chest 2008 warfarin in dvt
DESCRIPTION
warfarin in DVTTRANSCRIPT
DOI 10.1378/chest.08-0658 2008;133;454S-545SChest
Gary E. Raskob and Anthony J. ComerotaClive Kearon, Susan R. Kahn, Giancarlo Agnelli, Samuel Goldhaber, Clinical Practice Guidelines (8th Edition)
Evidence-BasedCollege of Chest Physicians : American*Thromboembolic Disease
Antithrombotic Therapy for Venous
http://chestjournal.chestpubs.org/content/133/6_suppl/454S.full.html
services can be found online on the World Wide Web at: The online version of this article, along with updated information and
454S.DC1.html http://chestjournal.chestpubs.org/content/suppl/2008/06/23/133.6_suppl.Supplemental material related to this article is available at:
ISSN:0012-3692)http://chestjournal.chestpubs.org/site/misc/reprints.xhtml(
written permission of the copyright holder.this article or PDF may be reproduced or distributed without the priorDundee Road, Northbrook, IL 60062. All rights reserved. No part of Copyright2008by the American College of Chest Physicians, 3300Physicians. It has been published monthly since 1935.
is the official journal of the American College of ChestChest
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Antithrombotic Therapy for VenousThromboembolic Disease*
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Clive Kearon, MB, PhD; Susan R. Kahn, MD; Giancarlo Agnelli, MD;Samuel Goldhaber, MD, FCCP; Gary E. Raskob, PhD;and Anthony J. Comerota, MD
This chapter about treatment for venous thromboembolic disease is part of the American College of ChestPhysicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strongand indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggests that individualpatient values may lead to different choices (for a full understanding of the grading, see “Grades ofRecommendation” chapter). Among the key recommendations in this chapter are the following: for patientswith objectively confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE), we recommendanticoagulant therapy with subcutaneous (SC) low-molecular-weight heparin (LMWH), monitored IV, or SCunfractionated heparin (UFH), unmonitored weight-based SC UFH, or SC fondaparinux (all Grade 1A). Forpatients with a high clinical suspicion of DVT or PE, we recommend treatment with anticoagulants whileawaiting the outcome of diagnostic tests (Grade 1C). For patients with confirmed PE, we recommend earlyevaluation of the risks to benefits of thrombolytic therapy (Grade 1C); for those with hemodynamiccompromise, we recommend short-course thrombolytic therapy (Grade 1B); and for those with nonmassivePE, we recommend against the use of thrombolytic therapy (Grade 1B). In acute DVT or PE, werecommend initial treatment with LMWH, UFH or fondaparinux for at least 5 days rather than a shorterperiod (Grade 1C); and initiation of vitamin K antagonists (VKAs) together with LMWH, UFH, orfondaparinux on the first treatment day, and discontinuation of these heparin preparations when theinternational normalized ratio (INR) is > 2.0 for at least 24 h (Grade 1A). For patients with DVT or PEsecondary to a transient (reversible) risk factor, we recommend treatment with a VKA for 3 months overtreatment for shorter periods (Grade 1A). For patients with unprovoked DVT or PE, we recommendtreatment with a VKA for at least 3 months (Grade 1A), and that all patients are then evaluated for the risksto benefits of indefinite therapy (Grade 1C). We recommend indefinite anticoagulant therapy for patientswith a first unprovoked proximal DVT or PE and a low risk of bleeding when this is consistent with thepatient’s preference (Grade 1A), and for most patients with a second unprovoked DVT (Grade 1A). Werecommend that the dose of VKA be adjusted to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for alltreatment durations (Grade 1A). We recommend at least 3 months of treatment with LMWH for patientswith VTE and cancer (Grade 1A), followed by treatment with LMWH or VKA as long as the cancer is active(Grade 1C). For prevention of postthrombotic syndrome (PTS) after proximal DVT, we recommend use ofan elastic compression stocking (Grade 1A). For DVT of the upper extremity, we recommend similartreatment as for DVT of the leg (Grade 1C). Selected patients with lower-extremity (Grade 2B) andupper-extremity (Grade 2C). DVT may be considered for thrombus removal, generally using catheter-basedthrombolytic techniques. For extensive superficial vein thrombosis, we recommend treatment with prophy-lactic or intermediate doses of LMWH or intermediate doses of UFH for 4 weeks (Grade 1B).
(CHEST 2008; 133:454S–545S)
Key words: cancer; chronic thromboembolic pulmonary hypertension; deep vein thrombosis; fondaparinux; low-molecular-weightheparin; plasminogen activator; pulmonary embolism; thrombectomy; thrombolytic therapy; thrombophlebitis; unfractionated heparin;vena caval filter; venous thromboembolism; vitamin K antagonist
Abbreviations: APTT � activated partial thromboplastin time; CDT � catheter-directed thrombolysis; CI � confidence interval;CTPH � chronic thromboembolic pulmonary hypertension; DVT � deep venous thrombosis; INR � international normalized ratio;IPC � intermittent pneumatic compression; IVC � inferior vena cava; LMWH � low-molecular-weight heparin;MPFF � micronized purified flavonoid fraction; NSAID � nonsteroidal antiinflammatory drug; OR � odds ratio; PE � pulmonaryembolism; PTS � postthrombotic (phlebitic) syndrome; QOL � quality of life; RCT � randomized controlled trial; RR � relative risk;rt-PA � recombinant tissue plasminogen activator; SC � subcutaneous; SVC � superior vena cava; SVT � superficial venous throm-bosis; tPA � tissue plasminogen activator; UEDVT � upper-extremity deep vein thrombosis; UFH � unfractionated heparin;VKA � vitamin K antagonist; VTE � venous thromboembolism
SupplementANTITHROMBOTIC AND THROMBOLYTIC THERAPY 8TH ED: ACCP GUIDELINES
454S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Summary of Recommendations
1.1 Initial Anticoagulation of Acute DVT of the Leg
1.1.1. For patients with objectively confirmedDVT, we recommend short-term treatmentwith SC LMWH (Grade 1A), IV UFH (Grade 1A),monitored SC UFH (Grade 1A), fixed-dose SCUFH (Grade 1A), or SC fondaparinux (Grade 1A)rather than no such short-term treatment.1.1.2. For patients with a high clinical suspicionof DVT, we recommend treatment with antico-agulants while awaiting the outcome of diagnos-tic tests (Grade 1C).1.1.3. In patients with acute DVT, we recom-mend initial treatment with LMWH, UFH, orfondaparinux for at least 5 days and until theINR is > 2.0 for 24 h (Grade 1C).1.1.4. In patients with acute DVT, we recom-mend initiation of VKA together with LMWH,UFH, or fondaparinux on the first treatmentday rather than delayed initiation of VKA(Grade 1A).
1.2 IV UFH for the Initial Treatment of DVT
1.2.1. In patients with acute DVT, if IV UFH ischosen, we recommend that after an initial IVbolus (80 U/kg or 5,000 U), it be administeredby continuous infusion (initially at a dose of 18U/kg/h or 1,300 U/h) with dose adjustment toachieve and maintain an activated partialthromboplastin time (APTT) prolongation thatcorresponds to plasma heparin levels of 0.3 to0.7 IU/mL anti-Xa activity by the amidolyticassay rather than administration as IV bolusesthroughout treatment, or administration with-out coagulation monitoring (Grade 1C).
1.3 SC UFH Compared With IV Heparin for theInitial Treatment of DVT
1.3.1. In patients with acute DVT, if monitored SCUFH is chosen, we recommend an initial dose of17,500 U, or a weight-adjusted dose of about 250U/kg bid, with dose adjustment to achieve andmaintain an APTT prolongation that correspondsto plasma heparin levels of 0.3 to 0.7 IU/mLanti-Xa activity when measured 6 h after injectionrather than starting with a smaller initial dose (seealso Section 1.5) [Grade 1C].1.3.2. In patients with acute DVT, if fixed-dose,unmonitored SC UFH is chosen, we recommendan initial dose of 333 U/Kg followed by 250 U/kgbid rather than non–weight-based dosing (seealso Section 1.5) [Grade 1C].
1.4 LMWH for the Initial Treatment of DVT
1.4.1. In patients with acute DVT, we recom-mend initial treatment with LMWH SC once ortwice daily, as an outpatient if possible (Grade1C), or as an inpatient if necessary (Grade 1A),rather than treatment with IV UFH.1.4.2. In patients with acute DVT treated withLMWH, we recommend against routine moni-toring with anti-factor Xa level measurements(Grade 1A).1.4.3. In patients with acute DVT and severerenal failure, we suggest UFH over LMWH(Grade 2C).
1.9 Catheter-Directed Thrombolysis for Acute DVT
1.9.1. In selected patients with extensive acuteproximal DVT (eg, iliofemoral DVT, symptoms for< 14 days, good functional status, life expectancy of> 1 year) who have a low risk of bleeding, wesuggest that catheter-directed thrombolysis (CDT)may be used to reduce acute symptoms and post-thrombotic morbidity if appropriate expertise andresources are available (Grade 2B).1.9.2. After successful CDT in patients withacute DVT, we suggest correction of underlyingvenous lesions using balloon angioplasty and stents(Grade 2C).1.9.3. We suggest pharmacomechanical throm-bolysis (eg, with inclusion of thrombus fragmen-tation and/or aspiration) in preference to CDTalone to shorten treatment time if appropriateexpertise and resources are available (Grade 2C).1.9.4. After successful CDT in patients with acuteDVT, we recommend the same intensity andduration of anticoagulant therapy as for compa-rable patients who do not undergo CDT (Grade1C).
*From McMaster University Clinic (Dr. Kearon), HendersonGeneral Hospital, Hamilton, ON, Canada; Thrombosis Clinicand Centre for Clinical Epidemiology and Community Studies(Dr. Kahn), Sir Mortimer B. Davis Jewish General Hospital,Montreal, QC, Canada; University of Perugia (Dr. Agnelli),Perugia, Italy; Brigham and Women’s Hospital (Dr. Goldhaber),Boston, MA; College of Public Health, University of OklahomaHealth Science Center (Dr. Raskob), Oklahoma City, OK; andJobst Vascular Center (Dr. Comerota), Toledo, OH.Manuscript accepted December 20, 2007.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Clive Kearon, MB, PhD, Hamilton HealthSciences, Henderson Division, 711 Concession St, Hamilton, ON,L8V 1C3, Canada; e-mail: [email protected]: 10.1378/chest.08-0658
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 455S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
1.10 Systemic Thrombolytic Therapy forAcute DVT
1.10.1. In selected patients with extensive prox-imal DVT (eg, symptoms for < 14 days, goodfunctional status, life expectancy of > 1 year)who have a low risk of bleeding, we suggest thatsystemic thrombolytic therapy may be used toreduce acute symptoms and postthromboticmorbidity if CDT is not available (Grade 2C).
1.11 Percutaneous Venous Thrombectomy
1.11.1. In patients with acute DVT, we suggestthat they should not be treated with percutaneousmechanical thrombectomy alone (Grade 2C).
1.12 Operative Venous Thrombectomy forAcute DVT
1.12.1. In selected patients with acute iliofemoralDVT (eg, symptoms for < 7 days, good functionalstatus, and life expectancy of > 1 year), we sug-gest that operative venous thrombectomy may beused to reduce acute symptoms and postthrom-botic morbidity if appropriate expertise and re-sources are available (Grade 2B). If such patientsdo not have a high risk of bleeding, we suggestthat catheter-directed thrombolysis is usuallypreferable to operative venous thrombectomy(Grade 2C).1.12.2. In patients who undergo operative venousthrombectomy, we recommend the same inten-sity and duration of anticoagulant therapy after-wards as for comparable patients who do notundergo venous thrombectomy (Grade 1C).
1.13 Vena Caval Filters for the Initial Treatmentof DVT
1.13.1. For patients with DVT, we recommendagainst the routine use of a vena cava filter inaddition to anticoagulants (Grade 1A).1.13.2. For patients with acute proximal DVT,if anticoagulant therapy is not possible be-cause of the risk of bleeding, we recommendplacement of an inferior vena cava (IVC) filter(Grade 1C).1.13.3. For patients with acute DVT who havean IVC filter inserted as an alternative toanticoagulation, we recommend that theyshould subsequently receive a conventionalcourse of anticoagulant therapy if their risk ofbleeding resolves (Grade 1C).
1.14 Immobilization for the Treatment ofAcute DVT
1.14.1. In patients with acute DVT, we recom-mend early ambulation in preference to initialbed rest when this is feasible (Grade 1A).
2.1 Duration of Anticoagulant Therapy
2.1.1. For patients with DVT secondary to atransient (reversible) risk factor, we recom-mend treatment with a VKA for 3 months overtreatment for shorter periods (Grade 1A).2.1.2. For patients with unprovoked DVT, werecommend treatment with a VKA for at least 3months (Grade 1A). We recommend that after 3months of anticoagulant therapy, all patients withunprovoked DVT should be evaluated for therisk-benefit ratio of long-term therapy (Grade 1C).For patients with a first unprovoked VTE that is aproximal DVT, and in whom risk factors forbleeding are absent and for whom good anticoag-ulant monitoring is achievable, we recommendlong-term treatment (Grade 1A).Values and preferences: This recommendation attachesa relatively high value to prevention of recurrent VTEand a lower value to the burden of long-term antico-agulant therapy.
For patients with a second episode of unpro-voked VTE, we recommend long-term treat-ment (Grade 1A). For patients with a first iso-lated distal DVT that is unprovoked, we suggestthat 3 months of anticoagulant therapy is suffi-cient rather than indefinite therapy (Grade 2B).2.1.3. For patients with DVT and cancer, werecommend LMWH for the first 3 to 6 monthsof long-term anticoagulant therapy (Grade 1A).For these patients, we recommend subsequentanticoagulant therapy with VKA or LMWH in-definitely or until the cancer is resolved (also,see Section 2.4) [Grade 1C].2.1.4. In patients who receive long-term anticoagu-lant treatment, the risk-benefit ratio of continuingsuch treatment should be reassessed in the individ-ual patient at periodic intervals (Grade 1C).
2.2 Intensity of Anticoagulant Effect
2.2.1. In patients with DVT, we recommendthat the dose of VKA be adjusted to maintain atarget INR of 2.5 (range, 2.0 to 3.0) for alltreatment durations (Grade 1A). For patientswith unprovoked DVT who have a strong pref-erence for less frequent INR testing to monitortheir therapy, after the first 3 months of con-
456S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
ventional-intensity anticoagulation (INR range,2.0 to 3.0), we recommend low-intensity ther-apy (range, 1.5 to 1.9) with less frequent INRmonitoring over stopping treatment (Grade 1A).We recommend against high-intensity VKAtherapy (INR range, 3.1 to 4.0) compared to anINR range of 2.0 to 3.0 (Grade 1A).
2.6 Treatment of Asymptomatic DVT of the Leg
2.6.1. In patients who are unexpectedly foundto have asymptomatic DVT, we recommend thesame initial and long-term anticoagulation asfor comparable patients with symptomatic DVT(Grade 1C).
3.1 Elastic Stockings and Compression BandagesTo Prevent PTS
3.1.1. For a patient who has had a symptomaticproximal DVT, we recommend the use of anelastic compression stocking with an ankle pres-sure gradient of 30 to 40 mm Hg if feasible(Grade 1A). Compression therapy, which mayinclude use of bandages acutely, should bestarted as soon as feasible after starting antico-agulant therapy and should be continued for aminimum of 2 years, and longer if patients havesymptoms of PTS. (Note: feasibility, both shortand long term, refers to ability of patients andtheir caregivers to apply and remove stockings.)Values and preferences: This recommendation at-taches a relatively high value to long-term preventionof the PTS and a low value to the burden (eg,inconvenience or discomfort) associated with wear-ing stockings.
3.2 Physical Treatment of PTS Without Venous LegUlcers
3.2.1. For patients with severe edema of the legdue to PTS, we suggest a course of intermittentpneumatic compression (IPC) [Grade 2B].3.2.2. For patients with mild edema of the legdue to PTS, we suggest the use of elastic com-pression stockings (Grade 2C).
3.3 Physical Treatment of Venous Leg Ulcers
3.3.1. In patients with venous ulcers resistant tohealing with wound care and compression, wesuggest the addition of IPC (Grade 2B).
3.4 Hyperbaric Oxygen and the Management ofPatients With Venous Ulcers
3.4.1. For patients with venous ulcers, we suggestthat hyperbaric oxygen not be used (Grade 2B).
3.5.1. Pentoxifylline
3.5.1. In patients with venous leg ulcers, wesuggest pentoxifylline, 400 mg po tid, in addi-tion to local care and compression and/or IPC(Grade 2B).
3.5.2. Micronized Purified Flavonoid Fraction orSulodexide for the Treatment of Venous Leg Ulcers
3.5.2. In patients with persistent venous ulcers,we suggest that rutosides, in the form of mi-cronized purified flavonoid fraction adminis-tered orally, or sulodexide administered intra-muscularly and then orally, be added to localcare and compression (Grade 2B).
4.1 IV or SC UFH, SC LMWH, SC Fondaparinux,and VKA for the Initial Treatment of PE
4.1.1. For patients with objectively confirmed PE,we recommend short-term treatment with SCLMWH (Grade 1A), IV UFH (Grade 1A), moni-tored SC UFH (Grade 1A), fixed-dose SC UFH(Grade 1A), or SC fondaparinux (Grade 1A) ratherthan no such acute treatment. Patients with acutePE should also be routinely assessed for treat-ment with thrombolytic therapy (see Section 4.3for related discussion and recommendations).4.1.2. For patients in whom there is a high clinicalsuspicion of PE, we recommend treatment withanticoagulants while awaiting the outcome of di-agnostic tests (Grade 1C).4.1.3. In patients with acute PE, we recommendinitial treatment with LMWH, UFH or fondapa-rinux for at least 5 days and until the INR is > 2.0for at least 24 h (Grade 1C).4.1.4. In patients with acute PE, we recommendinitiation of VKA together with LMWH, UFH, orfondaparinux on the first treatment day ratherthan delayed initiation of VKA (Grade 1A).4.1.5. In patients with acute PE, if IV UFH ischosen, we recommend that after an initial IVbolus (80 U/kg or 5,000 U), it be administered bycontinuous infusion (initially at dose of 18 U/kg/hor 1,300 U/h) with dose adjustment to achieve andmaintain an APTT prolongation that correspondsto plasma heparin levels of 0.3 to 0.7 IU/mLanti-Xa activity by the amidolytic assay ratherthan administration as IV boluses throughouttreatment, or administration without coagulationmonitoring (Grade 1C).4.1.6. In patients with acute PE, if monitored SCUFH is chosen, we recommend an initial dose of17,500 U, or a weight-adjusted dose of approxi-mately 250 U/kg bid, with dose adjustment to
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 457S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
achieve and maintain an APTT prolongation thatcorresponds to plasma heparin levels of 0.3 to 0.7IU/mL anti-Xa activity when measured 6 h afterinjection rather than starting with a smaller initialdose (Grade 1C).4.1.7. In patients with acute PE, if fixed-dose,unmonitored SC UFH is chosen, we recommendan initial dose of 333 U/Kg followed by a twice-daily dose of 250 U/kg rather than non–weight-based dosing (Grade 1C).4.1.8. In patients with acute nonmassive PE, werecommend initial treatment with LMWH over IVUFH (Grade 1A). In patients with massive PE, inother situations where there is concern about SCabsorption, or in patients for whom thrombolytictherapy is being considered or planned, we sug-gest IV UFH over SC LMWH, SC fondaparinux,or SC UFH (Grade 2C).4.1.9. In patients with acute PE treated withLMWH, we recommend against routine monitor-ing with anti-factor Xa level measurements (Grade1A).4.1.10. In patients with acute PE and severe renalfailure, we suggest UFH over LMWH (Grade 2C).
4.3 Systemically and Locally AdministeredThrombolytic Therapy for PE
4.3.1. All PE patients should undergo rapidrisk stratification (Grade 1C). For patientswith evidence of hemodynamic compromise,we recommend use of thrombolytic therapyunless there are major contraindications ow-ing to bleeding risk (Grade 1B). Thrombolysisin these patients should not be delayed be-cause irreversible cardiogenic shock may en-sue. In selected high-risk patients withouthypotension who are judged to have a low riskof bleeding, we suggest administration ofthrombolytic therapy (Grade 2B). The decisionto use thrombolytic therapy depends on theclinician’s assessment of PE severity, progno-sis, and risk of bleeding. For the majority ofpatients with PE, we recommend against us-ing thrombolytic therapy (Grade 1B).4.3.2. In patients with acute PE, when a thrombo-lytic agent is used, we recommend that treatmentbe administered via a peripheral vein rather thanplacing a pulmonary artery catheter to administertreatment (Grade 1B).4.3.3. In patients with acute PE, with administra-tion of thrombolytic therapy, we recommend useof regimens with short infusion times (eg, a 2-hinfusion) over those with prolonged infusiontimes (eg, a 24-h infusion) [Grade 1B].
4.4 Catheter Extraction or Fragmentation for theInitial Treatment of PE
4.4.1. For most patients with PE, we recom-mend against use of interventional catheteriza-tion techniques (Grade 1C). In selected highlycompromised patients who are unable to re-ceive thrombolytic therapy because of bleedingrisk, or whose critical status does not allowsufficient time for systemic thrombolytic ther-apy to be effective, we suggest use of interven-tional catheterization techniques if appropriateexpertise is available (Grade 2C).
4.5 Pulmonary Embolectomy for the InitialTreatment of PE
4.5.1. In selected highly compromised patientswho are unable to receive thrombolytic therapybecause of bleeding risk, or whose critical sta-tus does not allow sufficient time for systemicthrombolytic therapy to be effective, we suggestthat pulmonary embolectomy may be used ifappropriate expertise is available (Grade 2C).
4.6 Vena Caval Filters for the Initial Treatmentof PE
4.6.1. For most patients with PE, we recom-mend against the routine use of a vena cavalfilter in addition to anticoagulants (Grade 1A).4.6.2. In patients with acute PE, if anticoagu-lant therapy is not possible because of risk ofbleeding, we recommend placement of an IVC filter(Grade 1C).4.6.3. For patients with acute PE who have an IVCfilter inserted as an alternative to anticoagulation,we recommend that they should subsequently re-ceive a conventional course of anticoagulant ther-apy if their risk of bleeding resolves (Grade 1C).
5.0 Long-term Treatment of Acute PE
5.1.1. For patients with PE secondary to a tran-sient (reversible) risk factor, we recommend treat-ment with a VKA for 3 months over treatment forshorter periods (Grade 1A).5.1.2. For patients with unprovoked PE, we rec-ommend treatment with a VKA for at least 3months (Grade 1A). We recommend that after 3months of anticoagulant therapy, all patients withunprovoked PE should be evaluated for the risk-benefit ratio of long-term therapy (Grade 1C). Forpatients with a first unprovoked episode of VTEthat is a PE, and in whom risk factors for bleedingare absent and for whom good anticoagulant
458S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
monitoring is achievable, we recommend long-term treatment (Grade 1A).Values and preferences: This recommendation attachesa relatively high value to prevention of recurrent VTEand a lower value to the burden of long-term antico-agulant therapy.
For patients with a second episode of unpro-voked VTE, we recommend long-term treatment(Grade 1A).5.1.3. For patients with PE and cancer, we recom-mend LMWH for the first 3 to 6 months of long-term anticoagulant therapy (Grade 1A). For thesepatients, we recommend subsequent anticoagulanttherapy with VKA or LMWH indefinitely or untilthe cancer is resolved (Grade 1C).5.1.4. In patients who receive long-term anticoagu-lant treatment, the risk-benefit ratio of continuingsuch treatment should be reassessed in the individ-ual patient at periodic intervals (Grade 1C).5.1.5. In patients with PE, we recommend that thedose of VKA be adjusted to maintain a target INRof 2.5 (INR range, 2.0 to 3.0) for all treatmentdurations (Grade 1A). For patients with unpro-voked PE who have a strong preference for lessfrequent INR testing to monitor their therapy,after the first 3 months of conventional-intensityanticoagulation (INR range, 2.0 to 3.0), we rec-ommend low-intensity therapy (INR range, 1.5 to1.9) with less frequent INR monitoring over stop-ping treatment (Grade 1A). We recommendagainst high-intensity VKA therapy (INR range,3.1 to 4.0) compared with an INR range of 2.0 to3.0 (Grade 1A).5.1.6. In patients who are unexpectedly found tohave asymptomatic PE, we recommend the sameinitial and long-term anticoagulation as for com-parable patients with symptomatic PE (Grade 1C).
6.1 Pulmonary Thromboendarterectomy, VKA, andVena Caval Filter for the Treatment of ChronicThromboembolic Pulmonary Hypertension
6.1.1. In selected patients with chronic throm-boembolic pulmonary hypertension (CTPH),such as those with central disease under thecare of an experienced surgical/medical team,we recommend pulmonary thromboendarterec-tomy (Grade 1C).6.1.2. For all patients with CTPH, we recom-mend life-long treatment with a VKA targetedto an INR of 2.0 to 3.0 (Grade 1C).6.1.3. For patients with CTPH undergoing pulmo-nary thromboendarterectomy, we suggest theplacement of a permanent vena caval filter beforeor at the time of the procedure (Grade 2C).
6.1.4. For patients with inoperable CTPH, wesuggest referral to a center with expertise inpulmonary hypertension so that patients can beevaluated for alternative treatments, such as va-sodilator therapy or balloon pulmonary angio-plasty (Grade 2C).
7.1 Treatment of Infusion Thrombophlebitis
7.1.1. For patients with symptomatic infusionthrombophlebitis as a complication of IV infu-sion, we suggest oral diclofenac or another non-steroidal antiinflammatory drug (Grade 2B), topi-cal diclofenac gel (Grade 2B), or heparin gel(Grade 2B) until resolution of symptoms or for upto 2 weeks. We recommend against the use ofsystemic anticoagulation (Grade 1C).
7.2 Treatment of SVT
7.2.1. For patients with spontaneous superficialvein thrombosis, we suggest prophylactic orintermediate doses of LMWH (Grade 2B) orintermediate doses of UFH (Grade 2B) for atleast 4 weeks. We suggest that as an alternativeto 4 weeks of LMWH or UFH, VKA (target INR,2.5; range, 2.0 to 3.0) can be overlapped with 5days of UFH and LMWH and continued for 4weeks (Grade 2C). We suggest that oral nonste-riodal antiinflammatory drugs should not beused in addition to anticoagulation (Grade 2B).We recommend medical treatment with antico-agulants over surgical treatment (Grade 1B).
Remark: It is likely that less extensive superficial veinthrombosis (ie, where the affected venous segment isshort in length or further from the saphenofemoraljunction) does not require treatment with anticoagu-lants. It is reasonable to use oral or topical nonsteriodalantiinflammatory drugs for symptom control in suchcases.
8.1. IV UFH or LMWH for the Initial Treatmentof Upper-Extremity DVT
8.1.1. For patients with acute upper-extremityDVT (UEDVT), we recommend initial treat-ment with therapeutic doses of LMWH, UFH,or fondaparinux as described for leg DVT (seeSection 1) [Grade 1C].
8.2 Thrombolytic Therapy for the Initial Treatmentof UEDVT
8.2.1. For most patients with acute UEDVT, werecommend against the routine use of systemic orcatheter-directed thrombolytic therapy (Grade 1C).
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 459S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
8.2.2. In selected patients with acute UEDVT (eg, inthose with a low risk of bleeding and severe symp-toms of recent onset), we suggest that CDT may beused for initial treatment if appropriate expertiseand resources are available (Grade 2C).
8.3 Catheter Extraction, Surgical Thrombectomy,Transluminal Angioplasty, Stent Placement, StagedApproach of Lysis Followed by Interventional orSurgical Procedure, Superior Vena Cava FilterInsertion for the Initial Treatment of UEDVT
8.3.1. For most patients with acute UEDVT, werecommend against the routine use of catheterextraction, surgical thrombectomy, transluminalangioplasty, stent placement, staged approach oflysis followed by interventional or surgical proce-dure, or superior vena cava (SVC) filter place-ment (Grade 1C).8.3.2. In selected patients with acute UEDVT(eg, those with primary UEDVT and failure ofanticoagulant or thrombolytic treatment whohave severe persistent symptoms), we suggestthat catheter extraction, surgical thrombec-tomy, transluminal angioplasty, or a stagedapproach of lysis followed by a vascular inter-ventional or surgical procedure may be usedif appropriate expertise and resources areavailable (all Grade 2C).8.3.3. In selected patients with acute UEDVT(eg, those for whom anticoagulant treatmentis contraindicated and there is clear evidenceof DVT progression or clinically significantPE), we suggest placement of an SVC filter(Grade 2C).
8.4 Anticoagulants for the Long-term Treatment ofUEDVT
8.4.1. For patients with acute UEDVT, we rec-ommend treatment with a VKA for > 3 months(Grade 1C).
Remark: A similar process as for lower-extremityDVT (see Section 2) should be used to determinethe optimal duration of anti-coagulation.8.4.2. For most patients with UEDVT in associ-ation with an indwelling central venous cathe-ter, we suggest that the catheter not be re-moved if it is functional and there is an ongoingneed for the catheter (Grade 2C).8.4.3. For patients who have UEDVT in asso-ciation with an indwelling central venouscatheter that is removed, we do not recom-mend that the duration of long-term antico-agulant treatment be shortened to < 3months (Grade 2C).
8.5 Prevention of PTS of the Arm
8.5.1. For patients at risk for PTS after UEDVT,we do not suggest routine use of elastic com-pression or venoactive medications (Grade 2C).
8.6 Treatment of PTS of the Arm
8.6.1. In patients with UEDVT who have persis-tent edema and pain, we suggest elastic bandagesor elastic compression sleeves to reduce symp-toms of PTS of the upper extremity (Grade 2C).
T his section will describe the role of antithromboticagents as well as devices or surgical techniques that
are used in the treatment of patients with acute venousthromboembolism (VTE), a disease that encompassesboth deep venous thrombosis (DVT) and pulmonaryembolism (PE). In addition, the treatment of patients withacute upper-extremity DVT (UEDVT), superficial veinthrombosis (SVT), and the two most important long-termcomplications of VTE, postthrombotic syndrome (PTS)and chronic thromboembolic pulmonary hypertension(CTPH), are discussed. In this chapter, consistent withmost previous reports, patients with VTE are dichoto-mized into those with symptoms of PE (with or withoutconcomitant symptoms of DVT), and those who presentonly with symptoms of DVT. Table 1 describes theeligibility criteria for the studies considered in each sectionof the recommendations that follow.
1.0 Initial Treatment of Acute DVT of theLeg
1.1. Initial Anticoagulation of Acute DVT of theLeg
Anticoagulation is the main therapy for acute DVT ofthe leg. The main objectives of anticoagulant therapy inthe initial treatment of this disease are to preventthrombus extension and early and late recurrences ofVTE. The evidence for the need for anticoagulation inpatients with DVT is based on studies performed � 40years ago. The first and only trial1 that comparedanticoagulant therapy with no anticoagulant therapy inpatients with symptomatic DVT or PE was published in1960 (Barritt and Jordan; Table 15). This trial ofpatients with acute PE showed that 1.5 days of heparinand 14 days of vitamin K antagonist (VKA) therapymarkedly reduced recurrent PE and mortality. Subse-quent uncontrolled studies2–4 support that mortality isreduced when heparin is used to treat VTE andreported a high mortality when patients did not receiveanticoagulant therapy. Comparatively recently, the re-quirement for an initial course of heparin in addition to
460S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Table 1—Question Definition and Eligibility Criteria (Section: Introduction)
Section Population Intervention or Exposure Outcome Methodology
1.1 Initial treatment ofacute DVT of the leg
IV UFH or LMWH, fondaparinux, and VKA (directcomparison of any of these treatments or theircombinations with a shorter or no treatment )
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
1.2 Initial treatment ofacute DVT of the leg
IV UFH; comparison of different regimens of IVUFH
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
1.3 Initial treatment ofacute DVT of the leg
SC UFH vs IV UFH Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
1.4 Initial treatment ofacute DVT of the leg
LMWH vs IV UFH, SC UFH, and comparison ofdifferent regimens of SC LMWH
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
1.5 Initial treatment ofacute DVT of the leg
SC UFH vs SC LMWH Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
1.7 Initial treatment ofacute DVT of the leg
New antithrombotic agents Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
1.6 Initial treatment ofacute DVT of the leg
Fondaparinux vs UFH or LMWH Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
1.9 Initial treatment ofacute DVT of the leg
CDT vs placebo or systemically administeredthrombolysis
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs and cohortstudies
1.10 Initial treatment ofacute DVT of the leg
Systemically administered thrombolysis vsanticoagulant therapy alone
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs and cohortstudies
1.11 Initial treatment ofacute DVT of the leg
Percutaneous venous thrombectomy vs otherendovascular techniques or anticoagulant therapyalone
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs and cohortstudies
1.12 Initial treatment ofacute DVT of the leg
Operative venous thrombectomy vs any other modeof treatment
Recurrent DVT and PE, totalmortality, QOL, and PTS
RCTs and cohortstudies
1.13 Initial treatment ofacute DVT of the leg
Vena caval filter insertion vs no venal caval filter Recurrent DVT and PE, totalmortality, QOL, and PTS
RCTs and cohortstudies
1.14 Initial treatment ofacute DVT of the leg
Immobilization vs active mobilization Recurrent DVT and PE, totalmortality, QOL, and PTS
RCTs and cohortstudies
2.1 Long-term treatment ofacute DVT of the leg
Comparison of different durations of VKA therapy Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
2.2 Long-term treatment ofacute DVT of the leg
Comparison of intensities of VKA therapy Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
2.3 Long-term treatment ofacute DVT of the leg
SC UFH vs VKA Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
2.4 Long-term treatment ofacute DVT of the leg
LMWH vs VKA Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
2.5 Long-term treatment ofacute DVT of the leg
New antithrombotic agents (eg, ximelagatran,idraparinux) vs no treatment or otheranticoagulants
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
2.6 Treatment ofasymptomatic DVT
Treatment with any anticoagulant therapy vs notreatment
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs and cohortstudies
3.1 Prophylaxis for PTS Compression stockings vs no stockings Symptomatic PTS RCTs3.2 Treatment of PTS Physical measures vs no intervention in patients
without leg ulcersSymptomatic relief, QOL and
ulcerationRCTs and cohort
studies3.3 Treatment of PTS Physical measures vs no intervention in patients
with leg ulcersSymptomatic relief, ulcer
healing, QOL, and ulcerationRCTs and cohort
studies3.4 Treatment of PTS Hyperbaric oxygen vs no hyperbaric oxygen in
patients with leg ulcersSymptomatic relief, ulcer
healing, QOL, and ulcerationRCTs and cohort
studies
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 461S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Table 1—Continued
Section Population Intervention or Exposure Outcome Methodology
3.5TC Treatment of PTS Drug therapies vs control in patients with leg ulcers Symptomatic relief, QOL, andulceration
RCTs and cohortstudies
4.1 Initial treatment ofacute PE
IV UFH, LMWH, fondaparinux, and/or VKA vs noanticoagulation; comparisons among these agents,and of different regimens of the same agent
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and CTPH
RCTs
4.2 Initial treatment ofacute PE
New antithrombotic agent (eg, ximelagatran,idraparinux) compared to no treatment orconventional therapy
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and CTPH
RCTs and cohortstudies
4.3 Initial treatment ofacute PE
Systemically and locally administered thrombolytictherapy compared to anticoagulant therapy alone,or comparisons of different thrombolytic agents ordifferent regimens of the same agent
Recurrent DVT and PE, totalmortality, QOL, and CTPH
RCTs and cohortstudies
4.4 Initial treatment ofacute PE
Catheter extraction or fragmentation vs no suchtherapy
Recurrent DVT and PE, totalmortality, QOL, and CTPH
RCTs and cohortstudies
4.5 Initial treatment ofacute PE
Pulmonary embolectomy vs no such surgery Recurrent DVT and PE, totalmortality, QOL, and CTPH
RCTs and cohortstudies
4.6 Initial treatment ofacute PE
Vena caval filter insertion vs no vena caval filter Recurrent DVT and PE, totalmortality, QOL, and CTPH
RCTs and cohortstudies
5.1 Long-term treatment ofacute PE
Comparison of different durations of VKA therapy Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
5.2 Long-term treatment ofacute PE
LMWH vs VKA therapy Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
5.3 Long-term treatment ofacute PE
New antithrombotic agents (eg, ximelagatran,idraparinux) compared to no treatment orconventional therapy
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs
5.4 Treatment ofasymptomatic PE
Treatment with any anticoagulant therapy vs notreatment
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs and cohortstudies
6.1 CTPH Pulmonary thrombo endarterectomy, vasodilatorsand/or vena caval filter vs not using theseinterventions
Mortality, recurrent DVT andPE, and QOL
RCTs and cohortstudies
7.1 Treatment of infusionthrombophlebitis
VKA, UFH, LMWH, NSAIDs, aspirin, vs no suchtreatment, each other, or different durations orregimens of the same agent
Extension of thrombus,symptomatic relief,symptomatic DVT and PE,major bleeding
RCTs and cohortstudies
7.2 Treatment of SVT VKA, UFH, LMWH, NSAIDs, aspirin, vs no suchtreatment, each other, or different durations orregimens of the same agent
Extension of thrombus,symptomatic relief,symptomatic DVT and PE,major bleeding
RCTs and cohortstudies
8.1 Initial treatment ofacute UEDVT
IV UFH or LMWH compared to placebo or eachother
Recurrent DVT and PE, majorbleeding, total mortality, andPTS of the arm
RCTs and cohortstudies
8.2 Initial treatment ofacute UEDVT
Thrombolytic therapy compared to no thrombolytictherapy
Recurrent DVT and PE, majorbleeding, total mortality, andPTS of the arm
RCTs and cohortstudies
8.3 Initial treatment ofacute UEDVT
Catheter extraction, surgical thrombectomy,transluminal angioplasty, stent placement, stagedapproach of lysis followed by interventional orsurgical procedure, SVC filter insertion, comparedwith no interventions
Recurrent DVT and PE, majorbleeding, total mortality, andPTS of the arm
RCTs and cohortstudies
8.4 Long-term treatment ofacute UEDVT
VKA, UFH, LMWH or fondaparinux; comparisonsof different durations or different agents
Recurrent DVT and PE, majorbleeding, total mortality,QOL, and PTS
RCTs and cohortstudies
8.5 Prevention of PTS ofthe arm
Compression glove or elastic bandages vs nocompression therapy
Symptomatic PTS RCTs and cohortstudies
8.6 Treatment of PTS of thearm
Compression glove or elastic bandages vs nocompression therapy
Symptomatic relief, QOL RCTs and cohortstudies
462S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
VKA, as compared to starting treatment with VKAtherapy alone, was established in a randomized con-trolled study5 that reported a threefold-higher rate ofrecurrent VTE in patients who received VKA only.Patients with DVT should be treated with anticoagu-lants as soon as the diagnosis is confirmed by objectivetesting. If the clinical suspicion is high, or if there is adelay before diagnostic testing can be performed,treatment should be started before such testing. Fiveoptions are available for the initial treatment of DVT:(1) low-molecular-weight heparin (LMWH), adminis-tered subcutaneous (SC), without monitoring; (2) IVunfractionated heparin (UFH), with monitoring; (3) SCUFH, with monitoring (4); weight-based SC UFH,without monitoring; and (5) SC fondaparinux, withoutmonitoring.
In relationship to the duration of initial heparintherapy, two randomized clinical trial (RCTs)6,7 inpatients with proximal DVT reported that IV UFHadministered for 5 to 7 days is as effective as UFHadministered for 10 to 14 days, providing that it isfollowed by adequate long-term anticoagulant therapy.The efficacy of this therapeutic approach is supportedby subsequent studies that showed acceptable rates ofrecurrent VTE during 3 months of VKA therapy after 5to7 days of heparin. Shortening the duration of initialheparin therapy from approximately 10 to 5 days isexpected to have the added advantage of reducing therisk of heparin-induced thrombocytopenia. The cur-rently recommended approach is to start both heparinand VKA at the time of diagnosis, and to discontinueheparin after 5 days provided the international normal-ized ratio (INR) is � 2.0 for at least 24 h.
Warfarin is generally started at a dose of 2.5 to10 mg. Two trials9,10 performed in hospitalizedpatients showed that starting warfarin at a dose of5 mg, compared to 10 mg, is associated with lessexcessive anticoagulation (see also chapter byAnsell et al8 in this supplement). A similar study11
in outpatients failed to demonstrate an advantageto starting warfarin at a dose of 5 mg comparedwith 10 mg. Observational studies8,12 have shownthat lower VKA maintenance doses are required inolder patients, women, and those with impairednutrition and vitamin K deficiency. Taken to-gether, these data suggest that warfarin can usuallybe started at a dose of 10 mg in younger (eg, � 60years), otherwise healthy outpatients, and at a doseof 5 mg in older patients and in those who arehospitalized. Subsequent doses should be adjustedto maintain the INR at a target of 2.5 (range 2.0 to3.0) [see Section 2.2].
Recommendations
1.1.1. For patients with objectively confirmedDVT, we recommend short-term treatment
with SC LMWH (Grade 1A), IV UFH (Grade 1A),monitored SC UFH (Grade 1A), fixed-dose SCUFH (Grade 1A), or SC fondaparinux (Grade 1A)rather than no such short-term treatment.1.1.2. For patients with a high clinical suspicionof DVT, we recommend treatment with antico-agulants while awaiting the outcome of diagnos-tic tests (Grade 1C).1.1.3. In patients with acute DVT, we recom-mend initial treatment with LMWH, UFH, orfondaparinux for at least 5 days and until theINR is > 2.0 for 24 h (Grade 1C).1.1.4. In patients with acute DVT, we recommendinitiation of VKA together with LMWH, UFH, orfondaparinux on the first treatment day ratherthan delayed initiation of VKA (Grade 1A).
1.2. IV UFH for the Initial Treatment of DVT
Heparin was initially administered by intermittentIV boluses, but this practice was replaced by contin-uous IV infusion, which was shown to be associatedwith a lower risk of bleeding.13 Initially, continuousIV infusions of UFH were administered at a startingdose of 1,000 U/h. A prospective observationalstudy14 showed that adjustment of the initial infusionrate of 1,000 U/h to achieve an activated partialthromboplastin time (APTT) ratio � 1.5 improvedefficacy. Such adjustment also resulted in patientsreceiving a mean UFH dose of adpproximately 1,300U/h, rather than the initial infusion dose of 1,000U/h,and the higher initial infusion rate was adopted inclinical practice.15 Adjustment of initial heparindose in proportion to body weight has also beenshown to be of value.8,16,17 When patients aretreated with an initial heparin infusion of at least1,250 U/h (corresponding to 30,000 U/d), or 18U/kg/h, it is uncertain if adjustment of heparin dosein response to the APTT or heparin levels im-proves efficacy or safety.18 –21 However, as allstudies that have used continuous IV UFH fortreatment of thrombosis have adjusted UFH dosein response to coagulation monitoring, this prac-tice is standard and uniformly recommended.Single randomized trials support the following: (1)use of a weight-adjusted initial infusion dose ofUFH in preference to starting with an infusiondose of 1,000 U/h17; and (2) that it is not necessaryto increase UFH infusion dose � 1,667 U/h (cor-responding to 40,000 U/d) if the anti-factor Xaheparin level is at least 0.35 U/mL even if theAPTT ratio is below the therapeutic range.22
The starting dose of IV UFH for the treatment ofDVT is either of the following: (1) a bolus dose of 5,000U, followed by a continuous infusion of at least 30,000U for the first 24 h; or (2) a weight-adjusted regimen of
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 463S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
a 80 U/kg bolus, followed by 18 U/kg/h. With both ofthese regimens, the infused dose of UFH should beadjusted using a standard nomogram to rapidly reach,and maintain, the APTT at levels that correspond totherapeutic heparin levels.8,15,17 As noted in the pre-ceding section, the requirement for an initial course ofheparin was confirmed in a randomized controlledstudy5 that reported a threefold-higher rate of recur-rent VTE in patients who received VKA only.
Recommendation
1.2.1. In patients with acute DVT, if IV UFH ischosen, we recommend that after an initial IVbolus (80 U/kg or 5,000 U), it be administeredby continuous infusion (initially at a dose of 18U/kg/h or 1,300 U/h), with dose adjustment toachieve and maintain an APTT prolongationthat corresponds to plasma heparin levels of 0.3to 0.7 IU/mL anti-Xa activity by the amidolyticassay rather than administration as IV bolusesthroughout treatment, or administration with-out coagulation monitoring (Grade 1C).
1.3 SC UFH Compared With IV Heparin for theInitial Treatment of DVT
UFH can be administered SC twice daily as analternative to continuous IV infusion for the initialtreatment of DVT. The relative value of IV and SCadministration of UFH has been evaluated in eightclinical studies that included a total of 972 patients, andwere reviewed in a metaanalysis.23 SC UFH adminis-tered twice daily appeared to be more effective (rela-tive risk [RR] of extension or recurrence of VTE, 0.62;95% confidence interval [CI], 0.39 to 0.98), and at leastas safe (RR of major bleeding, 0.79; 95% CI, 0.42 to1.48) as IV UFH, provided an adequate starting dose ofSC UFH was administered. The usual regimen in thesestudies included an initial IV bolus of approximately5,000 U followed by an SC dose of approximately17,500 U bid on the first day, with subsequent adjust-ment to achieve a 1.5 to 2.5 prolongation of the APTTdrawn 6 h after the morning dose. More recently, SCUFH, with24 and without25 dose adjustment in re-sponse to APTT measurements, has been comparedwith LMWH (see Section 1.5).
Recommendations
1.3.1. In patients with acute DVT, if monitoredSC UFH is chosen, we recommend an initialdose of 17,500 U, or a weight-adjusted dose ofapproximately 250 U/kg bid, with dose adjust-ment to achieve and maintain an APTT prolon-gation that corresponds to plasma heparin lev-els of 0.3 to 0.7 IU/mL anti-Xa activity whenmeasured 6 h after injection rather than start-
ing with a smaller initial dose (see also Section1.5) [Grade 1C].1.3.2. In patients with acute DVT, if fixed-dose,unmonitored SC UFH is chosen, we recommendan initial dose of 333 U/Kg followed by a twice-daily dose of 250 U/kg rather than non–weight-based dosing (see also Section 1.5) [Grade 1C].
1.4 LMWH for the Initial Treatment of DVT
LMWHs have more predictable pharmacokineticsand greater bioavailability than UFH.8 Due to thesepharmacologic features, body weight-adjusted doses ofLMWH can be administered SC once or twice dailywithout laboratory monitoring in the majority of pa-tients. However, in certain clinical situations, such assevere renal failure26 or pregnancy (see chapter byBates and colleagues in this supplement27), LMWHdose adjustment may be required using anti-Xa heparinlevels. The usual time to perform the anti-Xa assay is4 h after an injection, when heparin levels are expectedto be at their highest. A target range of 0.6 to 1.0IU/mL is suggested for twice-daily administration, anda target range of 1.0 to 2.0 IU/mL is suggested foronce-daily administration, although neither recommen-dation is firmly founded.8
A large number of well-designed studies28–44 havecompared the efficacy and safety of body weight-adjusted LMWH, administered SC without monitor-ing, with IV UFH administered with monitoring andsubsequent dose adjustment. The results of these stud-ies have been combined in a number of recent meta-analyses.45–47 The most recent such analysis included17 studies28–44,48 in which UFH was administered IV(3,614 patients) and 3 older studies48–50 in which UFHwas administered SC (206 patients).47 LMWH wasassociated with fewer thrombotic complications (3.6%vs 5.4%; odds ratio [OR], 0.68; 95% CI, 0.55 to 0.84),less major bleeding (1.2% vs 2.0%; OR, 0.57; 95% CI,0.39 to 0.83), and fewer deaths (4.5% vs 6.0%; OR,0.76; 95% CI, 0.62 to 0.92).47 The mortality advantagewith LMWH compared to UFH appeared to be con-fined to those with (OR, 0.53; 95% CI, 0.33 to 0.85)rather than without (OR, 0.97; 95% CI, 0.61 to 1.56)cancer.47
Direct Comparisons Among LMWH Regimens forInitial Treatment of VTE
Once-daily and twice-daily administration of thesame LMWH have been directly compared in sixstudies28,39,51–54 (the same total daily dose of LMWHhas not always been compared within studies). Ametaanalysis55 of five of these studies39,51–54 that hadunconfounded comparisons between once- and twice-daily administration found no difference in recurrent
464S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
VTE (3 months: OR, 0.85; 95% CI, 0.48 to 1.49), majorbleeding (at 10 days: OR, 1.2; 95% CI, 0.4 to 3.2), ormortality (3 months: OR, 1.05; 95% CI, 0.53 to 2.09).Outpatient and inpatient administration of LMWH(three preparations were used) were compared in asingle study56 of 201 patients: one recurrent VTE andtwo major bleeds occurred in the inpatient group, andtwo recurrent VTEs and two major bleeds occurred inthe outpatient group.
