

9%

C

: Der

mat

an s

ulfa

te 2

00 m

g in

tram

uscu

lar

once

dai

ly P

not s

tate

d

(Con

tinu

ed)

Tabl

e S4

4—C

onti

nued




Aut

hor/

Year

Type

of

Publ

icat

ion a

Part

icip

ants

Inte

rven

tion b

Out

com

es c

Fol

low

-up

Res

ults

Tr

eatm

ent g

iven

for

30 d

Incr

ease

in a

bilit

y to

per

form

nor

mal

dai

ly

activ

ities

, day

30:

Gro

up A

: 44%

Gro

up B

: 67

% G

roup

C: 8

4%

P

, .0

5 gr

oups

B a

nd C

vs

grou

p A

Loc

al e

dem

a, d

ay 3

0: P

rogr

essi

ve

impr

ovem

ent i

n al

l 3 g

roup

s; n

o si

gnifi

cant

di

ffer

ence

s be

twee

n gr

oups

The

CA

LIS

TO

stu

dy th

at c

ompa

red

fond

apar

inux

with

no

fond

apar

inux

is d

escr

ibed

in T

able

28

and

Tabl

e S4

2. H

IT 5

hep

arin

-indu

ced

thro

mbo

cyto

peni

a; N

SAID

5 n

onst

eroi

dal a

ntiin

fl am

mat

ory

drug

; ST

EN

OX

5 S

uper

fi cia

l Thr

ombo

phle

bitis

Tre

ated

by

Eno

xapa

rin.

See

Tab

le S

1, S

2, S

5, S

21, a

nd S

43 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a Stu

dy d

esig

n: R

CT,

coh

ort.

b Dru

gs: V

KA

, UF

H, L

MW

H, N

SAID

s, a

spir

in, t

opic

al tr

eatm

ents

, sur

gery

vs

plac

ebo,

no

trea

tmen

t, ea

ch o

ther

or

diff

eren

t dur

atio

ns o

r re

gim

ens

of th

e sa

me

agen

t. c O

utco

mes

: ext

ensi

on o

f thr

ombu

s, s

ympt

omat

ic r

elie

f, D

VT

and

PE

, maj

or b

leed

ing,

sur

gica

l com

plic

atio

ns, a

nd d

eath

.

Tabl

e S4

4—C

onti

nued




Table S45 —[Section 8.1] SVT Treatment: Methodologic Quality

Author/Year Randomization Allocation Concealment Blinding Loss to Follow-up/ ITT

STENOX Study Group 163 /2003

Central randomization Visually identical drugs and packaging; triple dummy design

Investigators, patients, and assessors blinded

9 lost to follow-up/ ITT

Titon et al 164 /1994 Randomized to one of three treatment groups; method of randomization not specifi ed

Open label Not blinded 8 lost to follow-up/ not specifi ed

Prandoni for Vesalio group et al 165 /2005

Computer-generated random number sequence assigned to each patient to determine treatment group

Double dummy Patients and adjudicators of outcome events blind

0 lost to follow-up/ ITT

Marchiori et al 166 /2002 Randomized to treatment group by computer-generated list

Not specifi ed Assessors blinded 0 lost to follow-up/ not specifi ed

Belcaro et al 167 /1999 Not specifi ed Not blinded Not blinded 118 lost to follow-up/not specifi ed

Lozano et al 168 /2003 Method not specifi ed Not blinded Not blinded 3 lost to follow-up/not specifi ed

Sullivan et al 169 /2001 Review of six studies; includes one RCT (Belcaro [14 patients]) and fi ve small case series

N/A N/A N/A

Andreozzi et al 170 /1996 Patients randomly assigned to one of three therapeutic groups (method not specifi ed)

Open label Not blinded Not specifi ed/not specifi ed

Górski et al 171 /2005 Performed according to a prespecifi ed randomization list; treatment allocated according to next number on list; no stratifi cation was performed

Open trial Not blinded 6 lost to follow-up/ITT

See Table S5, S12, S43, and S44 legends for expansion of abbreviations.