Dalteparin and tinzaparin, each administered oncedaily, have been compared for outpatient treatmentof VTE in a study57 of 497 patients. There was noapparent difference in recurrent VTE at 3 months(4.5% vs 5.9%; RR, 0.91; 95% CI, 0.38 to 2.2), majorbleeding at 7 days (0.4% vs 1.2%; RR, 0.34; 95% CI,0.04 to 3.26), or death at 3 months (4.8% vs 5.5%;RR, 0.0.87; 95% CI, 0.41 to 1.84). Indirect compar-isons across studies also support that there is similarefficacy and safety with the following: (1) once- andtwice-daily administration, (2) outpatient and inpa-tient administration, and (3) use of different prepa-rations of LMWH.45–47
Recommendations
1.4.1. In patients with acute DVT, we recom-mend initial treatment with LMWH SC once ortwice daily, as an outpatient if possible (Grade1C), or as an inpatient if necessary (Grade 1A),rather than treatment with IV UFH.1.4.2. In patients with acute DVT treated withLMWH, we recommend against routine monitoringwith anti-factor Xa level measurements (Grade 1A).1.4.3. In patients with acute DVT and severe renalfailure, we suggest UFH over LMWH (Grade 2C).
1.5 SC UFH Compared With SC LMWH for theInitial Treatment of DVT
Four randomized trials24,25,50,58 that included a totalof 1,645 patients have compared SC UFH with SCLMWH (Table 2). Two of these trials50,58 were small(total of 217 patients) and were performed � 15 yearsago, and two were large studies24,25 (total of 1,428patients) and were recently performed. In the Galileistudy,24 UFH was administered as an initial IV bolusfollowed by twice-daily SC injections of 12,500, 15,000,or 17,500 U initially, depending on the patient’s weight;subsequent UFH dosing was adjusted in response toAPTT measurements. There was no difference inrecurrent VTE, major bleeding, or deaths during fol-low-up (Table 2). The upper 95% CI on the differenceindicated that, compared with LMWH, monitored SCUFH was unlikely to be associated with an absoluteincrease of recurrent VTE of � 3.1% or major bleedingof � 1.7% at 3 months24 (judged Grade 1B evidencefor noninferiority). In the FIDO study, 25 UFH was
administered at an initial SC dose of 333 U/kg (no IVbolus), followed by a fixed SC dose of 250 U/kg bid;subsequent UFH dosing was kept constant, withoutcoagulation monitoring. There was no difference inrecurrent VTE, major bleeding, or death during fol-low-up (Table 2). The upper 95% CI on the differenceindicated that, compared with LMWH, unmonitored,fixed-dose, SC UFH was unlikely to be associated withan absolute increase of recurrent VTE of � 3.3% ormajor bleeding of � 0.8% at 3 months25 (judged Grade1B evidence for noninferiority).
1.6 Fondaparinux Compared With LMWH for theInitial Treatment of DVT
The synthetic pentasaccharide fondaparinux hasbeen evaluated for short-term treatment of DVT andPE (see Section 4.1) in the Matisse studies.59,60 Inthe Matisse DVT trial,59 2,205 patients were treatedwith a once-daily SC dose of fondaparinux (7.5 mg if50 to 100 kg; 5.0 mg if � 50 kg; 10 mg if � 100 kg)or twice-daily SC LMWH (enoxaparin 1 mg/kg) forat least 5 days using a blinded design. With fondapa-rinux vs LMWH, there was no difference in recur-rent VTE at 3 months (3.9% vs 4.1%; difference,� 0.15%; 95% CI, – 1.8 to 1.5%]), major bleedingduring treatment (1.1% vs 1.2%; difference, – 0.1%;95% CI, – 1.0 to 0.8%), or death at 3 months (3.8%vs 3.0%; difference, 0.8%; 95% CI, – 0.8 to 2.3%)59
(judged Grade 1A for noninferiority).
1.7 New Antithrombotic Agents for the Short-termTreatment of DVT
A comparison of 6 months of ximelagatran61 (sincewithdrawn because of hepatic toxicity) with standardtherapy in patients with DVT, and a comparison of 3months or 6 months of idraparinux62 with standardtherapy, are described in Section 2.5.
1.8 Treatment Strategies of Thrombus Removal forAcute DVT
Treatments that actively remove thrombus in pa-tients with acute DVT have the potential to reduceacute symptoms and the risk for PTS. Thrombusremoval directly reverses venous obstruction and canrestore function in valves that were immobilized bythrombus. Indirectly, early removal of thrombus ob-struction can prevent late development of venous val-vular incompetence secondary to venous dilatation indistal venous segments that were never involved withthrombosis.63–71 Randomized trials,72,73 patient regis-tries,74,75 and studies of other designs76–81 support thatsuccessful thrombus removal, using a variety of tech-niques, can improve patient outcomes (see follow-ing).79,81–83 It is also possible that thrombus removal
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 465S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
and relief of venous obstruction may reduce the risk ofrecurrent VTE. Patients with iliofemoral DVT are thesubset of patients with the largest thrombus burdenand highest risk for postthrombotic morbidity, with upto 75% having chronic painful edema and 40% havingvenous claudication when treated with anticoagulanttherapy alone.84–87
1.9 Catheter-Directed Thrombolysis for Acute DVT
The rationale for catheter-directed thrombolysis(CDT), which was established in patients with acutearterial occlusion,88 is that rapid lysis is achieved withlower doses of thrombolytic therapy, resulting in fewerserious bleeding complications. A single-center trial72
Table 2—Comparison of SC LMWH and SC UFH for Short-term Treatment of VTE: Clinical Description andResults (Section 1.5)*
Author/yr(Acronym) Interventions
PatientsAnalyzed†
Recurrent DVTor PE Major Bleeding Total Mortality Comments
Lopaciuk et al50/1992
UFH at 5,000 U IV followedby 250 U/kg SC bidinitially and adjusted toAPTT for 10 d
Fraxiparine at 97 IU/kg SCbid for 10 d
72/75
74/74
1/72 (1.4)
0/74RR, 3.1 (95%CI, 0.1–7.5)
1/72 (1.4)
0/74;RR, 3.1 (95%CI, 0.1–7.5)
3/72 (4.2)
0/74RR, 7.2 (95%CI, 0.4–137)
Population: femoralDVT in 81% andpopliteal or moredistal DVT in19%
Primary outcomewas repeatvenography
Faivre et al58/1988
UFH at 5,000 U IV followedby 250 U/kg SC bid andadjusted to APTT for 10 d
CY222 at 2,000 IU IVfollowed by 150 IU/kg SCbid for 10 d
29/35
30/33
1/35
1/33RR, 0.9 (95%CI, 0.1–14.5)
3/35
0/33RR, 6.6 (95%CI, 0.3–123)
1/35
0/33RR, 2.8 (95%CI, 0.1–67)
Population:DVT (proportionof proximal anddistal not reported)
Primary outcome wasrepeat venography
Prandoni et al24/2004 (Galilei)
UFH IV (� 50 kg, 4,000 U;50 to 70 kg, 5,000 U;� 70 kg, 6,000 U) followedby SC bid doses (initially:� 50 kg, 12,500 U; 50 to70 kg, 15,000 U; � 70 kg,17,500 U) adjusted toAPTT for approximately5 d
Nadroparin at 85 IU/kg SCbid for approximately 6.5 d
360/360
360/360
15/360 (4.2)
14/360 (3.9)RR, 1.1 (95%CI, 0.5–2.2)
5/360 (1.4)
7/360 (1.9)RR, 0.7 (95%CI, 0.2–2.2)
12/360 (3.3)
12/360 (3.3)RR, 1.0; 95%CI, 0.5–2.2)
Population:proximal DVT in65%, distal DVTin 18%, PE in17%
Kearon et al25/2006 (FIDO)
UFH at 333 U/kg SCfollowed by 250 U/kg SCbid (no adjustment) for6.3 d
Dalteparin (n � 261) orenoxaparin (n � 91) at 100IU/kg SC bid for 7.1 d
345/355
352/353
13/345 (3.8)
12/352 (3.4)RR, 1.1 (95%CI, 0.5–2.3)
6/348 (1.7)
12/352 (3.4)RR, 0.5 (95%CI, 0.2–1.3)
18/348 (5.2)
22/352 (6.3)RR, 0.8 (95%CI, 0.4–1.5)
Population:proximal DVTin 77%,asymptomatic ordistal DVT in4%, PE in 19%
70% of patientswere treatedentirely as anoutpatient (76%of DVT and 39%of PE)
Postrandomizationexclusions in 10UFH patients and1 LMWH patient
*Data are presented as No. of patients/total patients (%) unless otherwise indicated. The methodologic quality description portion of this tablecan be found in the online version of this article as a data supplement.†Follow-up was for 3 mo except for the study by Faivre et al,58 for which it was 10 days.
466S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
randomized 35 patients with acute iliofemoral DVTto catheter-directed, pulse-spray, intrathrombusstreptokinase or to anticoagulation alone. Six-monthpatency was improved in the thrombolysis group(72% vs 12%, p � 0.001), as was preservation ofnormal venous valve function (89% vs 59%,p � 0.04); postthrombotic symptoms were not eval-uated. In the 19 studies72,75,76,78,81,89–102 of heteroge-neous designs listed in Table 3, significant lysis wasobserved in 79% of the 945 limbs treated with CDT.In an evaluation of 98 patients with iliofemoral DVTtreated with CDT (n � 68) or anticoagulation(n � 30), quality of life (QOL) was better in patientstreated with CDT and correlated with the degree oflysis.79
In the National Venous Registry, patientstreated with short-term thrombosis (� 10 days)had better outcomes than those with older clot andcorrection of underlying venous lesions after suc-cessful thrombolysis, usually with intravascularstenting, appeared to be beneficial.75 Althoughbleeding complications are the major concern withlytic therapy, reports published during the past 6have shown bleeding complication rates less thanhalf (ie, average of 4.8%; Table 4) the rates inearlier reports, which is likely due to more appro-priate patient selection and experience with thetechnique. Data are not available for comparingone plasminogen activator to another or a partic-ular catheter or catheter-based technique to oth-ers, and there are inadequate data to assess thebenefit or risk of inferior vena cava (IVC) filters inthis setting (recommended by manufacturer withsome endovascular devices and techniqueswhereas not with others).
The addition of mechanical thrombus fragmentation,with or without aspiration, during CDT is commonlyused as part of the procedure (collectively referred to aspharmacomechanical thrombolysis). While random-ized comparisons of CDT alone vs pharmacomechani-cal thrombolysis are not available, retrospective analy-ses95,96 suggest they are associated with similar rates ofsuccessful thrombolysis (70 to 80%) and of majorbleeding (5 to 8%); however, pharmacomechanicalthrombolysis is associated with shorter treatment times,shorter ICU and hospital stays, and reduced costs. Norandomized trial has compared CDT with systemicthrombolysis (see following); however, a single-center,retrospective study81 suggests that CDT achieves betterlysis (50% vs 31%) and preservation of valve function(44% vs 13%).
Recommendations
1.9.1. In selected patients with extensive acuteproximal DVT (eg, iliofemoral DVT, symptoms
for < 14 days, good functional status, life ex-pectancy > 1 year) who have a low risk ofbleeding, we suggest that CDT may be used toreduce acute symptoms and postthromboticmorbidity if appropriate expertise and re-sources are available (Grade 2B).1.9.2. After successful CDT in patients withacute DVT, we suggest correction of underlyingvenous lesions using balloon angioplasty and stents(Grade 2C).1.9.3. We suggest pharmacomechanical throm-bolysis (eg, with inclusion of thrombus fragmen-tation and/or aspiration) in preference to CDTalone to shorten treatment time if appropriateexpertise and resources are available (Grade 2C).1.9.4. After successful CDT in patients with acuteDVT, we recommend the same intensity andduration of anticoagulant therapy as for compa-rable patients who do not undergo CDT (Grade1C).
1.10 Systemic Thrombolytic Therapy for Acute DVT
In 15 trials81,103–120 that randomized a total of 811patients with acute DVT to systemic thrombolytictherapy or to anticoagulant therapy alone, as assessedby early repeat phlebography, systemic thrombolytictherapy achieved a higher frequency of complete orsignificant lysis (54% vs 4%) or partial lysis (18% vs14%) [Table 4]. Three of the randomized trialsreported postthrombotic symptoms after follow-upof 1.0 year,115 1.6 years,107 and 6.5 years103 (Table 4).A Cochrane analysis121 that included two of thesestudies103,115 and a total of 101 patients suggests thatthrombolytic therapy reduced postthrombotic mor-bidity (RR, 0.7; 95% CI, 0.5 to 0.9) and leg ulceration(RR, 0.5; 95% CI, 0.1 to 2.4).
In the same Cochrane analysis,121 which in-cluded a total of 12 studies and 701 patients(number of included studies and patients differedwith the outcome assessed), the following esti-mates were obtained with thrombolytic therapy(various agents, mostly administered systemically)vs anticoagulation alone: early PE: RR, 1.2 (95%CI, 0.3 to 4.4; 382 patients in 5 trials); laterecurrent DVT: RR, 1.4 (95% CI, 0.4 to 5.4; 35patients in 1 trial); and early significant or majorbleeding: RR, 1.7 (95% CI, 1.04 to 2.9; 668patients in 10 trials); intracranial bleeding: RR, 1.7(95% CI, 0.2 to 14; 701 patients in 5 trials). Therehave been no direct comparisons of differentthrombolytic agents; however, prolonged infusionsof streptokinase that were used predominantly inthe earlier studies appear to be associated withhigher bleeding rates than other regimens(Table 4).
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 467S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le3—
Cat
hete
r-D
irec
ted
Thr
omb
olys
isfo
rA
cute
DV
T:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
1.9)
*
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Sem
baan
dD
ake98
/19
94Pr
ospe
ctiv
ere
gist
ry21
patie
nts
(27
limbs
)w
ithili
ofem
oral
DV
T�
14d
(n�
20)
or�
14d
(n�
7)du
ratio
n
4.9
mill
ion
Uof
urok
inas
e(m
ean)
infu
sed
over
30h
(mea
n),f
ollo
wed
byhe
pari
nan
dth
enw
arfa
rin
for
8–12
wk
Adj
unct
ive
ther
apy:
limbs
w/
resi
dual
sten
oses
�50
%re
ceiv
edan
giop
last
y(n
�2)
orst
entin
g(n
�14
)
Clo
tly
sis,
com
plic
atio
ns3
mo
Sign
ifica
ntly
sis:
18/2
5(7
2%)�
25/2
7lim
bstr
eate
dw
ithC
DT
;2co
uld
not
becr
osse
dw
ithgu
ide
wir
e�Pa
rtia
llys
is:5
/25
(20%
)N
oly
sis:
2/25
(8%
)C
ompl
icat
ions
:one
smal
lhem
atom
aat
punc
ture
site,
noin
terv
entio
n/tr
ansf
usio
nSe
mba
and
Dak
e99/
1996
Cas
ese
ries
32pa
tient
s(4
1lim
bs)
with
iliof
emor
alD
VT
�14
d(n
�25
)or
�14
d(n
�16
)du
ratio
n
3.5
mill
ion
Uof
urok
inas
e(m
ean)
infu
sed
over
30h
(mea
n),f
ollo
wed
byw
arfa
rin
with
INR
2.0–
3.0
for
�6
mo
Adj
unct
ive
ther
apy:
limbs
with
resi
dual
sten
oses
of�
50%
rece
ived
angi
opla
sty
(n�
2)or
angi
o/st
entin
g(n
�20
)
Clo
tly
sis,
com
plic
atio
ns6
mo
Sign
ifica
ntly
sis:
21/3
2(6
6%)
�32
limbs
trea
ted
with
CD
T;4
coul
dno
tbe
cros
sed
with
guid
ewir
e,5
trea
ted
with
angi
opla
sty
and
sten
tal
one�
Part
iall
ysis
:9/3
2(2
8%)
No
lysi
s:2/
32(6
%)
Com
plic
atio
ns:0
Ver
haeg
heet
al10
2 /19
97Pr
ospe
ctiv
est
udy
24pa
tient
sw
ithili
ofem
oral
DV
T�
14d
(n�
16)
or�
14d
(n�
8)du
ratio
n
3m
g/h
rt-P
A(m
ean,
86m
g)in
fuse
dw
ith1,
000
U/h
ofIV
hepa
rin,
follo
wed
byhe
pari
n,ad
just
edto
APT
TA
djun
ctiv
eth
erap
y:hy
drod
ynam
icth
rom
bect
omy
(n�
3)an
dst
ents
(n�
9)
Clo
tly
sis,
blee
ding
13m
o(m
ean)
Sign
ifica
ntly
sis:
19/2
4(7
9%)
Part
iall
ysis
:5/2
4(2
1%)
Ble
edin
g:6/
24(2
5%)
Pate
ncy
at3
mo,
84%
Pate
ncy
at1
yr,7
8%B
jarn
ason
etal
76/
1997
Pros
pect
ive
regi
stry
77pa
tient
s(8
7lim
bs)
with
iliof
emor
alD
VT
�14
d(n
�69
)or
�14
d(n
�18
)dur
atio
n
2,00
0–2,
500
U/k
g/h
urok
inas
ein
fuse
dfo
r75
h(m
ean)
,with
5,00
0IU
bolu
she
pari
npl
usin
fusi
onad
just
edto
APT
TA
djun
ctiv
eth
erap
y:an
giop
last
y(5
2lim
bs),
sten
t(3
8lim
bs),
AV
F(1
5lim
bs),
surg
ical
thro
mbe
ctom
y(1
3lim
bs),
mec
hani
cal
thro
mbe
ctom
y(4
limbs
),su
rgic
alby
pass
(3lim
bs)
Clo
tly
sis,
PE,
blee
ding
1yr
Ear
lyre
sults
:Si
gnifi
cant
lysi
s:69
/87
(79%
)Il
iac
(63%
)F
emor
al(4
0%)
No
lysi
s:18
/87
(21%
)PE
:n�
1(1
%)
Ble
edin
g:M
ajor
:5/7
7(6
%)
Min
or:1
1/77
(14%
)Pa
tenc
yat
1yr
:Il
iac
(63%
)F
emor
al(4
0%)
Mew
isse
net
al75
/19
99(N
atio
nal
mul
tice
nter
regi
stry
)
Pros
pect
ive
mul
ticen
ter
regi
stry
287
patie
nts
(312
infu
sion
s)w
ithlo
wer
-lim
bD
VT
�10
d(n
�18
8)or
�10
d(n
�99
)du
ratio
n
7.8
mill
ion
Uof
urok
inas
e(m
ean)
infu
sed
for
53.4
h(m
ean)
in29
7lim
bsIn
6lim
bs,o
nly
syst
emic
infu
sion
(no
CD
T)
Adj
unct
ive
ther
apy:
sten
ts(1
04lim
bs),
syst
emic
infu
sion
(54
limbs
)
Clo
tly
sis,
PE,
blee
ding
,de
ath
1yr
Ear
lyre
sults
:50
–100
%ly
sis:2
58/3
12(8
3%)
�50
%ly
sis:5
4/31
2(1
7%)
PE:6
/473
(1%
)�ca
lcul
ated
from
tota
lNo.
ofpa
tient
sin
Veno
usR
egist
ry�
Ble
edin
g:54
/473
(11%
)�ca
lcul
ated
from
tota
lN
o.of
patie
nts
inVe
nous
Reg
istry
�D
eath
:2/4
73(�
1%)
�Cal
cula
ted
from
tota
lNo.
ofpa
tient
sin
Veno
usR
egist
ry�;
Pate
ncy
at1
yrIli
ac(6
4%)
Fem
oral
(47%
)C
omer
ota
and
Kag
an78
/200
0R
etro
spec
tive
stud
y54
patie
nts
(54
limbs
)w
ithili
ofem
oral
DV
T,a
vera
gedu
ratio
nof
leg
sym
ptom
sof
5.2
d
250,
000–
500,
000
Uof
urok
inas
ebo
lus
follo
wed
by25
0,00
0–30
0,00
0U
/hof
cont
inuo
usin
fusio
nfo
r30
h(m
ean)
in47
patie
nts;
allp
atie
nts
rece
ived
hepa
rinin
fusio
nat
500–
1,00
0U
/hor
4-to
8-m
gbo
lus
ofrt
-PA
follo
wed
by2–
4m
g/h
in7
patie
nts,
with
hepa
rinas
note
dab
ove
Adj
unct
ive
ther
apy:
surg
ical
thro
mbe
ctom
y(n
�5)
Clo
tly
sis,
com
plic
atio
nsN
DE
arly
resu
lts:
Sign
ifica
ntly
sis:
45/5
4(8
3%)
Ilia
c(7
8%)
Com
plic
atio
ns:
Maj
orbl
eed:
4/54
(7%
)H
emat
oma,
punc
ture
site
:8(1
5%)
Hem
atom
a,in
guin
al:1
(2%
)
468S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le3—
Con
tinu
ed
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Hor
neet
al92
/200
0Pr
ospe
ctiv
e,st
udy
10pa
tient
s(1
0lim
bs)
with
low
er-e
xtre
mity
DV
T�
14d
dura
tion
rt-P
Ado
seof
0.6
mg/
kgto
am
axim
umof
50m
g/kg
per
leg
infu
sed
via
daily
pulse
-spr
ayca
thet
erfo
rup
to4
dof
trea
tmen
t;he
parin
was
adju
sted
toa
prot
hrom
bin
time
of1.
5–2.
5�
base
line
Clo
tly
sis,
PE,
blee
ding
2–6
mo
Sign
ifica
ntly
sis:
9/10
(90%
)Pa
rtia
llys
is:1
/10
(10%
)PE
:2/1
0(2
0%)
Ble
edin
g:1/
10(1
0%)
Kas
iraj
anet
al94
/20
01R
etro
spec
tive
regi
stry
Nin
epa
tient
sw
ith�
90%
thro
mbu
sex
trac
tion
follo
win
gpe
rcut
aneo
usm
echa
nica
lthr
ombe
ctom
yfo
rili
ofem
oral
/IV
CD
VT
Uro
kina
se,r
t-PA
,or
rPA
for
mea
nof
20h
Com
plet
e,pa
rtia
l,no
lysi
s
9m
o(m
ean)
Com
plet
ely
sis:
7/9
(78%
)Pa
rtia
llys
is:1
/9(1
1%)
No
lysi
s:1/
9(1
1%)
Abu
Rah
ma
etal
89/
2001
Pros
pect
ive
stud
y51
patie
nts
(51
limbs
)w
ithili
ofem
oral
DV
Tgi
ven
choi
cebe
twee
nco
nven
tiona
lthe
rapy
(hep
arin
plus
war
fari
n)or
lysi
spl
usan
gio/
sten
t(if
need
ed);
lysi
sof
fere
don
lyto
patie
nts
with
DV
T�
14d
dura
tion
and
noco
ntra
indi
catio
ns
Ant
icoa
gula
tion:
33pa
tient
sad
min
ister
ed1,
000–
2,00
0U
/hof
hepa
rinin
fusio
nfo
r5–
7d
CD
T:18
patie
nts
adm
inist
ered
load
ing
dose
of4,
500
Uof
urok
inas
efo
llow
edby
4,50
0U
/kg/
hfo
r24
–48
h,or
4-to
8-m
gbo
lus
ofrt
-PA
follo
wed
by2
to4/
mg/
hin
fusio
nA
djun
ctiv
eth
erap
y:pa
tient
sw
ithre
sidua
lste
nosis
�50
%re
ceiv
edst
ents
(n�
10)
Clo
tly
sis,
PE,
blee
ding
Ant
icoa
gula
tion
for
6m
oC
DT
for
6m
o
Ant
icoa
gula
tion:
30-d
sign
ifica
ntly
sis:
1/33
(3%
)6-
mo
pate
ncy:
8/33
(24%
)B
leed
ing:
2/33
(6%
)PE
:2/3
3(6
%)
CD
T:
30-d
sign
ifica
ntly
sis:
15/1
8(8
3%)
6-m
opa
tenc
y:15
/18
(83%
)B
leed
ing:
2/18
(11%
)
Ved
anth
amet
al10
1 /20
02R
etro
spec
tive
stud
y20
patie
nts
(28
limbs
)w
ithsy
mpt
omat
iclo
wer
-ex
trem
ityD
VT
Intr
athr
ombu
sde
liver
yof
eith
erof
the
follo
win
g:(1
)ur
okin
ase,
mea
n16
6,00
0U
/h(7
limbs
)(2
)tP
Am
ean
1.74
mg/
h(7
limbs
)(3
)rP
Am
ean
0.89
U/h
(14
limbs
)A
djun
ctiv
eth
erap
y:m
echa
nica
lthr
ombe
ctom
yby
cath
eter
(28
proc
edur
es);
iliac
sten
ts(1
5pa
tient
s)
Proc
edur
alsu
cces
s(�
30%
resid
ual
sten
osis)
,maj
orbl
eedi
ng
Aft
erpr
oced
ure
Proc
edur
alsu
cces
s:23
/28
(82%
)M
ajor
blee
ding
:14%
Els
hara
wy
and
Elz
ayat
72/2
002
RC
T,s
ingl
ece
nter
35pa
tient
sw
ithD
VT
�10
ddu
ratio
nra
ndom
ized
toC
DT
oran
ticoa
gula
tion
alon
e
CD
T:1
8pa
tient
sre
ceiv
edap
prox
imat
ely
1m
illio
nU
ofst
rept
okin
ase
puls
esp
ray
for
1h,
follo
wed
by10
0,00
0U
/hof
stre
ptok
inas
ein
fusi
onun
tilco
mpl
ete
lysi
s,no
chan
gein
12h,
orco
mpl
icat
ion;
adju
nctiv
eth
erap
y:an
giop
last
y/st
ent
(n�
1)A
ntic
oagu
latio
n:17
patie
nts
rece
ived
5,00
0U
ofhe
pari
nbo
lus,
follo
wed
byhe
pari
nad
just
edto
APT
T
Clo
tly
sis,
PE,
blee
ding
1w
eek
and
6m
oC
DT
at1
wk
Com
plet
ely
sis:
11/1
8(6
1%)
No
lysi
s:0
(0%
)PE
:0B
leed
ing:
0A
ntic
oagu
latio
nat
1w
k:C
ompl
ete
lysi
s:0/
17(0
%)
No
lysi
s:17
/17
(100
%)
PE:1
/17
(6%
)B
leed
ing:
0C
DT
at6
mo:
Com
plet
ely
sis:
13/1
8(7
2%)
No
lysi
s:0
(0%
)A
ntic
oagu
latio
nat
6m
o:Si
gnifi
cant
lysi
s:2/
17(1
2%)
No
lysi
s:7/
17(4
1%)
Cas
tane
daet
al90
/20
02Pr
ospe
ctiv
est
udy
15pa
tient
sw
ithac
ute
orch
roni
cD
VT
oflo
wer
extr
emity
(n�
14)
orIV
C(n
�1)
16.5
U/h
(med
ian)
ofrt
-PA
infu
sed
over
29h
(med
ian)
with
hepa
rin
dose
sof
300–
400
U/h
Adj
unct
ive
ther
apy:
sten
ting
(n�
4);
angi
opla
sty/
sten
t(n
�6)
Clo
tly
sis,
PE,
blee
ding
Aft
erpr
oced
ure
Sign
ifica
ntly
sis:
15/1
5(1
00%
)PE
:0B
leed
ing:
0
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 469S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le3—
Con
tinu
ed
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Gru
nwal
dan
dH
ofm
ann91
/200
5R
etro
spec
tive
stud
y74
patie
nts
(82
limbs
)w
ithD
VT
ofup
per
(n�
23)
orlo
wer
(n�
59)
extr
emity
,with
dura
tion
of�
14d
(n�
74)
or�
14d
(n�
8)
Uro
kina
se:1
1.3
U/h
ofur
okin
ase
for
40.6
h(3
8lim
bs)
with
ther
apeu
tiche
pari
ndo
sing
tPA
:0.5
7m
g/h
tPA
for
30.8
h(3
2lim
bs)
with
subt
hera
peut
iche
pari
nrt
-PA
:0.7
4U
/hrt
-PA
for
24.3
h(1
2lim
bs)
with
subt
hera
peut
iche
pari
nA
djun
ctiv
eth
erap
y:m
echa
nica
lthr
ombo
lysi
s,an
giop
last
y,st
entin
g;ur
okin
ase
(n�
30),
tPA
(n�
24),
rt-P
A(n
�12
)
Clo
tly
sis,
PE,
blee
ding
Aft
erpr
oced
ure
Uro
kina
se:
Sign
ifica
ntly
sis:
27/3
871
%)
PE:0
Ble
edin
g:2/
38(5
%)
tPA
:Si
gnifi
cant
lysi
s:21
/32
(66%
)PE
:0B
leed
ing:
1/32
(3%
)rt
-PA
:Si
gnifi
cant
lysi
s:6/
12(5
0%)
PE:0
Ble
edin
g:1/
12(8
%)
Lai
hoet
al81
/200
4R
etro
spec
tive
stud
y32
patie
nts
with
iliof
emor
alD
VT
�14
din
dura
tion
rece
ived
eith
erca
thet
er-
dire
cted
(n�
16)
orsy
stem
ic(n
�16
)th
rom
boly
sis
CD
Ttr
eatm
ent:
73m
g(m
ean)
rt-P
Afo
r33
h(m
ean)
via
cath
eter
deliv
ery,
with
LM
WH
and
oral
antic
oagu
lant
s
Clo
tly
sis,
PE,
blee
ding
,va
lvul
arco
mpe
tenc
e
2–3
yrC
DT
trea
tmen
tSi
gnifi
cant
lysi
s:8/
16(5
0%)
PE:2
/16
(13%
)B
leed
ing:
2/16
(13%
)V
alvu
lar
com
pete
nce:
7/16
(44%
)A
nyde
epve
inin
com
pete
nce:
44%
Sille
sen
etal
100 /2
005
Ret
rosp
ectiv
est
udy
45pa
tient
sw
ithili
ofem
oral
DV
T�
14d
indu
ratio
n1
mg
rt-P
Ast
artin
gdo
sepl
us1,
000–
5,00
0U
ofU
FH
follo
wed
byco
ntin
uous
infu
sion
of1
mg
rt-P
Aan
d1,
000
Uof
UF
Hpe
rho
ur(n
�9)
10m
grt
-PA
pulse
spra
ypl
us1,
000–
5,00
0U
ofU
FH
for
initi
al15
–30
min
,fol
low
edby
cont
inuo
usin
fusio
nof
1m
grt
-PA
and
1,00
0U
UF
Hpe
rho
ur(n
�36
)A
djun
ctiv
eth
erap
y:an
giop
last
y/st
entin
g(n
�30
)
Clo
tly
sis,
PE,
blee
ding
,de
ath
24m
o(m
edia
n)Si
gnifi
cant
lysi
s:42
/45
(93%
)PE
:1/4
5(2
%)
Min
orbl
eedi
ng:4
(8%
)
Jack
son
etal
93/2
005
Ret
rosp
ectiv
est
udy
28pa
tient
sw
ithlo
wer
-ex
trem
ityD
VT
of�
14d
(n�
20)
or�
14d
indu
ratio
n(n
�4)
orre
curr
ent
DV
T(n
�4)
60,0
00–1
80,0
00U
/hur
okin
ase
infu
sed
over
24–4
8h
(n�
2)1–
2m
g/h
tPA
for
24–4
8h
(n�
16)
1–2
U/h
rt-P
Afo
r24
–48
h(n
�9)
Mec
hani
calt
hrom
bect
omy
only
(n�
1)A
djun
ctiv
eth
erap
y:m
echa
nica
lthr
ombe
ctom
y(n
�20
),st
entin
g(n
�12
)
Clo
tly
sis,
PE,
blee
ding
,de
ath
15.5
mo
Lys
is�
90%
:6/2
8(2
1%)
Lys
is80
–89%
:2/2
8(7
%)
Lys
is60
–79%
:2/2
8(7
%)
Lys
is�
60%
:11/
28(3
9%)
PE:0
Min
orbl
eedi
ng:2
/28
(7%
)Im
med
iate
pate
ncy:
92%
Lon
g-te
rmpa
tenc
y:80
%O
gaw
aet
al97
/200
5Pr
ospe
ctiv
e,st
udy
24pa
tient
sw
ithlo
wer
-ex
trem
ityD
VT
CD
T:2
40,0
00U
ofur
okin
ase
infu
sed
for
1h,
follo
wed
by2
dof
1-h
infu
sion
of12
0,00
0U
ofur
okin
ase
bid,
with
IVU
FH
tore
ach
APT
Ttim
era
tiofr
om1.
5–2.
0w
ithin
24h
(n�
10)
CD
Tpl
usIP
C/I
VC
:thr
ombo
lysi
spe
rfor
med
asin
CD
T-o
nly
grou
p;te
mpo
rary
IVC
filte
rpl
aced
inin
frar
enal
IVC
and
rem
oved
afte
rC
DT
;IPC
with
foot
-cal
fcy
cle
begu
naf
ter
urok
inas
ein
fusi
onan
dco
ntin
ued
24h/
dun
tilC
DT
stop
ped
(n�
14)
Clo
tly
sis,
PE,
blee
ding
CD
Tgr
oup:
22m
o;
CD
Tpl
usIP
Cgr
oup:
14m
o
CD
T:
100%
lysi
s:0/
10(5
0–99
%)
lysi
s:2/
10(2
0%)
�50
%ly
sis:
8/10
(80%
)PE
:0B
leed
ing:
0C
DT
plus
IPC
/IV
C10
0%ly
sis:
5/14
(36%
)50
–99%
lysi
s:6/
14(4
3%)
�50
%ly
sis:
3/14
(21%
)PE
:0B
leed
ing:
0
470S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le3—
Con
tinu
ed
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Kim
etal
95/2
006
Ret
rosp
ectiv
est
udy
37pa
tient
s(4
5lim
bs)
with
acut
e(�
14d)
iliof
emor
alD
VT
CD
T:6
.70
�5.
9m
illio
nU
ofur
okin
ase
(mea
n)in
fuse
dfo
rm
ean
of56
.5�
27.4
hin
26lim
bs(2
3pa
tient
s)C
DT
plus
phar
mac
omec
hani
cal:
lytic
trea
tmen
tpe
rfor
med
asde
scri
bed
inC
DT
grou
ppl
usA
ngio
Jet
thro
mbe
ctom
yde
vice
Clo
tly
sis,
blee
ding
,PE
,tr
eatm
ent
dura
tion,
cost
,re
curr
entD
VT
32m
oC
ompl
ete
lysi
s:C
DT
:21/
26(8
1%)
CD
Tpl
usPM
T:1
6/21
(84%
)M
ajor
blee
ding
:C
DT
:2/2
6(7
%)
CD
Tpl
usPM
T:1
/21
(5%
)PE
:C
DT
:1/2
6(4
%)
CD
Tpl
usPM
T:1
/21
(5%
)T
reat
men
tdu
ratio
n:C
DT
:57
hC
DT
plus
PMT
:30
hC
ost
(dru
gpl
usde
vice
):C
DT
:$10
,127
CD
Tpl
usPM
T:$
5,12
8R
ecur
rent
DV
T:
CD
T:4
/16
(25%
)C
DT
plus
PMT:
2/13
(15%
)L
inet
al96
/200
6R
etro
spec
tive
stud
y93
patie
nts
(98
proc
edur
es)
with
sym
ptom
atic
DV
TC
DT
:46
proc
edur
esus
ing
tPA
,rt-
PA,o
rur
okin
ase
PMT
:52
proc
edur
esus
ing
Ang
ioJe
trh
eoly
ticth
rom
bect
omy
syst
emw
ithtP
A,r
t-PA
,or
urok
inas
e
Clo
tly
sis,
No.
ofve
nogr
ams,
imm
edia
tecl
inic
alim
prov
emen
t,bl
eedi
ng,
ICU
/hos
pita
lst
ay,1
-yr
prim
ary
pate
ncy,
cost
1yr
Com
plet
e/pa
rtia
llys
is:
CD
T:3
2/46
(70%
)/14
/46
(30%
)C
DT
plus
PMT
:39/
52(7
5%)/1
3/52
(25%
)N
o.of
veno
gram
s:C
DT
:2.5
CD
Tpl
usPM
T:0
.4(p
�0.
001)
Imm
edia
tecl
inic
alim
prov
emen
t:C
DT
:33/
46(7
2%)
CD
Tpl
usPM
T:4
2/52
(81%
)B
leed
ing:
CD
T:2
/49
(4%
)C
DT
plus
PMT
:3/4
6(7
%)
ICU
stay
:C
DT
:2.4
dC
DT
plus
PMT
:0.6
dH
ospi
tals
tay:
CD
T:8
.4d
CD
Tpl
usPM
T:2
.4d
1-yr
prim
ary
pate
ncy:
CD
T:6
4%C
DT
plus
PMT
:68%
Cos
t:C
DT
:$85
,301
CD
Tpl
usPM
T:$
47,7
42
*ND
�no
tde
term
ined
.The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 471S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le4
—Sy
stem
icT
hrom
bol
ytic
The
rapy
for
Acu
teD
VT
:C
lini
cal
Des
crip
tion
and
Res
ult
s(S
ecti
on1.
9)*
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Bro
wse
etal
105 /
1968
RC
T,s
ingl
ece
nter
10pa
tient
sw
ithlo
wer
-ext
rem
ityD
VT
conf
irm
edby
phle
bogr
aphy
Lys
is:6
00,0
00U
ofst
rept
okin
ase
plus
100
mg
ofhy
droc
ortis
one
for
first
hour
,the
nco
ntin
ued
ever
y6
hfo
r3
d(n
�5)
Ant
icoa
gula
tion:
4-to
6-h
dose
sof
5,00
0U
hepa
rin
for
48h
follo
wed
byw
arfa
rin
(n�
5)
Clo
tly
sis,
PE,
blee
ding
7–10
dT
hrom
boly
sis:
Com
plet
ecl
otly
sis:
3/5
(60%
)Pa
rtia
llys
is:1
/5(2
0%)
No
lysi
s:1
(20%
)PE
:0B
leed
ing:
0A
ntic
oagu
latio
n:C
ompl
ete
clot
lysi
s:0/
5Pa
rtia
llys
is:0
/5N
oly
sis:
5/5
(100
%)
PE:0
Ble
edin
g:0
Rob
erts
onet
al11
3 /19
68R
CT
,sin
gle
cent
er16
patie
nts
with
DV
TT
hrom
boly
sis:
200,
000
Uof
stre
ptok
inas
eov
er90
min
,the
n10
0,00
0U
asm
aint
enan
cedo
sefo
r22
.5h;
500
mg
ofhe
pari
nad
min
iste
red
over
24h,
plus
pred
niso
ne(n
�8)
Ant
icoa
gula
tion:
hepa
rin
plus
pred
niso
ne(n
�8)
Clo
tly
sis,
blee
ding
7d
Thr
ombo
lysi
s:Si
gnifi
cant
lysi
s:5/
8(6
3%)
Part
iall
ysis
:2/8
(25%
)N
oly
sis:
1/8
(12%
)B
leed
ing:
Maj
or:2
/8(2
5%)
Min
or:2
/8(2
5%)
Ant
icoa
gula
tion:
Sign
ifica
ntly
sis:
1/8
(12%
)Pa
rtia
llys
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%
)K
akka
ret
al10
9 /19
69R
CT
,sin
gle
cent
er30
patie
nts
with
DV
Tof
�4
dT
hrom
boly
sis:
stre
ptok
inas
eat
500,
000
UIV
over
30m
in,9
00,0
00U
ever
y6
hfo
r5
d(n
�10
)A
rvin
:arv
inlo
adin
gdo
se80
UIV
over
6h,
80U
over
15m
in,4
0to
80U
ever
y6
hfo
r5
d(n
�10
)A
ntic
oagu
latio
n:he
pari
nat
10,0
00U
IVov
er5
min
,the
n10
,000
–15,
000
Uev
ery
6h
for
5d
(n�
10)
Clo
tly
sis,
PE,
blee
ding
,dea
th6–
12m
oT
hrom
boly
sis:
Com
plet
ecl
otly
sis:
6/9
(67%
)Pa
rtia
llys
is:1
/9(1
1%)
No
lysi
s:2/
9(2
2%)
PE:0
Ble
edin
g:4/
10(4
0%)
Dea
th:2
/9(2
2%)
�1pa
tient
excl
uded
from
trea
tmen
t�A
rvin
:C
ompl
ete
lysi
s:1/
10(1
0%)
Part
iall
ysis
:3/1
0(3
0%)
No
lysi
s:6/
10(6
0%)
PE:0
Ble
edin
g:0
Dea
th:0
Ant
icoa
gula
tion:
Com
plet
ecl
otly
sis:
2/9
(22%
)Pa
rtia
llys
is:2
/9(2
2%)
No
lysi
s:5/
9(5
5%)
PE:1
/10
Dea
th:2
/9(2
2%)
Ble
edin
g:2/
9(2
2%)
�not
e:1
patie
ntex
clud
edfr
omtr
eatm
ent�
472S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le4
—C
onti
nued
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Tsa
poga
set
al11
7 /19
73R
CT
,sin
gle
cent
er34
patie
nts
with
DV
Tof
�5
dT
hrom
boly
sis:
titra
ted
initi
aldo
seof
stre
ptok
inas
eIV
,the
nst
rept
okin
ase
at10
0,00
0U
/hm
aint
aine
dan
dad
just
edup
to72
h;IV
hepa
rin
for
1w
k6–
12h
afte
rst
rept
okin
ase
(n�
19)
Ant
icoa
gula
tion:
hepa
rin
IVin
toaf
fect
edlim
b,7,
000
Ubo
lus
then
1,50
0U
/had
just
ed;c
ontin
ued
for
7d
(n�
15)
Clo
tly
sis,
PE,
blee
ding
7d
Thr
ombo
lysi
s:C
ompl
ete/
part
iall
ysis
:10/
19(5
3%)
No
lysi
s:9/
19(4
7%)
PE:0
Ble
edin
g:m
inor
:3(1
6%)
Ant
icoa
gula
tion:
Com
plet
e/pa
rtia
llys
is:1
/15
(7%
)N
oly
sis:
14/1
5(9
3%)
PE:1
/15
(7%
)B
leed
ing:
0D
ucke
rtet
al10
6 /19
75Pr
ospe
ctiv
est
udy
134
patie
nts
with
acut
eor
suba
cute
DV
T
Thr
ombo
lysi
s:in
itial
dose
ofst
rept
okin
ase
calc
ulat
edac
cord
ing
toto
lera
nce
inje
cted
over
15–3
0m
in;m
aint
enan
cedo
seat
30m
L/h
was
two
thir
dsof
first
dose
(n�
92)
Ant
icoa
gula
tion:
5,00
0U
hepa
rin
for
initi
aldo
sefo
llow
edby
25,0
00U
/24
hin
fusi
on(n
�42
)
Clo
tly
sis,
PE,
blee
ding
App
roxi
mat
ely
7d
Thr
ombo
lysi
s:Si
gnifi
cant
lysi
s:39
/92
(42%
)Pa
rtia
llys
is:2
3/92
(25%
)N
oly
sis:
30/9
2(3
3%)
PE:7
(8%
)B
leed
ing:
Maj
or:5
8(6
2%)
Min
or:2
4(2
6%)
Ant
icoa
gula
tion:
Sign
ifica
ntly
sis:
0/42
(0%
)Pa
rtia
llys
is:4
/42
(10%
)N
oly
sis:
38/4
2(9
0%)
PE:5
/42
(12%
)B
leed
ing:
Maj
or:2
/42
(5%
)M
inor
:4/4
2(1
0%)
Port
eret
al11
2 /19
75R
CT
,sin
gle
cent
er50
patie
nts
with
DV
T�
14d
indu
ratio
n
Thr
ombo
lysi
s:st
rept
okin
ase
IVat
250,
000
Uov
er30
min
,the
n10
0,00
0U
/htit
rate
dfo
r72
h;fo
llow
edby
IVhe
pari
ntit
rate
dov
er7
d(n
�23
)A
ntic
oagu
latio
n:IV
hepa
rin
at15
0U
/kg
load
ing
dose
then
titra
ted
for
10d
(n�
26)
Clo
tly
sis,
PE,
blee
ding
,dea
thdu
eto
trea
tmen
t
10d
Thr
ombo
lysi
s:C
ompl
ete
lysi
s:6/
23(2
6%)
Part
iall
ysis
:15/
23(6
5%)
No
lysi
s:2/
23(9
%)
PE:0
Ble
edin
g:4/
23(1
7%)
Dea
th:1
(4%
)A
ntic
oagu
latio
n:C
ompl
ete
lysi
s:1/
26(4
%)
Part
iall
ysis
:20/
26(7
7%)
No
lysi
s:5/
26(1
9%)
PE:0
Ble
edin
g:1/
26(4
%)
Dea
th:0
Mar
der
etal
111 /
1977
RC
T,s
ingl
ece
nter
24pa
tient
sw
ithD
VT
Thro
mbo
lysis
:ini
tiald
ose
of25
0,00
0U
ofst
rept
okin
ase
for
20m
in,f
ollo
wed
by10
0,00
0U
/hfo
r72
h(n
�12
)A
ntic
oagu
latio
n:in
itial
IVhe
parin
dose
of15
0U
/kg,
follo
wed
bytit
rate
din
fusio
nfo
r72
hC
otre
atm
ent:
100
mg
bolu
shy
droc
ortis
one
prio
rto
trea
tmen
t
Clo
tly
sis,
deat
hdu
eto
trea
tmen
t5
dT
hrom
boly
sis:
Sign
ifica
ntly
sis:
5/12
(42%
)Pa
rtia
llys
is:2
/12
(16%
)N
oly
sis:
5/12
(42%
)D
eath
:1/1
2(8
%)
Ant
icoa
gula
tion:
Sign
ifica
ntly
sis:
0/12
(0%
)Pa
rtia
llys
is:3
/12
(25%
)N
oly
sis:
9/12
(75%
)D
eath
:0
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 473S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le4
—C
onti
nued
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Arn
esen
etal
103 /
1978
RC
T,s
ingl
ece
nter
42pa
tient
sw
ithpr
oxim
alD
VT
of�
5d
Thr
ombo
lysis
:250
,000
Ulo
adin
gof
IVst
rept
okin
ase,
then
100,
000
IU/h
IVfo
r72
–96
h(n
�21
)A
ntic
oagu
latio
n:15
,000
IUIV
bolu
she
parin
,the
nto
talo
f30
,000
IUIV
infu
sion
for
72–9
0h
(n�
21)
Clo
tly
sis,
PE,
blee
ding
21d
to6
yrT
hrom
boly
sis:
Sign
ifica
ntly
sis:
15/2
1(7
1%)
No
lysi
s:6/
21(2
9%)
PE:1
/21
(5%
)B
leed
ing:
2/21
(9%
)A
ntic
oagu
latio
n:Si
gnifi
cant
lysi
s:5/
21(2
4%)
No
lysi
s:16
/21
(76%
)PE
:0B
leed
ing:
2/21
(9%
)E
lliot
etal
107 /
1979
RC
T,s
ingl
ece
nter
51pa
tient
sw
ithcl
inic
alhi
stor
yof
DV
Tof
�8
d
Thr
ombo
lysi
s:lo
adin
gdo
seof
600,
000
Uof
stre
ptok
inas
ein
fuse
dov
er30
min
,fol
low
edby
100,
000/
hfo
r3
d;he
pari
nfo
r4
dfo
llow
ing
stre
ptok
inas
e(n
�26
)A
ntic
oagu
latio
n:10
,000
Uof
IVhe
pari
nin
itial
ly,f
ollo
wed
by10
,000
UIV
daily
for
a6-
hin
fusi
onto
mai
ntai
ncl
ottin
gtim
eof
2.5
to3
times
norm
al,f
or7
d(n
�25
)
Imm
edia
te:c
lot
lysi
s,PE
,ble
edin
g
Lon
gte
rm:s
ympt
omfr
ee
Imm
edia
te:5
d
Lon
g-te
rm:1
9m
o(m
ean)
Imm
edia
te:
Thr
ombo
lysi
s:Si
gnifi
cant
lysi
s:17
/26
(65%
)Pa
rtia
llys
is:1
/26
(4%
)N
oly
sis:
8/26
(31%
)PE
:0B
leed
ing:
2(8
%)
Ant
icoa
gula
tion:
Sign
ifica
ntly
sis:
0/25
(0%
)Pa
rtia
llys
is:0
/25
(0%
)N
oly
sis:
25/2
5(1
00%
)PE
:0B
leed
ing:
2/21
(9%
)L
ong-
term
Thr
ombo
lysi
s:Sy
mpt
omfr
ee:1
2/20
(60%
)�f
our
deat
hs,o
ther
caus
es,t
wo
unav
aila
ble
for
follo
w-u
p�;
Tre
atm
ent
2:Sy
mpt
omfr
ee:2
/21
(9%
)�f
our
deat
hs,t
wo
PE,t
wo
othe
rca
uses
�W
atz
etal
120 /
1979
Pros
pect
ive
stud
y35
patie
nts
with
DV
TT
hrom
boly
sis:
initi
aldo
seof
250,
000
Uof
stre
ptok
inas
ein
30m
in,
follo
wed
bym
aint
enan
ceof
100,
000
U/h
for
how
long
????