Tabl

e S4

6 —[S

ecti

on 9

.1]

Init

ial

Tre

atm

ent

of A

cute

UE

DV

T W

ith

Ant

icoa

gula

nt T

hera

py: C

lini

cal

Des

crip

tion

and

Res

ult

s (R

ando

miz

ed T

rial

s [N

one

Per

form

ed]

and

Pro

spec

tive

Ob

serv

atio

nal

Stu

dies

of

at L

east

20

Pat

ient

s)

Aut

hor/

Year

Type

of P

ublic

atio

n a Pa

rtic

ipan

tsIn

terv

entio

n b O

utco

mes

c F

ollo

w-u

pR

esul

ts

Sava

ge e

t al 17

2 /199

9

Pros

pect

ive

coho

rt,

two

cent

er46

out

patie

nts

with

UE

DV

T

(incl

udes

16

with

CV

C)

Dal

tepa

rin

daily

for

5-7

d (2

00 I

nter

natio

nal U

nits

/kg)

an

d V

KA

with

targ

et I

NR

of

2.0-

3.0

Dur

atio

n of

VK

A n

ot p

rovi

ded

Sym

ptom

atic

re

curr

ence

/ext

ensio

n of

DV

TPE M

ajor

ble

edin

gD

eath

3 m

oR

ecur

renc

e/ex

tens

ion

DV

T: 1

/46

(2%

) PE

: 0/4

6 M

ajor

ble

edin

g: 1

/46

(2%

) (on

VK

A)

Dea

th: 7

/46

(15%

) (no

ne fr

om P

E o

r bl

eedi

ng)

Kar

abay

et a

l 173 /2

003

Pros

pect

ive

coho

rt,

sing

le c

ente

r36

inpa

tient

s w

ith U

ED

VT

(in

clud

es 1

3 w

ith C

VC

)N

adro

pari

n SC

bid

, 86

anti-

Xa

Inte

rnat

iona

l Uni

ts/k

g fo

r up

to 7

d, t

hen

VK

A (s

tart

ed

on d

ay 3

; tar

get I

NR

2-2

.5)

for

mea

n of

4.7

mo

Sym

ptom

rel

ief

Lys

is o

f thr

ombu

s on

ul

tras

ound

Rec

urre

nt D

VT

PE Dea

th

1 y

Sign

ifi ca

nt s

ympt

om r

elie

f, da

y 7:

32

/36

(89%

) L

ysis

, day

10:

� 3

5%: 1

6/36

(45%

) ,

35%

: 17/

36 (4

7%) N

one:

3/3

6 (8

%)

Rec

urre

nt D

VT:

0/3

6 PE

: 0/3

6 D

eath

: 9/3

6 (2

5%) (

none

due

to P

E

or b

leed

ing)

Pran

doni

et a

l 120 /2

004

Pros

pect

ive

coho

rt,

num

ber

of c

ente

rs

not s

tate

d

53 p

atie

nts

with

fi rs

t UE

DV

T

(incl

uded

6 w

ith C

VC

)T

hera

peut

ic-d

ose

hepa

rin

(81%

rec

eive

d U

FH

, 19%

re

ceiv

ed L

MW

H) t

hen

VK

A

(med

ian,

3 m

o)

Rec

urre

nt V

TE

Dea

thM

edia

n of

48

mo

Res

ults

not

pre

sent

ed a

ccor

ding

to in

itial

tr

eatm

ent w

ith U

FH

vs

LM

WH

R

ecur

rent

VT

E: 3

/53

(5.7

%)

(2 a

rm, 1

leg)

C

umul

ativ

e in

cide

nce

1, 2

, and

5 y

: 2.

0%, 4

.2%

, 7.7

%

Dea

th: 1

1/53

(20.