?(n
�18
)A
ntic
oagu
latio
n:45
,000
Uof
hepa
rin
daily
with
war
fari
n(n
�17
)
Clo
tly
sis,
PE,
blee
ding
1–2
mo
Thro
mbo
lysis
:Si
gnifi
cant
lysis
:8/1
8(4
4%)
Part
iall
ysis:
4/18
(22%
)N
oly
sis:6
/18
(34%
)PE
:1/1
8(5
%)
Ble
edin
g:m
inor
:3/1
8(1
2%)
Ant
icoa
gula
tion:
Sign
ifica
ntly
sis:1
/17
(6%
)Pa
rtia
llys
is:5/
17(2
9%)
No
lysis
:11/
17(6
5%)
PE:1
/17
(6%
)B
leed
ing:
min
or2/
17(1
2%)
474S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le4
—C
onti
nued
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Kiil
etal
110 /
1981
RC
T,s
ingl
ece
nter
20pa
tient
sw
ithD
VT
of�
72h
Thr
ombo
lysi
s:ur
okin
ase
at20
0,00
0U
IVfo
r24
h;af
ter
18h,
hepa
rin
load
ing
dose
of15
,000
U,t
hen
40,0
00U
/dfo
r5
d(n
�11
)A
ntic
oagu
latio
n:he
pari
nat
40,0
00U
/dIV
for
6d
(n�
9)
Clo
tly
sis,
PE,
blee
ding
2w
kT
hrom
boly
sis:
Part
iall
ysis
:1/1
1(9
%)
No
lysi
s:10
/11
(91%
)PE
:0B
leed
ing:
3/11
(27%
)A
ntic
oagu
latio
n:Pa
rtia
llys
is:1
/8(1
2%)
No
lysi
s:7/
8(8
8%)
PE:0
Ble
edin
g:3/
9(3
3%)
�not
e:1
patie
ntex
clud
edfr
omgr
oup�
Arn
esen
etal
104 /
1982
Fol
low
-up
toR
CT
ofA
rnes
en/1
978
(n�
48)
35/4
2pa
tient
sfr
omR
CT
Phle
bogr
aphy
and
clin
ical
exam
inat
ion
bybl
inde
dev
alua
tors
Nor
mal
legs
,PT
Ssy
mpt
oms
6.5
yrT
hrom
boly
sis:
Nor
mal
legs
:13/
17(7
7%)
PTS:
sym
ptom
s(m
oder
ate)
:4/1
7(2
4%)
Ant
icoa
gula
tion:
Nor
mal
legs
:6/1
8(3
3%)
PTS
sym
ptom
s(m
oder
ate)
:9/1
8(5
0%)
Schu
lman
etal
114 /
1986
RC
T,s
ingl
ece
nter
36pa
tient
sw
ithca
lfD
VT
of�
7d
Thr
ombo
lysi
s:st
rept
okin
ase
at50
,000
IUIV
over
15m
in,t
hen
100,
000
IUov
er12
hfo
rup
to7
d,tit
rate
d;ad
min
iste
red
with
5,00
0IU
ofhe
pari
nIV
over
12h
(n�
17)
Ant
icoa
gula
tion:
hepa
rin
at5,
000
IUIV
for
15m
inth
en30
,000
IU/d
,tit
rate
dov
er7
d(n
�19
)
Clo
tly
sis,
blee
ding
,PE
5yr
Thr
ombo
lysi
s:C
ompl
ete
lysi
s:7/
17(4
1%)
Ble
edin
g:3/
17(1
8%);
PE:0
Ant
icoa
gula
tion:
Com
plet
ely
sis:
2/19
(10%
)B
leed
ing:
1/19
(5%
)PE
:0V
erha
eghe
etal
119 /
1989
Pros
pect
ive
coho
rtst
udy
(stu
dyA
)an
dm
ultic
ente
rR
CT
(stu
dyB
)
32pa
tient
sw
ithD
VT
of�
10d
Stud
yA
:O
pen-
labe
lstu
dyw
ithIV
rt-P
A10
0m
gov
er8
h(d
ay1)
,50
mg
rt-P
Aov
er8
h(d
ay2)
;10%
dose
asbo
lus
(n�
11)
Stud
yB
:rt
-PA
at10
0m
g;IV
of10
0m
Lco
ntai
ning
rt-P
A10
0m
gin
fuse
dov
er8
h(d
ay1)
,IV
of10
0m
Lco
ntai
ning
50m
gof
rt-
PAin
fuse
dov
er8
h(d
ay2)
;10%
dose
asbo
lus
(n�
8)rt-
PA50
mg:
IVof
100
mL
cont
aini
ngrt-
PA50
mg
infu
sed
over
8h
onbo
thda
ys1
and
2;10
%do
seas
bolu
s(n
�6)
Plac
ebo:
IVof
100
mL
cont
aini
ngpl
aceb
oin
fuse
dov
er8
hon
both
days
1an
d2
(n�
7)C
otre
atm
ent:
hepa
rinat
5,00
0U
IVbo
lus
then
cont
inuo
usin
fusio
n1,
000
U/h
for
upto
72h
Clo
tly
sis,
blee
ding
72h
Not
e:au
thor
sas
signe
dve
ins
are
lativ
eva
lue
refle
ctin
gde
gree
ofth
rom
bosis
(max
imum
of40
U:c
ompl
ete
thro
mbo
sis);
the
unit
scor
esre
flect
the
redu
ctio
nin
thro
mbo
sisaf
ter
lysis
Stud
yA
:C
hang
ein
unit
scor
e�
3.2
Stud
yB
:rt
-PA
100
mg
Cha
nge
inun
itsc
ore
�24
.3B
leed
ing:
6rt
-PA
:50
mg
Cha
nge
inun
itsc
ore
�34
.3B
leed
ing:
3Pl
aceb
o:C
hang
ein
unit
scor
e�
2.8
Ble
edin
g:0
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 475S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le4
—C
onti
nued
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Gol
dhab
eret
al10
8 /19
90R
CT
,mul
ticen
ter
64pa
tient
s(6
5ra
ndom
izat
ions
)w
ithD
VT
of�
14d
rt-P
A:r
t-PA
0.05
mg/
kg/h
IVfo
r24
h,th
enhe
parin
100
U/k
gbo
lus,
then
1,00
0U
/h,a
djus
ted
(n�
36)
rt-P
Apl
ushe
parin
:rt-P
Aas
ingr
oup
1pl
ushe
parin
conc
omita
ntly
(n�
17)
Ant
icoa
gula
tion:
hepa
rin10
0U
/kg
bolu
s,th
en1,
000
U/h
(n�
12)
Clo
tly
sis,
blee
ding
36h
rt-P
A:
Com
plet
ely
sis:
2/32
(6%
)Pa
rtia
llys
is:1
8/32
(57%
)N
oly
sis:
12/3
2(3
8%)
Ble
edin
g:1/
32(3
%)
rt-P
Apl
ushe
pari
n:C
ompl
ete
lysi
s:1/
17(6
%)
Part
iall
ysis
:8/1
7(4
8%)
No
lysi
s:8/
17(4
8%)
Ble
edin
g:0
Ant
icoa
gula
tion:
Part
iall
ysis
:2/1
1(1
8%)
No
lysi
s:9/
11(8
9%)
Ble
edin
g:0
(not
e:5
of65
veno
gram
sw
ere
not
anal
yzed
)T
urpi
eet
al11
8 /19
90R
CT
,mul
ticen
ter
83pa
tient
sw
ithD
VT
of�
7d
Phas
e1:
Lys
ispl
ushe
pari
n:tw
o-ch
ain
rt-P
A0.
5m
g/kg
IVfo
r4
h(n
�12
)Pl
aceb
opl
ushe
pari
n(n
�12
)Ph
ase
2:L
ysis
plus
hepa
rin:
one-
chai
nrt
-PA
0.5
mg/
kgIV
for
8h
and
repe
ated
in24
h(n
�29
)Pl
aceb
opl
ushe
pari
n(n
�30
)C
otre
atm
ent:
IVhe
pari
n5,
000
Ubo
lus
then
30,0
00U
/24
h,ad
just
edfo
r7–
10d
Clo
tly
sis,
blee
ding
24–4
8h
Phas
e1:
Lys
ispl
ushe
pari
n:�
50%
lysi
s:7/
12(5
8%)
�50
%ly
sis:
2/12
(17%
)N
oly
sis:
3/12
(25%
)B
leed
ing:
4/12
(33%
)Pl
aceb
opl
ushe
pari
n:�
50%
lysi
s:2/
12(1
7%)
No
lysi
s:10
/12
(83%
)B
leed
ing:
1/12
(8%
)Ph
ase
2:L
ysis
plus
hepa
rin:
�50
%ly
sis:
6/29
(21%
);�
50%
lysi
s:7/
29(2
4%)
No
lysi
s:15
/29
(52%
)B
leed
ing:
1/29
(3%
)Pl
aceb
opl
ushe
pari
n:�
50%
lysi
s:2/
30(7
%);
�50
%ly
sis:
5/30
(17%
)N
oly
sis:
23/3
0(7
7%)
Ble
edin
g:1/
30(3
%)
Schw
eize
ret
al11
5 /19
98R
CT
,sin
gle
cent
er69
patie
nts
with
DV
Tof
�7
drt
-PA
:20
mg
IVin
tope
dalv
ein
4h/
dfo
r7
d;he
parin
IVad
min
ister
edco
ncom
itant
ly;w
arfa
rinda
y7
to12
mo
Uro
kina
se:1
00,0
00IU
/hIV
into
peda
lve
inco
ntin
uous
ly7
d;he
parin
IV7
d;pl
asm
inog
enm
onito
red;
war
farin
day
7–12
mo
Ant
icoa
gula
tion:
hepa
rinIV
adju
sted
for
7d;
.war
farin
,day
1to
12m
o
7d:
clot
lysi
s,bl
eedi
ng1
yr:P
TS
sym
ptom
s
7d
and
1yr
rt-P
A:
Com
plet
ely
sis:
6/22
(27%
)B
leed
ing:
1/22
(5%
)PT
Ssy
mpt
oms:
14/2
2(6
4%)
Uro
kina
se:
Com
plet
ely
sis:
11/2
2(5
0%)
Ble
edin
g:1/
22(5
%)
PTS
sym
ptom
s:9/
22(4
1%)
Ant
icoa
gula
tion:
Com
plet
ely
sis:
0B
leed
ing:
0PT
Ssy
mpt
oms:
15/2
2(6
8%)
476S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le4
—C
onti
nued
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Schw
eize
ret
al11
6 /20
00R
CT
,mul
ticen
ter
250
patie
nts
with
DV
Tof
�9
drt
-PA
:loc
oreg
iona
lrt-P
A20
mg/
dfo
r4
hvi
ape
dalv
ein
for
4–7
d;IV
hepa
rinad
min
ister
edsim
ulta
neou
slyat
1,00
0IU
/h;a
djus
ted
Uro
kina
se:l
ocor
egio
nalu
roki
nase
100,
000
IU/i
nfus
edco
ntin
uous
ly;f
ibrin
ogen
and
plas
min
ogen
mon
itore
d;IV
hepa
rinad
min
ister
edco
ncom
itant
lySy
stem
icst
rept
okin
ase:
3,00
0,00
0U
/dfo
r6
hw
ithhe
parin
for
upto
7d;
prem
edic
atio
ns:h
ydro
cort
isone
at10
0m
g,ra
nitid
ine
at50
mg,
clem
astin
eat
2m
gSy
stem
icur
okin
ase:
5,00
0,00
0IU
/dfo
r4
hup
to7
d;IV
hepa
rinad
min
ister
edco
ncom
itant
lyA
ntic
oagu
latio
n:he
parin
IV,a
djus
ted
Cot
reat
men
t:be
dre
st,c
ompr
essio
nba
ndag
es,c
ompr
essio
nth
erap
y,w
arfa
rinfo
r12
mo
Clo
tly
sis,
blee
ding
,m
orta
lity
1yr
rt-P
A:
Com
plet
ely
sis:
10/5
0(2
0%)
�50
%ly
sis:
7/50
(14%
)�
50%
lysi
s:16
/50
(32%
)N
oly
sis:
13/5
0(2
6%)
Ble
edin
g:2/
50(4
%)
Uro
kina
se:
Com
plet
ely
sis:
10/5
0(2
0%)
�50
%ly
sis:
9/50
(18%
);�
50%
lysi
s:17
/50
(34%
)N
oly
sis:
11/5
0(2
2%)
Ble
edin
g:1/
50(2
%)
Syst
emic
stre
ptok
inas
e:C
ompl
ete
lysi
s:20
/50
(40%
)�
50%
lysi
s:7/
50(1
4%)
�50
%ly
sis:
13/5
0(2
6%)
No
lysi
s:8/
50(1
6%)
Ble
edin
g:5/
50(1
0%)
PE:5
/50
(10%
)Sy
stem
icur
okin
ase:
Com
plet
ely
sis:
17/5
0(3
4%)
�50
%ly
sis:
10/5
0(2
0%)
�50
%ly
sis:
13/5
0(2
6%)
No
lysi
s:8/
50(1
6%)
Ble
edin
g:4/
50(8
%)
PE:4
/50
(8%
)L
aiho
etal
81/
2004
Ret
rosp
ectiv
est
udy,
sing
lece
nter
32pa
tient
sw
ithili
ofem
oral
DVT
�14
din
dura
tion
rece
ived
eith
erC
DT
(n�
16)o
rsy
stem
icth
rom
boly
sis(n
�16
)
Thr
ombo
lysi
s:22
9m
g(m
ean)
ofrt
-PA
(n�
4)or
6.5
mill
ion
Uof
stre
ptok
inas
e(n
�12
)fo
r62
h(m
ean)
plus
LM
WH
and
oral
antic
oagu
lant
s
Clo
tly
sis,
PE,
blee
ding
,val
vula
rco
mpe
tenc
e
2–3
yrT
hrom
boly
sis:
Sign
ifica
ntly
sis:
5/16
(31%
)PE
:5/1
6(3
1%)
Ble
edin
g:1/
16(6
%)
Val
vula
rco
mpe
tenc
e:2/
16(1
3%)
Any
deep
vein
inco
mpe
tenc
e:81
%
*The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 477S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Recommendation
1.10.1. In selected patients with extensive prox-imal DVT (eg, symptoms for < 14 days, goodfunctional status, life expectancy of > 1 year)who have a low risk of bleeding, we suggest thatsystemic thrombolytic therapy may be used toreduce acute symptoms and postthromboticmorbidity if CDT is not available (Grade 2C).
1.11 Percutaneous Venous Thrombectomy
Percutaneous mechanical venous thrombectomyrefers to catheter-based fragmentation of thrombus(eg, with pulse-spray or rotational devices) with, orwithout, aspiration of thrombus fragments.101 Percu-taneous mechanical venous thrombectomy is oftencombined with CDT, which, collectively, are re-ferred to as pharmacomechanical thrombolysis. Be-cause pharmacomechanical thrombolysis was in-cluded in the preceding section on CDT (Section1.9), the current section will be confined to percu-taneous mechanical venous thrombectomy withoutconcomitant thrombolysis.
No randomized trials have compared percutaneousmechanical venous thrombectomy with other catheter-based, or noncatheter-based, treatments for DVT.Small retrospective studies suggest that percutaneousmechanical venous thrombectomy alone often fails toremove much of the thrombus94,101 and is associatedwith a high risk of PE.122,123
Recommendation
1.11.1. In patients with acute DVT, we suggestthat they should not be treated with percutaneousmechanical thrombectomy alone (Grade 2C).
1.12 Operative Venous Thrombectomy for Acute DVT
Operative venous thrombectomy is an alternativeapproach for thrombus removal that is generallyreserved for patients with iliofemoral DVT. Contem-porary operative techniques124 and more effectiveanticoagulant regimens have improved outcomescompared to earlier reports.125,126 Iliofemoral venousthrombectomy with a temporary arteriovenous fis-tula plus anticoagulation was compared with antico-agulation alone in a randomized trial of 63 patientswho were followed for a long term.73,82,83 Results at6 months, 5 years, and 10 years were consistent withimproved iliac vein patency, less leg swelling, andfewer leg ulcers (Table 5).73,82,83 In nine nonrandom-ized studies73,80,82,83,127–134 that evaluated venousthrombectomy in 520 limbs of 509 patients, sus-tained patency was achieved in 65 to 85%, and
preservation of femoral-popliteal valve function oc-curred in 65 to 75% of operated patients. Althoughoperative pulmonary embolization is a concern withthis procedure, it is an infrequent complication.130
Recommendations
1.12.1. In selected patients with acute iliofemoralDVT (eg, symptoms for < 7 days, good functionalstatus, and life expectancy > 1 year), we suggestthat operative venous thrombectomy may be usedto reduce acute symptoms and postthromboticmorbidity if appropriate expertise and resourcesare available (Grade 2B). If such patients do nothave a high risk of bleeding, we suggest that CDTis usually preferable to operative venous throm-bectomy (Grade 2C).1.12.2. In patients who undergo operative venousthrombectomy, we recommend the same inten-sity and duration of anticoagulant therapy after-wards as for comparable patients who do notundergo venous thrombectomy (Grade 1C).
1.13 Vena Caval Filters for the Initial Treatment ofDVT
IVCs (and rarely superior vena caval [SVC]) filterscan be used instead of initial anticoagulation (eg, unac-ceptable risk of bleeding), or as an adjunct to anticoag-ulation, in patients with acute DVT. No randomizedtrial or prospective cohort study have evaluated IVCfilters as sole therapy in patients with DVT (ie, withoutconcurrent anticoagulation). Permanent IVC filter in-sertion as an adjunct to anticoagulant therapy has beenevaluated in a single, large RCT of patients with acuteDVT who were considered to be at high risk for PE(PREPIC study; Table 6). The findings of that study,which were reported after 2 years29 and 8 years135 offollow-up (Table 6), provide the strongest evidence toguide use of IVC filters in patients with acute VTE, andcan be summarized as follows. First, routine insertionof filters in patients who are also anticoagulated doesnot alter the frequency of recurrent VTE (RR, 1.34 at2 years; and RR, 1.03 at 8 years) or total mortality (RR,1.08 at 2 years; and RR, 0.95 at 8 years). Second, filtersreduce PE at 12 days (RR, 0.4; this estimate includesasymptomatic PE detected by routine lung scanning), 2years (RR, 0.54), and at 8 years (RR, 0.41). Third, filtersincrease DVT at 2 years (RR, 1.8) and at 8 years (RR,1.3; hazard ratio, 1.5; 95% CI, 1.02 to 2.3 in the originalreport29). Fourth, despite more frequent DVT duringfollow-up and frequent evidence of thrombosis at thefilter site in those with recurrent VTE (43% of cases),filters were not associated with a higher frequency ofPTS (defined as presence of at least one of edema,varicose veins, trophic disorders or ulcers) [hazard
478S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le5—
Ope
rati
veV
enou
sT
hrom
bec
tom
yfo
rA
cute
DV
T:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
1.12
)*
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Kis
tner
and
Spar
kuhl
130 /
1979
Cas
ese
ries
70pa
tient
s(7
7ex
trem
ities
)w
ithac
ute
iliof
emor
alD
VT
conf
irm
edby
veno
grap
hy
Ope
rativ
eve
nous
thro
mbe
ctom
yPa
tenc
y,cl
inic
alsu
cces
s,op
erat
ive
PE4
yr(m
ean)
Pate
ncy:
75%
Clin
ical
succ
ess:
Exc
elle
nt,5
4%G
ood,
32%
Fai
r,7%
Poor
,7%
Ope
rativ
ePE
:8%
(thr
eeas
ympt
omat
ic)
Plat
eet
al73
/198
4R
CT
,mul
ticen
ter
58pa
tient
sw
ithac
ute
iliof
emor
alve
nous
thro
mbo
sis
Med
ical
:5,0
00U
bolu
she
pari
nfo
llow
edby
500
U/k
g/24
had
just
edto
APT
T,a
ndor
alan
ticoa
gula
tion
(n�
31)
Surg
ical
:ope
rativ
eve
nous
thro
mbe
ctom
yw
ithte
mpo
rary
arte
riov
enou
sfis
tula
plus
antic
oagu
latio
nas
abov
e(n
�27
)
PTS
sequ
elae
:ilio
fem
oral
pate
ncy,
valv
eco
mpe
tenc
e6
mo
Med
ical
:PT
Sse
quel
ae:2
5/27
(93%
)Il
iofe
mor
alpa
tenc
y:9/
26(3
5%)
Val
veco
mpe
tenc
e:7/
27(2
6%)
(PE
in1
patie
nt)
Surg
ical
:PT
Sse
quel
ae:1
4/24
(58%
;p
�0.
005)
Ilio
fem
oral
pate
ncy:
16/2
1(7
6%,
p�
0.02
5)V
alve
com
pete
nce:
13/2
3(5
2%;
p�
0.05
)(v
enou
sga
ngre
nein
1pa
tient
)E
inar
sson
etal
127 /
1986
Pros
pect
ive
regi
stry
70pa
tient
s(7
1le
gs)
with
iliof
emor
alD
VT
(age
ofcl
ot:m
ean
3d)
Ilio
fem
oral
veno
usth
rom
bect
omy
with
tem
pora
ryA
VF
clos
edat
6–8
wk,
hepa
rin
befo
rean
daf
ter
oper
ativ
ion,
plus
war
fari
npo
stop
erat
ivel
y
Ven
ous
pate
ncy,
hem
atom
a,A
VF
pate
ncy,
PE,w
ound
infe
ctio
n56
d(m
ean)
Pate
ntili
acve
in:8
8%H
emat
oma:
11%
AV
Fpa
tenc
y:86
%PE
:4%
Wou
ndin
fect
ion:
26%
:
Ein
arss
onet
al12
8 /19
86F
ollo
w-u
pto
(66)
57pa
tient
s(5
8lim
bs)
with
prio
rop
erat
ive
veno
usth
rom
bect
omy
and
AV
Fcl
osed
at6–
8w
kfo
rili
ofem
oral
DV
T
Clin
ical
PTS;
veno
grap
hy;
veno
uspr
essu
re;v
enou
spl
ethy
smog
raph
y,fo
otvo
lum
etry
Ven
ous
insu
ffic
ienc
y:G
ood,
fair
,poo
r
Ven
ogra
phy
(vei
nse
gmen
t):
Nor
mal
;pos
tthr
ombo
tic,o
cclu
ded
Ven
ous
pres
sure
:N
orm
al;a
bnor
mal
Plet
hysm
ogra
phy:
Nor
mal
,abn
orm
al
Foo
tvo
lum
etry
:N
orm
al,a
bnor
mal
9–10
mo
Ven
ous
insu
ffic
ienc
y:G
ood:
75%
Fai
r:20
%Po
or:5
%V
enog
raph
y(il
iofe
mor
al):
Nor
mal
:61%
Post
thro
mbo
tic:2
3%O
cclu
ded:
39%
IVpr
essu
re:
Nor
mal
:82%
Abn
orm
al:1
8%Pl
ethy
smog
raph
y:N
orm
al:2
9%A
bnor
mal
:71%
Foo
tvo
lum
etry
:N
orm
al:2
9%A
bnor
mal
:71%
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 479S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le5—
Con
tinu
ed
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Juha
net
al12
9 /19
87R
etro
spec
tive
stud
y41
patie
nts
with
42ili
ofem
oral
(n�
24)
orili
ocav
al(n
�18
)re
cent
thro
mbo
ses
Ope
rativ
eve
nous
thro
mbe
ctom
yw
ithte
mpo
rary
arte
riov
enou
sfis
tula
(n�
31),
IVC
inte
rrup
tion
(n�
21)
Ven
ous
pate
ncy,
PE,d
eath
,he
mat
oma
4yr
Imm
edia
tePa
tenc
y:Il
iac:
93%
IVC
:100
%Su
perf
icia
lfem
oral
:66%
Popl
iteal
:82%
PE:0
Dea
th:0
Hem
atom
a:6
Lat
efo
llow
-up:
4yr
pate
ncy
(33
patie
nts)
:93%
Tor
ngre
nan
dSw
ende
nbor
g134 /
1988
Ret
rosp
ectiv
est
udy
60pa
tient
sw
ithili
ofem
oral
DV
TO
pera
tive
veno
usth
rom
bect
omy
with
tem
pora
ryA
VF
(clo
sed
at3
mo)
and
antic
oagu
latio
nfo
r6
mo
Ven
ous
pate
ncy
3m
o–5
yrE
arly
:Pa
tenc
y:70
%
Fol
low
-up:
Pate
ncy:
54%
Plat
eet
al82
/19
905-
yrfo
llow
-up
toR
CT
(Pla
te19
84,n
�10
)
41/5
8pa
tient
s(2
2m
edic
al,
19su
rgic
al)
avai
labl
efo
rev
alua
tion
at5
yr
Prio
rtr
eatm
ent
Med
ical
:ant
icoa
gula
tion
alon
e
vs Surg
ical
:ope
rativ
eve
nous
thro
mbe
ctom
ypl
usan
ticoa
gula
tion
PTS
sequ
elae
,ilia
cpa
tenc
y,ve
nous
pres
sure
5yr
Med
ical
:PT
Sse
quel
ae:6
/22
(27%
)Il
iac
pate
ncy:
11/2
2(5
0%)
Ven
ous
pres
sure
:60
mm
Hg
(mea
n)
Surg
ical
:PT
Sse
quel
ae:2
/19
(11%
)Il
iac
pate
ncy:
15/1
9(7
8%)
Ven
ous
pres
sure
:43
mm
Hg
(mea
n;p
�0.
05)
Neg
len
etal
132 /1
991
Pros
pect
ive
regi
stry
48pa
tient
sw
ithili
ofem
oral
DV
Tof
1–14
dO
pera
tive
veno
usth
rom
bect
omy
with
tem
pora
ryA
VF
(clo
sed
6–12
wk
afte
rop
erat
ion)
Adj
unct
ive
ther
apy:
tran
sven
ous
perc
utan
eous
dila
tatio
nof
seve
reili
acst
enos
is(n
�3)
Pate
ncy,
PE,c
linic
alsy
mpt
oms,
norm
alph
otop
leth
ysm
ogra
phy,
succ
essf
ulA
VF
clos
ure
24m
o(m
ean)
Pate
ncy:
Ilio
fem
oral
:88%
Popl
iteal
:94%
PE:1
6%sy
mpt
omat
ic,3
1%as
ympt
omat
icSy
mpt
omfr
ee:8
1%N
orm
alph
otop
leth
ysm
ogra
phy
(no
reflu
x):5
6%A
VF
clos
ure
succ
ess
rate
:87%
Mei
ssne
ran
dH
usze
za13
1 /199
6R
etro
spec
tive
stud
y30
patie
nts
with
acut
eD
VT
ofth
elo
wer
extr
emiti
es
Ope
rativ
eve
nous
thro
mbe
ctom
yw
ithte
mpo
rary
AV
FPa
tenc
y,PE
,sw
ellin
g30
d–12
wk
Ear
ly:
Pate
ncy:
100%
PE:0
Fol
low
-up:
Pate
ncy:
89%
480S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le5—
Con
tinu
ed
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Plat
eet
al83
/199
710
-yr
follo
w-u
pto
RC
T(P
late
1984
,n�
10;
1990
,n�
20)
30/5
8pa
tient
s(1
7fr
omm
edic
alar
m,1
3fr
omsu
rgic
alar
m)
avai
labl
efo
rev
alua
tion
Prio
rtr
eatm
ent:
Med
ical
:ant
icoa
gula
tion
alon
e
vs Surg
ical
:ope
rativ
eve
nous
thro
mbe
ctom
ypl
usan
ticoa
gula
tion
PTS
sequ
elae
,ilia
cpa
tenc
y,ve
nous
pres
sure
10yr
Med
ical
:PT
Sse
quel
ae:1
5/17
(88%
)Il
iac
pate
ncy:
7/17
(41%
)V
enou
spr
essu
re:6
3m
mH
g(m
ean)
Surg
ical
:PT
Sse
quel
ae:7
/13
(54%
)Il
iac
pate
ncy:
10/1
2(8
3%)
Ven
ous
pres
sure
:55
mm
Hg
(mea
n)Ju
han
etal
80/1
997
Ret
rosp
ectiv
est
udy
75pa
tient
s(7
7lim
bs)
with
acut
eili
ofem
oral
veno
usth
rom
bosi
s
Ope
rativ
eve
nous
thro
mbe
ctom
yw
ithA
VF
ligat
edat
6–8
wk
Ilio
fem
oral
syst
empa
tenc
y,va
lvul
arco
mpe
tenc
e,C
VI
8.5
yr(m
ean)
5-yr
resu
lts(4
4lim
bs):
Ilio
fem
oral
pate
ncy:
84%
Val
vula
rco
mpe
tenc
e:80
%C
VI,
Gra
de0/
1:93
%
10-y
rre
sults
(16
limbs
):Il
iofe
mor
alpa
tenc
y:84
%V
alvu
lar
com
pete
nce:
56%
CV
I,G
rade
0/1:
94%
Schw
arzb
ach
etal
133 /2
005
Ret
rosp
ectiv
est
udy
20pa
tient
sw
ithac
ute
iliof
emor
alor
ilioc
aval
thro
mbo
sis
Ope
rativ
eve
nous
thro
mbe
ctom
yw
ithen
dova
scul
arco
rrec
tion
ofre
sidu
alle
sion
s
Prim
ary
and
seco
ndar
ypa
tenc
y,cl
inic
alou
tcom
epe
rC
EA
Pst
age
21m
o(m
ean)
Pate
ncy:
Prim
ary:
80%
Seco
ndar
y:90
%
Clin
ical
outc
ome:
13pa
tient
s,as
ympt
omat
ic1
patie
nt;r
etic
ular
vein
s4
patie
nts;
asym
ptom
atic
edem
a4
patie
nts;
sym
ptom
atic
edem
a,pa
in
*AV
F�
arte
riov
enou
sfis
tula
;CV
I�
chro
nic
veno
usin
suff
icie
ncy;
V-Q
�ve
ntila
tion-
perf
usio
n;C
EA
P�
clin
ical
etio
logi
can
atom
icpa
thop
hysi
olog
ic(c
lass
ifica
tion)
.The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 481S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
ratio, 0.87; 95% CI, 0.66 to 1.13]. Fifth, 2.5% (fivepatients) of the nonfilter group and 1.0% (two patients)of the filter group died of PE during 8 years offollow-up. Sixth, other complications of filter place-ment are rare (none were reported).
A comprehensive review136 of mostly retrospec-tive case series of vena caval filter insertions (atotal of 6,500 patients in 89 reports who had filtersinserted for many different reasons) suggests thatvenous thrombosis at the site of filter insertionsites is common (eg, approximately 10% of pa-tients), that filters can be placed above the renalveins if necessary, and that it is feasible to placefilters in the SVC. Epidemiologic data suggest thatIVC filters are not associated with an increasedrisk of recurrent VTE in patients who present withDVT.137 If an IVC filter is being inserted in apatient with acute DVT or PE because anticoagu-lant therapy is temporarily contraindicated (eg,active bleeding), there is the option of inserting aretrievable filter and removing the filter when it issafe to start anticoagulant therapy. However, therisks and benefits of using a retrievable filtercompared with a permanent filter in this settingare uncertain.
Recommendations
1.13.1. For patients with DVT, we recommendagainst the routine use of a vena cava filter inaddition to anticoagulants (Grade 1A).1.13.2. For patients with acute proximal DVT ifanticoagulant therapy is not possible because ofrisk of bleeding, we recommend placement ofan IVC filter (Grade 1C).1.13.3. For patients with acute DVT who havean IVC filter inserted as an alternative to anti-coagulation, we recommend that they shouldsubsequently receive a conventional course ofanticoagulant therapy if their risk of bleedingresolves (Grade 1C).
1.14 Immobilization for the Treatment of AcuteDVT
The early treatment of acute DVT with bed restand anticoagulation has given way to anticoagula-tion with early mobilization. Randomized trials138 –
142 and observational studies143–145 show fasterresolution of pain and swelling with early ambula-tion and leg compression compared with immobi-lization, and a similar incidence of new PE onroutine repeat lung scanning after 10 days oftreatment (Table 7). These observations suggestthat mobile patients with DVT should remainambulant.
Recommendation
1.14.1. In patients with acute DVT, we recom-mend early ambulation in preference to initialbed rest when this is feasible (Grade 1A).
2.0 Long-term Treatment of Acute DVT ofthe Leg
In this review, long-term treatment refers to treat-ments that are continued after initial therapy, such aswith heparin or thrombolytic agents, has been com-pleted. Long-term therapy has two goals: (1) tocomplete treatment of the acute episode of VTE;and (2) to prevent new episodes of VTE that are notdirectly related to the acute event. During the earlyphase of long-term treatment (ie, first 3 months),treatment of the acute episode of VTE predomi-nates. During the late phase of long-term treatment(ie, after the first 3 months), prevention of newepisodes of VTE predominates. We will use the termindefinite anticoagulation to refer to anticoagulationthat is continued without a scheduled stop date, butwhich may be stopped because of a subsequentincrease in the risk of bleeding or change in patientpreference.
The need for long-term anticoagulant treatment ofDVT after 5 to 10 days of initial heparin therapy issupported by three lines of evidence from RCTs: (1)a randomized trial in which no long-term anticoag-ulant treatment was administered to patients withsymptomatic calf-vein thrombosis, which docu-mented a 20% rate of symptomatic extension and/orrecurrence of thrombosis within 3 months146; (2) arandomized trial that evaluated SC low-dose UFH(5,000 U bid) as an alternative to VKA for long-termtreatment after proximal DVT, in which the low-doseUFH regimen proved ineffective and resulted in ahigh rate of recurrent VTE (47% within 3months)147; and (3) randomized trials in which re-duced durations of treatment of 4 or 6 weeksresulted in clinically important increases in recurrentVTE, compared to conventional durations of treat-ment of 3 months or 6 months.148–150
In this section, we will address three issuesrelating to long-term anticoagulant therapy forDVT: (1) the optimal duration of treatment (usu-ally with VKA), (2) the optimal intensity of treat-ment with VKA, and (3) the relative effectivenessand safety of alternative approaches to long-termVKA treatment, particularly LMWH. We will re-view studies that included patients with symptom-atic DVT, or both symptomatic DVT and PE.Studies that only included patients with symptom-atic PE, with or without concomitant symptomaticDVT, are considered in later sections of this
482S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le6
—R
ando
miz
edT
rial
ofIV
CF
ilte
ras
anA
dju
nct
toA
ntic
oagu
lati
onin
Pat
ient
sW
ith
DV
T:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
1.13
)*
Stud
y/yr
Inte
rven
tions
Patie
nts
Ana
lyze
dL
engt
hof
Fol
low
-up
Rec
urre
ntV
TE
Maj
orB
leed
ing
Tot
alM
orta
lity
Com
men
ts
PRE
PIC
29/
1998
Perm
anen
tIV
Cfil
ter
(56%
Ven
aT
ech
LG
M;2
6%G
reen
field
;16%
Car
dial
orB
irds
Nes
t;2%
nofil
ter)
No
IVC
filte
r
12d
372
patie
nts
(rea
sons
why
28pa
tient
sw
ere
not
anal
yzed
are
desc
ribe
d;es
timat
edth
at18
3fil
ter
and
189
nofil
ter
wer
ean
alyz
ed)
12d
All
PEat
12d
Filt
er:2
/183
(1.1
%)
No
filte
r:9/
189
(4.8
%)
RR
,0.2
3(9
5%C
I,0.
05–1
.05)
Sym
ptom
atic
PEat
12d
Filt
er:2
/183
(1.1
%)
No
filte
r:5/
189
(2.6
%)
RR
,0.4
1(9
5%C
I,0.
08–2
.1)
Maj
orbl
eedi
ngat
12d
Filt
er:9
/200
No
filte
r:6/
200
RR
:1.5
(95%
CI,
0.54
–4.
14)
Mor
talit
yat
12d
Filt
er:5
/200
No
filte
r:5/
200
RR
,1.0
(95%
CI,
0.29
–3.
40)
400
patie
nts
with
prox
imal
DV
T:
fem
oral
orm
ore
prox
imal
vein
invo
lved
in94
%;c
onco
mita
ntsy
mpt
omat
icPE
in36
%;m
ean
age,
72yr
;all
patie
nts
wer
etr
eate
dw
ithL
MW
Hor
UF
H(r
ando
miz
edal
loca
tion;
fact
oria
ldes
ign)
follo
wed
byV
KA
s(I
NR
2–3)
for
atle
ast
3m
o;pr
imar
you
tcom
ew
assy
mpt
omat
icor
asym
ptom
atic
PEat
12d
Oth
erth
anth
rom
bosi
sat
the
filte
rsi
teth
atw
asde
tect
edin
16of
the
37fil
ter
patie
nts
with
recu
rren
tV
TE
,“no
othe
rm
ajor
com
plic
atio
nsw
ere
obse
rved
”in
the
filte
rgr
oup.
Enr
ollm
ent
was
stop
ped
at40
0in
stea
dof
800
patie
nts
beca
use
ofsl
owre
crui
tmen
t2
yr39
9pa
tient
san
alyz
edfo
rde
ath;
deno
min
ator
sar
ees
timat
edfr
ompe
rcen
tage
san
dre
ason
for
diffe
renc
esar
eno
tdes
crib
ed
2yr
Sym
ptom
atic
PEat
2yr
Filt
er:6
/176
(3.4
%)
No
filte
r:12
/190
(6.3
%)
RR
,0.5
4(9
5%C
I,0.
21–1
.41)
Sym
ptom
atic
DV
Tat
2yr
Filt
er:3
7/17
8(2
0.8%
)N
ofil
ter:
21/1
81(1
1.6%
)R
R,1
.78
(95%
CI,
1.09
–2.9
4)
Sym
ptom
atic
VT
Eat
2yr
Filt
er:3
7/17
8(2
0.8%
)N
ofil
ter:
29/1
87(1
5.5%
)R
R,1
.34
(95%
CI,
0.86
–2.0
8)
Maj
orbl
eedi
ngat
2yr
Filt
er:1
7/19
3(8
.8%
)N
ofil
ter:
22/1
86(1
1.8%
)R
R,0
.74
(95%
CI,
0.41
–1.3
6)
Mor
talit
yat
2yr
Filt
er:4
3/19
9(2
1.6%
)N
ofil
ter:
40/1
99(2
0.1)
RR
,1.0
8(9
5%C
I,0.
73–1
.58)
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 483S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
chapter (Sections 4.0 and 5.0). However, for thereasons noted in Section 4.0, the results of allstudies of VTE have been considered when for-mulating recommendations for long-term treat-ment of DVT and PE, and the main recommen-dations for long-term anticoagulant therapy do notdiffer for proximal DVT or PE.
2.1. Duration of Anticoagulant Therapy
Anticoagulant therapy for VTE should be contin-ued for the following: (1) until its benefits (reductionof recurrent VTE) no longer clearly outweigh itsrisks (increase in bleeding), or (2) it is patientpreference to stop treatment even if continuingtreatment is expected to be of net benefit. In orderto assess if the benefits of continuing anticoagulanttherapy will outweigh its risks, the increase in recurrentVTE and the decrease in bleeding that will occur withstopping treatment need to be known or estimated. Inaddition, the consequences of a new episode of VTEand of an episode of bleeding need to considered.151,152
In patients with an average risk of bleeding whilereceiving anticoagulant therapy, therefore, the decisionto stop or continue therapy is dominated by the risk ofrecurrent VTE if treatment is stopped.
Current evidence suggests that the risk of recur-rence after stopping therapy is largely determined bytwo factors: (1) whether the acute episode of VTEhas been effectively treated; and (2) the patient’sintrinsic risk of having a new episode of VTE (ie, notarising directly from the episode of thrombosis forwhich patients have been receiving treatment). Iftherapy is stopped before the acute episode ofthrombosis is adequately treated, the risk of recur-rent VTE will be higher than if anticoagulants werestopped after a longer course of treatment. If pa-tients have a persistently high intrinsic risk forthrombosis, even if the acute episode of thrombosishas effectively been treated, they will have a high riskof recurrence once anticoagulant therapy is stopped;if this risk is sufficiently high relative to the patient’srisk of bleeding, long-term anticoagulant therapy willbe indicated.
During the past 15 years, a series of trials148–150,153–162
have compared different durations of antico-agulant therapy for VTE (Table 8). Most of thesestudies163–166 excluded patients with active cancerbecause they were judged to require long-termanticoagulant therapy because of a high risk ofrecurrence. The earlier trials,148,149,162 in addition tocomparing outcomes with different durations oftreatment, identified that the risk of recurrentVTE after stopping VKA therapy was much lowerif VTE had been provoked by a reversible riskfactor, such as surgery, rather than if the episode
Tab
le6
—C
onti
nued
Stud
y/yr
Inte
rven
tions
Patie
nts
Ana
lyze
dL
engt
hof
Fol
low
-up
Rec
urre
ntV
TE
Maj
orB
leed
ing
Tot
alM
orta
lity
Com
men
ts
PRE
PIC
135 /
2005
Sam
epa
tient
sas
for
PRE
PIC
1998
399
anal
yzed
for
deat
hD
enom
inat
ors
are
estim
ated
from
perc
enta
ges
and
reas
onfo
rdi
ffere
nces
are
notd
escr
ibed
8yr
Sym
ptom
atic
PEat
8yr
Filt
er:9
/145
(6.2
%)
No
filte
r:24
/159
(15.
1%)
RR
,0.4
1(9
5%C
I,0.
20–0
.86)
Sym
ptom
atic
DV
Tat
8yr
Filt
er:5
7/16
0(3
5.7%
)N
ofil
ter:
41/1
50(2
7.5%
)R
R,1
.3(9
5%C
I:0.
93–1
.82)
Sym
ptom
atic
DV
Tan
dPE
at8
yrF
ilter
:58/
159
(36.
4%)
No
filte
r:55
/155
(35.
4%)
RR
,1.0
3(9
5%C
I,0.
72–1
.38)
Maj
orbl
eedi
ngat
8yr
Filt
er:2
6/16
9(1
5.4%
)N
ofil
ter:
31/1
68(1
8.5%
)R
R,0
.83
(95%
CI.
0.52
–1.3
4)
Mor
talit
yat
8yr
Filt
er:9
8/20
0(4
9%)
No
filte
r:10
3/20
0(5
1%)
RR
,0.9
5(9
5%C
I,0.
78–1
.16)
Fat
alPE
at8
yrF
ilter
:2/2
00(1
.0%
)N
ofil
ter:
5/20
0(2
.5%
)R
R,0
.40
(95%
CI,
0.08
–2.0
4)
Lon
g-te
rmfo
llow
-up
ofPR
EPI
Cst
udy;
VK
As
wer
est
oppe
dat
3m
oin
38%
offil
ter
grou
pan
d36
%of
no-f
ilter
grou
p;V
KA
sw
ere
used
thro
ugho
ut8
yrfo
llow
-up
by35
%of
both
grou
ps;e
last
icst
ocki
ngs
wer
ew
orn
thro
ugho
ut8-
yrfo
llow
-up
by45
%of
filte
ran
d47
%of
no-
filte
rgr
oup
*The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
484S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le7—
Imm
obil
izat
ion
for
the
Tre
atm
ent
ofA
cute
DV
T:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
1.14
)*
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Sche
llong
etal
142 /
1999
RC
T,s
ingl
ece
nter
126
patie
nts
with
acut
epr
oxim
alD
VT
Am
bula
tion:
leg
elev
atio
nun
tilda
y2,
then
ambu
latio
n,co
mpr
essi
on(n
�64
)B
edre
st:B
edre
stfo
r8
dw
ithle
gel
evat
ion,
com
pres
sion
(n�
62)
PEby
vent
ilatio
n/pe
rfus
ion
scan
10d
Am
bula
tion:
PE:1
0/59
(17%
)
Bed
rest
:PE
:14/
63(2
2%)
Part
sch
and
Bla
ttle
r141 /
2000
RC
T,m
ultic
ente
r45
patie
nts
with
prox
imal
DV
T�
14d
dura
tion
Am
bula
tion
plus
band
ages
:ine
last
icU
nna
boot
band
ages
plus
wal
king
exer
cise
s,(n
�15
)
Am
bula
tion
plus
stoc
king
s:el
astic
com
pres
sion
stoc
king
spl
usw
alki
ngex
erci
ses
(n�
15)
Bed
rest
:bed
rest
,no
com
pres
sion
,L
MW
H(n
�15
)
Wal
king
dist
ance
,pai
nle
vels
,leg
circ
umfe
renc
e,cl
inic
alsc
ores
,PE
,si
deef
fect
s
9d
Sum
mar
yre
sults
betw
een
grou
ps:
Wal
king
dist
ance
,pai
n,le
gci
rcum
fere
nce
and
clin
ical
scor
essi
gnifi
cant
lyim
prov
edin
grou
psA
and
Bco
mpa
red
togr
oup
C
PE,g
roup
A:2
/15
(13%
)PE
,gro
upB
:1/1
5(7
%)
PE,g
roup
C:1
/15
(7%
)
Asc
hwan
den
etal
138 /2
001
RC
T,s
ingl
ece
nter
129
patie
nts
with
acut
eD
VT
Am
bula
tion:
Am
bula
tion
�4
h/d
for
4d
unde
rsu
perv
isio
n,L
MW
H(n
�69
)
Bed
rest
:B
edre
stfo
r4
(n�
60)
New
PEbe
twee
nba
selin
ean
dda
y4
byve
ntila
tion/
perf
usio
nsc
an
3m
oA
mbu
latio
n:PE
:10/
69(1
4%)
Bed
rest
PE:6
/60
(10%
)
Not
e:ne
wPE
sw
ere
asym
ptom
atic
;12/
16pa
tient
sha
dba
selin
ePE
sPa
rtsc
h143 /2
001
Pros
pect
ive
stud
y1,
289
patie
nts
with
acut
eD
VT
All
trea
ted
with
LM
WH
,co
mpr
essi
on,a
ndim
med
iate
ambu
latio
n
PEon
vent
ilatio
n/pe
rfus
ion
scan
atho
spita
ladm
issio
nan
daf
ter
10d
oftr
eatm
ent
10d
PEat
adm
issi
on:6
29/1
,270
(50%
)PE
at10
d:77
/1,2
56(6
1%)
Not
e:in
itial
lung
scan
sw
ere
perf
orm
edin
1,27
0/1,
289
patie
nts;
f/usc
ans
wer
epe
rfor
med
in1,
256/
1,28
9pa
tient
s.B
latt
ler
and
Part
sch13
9 /200
3R
CT
53pa
tient
sw
ithpr
oxim
alD
VT
Am
bula
tion
plus
band
ages
:fir
min
elas
ticba
ndag
es,
ambu
latio
n(n
�18
)
Am
bula
tion
plus
stoc
king
s:el
astic
com
pres
sion
stoc
king
s,am
bula
tion
(n�
18)
Bed
rest
only
(n�
17)
Wal
king
dist
ance
,wel
l-be
ing
and
DV
T-
rela
ted
QO
L,l
egpa
inby
VA
S,ed
ema,
clin
ical
scor
es,
thro
mbu
spr
ogre
ssio
n
9d
Wel
l-bei
ng/Q
OL
:Im
prov
edw
ithst
ocki
ngs
(p�
0.05
)ba
ndag
es(p
�0.
01)
Leg
pain
:D
ecre
ased
fast
erdu
ring
first
4d
with
band
ages
and
stoc
king
svs
bed
rest
(p[lt
0.01
);ne
arab
senc
eof
pain
at9
dac
hiev
edw
ithba
ndag
eson
lyE
dem
a:M
arke
dre
duct
ion
inle
gsi
zew
ithba
ndag
esan
dst
ocki
ngs
vsbe
dre
st(p
�0.
001)
Clin
ical
scor
es:
Impr
oved
with
band
ages
and
stoc
king
svs
bed
rest
(p�
0.00
1)T
hrom
bus
prog
ress
ion:
Impr
oved
with
band
ages
and
stoc
king
svs
bed
rest
(p�
0.01
)PE
:N
odi
ffer
ence
betw
een
grou
ps
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 485S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le7—
Con
tinu
ed
Aut
hor/
yrT
ype
ofSt
udy
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Part
sch
etal
144 /
2004
2-yr
follo
w-u
pto
RC
T(n
�77
)37
patie
nts
follo
wed
up2
yraf
ter
RC
T
Ant
icoa
gula
tion
and
bed
rest
vs Ant
icoa
gula
tion
and
ambu
latio
nw
ithco
mpr
essi
onba
ndag
esor
stoc
king
s
PTS
asse
ssm
ent
(Vill
alta
-Pra
ndon
isc
ale)
Pain
asse
ssm
ent
byV
AS
and
mod
ified
Low
enbe
rgte
st
Thr
ombu
sre
gres
sion
2yr
PTS
scor
es:
Am
bula
tory
grou
p(m
ean
scor
e,5.
1)ha
dim
prov
edou
tcom
evs
bed
rest
grou
p(m
ean
scor
e,8.
2)�p
�0.
01�
Pain
:L
ower
pain
leve
lsin
mob
ilegr
oup
vsbe
dre
st(n
otsi
gnifi
cant
)T
hrom
bus
exte
nsio
n:N
odi
ffer
ence
inth
rom
bus
regr
essi
onof
thro
mbu
sre
mna
nts
betw
een
grou
psT
rujil
lo-S
anto
set
al14
5 /200
5Pr
ospe
ctiv
est
udy
2,65
0pa
tient
sw
ithac
ute
DV
T(n
�20
38,7
7%)
orPE
(n�
612
,23
%)
DV
Tgr
oup:
bed
rest
oram
bula
tion:
1,05
0(5
2%)
patie
nts
rece
ived
bed
rest
and
988
patie
nts
(48%
)w
ere
ambu
late
d;al
lrec
eive
dL
MW
H.
PEgr
oup,
bed
rest
oram
bula
tion:
385
patie
nts
(63%
)re
ceiv
edbe
dre
st,a
nd22
7pa
tient
s(3
7%)
wer
eam
bula
ted;
allr
ecei
ved
LM
WH
Sym
ptom
atic
,co
nfir
med
PEdu
ring
first
15d
ofth
erap
y
3m
oD
VT
grou
p:be
dre
st:
PE:7
/1,0
50(0
.7%
)D
VT
grou
p:am
bula
te:
PE:4
/988
(0.4
%)
PEgr
oup:
bed
rest
:PE
:2/3
85(0
.5%
)PE
grou
p:am
bula
te:
PE:2
/227
(0.9
%)
Jung
eret
al14
0 /20
06R
CT
,mul
ticen
ter
open
desi
gnst
ratif
ied
byag
e
103
patie
nts
with
prox
imal
DV
TB
edre
st:5
0pa
tient
sre
ceiv
ed5
dof
stri
ctbe
dre
st,L
MW
H,
com
pres
sion
band
ages
Am
bula
tion:
52pa
tient
sam
bula
ted
for
5d,
LM
WH
,com
pres
sion
band
ages
PE,p
rogr
essi
onof
orne
wth
rom
bosi
s,in
fect
ion
orse
riou
sad
vers
eev
ent
5d
New
PEB
edre
st:8
/50
(16%
)A
mbu
latio
n:2/
52(4
%)
Prim
ary
targ
etva
riab
leB
edre
st:1
4/50
(28%
)A
mbu
latio
n:7/
52(1
3%)
*VA
S�
visu
alan
alog
uesc
ale.
The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
486S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le8
—C
ompa
riso
nsof
Du
rati
ons
and
Inte
nsit
ies
ofA
ntic
oagu
lant
The
rapy
for
DV
Tan
dP
E:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
2.1)
*
Aut
hor/
yr(A
cron
ym)
Inte
rven
tion
Pate
ints
Ana
lyze
d,N
o.L
engt
hof
Fol
low
-up
Rec
urre
ntD
VT
orPE
,No.
(Tot
al)
Maj
orB
leed
ing,
No.
(Tot
al)
Tot
alM
orta
lity,
No.
(%)
Com
men
ts
Shor
t(4
wk
or6
wk)
vsin
term
edia
te(3
mo
or6
mo)
dura
tion
sof
anti
coag
ulat
ion
Kea
ron
etal
157 /2
004
(SO
FA
ST)
VK
Ast
oppe
d(p
lace
bo)
VK
A(I
NR
,2.0
–3.0
)fo
r2
mor
em
o
84/8
4
81/8
1
11m
o
11m
o.
5/84
(6%
)
3/81
(4%
)R
R,0
.6(9
5%C
I,0.
1–2.
5)
0/84
0/81
RR
,1.0
(95%
CI,
0.0–
51.6
)
0/84
1/81
(1%
)R
R3.
1(9
5%C
I,0.
1–74
.4)
Popu
latio
n:fir
stD
VT
orPE
:tr
eate
dfo
r1
mo;
VT
Ew
asas
ympt
omat
icin
9%,a
ndis
olat
edca
lfD
VT
in18
%;o
neV
TE
occu
rred
whi
ledu
ring
war
fari
ntr
eatm
ent
Pine
deet
al16
0 /200
1(D
OT
AV
K)
VK
A(I
NR
,2.0
–3.0
)fo
r1.
5m
o.
VK
A(I
NR
,2.0
–3.0
)fo
r3
mo
105/
105
92/9
2
15m
o2/
105
(2%
)
3/92
RR
,1.7
(95%
CI,
0.3–
10.0
)
1/10
5(1%
)
3/92
RR
,3.4
(95%
CI,
0.4–
33.4
)
Not
spec
ified
Popu
latio
n:fir
stis
olat
edca
lfD
VT
Schu
lman
etal
162 /
1995
(DU
RA
C1)
VK
A(I
NR
,2.0
–2.8
5)fo
r1.
5m
o
VK
A(I
NR
,2.0
–2.8
5)fo
r6
mo
443/
443
454/
454
2yr
80/4
43(1
8%)
43/4
54(9
%)
RR
,0.5
(95%
CI,
0.4–
0.7)
1/44
3
5/45
4(1
%)
RR
,4.9
(95%
CI,
0.6–
41.6
)
22/4
43(5
%)
17/4
54(4
%)
RR
0.75
(95%
CI,
0.4–
1.4)
Fir
stV
TE
:DV
T(d
ista
lor
prox
imal
)or
PE;o
nly
aske
dab
out
blee
ding
whi
lere
ceiv
ing
VK
As
Lev
ine
etal
148 /1
995
VK
Ast
oppe
d(p
lace
bo)
VK
A(I
NR
,2.0
–3.0
)fo
r2
mor
em
o
105/
107
109/
113
9m
o12
/105
(11%
)
7/10
9(6
%)
RR
,0.6
(95%
CI,
0.2–
1.4)
0/10
5
1/10
9(1
%)
RR
,2.9
(95%
CI,
0.1–
70.2
)w
ithin
2m
oof
rand
omiz
atio
n
9/10
5(9
%)
9/10
9(8
%)
RR
,1.0
(95%
CI,
0.4–
2.5)
Prox
imal
DV
T(f
irst
epis
ode
in91
%);
canc
erin
21%
Bri
tish
Tho
raci
cSo
ciet
y149
VK
A(I
NR
,2.0
–3.0
)fo
r1
mo
VK
A(I
NR
,2.0
–3.0
)fo
r3
mo
358/
358
354/
354
1yr
1yr
28/3
58(1
1%)
14/3
54(4
%)
RR
,0.5
(95%
CI,
0.3–
0.9)
5/35
8(1
%)
4/35
4(1
%)
RR
,0.8
(95%
CI,
0.2–
3.0)
26/3
58(7
%)
28/3
54(8
%)
RR
,1.1
(95%
CI,
0.6–
1.8)
Popu
latio
n:D
VT
orPE
;onl
y71
%ob
ject
ivel
ydi
agno
sed;
prop
ortio
nw
itha
prev
ious
VT
Eno
tkn
own.
All
blee
dsw
ere
rece
ivin
gV
KA
;on
lyon
ere
curr
ent
VT
Eam
ong
116
patie
nts
with
post
oper
ativ
eV
TE
Sum
mar
y2,
198
RR
0.53
(0.4
0,0.
70)
RR
1.84
(0.7
6,4.
50)
RR
1.04
(0.7
4,1.
48)
For
alla
naly
ses,
p�
�0.
1fo
rhe
tero
gene
ity.S
OF
AST
80no
tin
clud
edin
estim
ate
for
maj
orbl
eedi
ngas
noev
ents
inei
ther
grou
p
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 487S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le8
—C
onti
nued
Aut
hor/
yr(A
cron
ym)
Inte
rven
tion
Pate
ints
Ana
lyze
d,N
o.L
engt
hof
Fol
low
-up
Rec
urre
ntD
VT
orPE
,No.
(Tot
al)
Maj
orB
leed
ing,
No.
(Tot
al)
Tot
alM
orta
lity,
No.
(%)
Com
men
ts
Dif
fere
ntin
term
edia
tedu
rati
ons
(6m
oor
12m
ovs
3m
o)of
anti
coag
ulat
ion
Cam
pbel
let
al15
5 /200
7V
KA
(IN
R2.
.0–3
.5)
for
3m
o
VK
A(I
NR
2.0–
3.5)
for
6m
o
369/
396
380/
414
1yr
1yr
31/3
69(8
%)
29/3
80(8
%)
RR
,0.9
(95%
CI,
0.6–
1.5)
0/36
9(d
urin
g3
mo
oftr
eatm
ent)
8/38
0(2
%)
duri
ng6
mo
oftr
eatm
ent
RR
,16.
5(9
5%C
I,(1
.0–2
85)
15/3
69(4
%)
9/36
9(5
%)
RR
,1.3
(95%
CI,
0.6–
2.5)
Popu
latio
n:D
VT
orPE
;pro
port
ion
with
calf
DV
Tno
tkn
own;
Onl
ybl
eedi
ngdu
ring
trea
tmen
tis
repo
rted
.20%
ofV
TE
outc
omes
wer
eno
tob
ject
ivel
yve
rifie
dA
gnel
liet
al15
3 /200
3(W
OD
IT-P
E)
VK
Ast
oppe
d
VK
A(I
NR
,2.0
–3.0
)fo
r9
mor
em
o
91/9
1
90/9
0
2.6
yr(m
ean)
2.9
yr(m
ean)
11/9
1(1
2%)
11.9
0(1
2%)
RR
,1.0
(95%
CI,
0.5–
2.2)
1/91
(1%
)
2/90
(2%
)R
R,2
.0(9
5%C
I,0.
5–21
.9)
7/91
(8%
)
8/90
(9%
)R
R,1
.16
(95%
CI,
0.4–
3.0)
Popu
latio
n:fir
stun
prov
oked
PE;
trea
ted
for
�3
mo;
amon
gth
efo
urgr
oups
,onl
yon
ere
curr
ent
VT
Ew
hile
rece
ivin
gV
KA
VK
Ast
oppe
d
VK
A(I
NR
,2.0
–3.0
)fo
r3
mor
em
o
70/7
0
75/7
5
2.8
yr(m
ean)
2.9
yr(m
ean)
7/70
(10%
)
4/75
(5%
)R
R,0
.5(9
5%C
I,0.
2–1.
7)
0/70
(0%
)
1/75
(1%
)R
R,1
.9(9
5%C
I,0.
1–56
)
0/70
(0%
)
4/75
(5%
)R
R,8
.4(9
5%C
I,0.
5–15
3)
Popu
latio
n:fir
stpr
ovok
edPE
;tr
eate
dfo
r�
3m
o(s
eepr
evio
us)
Agn
elli
etal
154 /2
001
(WO
DIT
–D
VT
)V
KA
stop
ped
VK
A(I
NR
,2.0
–3.0
)fo
r9
mo
133/
133
134/
134
3.2
yr(m
ean)
3.1
yr(m
ean)
21/1
33(1
6%)
21/1
34(1
6%)
RR
,1.0
(95%
CI,
0.6–
1.7)
2/13
3(2
%)
4/13
4(3
%)
RR
,2.0
(95%
CI,
0.4–
10.7
)
7/13
3(5
%)
7/13
4(5
%)
RR
,1.0
(95%
CI,
0.4–
2.8)
Popu
latio
n:F
irst
unpr
ovok
edpr
oxim
alD
VT
trea
ted
for
3m
o;on
epa
tient
had
recu
rren
tV
TE
whi
lere
ceiv
ing
VK
A;b
leed
ing
inth
ein
terv
entio
ngr
oup
was
whi
lere
ceiv
ing
VK
APi
nede
etal
160 /2
001
(DO
TA
VK
)V
KA
(IN
R,2
.0–3
.0)
for
3m
oV
KA
(IN
R,1
.0–3
.0)
for
6m
o
270/
270
269/
269
15m
o21
/270
(8%
)
23/2
69(9
%)
RR
,1.1
(95%
CI,
0.6–
1.9)
5/27
0(2
%)
7/26
9(3
%)
RR
,1.4
(95%
CI,
0.4–
4.4)
Not
spec
ified
Popu
latio
n:fir
stpr
oxim
alD
VT
orPE
;rec
urre
ntV
TE
occu
rred
afte
rV
KA
in26
/28
ofth
esh
ort-
dura
tion
grou
psan
d21
/27
ofth
elo
ng-d
urat
ion
grou
psSu
mm
ary
1,88
1R
R,0
.95
(95%
CI,
0.72
–1.2
6)R
R,2
.53
(95%
CI,
1.18
–5.4
6)R
R,1
.3(9
5%C
I,0.
82–2
.08)
For
alla
naly
ses,
p�
0.1
for
hete
roge
neity
Inde
fini
tevs
inte
rmed
iate
dura
tion
sof
anti
coa
gula
tion
(IN
R,
appr
oxim
atel
y20
–3.0
)Pa
lere
tiet
al15
9 /200
6(P
RO
LO
NG
)R
emai
nof
f(s
top)
VK
A
Res
tart
Inde
finite
VK
A(I
NR
,2.
0–3.
0)no
tbl
inde
d
103/
105
120/
122
1.4
yr(m
ean)
,m
axim
um1.
5yr
18/1
03(1
7%)
2/12
0(2
%)
RR
,0.1
(95%
CI,
0.0–
0.4)
0/10
3
1/12
0(1
%)
RR
,2.6
(95%
CI,
0.1–
62.6
)
1/10
3(1
%)
1/12
0(1
%)
RR
,0.9
(95%
CI,
0.1–
13.6
)
Popu
latio
n:F
irst
unpr
ovok
edpr
oxim
alD
VT
orPE
;tre
ated
for
�3
mo;
VK
Ast
oppe
dan
dd-
dim
erpo
sitiv
e1
mo
late
r
Eig
htco
ntro
lpat
ient
s;re
star
ted
VK
A,s
ome
afte
rsu
perf
icia
lph
lebi
tis;o
nere
curr
ent
VT
Ein
VK
Agr
oup
afte
rV
KA
stop
ped.
488S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le8
—C
onti
nued
Aut
hor/
yr(A
cron
ym)
Inte
rven
tion
Pate
ints
Ana
lyze
d,N
o.L
engt
hof
Fol
low
-up
Rec
urre
ntD
VT
orPE
,No.
(Tot
al)
Maj
orB
leed
ing,
No.
(Tot
al)
Tot
alM
orta
lity,
No.
(%)
Com
men
ts
Kea
ron
etal
156 /1
999
(LA
FIT
)V
KA
stop
ped
(Pla
cebo
)
VK
A(I
NR
,2.0
–3.0
)fo
r2
mor
eyr
83/8
379
/79
10m
o(m
ean)
,m
axim
um2
yr)
17/8
3(2
0%)
1/79
(1%
)R
R,0
.1(9
5%C
I,0.
0–0.
5)
0/83
3/79
(4%
)R
R,7
.4(9
5%C
I,0.
4–14
0)
3/83
(4%
)
1/79
(1%
)R
R,0
.3(9
5%C
I,0.
0–3.
3)
Popu
latio
n:fir
stun
prov
oked
prox
imal
DV
Tor
PE(5
%)
had
prev
ious
prov
oked
VT
E;
recu
rren
tV
TE
inth
eV
KA
patie
ntw
asaf
ter
stop
ping
VK
A
Schu
lman
etal
150 /1
997
(DU
RA
C2)
VK
A(I
NR
,2.0
–2.8
5)fo
r6
mo
VK
A(I
NR
,2.0
–2.8
5)In
defin
itely
111/
111
116/
116
4yr
23/1
11(2
%)
3/11
6(3
%)
RR
,0.1
(95%
CI,
0.0–
0.4)
3/11
1(3
%)
10/1
16(9
%)
RR
,3.2
(95%
CI,
0.9–
11.3
)
16/1
11(1
4%)
10/1
16(9
%)
RR
,0.6
(95%
CI,
0.3–
1.3)
Seco
ndV
TE
:DV
T(d
ista
lor
prox
imal
)or
PE;a
llre
curr
ent
VT
Es
inth
ein
defin
iteV
KA
grou
pw
ere
afte
rst
oppi
ngV
KA
s;bl
eedi
ngdu
ring
the
first
6m
oof
VK
Ain
one
patie
nts
in6-
mo
grou
pan
dsi
xpa
tient
sin
inde
finite
grou
p(o
nly
aske
dab
out
blee
ding
whi
lere
ceiv
ing
VK
As)
Sum
mar
yR
R,0
.1(9
5%C
I,0.
04–0
.22)
RR
,3.6
1(9
5%C
I,1.
22–1
0.7)
RR
,0.5
8(9
5%C
I,0.
29–1
.14)
For
alla
naly
ses,
p�
0.1
for
hete
roge
neity
Inde
fini
tevs
inte
rmed
iate
dura
tion
sof
anti
coag
ulat
ion
(IN
R,
appr
oxim
atel
y5–
2.0
afte
rin
itia
lIN
Rof
2.0–
3.0
inbo
thgr
oups
)R
idke
r161 /2
003
(PR
EV
EN
T)
VK
Ast
oppe
dor
not
rest
arte
d(P
lace
bo)
VK
A(I
NR
,1.5
–2.0
)
253/
253
255/
255
2.1
yr(m
ean)
,m
axim
um,
4.3
yr
37/2
53(1
5%)
14/2
55(5
%)
RR
,0.4
(95%
CI,
0.2–
0.7)
2/25
3(1
%)
5/25
5(2
%)
RR
,2.5
(95%
CI,
0.5–
12.7
)
8/25
3(3
%)
4/25
5(2
%)
RR
,0.5
(95%
CI,
0.1–
1.6)
Popu
latio
n:U
npro
voke
dD
VT
(dis
talo
rpr
oxim
al)
orPE
(fir
step
isod
ein
38%
);ei
ght
recu
rren
tV
TE
sin
the
VK
Agr
oup
afte
rst
oppi
ngV
KA
sL
ow-i
nten
sity
(IN
R,
1.5–
1.9)
vsco
nven
tion
alin
tens
ity
(IN
R,
2.0–
3.0)
Kea
ron18
5 /200
3(E
LA
TE
)V
KA
(IN
R,1
.5–1
.9)
VK
A(I
NR
,2.0
–3.0
),bl
inde
d
369/
369
369/
369
2.4
yr(m
ean)
16/3
69(4
%)
6/36
9(2
%)
RR
,0.4
(95%
CI,
0.1–
0.9)
9/36
9(2
%)
8/36
9(2
%)
RR
,0.9
(95%
CI,
0.3–
2.3)
16/3
69(4
%)
8/36
9(2
%)
RR
,0.5
(95%
CI,
0.2–
1.2)
Popu
latio
n:U
npro
voke
dpr
oxim
alD
VT
orPE
(fir
step
isod
ein
31%
);tr
eate
dfo
r�
3m
o.V
KA
(IN
R,2
.0–
3.0)
;mea
n,12
mo;
five
recu
rren
tV
TE
sin
INR
of1.
5–1.
9an
dth
ree
inIN
Rof
2.0–
3.0
grou
paf
ter
stop
ping
VK
As
*The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 489S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
of VTE was unprovoked (also called idiopathicVTE). This observation was also made in a numberof other prospective studies166,167 during the sameperiod. Consequently, many of the more recenttrials that compared durations of VKA therapyselectively enrolled patients with either unpro-voked VTE,153,154,156,158,159,161 or VTE that wasprovoked by a reversible risk factor157 (Table 8).Longer or indefinite durations of anticoagulanttherapy were generally evaluated in patients withunprovoked VTE, and shorter durations of therapywere evaluated in patients with a reversible provok-ing factor. Because the presence of a reversibleprovoking risk factor,148,149,160,162,163,165–170 unpro-voked VTE,148,149,160,162,163,165–170 and presence ofactive cancer163–166 were used to select patients formany of the studies, and have been shown to be themost important factors that influence risk of recur-rent VTE after stopping VKA, separate recommen-dations for duration of anticoagulant therapy will bemade for each of these three categories of patientswith VTE. Reversible provoking risk factors includethe following: major factors such as surgery, hospi-talization, or plaster cast immobilization, all within 1month; and minor factors such as estrogen therapy,pregnancy, prolonged travel (eg, � 8 h), or thepreviously noted major factors when they have oc-curred 1 to 3 months before diagnosis of VTE. Thegreater the provoking reversible risk factor (eg, suchas recent major surgery), the lower the expected riskof recurrence after stopping anticoagulant thera-py.168 Within each of these three groups, we willconsider if there are additional factors that influencethe risk of recurrence enough to modify recommen-dations about duration of therapy. The most impor-tant of such factors are the following: (1) whetherDVT was confined to the distal veins (often calledisolated calf DVT) or involved the proximalveins,160,162,170 and (2) whether the DVT was a firstepisode of VTE or a second or subsequent episode ofVTE.161,164,171 The presence of hereditary thrombo-philia has not been used as a major factor to guideduration of anticoagulation for VTE in these guide-lines because evidence from prospective stud-ies156,161,168,169,172–180 suggests that these factors arenot major determinants of the risk of recurrence.
VKAs for the Long-term Treatment of DVT
Clinical trials that have evaluated different dura-tions of anticoagulant therapy can be divided intothree categories according to the durations oftherapy that were compared: (1) short vs intermedi-ate durations, (2) different intermediate durations,and (3) indefinite therapy vs intermediate durations.Within each of these categories we will first consider
studies that included heterogeneous (ie, less se-lected) patients with VTE, and then studies thatenrolled subgroups of (ie, selected) patients whowere expected to have either a lower (eg, associatedwith reversible risk factors) or a higher (eg,unprovoked, or second episodes, of VTE) risk ofrecurrence.
Short (4 Weeks or 6 Weeks) vs Intermediate (3Months or 6 Months) Durations of Therapy
Five trials148,149,160,162 have evaluated shortening theduration of oral anticoagulant therapy from 3 or 6months to 4 or 6 weeks in patients with mostly firstepisodes of VTE (Table 8). The first three studies(British Thoracic Society, Levine, DURAC 1; Table 8),which mainly enrolled unselected patients with proxi-mal DVT or PE, found that shortening the duration ofanticoagulation was associated with about double thefrequency of recurrent VTE during follow-up of 1 to 2years (an absolute risk increase of approximately5%).148,149,162 Major bleeding was uncommon duringthe incremental period of anticoagulation in these threestudies (estimated at seven episodes among 1,009patients during 259 patient-years of additional treat-ment [2.7%/yr]).148,149,162 Therefore, the main findingof these studies was that anticoagulant therapy shouldnot be shortened to 4 or 6 weeks in patients with VTE.
Subgroup analyses of one of the above studies (DU-RAC 1) suggests that isolated distal DVT provoked bya major transient risk factor can safely be treated withonly 6 weeks of therapy.162 A subsequent study,160
(component of DOTVAK), which compared 6 vs 12weeks of therapy in patients with isolated calf DVT(unprovoked or provoked; mostly diagnosed by ultra-sound), found no suggestion that shortening therapyincreased the risk of recurrence (RR, 0.6; 95% CI, 0.01to 3.4) and, in general, observed a low frequency ofrecurrent VTE with isolated calf DVT (approximately2% in the first year) compared to proximal DVT or PE(approximately 6% in the first year). These findingssuggest that if anticoagulants need to be stopped after6 weeks of therapy in patients with isolated distal DVT,the subsequent risk of recurrence is not expected to beexcessive. The fifth of these studies157 enrolled onlypatients with VTE associated with a major reversiblerisk factor (SOFAST; Table 8); however, because only165 patients were enrolled, its findings were not defin-itive. A metaanalysis of five studies (retrospective iden-tification of the patient’s subgroup in four stud-ies,148,149,162,181 selective enrollment of patients in 1study157) that compared 4 or 6 weeks with 3 or 6months of treatment among 725 patients with VTEprovoked by a reversible risk factor found that theshorter durations of therapy were associated with more
490S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
than double the risk of recurrent VTE during the nextyear (OR, 2.9; 95% CI, 1.2 to 6.9; absolute increase ofapproximately 3.4%).157
Different Intermediate Durations of Therapy (6Months or 12 Months vs 3 Months)
Two studies155,160 have compared 6 months vs 3months of anticoagulant therapy in patients withpredominantly first episodes of DVT or PE (unpro-voked, or provoked by a reversible risk factor)[DOTAVK, Campbell; Table 8]. There was no dif-ference in the risk of recurrence during follow-up inboth studies, and one study155 reported a lowerrisk of bleeding in the 3-month group (Campbell;Table 8).
Agnelli and colleagues154 compared stopping antico-agulant therapy at 3 months with continuing it foranother 9 months after a first episode of unprovokedproximal DVT (WODIT-DVT; Table 8). At the end ofthe first year, recurrent VTE was less frequent in thegroup that remained on anticoagulant therapy (3.0% vs8.3%), but this benefit was lost 2 years after thesepatients stopped anticoagulant therapy (RR, 1.0; 95%CI, 0.6 to 1.7). The same investigators obtained similarresults in a comparable study153 of patients with unpro-voked PE (WODIT PE; Section 5.1, Table 8).
Based on the findings of these five studies (the“provoked” and “unprovoked” components of theWODIT-PE study are have been condidered separatestudies),153–155,160 anticoagulants are very effective atpreventing recurrence while patients are receiving ther-apy; but, at the end of extended follow- up after stoppingtreatment, a similar risk of recurrence is expected ifanticoagulants are stopped at 6 or 12 months, com-pared to at 3 months (RR for the five studies, 0.95;95% CI, 0.72 to 1.26; Table 8), including amongpatients with unprovoked proximal DVT or PE.
Indefinite vs Intermediate Durations ofAnticoagulant Therapy
Four trials have compared indefinite (where indef-inite refers to extended therapy without scheduledstopping of treatment) anticoagulation (target INRs,2.0 to 2.85,150 2.0 to 3.0,156,159 and 1.5 to 2.0161) withstopping therapy in patients with VTE who werebelieved to have a high risk of recurrence becausethrombosis was a second episode,150 unpro-voked,156,161 or was unprovoked and had a positived-dimer result 1 month after stopping therapy159
(DURAC 2, LAFIT, PREVENT, PROLONG; Table8). The results indicate that randomization to indef-inite treatment with conventional-intensity VKA (tar-get INR, 2.5) reduces recurrent VTE by approxi-mately 90% (RR for the three studies, 0.10; 95% CI,
0.04 to 0.22; Table 8),150,156,159 and randomization tolow-intensity therapy (target INR, 1.75) reducesVTE by 64% (95% CI for HR, 23 to 81%)161 (Table8; both RRs are appreciably greater among patientswho remain on VKA therapy).
The benefit of indefinite treatment with VKA ispartially offset by the risk of major bleeding. In thetwo initial studies150,156,182 of extended treatment(DURAC 2, LAFIT; Table 8), the incidence of majorbleeding was approximately 3%/yr during extendedtreatment with conventional-intensity warfarin (in-cluded bleeding during the first 6 months of therapyin DURAC 2). However, in the more recent PRO-LONG study159 and a randomized comparison ofconventional-intensity and low-intensity VKA (ELATE;Table 8),158 extended treatment with conventional-intensity VKA was associated with a risk of majorbleeding of approximately 1% per patient-year (low-intensity VKA is considered in Section 2.2). A meta-analysis184 of seven studies115,148,154,156,161,171,183 thatcompared durations of conventional-intensity antico-agulant therapy for VTE estimated the rate of majorbleeding to be 1.1% per patient-year (18 episodes in1,571 patient-years) during the extended phase ofanticoagulation compared with 0.6% per patient-year (9 episodes during 1,497 patient-years) withoutanticoagulation (RR, 1.80; 95% CI, 0.72 to 4.51).Thus, for patients with unprovoked DVT (and PE),the benefit of long-term treatment is partially offsetby a higher risk of bleeding, and patients loseprotection against recurrent VTE if anticoagulantsare withdrawn. For these reasons, values and pref-erences regarding preventing recurrent thromboem-bolism, avoiding bleeding complications and incon-venience of treatment, bear on the recommendationfor long-term anticoagulant treatment for unpro-voked VTE, particularly after a first episode of DVT(lower risk of recurrence than after a second episodeof VTE,161,164,171 and expected to have a lower risk ofdeath with a recurrence than after a first episode ofPE164,185).186 Individual patient risk of recurrentVTE and of major bleeding may differ from theaverage values that have been reported in the previ-ously noted trials and, in selected patients, mayinfluence the decision to continue or stop anticoag-ulant therapy once 3 months of initial treatment hasbeen completed, or subsequently.
Of factors that have been evaluated as risk factors forrecurrent VTE among patients with unprovoked DVT,the following appear to have the greatest potential to beclinically useful: isolated calf DVT vs proximal DVT(RR, approximately 0.5)160,162,170; one or more previousepisodes of VTE (RR, approximately 1.5)161,164,171;negative d-dimer findings 1 month after withdrawal ofVKA (RR, approximately 0.4)159,177,187,188; antiphos-pholipid antibody (RR, approximately 2)156,179,189;
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 491S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
hereditary thrombophilia (RR, approximately1.5)156,161,168,169,173–175,177; males vs females (relativerisk 1.6)190; Asian ethnicity (RR, approximately0.8)191; and residual thrombosis in the proximal veins(RR, approximately 1.5).153,156,157,192–194
Of factors that have been evaluated as risk factorsfor major bleeding during anticoagulant therapy, thefollowing appear to have the greatest potential to beclinically useful markers of increased risk: older age,particularly after 75 years; previous GI bleeding,particularly if not associated with a reversible cause;previous noncardioembolic stroke; chronic renal orhepatic disease; concomitant antiplatelet therapy (tobe avoided if possible); other serious acute orchronic illness; poor anticoagulant control; subopti-mal monitoring of anticoagulant therapy (see chapteron Hemorrhagic Complications of Anticoagulant andThrombolytic Therapy195).158,195–202
Recommendations
2.1.1. For patients with DVT secondary to atransient (reversible) risk factor, we recom-mend treatment with a VKA for 3 months overtreatment for shorter periods (Grade 1A).2.1.2. For patients with unprovoked DVT, werecommend treatment with a VKA for at least 3months (Grade 1A). We recommend that after 3months of anticoagulant therapy, all patientswith unprovoked DVT should be evaluated forthe risk-to-benefit ratio of long-term therapy(Grade 1C). For patients with a first unprovokedVTE that is a proximal DVT, and in whom riskfactors for bleeding are absent and for whomgood anticoagulant monitoring is achievable,we recommend long-term treatment (Grade 1A).Values and preferences: This recommendation at-taches a relatively high value to prevention of recur-rent VTE and a lower value to the burden oflong-term anticoagulant therapy.
For patients with a second episode of unpro-voked VTE, we recommend long-term treat-ment (Grade 1A). For patients with a first iso-lated distal DVT that is unprovoked, we suggestthat 3 months of anticoagulant therapy is suffi-cient rather than indefinite therapy (Grade 2B).2.1.3. For patients with DVT and cancer, werecommend LMWH for the first 3 to 6 monthsof long-term anticoagulant therapy (Grade 1A).For these patients, we recommend subsequentanticoagulant therapy with VKA or LMWH in-definitely or until the cancer is resolved (also,see Section 2.4) [Grade 1C].2.1.4. For patients who receive long-term anticoag-ulant treatment, the risk-benefit ratio of continuing
such treatment should be reassessed in the individ-ual patient at periodic intervals (Grade 1C).
2.2 Intensity of Anticoagulant Effect
The preferred intensity of the anticoagulant effectof treatment with VKA has been established by theresults of randomized trials.158,203–205 The ELATEstudy was a randomized, blinded trial that comparedlow-intensity VKA (target INR, 1.5 to 1.9) withconventional-intensity VKA (INR, 2.0 to 3.0) forindefinite treatment of patients with unprovokedVTE who had completed at least 3 months of initialconventional-intensity anticoagulation (Table 8). Theincidences of recurrent VTE were 1.9% per patient-year in the low-intensity group, and 0.6% per pa-tient-year in the conventional-intensity group (haz-ard ratio, 3.3; 95% CI, 1.2 to 9.1).158 The incidencesof major bleeding were 0.96% per patient-year in thelow-intensity group and 0.93% per patient-year inthe conventional-intensity group; the correspondingincidences of all bleeding (major and minor) were4.9% per patient-year and 3.6% per patient-year.Thus, low-intensity VKA treatment was less effectivethan conventional-intensity therapy and did not pro-vide a safety advantage.158 The observed incidence ofrecurrent VTE of 1.9% per patient-year in thelow-intensity group is similar to the incidence of2.6% per patient-year in the PREVENT study,161
which compared low-intensity warfarin therapy(INR, 1.5 to 2.0) with placebo (the latter group hadan incidence of recurrent VTE of 7.2% per patient-year; hazard ratio, 0.36 compared with placebo; 95%CI, 0.19 to 0.67). Taken together, the results of thesetwo randomized trials158,161 indicate that after 3months of conventional-intensity therapy, althoughlow-intensity warfarin therapy is much more effec-tive than placebo, it is less effective than convention-al-intensity therapy and does not appear to reducethe incidence of bleeding complications.
In the PREVENT trial,161 low-intensity anticoagula-tion was delivered using a dosing nomogram thatscheduled INR measurements 8 weeks apart, providedthe current INR result was 1.3 to 3.0. This nomogramresulted in an average interval between INR tests of 61days compared with an average interval of 26 days inthe conventional-intensity group of the ELATE trial,158
in which ordering of INR measurements was at thediscretion of the responsible clinician. Thus, the find-ings of the PREVENT trial suggest that anticoagulantmonitoring can be simplified, and made less burden-some to patients and health-care providers, when thetarget INR is 1.75 (range, 1.5 to 2.0) rather than 2.5(range, 2.0 to 3.0). Some patients may prefer to betreated with a lower intensity of VKA therapy that isdelivered with less frequent INR monitoring that to
492S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
receive conventional-intensity therapy that, althoughmore effective, requires more frequent INR monitor-ing.
Additional important evidence regarding the opti-mal intensity of anticoagulant therapy with VKA isprovided by the PAPRE203 and WAPS204 random-ized trials that compared conventional-intensity VKAtherapy (INR, 2.0 to 3.0) with high-intensity warfarintherapy (INR, 3.1 to 4.0203 and 3.0 to 4.5204) for theprevention of recurrent thromboembolism in pa-tients with antiphospholipid antibodies and a historyof venous or arterial thromboembolism (Table 9). Inthe two studies combined, there was no evidencethat the higher intensity of anticoagulation was asso-ciated with a lower frequency of recurrent thrombo-embolism (OR, 2.49; 95% CI, 0.93 to 6.67), and nodifference in major bleeding (OR, 0.73; 95% CI, 0.23to 2.31), or minor bleeding (OR, 1.75; 95% CI, 0.93to 3.31).204 However, high-intensity VKA therapy haspreviously been shown to be associated with highrates of bleeding in patients with VTE.147,205,206 Theevidence outlined above provides the basis for therecommendation of an INR of 2.0 to 3.0 as thepreferred intensity of long-term anticoagulant treat-ment with VKA in all patients with VTE.
Recommendation
2.2.1. In patients with DVT, we recommendthat the dose of VKA be adjusted to maintain atarget INR of 2.5 (range, 2.0 to 3.0) for alltreatment durations (Grade 1A). For patientswith unprovoked DVT who have a strong pref-erence for less frequent INR testing to monitortheir therapy, after the first 3 months of con-ventional-intensity anticoagulation (INR range,2.0 to 3.0), we recommend low-intensity ther-apy (INR range, 1.5 to 1.9) with less frequentINR monitoring over stopping treatment (Grade1A). We recommend against high-intensity VKAtherapy (INR range, 3.1 to 4.0) compared to anINR range of 2.0 to 3.0 (Grade 1A).
2.3 SC UFH for the Long-term Treatment of DVT
Adjusted-dose SC UFH is an effective approach forthe long-term treatment of DVT,206 whereas low-doseUFH (5,000 U bid) is inadequate for this pur-pose.147,207 In a study208 of 80 patients with DVT andcontraindications to VKA therapy that compared10,000 U of UFH with 5,000 IU of dalteparin, eachadministered SC twice daily for 3 months, there was asimilar low frequency of recurrent VTE and bleeding inboth groups, but less frequent spinal fracture in theLMWH group. Because of the lower potential forosteoporosis with LMWH and because it can be ad-
ministered once daily without the need for anticoagu-lant monitoring, LMWH is preferred to UFH forlong-term therapy.
2.4 LMWH for the Long-term Treatment of DVT
Twelve randomized trials have compared VKA(INR, 2.0 to 3.0) with widely differing regimens of fiveLMWH preparations (dalteparin,209–211 enoxapa-rin,167,212–214 nadroparin,215,216 tinzaparin,217,218 bemi-parin34). In these studies, the daily LMWH dose was aslow as 4,000 IU167,212 to as high as 200 IU/kg211,216;approximately a 3.5-fold difference. Two metaanalysesof studies that compared LMWH with VKAs, eachadministered for 3 months after initial heparin therapy,have been performed.219,220 In the analysis by Iorioand colleagues,219 which includes seven stud-ies167,209,212,214–217 and a total of 1,379 patients, therewere trends toward less recurrent VTE (OR, 0.66; 95%CI, 0.41 to 1.07) and less major bleeding (OR, 0.45;95% CI, 0.18 to 1.11) with 3 months of LMWHcompared with VKA. Compared with outcomes inpatients who received VKA therapy, between studydifferences of mean daily dose of LMWH had littleeffect on efficacy but did appear to influence the risk ofmajor bleeding (OR, approximately 0.2 with approxi-mately 4,000 IU/d to approximately 0.7 with 12,000IU/d, relative to the VKA groups [p � 0.03]).219 Threesubsequent studies that selectively enrolled a total of1,029 patients with VTE in association with activecancer found that, compared to VKA therapy, 3months213,221 or 6 months211 of therapeutic-doseLMWH was associated with less recurrent VTE in onestudy211 and less bleeding in another study213 (Table10) [RR for the three studies: recurrent VTE, 0.56;95% CI, 0.38 to 0.82; major bleeding, 1.01; 95% CI,0.62 to 1.64; mortality, 0.92; 95% CI, 0.78 to 1.10;Table 4].213,219,221 Randomized trials have not evalu-ated approaches to anticoagulant therapy after the first6 months of VKA or LMWH therapy in patients withVTE and cancer, either to assess duration of therapy orto compare extended therapy with VKA or LMWH.Observational studies163–166 suggest that the risk ofrecurrent VTE is unacceptably high in patients withactive cancer who stop anticoagulant therapy.
2.5 New Antithrombotic Agents for Long-termTreatment of DVT
Ximelagatran (since withdrawn because of hepatictoxicity) has been evaluated for both short-term andlong-term treatment of VTE.61,171 In the short-termtreatment study,61 2,491 patients with acute DVT weretreated for 6 months with ximelagatran, 36 mg bid, orLMWH followed by VKA therapy (INR, 2.0 to 3.0),using a blinded design. The frequency of recurrentVTE at 6 months was similar with ximelagatran (2.1%)
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 493S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
and usual therapy (2.0%), and an “on treatment”analysis (“intention to treat” analysis was not reported)suggested less major bleeding with ximelagatran (1.3%vs 2.2%; 95% CI for difference, � 2.0% to 0.2%). Inthe long-term treatment study,171 18 months of ximel-agatran (24 mg bid) was compared with placebo in1,224 patients with DVT or PE who had completed 6months of initial treatment with VKA. Ximelagatranreduced recurrent VTE by 84% (95% CI, 70 to 91%)without an apparent increase in major bleeding (hazardratio, 1.2; 95% CI, 0.4 to 3.8). Many new anticoagulantsare being evaluated in ongoing trials (see chapter byWeitz et al222 on new anticoagulant drugs).
The long-acting pentasaccharide idraparinuxwas reported to be as effective and as safe as VKAfor the first 3 or 6 months of treatment of DVT(but less effective that VKA in patients withPE).223 After an initial 6 months of treatment witheither idraparinux or warfarin (52% of patientsinitially presented with symptomatic DVT), com-pared with placebo, 6 months of extended therapywith idraparinux markedly reduced recurrent VTEand increased bleeding.223
2.6 Treatment of Asymptomatic DVT of the Leg
Screening of postoperative patients for the pres-ence of asymptomatic DVT is not recommended224;instead, surgical patients should receive appropriateprimary prophylaxis for VTE. If asymptomatic prox-imal DVT is detected, for example, in patients whohave screening performed because they could notreceive recommended VTE prophylaxis or in pa-tients who have imaging studies performed for otherreasons (eg, staging of cancer), care should be takento ensure that DVT is truly present and patientsshould be treated as described elsewhere in thischapter (also see Section 5.4, “Treatment of Asymp-tomatic PE”). Asymptomatic proximal DVT detectedby routine ultrasound screening in the setting of aclinical trial evaluating VTE prophylaxis in hospital-ized medical patients has been shown to be associ-ated with increased mortality at 3 months.225
Recommendation
2.6.1. In patients who are unexpectedly foundto have asymptomatic DVT, we recommend thesame initial and long-term anticoagulation asfor comparable patients with symptomatic DVT(Grade 1C).
3.0 Postthrombotic Syndrome
PTS is a cluster of leg symptoms and signs inpatients with previous DVT. PTS occurs in 20 to
Tab
le9
—C
ompa
riso
nof
Hig
h-In
tens
ity
and
Con
vent
iona
l-In
tens
ity
VK
AT
hera
pyin
Pat
ient
sW
ith
Ven
ous
orA
rter
ial
Thr
omb
osis
and
anA
ntip
hosp
holi
pid
Ant
ibod
y:C
lini
cal
Des
crip
tion
and
Res
ult
s(S
ecti
on2.
2)*
Aut
hor/
yr(A
cron
ym)
Inte
rven
tions
Patie
nts
Ana
lyze
d,N
o.(%
)L
engt
hof
Fol
low
-up
Rec
urre
ntV
enou
sor
Art
eria
lT
hrom
bosi
s,N
o.(T
otal
)M
ajor
Ble
edin
g,N
o.(T
otal
)T
otal
Mor
talit
y,N
o.(%
)C
omm
ents
Cro
wth
eret
al20
3 /200
3(P
APR
E)
VK
A(I
NR
,2.0
–3.0
)
VK
A(I
NR
,3.1
–4.0
)
58/5
8
56/5
6
2.7
yr(m
ean)
2.6
yr(m
ean)
2/58
(3.4
%)
6/56
(10.
7%)
RR
,3.1
(95%
CI,
0.6–
15)
4/58
(6.9
)
3/56
(5.4
)R
R,0
.8(9
5%C
I,0.
2–3.
3)
0/58
0/56
RR
,1.0
(95%
CI,
0.0–
48)
Popu
latio
n:76
%ha
dV
TE
and
24%
had
arte
rial
thro
mbo
embo
lism
only
,ac
utel
yor
rem
otel
y;al
lhad
anan
tipho
spho
lipid
antib
ody
ontw
ooc
casi
ons
3m
oap
art;
four
ofei
ght
thro
mbo
ticep
isod
esw
ere
arte
rial
Fin
azzi
etal
204 /2
004
(WA
PS)
VK
A(I
NR
,2.0
–3.0
),n
�52
,or
aspi
rin
at10
0m
g/d
ifno
VT
Eor
card
ioem
bolis
m(n
�3)
VK
A(I
NR
,3.0
–4.5
)
55/5
5
54/5
4
Med
ian
of3–
6yr
for
allp
atie
nts
3/55
(5.5
%)
6/54
(11.
1%)
RR
,2.0
(95%
CI,
0.5–
7.7)
3/55
(5.5
%)
2/54
(3.7
%);
RR
,0.7
(95%
CI,
0.1–
3.9)
2/55
(3.6
)
3/54
(5.6
)R
R,0
1.64
(95%
CI,
0.3–
8.8)
Popu
latio
n:69
%ha
veV
TE
and
405
had
arte
rial
thro
mbo
embo
lism
,acu
tely
orre
mot
ely
All
had
anan
ticar
diol
ipin
antib
ody
ontw
ooc
casi
ons
6–8
wk
apar
t;of
nine
thro
mbo
ticep
isod
es,s
ixw
ere
arte
rial
and
one
was
supe
rfic
ial
phle
bitis
*The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
494S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
50% of patients after acute DVT.226 The initialtreatment of acute DVT may influence the presenceand severity of PTS, as discussed earlier (Section2.0). The most prominent symptoms are chronicpostural dependent swelling and pain, ambulatorydiscomfort, and skin pigmentation. The severity ofsymptoms may vary over time, and the most extrememanifestation is a venous ulcer of the lower leg.First, the studies on the prevention of PTS arediscussed, followed by the trials on the treatment ofthis syndrome, with and without venous ulcers.
3.1 Elastic Stockings and Compression BandagesTo Prevent PTS
Four randomized trials144,227–229 have evaluated theefficacy of compression stockings for the prevention ofPTS following DVT (Table 11). Two trials, namelythose of Brandjes et al227 and Prandoni et al,229 ran-domized patients to stockings (30 to 40 mm Hg anklegradient) or no stockings after a first episode ofacute symptomatic proximal DVT. A third trial byGinsberg et al228 evaluated 47 asymptomatic pa-tients with evidence of venous valvular incompe-tence 1 year following their acute DVT. Twenty-six percent of the patients had asymptomatic DVTdetected by phlebography after orthopedic sur-gery. A lower compression stocking of 20 to 30 mmHg ankle pressure was compared with a placebostocking.
Blattler and Partsch139 randomized 53 patients withacute symptomatic DVT to anticoagulation and bedrest for 9 days or anticoagulation and ambulation witheither inelastic bandages or compression stockings (30mm Hg). Early and long-term results favored theambulation-with-compression group (Table 11).144
Brandjes et al227 demonstrated that 47% of thecontrol group had mild-to-moderate PTS comparedwith 20% of patients in the stocking group. Twenty-three percent of patients in the control group vs 11%of patients in the stocking group had severe PTS.Prandoni et al229 made similar observations, in thatPTS developed in 49% of control patients comparedwith 25% in the treatment group after 2 years.
Ginsberg et al228 observed no difference in the 47patients who were randomized to 20 to 30 mm Hgcompression stockings compared with a placebostocking. Since all patients were asymptomatic atentry into the study 1 year after diagnosis, and as26% initially had asymptomatic DVT, it appears thatthe patients in this trial were unlikely to benefit fromany measure to prevent PTS, since PTS was unlikelyto develop without treatment.
A Cochrane review230 that combined the findings ofBrandjes, Prandoni, and Ginsberg (421 patients) esti-mated that stockings markedly reduced the cumulative
incidence of PTS at 2 years (OR, 0.3; 95% CI, 0.2 to0.5). An ongoing placebo-controlled study is furtherevaluating whether routine wearing of graduated com-pression stockings prevents the development of PTS.231
Recommendation
3.1.1. For a patient who has had a symptomaticproximal DVT, we recommend the use of anelastic compression stocking with an anklepressure gradient of 30 to 40 mm Hg iffeasible (Grade 1A). Compression therapy,which may include use of bandages acutely,should be started as soon as feasible afterstarting anticoagulant therapy and should becontinued for a minimum of 2 years, andlonger if patients have symptoms of PTS.(Note: feasibility, both short-term and long-term, refers to ability of patients and theircaregivers to apply and remove stockings.)Values and preferences: This recommendation attachesa relatively high value to long-term prevention of thePTS and a low value to the burden (eg, inconvenienceor discomfort) associated with wearing stockings.
3.2 Physical Treatment of PTS Without Venous LegUlcers
The treatment of PTS has been evaluated onlyin small or methodologically flawed trials. Treat-ment is usually based on physical methods de-signed to counteract the raised venous pressure.Of these approaches, elastic stockings have beenevaluated in asymptomatic and symptomatic pa-tients in a small underpowered trial228; the resultsfailed to show a benefit, possibly due to milddisease and small patient numbers. In a cross-overstudy232 of 15 patients with a severe PTS, inter-mittent pneumatic compression (IPC) at 40 mmHg was more effective than a lower (placebo)pressure. Twelve of 15 patients preferred thetherapeutic pressure.
Recommendations
3.2.1. For patients with severe edema of the leg dueto PTS, we suggest a course of IPC (Grade 2B).3.2.2. For patients with mild edema of the leg due toPTS, we suggest the use of elastic compressionstockings (Grade 2C).
3.3 Physical Treatment of Venous Leg Ulcers
Venous leg ulcers represent the most severe com-plication of PTS. While most reports of venous legulcers fail to differentiate a postthrombotic etiologyfrom primary venous insufficiency, it is recognized thatthe postthrombotic limb is likely to have higher venous
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 495S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le10
—L
MW
Hvs
VK
Afo
rL
ong-
Ter
mT
reat
men
tof
VT
Ein
Pat
ient
sW
ith
Act
ive
Can
cer:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
2.4)
*
Aut
hor/
yr(A
cron
ym)
Inte
rven
tions
Patie
nts
Ana
lyze
d,N
o./T
otal
(%)
Len
gth
ofF
ollo
w-u
pR
ecur
rent
DV
Tor
PE,N
o./T
otal
(%)
Maj
orB
leed
ing,
No.
/Tot
al(%
)T
otal
Mor
talit
y,N
o./T
otal
(%)
Com
men
ts
Mey
eret
al21
3 /200
2V
KA
(IN
R,2
.0–3
.0)
for
3m
oaf
ter
initi
alen
oxap
arin
Eno
xapa
rin
at1.
5m
g/kg
once
daily
for
3m
o
75/7
5
71/7
1
3m
o
3m
o.
3/75
(4%
)
2/71
(3%
)R
R,0
.7(9
5%C
I,0.
1–4.
1)
12/7
5(1
6%)
5/71
(7%
)R
R,0
.4(9
5%C
I,0.
2–1.
2)
17/7
5(2
3%)
8/71
(11%
)R
R,0
.5(9
5%C
I,0.
2–1.
1)
Popu
latio
n:D
VT
(pro
port
ion
with
calf
DV
Tno
tkn
own)
orPE
and
activ
eca
ncer
;al
lfat
albl
eedi
ngs
(n�
6)w
ere
inV
KA
grou
p.
Lee
etal
211 /2
003
(CL
OT
)V
KA
(IN
R,2
.0–3
.0)
for
6m
oaf
ter
initi
alda
ltepa
rin
Dal
tepa
rin
at20
0U
/kg
once
daily
for
1m
ofo
llow
edby
150
U/k
gfo
r5
mo
336/
338
336/
338
6m
o
6m
o
53/3
36(1
6%)
27/3
36(8
%)
RR
,0.5
(95%
CI,
0.3–
0.8)
12/3
35(4
%)
19/3
38(6
%)
RR
,1.6
(95%
CI,
0.8–
3.2)
136/
336
(40%
)
130/
336
(37%
)R
R,1
.0(9
5%C
I,0.
8–1.