8%) (

due

to c

ance

r, PE

, con

gest

ive

hear

t fai

lure

[num

bers

no

t pro

vide

d])

(Con

tinu

ed)




Aut

hor/

Year

Type

of P

ublic

atio

n a Pa

rtic

ipan

tsIn

terv

entio

n b O

utco

mes

c F

ollo

w-u

pR

esul

ts

Kov

acs

et a

l 174 /2

007

Pros

pect

ive

coho

rt,

mul

ticen

ter

74 c

ance

r pa

tient

s w

ith

confi

rm

ed U

ED

VT

(all

had

CV

C)

Dal

tepa

rin

daily

for

5-7

d (2

00 I

nter

natio

nal U

nits

/kg)

an

d V

KA

to a

chie

ve ta

rget

IN

R o

f 2.0

-3.0

Rec

urre

nt V

TE

PE Maj

or b

leed

ing

Dea

thC

athe

ter

failu

re d

ue

to D

VT

or

inab

ility

to in

fuse

3 m

oR

ecur

rent

VT

E: 0

/74

PE: 0

/74

Maj

or b

leed

ing:

3/7

4 (4

%)

Dea

th: 7

/74

(6 c

ance

r, 1

maj

or b

leed

) C

athe

ter

failu

re d

ue to

DV

T o

r in

abili

ty

to in

fuse

: 0/7

4

CV

C 5

cent

ral v

enou

s ca

thet

er; U

ED

VT

5 u

pper

-ext

rem

ity D

VT.

See

Tab

le S

2, S

7, a

nd S

41 le

gend

s fo

r ex

pans

ion

of o

ther

abb

revi

atio

ns.

a Stu

dy d

esig

n: p

rosp

ectiv

e co

hort

stu

dies

. b D

rugs

: IV

UF

H o

r L

MW

H fo

llow

ed b

y O

AC

s.

c Out

com

es: r

ecur

rent

DV

T a

nd P

E, m

ajor

ble

edin

g, to

tal m

orta

lity,

and

ear

ly s

ympt

om r

elie

f.

Tabl

e S4

6—C

onti

nued




Table S49 —[Section 9.2] Initial Treatment of Acute UEDVT With Thrombolytic Therapy: Methodologic Quality


Horne et al 175 /2000 No N/A N/A Not specifi ed

Lee et al 176 /2006 No N/A N/A 0 lost to follow-up

See Table S12 legend for expansion of abbreviation.

Table S48 —[Section 9.2] Initial Treatment of Acute UEDVT With Thrombolytic Therapy: Clinical Description and Results (Randomized Trials [None Performed] and Prospective Observational Studies of at Least 10 Patients)

Author/Year Type of Publication a Participants Intervention b Outcomes c Follow-up Results

Horne et al 175 /2000 Prospective cohort, single center

18 patients with axillary or subclavian DVT

Catheter-directed rt-PA (2 mg/cm of thrombus to maximum of 20 mg) then VKA for 3 mo

Immediate patency 6 mo Immediate patency: 10/18 (56%)

Establishment of antegrade fl ow

Antegrade fl ow: 11/18 (61%)

Bleeding events Bleeds (all minor): 5/18 (28%)

Lee et al 176 /2006 Prospective case series, single center

35 patients with primary UEDVT who had complete resolution of acute symptoms with CDT (n 5 29) or IV heparin (n 5 6)

Oral VKA for mean of 5.2 mo

Recurrent DVT 54 mo Ipsilateral recurrent DVT: 8/35 (23%)

Early prospective observational studies with , 10 patients and retrospective studies are described in Table 3 of the eighth edition of these guide-lines. 46 See Table S2, S10, S11, and S46 legends for expansion of abbreviations. a Study design: retrospective and prospective cohort studies. b Drugs: thrombolytic therapy compared with different types of lytic therapy or with anticoagulants. c Outcomes: recurrent DVT and PE, vein patency, major bleeding, total mortality, and PTS of the arm.

Table S47 —[Section 9.1] Initial Treatment of Acute UEDVT With Anticoagulant Therapy: Methodologic Quality

Author/Year Randomization Allocation Concealment Blinding Loss to Follow-up/ ITT

Savage et al 172 /1999 N/A N/A N/A 1 lost to follow-up/N/A

Karabay et al 173 /2003 N/A N/A N/A 0 lost to follow-up/N/A

Prandoni et al 120 /2004 N/A N/A N/A 2 lost to follow-up/N/A

Kovacs et al 174 /2006 N/A N/A N/A 0 lost to follow-up/N/A





(Con

tinu

ed)

Tabl

e S5

0 —[S

ecti

on 9

.3]