2)
Popu
latio
n:Pr
oxim
alD
VT
orPE
and
activ
eca
ncer
Diff
eren
cein
effic
acy
mai
nly
due
tore
curr
ent
DV
T(1
4vs
37ep
isod
es)
Hul
let
al22
1/2
006
(Mai
nL
ITE
-ca
ncer
)
VK
A(I
NR
2.0–
3.0)
for
3m
oaf
ter
initi
alIV
UF
H
Tin
zapa
rin
at17
5m
g/kg
once
for
3m
o
100/
100
100/
100
3m
o
3m
o.
10/1
00(1
0%)
6/10
0(6
%)
RR
,0.6
(95%
CI,
0.2–
1.6)
7/10
0(7
%)
7/10
0(7
%)
RR
,1.0
(95%
CI,
0.4–
2.8)
19/1
00(1
9%)
20/1
00(2
0%)
RR
,1.0
(95%
CI,
0.6–
1.9)
Popu
latio
n:Pr
oxim
alD
VT
and
activ
eca
ncer
Pres
peci
fied,
stra
tific
atio
n,su
bgro
upw
ithin
ala
rger
tria
l;O
utco
mes
at12
mo
wer
eal
sore
port
edSu
mm
ary
RR
,0.7
(95%
CI,
0.4–
0.8)
RR
,1.0
(95%
CI,
0.6–
1.6)
RR
,0.9
(95%
CI,
0.8–
1.1)
*The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
496S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
pressures and, therefore, more likely to have ulcerationthan patients with primary venous insufficiency.65
Smith et al233 demonstrated that in patients withvenous leg ulcers, IPC for 4 h daily added to standardwound care and compression significantly increasedhealing (p � 0.009) [Table 12]. Kumar et al234 foundthat IPC in addition to standard four-layered compres-sion increased rate of ulcer healing (p � 0.046) andreduced time to a healed ulcer (p � 0.05) [Table 12].In 10 patients with postthrombotic venous ulcers, 60min of IPC was found to increase transcutaneousoxygen tension, reduce edema, and increase skin tem-perature in the short-term (Table 12).235 As compres-sion pressures and cycles have varied in the studies thathave been performed, IPC prescription for treatment
of PTS and venous ulcers has not been standardized.Surgical correction of superficial venous reflux in addi-tion to compression bandaging was shown to reducerecurrent ulceration compared with compression ther-apy alone in a randomized trial236,237 of 500 patientswith open or recently healed leg ulcers and ultrasound-confirmed superficial venous reflux (recurrent ulcer-ation of 31% vs 56% at 4 years; p � 0.01).
Recommendation
3.3.1. In patients with venous ulcers resistant tohealing with wound care and compression, wesuggest the addition of IPC (Grade 2B).
Table 11—Elastic Stockings for the Prevention of PTS: Clinical Description and Results (Section 3.1)*
Author/yrType ofStudy Participants Interventions Outcomes Follow-up Results
Brandjes et al227/1997
RCT 194 patientswith firstsymptomatic,proximal DVT
Compression stockings:below-kneecustomizedelastic compressionstockings withankle pressure30–40 mm Hg(96 patients)
Control group: nointervention (n � 98)
Cumulativeincidence ofmild-to-moderateand severe PTS
3 mo and 6 mo,then every6 mo to amedian of76 mo
Compression stockings:Mild-to-moderate PTS:
20% (RR, 0.42; 95%CI, 0.27–0.66; p �0.001)
Severe PTS: 11% (RR,0.49; 95% CI, 0.25–0.95; p � 0.001)
Control group:Mild-to-moderate PTS:
47%Severe PTS: 23%
Ginsberg et al228/2001
RCT 47 asymptomaticpatients withvalvularincompetence1 yr afterDVT
Compression stockings:below-knee elasticcompression stockings20–30 mm Hg(n � 24)
Placebo: placebostocking (n � 23)
PTS symptoms 57 mo (mean) Compression stockings:PTS symptoms: 0%
Placebo:PTS symptoms: 4%
Prandoni et al229/2004
RCT 180 patients withfirst episode ofsymptomatic,acute proximalDVT
Compression stockings:below-knee elasticcompression stockings30–40 mm Hg(n � 90)
Control group: nointervention(n � 90)
Cumulativeincidence ofmild-to-moderateand severe PTS
3 to 5 yr Compression stockings:PTS symptoms: 25%
(95% CI, 15.6–33.4%)
Control group:PTS symptoms: 49%
(95% CI, 38.7–59.4%)
Partsch et al144/2004
2-yr follow-upto RCT141
37 symptomaticpatients withacute DVTfollowed uplong term
All anticoagulated withLMWH followed byoral anticoagulation
Inelastic bandages plusearly ambulation (n �13)
Elastic stockings (30 mmHg) plus earlyambulation (n � 13)
Bed rest for 9 d, nocompression (n � 11)
Overall leg pain,leg circumference,PTS score(Villalta-Prandoni)
2 yr Leg painNo difference between
groups
Calf circumferenceNo difference between
groups
PTS scoreSignificantly better
outcome withambulation andbandaging or stockingscompared to bed rest(p � 0.01)
*The methodologic quality description portion of this table can be found in the online version of this article as a data supplement.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 497S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
3.4 Hyperbaric Oxygen and the Management ofPatients With Venous Ulcers
Only one small trial238 of acceptable methodologicquality has evaluated hyperbaric oxygen in the treatmentof patients with venous leg ulcers, and this study of 16patients failed to show any benefit on the rate of healing.
Recommendation
3.4.1. For patients with venous ulcers, we suggestthat hyperbaric oxygen not be used (Grade 2B).
3.5 Pharmacologic Treatment of Venous Ulcers
Not all venous ulcers heal in a timely manner withcompression and/or IPC, and such patients maybenefit from the addition of pharmacologic agents.
Pentoxifylline
Pentoxifylline affects the membrane of blood cells,resulting in changes in the rheology of blood and themicrocirculation.239 A Cochrane review evaluatedeight randomized studies240–247 with a total of 547patients with venous leg ulcers who were treatedwith pentoxifylline vs placebo and in which there wasobjective measurement of wound healing (Table 13).Compression therapy was used in five of the eighttrials,241–244,246 and in three trials no compressionwas used.240,245,247 There was a tendency for com-plete healing or significant improvement to occurmore frequently in pentoxifylline-treated patients(RR, 1.5; 95% CI, 1.1 to 2.0). In the five studies inwhich compression was used, the addition of pen-toxifylline resulted in an RR of healing of 1.3 (95%
Table 12—Physical Treatment of PTS With Venous Ulcers: Clinical Description and Results (Section 3.3)*
Author/yrType ofStudy Participants Interventions Outcomes Follow-up Results
Kolari et al235/1988
Prospectivestudy
10 patients (studygroup) withPTS leg ulcers,and 9 patientswith noevidence ofperipheralarterial disease
1 h of IPC at 50 mm Hg(inflation time of 12 s,deflation time of 18 s);leg volume and skintemperature measuredbefore and aftercompression
Before/afterinterventionTcPO2 (supineat ulcer edge),leg volume(waterdisplacement),skintemperature
Immediately afterprocedure
Before/after TcPO2:Study group: before,
26.2 � 7.0, after, 42.7� 6.4 (p � 0.005)
Control subjects: before,59.7 � 2/9; after, ND
Change in TcPO2correlated significantlywith reduction inedema and inversechange in skintemperature (R �0.912, p � 0.002)
Smith et al233/1990
RCT 45 patients withnonhealingvenous ulcers
Stockings: ulcerdebridement, cleaning,nonadherent dressing,graduated compressionstockings 30–40 mmHg
Stockings plus IPC: sameprotocol ascompression group plusIPC 4 h/d
Healed ulcer,median rate ofhealing perweek
3.7 yr (mean) StockingsHealed ulcer: 1/24 (4%)Median healing rate:
2.1%
Stockings plus IPCHealed ulcer: 10/21
(48%) �p � 0.009�Median healing rate:
19.8% (p � 0.046)
Kumar et al234/2002
RCT 47 patients withnonhealingvenous ulcers
Bandages: weekly four-layer bandaging
Bandages plus IPC:weekly four-layerbandaging plus IPC for1 h bid at 60 mm Hg
Mean number ofdays to healedulcer, meanrate of healing
4 mo BandagesMean days to healed
ulcer: 73.7 dMean rate of healing:
0.05 cm2/d (95% CI,0.03–0.07; SD �0.046)
Bandages plus IPCMean days to healed
ulcer: 53.5 dMean rate of healing:
0.14 cm2/d (95% CI,0.03–0.25; SD � 0.22)�p � 0.05�
*TcPO2 � transcutaneous oxygen pressure; ECS � elastic compression stocking; IPC � intermittent pneumatic compression; ND � not determined.The methodologic quality description portion of this table can be found in the online version of this article as a data supplement.
498S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
CI, 1.1 to 1.5). In the three studies in whichcompression was not used as standard therapy, pen-toxifylline also promoted healing (RR, 2.4; 95% CI,1.3 to 4.3). A subsequent trial248 of 80 patientsshowed similar results.
Micronized Purified Flavonoid Fraction orSulodexide for the Treatment of Venous Leg Ulcers
Hydroxyrutosides are a class of flavonoid drugproduced from plant glycosides. Although theirmechanism of action is not entirely known, theyappear to reduce capillary permeability, reduceinflammation, improve lymphatic function, andimprove symptoms relating to chronic venousinsufficiency249,250 (Table 14). Micronization ofthe flavonoid compound improves intestinal ab-sorption and bioavailability and, therefore, isthought to improve clinical effects.251 A meta-analysis252 of five studies evaluated micronizedpurified flavonoid fraction (MPFF) in the manage-ment of patients with venous ulceration who wereall treated with compression. Two of the fivestudies were placebo-controlled trials, whereasthree studies did not incorporate a placebo. At 6months, complete ulcer healing had occurred in61% of the MPFF patients and in 48% of thecontrol patients (RR reduction for persistent ul-ceration, 32%; 95% CI, 3 to 70%; p � 0.03).Subgroup analyses suggested that the benefits ofMPFF were greatest in ulcers � 5 cm2 and � 6months in duration. Sulodixide, a glycosaminogly-can preparation that is administered intraamuscu-larly or orally, was shown to increase venous ulcerhealing in a placebo-controlled trial253 of 235patients (RR for healing, 1.37; 95% CI, 1.07 to1.74) without an apparent increase in side effects.
Recommendations
3.5.1. In patients with venous leg ulcers, wesuggest pentoxifylline, 400 mg po tid, in ad-dition to local care and compression and/orIPC (Grade 2B).3.5.2. In patients with persistent venous ul-cers, we suggest that rutosides, in the form ofMPFF adminstered orally, or sulodexide ad-ministered intramuscularly and then orally,be added to local care and compression(Grade 2B).
4.0 Initial Treatment of Acute PE
Treatment regimens for DVT and PE are similarbecause the two conditions are manifestations of the
same disease process. When patients with VTE arecarefully studied, the majority of those with proximalDVT also have PE (symptomatic or asymptomatic) andvice versa.185 Furthermore, clinical trials of anticoagu-lant therapy have yielded similar estimates for efficacyand safety in patients with DVT alone, in those withboth DVT and PE, and in patients with only PE. Therisk of recurrence also appears to be similar after PEand after proximal DVT.164,185 The vast majority ofpatients with VTE who receive adequate anticoagula-tion survive. However, there are some important dif-ferences between patients who present with PE andthose who present with DVT that justify separateconsideration of treatment for PE. First, the risk ofearly death (within 1 month) from VTE, due to eitherthe initial acute episode or recurrent VTE, is muchgreater after presenting with PE than after DVT164; thisdifference may justify more aggressive initial treatmentfor PE (eg, thrombolytic therapy, insertion of an IVCfilter, more intensive anticoagulant therapy) com-pared with DVT. Second, recurrent episodes ofVTE are about three times as likely to be PE afteran initial PE than after an initial DVT (ie, approx-imately 60% after a PE vs 20% after a DVT)164,185;this difference may justify more aggressive, ormore prolonged, long-term therapy. Third, thelong-term sequelae of PE are cardiorespiratoryimpairment, especially due to pulmonary hyper-tension, rather than PTS of the legs or arms. As therecommendation for anticoagulant therapy andIVC filter insertion in patients with PE are partlybased on studies that enrolled DVT patients alone,or both DVT and PE patients, see correspondingsections for treatment of patients with DVT.
4.1 IV or SC UFH, SC LMWH, SC Fondaparinux,and VKA for the Initial Treatment of PE
Anticoagulant Therapy vs No Anticoagulant Therapy
In their landmark RCT, Barritt and Jordan1
showed that short-term treatment with intermittentboluses of IV UFH and VKA therapy was effective inpatients with a clinical diagnosis of PE (Table 15);this trial also reported very favorable outcomes in acohort of 38 patients with severe PE who were alltreated with anticoagulants (one nonfatal recurrentPE, and one death not due to PE or bleeding) afterthe RCT was stopped early because of benefit fromactive therapy.
SC LMWH vs IV UFH
Consistent with findings in patients with DVT,LMWH has been found to be at least as effective
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 499S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
and safe as IV UFH in studies that included bothpatients with PE and/or DVT, or only patients withPE (Table 15). In a metaanalysis259 of 12 stud-ies29,30,33,35,39,43,44,254 –258 that included a total of1,951 patients with either submassive symptomaticPE, or asymptomatic PE in conjunction withsymptomatic DVT, at the end of treatment (5 to 14days), LMWH was associated with a tendency toless recurrent VTE (OR, 0.63; 95% CI, 0.33 to1.18), less major bleeding (OR, 0.67; 95% CI, 0.36to 1.27), and similar all-cause mortality (OR, 1.20;95% CI, 0.59 to 2.45).
SC UFH vs SC LMWH
Two recent large studies of patients with acuteVTE (total of 1,478 patients, of whom 253 presentedwith PE) found no difference in recurrent VTE,bleeding, or all-cause mortality between patientswho were treated with either partially24 or fully25
weight-adjusted SC UFH (dose adjusted to APTTresults in one study,24 and in fixed-doses withoutAPTT monitoring in the other study25), comparedwith those who were treated with LMWH (Galilie,FIDO; Table 2) [judged Grade 1B evidence fornoninferiority of monitored and fixed-dose SC UFHcompared with LMWH].
Fondaparinux vs IV UFH
The Matisse PE study,60 an open-label trial thatenrolled 2,213 patients with acute PE (including majorPE, provided thrombolytic therapy was not required),found that partially weight-adjusted, fixed-dose, SCfondaparinux was associated with a similar frequency ofrecurrent VTE (3.8% vs 5.0% at 3 months) and majorbleeding (1.3% vs 1.1% during initial treatment) asadjusted-dose IV UFH (Table 15) [judged Grade 1Aevidence for noninferiority of fondaparinux comparedwith IV UFH or SC LMWH].
Treatment of PE on an Outpatient Basis
No published trials have specifically randomizedpatients with acute PE to either be treated in hospitalor at home. Two randomized trials25,57 included pa-tients with acute PE who were treated as outpatients.The first trial,57 which compared two LMWH prepa-rations for outpatient treatment of acute VTE, in-cluded 90 patients with acute PE. The second trial,25
which compared subcutaneous fixed-dose UFH andLMWH in patients with acute VTE, included 52patients with acute PE who were treated entirely asoutpatients. Among the 142 patients, there was a lowfrequency of recurrent VTE (3.5%) and major bleed-ing (1.4%). The feasibility of treating a substantial
proportion of patients with symptomatic PE withLMWH at home is also supported by the findingsof three observational studies260 –262 in which 158patients (35% of total) with PE were treatedentirely at home. Two prediction rules have beendeveloped to aid with selection of patients withacute PE who are suitable for treatment out ofhospital.263–265 Recommendations about the initi-ation of UFH or LMWH as well as the overlapwith VKA and monitoring of the anticoagulanteffects are largely based on the findings in patientswith DVT and, therefore, are the same as for DVT(see Section 1).
Recommendations
4.1.1. For patients with objectively confirmedPE, we recommend short-term treatment withSC LMWH (Grade 1A), IV UFH (Grade 1A),monitored SC UFH (Grade 1A), fixed-dose SCUFH (Grade 1A), or SC fondaparinux (Grade 1A)rather than no such short-term treatment. Pa-tients with acute PE should also be routinelyassessed for treatment with thrombolytic ther-apy (see Section 4.3 for related discussion andrecommendations).4.1.2. For patients for whom there is a highclinical suspicion of PE, we recommend treat-ment with anticoagulants while awaiting theoutcome of diagnostic tests (Grade 1C).4.1.3. In patients with acute PE, we recommendinitial treatment with LMWH, UFH, orfondaparinux for at least 5 days and until theINR is > 2.0 for at least 24 h (Grade 1C).4.1.4. In patients with acute PE, we recommendinitiation of VKA together with LMWH, UFH, orfondaparinux on the first treatment day ratherthan delayed initiation of VKA (Grade 1A).4.1.5. In patients with acute PE, if IV UFH ischosen, we recommend that after an initial IVbolus (80 U/kg or 5,000 U), it be administeredby continuous infusion (initially at dose of 18U/kg/h or 1,300 U/h) with dose adjustment toachieve and maintain an APTT prolongationthat corresponds to plasma heparin levels of0.3 to 0.7 IU/mL anti-Xa activity by the amido-lytic assay rather than administration as IVboluses throughout treatment, or administra-tion without coagulation monitoring (Grade1C).4.1.6. In patients with acute PE, if monitoredSC UFH is chosen, we recommend an initialdose of 17,500 U, or a weight-adjusted dose ofabout 250 U/kg bid, with dose adjustment toachieve and maintain an APTT prolongationthat corresponds to plasma heparin levels of
500S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Table 13—Pentoxifylline for the Treatment of PTS With Venous Ulcers: Clinical Description and Results(Section 3.5.1)*
Author/yr Type of Study Participants Interventions Outcomes Follow-up Results
Weitgasser247/1983
RCT 60 patients withnonhealingvenous legulcers
Pentoxifylline: 400 mg tid(n � 30)
Placebo (n � 30)
Healed ulcer (ulcerclosed or sizeconsiderablyreduced)
6–8 wk PentoxifyllineComplete ulcer healing:
20/30 (67%)
PlaceboComplete ulcer healing:
7/29 (24%)Schürman
et al246/1986RCT 24 patients with
nonhealingvenous ulcers
Pentoxifylline pluscompression: 400 mgTID plus compression(n � 12)
Placebo plus compression(n � 12)
Healed ulcer 8 wk Pentoxifylline pluscompression
Complete ulcer healing:2/12 (16%)
Placebo plus compression:Complete ulcer healing:
3/12 (25%)Arenas and
Atoche240/1988
RCT 30 patients withnonhealingvenous ulcers
Pentoxifylline: 400 mgTID (n � 18)
Placebo (n � 12)
Healed ulcer 6 mo PentoxifyllineComplete ulcer healing:
7/18 (39%)
PlaceboComplete ulcer healing:
3/12 (25%)Colgan242/
1990RCT,
multicenter80 patients with
nonhealingvenous ulcers
Pentoxifylline pluscompression: 400 mgTID plus layeredcompression (n � 38)
Placebo plus compression:placebo plus layeredcompression (n � 42)
Healed ulcer 24 wk Pentoxifylline pluscompression
Complete ulcer healing:23/38 (60%)
Placebo plus compressionComplete ulcer healing:
12/42 (29%)Barbarino241/
1992RCT 12 patients with
nonhealingvenous ulcers
Pentoxifylline pluscompression: 400 mgTID plus layeredcompression (n � 6)
Placebo plus compression:placebo plus layeredcompression (n � 6)
Healed ulcer 2–3 mo Pentoxifylline pluscompression
Complete ulcer healing: 4/6(66%)
Placebo plus compressionComplete ulcer healing: 1/6
(17%)Apollonio and
Angeletti385/1992
RCT 23 patients withnonhealingvenous ulcers
Defibrotide: 800 mg intwo doses daily(n � 12)
Pentoxifylline: 400 mgof pentoxifylline tid(n � 11)
Healed ulcer 6 mo DefibrotideComplete ulcer healing:
11/12 (92%)
PentoxifyllineComplete ulcer healing:
9/11 (82%)Herdy et al245/
1997RCT 12 patients with
nonhealingvenous ulcers
Pentoxifylline: 400 mgpentoxifylline TID(n � 6)
Placebo (n � 6)
Reduction in ulcerarea
12 wk PentoxifyllineUlcer reduction: 2.2 cm2
PlaceboUlcer reduction: 0.4 cm2
Dale et al243/1999
Factorial RCT,multicenter
200 patientswithnonhealingvenous ulcers
Pentoxifylline pluscompression: 400 mgTID plus compressionplus wound dressing(n � 101)
Placebo plus compression:placebo plus compressionplus wound dressing(n � 99)
Healed ulcer 24 wk Pentoxifylline pluscompression
Complete ulcer healing:65/101 (64%)
Placebo plus compressionComplete ulcer healing:
52/99 (52%)
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 501S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
0.3 to 0.7 IU/mL anti-Xa activity when mea-sured 6 h after injection rather than startingwith a smaller initial dose (Grade 1C).4.1.7. In patients with acute PE, if fixed-dose,unmonitored SC UFH is chosen, we recom-mend an initial dose of 333 U/Kg followed bya twice-daily dose of 250 U/kg rather thannon–weight-based dosing (Grade 1C).4.1.8. In patients with acute nonmassive PE, werecommend initial treatment with LMWH over IVUFH (Grade 1A). In patients with massive PE, inother situations where there is concern about SCabsorption, or in patients for whom thrombolytictherapy is being considered or planned, we sug-gest IV UFH over SC LMWH, SC fondaparinux,or SC UFH (Grade 2C).4.1.9. In patients with acute PE treated withLMWH, we recommend against routine monitoringwith anti-factor Xa level measurements (Grade 1A).4.1.10. In patients with acute PE and severe renalfailure, we suggest UFH over LMWH (Grade 2C).
4.2 New Antithrombotic Agents for the InitialTreatment of PE
In addition to the synthetic pentasaccharidefondaparinux (Section 4.1), several other new anti-thrombotic agents have recently been developed(see chapter by Weitz et al222 in this supplement). Aspreviously noted (Section 2.5), ximelagatran hasbeen compared with LMWH and VKA therapy forthe initial 6 months of short-term treatment of DVT,and one third of these patients had concomitant PE(not available for clinical use because of associatedliver toxicity).61 The long-acting pentasaccharideidraparinux was reported to be less effective thanstandard therapy with heparins and VKA for the first3 to 6 months of treatment of PE.62
4.3 Systemically and Locally AdministeredThrombolytic Therapy for PE
Thrombolytic therapy for PE remains controver-sial. The fundamental problem is that � 800 PE
Table 13—Continued
Author/yr Type of Study Participants Interventions Outcomes Follow-up Results
Falanga etal244/1999
RCT 129 patients withnonhealingvenous ulcers
Placebo plus compression(n � 45)
Pentoxifylline pluscompression: 400 mgTID plus compression(n � 41)
Pentoxifylline pluscompression: 800 mgTID plus compression(n � 43)
Healed ulcer 24 wk Placebo plus compressionComplete ulcer healing:
28/45 (63%)
Pentoxifylline 400 mg tidplus compression:
Complete ulcer healing:31/41 (75%)
Pentoxifylline 800 mg tidplus compression
Complete ulcer healing:31/43 (73%)
Belcaro etal386/2002
RCT 172 patients withnonhealingvenous ulcers
Pentoxifylline: 400 mg tid(n � 82)
Placebo (n � 88)
Healed ulcer 6 mo PentoxifyllineComplete ulcer healing:
67%
PlaceboComplete ulcer healing:
31%De Sanctis et
al387/2002RCT 85 patients with
nonhealingvenous ulcers
Pentoxifylline: 400 mg tid(n � 41)
Placebo (n � 39)
Healed ulcer 12 mo PentoxifyllineComplete ulcer healing:
88%
PlaceboComplete ulcer healing:
44%Nikolovska et
al248/2002RCT 80 patients with
nonhealingvenous ulcers
Pentoxifylline: 400 mg tid(n � 40)
Placebo (n � 40)
Healed ulcer 6 mo PentoxifyllineComplete ulcer healing:
23/40 (58%)
PlaceboComplete ulcer healing: 11/
40 (28%)
*The methodologic quality description portion of this table can be found in the online version of this article as a data supplement.
502S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
patients have been enrolled in randomized trials ofthrombolysis plus anticoagulation vs anticoagulationalone (Table 16). The results of such trials havebeen summarized in three recently publishedmetaanalyses.266–268 In one overview, which included11 studies269–278 totalling 748 patients with PE ofvarying severity, thrombolysis was associated withtrends toward reduction in recurrent PE (2.7% vs
4.3%; OR, 0.67; 95% CI, 0.33 to 1.37), reduction inall-cause mortality (4.3% vs 5.9%; OR, 0.70; 95%CI, 0.37 to 1.30), and an increase in major bleed-ing (9.1% vs 6.1%; OR, 1.42; 95% CI, 0.81 to2.46). In the subset of five trials269,271,273,275,278
(total of 254 patients) that focused on patients withmore severe PE, the reduction in mortality (6.2%vs 12.7%; OR, 0.47; 95% CI, 0.20 to 1.10) and the
Table 14—MPFF for the Treatment of PTS With Venous Ulcers: Clinical Description and Results (Section 3.5)*
Author/yr Type of Study Participants Interventions OutcomesFollow-
up Results
Guilhou etal388/1997
RCT, placebocontrolled,multicenter
105 patients withvenous ulcers,stratified byulcer size: �10cm (n � 91),� 10 cm (n � 14)
MPFF pluscompression:500 mg bid pluscompression
Placebo pluscompression
Complete ulcerhealing
Symptoms of CVI,time to heal
2 mo Healed ulcersTreatment: 14/44 (32%)Control: 6/47 (13%)p � 0.028;
No ulcer � 10 cm2
Glinski etal389/2001
RCT, open label 140 patients withvenous leg ulcers,stratified byulcer size:� 3 cm, 3–6 cm,� 6 cm
MPFF pluscompression: 500 mgbid plus compression
Compression alone
Complete ulcerhealing
Reduction in ulcersize, cost-effectiveness
6 mo Healed ulcersTreatment: 47%Control: 28%(p � 0.05; RR, 2.3; 95% CI,
1.1–4.6)
Ulcer: � 3 cmTreatment: 71%Control: 50%
Ulcer 3–6 cmTreatment: 60%Control: 32%
Ulcer � 6 cmTreatment: 9%Control: 13%
Cost per healed ulcerTreatment: €1026.20Control: €1871.80
Roztocil etal390/2003
RCT, openlabel,multicenter
150 patients withvenous legulcers 2–10 cmin diameter
MPFF pluscompression
Complete healingat 6 mo
6 mo Healed ulcersTreatment: 65%Control: 41%(p � 0.004)
Days to achieve healingTreatment: 137 dControl: 166 d(p � 0.004)
Coleridge-Smithet al252/2005
Metaanalysis,three trialssummarizedabove, plustwounpublishedtrials
723 patients withvenous legulcers
Two studiesMPFF plus compression
vs compression plusplacebo
Three studiesMPFF plus compression
vs compression alone
Complete healing 2–6 mo Healing increased by 32%(RR, 1.3.2; 95% CI, 1.03–1.70) at 6 mo
Healing time shortened by 5wk
Healing increased in ulcers� 5 cm2 (RR, 1.53; 95%CI, 1.15–2.03) and � 6mo old (RR, 1.41; 95%CI, 1.09–1.81)
*The methodologic quality description portion of this table can be found in the online version of this article as a data supplement.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 503S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
increase in major bleeding (21.9% vs 11.9%; OR,1.98; 95% CI, 1.00 to 3.92) were more markedwith thrombolytic therapy.268
MAPPET-3,279 the largest and most recent random-ized trial of thrombolytic therapy vs heparin alone,studied patients with the combination of normal BPand either echocardiographic or ECG evidence of rightventricular dysfunction (Table 16). The principal endpoint was escalation of therapy, defined as the need forpressors, mechanical ventilation, cardiopulmonary re-suscitation, or open-label thrombolysis. Tissue plasmin-ogen activator (tPA), compared with placebo, halvedthe frequency of escalation of therapy and did notincrease major bleeding. However, open-label throm-bolysis as rescue therapy was the main form of escala-tion of therapy, and as the decision to use open label“rescue thrombolysis” was subjective and could bemake after unblinding, this component of the primaryoutcome has been criticized.279
In the International Cooperative Pulmonary Em-bolism Registry, which enrolled 2,454 PE patientsfrom 52 hospitals in seven countries, intracranialbleeding occurred in 3.0% of the 304 patients whoreceived thrombolytic therapy, compared with 0.3%of the nonthrombolysis treated patients.280 The over-all mortality rate from PE was approximately 8%after 3 months,281 about double the frequency re-ported in randomized trials; this higher mortalityrate probably reflects exclusion of the sickest pa-tients from participating in randomized trials43,60
(Table 16). There was no apparent survival benefitfrom thrombolysis in this registry, even among thesickest patients with massive PE.280
There is widespread agreement that thrombolytictherapy should be used to treat PE associated withhemodynamic compromise. Justification for this is that,compared with anticoagulation alone, thrombolytictherapy has demonstrated the following: (1) accelera-tion of thrombus lysis as evidenced by more rapidresolution of perfusion scan abnormalities, decrementin angiographic thrombus, reduction in elevated pul-monary artery pressures, and normalization of rightventricular dysfunction (Table 16); and (2) trends to-ward improved clinical outcomes in subgroups of pa-tients with hemodynamic compromise. However, de-laying thrombolytic therapy until patients with PE arepressor dependent is detrimental because prolongedinadequate tissue perfusion can cause irreversible mul-tisystem organ failure. Consequently, selection of pa-tients with PE to receive thrombolytic therapy requiresrapid and accurate risk stratification of the competingrisks of death from PE and of bleeding.
The risk of death is very high in the presence ofsustained hypotension and cardiogenic shock.280,281
However, such patients are rare, accounting forapproximately 5% of patients with a diagnosis ofPE.280,281
In the presence of normal systemic arterial pressure,prognostication depends on the following: (1) clinicalevaluation,281 (2) cardiac biomarkers such as tropo-nin,282–286 and (3) assessment of right ventricular sizeand function.280,283,285,287–289 Clinical evaluation beginswith general appearance, BP, heart rate, respiratoryrate, temperature, and pulse oximetry. The next step isphysical examination to detect findings of right ventric-ular dysfunction such as distended jugular veins, asystolic murmur of tricuspid regurgitation, or an accen-tuated P2. Clues on the ECG include right-bundle-branch block, SIQIIITIII, and T wave inversion in leadsV1 through V4. Elevation of cardiac troponins indicatesright ventricular microinfarction; echocardiographymay show right ventricular hypokinesis; both are inde-pendent risk factors for early mortality and are associ-ated with a worse outcome when they occur togeth-er.282–286 Right ventricular enlargement on the CTpulmonary angiogram, defined as a right ventriculardiameter � 90% than the left ventricular diameter,appears to be an independent risk factor for death andnonfatal clinical complications.280,288
Among patients without hemodynamic compromise,poor prognostic indicators include the following: (1)patients who appear ill, with marked dyspnea, anxiety,and low oxygen satuartion; (2) elevated troponin, indi-cating right ventricular microinfarction; (3) right ven-tricular dysfunction on echocardiography; and (4) rightventricular enlargement on chest CT. These sick pa-tients are at high risk for an adverse outcome and mayderive benefit from thrombolytic therapy, even if theyinitially maintain systemic arterial pressure. Conse-quently, in distinction to the last version of theseguidelines that generally discouraged treatment of PEwith thrombolytic therapy unless there was hemody-namic compromize, we suggest administration ofthrombolytic therapy in selected high-risk patientswithout hypotension who are judged to have a low riskof bleeding.
Assessment of bleeding risk with thrombolytictherapy is similar in patients with PE and withacute ST-segment elevation myocardial infarc-tion.290,291 Major contraindications to thrombolytictherapy include intracranial disease, uncontrolledhypertension at presentation, and recent majorsurgery or trauma.291
Because of the inadequacy of currently availabledata, further studies are required to determine therisk and benefits of thrombolytic therapy in patientswith severe PE who do not have hemodynamiccompromise. In 2007, a European trial began enroll-ing patients with submassive PE who had preservedsystolic BP, elevated troponin levels, and right ven-
504S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le15
—R
CT
sof
Init
ial
Tre
atm
ent
ofA
cute
PE
:C
lini
cal
Des
crip
tion
and
Res
ult
s(S
ecti
on4.
1.1)
*
Aut
hor/
yrIn
terv
entio
nsPa
tient
sA
naly
zed,
No.
/Tot
alL
engt
hof
Fol
low
-up
Rec
urre
ntD
VT
and
PE,
No.
/Tot
alM
ajor
Ble
edin
g,N
o./T
otal
Tot
alM
orta
lity,
No.
/Tot
alC
omm
ents
Ant
icoa
gula
tion
vsno
anti
coag
ulat
ion
Bar
ritt
and
Jord
an1 /
1960
UF
Hat
10,0
00U
IVq6
hfo
r1.
5d
and
nico
umal
one
adju
sted
topr
othr
ombi
ntim
efo
r14
d
Unt
reat
edco
ntro
ls
16/1
6
19/1
9
App
roxi
mat
ely
14d
Rec
urre
ntPE In
t:0/
16C
ontr
:10/
16R
R,0
.05
(95%
CI,
0.00
–0.7
5)
Fat
alPE
Int:
0/16
Con
tr:5
/19
RR
,0.1
1(9
5%C
I,0.
01–1
.80)
NR (1
/16
fata
lble
eds)
NR (0
/19
fata
lble
eds)
Int:
1/16
Con
tr:5
/19
RR
,0.3
2(9
5%C
I,0.
06–1
.73)
Popu
latio
n:cl
inic
aldi
agno
sis
ofac
ute
PE(r
ight
hear
tfa
ilure
,pu
lmon
ary
infa
rctio
n)
LM
WH
vsU
FH
Pere
zde
Lla
noet
al25
7 /200
3E
noxa
pari
nat
1m
g/kg
SCbi
d
UF
Hat
5,00
0IU
follo
wed
byin
fusi
onof
appr
oxim
atel
y35
,000
IU/2
4h
Eno
xapa
rin:
29/2
9U
FH
:21
/21
6m
oE
noxa
pari
n:3/
29(1
0%)
UF
H:
2/21
(10%
)
RR
,1.0
9(9
5%C
I,0.
20–5
.94)
Eno
xapa
rin:
0/29
(0%
);U
FH
:0/
21(0
%)
Eno
xapa
rin:
2/29
(8%
)U
FH
:0/
21(0
%)
RR
,3.6
7(9
5%C
I,0.
19–7
2.63
)
Fou
rpa
tient
sw
ithdr
awn
and
two
unav
aila
ble
for
follo
w-u
p;al
loca
tion
grou
pno
tre
port
ed
Sim
onne
auet
al43
/19
97T
inza
pari
n:17
5IU
/kg
SCqd
UF
H:5
0IU
/kg
follo
wed
byin
fusi
onof
500
IU/k
g/24
h
LM
WH
:30
4/30
4U
FH
:30
8/30
8
90d
LM
WH
:5/
304
(2%
)
UF
H:
6/30
8(2
%)
RR
,0.8
4(9
5C
I,0.
26–2
.74)
LM
WH
:6/
304
(2.0
%);
UF
H:
8/30
8(3
%)
RR
,0.7
6(9
5%C
I,0.
27–2
.16)
LM
WH
:12
/304
(4%
)U
FH
:14
/308
(5%
)R
R,0
.87
(95%
CI,
0.41
–1.8
5)
Mey
eret
al25
6 /199
5D
alte
pari
n:12
0an
ti-X
aIU
/kg
SCbi
d
UF
H:i
nfus
ion
of50
0IU
/kg
/24
h(n
obo
lus)
LM
WH
:29
/29
UF
H:
31/3
1
3m
oL
MW
H:
0/29
(0%
)
UF
H:
0/31
(0%
)
LM
WH
:0/
29(0
%)
UF
H:
0/31
(0%
)
LM
WH
:1/
29(3
%)
UF
H:
1/31
(3%
)
RR
,1.0
7(9
5%C
I,0.
07–1
6.31
)
Dal
tepa
rin
dose
ishi
gher
than
iscu
rren
tlyre
com
men
ded
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 505S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le15
—C
onti
nued
Aut
hor/
yrIn
terv
entio
nsPa
tient
sA
naly
zed,
No.
/Tot
alL
engt
hof
Fol
low
-up
Rec
urre
ntD
VT
and
PE,
No.
/Tot
alM
ajor
Ble
edin
g,N
o./T
otal
Tot
alM
orta
lity,
No.
/Tot
alC
omm
ents
The
ryet
al25
8 /199
2G
roup
1:U
FH
at50
IU/k
gfo
llow
edby
infu
sion
of60
0IU
/kg/
24h
Gro
up2:
nadr
opar
inat
appr
oxim
atel
y16
0IU
/kg
SCbi
d
Gro
up3:
nadr
opar
in,a
ppro
xim
atel
y24
0IU
/kg
SCtid
Gro
up4:
nadr
opar
in,a
ppro
xim
atel
y36
0IU
/kg
SCtid
Gro
up1:
33/3
3
Gro
up2:
35/3
5
Gro
up3:
26/2
6
Gro
up4:
0/7
14d
Gro
up1:
0/33
(0%
)
Gro
up2:
0/35
(0%
);
Gro
up3:
0/26
(0%
);
Gro
up4:
0/7
(0%
)
Gro
up1:
2/33
(6%
);
Gro
up2:
0/35
(0%
)R
R,0
.19
(95%
CI,
0.01
–3.7
9)G
roup
3:5/
26(1
9%)
RR
,3.1
7(9
5%C
I,0.
67–1
5.06
)G
roup
4:4/
7(5
7%)
RR
,9.4
3(9
5%C
I,2.
13–4
1.78
)
Gro
up1:
1/33
(3)
Gro
up2:
1/35
(3)
RR
,0.9
4(9
5%C
I,0.
06–1
4.47
)G
roup
3:0/
26(0
%)
RR
,0.4
2(9
5%C
I,0.
02–9
.90)
;G
roup
4:1/
7(1
4%)
RR
,4.7
1(9
5%C
I,0.
33–6
6.67
)
Enr
ollm
ent
stop
ped
beca
use
ofbl
eedi
ngin
grou
ps3
and
4;do
ses
ingr
oups
1,3,
and
4ar
ehi
gher
than
curr
ently
reco
mm
ende
d
Fon
dapa
rinu
xvs
UF
HB
ulle
ret
al60
/20
03F
onda
pari
nux
at7.
5m
g(5
0-10
0kg
)or
5.0
mg
(�50
kg),
or10
.0m
g(�
100
kg)
SCda
ily
UF
Hby
IVin
fusi
onad
just
edto
APT
T
1,10
3/1,
103
1,11
0/1,
110
3m
oIn
t:43
/1,1
03C
ontr
:56/
1,11
0R
R,0
.77
(95%
CI,
0.52
–1.1
4)
Int:
14/1
,103
Con
tr:1
2/1,
110
RR
,1.1
7(9
5%C
I,0.
55–2
.53)
Int:
57/1
,103
Con
tr:4
8/1,
110
RR
,1.2
0(9
5%C
I,0.
82–1
.74)
Ave
rage
dose
ofU
FH
was
26,1
00U
onth
ese
cond
day
oftr
eatm
ent
*Int
�in
terv
entio
n;co
ntr
�co
ntro
l.T
hem
etho
dolo
gic
qual
ityde
scri
ptio
npo
rtio
nof
this
tabl
eca
nbe
foun
din
the
onlin
eve
rsio
nof
this
artic
leas
ada
tasu
pple
men
t.
506S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le16
—R
ando
miz
edT
rial
sof
Thr
omb
olyt
icT
hera
pyvs
No
Thr
omb
olyt
icT
hera
pyfo
rA
cute
PE
:C
lini
cal
Des
crip
tion
and
Res
ult
s(S
ecti
on4.
3)*
Aut
hor/
yrIn
terv
entio
nsPa
tient
sA
naly
zed,
No.
/Tot
al(%
)L
engt
hof
Fol
low
-up
Rec
urre
ntD
VT
and
PE,N
o./T
otal
(%)
Maj
orB
leed
ing,
No.
/Tot
al(%
)T
otal
Mor
talit
y,N
o./T
otal
(%)
Com
men
ts
Stre
ptok
inas
epl
ushe
pari
nvs
hepa
rin
Tib
butt
etal
277 /1
974
Stre
ptok
inas
eat
600,
000
Uin
trap
ulm
onar
yfo
llow
edby
100,
000
Ufo
r72
h
Hep
arin
at5,
000
Uin
trap
ulm
onar
y,fo
llow
edby
2,50
0U
for
72h
Stre
ptok
inas
e:11
/13
(84.
6%)
Hep
arin
:12/
17(7
0.6%
)
72h
Stre
ptok
inas
e:0/
11
Hep
arin
:0/
12
Stre
ptok
inas
e:1/
11:(9
.1%
)
Hep
arin
:1/
12(8
.3%
)
RR
,0.9
2(9
5%C
I,0.
06–1
2.95
)
Stre
ptok
inas
e:0/
11
Hep
arin
:0/
12
All
hydr
ocor
tison
eat
100
mg
and
at60
hof
trea
tmen
t;w
arfa
rin
initi
aldo
se25
mg
for
6m
o
Seve
npa
tient
sfa
iled
toco
mpl
ete
the
trea
tmen
tre
gim
enan
dw
ere
excl
uded
from
the
anal
ysis
Patie
nts
repo
rtin
gm
ajor
blee
ding
requ
ired
abl
ood
tran
sfus
ion
Som
e6-
mo
follo
w-u
pda
taav
aila
ble
Ly
etal
275 /1
978
Stre
ptok
inas
eat
250,
000
Ufo
llow
edby
100,
000
U/h
for
72h
Hep
arin
at15
,000
Ufo
llow
edby
1,25
0U
/hfo
r7
d
Stre
ptok
inas
e:14
/14
Hep
arin
:11/
11
10d
Stre
ptok
inas
e:1/
14(7
.1%
)
Hep
arin
:2/
11(1
8.2%
)
RR
,2.5
5(9
5%C
I,0.
26–2
4.56
)
Stre
ptok
inas
e:4/
14(2
8.6%
)
Hep
arin
:2/
11(1
8.2%
)
RR
,0.6
4(9
5%C
I,0.
14–2
.86)
Stre
ptok
inas
e:1/
14(7
.1%
)
Hep
arin
:2/
11(1
8.2%
)
RR
,2.5
5(9
5%C
I,0.
26–2
4.56
)
Prim
ary
outc
ome
was
angi
ogra
phic
repe
rfus
ion
5of
the
25pa
tient
sre
ceiv
edno
nran
dom
ized
ther
apy
Dot
ter
etal
271 /1
979
Stre
ptok
inas
eat
250,
000
Ufo
llow
edby
100,
000
U/h
for
18–7
2h
Hep
arin
at1,
500
Upe
rkg
for
2–7
d
Stre
ptok
inas
e:15
/15
Hep
arin
:16/
16
In-h
ospi
tal
Stre
ptok
inas
e:0/
15
Hep
arin
:1/
16(6
.3%
)
RR
,2.8
2(9
5%C
I,0.
12–6
4.39
)
Stre
ptok
inas
e:3/
15(2
0.0%
)
Hep
arin
:4/
16(2
5.0%
)
RR
,1.2
5(9
5%C
I,0.
33–4
.68)
Stre
ptok
inas
e:1/
15(6
.7%
)
Hep
arin
:2/
16(1
2.5%
)
RR
,1.8
8(9
5%C
I,0.
19–1
8.60
)
All:
war
fari
n/V
KA
:
Prim
ary
outc
ome
was
angi
ogra
phic
repe
rfus
ion
(not
clea
rly
stat
ed)
Jerj
es-S
anch
ezet
al27
3 /199
5St
rept
okin
ase
at1,
500,
000
Uov
er1
hfo
llow
edby
abo
lus
ofhe
pari
n10
,000
Upl
usco
nsta
ntin
fusi
onof
1,00
0U
/h;h
epar
inat
10,0
00U
follo
wed
by1,
000
U/h
Hep
arin
:4/4
Stre
ptok
inas
e:4/
4
In-h
ospi
tal
Stre
ptok
inas
e:0/
40%
)
Hep
arin
:4/
4(1
00%
)
RR
.9.0
0(9
5%C
I,0.
64–1
26.8
5)
Stre
ptok
inas
e:0/
4(0
%)
Hep
arin
:0/
4(0
%)
Stre
ptok
inas
e:0/
4(0
%)
Hep
arin
:4/
4(1
00%
)
RR
,9.0
0(9
5%C
I,0.
64–1
26.8
5)
Prim
ary
outc
ome
not
stat
ed;
tria
lsto
pped
earl
yfo
rbe
nefit
;all
patie
nts
had
card
ioge
nic
shoc
kat
rand
omiz
atio
n;he
pari
n-tr
eate
dpa
tient
sap
pear
toha
vefa
iled
hepa
rin
ther
apy
befo
rera
ndom
izat
ion,
whe
reas
the
stre
ptok
inas
epa
tient
sha
dno
t
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 507S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le16
—C
onti
nued
Aut
hor/
yrIn
terv
entio
nsPa
tient
sA
naly
zed,
No.
/Tot
al(%
)L
engt
hof
Fol
low
-up
Rec
urre
ntD
VT
and
PE,N
o./T
otal
(%)
Maj
orB
leed
ing,
No.
/Tot
al(%
)T
otal
Mor
talit
y,N
o./T
otal
(%)
Com
men
ts
Uro
kina
sevs
hepa
rin
UPE
TSt
udy
Gro
up26
9,27
8 /197
0U
roki
nase
:inf
usio
nof
2,00
0C
TA
U/lb
follo
wed
by2,
000
CT
AU
/lb/h
Hep
arin
:inf
usio
nof
75U
/lbfo
llow
edby
10U
/lb/h
Uro
kina
se,8
2/82
Hep
arin
:78/
78
2w
kU
roki
nase
:12
/82
(14.
6%)
Hep
arin
:15
/78
(19.
2%)
RR
,1.3
1(9
5%C
I,0.
66–2
.63)
Uro
kina
se:3
7/82
(45.
1%)
Hep
arin
:21
/78
(26.
9%)
RR
,0.6
0(9
5%C
I,0.
39–0
.92)
Uro
kina
se:6
/82
(7.3
%)
Hep
arin
:7/
78(8
.9%
)
RR
,1.2
3(9
5%C
I,0.
43–3
.49)
All:
hepa
rin
for
am
inim
umof
5d
The
maj
orbl
eedi
ngre
port
edin
clud
esm
oder
ate
plus
seve
rebl
eedi
ng
Ang
iogr
aphi
cda
tafo
llow
-up
data
avai
labl
eup
to12
mo
Mar
inie
tal
276 /1
988
Hig
hdo
se:u
roki
nase
at3,
300,
000
Uov
er12
h
Low
-dos
e:ur
okin
ase
at80
0,00
0U
over
12h
daily
for
3d
Hep
arin
at30
,000
U/d
for
7d
follo
wed
byor
alan
ticoa
gula
nts
Hig
hdo
se:u
roki
nase
:10
/10
Low
dose
:uro
kina
se:
10/1
0
Hep
arin
:10/
10
7d
Hig
hdo
se:u
roki
nase
:0/
10
Low
dose
:uro
kina
se:
0/10
Hep
arin
:0/1
0
Hig
hdo
se:u
roki
nase
:0/
10
Low
dose
:uro
kina
se:
0/10
Hep
arin
:0/1
0
Hig
hdo
se:u
roki
nase
:0/
10
Low
dose
:uro
kina
se:
0/10
Hep
arin
:0/1
0
Prim
ary
outc
ome
was
lung
scan
perf
usio
n
Thr
ombo
lysi
sar
ms
did
not
rece
ive
hepa
rin
All
patie
nts:
oral
Ant
icoa
gula
nts
cont
inue
dfo
r1
yrrt
-PA
plus
hepa
rin
vshe
pari
nD
alla
-Vol
taan
dPa
lla27
0 /199
2rt
-PA
at10
mg
follo
wed
by90
mg
over
2h
Hep
arin
at10
,000
Ufo
llow
edby
1,75
0U
/hfo
r7
to10
d
rt-P
A:2
0/20
Hep
arin
:16/
16
30d
rt-P
A:1
/20
(5.0
%)
Hep
arin
:0/1
6
RR
,2.4
3(9
5%C
I,0.
11–5
5.89
)
rt-P
A:3
/20
(15.
0%)
Hep
arin
:2/1
6(1
2.5%
)
RR
,1.2
0(9
5%C
I,0.
23–6
.34)
rt-P
A:2
/20
(10.
0%)
Hep
arin
:0/1
6
RR
,4.0
5(9
5%C
I,0.
21–7
8.76
)
Prim
ary
outc
ome
was
angi
ogra
phic
repe
rfus
ion
Gol
dhab
eret
al39
1 /19
93rt
-PA
at10
0m
gov
er2
hfo
llow
edby
hepa
rin
at1,
000
U/h
Hep
arin
at5,
000
Ufo
llow
edby
1,00
0U
/h
rt-P
A:4
6/46
Hep
arin
:55/
55
In-h
ospi
tal
14–2
1d
rt-P
A:0
/46;
Hep
arin
:5/5
5(9
.1%
)
RR
,0.1
1(9
5%C
I,0.
01–1
.91)
rt-P
A:3
/46
(6.5
%)
Hep
arin
:1/5
5(1
.8%
)
RR
,3.5
9(9
5%C
I,0.
39–3
3.33
)
rt-P
A:0
/46
Hep
arin
:2/5
53.