Lon

g-te

rm T

reat

men

t of

Acu

te U

ED

VT

: Cli

nica

l D

escr

ipti

on a

nd R

esu

lts

Aut

hor/

Year

Type

of P

ublic

atio

nPa

rtic

ipan

tsIn

terv

entio

n a O

utco

mes

b F

ollo

w-u

pR

esul

ts

Sava

ge e

t al 17

2 /199

9

Pros

pect

ive

coho

rt,

two

cent

er46

out

patie

nts

with

co

nfi r

med

UE

DV

T

(incl

udes

16

with

CV

C)

Dal

tepa

rin

200

Inte

rnat

iona

l U

nits

/kg

daily

for

5-7

d an

d V

KA

to a

chie

ve ta

rget

IN

R o

f 2.0

-3.0

for

3 m

oD

urat

ion

of V

KA

no

t pro

vide

d

Sym

ptom

atic

rec

urre

nce/

exte

nsio

n of

DV

TPE M

ajor

ble

edin

gD

eath

3 m

oR

ecur

renc

e/ex

tens

ion:

1/4

6 (2

%)

PE: 0

M

ajor

ble

edin

g: 1

/46

(2%

) (o

n V

KA

) D

eath

: 7/4

6 (1

5%) (

none

from

PE

or

ble

edin

g)

Kar

abay

et a

l 173 /2

003

Pros

pect

ive

coho

rt,

sing

le c

ente

r36

inpa

tient

s w

ith

confi

rm

ed U

ED

VT

(in

clud

es 1

3 w

ith C

VC

)

Nad

ropa

rin

SC b

id, 8

6 an

ti-X

a In

tern

atio

nal

Uni

ts/k

g fo

r up

to 7

d,

then

VK

A (s

tart

ed o

n da

y 3;

targ

et I

NR

2-2

.5)

for

mea

n of

4.7

mo

Sym

ptom

rel

ief

Lys

is o

f thr

ombu

s on

ul

tras

ound

Rec

urre

nt D

VT

PE Dea

thPT

S

1 y

Sign

ifi ca

nt s

ympt

om r

elie

f, da

y 7:

32

/36

(89%

) L

ysis

, day

10:

� 3

5%: 1

6/36

(45%

) ,

35%

: 17/

36 (4

7%)

Non

e: 3

/36

(8%

) R

ecur

rent

DV

T: 0

PE

: 0

Dea

th: 9

/36

(25%

) (no

ne d

ue to

PE

or

blee

ding

) PT

S: 0

Mar

tinel

li et

al 17

7 /200

4

Cas

e-co

ntro

l stu

dy w

ith

pros

pect

ive

follo

w-u

p of

cas

es, s

ingl

e ce

nter

98 p

atie

nts

with

pr

imar

y U

ED

VT

(n

one

with

CV

C)

VK

A fo

r m

ean

6 m

o (7

7 pa

tient

s), h

epar

in

SC (1

4 pa

tient

s), o

r an

tipla

tele

t age

nts

(7 p

atie

nts)

for

� 3

mo

Rec

urre

nt V

TE

aft

er

antic

oagu

lant

s st

oppe

dM

edia

n of

5.1

yR

ecur

rent

VT

E: 1

2/98

(12%

) ov

eral

l (al

l UE

DV

T)

Ann

ual i

ncid

ence

rec

urre

nt V

TE

: 2.

4% (9

5% C

I, 1

.2%

-4.0

%)

(res

ults

not

pro

vide

d by

tr

eatm

ent g

roup

)

Pran

doni

et a

l 178 /2

004

Pros

pect

ive

coho

rt,

num

ber

of c

ente

rs

not s

tate

d

53 p

atie

nts

with

con

fi rm

ed

fi rst

UE

DV

T (i

nclu

ded

6 w

ith C

VC

)

The

rape

utic

-dos

e he

pari

n (8

1% r

ecei

ved

UF

H, 1

9%

rece

ived

LM

WH

) the

n V

KA

(med

ian,

3 m

o)

Rec

urre

nt V

TE

Med

ian

of 4

8 m

oR

esul

ts n

ot p

rese

nted

acc

ordi

ng

to in

itial

trea

tmen

t with

UF

H v

s L

MW

H




Aut

hor/

Year

Type

of P

ublic

atio

nPa

rtic

ipan

tsIn

terv

entio

n a O

utco

mes

b F

ollo

w-u

pR

esul

ts

Dea

thPT

SR

ecur

rent

VT

E: 3

/53

(5.7

%)

(2 a

rm, 1

leg)

C

umul

ativ

e in

cide

nce

1, 2

, and

5 y

: 2.