6%)
RR
,0.2
4(9
5%C
I,0.
01–4
.84)
Prim
ary
outc
ome
was
echo
card
iogr
aphi
cri
ght
vent
ricu
lar
func
tion
Kon
stan
tinid
eset
al27
9 /200
2rt
-PA
at10
0m
g,fo
llow
edby
alte
plas
eat
90m
gov
er2
hpl
ushe
pari
nat
1,00
0U
/h
Hep
arin
at5,
000
Ufo
llow
edby
1.00
0U
/hpl
uspl
aceb
o
rt-P
A:1
18/1
18
Hep
arin
plus
plac
ebo:
138/
138
30d
rt-P
A:4
/118
(3.4
%)
Hep
arin
plus
plac
ebo:
4/13
8(2
.9%
)
RR
,1.1
7(9
5%C
I,0.
30–4
.57)
rt-P
A:1
/118
(0.8
%)
Hep
arin
plus
plac
ebo:
5/13
8(3
.6%
)
RR
,0.2
3(9
5%C
I,0.
03–1
.97)
rt-P
A:4
/118
(3.4
%)
Hep
arin
plus
plac
ebo:
3/13
8(2
.2%
)
RR
,1.5
6(9
5%C
I,0.
36–6
.83)
Prim
ary
outc
ome
was
deat
hor
need
for
esca
latio
nof
ther
apy
(late
rde
cisi
onco
uld
bem
ade
afte
run
blin
ding
)
508S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
tricular enlargement on echocardiography. This trialwill randomize approximately 1,000 patients tothrombolysis with a bolus regimen of tenecteplaseplus heparin vs heparin alone.
In summary, there is good evidence that throm-bolytic therapy accelerates resolution of PE andresults in more rapid hemodynamic improvement.The evidence that thrombolytic therapy improvesclinical outcome is less secure. In the absence of riskfactors for bleeding, patients who are hemodynami-cally compromised are very likely to benefit, as aresick patients with major pulmonary arterial obstruc-tion, although the evidence supporting the lattergroup is indirect.
Choice of Thrombolytic Therapy Regimen
Nine randomized trials292–299 (total of 621 patients)have compared the rate of thrombus resolutionachieved with various IV thrombolytic regimens. Theseregimens included urokinase administered over 2 h 295
or 12 h292,298; streptokinase given over 2 h296, 12 h297 or24 h292; and recombinant tissue plasminogen activator(rt-PA) administered over 15 min293,299 or 2 h.42,293–299
An additional study300 compared IV with catheter-directed pulmonary arterial administration of rt-PA (50mg � 2 h). The results of these studies suggest thefollowing: (1) prolonged infusions of thrombolyticagents (eg, � 12 h) are associated with higher rates ofbleeding292,294; (2) 2-h infusions achieve more rapidclot lysis than 12- or 24- h infusions294,297,298; (3) whena high-concentration, 2-h infusion of thrombolysis isadministered, there is no clear difference in the efficacyor safety of rt-PA vs streptokinase296; (4) the relativeefficacy and safety of bolus rt-PA regimens (eg, approx-imately 50 mg in � 15 min) compared with a 2-hinfusion of 100 mg of rt-PA is uncertain293,299,301; and(5) infusion of rt-PA directly into a pulmonary artery asopposed to a peripheral vein does not acceleratethrombolysis but does cause more frequent bleeding atthe catheter insertion site (there was no attempt toinfuse rt-PA directly into, or to mechanically disrupt,the thrombus in this study from 1988).300 When a lyticagent is appropriate for PE, current evidence supportsthat thrombolytic therapy should be infused into aperipheral vein over 2 h or less. rt-PA, at a dose of 100mg over 2 h, is currently the most widely used andevaluated regimen. In patients with imminent or actualcardiac arrest, bolus infusion of thrombolytic therapy isindicated.
Initial Anticoagulant Therapy in Patients TreatedWith Thrombolytic Therapy
In the absence of a contraindication, anticoagula-tion with UFH, LMWH, or fondaparinux should not
Tab
le16
—C
onti
nued
Aut
hor/
yrIn
terv
entio
nsPa
tient
sA
naly
zed,
No.
/Tot
al(%
)L
engt
hof
Fol
low
-up
Rec
urre
ntD
VT
and
PE,N
o./T
otal
(%)
Maj
orB
leed
ing,
No.
/Tot
al(%
)T
otal
Mor
talit
y,N
o./T
otal
(%)
Com
men
ts
Lev
ine
etal
301 /1
990
rt-P
Aat
0.6
mg/
kgov
er2
min
Plac
ebo
plus
hepa
rinat
5,00
0U
follo
wed
by30
,000
U/d
rt-P
A:3
3/33
Plac
ebo:
25/2
5
10d
rt-P
A:0
/33
Plac
ebo:
0/25
rt-P
A:0
/33
Plac
ebo:
0/25
rt-P
A:1
/33
(3.0
%)
Plac
ebo:
0/25
RR
,2.2
9(9
5%C
I,0.
10–5
4.06
)
Prim
ary
outc
ome
was
lung
scan
repe
rfus
ion
PIO
PED
Inve
stig
ator
s272 /1
990
rt-P
Aat
40–8
0m
gat
1m
g/m
in
Plac
ebo
plus
hepa
rin
(dos
esde
term
ined
byph
ysic
ian)
rt-P
A:9
/9
Plac
ebo:
4/4
7d
rt-P
A:0
/9
Plac
ebo:
0/4
rt-P
A:1
/9(1
1.1%
)
Plac
ebo:
0/4
RR
,1.5
0(9
5%C
I,0.
07–3
0.59
)
rt-P
A:0
/9
Plac
ebo:
0/4
Prim
ary
outc
ome
not
stat
ed(s
eria
lang
iogr
aphi
can
dlu
ngsc
ans
wer
eas
sess
ed)
Hep
arin
dose
sw
ere
dete
rmin
edby
atte
ndin
gph
ysic
ian
inbo
thgr
oups
One
deat
hoc
curr
ed19
daf
ter
trea
tmen
t
*CT
A�
Com
mitt
eeon
Thr
ombo
lytic
Age
nts.
The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 509S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
be delayed until diagnostic testing for PE has beencompleted (see Section 4.1). IV UFH has been usedin conjunction with thrombolytic therapy in the trialsthat have evaluated thrombolysis for PE (Table 16).Consequently, initial anticoagulation with IV UFH isappropriate if thrombolytic therapy is being consid-ered. Different regimens of IV UFH have not beencompared in randomized trials in patients with PEwho are treated with thrombolytic therapy.
Before thrombolytic therapy is administered, IVUFH should be administered in full therapeuticdoses (eg, bolus of 80 U/kg followed by 18U/kg/hinitially [Sections 1.1 and 4.1]). During administra-tion of thrombolytic therapy, it is acceptable to eithercontinue, or suspend, the UFH infusion (these twopractices have never been compared). During a 2-hinfusion of 100 mg of tPA, US regulatory bodiesrecommend suspension of IV UFH, whereas IVUFH is continued during the tPA infusion in manyother countries. After administration of thrombolytictherapy, IV UFH should be restarted or continued.In the United States, it is recommended that theAPTT is checked immediately after completion ofthe tPA infusion and that, provided the APTT is not� 80 s, IV UFH is restarted without a bolus at thesame rate of infusion as was being used before tPAwas started. If UFH has not been suspended, theinfusion is continued at the same rate with ongoingadjustment according to APTT results.
Recommendations
4.3.1. All PE patients should undergo rapid riskstratification (Grade 1C). For patients with evi-dence of hemodynamic compromise, we recom-mend use of thrombolytic therapy unless thereare major contraindications owing to bleedingrisk (Grade 1B). Thrombolysis in these patientsshould not be delayed because irreversible car-diogenic shock may ensue. In selected high-riskpatients without hypotension who are judged tohave a low risk of bleeding, we suggest admin-istration of thrombolytic therapy (Grade 2B).The decision to use thrombolytic therapy de-pends on the clinician’s assessment of PE sever-ity, prognosis, and risk of bleeding. For themajority of patients with PE, we recommendagainst using thrombolytic therapy (Grade 1B).4.3.2. In patients with acute PE, when a throm-bolytic agent is used, we recommend that treat-ment be administered via a peripheral veinrather than placing a pulmonary artery catheterto administer treatment (Grade 1B).4.3.3. In patients with acute PE, with adminis-tration of thrombolytic therapy, we recommenduse of regimens with short infusion times (eg, a
2-h infusion) over those with prolonged infusiontimes (eg, a 24-h infusion) [Grade 1B].
4.4 Catheter Extraction or Fragmentation for theInitial Treatment of PE
Interventional catheterization techniques for massivePE include mechanical fragmentation of thrombuswith a standard pulmonary artery catheter, clot pulver-ization with a rotating basket catheter, percutaneousrheolytic thrombectomy, or pigtail rotational catheterembolectomy.302–305 Pharmacologic thrombolysis andmechanical interventions can be combined whenbleeding risk is not high. The goal of catheter extractionof thrombus is to reduce pulmonary arterial resistanceenough to reduce pulmonary artery hypertension, alle-viating right ventricular dilatation and dysfunction, andrapidly increase cardiac output. Catheter embolectomyrarely results in extraction of massive pulmonary arte-rial thrombus. More often, clot fragments are suctionedthrough the catheter or displaced distally with modestangiographic improvement.
There are no randomized trials or prospective cohortstudies that have evaluated interventional catheteriza-tion techniques for massive PE. Case series302–305 thathave included modest numbers of patients (eg, � 50)suggest that these techniques can be lifesaving.
Recommendation
4.4.1. For most patients with PE, we recom-mend against use of interventional catheteriza-tion techniques (Grade 1C). In selected highlycompromised patients who are unable to re-ceive thrombolytic therapy because of bleedingrisk, or whose critical status does not allowsufficient time for systemic thrombolytic ther-apy to be effective, we suggest use of interven-tional catheterization techniques if appropriateexpertise is available (Grade 2C).
4.5 Pulmonary Embolectomy for the InitialTreatment of PE
Emergency surgical embolectomy with cardiopul-monary bypass is another management strategy forwith massive PE.306–308 This operation is also suited foracute PE patients who require surgical excision of aright atrial thrombus or impending paradoxical arterialembolism, or closure of a patent foramen ovale. Surgi-cal embolectomy can also be performed to rescuepatients in whom thrombolysis has been unsuccessful.Outcomes are better when patients are referred beforethe onset of cardiogenic shock. At one hospital, 47patients underwent surgical embolectomy in a 4-yearperiod with a 96% survival rate.306 The procedure is
510S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
best performed on a warm, beating heart, withoutaortic cross-clamping, cardioplegia, or fibrillatory ar-rest.
Recommendation4.5.1. In selected highly compromised patientswho are unable to receive thrombolytic therapybecause of bleeding risk, or whose critical sta-tus does not allow sufficient time for systemicthrombolytic therapy to be effective, we suggestthat pulmonary embolectomy may be used ifappropriate expertise is available (Grade 2C).
4.6 Vena Caval Filters for the Initial Treatment ofPE
As previously noted in section 1.13, vena cavalfilters can be used instead of initial anticoagulanttherapy (eg, unacceptable risk of bleeding) or as anadjunct to anticoagulation in patients with acuteVTE. As for acute DVT, no randomized trials orprospective cohort studies have evaluated IVC filtersas sole therapy for acute PE (ie, without concurrentanticoagulation). As described in Section 1.13 andTable 6, the PREPIC study,29,135 which evaluatedIVC filters as an adjunct to anticoagulation in 400high-risk patients with proximal DVT, showed thatfilters reduced PE, increased DVT, and did notchange overall frequency of VTE (DVT and/or PEcombined). The PREPIC study29 included 145 pa-tients (36% of total) with symptomatic PE and 52patients (13% of total) with asymptomatic PE atenrolment in addition to proximal DVT. Multivari-able analyses did not find an association between thepresence of PE at entry and the frequency of PE at2 years; however, such an association was presentafter 8 years of follow-up.135
There is uncertainty about the risk and benefits ofinserting an IVC filter as an adjunct to anticoagulantand thrombolytic therapy in patients with massivePE. Among patients with hemodynamic compromisein the International Cooperative Pulmonary Embo-lism Registry, insertion of an IVC filter was associ-ated with a reduction of early recurrent PE anddeath.280 Epidemiologic data suggest that insertionof an IVC filter in patients who present with PE (withor without symptomatic DVT) is associated with abouta doubling of the frequency of VTE during follow-up;most of this increase is due to a higher frequency ofDVT (approximately 2.6-fold increase) rather than PE(approximately 1.3-fold increase).137
Recommendations4.6.1. For patients with PE, we recommendagainst the routine use of a vena caval filter inaddition to anticoagulants (Grade 1A).
4.6.2. In patients with acute PE, if anticoagulanttherapy is not possible because of risk of bleed-ing, we recommend placement of an IVC filter(Grade 1C).4.6.3. For patients with acute PE who have anIVC filter inserted as an alternative to antico-agulation, we recommend that they should sub-sequently receive a conventional course of an-ticoagulant therapy if the risk of bleedingresolves (Grade 1C).
5.0 Long-term Treatment of Acute PE
In the following sections, studies that were per-formed exclusively in patients with PE will be em-phasized. In addition, subgroup analyses of PE pa-tients enrolled in studies that included patients whoonly presented with symptoms of DVT will bepresented. As the findings of studies with DVTpatients are relevant to PE patients, and as thefindings of studies performed exclusively in patientswith PE have been consistent with studies thatincluded DVT patients, the recommendations forlong-term treatment of PE are the same as for DVT(see corresponding sections for treatment of DVT).
5.1 VKA for the Long-term Treatment of PE
There has been only one evaluation of duration ofVKA therapy exclusively in patients with PE. After 3months of initial treatment, patients with PE pro-voked by a temporary risk factor were randomized tostop or to receive 3 more months of therapy, andthose with unprovoked PE were randomized to stopor to receive 6 more months of therapy (WODITPE; Table 8). Consistent with studies that includedpatients who presented with DVT, extended VKAtherapy was effective while treatment was beingreceived. However, extending the duration of treat-ment beyond 3 months did not lower the rates ofrecurrence that were observed when anticoagulantswere subsequently stopped.
5.2 LMWH for the Long-term Treatment of PE
Two small studies309,310 from the same investigatorgroup have compared long-term LMWH (enoxaparin,1 mg/kg SC bid for approximately 14 days, followed by1.5 mg/kg/d SC) with long-term VKA exclusively inpatients who presented with PE. The combined resultsof these two studies are that there was a similarfrequency of recurrent VTE (enoxaparin: 4/60; VKA:1/40) and major bleeding (enoxaparin: 1/60; VKA: 2/40)with the two treatments.309 Of the 12 other studies thatcompared LMWH with VKA therapy for long termtreatment of VTE (see Section 2.3), only 2 studies211,213
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 511S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
included patients with PE; in these 2 studies, allpatients had cancer and 295 patients had PE (36% ofall enrolled patients; some PE may have been asymp-tomatic in one study213); subgroup analyses were notreported for the PE patients.
5.3 New Antithrombotic Agents for the Long-termTreatment of PE
Fondaparinux has not been evaluated as a long-termtreatment for VTE. As previously noted (Section 2.5),ximelagatran has been shown to markedly reduce re-current VTE (hazard ratio, 0.16) without increasingbleeding in patients with VTE who had completed 6months of initial treatment with VKAs.171 In this study,ximelagatran was noted to be equally effective in thesubgroup of 447 patients with PE (35% of total) as inthe patients with DVT alone.171 As previously noted(Section 4.2), the long-acting pentasaccharide idrapa-rinux was reported to be less effective than standardtherapy with heparins and VKA for the first 3 to 6months of treatment of PE.62 After an initial 6 monthsof treatment with either idraparinux or warfarin (48%of patients initially presented with symptomatic PE),compared with placebo, 6 months of extended therapywith idraparinux markedly reduced recurrent VTE andincreased bleeding.223
5.4 Treatment of Asymptomatic PE
Diagnosis of unexpected PE when contrast-en-hanced CT is performed for other indications hasbecome relatively common.311–314 Usually (eg, ap-proximately 80% of cases), CT has been performedto evaluate known cancer, and the prevalence ofincidental PE is higher in inpatients that in outpa-tients (eg, approximately 4% vs 1% of CTscans).311,314 When there is evidence of an unex-pected PE, the first priority is to review the CT scansto determine if the findings are convincing for acutePE. Other recent CT scans may be available forcomparison, or the current scan may also reveal DVTin the central deep veins (eg, subclavian, IVC, iliac).If there is any uncertainty about the presence ofacute PE, additional diagnostic testing is required(eg, d-dimer, ultrasonography of the deep veins,dedicated CT pulmonary angiography). When PE isdiagnosed unexpectedly in patients with cancer, theclinical history often reveals symptoms suggestive ofPE.312
Recommendations
5.1.1. For patients with PE secondary to atransient (reversible) risk factor, we recom-mend treatment with a VKA for 3 months overtreatment for shorter periods (Grade 1A).
5.1.2. For patients with unprovoked PE, werecommend treatment with a VKA for at least 3months (Grade 1A). We recommend that after 3months of anticoagulant therapy, all patientswith unprovoked PE should be evaluated forthe risk-benefit ratio of long-term therapy(Grade 1C). For patients with a first unprovokedepisode of VTE that is a PE, and in whom riskfactors for bleeding are absent and for whomgood anticoagulant monitoring is achievable,we recommend long-term treatment (Grade 1A).Values and preferences: This recommendation at-taches a relatively high value to prevention of recur-rent VTE and a lower value to the burden oflong-term anticoagulant therapy.
For patients with a second episode of unpro-voked VTE, we recommend long-term treat-ment (Grade 1A).5.1.3. For patients with PE and cancer, we recom-mend LMWH for the first 3 to 6 months oflong-term anticoagulant therapy (Grade 1A). Forthese patients, we recommend subsequent antico-agulant therapy with VKA or LMWH indefinitelyor until the cancer is resolved (Grade 1C).5.1.4. In patients who receive long-term anticoag-ulant treatment, the risk-benefit ratio of continu-ing such treatment should be reassessed in theindividual patient at periodic intervals (Grade 1C).5.1.5. In patients with PE, we recommend that thedose of VKA be adjusted to maintain a target INRof 2.5 (INR range, 2.0 to 3.0) for all treatmentdurations (Grade 1A). For patients with unpro-voked PE who have a strong preference for lessfrequent INR testing to monitor their therapy,after the first 3 months of conventional-intensityanticoagulation (INR range, 2.0 to 3.0), we rec-ommend low-intensity therapy (INR range, 1.5 to1.9) with less frequent INR monitoring over stop-ping treatment (Grade 1A). We recommendagainst high-intensity VKA therapy (INR range,3.1 to 4.0) compared with an INR range of 2.0 to3.0 (Grade 1A).5.1.6. In patients who are unexpectedly found tohave asymptomatic PE, we recommend the sameinitial and long-term anticoagulation as for com-parable patients with symptomatic PE (Grade 1C).
6.0 Chronic Thromboembolic PulmonaryHypertension
CTPH occurs much more frequently after acutePE than had previously been believed. The oldteaching was that CTPH had a prevalence of notmore than 1 in 500 cases of acute PE; however,data from prospective cohort studies indicate
512S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
the frequency is approximately 3%.315–317 Afteracute PE initiates CTPH, pulmonary vascularremodeling may cause severe pulmonary hyper-tension out of proportion to pulmonary vascularthrombosis.318
6.1 Pulmonary Thromboendarterectomy, VKA, andVena Cava Filter for the Treatment of CTPH
Primary therapy for CTPH is pulmonary throm-boendarterectomy, which, if successful, can re-duce and sometimes cure pulmonary hyperten-sion.318 The operation requires a mediansternotomy, institution of cardiopulmonary bypass,deep hypothermia with circulatory arrest periods,and exploration of both pulmonary arteries. Pul-monary thromboendarterectomy removes orga-nized thrombus by establishing an endarterectomyplane in all involved vessels. At the most experi-enced centers, the mortality rate is � 5%.318 Themost common postoperative problem is reperfu-sion pulmonary edema, generally managed withsupportive care that requires several days of me-chanical ventilation. When pulmonary thromboen-darterectomy is successful, patients can usuallyresume normal daily activities and experience agreatly improved quality of life. Management usu-ally includes insertion of a permanent vena cavafilter before or during pulmonary endarterectomyand indefinite anticoagulant therapy with a targetINR of 2.5.319 No randomized trials of CTPHtherapy have been undertaken. Patients with CTPHwho are not candidates for pulmonary endarterectomybecause of comorbid disease or surgically inaccessiblelesions may be candidates for pulmonary artery angio-plasty.320
Some patients with CTPH have predominantlydistal (ie, subsegmental) vascular involvement. Thepathophysiology of pulmonary microvascular diseaseremains uncertain but may involve release of medi-ators by endothelial cells or platelets, or plexiformlesions similar to idiopathic pulmonary hyperten-tion.321,322 It is possible that some of the medicaltherapies for idiopathic pulmonary hypertensionmight have a beneficial role in CTPH, especially inthose patients who are not surgical candidates or whohave a poor response to thrombendarterectomy dueto distal microvascular disease. Novel therapies in-clude prostacyclin analogs such as epoprostenol,beraprost, iloprost and treprostinil, endothelin re-ceptor antagonists such as bosentan, and phosphodi-esterase-5 inhibitors such as sildenafil.322–324 A co-hort study325 of 47 patients with inoperable CTPHwho were treated with bosentan therapy showedsustained functional and hemodynamic improve-ment with 96% survival after 1 year.
Recommendations
6.1.1. In selected patients with CTPH, such asthose with central disease under the care of anexperienced surgical/medical team, we recom-mend pulmonary thromboendarterectomy(Grade 1C).6.1.2. For all patients with CTPH, we recom-mend life-long treatment with a VKA targetedto an INR of 2.0 to 3.0 (Grade 1C).6.1.3. For patients with CTPH who undergopulmonary thromboendarterectomy, we sug-gest the placement of a permanent vena cavalfilter before or at the time of the procedure(Grade 2C).6.1.4. For patients with inoperable CTPH, wesuggest referral to a center with expertise inpulmonary hypertension so that patients can beevaluated for alternative treatments, such asvasodilator therapy or balloon pulmonary an-gioplasty (Grade 2C).
7.0 Superficial Vein Thrombosis
7.1 Treatment of Infusion Thrombophlebitis
Peripheral vein infusion thrombophlebitis is esti-mated to occur in 25 to 35% of hospitalized patientswho have peripheral IV catheters.326 In a three-armrandomized trial327 of 120 hospitalized patients withinfusion thrombophlebitis, diclofenac emulsion gelused topically three times daily and oral diclofenac (75mg bid) were superior to placebo in relieving localsymptoms of thrombophlebitis at 48 h, with positiveresponses in 60% in both active treatment groups vsonly 20% in the control group. Three other controlledtrials have assessed the effects of various topical gels orcreams compared with placebo for relief of symptomsor clinical resolution of SVT. The largest of thesetrials328 randomized 126 inpatients with infusionthrombophlebitis to heparin sodium gel or placebo gelthree times daily. At 7 days, phlebitis had resolved in44% of the heparin group and 26% of the placebogroup (p � 0.03). In a trial329 that included 68 patientswith spontaneous or infusion-related thrombophlebitiswho were randomized to heparinoid cream, piroxicamgel, or placebo, there were no differences amongtreatment groups in symptoms or size of affected areaat 14 days. Finally, a small trial330 of 23 patients withinfusion thrombophlebitis who were randomized totopical essaven gel (contains aescinate, phospholipids,heparin) or placebo found significant improvement inintensity of local symptoms in the group that receivedessaven. In this study, all patients were also treated withenoxaparin 0.1 mL/10 kg body weight daily (equivalentof 1 mg/kg) for 4 weeks (Table 17). No controlled trials
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 513S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Table 17—Infusion Thrombophlebitis Treatment: Clinical Description and Results (Section 7.1)*
Author/yrType ofStudy† Participants Intervention‡ Outcomes§ Follow-up Results
Becherucci etal327/2000
Parallel RCT,singlecenter
120 hospitalizedpatients withinfusionthrombophlebitis
Topical diclofenacemulsion gelq8h for six doses(n � 40)
Oral diclofenac at75 mg bid forfour doses(n � 40)
Untreated controls(n � 40)
Intensity of localsymptoms (flushing,swelling, warmth,pain)
48 h Intensity of local symptoms:
Topical diclofenac:60% reduction
Oral diclofenac:60% reduction
Control: 20% reduction
(p � 0.0001 for both treatmentgroups vs control)
De Sanctis etal330/2001
Parallel RCT,singlecenter
23 patients withconfirmedinfusionthrombophlebitis
Topical essavengel (containsaescinate,phospholipids,heparin) oncedaily (n � 12)
Placebo gel oncedaily (n � 11)
Each administeredfor 4 wk, alongwith enoxaparin1 mg/kg for 4 wk
Temperature ofaffected area
Symptom score(based on localpain, disability, andswelling)
4 wk Temperature at 4 wk:Essaven gel: 71% of baselinePlacebo: 86% of baseline
(p � 0.05)
Symptom score at 4 wk:Essaven gel: 33% of baselinePlacebo: 80% of baseline
(p � 0.05)
Vilardell etal328/1999
Parallel RCT,singlecenter
126 inpatientswithsuperficialphlebitissecondary toindwellingcatheter
Heparin sodiumgel (1,000 IU/g);
Placebo gel;
Each applied tiduntil resolutionof phlebitis or7 d maximum
Resolution ofphlebitis
7 d Resolution of phlebitis:Heparin gel: 27/61 (44.3%)Placebo: 17/65 (26.1%)RR, 1.69 (95% CI, 1.03–2.78;
p � 0.03)
Note: large No. of withdrawalsdue to hospital dischargecounted as “non-resolution”
Bergqvist etal329/1990
Parallel RCT,singlecenter
68 patients(30 inpatientswith infusionthrombophlebitisand 38outpatientswith spontaneousthrombophlebitis)
Topical piroxicamgel (0.5%; n �22), heparinoidcream (n � 22)or placebo (n �24) applied bidfor 14 d or untilsymptomsdisappeared
Intensity of localsymptoms
Size ofthrombophlebiticarea
Pain intensityby VAS
Approximately14 d
Intensity of local symptoms:Piroxicam gel: 50% of day 0;Heparinoid cream: 60%
of day 0Control: 45% of day 0
Size of involved area:Piroxicam gel: 5.4% of day 0Heparinoid cream: 7.8% of
day 0Control: 4.6% of day 0
Pain intensity:Piroxicam gel: 8.8% of day 0;Heparinoid cream: 2.9%
of day 0Control: 5.2% of day 0(p � not significant
for all comparisons)
*The methodologic quality description portion of this table can be found in the online version of this article as a data supplement.†Study design: RCT, cohort.‡Drugs: NSAIDs, topical treatments, vs placebo, no treatment, each other, or different durations or regimens of the same agent.§Symptomatic relief, resolution of phlebitis.
514S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
have evaluated systemic anticoagulants for the treat-ment of infusion thrombophlebitis.
Recommendation
7.1.1. For patients with symptomatic infusionthrombophlebitis as a complication of IV infusion,we suggest oral diclofenac or another nonsteroi-dal antiinflammatory drug (NSAID) [Grade 2B],topical diclofenac gel (Grade 2B), or heparin gel(Grade 2B) until resolution of symptoms or for upto 2 weeks. We recommend against the use ofsystemic anticoagulation (Grade 1C).
7.2 Treatment of SVT
SVT has been less well studied than DVT but isestimated to occur more often.331,332 It commonlyaffects the lower limbs, often involves a varicosevein, is associated with chronic venous insufficiency,malignancy, thrombophilia, pregnancy or exogenousestrogens, obesity, sclerotherapy and a history ofVTE, or it may be unprovoked.331–333
Although traditionally considered a benign dis-ease, a number of studies331,332 indicate that theconsequences of SVT may be more serious and haveled to trials of more aggressive treatment with thegoals of reducing symptoms, extension, recurrence,and progression to VTE (Table 18). The treatment ofsuperficial vein thrombosis has been the subject of arecent Cochrane Collaboration systematic review.334
Short-Duration Heparin, LMWH, and NSAIDs
In a placebo-controlled trial,335 462 patients withSVT were randomly allocated to receive 8 to 12 daysof enoxaparin in two dosages (40 mg and 1.5 mg/kgSC daily, tenoxicam 20 mg po daily, or placebo).During the treatment period and at 3-month follow-up, rates of SVT extension or recurrence were 29.5%and 33.0%, respectively, in the placebo group, sig-nificantly higher than that of the other three treat-ment groups (enoxaparin 40 mg, 8.3% and 14.5%;enoxaparin 1.5 mg/kg, 5.7% and 15.1%; tenoxicam,13.1% and 15.2%). Rates of DVT tended to be lowerin the treatment groups vs the placebo group duringthe initial treatment period, but this trend was lost by3 months, predominantly due to the occurrence ofVTE in the treatment groups during the first 3 weeksafter treatment was stopped, suggesting that theinitial duration of therapy was inadequate.
In an open-label randomized trial336 of 117 pa-tients, 6-day courses of calcium nadroparin adminis-tered SC daily at doses of 6,150 anti-Xa IU or 31.5anti-Xa IU/kg were superior to naproxen (500 mgonce daily) for relief of symptoms and signs of SVT,
but there was no difference in rates of SVT extensionat the end of treatment or at 8 weeks.
Longer Courses of Heparin or LMWH
A blinded randomized trial337 compared a 30-daycourse of low- vs high-dose SC nadroparin in 164patients with SVT. During 3 months of follow-up,there were five cases of SVT extension in the low-dose group (all occurred on treatment), comparedwith two cases in the high-dose group (one occurredon treatment). There were two symptomatic DVTsin the low-dose group vs three DVTs (two symptom-atic) and one symptomatic PE (occurred on treat-ment) in the high-dose group. Lack of a controlgroup precludes assessment of whether either of thetreatments was more effective than no treatment; forexample, the rate of VTE at 3 months in the highdose group (4.8%) was similar to the 3-month rate ofVTE in the placebo group (4.5%) of the previouslydescribed STENOX trial.335
Sixty patients with acute thrombosis of the greatsaphenous vein were randomized to receive a 4-weekcourse of SC UFH in moderately high unmonitoreddoses (12,500 IU bid for 1 week, followed by 10,000 IUbid) or prophylactic doses (5,000 IU bid).338 At 6months, 6 patients (20%) in the low-dose heparingroup had VTE (three symptomatic events), of whichfour episodes occurred during treatment, comparedwith 1 patient (3.3%) in the high-dose heparin group, whohad symptomatic DVT after treatment was completed.
One trial339 found that warfarin was superior tocontrol and had similar effectiveness to low-doseUFH and LMWH with regard to rate of SVTextension at 3 months; however, no information wasprovided on dose or duration of anticoagulants. Anumber of other small trials have compared topi-cal340 or alternate anticoagulants (eg, dermatan sul-fate)341 for variable time periods to treat SVT (Table18). No trials have evaluated the role of fondaparinuxin the management of SVT.
Surgical vs Medical Therapy
A nonblinded randomized trial339 with six treatmentarms that included approximately 70 patients per groupshowed that compression alone or in addition to flushligation of the saphenous vein were inferior to completevein stripping or treatment with UFH, LMWH, orwarfarin (doses and durations of treatment were notspecified) for the end point of SVT extension at 3months. A second trial342 compared saphenofemoralligation, performed under local anesthesia, with enox-aparin 1 mg/kg bid for 1 week, and then daily for 3weeks. During 6-month follow-up, VTE occurred intwo patients (6.7%) in the surgery group (both PE) vsnone in the enoxaparin group, while SVT occurred in
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 515S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
one patient (3.3%) in the surgery group and threepatients (10%) in the enoxaparin group. Two patients inthe surgical group had wound infections, and the costof surgical treatment was more than three times higherthat of medical treatment. Finally, a review of sixstudies (includes a study339 described above, and fivesmall case series) comparing surgical therapy to antico-agulation for SVT showed similar rates of SVT progres-sion but higher rates of VTE and complications withsurgical therapy.343
Recommendation
7.2.1. For patients with spontaneous superficialvein thrombosis, we suggest prophylactic orintermediate doses of LMWH (Grade 2B) orintermediate doses of UFH (Grade 2B) for atleast 4 weeks. We suggest that as an alternativeto 4 weeks of LMWH or UFH, VKA (target INR,2.5; range, 2.0 to 3.0) can be overlapped with 5days of UFH and LMWH and continued for 4weeks (Grade 2C). We suggest that oral NSAIDsshould not be used in addition to anticoagula-tion (Grade 2B). We recommend medical treat-ment with anticoagulants over surgical treat-ment (Grade 1B).
Remark: It is likely that less extensive superficialvein thrombosis (ie, where the affected venous seg-ment is short in length or further from the saphe-nofemoral junction) does not require treatment withanticoagulants. It is reasonable to use oral or topicalNSAIDs for symptom control in such cases.
8.0 Acute UEDVT
Although most episodes of DVT occur in the lowerlimbs, it is estimated that 1 to 4% of cases involve theupper extremities. UEDVT can be classified into twoetiologic groups: primary (includes unprovoked with orwithout thrombophilia, effort related, and thoracicoutlet syndrome) and secondary (provoked by centralvenous catheters, pacemakers, or cancer); secondaryUEDVT accounts for 75 to 80% of all cases.344–346
UEDVT may involve the subclavian, axillary or bra-chial veins. Clinical manifestations include edema, di-lated collateral veins over the arm, neck, or chest, andlimb pain or discoloration. The disease may lead tocomplications, including pulmonary embolism (esti-mated to occur in up to one third of patients346),recurrent UEDVT (a prospective study347 reportedcumulative incidence rates of 2.0%, 4.2% and 7.7%after 1, 2, and 5 years, respectively) and PTS of thearm.347,348 The treatment of patients with acuteUEDVT may be divided into the initial treatmentphase (with anticoagulants, thrombolytic therapy, cath-eter/surgical techniques, or filter placement) and long-
term treatment (or secondary prophylaxis) with antico-agulants to prevent recurrent VTE.
8.1 IV UFH or LMWH for the Initial Treatment ofUEDVT
It is generally accepted that, as for patients withlower-limb DVT, patients with UEDVT requiretreatment with anticoagulants to prevent throm-bus extension and PE (Table 19). To date, noRCTs have evaluated UFH, LMWH, or otheranticoagulants for the initial treatment of UEDVT.Several small prospective cohort studies have re-ported low rates of recurrent DVT, PE, and majorbleeds using treatment regimens for UEDVT sim-ilar to those for patients with lower-limb DVT(Table 19). In a prospective two-center cohortstudy,349 46 outpatients with UEDVT were treatedwith SC LMWH followed by warfarin. At 3months, there was one recurrence, one majorbleed, and no episodes of PE. In 36 inpatients withUEDVT, LMWH twice daily for up to 7 daysfollowed by warfarin for an average of 5 months(target INR, 2.0 to 2.5) led to significant earlysymptom relief and no recurrent DVT or PE at 1year.350 Rates of VTE recurrence were similarlylow in a cohort of 53 patients who received UFHor LMWH for the initial treatment of UEDVTfollowed by warfarin for 3 months,347 and in 74cancer patients with central venous catheter-asso-ciated UEDVT, in whom treatment with LMWHfor 5 to 7 days followed by warfarin for 3 monthsappeared to prevent catheter failure and was notassociated with any recurrent VTE351 (Table 19).
Recommendation
8.1.1. For patients with acute UEDVT, werecommend initial treatment with therapeuticdoses of LMWH, UFH, or fondaparinux asdescribed for leg DVT (see Section 1) [Grade1C].
8.2 Thrombolytic Therapy for the Initial Treatmentof UEDVT
No randomized controlled studies have evalu-ated the efficacy and safety of thrombolytic ther-apy compared with standard anticoagulation forthe initial treatment of patients with UEDVT(Table 20). A number of retrospective and smallprospective studies92,352–358 that included 6 to 118patients have evaluated streptokinase, urokinase,or rT-PA administered with varying doses, meth-ods of administration (IV, catheter directed), andinfusion durations. Three of these studies352,356,357
included control groups that received anticoagula-
516S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le18
—Su
perf
icia
lV
ein
Thr
omb
osis
Tre
atm
ent:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
7.2)
*
Aut
hor/
yrT
ype
ofSt
udy†
Part
icip
ants
Inte
rven
tion‡
Out
com
es§
Fol
low
-up
Res
ults
STE
NO
XSt
udy
Gro
up33
5 /20
03
Para
llelR
CT
,m
ultic
ente
r43
6pa
tient
sw
ithul
tras
ound
-co
nfir
med
acut
esy
mpt
omat
icSV
T(�
5cm
leng
th)
oflo
wer
extr
emity
Eno
xapa
rin
at40
mg/
dSC
Eno
xapa
rin
at1.
5m
g/kg
/dSC
Ten
oxic
amat
20m
g/d
po
Plac
ebo
once
daily
All
adm
inis
tere
dfo
r8–
12d
All
patie
nts
pres
crib
edel
astic
band
ages
orco
mpr
essi
onst
ocki
ngs
for
atle
ast
15d
Day
12(e
ndof
trea
tmen
t):
scre
enin
gul
tras
ound
orsy
mpt
omat
icre
curr
ence
:V
TE
SVT
recu
rren
ce/e
xten
sion
tosa
phen
ofem
oral
junc
tion
3m
oV
TE
SVT
recu
rren
ce/e
xten
sion
Maj
orbl
eed
Dea
th
3m
oV
TE
day
12:
Plac
ebo:
4/11
2(3
.6%
);PE
,0
Eno
xapa
rin,4
0m
g:1/
110
(0.9
%);
PE,0
;RR
,0.2
5(9
5%C
I,0.
03–2
.24)
Eno
xapa
rinat
1.5
mg/
kg:1
/106
(0.9
%);
PE,0
;RR
,0.2
6(9
5%C
I,0.
03–2
.33)
Ten
oxic
am:2
/99
(2.0
%);
PE,1
;RR
,0.5
7(9
5%C
I,0.
11–3
.02)
p�
not
signi
fican
tfo
ral
lcom
paris
ons
ofac
tive
trea
tmen
tvs
plac
ebo
SVT
;rec
urre
nce/
exte
nsio
nda
y12
:Pl
aceb
o:33
/112
(29.
5%)
Eno
xapa
rinat
40m
g:9/
110
(8.3
%)
RR
,0.2
8(9
5%C
I,0.
14–0
.55)
Eno
xapa
rinat
1.5
mg/
kg:6
/106
(5.7
%)
RR
,0.1
9(9
5%C
I,0.
08–0
.44)
Ten
oxic
am:1
3/99
(13.
1%)
RR
,0.4
5(9
5%C
I,0.
25–0
.80)
VT
Eat
3m
o:Pl
aceb
o:5/
112
(4.5
%);
PE,0
Eno
xapa
rinat
40m
g:6/
110
(5.7
%)
PE,2
;RR
,1.2
2(9
5%C
I,0.
38–3
.89)
Eno
xapa
rinat
1.5
mg/
kg:4
/106
(3.9
%);
PE,0
;RR
,0.8
5;95
%C
I,0.
23–3
.06
Ten
oxic
am:4
/99
(4.3
%);
PE,1
;RR
,0.9
1(9
5%C
I,0.
25–3
.28)
p�
not
signi
fican
tfo
ral
lcom
paris
ons
ofac
tive
trea
tmen
tvs
plac
ebo
SVT
;rec
urre
nce/
exte
nsio
nat
3m
o:Pl
aceb
o:37
/112
(33.
0%)
Eno
xapa
rinat
40m
g:16
/110
(14.
5%);
RR
,0.4
4(9
5%C
I,0.
26–0
.74)
Eno
xapa
rinat
1.5
mg/
kg:1
6/10
6(1
5.1%
);R
R,0
.46
(95%
CI,
0.27
-0.
77)
Ten
oxic
am:1
5/99
(15.
2%);
RR
,0.4
6(9
5%C
I,0.
27-
0.78
)
Maj
orbl
eed:
0D
eath
:0
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 517S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le18
—C
onti
nued
Aut
hor/
yrT
ype
ofSt
udy†
Part
icip
ants
Inte
rven
tion‡
Out
com
es§
Fol
low
-up
Res
ults
Tito
net
al33
6 /199
4Pa
ralle
lRC
T,
mul
ticen
ter
117
patie
nts
with
ultr
asou
nd-
conf
irm
edSV
Tof
low
erex
trem
ities
Nad
ropa
rin
fixed
dose
,6,
150
anti-
Xa
IU/d
Nad
ropa
rin
31.5
anti-
Xa
IU/k
g/d
SC
Nap
roxe
n50
0m
g/d
po
Tre
atm
ents
give
nfo
r6
dA
llpa
tient
sw
ore
com
pres
sion
stoc
king
sfo
r7
d
Ech
ogra
phic
exte
nsio
nof
thro
mbu
sat
day
7an
dat
8w
k
Cha
nges
insy
mpt
oms
and
clin
ical
sign
s(w
arm
th,
flush
ing,
edem
a,pa
inon
palp
atio
n)
DV
TPE M
ajor
blee
d
8w
eeks
Day
7ex
tens
ion
ofth
rom
bus:
Fix
ed-d
ose
nadr
opar
in:1
/38
(2.6
%)
Wei
ght-
base
dna
drop
arin
:2/4
0(5
%);
RR
,1.9
0(9
5%C
I,0.
18–2
0.1)
Nap
roxe
n:1/
39(2
.6%
);R
R,0
.97
(95%
CI,
0.06
–15.
02);
P�
not
signi
fican
t
8w
ks:e
xten
sion
ofth
rom
bus
orne
wSV
TF
ixed
dose
nadr
opar
in:2
/36
(5.6
%)
Wei
ght-
base
dna
drop
arin
:0/4
0(0
%);
RR
0.18
(95%
CI)
,0.
01–3
.64)
Nap
roxe
n:0/
39(0
%);
RR
,0.1
9(9
5%C
I,0.
01–3
.73)
No
DV
T,P
E,o
rm
ajor
blee
din
any
grou
p
Inte
nsity
ofsy
mpt
oms/
signs
:ove
rall
impr
ovem
ent
insc
ore
from
day
0to
day
7:F
ixed
–dos
ena
drop
arin
:79.
1%im
prov
edW
eigh
t-ba
sed
nadr
opar
in:6
3.0%
impr
oved
Nap
roxe
n:46
.4%
impr
oved
(p�
0.01
infa
vor
ofna
drop
arin
grou
psvs
napr
oxen
;thi
sdi
ffere
nce
was
mai
ntai
ned
at8
wk
Pran
doni
etal
337
for
Ves
alio
Inve
stig
ator
sG
roup
/200
5
Para
llelR
CT
,m
ultic
ente
r16
4pa
tient
sw
ithul
tras
ound
-co
nfir
med
acut
eSV
Tof
the
grea
ter
saph
enou
sve
in
Hig
h-do
se,w
eigh
t-ad
just
edna
drop
arin
(190
antiX
aIU
/kg
for
10d
follo
wed
by95
antiX
aIU
/kg
for
20d)
Low
-dos
ena
drop
arin
(2,8
50an
ti-X
aIU
)fo
r30
d;no
plac
ebo
grou
p;N
SAID
San
das
pirin
use
disc
oura
ged
Com
posi
teou
tcom
eof
asym
ptom
atic
orsy
mpt
omat
icSV
Tex
tens
ion,
asym
ptom
atic
orsy
mpt
omat
icD
VT
,sy
mpt
omat
icPE
at3
mo
Impr
ovem
ent
incl
inic
alsy
mpt
oms
and
sign
sat
1m
oM
ajor
blee
dD
eath
3m
o3
mo
follo
w-u
p:
SVT
:H
igh
dose
:2/8
3(2
.4%
;1oc
curr
edw
hile
rece
ivin
gtr
eatm
ent)
Low
dose
:5/8
1(6
.2%
;all
occu
rred
whi
lere
ceiv
ing
trea
tmen
t)R
R,2
.56
(95%
CI,
0.51
–12.
83)
VT
E:
Hig
hdo
se:4
/83
(4.8
%;3
sym
ptom
atic
even
ts;1
�PE
�oc
curr
edw
hile
rece
ivin
gtr
eatm
ent)
Low
dose
:2/8
1(2
.5%
;bot
hsy
mpt
omat
icD
VT
)R
R,0
.51
(95%
CI,
0.10
–2.7
2)
Rat
eof
impr
ovem
ent
incl
inic
alsy
mpt
oms
and
signs
simila
rbo
thgr
oups
Maj
orbl
eed:
0D
eath
:0
518S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le18
—C
onti
nued
Aut
hor/
yrT
ype
ofSt
udy†
Part
icip
ants
Inte
rven
tion‡
Out
com
es§
Fol
low
-up
Res
ults
Mar
chio
riet
al33
8 /20
02Pa
ralle
lRC
T,
sing
lece
nter
60pa
tient
sw
ithul
tras
ound
-co
nfir
med
first
acut
eSV
Tof
grea
ter
saph
enou
sve
in
Low
-dos
eU
FH
(5,0
00IU
SCbi
dfo
r4
wk)
Hig
h-do
seU
FH
(12,
500
IUfo
r1
wk,
then
10,0
00IU
for
3w
k)
Use
ofco
ncom
itant
syst
emic
orlo
cal
antii
nfla
mm
ator
ydr
ugs
perm
itted
,but
use
not
desc
ribe
d
VT
E
Ext
ensi
on/r
ecur
renc
eof
thro
mbo
sis
Maj
orbl
eed
Hep
arin
-indu
ced
thro
mbo
cyto
peni
a
Dea
th
6m
oV
TE
duri
ngtr
eatm
ent
peri
od:
Low
dose
:4/3
0(1
3.3%
;3as
ympt
omat
icD
VT
,1PE
)H
igh
dose
:0/3
0(0
%);
RR
,0.1
1(9
5%C
I,0.
01–1
.98;
p�
not
sign
ifica
nt)
Ext
ensi
on/r
ecur
renc
eSV
Tdu
ring
trea
tmen
tpe
riod
Low
dose
:7/3
0(2
3.3%
)H
igh
dose
:3/3
0(1
0%);
RR
,0.4
0(9
5%C
I,0.
11–1
.40;
p�
not
sign
ifica
nt)
Ove
rall
VT
Edu
ring
follo
w-u
ppe
riod
:L
owdo
se:6
/30
(20%
)H
igh
dose
:1/3
0(3
.3%
),R
R,0
.17
(95%
CI,
0.02
–1.3
0;p
�no
tsi
gnifi
cant
)O
vera
llex
tens
ion/
recu
rren
ceSV
Tdu
ring
follo
w-u
ppe
riod
:L
owdo
se:1
1/30
(36.
7%)
Hig
hdo
se:8
/30
(26.
7%)
RR
,0.7
3(9
5%C
I,0.
34–1
.55;
p�
not
sign
ifica
nt)
No
maj
orbl
eed,
hepa
rin-
indu
ced
thro
mbo
cyto
peni
a,or
deat
hin
any
grou
pB
elca
roet
al33
9 /19
99Pa
ralle
lRC
T,
mul
ticen
ter
562
patie
nts
with
ultr
asou
nd-
conf
irm
edSV
Tan
dla
rge
vari
cose
vein
sor
veno
usin
com
pete
nce
Gro
upA
:ela
stic
com
pres
sion
stoc
king
sal
one
Gro
upB
:ela
stic
com
pres
sion
stoc
king
san
dsi
mpl
eflu
shlig
atio
nG
roup
C:e
last
icco
mpr
essi
onst
ocki
ngs
and
com
plet
est
ripp
ing
and
perf
orat
orlig
atio
nG
roup
D:e
last
icco
mpr
essi
onst
ocki
ngs
and
low
-dos
eSC
hepa
rin
Gro
upE
:ela
stic
com
pres
sion
stoc
king
san
dL
MW
HG
roup
F:e
last
icco
mpr
essi
onst
ocki
ngs
and
VK
AD
oses
and
dura
tion
ofan
ticoa
gula
nts
not
spec
ified
Ext
ensi
onof
SVT
at3
mo
Ext
ensi
onof
SVT
at6
mo
New
DV
Tat
3m
o
6m
oE
xten
sion
ofth
rom
bus
at3
mo:
Gro
upA
:32/
78(4
1%)
Gro
upB
:11/
78(1
4.1%
);R
R,0
.34
(95%
CI,
0.19
–0.6
3)G
roup
C:0
/70;
RR
,0.0
2(9
5%C
I,0.
00–0
.27)
Gro
upD
:4/7
1(5
.6%
);R
R,0
.14
(95%
CI,
0.05
–0.3
7)G
roup
E:4
/76
(5.2
%);
RR
,0.1
3(9
5%C
I,0.
05–0
.35)
Gro
upF
:5/7
1(7
.0%
);R
R,0
.17
(95%
CI,
0.07
–0.4
2;p
�0.
05fo
rgr
oups
C,D
,E,a
ndF
vsgr
oups
Aor
B
Ext
ensi
onat
6m
o:G
roup
A:1
3/78
(16.
7%)
Gro
upB
:6/7
8(7
.7%
);R
R,0
.46
(95%
CI,
0.18
–1.1
5)G
roup
C:1
/70
(1.4
%);
RR
,0.0
9(9
5%C
I,0.
01–0
.64)
Gro
upD
:2/7
1(2
.8%
);R
R,0
.17
(95%
CI,
0.04
–0.7
2)G
roup
E:1
/76
(1.3
%);
RR
,0.0
8(95
%C
I,0.
01–0
.59)
Gro
upF
:5/7
1(7
%);
RR
,0.4
2(9
5%C
I,0.
16–1
.13
Pva
lue
not
stat
ed
New
DV
Tat
3m
o:G
roup
A:6
/78
(7.7
%)
Gro
upB
:2/7
8(2
.5%
);R
R,0
.33
(95%
CI,
0.07
–1.6
0)G
roup
C:2
/70
(2.8
%);
RR
.0.3
7(9
5%C
I,0.
08–1
.78)
Gro
upD
:0/7
1(0
%);
RR
,0.0
8(9
5%C
I,0.
0–1.
47)
Gro
upE
:0/7
6(0
%);
RR
,0.0
8(9
5%C
I,0.
0–1.
38)
Gro
upF
:0/7
1(0
%);
RR
,0.0
8(9
5%C
I,0.
0–1.
47)
P�
not
sign
ifica
nt
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 519S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le18
—C
onti
nued
Aut
hor/
yrT
ype
ofSt
udy†
Part
icip
ants
Inte
rven
tion‡
Out
com
es§
Fol
low
-up
Res
ults
Loz
ano
and
Alm
azan
342 /
2003
Para
llelR
CT
,si
ngle
cent
er60
patie
nts
with
ultr
asou
nd-
conf
irm
edab
ove-
knee
inte
rnal
saph
enou
sSV
T
Saph
enof
emor
aldi
scon
nect
ion
unde
rlo
cal
anes
thes
iaw
ithsh
ort-
term
use
ofa
com
pres
sion
band
age
Out
patie
nten
oxap
arin
at1
mg/
kgbi
dfo
r1
wk
and
then
once
daily
for
3w
k
No
plac
ebo/
cont
rolg
roup
All
patie
nts
wer
ein
stru
cted
tow
ear
elas
ticco
mpr
essi
onst
ocki
ngs
and
used
acet
amin
ophe
nfo
rpa
in
Rec
urre
nce/
exte
nsio
nof
SVT
VT
E
Com
plic
atio
nsof
surg
ery
Maj
orbl
eed
Dea
th
Cos
ts
6m
oR
ecur
rent
SVT
:Su
rgic
algr
oup:
1/30
(3.3
%)
Eno
xapa
rin
grou
p:3/
30(1
0%)
RR
,3.0
(95%
CI,
0.33
–27.
24)
VT
E:S
urgi
calg
roup
:2/3
0(6
.7%
;bot
hsy
mpt
omat
icPE
)E
noxa
pari
ngr
oup:
0/30
(0%
)R
R,0
.20;
95%
CI,
0.01
–4.0
Wou
ndin
fect
ions
:Su
rgic
algr
oup:
2/30
(6.7
%)
Maj
orbl
eedi
ng:0
Dea
th:0
Cos
tof
trea
tmen
t:Su
rgic
algr
oup:
$1,4
00pe
rpa
tient
;mea
n1.
6d
inho
spita
lE
noxa
pari
ngr
oup:
$300
per
patie
nt;0
din
hosp
ital
Sulli
van
etal
343 /
2001
Syst
emat
icre
view
ofsi
xst
udie
s(in
clud
esB
elca
ro33
9
abov
ean
dfiv
esm
allc
ase
seri
es)
Patie
nts
with
obje
ctiv
ely
conf
irm
edab
ove-
knee
SVT
Lig
atio
nof
grea
ter
saph
enou
sve
inat
saph
enof
emor
alju
nctio
n,w
ithor
with
out
vein
stri
ppin
g(n
�24
6)
Ant
icoa
gula
tion
(IV
hepa
rin
follo
wed
byV
KA
for
6w
k-6
mo;
n�
88)
SVT
prog
ress
ion
DV
T
PE Surg
ical
com
plic
atio
ns
Ble
edin
gco
mpl
icat
ions
Surg
ical
grou
p:4–
6m
o
Med
ical
grou
p:6
dto
14m
o
SVT
prog
ress
ion:
Surg
ical
grou
p:18
/148
(12%
)M
edic
algr
oup:
10/7
1(1
4%)
RR
,0.1
6(9
5%C
I,0.
56–2
.38)
DV
TSu
rgic
algr
oup:
7/20
4(3
.4%
)M
edic
algr
oup:
2/88
(2.2
%)
RR
,0.6
6(9
5%C
I,0.
14–3
.13)
PE Surg
ical
grou
p:2/
98(2
.0%
)M
edic
algr
oup:
0/17
(0%
)R
R,1
.10
(95%
CI,
0.06
–21.
98)
Surg
ical
com
plic
atio
ns:6
/78
(7.7
%;h
emat
oma,
sero
ma,
infe
ctio
n)
Ble
edin
gco
mpl
icat
ions
:0/1
7(0
%)
520S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le18
—C
onti
nued
Aut
hor/
yrT
ype
ofSt
udy†
Part
icip
ants
Inte
rven
tion‡
Out
com
es§
Fol
low
-up
Res
ults
Gor
skie
tal
340 /
2005
Para
llelR
CT
,m
ultic
ente
r46
patie
nts
with
ultr
asou
nd-
conf
irm
edSV
T
Top
ical
lipos
omal
hepa
rin
spra
yge
l(fo
ursp
rays
of45
8IU
tid)
Eno
xapa
rin
at40
mg
SCqd
Tre
atm
ent
for
7–14
d
Pain
byV
AS
(0–1
0sc
ale)
Are
aof
eryt
hem
a
Subj
ectiv
eef
ficac
yas
sess
men
tby
inve
stig
ator
and
patie
nt
Dup
lex
asse
ssm
ent
for
thro
mbu
sre
gres
sion
day
21
DV
T
Adv
erse
even
ts
Dea
th
21d
Dat
aex
trap
olat
edfr
omgr
aphs
and
figur
esin
pape
rby
revi
ewer
Pain
byV
AS
day
21T
opic
alhe
pari
n,0
LM
WH
,0Im
prov
emen
tno
ted
atea
chtim
epo
int;
nopa
inat
21d,
nosi
gnifi
cant
diff
eren
cebe
twee
ngr
oups
Are
aof
eryt
hem
a:Im
prov
emen
tno
ted
atea
chtim
epo
int;
noer
ythe
ma
at21
d,no
sign
ifica
ntdi
ffer
ence
betw
een
grou
psSu
bjec
tive
effic
acy
asse
ssed
Maj
ority
ofpa
tient
s(�
75%
)re
port
edgo
odor
very
good
trea
tmen
tef
ficac
y;no
sign
igic
ant
diff
eren
cebe
twee
ngr
oups
Thr
ombu
sre
gres
sion
Top
ical
hepa
rin:
10/2
1(4
7.6%
)L
MW
H:9
/23
(39.
1%)
RR
,0.8
2(9
5%C
I,0.
42–1
.62)
DV
TT
opic
alhe
pari
n:3/
21(1
4.3%
)L
MW
Hhe
pari
n:1/
23(4
.3%
)R
R,0
.30
(95%
CI,
0.03
–2.7
0)
Adv
erse
even
tsA
llerg
icre
actio
nin
one
patie
ntin
enox
apar
ingr
oup
Dea
th:0
And
reoz
ziet
al34
1 /199
6Pa
ralle
lRC
T,
mul
ticen
ter
56pa
tient
sw
ithSV
Tof
the
low
erlim
bs
Gro
upA
:der
mat
ansu
lfate
at10
0m
gSQ
qdG
roup
B:d
erm
atan
sulfa
teat
100
mg
SQbi
dG
roup
C:d
erm
atan
sulfa
teat
200
mg
IMqd
Tre
atm
ent
for
30d
Pain
Incr
ease
infu
nctio
nal
abili
ty
Loc
aled
ema
30d
Dat
aex
trap
olat
edfr
omgr
aphs
and
figur
esin
pape
rby
revi
ewer
Res
olut
ion
ofpa
in,d
ay30
:G
roup
A:4
7%G
roup
B:8
3%G
roup
C:7
9%(p
valu
eno
tst
ated
)In
crea
sein
abili
tyto
perf
orm
norm
alda
ilyac
tiviti
es:d
ay30
Gro
upA
:44%
Gro
upB
:67%
Gro
upC
:84%
(p�
0.05
;gro
ups
Ban
dC
vsgr
oup
A)
Loc
aled
ema:
day
30:
Prog
ress
ive
impr
ovem
ent
inal
lthr
eegr
oups
;no
sign
ifica
ntdi
ffer
ence
sbe
twee
ngr
oups
*The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
†Stu
dyde
sign
:RC
T,c
ohor
t2.
‡Dru
gs:V
KA
,UF
H,L
MW
H,N
SAID
s,as
piri
n,to
pica
ltre
atm
ents
,sur
gery
vspl
aceb
o,no
trea
tmen
t,ea
chot
her
ordi
ffer
ent
dura
tions
orre
gim
ens
ofth
esa
me
agen
t.§O
utco
mes
:ext
ensi
onof
thro
mbu
s,sy
mpt
omat
icre
lief,
DV
Tan
dPE
,maj
orbl
eedi
ng,s
urgi
calc
ompl
icat
ions
,dea
th.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 521S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
tion alone. In some studies, a few patients addi-tionally had venous angioplasty354 or surgical de-compression352,354,357 (Table 20).
In the largest of the studies,357 118 consecutivepatients with UEDVT were assessed retrospec-tively. At a median of 40 months of follow-up,venous patency on ultrasound was noted in 65% ofpatients who had been treated with IV urokinasecompared with 20% of patients treated with stan-dard anticoagulants; however, the rates of recur-rent VTE were similar in the two groups and thelysis group had a 15.2% rate of bleeding, com-pared with no bleeds in the anticoagulant group, adifference that was highly statistically significant.In the largest of the prospective studies,353 among35 patients with primary UEDVT treated withCDT followed by warfarin for a mean of 5 months,the rate of ipsilateral UEDVT recurrence at 54months of follow-up was substantial at 23%.
To summarize the heterogeneous, low-to-mod-erate quality data available, some studies352,356,357
report good-to-excellent success of thrombolytictherapy in terms of early and late venous patency.However, for important clinical end points such asPE, recurrent VTE, bleeding, and PTS, it is notknown if initial thrombolytic therapy is, on bal-ance, superior or inferior to anticoagulant therapy,or whether one thrombolytic approach is better orworse than another, as no prospective, controlledcomparisons have been performed.
Recommendations
8.2.1. For most patients with acute UEDVT, werecommend against the routine use of systemicor catheter-directed thrombolytic therapy(Grade 1C).8.2.2. In selected patients with acute UEDVT(eg, those with a low risk of bleeding andsevere symptoms of recent onset), we suggestthat CDT may be used for initial treatment ifappropriate expertise and resources are avail-able (Grade 2C).
8.3 Catheter Extraction, Surgical Thrombectomy,Transluminal Angioplasty, Stent Placement, StagedApproach of Lysis Followed by Interventional orSurgical Procedure, SVC Filter Insertion, for theInitial Treatment of UEDVT.
A number of reviews359,360 have advocatedstaged, multidisciplinary approaches to the man-agement of primary UEDVT that involve throm-bolysis and angioplasty or stent placement, fol-lowed by early or late surgical decompression ofthe thoracic outlet. However, data on the efficacy
and safety of these approaches are limited andderived from small, uncontrolled, prospec-tive361–363 or retrospective364 –372 case series, mostsingle-center (Table 21). In studies where resultswere reported separately for surgical and nonsur-gical approaches, surgery with or without lysistended to achieved higher late rates of vein pa-tency and lower rates of PTS than lysis alone.361,367
Among studies that only reported results for sur-gical treatment, rates of PTS ranged from 15 to50%,366,368,370,373 which are similar to rates reportedafter medical therapy alone.347,348 Most studies did notprovide data on surgical complications; however, onesmall prospective study362 reported a 26% rate ofserious postoperative complications.
SVC filters have been used in small series ofpatients with contraindications to or failure ofanticoagulant therapy.363,364 In a prospectivestudy363 of 41 patients with UEDVT who had SVCfilters placed, the rates of PE and PTS duringlong-term follow-up were 2.4% and 0%, respec-tively. In a retrospective series364 of 72 patientswith SVC filters, there were no episodes of PE orSVC thrombosis during long-term follow-up.
Recommendations
8.3.1. For most patients with acute UEDVT, werecommend against the routine use of catheterextraction, surgical thrombectomy, translumi-nal angioplasty, stent placement, staged ap-proach of lysis followed by interventional orsurgical procedure, or SVC filter placement(Grade 1C).8.3.2. In selected patients with acute UEDVT(eg, those with primary UEDVT and failure ofanticoagulant or thrombolytic treatment whohave severe persistent symptoms), we suggestthat catheter extraction, surgical thrombec-tomy, transluminal angioplasty, or a staged ap-proach of lysis followed by a vascular interven-tional or surgical procedure may be used ifappropriate expertise and resources are avail-able (all Grade 2C).8.3.3. In selected patients with acute UEDVT (eg,those in whom anticoagulant treatment is contra-indicated and there is clear evidence of DVTprogression or clinically significant PE), we sug-gest placement of an SVC filter (Grade 2C).
8.4 Anticoagulants for the Long-term Treatment ofUEDVT
There are no randomized studies of duration orintensity of long-term anticoagulation for the preven-tion of recurrent VTE in patients with UEDVT (Table
522S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
22). There is general agreement that, as for patientswith lower-extremity DVT, patients with symptomaticacute DVT of the upper extremity require long-termtreatment with anticoagulants following initialtreatment, and that a similar process as for lower-extremity DVT should be used to determine theoptimal duration of anticoagulation.374 –377 How-ever, there is little evidence to support indefiniteanticoagulant therapy for a first unprovokedUEDVT.
In prospective cohort studies346,349–351,378 of thetreatment of UEDVT, patients received VKA (targetINR, 2.5; range, 2.0 to 3.0) for periods of 3 to 6 monthsor longer. Similar regimens were reported in retrospec-tive studies.373,379–383 Rates of recurrent VTE, bleed-ing, PTS, and death reported during long-term fol-low-up in these studies are shown in Table 22. No dataare available regarding the long-term use of LMWHmonotherapy or newer anticoagulants, such asfondaparinux, for the long-term treatment of UEDVT.
Table 19—Initial Treatment of Acute UEDVT With IV UFH or LMWH: Clinical Description and Results (Section 8.1)*
Author/yr Type of Study† Participants Intervention‡ Outcomes§ Follow-up Results
Savage et al349/1999
Prospective cohort,two center
46 outpatientswith UEDVT(includes 16patients withcentral venouscatheter)
Dalteparin daily for5–7 d (200 IU/kg)and VKA withtarget INR of2.0–3.0
Duration of VKA notprovided
Symptomaticrecurrence/extension of DVT
PEMajor bleedDeath
3 mo Recurrence/extensionDVT: 1/46 (2%)
PE: 0/46Major bleed: 1/46 (2%;
on VKA)Death: 7/46 (15%; none
from PE or bleed)
Karabay et al350/2003
Prospective cohort,single center
36 inpatientswith UEDVT(includes 13with centralvenous catheter)
Nadroparin SC bid,86 aXa IU/kg forup to 7 d, thenVKA (started onday 3; target INR,2–2.5) for meanof 4.7 mo
Symptom reliefLysis of thrombus
on ultrasoundRecurrent DVTPEDeath
1 yr Significant symptomrelief: day 7: 32/36(89%)
Lysis: day 10� 35%: 16/36 (45%)� 35%: 17/36 (47%)none: 3/36 (8%)
Recurrent DVT: 0/36PE: 0/36Death: 9/36 (25%);
none due toPE or bleed
Prandoni et al229/2004
Prospective cohort,number ofcenters notstated
53 patients withfirst UEDVT(included 6 withcentral venouscatheter)
Therapeutic doseheparin (81%received UFH,19% receivedLMWH) thenVKA (median,3 mo)
Recurrent VTEDeath
Median,48 mo
Results not presentedaccording to initialtreatment withUFH vs LMWH
Recurrent VTE: 3/53(5.7%; 2 arm, 1 leg);cumulative incidence1 yr, 2 yr, and 5 yr:2.0%, 4.2%, 7.7%
Death: 11/53 (20.8%);due to cancer, PE,congestive heartfailure (numbersnot provided)
Kovacs et al351/2007
Prospective cohort,multicenter
74 cancer patientswith confirmedUEDVT (allhad centralvenous catheter)
Dalteparin daily for5–7 d (200 IU/kg)and VKA toachieve targetINR of 2.0–3.0
Recurrent VTEPEMajor bleedDeathCatheter failure due
to DVT or inabilityto infuse
3 mo Recurrent VTE: 0/74PE: 0/74Major bleed: 3/74 (4%)Death: 7/74 (6 cancer,
1 major bleed)Catheter failure due to
DVT or inability toinfuse: 0/74
*The methodologic quality description portion of this table can be found in the online version of this article as a data supplement.†Prospective cohort studies.‡Drugs: IV UFH or LMWH followed by oral anticoagulants.§Recurrent DVT and PE, major bleeding, total mortality, early symptom relief.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 523S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le20
—In
itia
lT
reat
men
tof
Acu
teU
ED
VT
Wit
hT
hrom
bol
ytic
The
rapy
:C
lini
cal
Des
crip
tion
and
Res
ult
s(S
ecti
on8.
2)*
Aut
hor/
yrT
ype
ofSt
udy†
Part
icip
ants
Inte
rven
tion‡
Out
com
es§
Fol
low
-up
Res
ults
Abu
Rah
ma
etal
352 /
1996
Ret
rosp
ectiv
eca
sese
ries
,sin
gle
cent
er
19pa
tient
sw
ithU
ED
VT
(13
prim
ary,
6ce
ntra
lve
nous
cath
eter
rela
ted)
Adj
uste
dIV
hepa
rin
then
VK
Afo
r3–
12m
o(n
�9)
Uro
kina
seat
4,50
0U
/kg
load
,th
en4,
500
U/k
g/h
for
24–4
8h
orst
rept
okin
ase
250,
000U
then
100,
000U
/hfo
r48
hpl
usIV
hepa
rin
plus
VK
A(n
�10
)T
hree
patie
nts
also
had
first
rib
rese
ctio
n
Ble
edw
ithin
itial
trea
tmen
tV
ein
pate
ncy
onul
tras
ound
atfin
alfo
llow
-up
Clin
ical
reso
lutio
nat
final
follo
w-u
p
Mea
n,36
mo
Ble
ed:0
/19
Vei
npa
tent
:A
ntic
oagu
latio
ngr
oup:
2/9
(22.
2%)
Lys
isgr
oup:
8/10
(80%
)p
�0.
018
Com
plet
ecl
inic
alre
solu
tion:
Ant
icoa
gula
tion
grou
p:2/
9(2
2.2%
)L
ysis
grou
p:8/
10(8
0%)
Pegi
set
al35
5 /199
7Pr
ospe
ctiv
eca
sese
ries
,sin
gle
cent
er
6pa
tient
sw
ithef
fort
-in
duce
dU
ED
VT
and
thor
acic
outle
tsy
ndro
me
Cat
hete
r-di
rect
edur
okin
ase
infu
sion
(2,5
00U
/kg
bolu
s,th
en2,
500
U/k
g/h)
and
hepa
rin
(100
U/k
gq1
2h)
duri
nga
mea
nof
64h
Imm
edia
tecl
otly
sis
(com
plet
e,pa
rtia
l,or
noly
sis)
Ble
edA
ble
tore
sum
eno
rmal
leve
lof
activ
ity
31m
o(m
ean)
Com
plet
ely
sis:
3/6
(50%
)Pa
rtia
llys
is:2
/6(3
3%)
No
lysi
s:1/
6(1
7%)
Ble
ed:0
/6A
ble
tore
sum
eus
uala
ctiv
ity:
5/6
(83%
)Pa
tient
with
noly
sis
was
the
one
not
able
tore
sum
eac
tivity
Schi
ndle
ret
al35
8 /19
99R
etro
spec
tive
case
seri
es,s
ingl
ece
nter
18ca
ncer
patie
nts
unde
rgoi
ngre
gion
alth
rom
boly
sis
for
cent
ral
veno
usca
thet
er-r
elat
edU
ED
VT
duri
nghi
gh-
dose
chem
othe
rapy
Uro
kina
seIV
infu
sion
ata
dose
of75
,000
–150
,000
U/h
for
24–9
6h,
then
adju
sted
IVhe
pari
nfo
r5–
7d
and
VK
A(t
arge
tIN
R,
2–3)
for
atle
ast
3m
o
VT
Ere
curr
ence
Ble
eddu
ring
lysi
sU
nspe
cifie
dV
TE
recu
rren
ce(a
llU
ED
VT
):4/
18(2
2.2%
)�d
ay13
,16,
48,5
4�,
allw
ithsu
bthe
rape
utic
INR
Ble
ed:4
/18
(22.
2%)
min
or;
1/18
(5.6
%)
maj
or
Petr
akis
etal
356 /
2000
Ret
rosp
ectiv
eca
sese
ries
,sin
gle
cent
er
20pa
tient
sw
ith1°
(n�
11)
and
2°(n
�9)
UE
DVT
Ant
icoa
gula
ntth
erap
y(a
djus
ted
IVhe
pari
nfo
r7
d,V
KA
toac
hiev
epr
othr
ombi
ntim
e1.
5–2
�co
ntro
lfor
6–12
mo;
n�
11)
Thr
ombo
lysi
s(u
roki
nase
at4,
500
U/k
glo
adin
gdo
se,t
hen
4,50
0U
/kg/
h,or
stre
ptok
inas
eat
250,
000
Ulo
ad,t
hen
100,
00U
/hfo
r24
–48
h,fo
llow
edby
IVhe
pari
nfo
r7
dan
dV
KA
for
3m
o(n
�9)
Vei
npa
tenc
yat
follo
w-u
pC
linic
alim
prov
emen
tin
sym
ptom
s
Ant
icoa
gula
tion
grou
p:82
mo
(mea
n)L
ysis
grou
p:52
mo
(mea
n)
Ven
ous
pate
ncy:
antic
oagu
latio
n:1/
11(9
%)
Lys
is:5
/9(5
6%)
�p�
0.04
0�C
linic
alim
prov
emen
t:an
ticoa
gula
tion:
4/11
(36%
)L
ysis
:8/9
(89%
)�p
�0.
028�
Hor
neet
al92
/200
0Pr
ospe
ctiv
eco
hort
,si
ngle
cent
er18
patie
nts
with
axill
ary
orsu
bcla
vian
DV
TC
athe
ter-
dire
cted
rt-P
A(2
mg/
cmof
thro
mbu
sto
max
imum
of20
mg)
,the
nV
KA
for
3m
o
Imm
edia
tepa
tenc
yE
stab
lishm
ent
ofan
tegr
ade
flow
Ble
edin
gev
ents
6m
oIm
med
iate
pate
ncy:
10/1
8(5
6%);
ante
grad
eflo
w:1
1/18
(61%
);bl
eeds
(all
min
or):
5/18
(28%
)
Lok
anat
han
etal
354 /
2001
Ret
rosp
ectiv
eca
sese
ries
,sin
gle
cent
er
28pa
tient
sw
ithfir
step
isod
eof
prim
ary
UE
DV
T(0
cent
ra;
veno
usca
thet
ers)
Uro
kina
sebo
lus
(ran
ge,1
0,00
0-1,
000,
000
U)
plus
cont
inuo
usin
fusi
on(5
0,00
0–24
0,00
0U
/h),
follo
wed
byIV
hepa
rin
then
VK
Afo
r3
mo
12pa
tient
sha
dan
giop
last
y;2
patie
nts
had
thor
acic
outle
tde
com
pres
sion
VT
Ere
curr
ence
PE Ble
edPT
Ssy
mpt
oms
2.9
yr(m
ean)
VT
Ere
curr
ence
:3/2
1(1
4%)
PE:1
/21
(5%
)B
leed
:0PT
S:no
ne:6
/21
(29%
)M
ild:1
3/21
(62%
)M
oder
ate:
2/21
(10%
)
524S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le20
—C
onti
nued
Aut
hor/
yrT
ype
ofSt
udy†
Part
icip
ants
Inte
rven
tion‡
Out
com
es§
Fol
low
-up
Res
ults
Sabe
tiet
al35
7 /200
2R
etro
spec
tive
coho
rtst
udy,
sing
lece
nter
118
cons
ecut
ive
inpa
tient
sw
ithU
ED
VT
Adj
uste
dIV
hepa
rin
orL
MW
H10
0IU
/kg
bid
plus
oral
VK
Afo
r6
mo
(IN
R,2
–3)
�n�
62�
Uro
kina
seat
150,
00IU
/hfo
r24
hpl
usor
alV
KA
for
6m
o(I
NR
,2–
3)�n
�33
�3
patie
nts
also
had
first
rib
rese
ctio
n
Vei
npa
tenc
yon
ultr
asou
nd(a
sses
sed
in83
patie
nts)
Rec
urre
ntV
TE
Ble
edPT
S
Med
ian,
40m
oV
enou
spa
tenc
yra
te:
signi
fican
tlyhi
gher
inly
sisgr
oup
than
antic
oagu
latio
ngr
oup
(p�
0.01
log
rank
test
);da
tano
tpro
vide
dR
ecur
rent
VT
E:
Ant
icoa
gula
tion
grou
p:5/
62L
ysis
grou
p:2/
33,
p�
0.9
Maj
orbl
eed:
Ant
icoa
gula
tion
grou
p:0/
62;
Lys
isgr
oup:
5/33
p�
0.00
01PT
S:A
ntic
oagu
latio
ngr
oup:
6/62
;L
ysis
grou
p:3/
33p
�0.
3L
eeet
al35
3 /200
6Pr
ospe
ctiv
eca
sese
ries
,sin
gle
cent
er
35pa
tient
sw
ithpr
imar
yU
ED
VT
who
had
com
plet
ere
solu
tion
ofac
ute
sym
ptom
sw
ithC
DT
(n�
29)
orIV
hepa
rin
(n�
6)
Ora
lVK
Afo
rm
ean
of5.
2m
oR
ecur
rent
DV
T54
mo
Ipsil
ater
alre
curr
entD
VT:
8/35
(23%
)
*The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
†Ret
rosp
ectiv
ean
dpr
ospe
ctiv
eco
hort
stud
ies.
‡Dru
gs:t
hrom
boly
ticth
erap
y,co
mpa
red
with
diff
eren
tty
pes
ofly
ticth
erap
yor
with
antic
oagu
lant
s.§O
utco
mes
:Rec
urre
ntD
VT
and
PE,v
ein
pate
ncy,
maj
orbl
eedi
ng,t
otal
mor
talit
y,an
dPT
Sof
the
arm
.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 525S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le21
—In
itia
lT
reat
men
tof
Acu
teU
ED
VT
Wit
hC
athe
ter
Ext
ract
ion,
Surg
ical
Thr
omb
ecto
my,
Tra
nslu
min
alA
ngio
plas
ty,
Sten
tP
lace
men
t,St
aged
App
roac
hto
Lys
isF
ollo
wed
by
Inte
rven
tion
orSu
rgic
alP
roce
dure
,or
SVC
Fil
ter
Inse
rtio
n:C
lini
cal
Des
crip
tion
and
Res
ult
s(S
ecti
on8.
3)*
Aut
hor/
yrT
ype
ofSt
udy†
Part
icip
ants
Inte
rven
tion‡
Out
com
es§
Fol
low
-up
Res
ults
Mac
hled
er36
1 /19
93Pr
ospe
ctiv
eca
sese
ries
,sin
gle
cent
er
50pa
tient
sw
ithpr
imar
yU
ED
VT
Stag
edm
ultid
isci
plin
ary
appr
oach
Syst
emic
orca
thet
er-d
irec
ted
lysi
sw
ithur
okin
ase
orst
rept
okin
ase,
follo
wed
byIV
hepa
rin
and
VK
Afo
r3
mo,
with
subs
eque
ntsu
rgic
altr
eatm
ent
(tra
nsax
illar
yfir
stri
bre
sect
ion)
inca
ses
whe
rean
unde
rlyi
ngco
mpr
essi
veab
norm
ality
ofve
inre
mai
ned
orob
stru
ctio
nof
veno
usco
llate
rals
with
arm
abdu
ctio
nw
aspr
esen
t35
patie
nts
(70%
)un
derw
ent
tran
saxi
llary
first
rib
rese
ctio
n
Ble
edPT
Ssy
mpt
oms
3.1
yr(m
ean)
Ble
ed:1
/50
(occ
urre
don
VK
A)
PTS
sym
ptom
s:In
thos
ew
hoha
dsu
rger
y:N
one:
25/3
5(7
2%)
Min
imal
:5/3
5(1
4%)
Pers
iste
nt:5
/35
(14%
)
Inth
ose
who
did
not
have
surg
ery:
Non
e:6/
15(4
0%)
Min
imal
:4/1
5(2
7%)
Pers
iste
nt:5
/15
(33%
)M
alcy
nski
etal
367 /1
993
Ret
rosp
ectiv
eca
sese
ries
,sin
gle
cent
er
12pa
tient
sw
ithpr
imar
yU
ED
VT
Stag
edm
ultid
isci
plin
ary
appr
oach
Cat
hete
r-di
rect
edly
sis
(uro
kina
seor
stre
ptok
inas
e),
then
IVhe
pari
npl
usV
KA
(3–6
mo)
�n�
9�Su
rgic
alde
com
pres
sion
(fir
stri
bre
sect
ion
orsc
alen
ecto
my;
n�
8;5
ofth
ese
also
trea
ted
with
lysi
s)
Ble
edV
ein
pate
ncy
PTS
Mea
n,3
yrB
leed
:1/1
2(8
.3%
)�m
inor
�V
ein
pate
ncy:
Lys
is:(
25%
)L
ysis
plus
surg
ery:
5/5
(100
%)
Surg
ery
alon
e:3/
3(1
00%
)
PTS:
Lys
isal
one:
3/4
(75%
)L
ysis
plus
surg
ery:
0/5
(0%
)Su
rger
yal
one:
0/3
(0%
)Sa
nder
san
dC
oope
r369 /
1995
Ret
rosp
ectiv
e,si
ngle
cent
er12
patie
nts
with
acut
eor
chro
nic
UE
DV
Tor
nont
hrom
botic
subc
lavi
anve
inob
stru
ctio
n
Var
ious
surg
ical
inte
rven
tions
incl
udin
gfir
stri
bre
sect
ion,
thro
mbe
ctom
y,ve
nous
bypa
ss,v
ein
patc
han
giop
last
y,th
rom
boly
sis
All
patie
nts
rece
ived
VK
Afo
r3–
6m
o
PTS
(pai
n,sw
ellin
g)26
mo
(mea
n)PT
S:6/
12(5
0%)
Mei
eret
al36
8 /19
96R
etro
spec
tive,
sing
lece
nter
11pa
tient
sw
ithpr
imar
yU
ED
VT
Thr
ombo
lysi
sw
ithca
thet
er-d
irec
ted
urok
inas
e(2
50,0
00–5
00,0
00U
bolu
s)fo
llow
edby
infu
sion
of60
,000
–180
,000
U/h
(n�
11),
veno
usst
ent
(Wal
lste
nt)
plac
emen
tin
som
epa
tient
s(n
�8)
;all
had
IVhe
pari
nan
dV
KA
for
3m
o;fiv
epa
tient
ssu
bseq
uent
lyha
dfir
stri
bre
sect
ion
Rec
urre
ntV
TE
Sten
tco
mpl
icat
ions
PTS
sym
ptom
s
12m
oR
ecur
rent
arm
DV
Ton
veno
gram
at8–
12w
k:2/
11(1
8%)
Sten
tfr
actu
re:2
/11
(18%
)PT
S:3/
11(2
7%)
Shee
ran
etal
370 /
1997
Ret
rosp
ectiv
eca
sese
ries
,sin
gle
cent
er
14pa
tient
sw
ithpr
imar
yU
ED
VT
Stag
edm
ultid
isci
plin
ary
appr
oach
Cat
hete
r-di
rect
edur
okin
ase
(240
/000
U/h
for
4h
then
120,
000
U/h
,fol
low
edby
IVhe
pari
nan
dV
KA
for
3m
o(p
roth
rom
bin
time
1.5–
2�
cont
rol)
Mos
tpa
tient
sal
soun
derw
ent
tran
slum
inal
angi
opla
sty
(n�
5)an
dfir
stri
bre
sect
ion
(n�
8)
Ble
edPT
S24
mo
Ble
ed:0
PTS:
2/14
(14.
3%)
526S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le21
—C
onti
nued
Aut
hor/
yrT
ype
ofSt
udy†
Part
icip
ants
Inte
rven
tion‡
Out
com
es§
Fol
low
-up
Res
ults
Lee
etal
366 /
1998
Ret
rosp
ectiv
eca
sese
ries
,sin
gle
cent
er
11pa
tient
sw
ithU
ED
VT
from
thor
acic
inle
tob
stru
ctiv
edi
seas
e
Cat
hete
r-di
rect
edly
sis
(uro
kina
se)
follo
wed
byad
just
edIV
hepa
rin
with
in5
dof
lysi
s,su
rgic
alde
com
pres
sion
,ven
ous
bypa
ssor
angi
opla
sty,
follo
wed
byV
KA
for
3–6
mo
PTS
(res
idua
lsy
mpt
oms,
limite
dfu
nctio
n)
24m
o(m
ean)
PTS:
2/11
(18.
2%)
Yilm
azet
al37
2 /20
00R
etro
spec
tive
case
seri
es,s
ingl
ece
nter
24pa
tient
sw
ithsp
onta
neou
sef
fort
thro
mbo
sis
ofth
esu
bcla
vian
vein
Stag
edm
ultid
isci
plin
ary
appr
oach
Stre
ptok
inas
eat
10,0
00U
load
ing
dose
then
10,0
00U
/hun
tilcl
otly
sis
then
UF
H(2
0,00
0U
/h)
follo
wed
byV
KA
for
3m
o6–
12w
ksla
ter,
19pa
tient
sha
dfir
stri
bre
sect
ion
Imm
edia
teou
tcom
es(n
�24
)C
lot;
lysi
sPE B
leed
Lon
g-te
rmsy
mpt
oms
(n�
13)
40m
o(m
ean)
Clo
tly
sis:
23/2
4(9
5.8%
)PE
:1/2
4(4
%)
Ble
ed(m
inor
):4/
24(1
6.7%
)Pe
rsis
tent
sym
ptom
:2/1
3(1
5%)
�all
refu
sed
rib
rese
ctio
n�
Feu
gier
etal
365 /
2001
Ret
rosp
ectiv
eca
sese
ries
,sin
gle
cent
er
10at
hlet
esw
ithex
ertio
nalU
ED
VT
Stag
edm
ultid
isci
plin
ary
appr
oach
Cat
hete
r-di
rect
edur
okin
ase
(2,5
00IU
/kg/
h)fo
r24
–72
h,fo
llow
edby
hepa
rin
and
VK
A(n
�6)
,LM
WH
and
VK
Aal
one
(n�
4);d
urat
ion
ofV
KA
not
prov
ided
All
patie
nts
subs
eque
ntly
had
surg
ical
trea
tmen
t9
d–9
mo
late
r
Pain
Abi
lity
tore
sum
esp
orts
activ
ities
Ede
ma
Dea
th
45m
o(m
ean)
Pain
:0/1
0(0
%)
Res
umpt
ion
ofac
tiviti
es:1
0/10
(100
%;w
ithin
mea
nof
71d)
Ede
ma:
3/10
(30%
)D
eath
:0/1
0(0
%)
�res
ults
not
prov
ided
byin
itial
trea
tmen
tgr
oup�
Urs
chel
and
Pate
l371 /2
003
Ret
rosp
ectiv
eca
sese
ries
406
patie
nts
with
prim
ary
UE
DV
T,
incl
udin
g22
refe
rred
for
sten
tth
rom
bosi
s
Cat
hete
r-di
rect
edly
sis
(uro
kina
seat
4,40
0U
/kg
bolu
sth
en4,
400
U/h
ortP
Aat
2m
g/h
for
8h,
then
1m
g/h
until
clot
lysi
s,fo
llow
edby
IVhe
pari
n,th
enfir
stri
bre
sect
ion)
PE Dea
thSy
mpt
oms
ofPT
S
Sten
tgr
oup:
3.5
yr;
Surg
ery
grou
p:7
yr
PE:0
Dea
th:0
PTS:
Initi
alst
ent
grou
p:5/
22(2
3%)
Surg
ery-
only
grou
p:4/
384
(1%
)Sc
hnei
der
etal
362 /2
004
Pros
pect
ive,
two-
cent
erst
udy
23pa
tient
sw
ithac
ute
subc
lavi
anve
inth
rom
bosi
s
Thr
ombo
lysi
s(n
�21
)fo
llow
edby
imm
edia
tede
com
pres
sion
surg
ery
(n�
7)or
dela
yed
surg
ical
deco
mpr
essi
onaf
ter
VK
Afo
r0.
5–7
mo
(n�
14);
antic
oagu
latio
nal
one
(n�
2)T
rans
lum
inal
angi
opla
sty
also
perf
orm
edin
16pa
tient
s
Surg
ical
com
plic
atio
nsSu
bcla
vian
vein
pate
ncy
atfo
llow
-up
Res
idua
lpai
nan
dsw
ellin
gD
eath
Mea
n,10
mo
Surg
ical
com
plic
atio
ns:
Wou
ndhe
mat
oma
requ
irin
gop
erat
ive
expl
orat
ion:
3(1
3%)
Phre
nic
nerv
edy
sfun
ctio
n:1
(4%
);Po
stop
erat
ive
subc
lavi
anre
thro
mbo
sis:
2(8
%)
Subc
lavi
anve
inpa
tenc
yat
follo
w-u
p:22
/23
(96%
)R
esid
ualp
ain
and
swel
ling:
1/23
(4%
)D
eath
:0/2
3
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 527S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Recommendations
8.4.1. For patients with acute UEDVT, we rec-ommend treatment with a VKA for > 3 months(Grade 1C).
Remark: A similar process as for lower-extremityDVT (see Section 2) should be used to determinethe optimal duration of anticoagulation.8.4.2. For most patients with UEDVT in associ-ation with an indwelling central venous cathe-ter, we suggest that the catheter not be re-moved if it is functional and there is an ongoingneed for the catheter (Grade 2C).8.4.3. For patients who have UEDVT in associ-ation with an indwelling central venous cathe-ter that is removed, we do not recommend thatthe duration of long-term anticoagulant treat-ment be shortened to < 3 months (Grade 2C).
8.5 Prevention of PTS of the Arm
PTS of the arm occurs in 15 to 25% of patientsafter treated UEDVT.347,348 Upper-extremity PTS isa potentially disabling condition that adversely affectQOL, particularly if the dominant arm is involved.384
To date, no controlled studies have evaluated theeffectiveness of elastic bandages, compressionsleeves, or venoactive drugs to prevent PTS afterUEDVT.
Recommendation
8.5.1. For patients at risk for PTS after UEDVT,we do not suggest routine use of elastic com-pression or venoactive medications (Grade 2C).
8.6 Treatment of PTS of the Arm
Symptoms of PTS of the arm include swelling,heaviness, and limb fatigue with exertion.347,384 Nocontrolled studies have evaluated the effectiveness ofelastic bandages, compression sleeves (as are usedfor lymphedema), or venoactive drugs to treat PTSafter UEDVT. Anecdotal evidence suggests thatpatients with persistent arm swelling and pain mayderive symptomatic relief from elastic bandages orcompression sleeves. As these are unlikely to causeharm, they could be tried.
Recommendation
8.6.1. In patients with UEDVT who have persis-tent edema and pain, we suggest elastic ban-dages or elastic compression sleeves to reducesymptoms of PTS of the upper extremity (Grade2C).
Tab
le21
—C
onti
nued
Aut
hor/
yrT
ype
ofSt
udy†
Part
icip
ants
Inte
rven
tion‡
Out
com
es§
Fol
low
-up
Res
ults
Spen
ceet
al36
3 /19
99Pr
ospe
ctiv
eco
hort
,si
ngle
cent
er41
patie
nts
with
UE
DV
Tw
ithfa
ilure
ofor
cont
rain
dica
tion
toan
ticoa
gula
tion
(cen
tral
veno
usca
thet
erin
36pa
tient
s)
Plac
emen
tof
Gre
enfie
ld(3
3pa
tient
s),S
imon
nitin
ol(5
patie
nts)
,Ven
aT
ech
(2pa
tient
s),o
rB
ird’
sN
est
(1pa
tient
)fil
ters
PE PTS
Dea
th
Med
ian,
12w
kPE
:1/4
1(2
.4%
)at
44m
oin
apa
tient
with
acut
ele
gD
VT
;PT
S:0/
41D
eath
(sur
viva
lana
lysi
s):5
9%at
12m
o(n
one
due
toPE
)
Asc
her
etal
364 /
2000
Ret
rosp
ectiv
eca
sese
ries
,sin
gle
cent
er
72pa
tient
sw
ithU
ED
VT
(20
with
cent
ralv
enou
sca
thet
er)
inw
hom
antic
oagu
latio
nw
asco
ntra
indi
cate
d(n
�67
)or
had
faile
d(n
�5)
.
Gre
enfie
ldSV
Cfil
ter
PE SVC
thro
mbo
sis
Filt
er;c
ompl
icat
ions
Dea
th
Mea
n,7.
8m
oPE
:0SV
Cth
rom
bosi
s:0
Com
plic
atio
ns:o
nefil
ter
inco
rrec
tlydi
scha
rged
into
inno
min
ate
vein
Dea
th:3
8/72
(53%
;non
edu
eto
VT
Ecl
inic
ally
;no
auto
psie
s)
*The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
†Ret
rosp
ectiv
ean
dpr
ospe
ctiv
eco
hort
stud
ies.
‡Cat
hete
rex
trac
tion,
surg
ical
thro
mbe
ctom
y,tr
ansl
umin
alan
giop
last
y,st
ent
plac
emen
t,st
aged
appr
oach
ofly
sis
follo
wed
byin
terv
entio
nalo
rsu
rgic
alpr
oced
ure,
SVC
filte
r.§R
ecur
rent
DV
Tan
dPE
,maj
orbl
eedi
ng,o
pera
tive
com
plic
atio
ns,t
otal
mor
talit
y,an
dPT
Sof
the
arm
.
528S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le22
—L
ong-
term
Tre
atm
ent
ofA
cute
UE
DV
T:
Cli
nica
lD
escr
ipti
onan
dR
esu
lts
(Sec
tion
8.4)
*
Aut
hor/
yrT
ype
ofSt
udy†
Part
icip
ants
Inte
rven
tion‡
Out
com
es§
Fol
low
-up
Res
ults
Lin
dbla
det
al38
2 /19
88R
etro
spec
tive
case
seri
es,m
ultic
ente
r12
0pa
tient
sw
ithco
nfir
med
UE
DV
T(in
clud
es29
with
cent
ralv
enou
sca
thet
er)
Hep
arin
then
VK
A(n
�59
),he
pari
nal
one
(n�
32),
notr
eatm
ent
(n�
5),V
KA
(n�
5),s
trep
toki
nase
(n�
5),o
rot
her
(n�
4)D
rug,
dose
s,du
ratio
nof
antic
oagu
latio
nno
tpr
ovid
ed
PE PTS
8yr
(mea
n)PE
:4/1
20(3
%;3
fata
l)PT
Spa
inor
disc
omfo
rt:
Mild
:29/
120
(24%
)M
oder
ate:
5/12
0(4
%)
Seve
re:0
(Res
ults
not
prov
ided
bytr
eatm
ent
grou
p)B
urih
anet
al37
9 /19
93R
etro
spec
tive
case
seri
es,s
ingl
ece
nter
52pa
tient
sw
ithco
nfir
med
UE
DV
T(in
clud
es15
with
cent
ralv
enou
sca
thet
er)
IVhe
pari
nth
enV
KA
(n�
43),
SChe
pari
n(n
�7)
,ven
ous
thro
mbe
ctom
y(n
�1)
,or
SVC
-rig
htat
rial
bypa
ss(n
�1)
Dru
gdo
ses
not
prov
ided
;dur
atio
nof
antic
oagu
latio
n,6
mo
PE Dea
thPT
S
6m
oPE
:2/5
2(4
%)
Dea
th:9
/52
(17%
)PT
S:Sy
mpt
omfr
ee:2
1/52
(40%
)M
inim
aled
ema:
11/5
2(2
1%)
Sym
ptom
atic
edem
a:7/
52(1
3%)
�Res
ults
not
prov
ided
bytr
eatm
ent
grou
p�H
ingo
rani
etal
380 /
1997
Ret
rosp
ectiv
eco
hort
stud
y,si
ngle
cent
er17
0pa
tient
sw
ithU
ED
VT
(97
with
cent
ralv
enou
sca
thet
er)
Adj
uste
dIV
hepa
rin
then
VK
Afo
r3–
6m
o(t
arge
tIN
R,2
–3;n
�87
)SV
Cfil
ter
(n�
23)
Thr
ombo
lysi
spl
usop
erat
ive
deco
mpr
essi
onof
thor
acic
outle
tsy
ndro
me
(n�
2)N
oan
ticoa
gula
ntth
erap
y(n
�58
)
Rec
urre
ntV
TE
Dea
thPT
S(s
igni
fican
tsw
ellin
g)
Mea
n,13
mo
Rec
urre
ntV
TE
:2/1
70(1
.2%
)D
eath
;1-
mo
mor
talit
y:25
/170
(15%
)3-
mo
mor
talit
y:58
/170
(34%
)�N
ode
aths
from
PE�
PTS:
7(4
%)
�Res
ults
not
prov
ided
bytr
eatm
ent
grou
p�M
arie
etal
373 /
1998
Ret
rosp
ectiv
eca
sese
ries
,sin
gle
cent
er49
patie
nts
with
conf
irm
edU
ED
VT
(incl
udes
3w
ithce
ntra
lven
ous
cath
eter
)
Hep
arin
ther
apy
(LM
WH
,n�
36;U
FH
,n
�11
);V
KA
(n�
44),
surg
ical
thro
mbe
ctom
ypl
usve
nous
ligat
ion
(n�
1)D
urat
ion
ofV
KA
,3–6
mo
Sym
ptom
atic
VT
E;
recu
rren
cePE PT
S(r
esid
uall
imb
edem
a,pa
inor
heav
ines
s);m
ajor
blee
d
6m
oV
TE
recu
rren
ce:1
/49
(2.2
%)
PE:6
/49
(12.
2%)
PTS:
19/4
9(3
8.8%
)M
ajor
blee
d:0
(Res
ults
not
prov
ided
bytr
eatm
ent
grou
p)
Sava
geet
al34
9 /19
99Pr
ospe
ctiv
eco
hort
,tw
oce
nter
46ou
tpat
ient
sw
ithco
nfir
med
UE
DV
T(in
clud
es16
with
cent
ral
veno
usca
thet
er)
Dal
tepa
rin
daily
for
5–7
d(2
00IU
/kg)
and
VK
Ato
achi
eve
targ
etIN
Rof
2.0–
3.0
for
3m
oD
urat
ion
ofV
KA
not
prov
ided
Sym
ptom
atic
recu
rren
ce/e
xten
sion
ofD
VT
PE Maj
orbl
eed
Dea
th
3m
oR
ecur
renc
e/ex
tens
ion:
1/46
(2%
)PE
:0M
ajor
blee
d:1/
46(2
%;o
nV
KA
)D
eath
:7/4
6(1
5%;n
one
from
PEor
blee
d)
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 529S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le22
—C
onti
nued
Aut
hor
Typ
eof
Stud
y†Pa
rtic
ipan
tsIn
terv
entio
n‡O
utco
mes
§F
ollo
w-u
pR
esul
ts
Mar
inel
laet
al38
3 /20
00R
etro
spec
tive
case
seri
es,s
ingl
ece
nter
90pa
tient
sw
ithco
nfir
med
UE
DV
T(in
clud
es65
with
cent
ralv
enou
sca
thet
er)
Hep
arin
(n�
65),
VK
A(n
�53
),ca
thet
erre
mov
al(in
39/6
5pa
tient
sw
ithce
ntra
lve
nous
cath
eter
)D
rug
dose
s,du
ratio
nof
antic
oagu
latio
nno
tpr
ovid
ed
Dea
thN
otsp
ecifi
edD
eath
:11/
90(1
2%)
�Res
ults
not
prov
ided
bytr
eatm
ent
grou
p�
Mas
sour
eet
al39
2 /20
00R
etro
spec
tive
case
seri
es,s
ingl
ece
nter
40pa
tient
sw
ithco
nfir
med
UE
DV
T(2
2w
ithce
ntra
lve
nous
cath
eter
)
LM
WH
(n�
27),
UF
H(n
�13
),ca
thet
er-
dire
cted
lysi
s(n
�4)
,VK
A(n
�26
;m
ean
dura
tion
not
spec
ified
)
PE Maj
orbl
eed
PTS
Dea
th
9m
o(m
ean)
PE:2
/40
(5%
)M
ajor
blee
d:2/
40(5
%)
PTS:
14/4
0(3
5%;s
ever
ein
2/40
�5%
�)D
eath
:16/
40(4
0%)
Hin
gora
niet
al38
1 /20
01R
etro
spec
tive
char
tre
view
,sin
gle
cent
er
165
patie
nts
with
conf
irm
edU
ED
VT
:144
with
UE
DV
Tal
one
(incl
udes
90w
ithce
ntra
lven
ous
cath
eter
),an
d21
with
both
UE
DV
Tan
dlo
wer
-ex
trem
ityD
VT
(incl
udes
14w
ithce
ntra
lven
ous
cath
eter
)
UE
DV
Tal
one:
syst
emic
antic
oagu
latio
n(n
�94
),no
antic
oagu
latio
n(n
�31
),SV
Cfil
ter
(n�
16),
aspi
rin
(n�
3)U
ED
VT
and
low
er-e
xtre
mity
DV
T:s
yste
mic
antic
oagu
latio
n(n
�17
);SV
Cpl
usIV
Cfil
ter
(n�
2);n
oan
ticoa
gula
tion
(n�
1),
aspi
rin
(n�
1)D
rug
dose
s,du
ratio
nof
antic
oagu
latio
nno
tpr
ovid
ed
PEat
time
ofU
ED
VT
diag
nosi
sD
eath
with
in2
mo
ofU
ED
VT
diag
nosi
s
2m
oPE
attim
eof
UE
DV
Tdi
agno
sis:
UE
DV
Tal
one:
16/1
44(1
1%)
UE
DV
Tpl
uslo
wer
-ext
rem
ityD
VT
:2/2
1(9
.5%
;p�
0.59
)A
ll-ca
use
deat
hw
ithin
2m
oof
diag
nosi
s:U
ED
VT
alon
e:38
/144
(26%
)U
ED
VT
plus
low
er-e
xtre
mity
DV
T:1
1/21
(52%
)��
0.02
�D
eath
from
PEno
tre
port
ed(R
esul
tsno
tpr
ovid
edby
trea
tmen
tgr
oup)
Kar
abay
etal
350 /
2003
Pros
pect
ive
coho
rt,
sing
lece
nter
36in
patie
nts
with
conf
irm
edU
ED
VT
(incl
udes
13w
ithce
ntra
lven
ous
cath
eter
)
Nad
ropa
rin
SCbi
d,86
aXa
IU/k
gfo
rup
to7
d,th
enV
KA
(sta
rted
onda
y3;
targ
etIN
R,2
–2.5
)fo
rm
ean
of4.