0%, 4

.2%

, 7.7

%

Dea

th: 1

1/53

(20.

8%) (

due

to c

ance

r, PE

, con

gest

ive

hear

t fai

lure

[b

reak

dow

n no

t pro

vide

d])

PTS:

13/

53 (2

4.5%

); 2

y C

umul

ativ

e in

cide

nce:

27.

3%

Kov

acs

et a

l 174 /2

007

Pros

pect

ive

coho

rt,

mul

ticen

ter

74 c

ance

r pa

tient

s w

ith

confi

rm

ed U

ED

VT

(a

ll ha

d C

VC

)

Dal

tepa

rin

200

Inte

rnat

iona

l U

nits

/kg

daily

for

5-7

d an

d V

KA

to a

chie

ve ta

rget

IN

R o

f 2.0

-3.0

Rec

urre

nt V

TE

PE Maj

or b

leed

ing

Dea

thC

athe

ter

failu

re d

ue to

D

VT

or

inab

ility

to

infu

se

3 m

oR

ecur

rent

VT

E: 0

PE

: 0

Maj

or b

leed

ing:

3 (4

%)

Dea

th: 7

(6 c

ance

r, 1

maj

or b

leed

) C

athe

ter

failu

re d

ue to

DV

T o

r in

abili

ty to

infu

se: 0

Ear

ly p

rosp

ectiv

e ob

serv

atio

nal s

tudi

es w

ith ,

20

patie

nts,

and

ret

rosp

ectiv

e st

udie

s, a

re d

escr

ibed

in T

able

3 o

f the

Eig

ht e

ditio

n of

thes

e gu

idel

ines

46 S

ee T

able

S2,

S7,

S10

, and

S46

lege

nds

for

expa

nsio

n of

abb

revi

atio

ns.

a Dru

gs: V

KA

, UF

H, L

MW

H v

s pl

aceb

o, c

ontr

ol o

r ea

ch o

ther

. b O

utco

mes

: rec

urre

nt D

VT

and

PE

, maj

or b

leed

ing,

tota

l mor

talit

y, a

nd P

TS

of th

e ar

m. Ta

ble

S50—

Con

tinu

ed




Table S51 —[Section 9.3] Long-term Treatment of Acute UEDVT: Methodologic Quality


Savage et al 172 /1999 N/A N/A N/A 1 lost to follow-up

Karabay et al 173 /2003 N/A N/A N/A 0 lost to follow-up

Martinelli et al 177 /2004 N/A N/A N/A Not specifi ed

Prandoni et al 178 /2004 N/A N/A N/A 2 patients lost to follow-up

Kovacs et al 174 /2007 N/A N/A N/A 0 lost to follow-up





References 1 . Brandjes DPM , Heijboer H , Büller HR , de Rijk M , Jagt H ,

ten Cate JW . Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis . N Engl J Med . 1992 ; 327 ( 21 ): 1485 - 1489 .

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14 . Levine M , Gent M , Hirsh J , et al . A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital

for proximal deep-vein thrombosis . N Engl J Med . 1996 ; 334 ( 11 ): 677 - 681 .

15 . Lindmarker P , Holmström M , Granqvist S , Johnsson H , Lockner D . Comparison of once-daily subcutaneous Frag-min with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis . Thromb Haemost . 1994 ; 72 ( 2 ): 186 - 190 .

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DOI 10.1378/chest.11-2301 2012;141; e419S-e494SChest

Michael K. Gould, Francesco Dentali, Mark Crowther and Susan R. KahnBounameaux, Samuel Z. Goldhaber, Michael E. Nelson, Philip S. Wells, Clive Kearon, Elie A. Akl, Anthony J. Comerota, Paolo Prandoni, Henri

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