7m
o
Sym
ptom
relie
f;ly
sis
ofth
rom
bus
onul
tras
ound
Rec
urre
ntD
VT
PE Dea
thPT
S
1yr
Sign
ifica
ntsy
mpt
omre
lief,
day
7:32
/36
(89%
)L
ysis
,day
10:
�35
%:1
6/36
(45%
)�
35%
:17/
36;(4
7%)
Non
e:3/
36(8
%)
Rec
urre
ntD
VT
:0PE
:0D
eath
:9/3
6(2
5%),
none
due
toPE
orbl
eed
PTS:
0M
artin
elli
etal
378 /
2004
Cas
e-co
ntro
lstu
dyw
ithpr
ospe
ctiv
efo
llow
-up
ofca
ses,
sing
lece
nter
98pa
tient
sw
ithpr
imar
yU
ED
VT
(non
ew
ithce
ntra
lven
ous
cath
eter
)
VK
Afo
rm
ean
6m
o(n
�77
),he
pari
nSQ
(n�
14),
oran
tipla
tele
tag
ents
(n�
7)fo
r�
3m
o
Rec
urre
ntV
TE
afte
ran
ticoa
gula
nts
stop
ped
Med
ian,
5.1
yrR
ecur
rent
VT
E:1
2/98
(12%
)ov
eral
l(a
llU
ED
VT
)A
nnua
linc
iden
ceof
recu
rren
tV
TE
:2.
4%(9
5%C
I,1.
2–4.
0%R
esul
tsno
tpr
ovid
edby
trea
tmen
tgr
oup)
530S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le22
—C
onti
nued
Aut
hor
Typ
eof
Stud
y†Pa
rtic
ipan
tsIn
terv
entio
n‡O
utco
mes
§F
ollo
w-u
pR
esul
ts
Pran
doni
etal
347 /
2004
Pros
pect
ive
coho
rt,
num
ber
ofce
nter
sno
tst
ated
53pa
tient
sw
ithco
nfir
med
first
UE
DV
T(in
clud
ed6
with
cent
ralv
enou
sca
thet
er)
The
rape
utic
dose
hepa
rin
(81%
rece
ived
UF
H,1
9%re
ceiv
edL
MW
H)
then
VK
A(m
edia
n,3
mo)
Rec
urre
ntV
TE
Dea
thPT
S
Med
ian,
48m
oR
esul
tsno
tpr
esen
ted
acco
rdin
gto
initi
altr
eatm
ent
with
UF
Hvs
LM
WH
;R
ecur
rent
VT
E:3
/53
(5.7
%;2
arm
,1le
g);c
umul
ativ
ein
cide
nce
at1
yr,2
yr,a
nd5
yr:2
.0%
,4.2
%,7
.7%
Dea
th:1
1/53
(20.
8%);
due
toca
ncer
,PE
,con
gest
ive
hear
tfa
ilure
(bre
akdo
wn
not
prov
ided
)PT
S:13
/53
24.5
%);
2-yr
cum
ulat
ive
inci
denc
e:27
.3%
Kah
net
al38
4 /200
5R
etro
spec
tive
coho
rt,
sing
lece
nter
24pa
tient
sw
ithco
nfir
med
UE
DV
T(in
clud
es11
with
cent
ralv
enou
sca
thet
er)
Hep
arin
(med
ian
of9
d,th
enV
KA
(med
ian,
5m
o;n
�23
),L
MW
Hm
onot
hera
py(n
�1)
PTS
Med
ian,
13m
oPT
S:11
/24
(46%
)
Pers
son
etal
393 /
2006
Ret
rosp
ectiv
eca
sese
ries
,sin
gle
cent
er31
patie
nts
with
conf
irm
edpr
imar
yU
ED
VT
(non
ew
ithce
ntra
lven
ous
cath
eter
)
LM
WH
follo
wed
byV
KA
for
3–6
mo
Rec
urre
ntV
TE
PTS
5yr
Rec
urre
ntV
TE
:0PT
S:9/
31(2
9%;n
one
seve
re)
Kov
acs
etal
351 /
2007
Pros
pect
ive
coho
rt,
mul
ticen
ter
74ca
ncer
patie
nts
with
conf
irm
edU
ED
VT
(all
had
cent
ralv
enou
sca
thet
er)
Dal
tepa
rin
(200
IU/k
g)da
ilyfo
r5–
7d
and
VK
Ato
achi
eve
targ
etIN
Rof
2.0–
3.0
Rec
urre
ntV
TE
PE Maj
orbl
eed
Dea
thC
athe
ter
failu
redu
eto
DV
Tor
inab
ility
toin
fuse
3m
oR
ecur
rent
VT
E:0
PE:0
Maj
orbl
eed:
3(4
%)
Dea
th:7
(6ca
ncer
,1m
ajor
blee
d)C
athe
ter
failu
redu
eto
DV
Tor
inab
ility
toin
fuse
:0
*The
met
hodo
logi
cqu
ality
desc
ript
ion
port
ion
ofth
ista
ble
can
befo
und
inth
eon
line
vers
ion
ofth
isar
ticle
asa
data
supp
lem
ent.
†Ret
rosp
ectiv
ean
dpr
ospe
ctiv
eco
hort
stud
ies
(incl
udes
stud
ies
inT
able
8.1)
.‡V
KA
,UF
H,L
MW
Hvs
plac
ebo,
cont
rol,
orea
chot
her.
§Rec
urre
ntD
VT
and
PE,m
ajor
blee
ding
,tot
alm
orta
lity,
and
PTS
ofth
ear
m.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 531S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
App
end
ix:S
um
mar
y
Tab
le23
—St
rept
okin
ase
Plu
sH
epar
invs
Con
trol
(Hep
arin
)
Qua
lity
Ass
essm
ent
Sum
mar
yof
Fin
ding
s
No.
ofPa
tient
s/T
otal
Patie
nts
(%)
Eff
ect
Qua
lity
Stud
ies,
No.
Des
ign
Lim
itatio
nsC
onsi
sten
cyD
irec
tnes
sPr
ecis
ion
Rep
ortin
gB
ias
Stre
ngth
ofA
ssoc
iatio
nSt
rept
okin
ase
Plus
Hep
arin
Con
trol
(Hep
arin
)
RR
(95%
CI)
orW
eigh
ted
Mea
nD
iffer
ence
Eve
nts
Prev
ente
dpe
r1,
000
Tre
ated
Rec
urre
ntD
VT
and
PE4*
RC
TSo
me
limita
tions
†N
oim
port
ant
inco
nsis
tenc
yN
o dire
ctne
ssSo
me
impr
ecis
ion‡
No re
port
ing
bias
No
stro
ngas
soci
atio
n‡1/
44(2
.27)
7/43
(16.
2%)
0.25
(0.0
6–1.
15)§
Not si
gnifi
cant
Mod
erat
e
Maj
orbl
eedi
ng4*
RC
TSo
me
limita
tions
No
impo
rtan
tin
cons
iste
ncy
No di
rect
ness
Som
eim
prec
isio
n‡N
o repo
rtin
gbi
as
No
stro
ngas
soci
atio
n8/
44(1
8.18
)7/
43(1
6.2)
1.07
6(0
.43–
2.72
)�N
ot sign
ifica
ntM
oder
ate
Tot
alm
orta
lity
4*R
CT
Som
elim
itatio
nsN
oim
port
ant
inco
nsis
tenc
yN
o dire
ctne
ssSo
me
impr
ecis
ion‡
No re
port
ing
bias
No
stro
ngas
soci
atio
n2/
44(4
.55)
4/43
(9.3
0)0.
46(0
.09–
2.29
)¶N
ot sign
ifica
ntM
oder
ate
*Inc
lude
sT
ibbu
ttD
,197
4;L
yB
,197
8;D
otte
rC
,197
9;an
dJe
rjes
-San
chez
C.1
995.
†See
met
hods
tabl
e.‡9
5%C
Iin
clud
esno
effe
cts.
§Bas
edon
met
aana
lysi
sof
thre
est
udie
s:T
ibbu
ttD
,197
4re
port
sno
case
sof
DV
Tin
eith
erth
etr
eatm
ent(
0of
11pa
tient
s)or
cont
rolg
roup
(0of
12pa
tient
s)an
dw
asno
tinc
lude
din
the
met
aana
lysi
s.�B
ased
onm
etaa
naly
sis
ofth
ree
stud
ies:
Jerj
es-S
anch
ezC
,199
5re
port
sno
case
sof
maj
orbl
eedi
ngin
eith
erth
etr
eatm
ent
(0of
4pa
tient
s)or
cont
rolg
roup
(0of
4pa
tient
s)an
dw
asno
tin
clud
edin
the
met
aana
lysi
s¶B
ased
onm
etaa
naly
sis
ofth
ree
stud
ies:
Tib
butt
D,1
974
and
Jerj
es-S
anch
ezC
,199
5re
port
node
aths
inei
ther
the
trea
tmen
tor
cont
rolg
roup
and
wer
eex
clud
edfr
omth
em
etaa
naly
sis.
532S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le24
—U
roki
nase
vsC
ontr
ol(H
epar
in)
Qua
lity
Ass
essm
ent
Sum
mar
yof
Fin
ding
s
No.
ofPa
tient
s/T
otal
(%)
Eff
ect
Qua
lity
No.
ofSt
udie
sD
esig
nL
imita
tions
Con
sist
ency
Dir
ectn
ess
Prec
isio
nR
epor
ting
Bia
sSt
reng
thof
Ass
ocia
tion
Uro
kina
seC
ontr
ol(H
epar
in)
RR
(95%
CI)
orW
eigh
ted
Mea
nD
iffer
ence
Eve
nts
Prev
ente
dpe
r1,
000
Tre
ated
Rec
urre
ntD
VT
and
PE2*
RC
TSo
me
limita
tions
†N
oim
port
ant
inco
nsis
tenc
yN
opr
oble
ms
Som
eim
prec
isio
n‡N
o repo
rtin
gbi
as
No
stro
ngas
soci
atio
n12
/98
(12.
24)
15/8
8(1
7.05
)0.
76(0
.38–
1.52
)§N
ot sign
ifica
ntM
oder
ate
Maj
orbl
eedi
ng2*
RC
TSo
me
limita
tions
No
impo
rtan
tin
cons
iste
ncy
No
prob
lem
sN
opr
oble
ms
No re
port
ing
bias
No
stro
ngas
soci
atio
n37
/92
(40.
22)
21/8
8(2
3.86
)1.
68(1
.08–
2.59
)§N
ot sign
ifica
ntM
oder
ate
Tot
alm
orta
lity
2*R
CT
Som
elim
itatio
nsN
oim
port
ant
inco
nsis
tenc
yN
opr
oble
ms
Som
eim
prec
isio
nN
o repo
rtin
gbi
as
No
stro
ngas
soci
atio
n6/
92(6
.52)
7/88
(7.9
5)0.
82(0
.29–
2.32
)§N
ot sign
ifica
ntM
oder
ate
*Inc
lude
sU
PET
stud
ygr
oup
1970
;Mar
iniC
1988
.†S
eem
etho
dsta
ble.
‡95%
CI
cont
ains
noef
fect
.§B
ased
onon
est
udy:
Mar
iniC
,198
8w
asex
clud
edbe
caus
eit
repo
rts
noca
ses
inei
ther
trea
tmen
tor
cont
rolg
roup
s.
Tab
le25
—rt
-PA
Plu
sH
epar
invs
Con
trol
(Hep
arin
)
Qua
lity
Ass
essm
ent
Sum
mar
yof
Fin
ding
s
No
ofPa
tient
sE
ffec
t
Qua
lity
Stud
ies,
No.
Des
ign
Lim
itatio
nsC
onsi
sten
cyD
irec
tnes
sPr
ecis
ion
Rep
ortin
gB
ias
Stre
ngth
ofA
ssoc
iatio
nrt
-PA
Plus
Hep
arin
Con
trol
(Hep
arin
)
RR
(95%
CI)
orW
eigh
ted
Mea
nD
iffer
ence
Eve
nts
Prev
ente
dpe
r1,
000
Tre
ated
Rec
urre
ntD
VT
and
PE1*
RC
TSo
me
limita
tions
†N
oim
port
ant
inco
nsis
tenc
yN
opr
oble
ms
Som
eim
prec
isio
n‡N
o repo
rtin
gbi
as
No
stro
ngas
soci
atio
n0/
465/
55(9
.09)
0.10
8(0
.01–
1.91
)N
otsi
gnifi
cant
Mod
erat
e
Maj
orbl
eedi
ng1*
RC
TSo
me
limita
tions
No
impo
rtan
tin
cons
iste
ncy
No
prob
lem
sSo
me
impr
ecis
ion
No re
port
ing
bias
No
stro
ngas
soci
atio
n3/
46(6
.52)
1/55
(1.8
2)3.
59(0
.39–
33.3
3)N
ot sign
ifica
ntM
oder
ate
Tot
alm
orta
lity
1*R
CT
Som
elim
itatio
nsN
oim
port
ant
inco
nsis
tenc
yN
opr
oble
ms
Som
eim
prec
isio
nN
o repo
rtin
gbi
as
No
stro
ngas
soci
atio
n0/
462/
53(3
.64)
0.24
(0.0
1–4.
84)
Not
sign
ifica
ntM
oder
ate
*Gol
dhab
erS,
1993
.†N
oev
iden
ceof
blin
ding
;see
met
hods
tabl
e.‡9
5%C
Ish
ows
noef
fect
.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 533S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Tab
le26
—rt
-PA
Plu
sH
epar
invs
Con
trol
(Hep
arin
Plu
sP
lace
bo)
Qua
lity
Ass
essm
ent
Sum
mar
yof
Fin
ding
s
No.
ofPa
tient
s/T
otal
(%)
Eff
ect
Qua
lity
Stud
ies,
No.
Des
ign
Lim
itatio
nsC
onsi
sten
cyD
irec
tnes
sPr
ecis
ion
Rep
ortin
gB
ias
Stre
ngth
ofA
ssoc
iatio
nrt
-PA
Plus
Hep
arin
Con
trol
(Hep
arin
Plus
Plac
ebo)
RR
(95%
CI)
orW
eigh
ted
Mea
nD
iffer
ence
Eve
nts
Prev
ente
dpe
r1,
000
Tre
ated
Rec
urre
ntD
VT
and
PE1*
RC
TN
ose
riou
slim
itatio
nsN
oim
port
ant
inco
nsis
tenc
yN
o dire
ctne
ssSo
me
impr
ecis
ion†
No re
port
ing
bias
No
stro
ngas
soci
atio
n4/
118
(3.3
9)4/
138
(2.9
)1.
17(0
.30–
4.58
)N
ot sign
ifica
ntM
oder
ate
Maj
orbl
eedi
ng1*
RC
TN
ose
riou
slim
itatio
nsN
oim
port
ant
inco
nsis
tenc
yN
o dire
ctne
ssSo
me
impr
ecis
ion
No re
port
ing
bias
No
stro
ngas
soci
atio
n4/
118
(3.3
9)4/
138
(2.9
0)0.
23(0
.03–
1.97
)N
ot sign
ifica
ntM
oder
ate
Tot
alm
orta
lity
1*R
CT
No
seri
ous
limita
tions
No
impo
rtan
tin
cons
iste
ncy
No di
rect
ness
Som
eim
prec
isio
nN
o repo
rtin
gbi
as
No
stro
ngas
soci
atio
n4/
118
(3.3
9)3/
138
(2.1
7)1.
56(0
.36–
6.83
)N
ot sign
ifica
ntM
oder
ate
*Kon
stan
tinid
esS,
2002
.†9
5%C
Ico
ntai
nsno
effe
ct.
Tab
le27
—rt
-PA
and
Hep
arin
vsC
ontr
ol(H
epar
in)
Qua
lity
Ass
essm
ent
Sum
mar
yof
Fin
ding
s
No.
ofPa
tient
s/T
otal
(%)
Eff
ect
Qua
lity
No.
ofst
udie
sD
esig
nL
imita
tions
Con
sist
ency
Dir
ectn
ess
Prec
isio
nR
epor
ting
Bia
sSt
reng
thof
Ass
ocia
tion
rt-P
APl
usH
epar
inC
ontr
ol(H
epar
in)
RR
(95%
CI)
orW
eigh
ted
Mea
nD
iffer
ence
Eve
nts
Prev
ente
dpe
r1,
000
Tre
ated
Rec
urre
ntD
VT
and
PE1*
RC
TSo
me
limita
tions
†N
oim
port
ant
inco
nsis
tenc
yN
o dire
ctne
ssSo
me
impr
ecis
ion‡
No re
port
ing
bias
No
stro
ngas
soci
atio
n1/
20(5
.00)
0/16
2.43
(0.1
1–55
.89)
Not
sign
ifica
ntM
oder
ate
Maj
orbl
eedi
ng1*
RC
TSo
me
limita
tions
No
impo
rtan
tin
cons
iste
ncy
No di
rect
ness
Som
eim
prec
isio
nN
o repo
rtin
gbi
as
No
stro
ngas
soci
atio
n3/
20(1
5.0%
)2/
16(1
2.5o
)1.
20(0
.23–
6.34
)N
ot sign
ifica
ntM
oder
ate
Tot
alm
orta
lity
1*R
CT
Som
elim
itatio
nsN
oim
port
ant
inco
nsis
tenc
yN
o dire
ctne
ssSo
me
impr
ecis
ion
No re
port
ing
bias
No
stro
ngas
soci
atio
n2/
20(1
0.00
)0/
164.
05(0
.21–
78.7
6)N
ot sign
ifica
ntM
oder
ate
*Dal
la-V
olta
S,19
92.
†No
evid
ence
onbl
indi
ng;s
eem
etho
dsta
ble.
‡95%
CI
cont
ains
noef
fect
.
534S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
References1 Barritt DW, Jordan SC. Anticoagulant drugs in the treat-
ment of pulmonary embolism: a controlled trial. Lancet1960; 1:1309–1312
2 Alpert JS, Smith R, Carlson J, et al. Mortality in patients treatedfor pulmonary embolism. JAMA 1976; 236:1477–1480
3 Kanis JA. Heparin in the treatment of pulmonary thrombo-embolism. Thrombos Diath Haemorrh 1974; 32:519
4 Kernohan RJ, Todd C. Heparin therapy in thromboemboliscdisease. Lancet 2007; 1:621–623
5 Brandjes DPM, Heijboer H, Buller HR, et al. Acenocou-marol and heparin compared with acenocoumarol alone inthe initial treatment of proximal-vein thrombosis. N EnglJ Med 1992; 327:1485–1489
6 Gallus AS, Jackaman J, Tillett J, et al. Safety and efficacy ofwarfarin started early after submassive venous thrombosis orpulmonary embolism. Lancet 1986; 2:1293–1296
7 Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 daysas compared with 10 days in the initial treatment of proximalvenous thrombosis. N Engl J Med 1990; 322:1260–1264
8 Ansell J, Hirsh J, Poller L, et al. Pharmacology and manage-ment of the vitamin K antagonists: American College ofChest Physicians evidence-based clinical practice guidelines(8th edition). Chest 2008; 133(suppl):160S–198S
9 Crowther MA, Ginsberg JS, Kearon C, et al. A randomizedtrial comparing 5 mg and 10 mg warfarin loading doses. ArchIntern Med 1999; 159:46–48
10 Harrison L, Johnston M, Massicotte MP, et al. Comparisonof 5-mg and 10-mg loading doses in initiation of warfarintherapy. Ann Intern Med 1997; 126:133–136
11 Kovacs MJ, Rodger M, Anderson DR, et al. Comparison of10-mg and 5-mg warfarin initiation nomograms togetherwith low-molecular-weight heparin for outpatient treatmentof acute venous thromboembolism: a randomized, double-blind, controlled trial. Ann Intern Med 2003; 138:714–719
12 Garcia D, Regan S, Crowther M, et al. Warfarin mainte-nance dosing patterns in clinical practice: implications forsafer anticoagulation in the elderly population. Chest 2005;127:2049–2056
13 Levine MN, Raskob G, Landefeld S, et al. Hemorrhagiccomplications of anticoagulant treatment. Chest 2001;119(suppl):108S–121S
14 Basu D, Gallus AS, Hirsh J, et al. A prospective study of thevalue of monitoring heparin treatment with the activated partialthromboplastin time. N Engl J Med 1972; 287:324–327
15 Cruickshank MK, Levine MN, Hirsh J, et al. A standardheparin nomogram for the management of heparin therapy.Arch Intern Med 1991; 151:333–337
16 Raschke RA, Gollihare B, Peirce JC. The effectiveness ofimplementing the weight-based heparin nomogram as apractice guideline. Arch Intern Med 1996; 156:1645–1649
17 Raschke RA, Reilly BM, Guidry JR, et al. The weight-basedheparin dosing nomogram compared with a “standard care”nomogram. Ann Intern Med 1993; 119:874–881
18 Anand S, Ginsberg JS, Kearon C, et al. The relation betweenthe activated partial thromboplastin time response andrecurrence in patients with venous thrombosis treated withcontinuous intravenous heparin. Arch Intern Med 1996;156:1677–1681
19 Anand SS, Bates S, Ginsberg JS, et al. Recurrent venousthrombosis and heparin therapy: an evaluation of the impor-tance of early activated partial thromboplastin time results.Arch Intern Med 1999; 159:2029–2032
20 Hull RD, Raskob G, Brant RF, et al. The importance of initialheparin treatment on long-term clinical outcomes of antithrom-botic therapy. Arch Intern Med 1997; 157:2317–2321
Tab
le28
—rt
-PA
vsC
ontr
ol(P
lace
bo)
Qua
lity
Ass
essm
ent
Sum
mar
yof
Fin
ding
s
No.
ofPa
tient
s/T
otal
(%)
Eff
ect
Qua
lity
Stud
ies,
No.
Des
ign
Lim
itatio
nsC
onsi
sten
cyD
irec
tnes
sPr
ecis
ion
Rep
ortin
gB
ias
Stre
ngth
ofA
ssoc
iatio
nrt
-PA
Con
trol
(Pla
cebo
)
RR
(95%
CI)
orW
eigh
ted
Mea
nD
iffer
ence
Eve
nts
Prev
ente
dpe
r1,
000
Tre
ated
Rec
urre
ntD
VT
and
PE2*
RC
TN
ose
riou
slim
itatio
nsN
oim
port
ant
inco
nsis
tenc
yN
opr
oble
ms
Not
appl
icab
leN
o repo
rtin
gbi
as
Not ap
plic
able
0/42
0/29
Not
appl
icab
leN
ot sign
ifica
ntM
oder
ate
Maj
orbl
eedi
ng2*
RC
TN
ose
riou
slim
itatio
nsN
oim
port
ant
inco
nsis
tenc
yN
opr
oble
ms
Som
eim
prec
isio
n†N
o repo
rtin
gbi
as
No
stro
ngas
soci
atio
n1/
42(2
.38)
0/29
1.50
(0.0
7–30
.59)
‡N
otsi
gnifi
cant
Mod
erat
e
Tot
alm
orta
lity
2*R
CT
No
seri
ous
limita
tions
No
impo
rtan
tin
cons
iste
ncy
No
prob
lem
sSo
me
impr
ecis
ion
No re
port
ing
bias
No
stro
ngas
soci
atio
n1/
42(2
.38)
0/29
2.29
(0.1
0,54
.05)
§N
ot sign
ifica
ntM
oder
ate
*Inc
lude
sL
evin
eM
,199
0;an
dPI
OPE
DIn
vest
igat
ors,
1990
.†9
5%C
Ico
ntai
nsno
effe
ct.
‡Bas
edon
one
stud
y:L
evin
eM
,199
0w
asex
clud
edbe
caus
eit
repo
rts
noca
ses
inei
ther
trea
tmen
tor
cont
rolg
roup
s.§B
ased
onon
est
udy:
PIO
PED
Inve
stig
ator
s19
90w
asex
clud
edbe
caus
eit
repo
rts
noca
ses
inei
ther
trea
tmen
tor
cont
rolg
roup
s.
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 535S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
21 Hull RD, Raskob GE, Brant RF, et al. Relation between thetime to achieve the lower limit of the APTT therapeuticrange and recurrent venous thromboembolism during hep-arin treatment for deep vein thrombosis. Arch Intern Med1997; 157:2562–2568
22 Levine MN, Hirsh J, Gent M, et al. A randomized trialcomparing the activated thromboplastin time with the hep-arin assay in patients with acute venous thromboembolismrequiring large daily doses of heparin. Arch Intern Med1994; 154:49–56
23 Hommes DW, Bura A, Mazzolai L, et al. Subcutaneousheparin compared with continuous intravenous heparinadministration in the initial treatment of deep vein throm-bosis. Ann Intern Med 1992; 116:279–284
24 Prandoni P, Carnovali M, Marchiori A. Subcutaneous ad-justed-dose unfractionated heparin vs fixed-dose low-molec-ular-weight heparin in the initial treatment of venous throm-boembolism. Arch Intern Med 2004; 164:1077–1083
25 Kearon C, Ginsberg JS, Julian JA, et al. Comparison offixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venousthromboembolism. JAMA 2006; 296:935–942
26 Lim W, Dentali F, Eikelboom JW, et al. Meta-analysis: low-molecular-weight heparin and bleeding in patients with severerenal insufficiency. Ann Intern Med 2006; 144:673–684
27 Bates SM, Greer IA, Papinger I, et al. Use of antithromboticagents during pregnancy: the Seventh ACCP Conference onAntithrombotic and Thrombolytic Therapy; evidence-basedguidelines. Chest 2004; 126(suppl):627S–644S
28 Breddin HK, Hach-Wunderle V, Nakov R, et al. Effects ofa low-molecular-weight heparin on thrombus regression andrecurrent thromboembolism in patients with deep-veinthrombosis. N Engl J Med 2001; 344:626–631
29 Decousus H, Leizorovicz A, Parent F, et al. A clinical trial ofvena caval filters in the prevention of pulmonary embolismin patients with proximal deep-vein thrombosis. N EnglJ Med 1998; 338:409–415
30 Duroux P. A randomised trial of subcutaneous low molecu-lar weight heparin (CY 216) compared with intravenousunfractionated heparin in the treatment of deep vein throm-bosis: a collaborative European multicentre study. ThrombHaemost 1991; 65:251–256
31 Fiessinger JN, Lopez-Fernandez M, Gatterer E, et al.Once-daily subcutaneous dalteparin, a low molecular weightheparin, for the initial treatment of acute deep vein throm-bosis. Thromb Haemost 1996; 76:195–199
32 Harenberg J, Schmidt JA, Koppenhagen K, et al. Fixed-dose,body weight-independent subcutaneous LMW heparin versusadjusted dose unfractionated intravenous heparin in the initialtreatment of proximal venous thrombosis: EASTERN Investiga-tors. Thromb Haemost 2000; 83:652–656
33 Hull RD, Raskob GE, Pineo GF, et al. Subcutaneouslow-molecular-weight heparin compared with continuousintravenous heparin in the treatment of proximal-veinthrombosis. N Engl J Med 1992; 326:975–982
34 Kakkar V, Gebska M, Kadziola Z, et al. Low-molecular-weight heparin in the acute and long-term treatment of deepvein thrombosis. Thromb Haemost 2003; 89:674–680
35 Kirchmaier CM, Wolf H, Schafer H, et al. Efficacy of a lowmolecular weight heparin administered intravenously orsubcutaneously in comparison with intravenous unfraction-ated heparin in the treatment of deep venous thrombosis:Certoparin Study Group. Int Angiol 1998; 17:135–145
36 Koopman MMW, Prandoni P, Piovella F, et al. Treatment ofvenous thrombosis with intravenous unfractionated heparinadministered in the hospital as compared with subcutaneouslow-molecular-weight heparin administered at home.
N Engl J Med 1996; 334:682–68737 Levine M, Gent M, Hirsh J, et al. A comparison of low-
molecular-weight heparin administered primarily at home withunfractionated heparin administered in the hospital for proxi-mal deep-vein thrombosis N Engl J Med 1996; 334:677–681
38 Lindmarker P, Holmstrom M, Granqvist S, et al. Comparisonof once-daily subcutaneous fragmin with continuous intrave-nous unfractionated heparin in the treatment of deep veinthrombosis. Thrombosis and Haemostasis 1994; 72:186–190
39 Merli G, Spiro TE, Olsson CG, et al. Subcutaneous enox-aparin once or twice daily compared with intravenousunfractionated heparin for treatment of venous thromboem-bolic disease. Ann Intern Med 2001; 134:191–202
40 Prandoni P, Lensing AWA, Buller HR, et al. Comparison ofsubcutaneous low-molecular-weight heparin with intrave-nous standard heparin in proximal deep-vein thrombosis.Lancet 1992; 339:441–445
41 Riess H, Koppenhagen K, Tolle A, et al. Fixed-dose, bodyweight-independent subcutaneous low molecular weightheparin certoparin compared with adjusted-dose intrave-nous unfractionated heparin in patients with proximal deepvenous thrombosis. Thromb Haemost 2003; 90:252–259
42 Simonneau G, Charbonnier B, Decousus H, et al. Subcutane-ous low-molecular-weight heparin compared with continuousintravenous unfractionated heparin in the treatment of proxi-mal deep vein thrombosis. Arch Intern Med 1993; 153:1541–1546
43 Simonneau G, Sors H, Charbonnier B, et al. A comparisonof low-molecular-weight heparin with unfractionated hepa-rin for acute pulmonary embolism. N Engl J Med 1997;337:663–669
44 The Columbus Investigators. Low molecular weight heparinis an effective and safe treatment for deep-vein thrombosisand pulmonary embolism. N Engl J Med 1997; 337:657–662
45 Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparing low-molecular-weight heparins with un-fractionated heparin in the treatment of venous thrombo-embolism: examining some unanswered questions regardinglocation of treatment, product type, and dosing frequency.Arch Intern Med 2000; 160:181–188
46 Gould MK, Dembitzer AD, Doyle RL, et al. Low-molecular-weight heparins compared with unfractionated heparin fortreatment of acute deep venous thrombosis: a meta-analysis ofrandomized, controlled trials. Ann Intern Med 1999; 130:800–809
47 van Dongen CJJ, van der Belt AGM, Prins MH, et al. Fixeddose subcutaneous low molecular weight heparins versusadjusted dose unfractionated heparin for venous thrombo-embolism. Cochrane Database Syst Rev 2004
48 Belcaro G, Nicolaides AN, Cesarone MR, et al. Comparisonof low-molecular-weight heparin, administered primarily athome, with unfractionated heparin, administered in hospital,and subcutaneous heparin, administered at home for deep-vein thrombosis. Angiology 1999; 50:781–787
49 Faivre R, Neuhart E, Kieffer Y, et al. Subcutaneous admin-istration of a low-molecular-weight-heparin (CY 222) com-pared with subcutaneous administration of standard heparinin patients with acute deep vein thrombosis [abstract].Thromb Haemost 1987; 58:1
50 Lopaciuk S, Meissner AJ, Filipecki S, et al. Subcutaneouslow molecular weight heparin versus subcutaneous unfrac-tionated heparin in the treatment of deep vein thrombosis: aPolish multicenter trial. Thromb Haemost 1992; 68:14–18
51 Charbonnier BA, Flessinger JN, Banga JD, et al. Compari-son of a once daily with a twice daily subcutaneous lowmolecular weight heparin regimen in the treatment of deepvein thrombosis. Thromb Haemost 1998; 79:897–901
52 Holmstrom M, Berglund S, Granquist S, et al. Fragmin onceor twice daily subcutaneously in the treatment of deep
536S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
venous thrombosis of the leg. Thromb Res 1992; 67:49–5553 Partsch H, Kechavarz B, Mostbeck A, et al. Frequency of
pulmonary embolism in patients who have iliofemoral deepvein thrombosis and are treated with once-or twice-dailylow-molecular-weight heparin. J Vasc Surg 1996; 24:774–782
54 Siegbahn A, Hassan S, Boberg J, et al. Subcutaneoustreatment of deep venous thrombosis with low molecularweight heparin: a dose finding study with LMWH-Novo.Thromb Res 1989; 55:767–778
55 Couturaud F, Julian JA, Kearon C. Low molecular weightheparin administered once versus twice daily in patientswith venous thromboembolism: a meta-analysis. ThrombHaemost 2001; 86:980–984
56 Boccalon H, Elias A, Chale JJ, et al. Clinical outcome and costof hospital vs home treatment of proximal deep vein thrombosiswith a low-molecular-weight heparin: the Vascular Midi-Pyrenees study. Arch Intern Med 2000; 160:1769–1773
57 Wells PS, Anderson DR, Rodger MA, et al. A randomizedtrial comparing 2 low-molecular-weight heparins for theoutpatient treatment of deep vein thrombosis and pulmo-nary embolism. Arch Intern Med 2005; 165:733–738
58 Faivre R, Neuhart Y, Kieffer Y, et al. A new treatment of deepvenous thrombosis: low molecular weight heparin fractions;randomized study. Presse Med 1988; 17:197–200
59 Buller HR, Davidson BL, Decousus H, et al. Fondaparinuxor enoxaparin for the initial treatment of symptomatic deepvenous thrombosis: a randomized trial. Ann Intern Med2004; 140:867–873
60 Buller HR, Davidson BL, Decousus H, et al. Subcutaneousfondaparinux versus intravenous unfractionated heparin inthe initial treatment of pulmonary embolism. N Engl J Med2003; 349:1695–1702
61 Fiessinger JN, Huisman MV, Davidson BL, et al. Ximelagat-ran vs low-molecular-weight heparin and warfarin for thetreatment of deep vein thrombosis: a randomized trial.JAMA 2005; 293:681–689
62 Buller HR, Cohen AT, Davidson B, et al. Idraparinux versusstandard therapy for venous thromboembolic disease.N Engl J Med 2007; 237:1094–1104
63 Bergan JJ, Schmid-Schonbein GW, Smith PD, et al. Chronicvenous disease. N Engl J Med 2006; 355:488–498
64 Cho JS, Martelli E, Mozes G, et al. Effects of thrombolysisand venous thrombectomy on valvular competence, throm-bogenicity, venous wall morphology, and function. J VascSurg 1998; 28:787–799
65 Johnson BF, Manzo RA, Bergelin RO, et al. Relationshipbetween changes in the deep venous system and the devel-opment of the postthrombotic syndrome after an acuteepisode of lower limb deep vein thrombosis: a one- tosix-year follow-up. J Vasc Surg 1995; 21:307–312
66 Killewich LA, Bedford GR, Beach KW, et al. Spontaneouslysis of deep venous thrombi: rate and outcome. J Vasc Surg1989; 9:89–97
67 Markel A, Manzo RA, Bergelin RO, et al. Valvular refluxafter deep vein thrombosis: incidence and time of occur-rence. J Vasc Surg 1992; 15:377–382
68 Meissner MH, Manzo RA, Bergelin RO, et al. Deep venousinsufficiency: the relationship between lysis and subsequentreflux. J Vasc Surg 1993; 18:596–605
69 Nicolaides AN, Schull K, Fernandes E, et al. Ambulatoryvenous pressure: new information: investigation of vasculardisorders. New York, NY: Churchill Livingstone, 1981; 488–494
70 Rhodes JM, Cho JS, Gloviczki P, et al. Thrombolysis forexperimental deep venous thrombosis maintains valvular compe-tence and vasoreactivity. J Vasc Surg 2000; 31:1193–1205
71 Shull KC, Nicolaides AN, Fernandes e Fernandes J, et al.Significance of popliteal reflux in relation to ambulatory venous
pressure and ulceration. Arch Surg 1979; 114:1304–130672 Elsharawy M, Elzayat E. Early results of thrombolysis vs
anticoagulation in iliofemoral venous thrombosis: a randomisedclinical trial. Eur J Vasc Endovasc Surg 2002; 24:209–214
73 Plate G, Einarsson E, Ohlin P, et al. Thrombectomy withtemporary arteriovenous fistula: the treatment of choice in acuteiliofemoral venous thrombosis. J Vasc Surg 1984; 1:867–876
74 Meissner MH, Mewissen M. Early outcome after catheter-directed thrombolysis for acute deep venous thrombosis: fol-low-up of a national multicenter registry. J Vasc Surg 2008 (inpress)
75 Mewissen MW, Seabrook GR, Meissner MH, et al. Cathe-ter-directed thrombolysis for lower extremity deep venousthrombosis: report of a national multicenter registry. Radi-ology 1999; 211:39–49
76 Bjarnason H, Kruse JR, Asinger DA, et al. Iliofemoral deepvenous thrombosis: safety and efficacy outcome during 5years of catheter-directed thrombolytic therapy. J VascInterv Radiol 1997; 8:405–418
77 Comerota AJ, Aldridge SC, Cohen G, et al. A strategy ofaggressive regional therapy for acute iliofemoral venous throm-bosis with contemporary venous thrombectomy or catheter-directed thrombolysis. J Vasc Surg 1994; 20:244–254
78 Comerota AJ, Kagan SA. Catheter-directed thrombolysis forthe treatment of acute iliofemoral deep venous thrombosis.Phlebology 2000; 15:149–155
79 Comerota AJ, Throm RC, Mathias SD, et al. Catheter-directedthrombolysis for iliofemoral deep venous thrombosis improveshealth-related quality of life. J Vasc Surg 2000; 32:130–137
80 Juhan CM, Alimi YS, Barthelemy PJ, et al. Late results ofiliofemoral venous thrombectomy. J Vasc Surg 1997; 25:417–422
81 Laiho MK, Oinonen A, Sugano N, et al. Preservation ofvenous valve function after catheter-directed and systemicthrombolysis for deep venous thrombosis Eur J Vasc Endo-vasc Surg 2004; 28:391–396
82 Plate G, Akesson H, Einarsson E, et al. Long-term results ofvenous thrombectomy combined with a temporary arterio-venous fistula. Eur J Vasc Surg 1990; 4:483–489
83 Plate G, Eklof B, Norgren L, et al. Venous thrombectomy foriliofemoral vein thrombosis: 10-year results of a prospectiverandomised study. Eur J Vasc Endovasc Surg 1997; 14:367–374
84 Akesson H, Brudin L, Dahlstrom JA, et al. Venous functionassessed during a 5 year period after acute ilio-femoralvenous thrombosis treated with anticoagulation. Eur J VascSurg 1990; 4:43–48
85 Delis KT, Bountouroglou D, Mansfield AO. Venous claudi-cation in iliofemoral thrombosis: long-term effects on ve-nous hemodynamics, clinical status, and quality of life. AnnSurg 2004; 239:118–126
86 O’Donnell TF, Browse NL, Burnand KG, et al. The socio-economic effects of an iliofemoral venous thrombosis. J SurgRes 1977; 22:483–488
87 Strandness DE Jr, Langlois Y, Cramer M, et al. Long-termsequelae of acute venous thrombosis. JAMA 1983; 250:1289–1292
88 Berridge DC, Gregson RH, Hopkinson BR, et al. Random-ized trial of intra-arterial recombinant tissue plasminogenactivator, intravenous recombinant tissue plasminogen acti-vator and intra-arterial streptokinase in peripheral arterialthrombolysis. Br J Surg 1991; 78:988–995
89 AbuRahma AF, Perkins SE, Wulu JT, et al. Iliofemoral deepvein thrombosis: conventional therapy versus lysis and per-cutaneous transluminal angioplasty and stenting. Ann Surg2001; 233:752–760
90 Castaneda F, Li R, Young K, et al. Catheter-directedthrombolysis in deep venous thrombosis with use of rete-plase: immediate results and complications from a pilot
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 537S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
study. J Vasc Interv Radiol 2002; 13:577–58091 Grunwald MR, Hofmann LV. Comparison of urokinase,
alteplase, and reteplase for catheter-directed thrombolysisof deep venous thrombosis. J Vasc Interv Radiol 2005;15:347–352
92 Horne MK, III, Mayo DJ, Cannon RO III, et al. Intraclotrecombinant tissue plasminogen activator in the treatmentof deep venous thrombosis of the lower and upper extrem-ities. Am J Med 2000; 108:251–255
93 Jackson LS, Wang XJ, Dudrick SJ, et al. Catheter-directedthrombolysis and/or thrombectomy with selective endovas-cular stenting as alternatives to systemic anticoagulation fortreatment of acute deep vein thrombosis. Am J Surgery2005; 190:864–868
94 Kasirajan K, Gray B, Ouriel K. Percutaneous AngioJetthrombectomy in the management of extensive deep venousthrombosis. J Vasc Interv Radiol 2001; 12:179–185
95 Kim HS, Patra A, Paxton BE, et al. Adjunctive percutaneousmechanical thrombectomy for lower-extremity deep veinthrombosis: clinical and economic outcomes. J Vasc IntervRadiol 2006; 17:1099–1104
96 Lin PH, Zhou W, Dardik A, et al. Catheter-direct throm-bolysis versus pharmacomechanical thrombectomy for treat-ment of symptomatic lower extremity deep venous throm-bosis. Am J Surg 2006; 192:782–788
97 Ogawa T, Hoshino S, Midorikawa H, et al. Intermittentpneumatic compression of the foot and calf improves theoutcome of catheter-directed thrombolysis using low-doseurokinase in patients with acute proximal venous thrombosisof the leg. J Vasc Surg 2005; 42:940–944
98 Semba CP, Dake MD. Iliofemoral deep venous thrombosis:aggressive therapy with catheter-directed thrombolysis. Ra-diology 1994; 191:487–494
99 Semba CP, Dake MD. Catheter-directed thrombolysis foriliofemoral venous thrombosis. SeminVasc Surg 1996; 9:26–33
100 Sillesen H, Just S, Jorgensen M, et al. Catheter-directedthrombolysis for treatment of ilio-femoral deep venousthrombosis is durable, preserves venous valve function andmay prevent chronic venous insufficiency. Eur J Vasc En-dovasc Surg 2005; 30:556–562
101 Vedantham S, Vesely TM, Parti N, et al. Lower extremityvenous thrombolysis with adjunctive mechanical thrombec-tomy. J Vasc Interv Radiol 2002; 13:1001–1008
102 Verhaeghe R, Stockx L, Lacroix H, et al. Catheter-directedlysis of iliofemoral vein thrombosis with use of rt-PA. EurRadiol 1997; 7:996–1001
103 Arnesen H, Heilo A, Jakobsen E, et al. A prospective studyof streptokinase and heparin in the treatment of deep veinthrombosis. Acta Med Scand 1978; 203:457–463
104 Arnesen H, Hoiseth A, Ly B. Streptokinase or heparin in thetreatment of deep vein thrombosis: follow-up results of aprospective study. Acta Med Scand 1982; 211:65–68
105 Browse NL, Thomas ML, Pim HP. Streptokinase and deepvein thrombosis. Br Med J 1968; 3:717–720
106 Duckert F, Muller G, Nyman D, et al. Treatment of deepvein thrombosis with streptokinase. Br Med J 1975; 1:479–481
107 Elliot MS, Immelman EJ, Jeffery P, et al. A comparativerandomized trial of heparin versus streptokinase in thetreatment of acute proximal venous thrombosis: an interimreport of a prospective trial. Br J Surg 1979; 66:838–843
108 Goldhaber SZ, Meyerovitz MF, Green D, et al. Randomizedcontrolled trial of tissue plasminogen activator in proximaldeep venous thrombosis Am J Med 1990; 88:235–240
109 Kakkar VV, Flanc C, Howe CT, et al. Treatment of deepvein thrombosis: a trial of heparin, streptokinase, and arvin.Br Med J 1969; 1:806–810
110 Kiil J, Carvalho A, Sakso P, et al. Urokinase or heparin in the
management of patients with deep vein thrombosis? ActaChir Scand 1981; 147:529–532
111 Marder VJ, Soulen RL, Atichartakarn V, et al. Quantitativevenographic assessment of deep vein thrombosis in theevaluation of streptokinase and heparin therapy. J Lab ClinMed 1977; 89:1018–1029
112 Porter JM, Seaman AJ, Common HH, et al. Comparison ofheparin and streptokinase in the treatment of venous throm-bosis. Am Surg 1975; 41:511–519
113 Robertson BR, Nilsson IM, Nylander G. Value of streptokinaseand heparin in treatment of acute deep venous thrombosis: acoded investigation. Acta Chir Scand 1968; 134:203–208
114 Schulman S, Granqvist S, Juhlin-Dannfelt A, et al. Long-termsequelae of calf vein thrombosis treated with heparin or low-dosestreptokinase. Acta Med Scand 1986; 219:349–357
115 Schweizer J, Elix H, Altmann E, et al. Comparative results ofthrombolysis treatment with rt-PA and urokinase: a pilotstudy. VASA 1998; 27:167–171
116 Schweizer J, Kirch W, Koch R, et al. Short- and long-termresults after thrombolytic treatment of deep venous throm-bosis. J Am Coll Cardiol 2000; 36:1336–1343
117 Tsapogas MJ, Peabody RA, Wu KT, et al. Controlled studyof thrombolytic therapy in deep vein thrombosis. Surgery1973; 74:973–984
118 Turpie AG, Levine MN, Hirsh J, et al. Tissue plasminogenactivator (rt-PA) vs heparin in deep vein thrombosis: resultsof a randomized trial. Chest 1990; 97(suppl):172S–175S
119 Verhaeghe R, Besse P, Bounameaux H, et al. Multicenter pilotstudy of the efficacy and safety of systemic rt-PA administrationin the treatment of deep vein thrombosis of the lower extrem-ities and/or pelvis. Thromb Res 1989; 55:5–11
120 Watz R, Savidge GF. Rapid thrombolysis and preservationof valvular venous function in high deep vein thrombosis: acomparative study between streptokinase and heparin ther-apy. Acta Med Scand 1979; 205:293–298
121 Watson LI, Armon MP. Thrombolysis for acute deep veinthrombosis. Cochrane Database Syst Rev 2004; CD002783
122 Delomez M, Beregi JP, Willoteaux S, et al. Mechanicalthrombectomy in patients with deep venous thrombosis.Cardiovasc Intervent Radiol 2001; 24:42–48
123 Kinney TB, Valji K, Rose SC, et al. Pulmonary embolismfrom pulse-spray pharmacomechanical thrombolysis of clot-ted hemodialysis grafts: urokinase versus heparinized saline.J Vasc Interv Radiol 2000; 11:1143–1152
124 Comerota AJ, Gale SS. Technique of contemporary iliofem-oral and infrainguinal venous thrombectomy. J Vasc Surg2006; 43:185–191
125 Karp RB, Wylie EJ. Recurrent thrombosis after iliofemoralvenous thrombectomy. Surg Forum 1966; 17:147
126 Lansing AM, Davis WM. Five-year follow-up study of iliofem-oral venous thrombectomy. Ann Surg 1968; 168:620–628
127 Einarsson E, Albrechtsson U, Eklof B. Thrombectomy andtemporary AV-fistula in iliofemoral vein thrombosis: technicalconsiderations and early results. Int Angiol 1986; 5:65–72
128 Einarsson E, Albrechtsson U, Eklof B, et al. Follow-up evalu-ation of venous morphologic factors and function after throm-bectomy and temporary arteriovenous fistula in thrombosis ofiliofemoral vein. Surg Gynecol Obstet 1986; 163:111–116
129 Juhan C, Cornillon B, Tobiana F, et al. Patency afteriliofemoral and iliocaval venous thrombectomy. Ann VascSurg 1987; 1:529–533
130 Kistner RL, Sparkuhl MD. Surgery in acute and chronicvenous disease. Surgery 1979; 85:31–43
131 Meissner AJ, Huszcza S. Surgical strategy for managementof deep venous thrombosis of the lower extremities. WorldJ Surg 1996; 20:1149–1155
132 Neglen P, al-Hassan HK, Endrys J, et al. Iliofemoral venous
538S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
thrombectomy followed by percutaneous closure of thetemporary arteriovenous fistula. Surgery 1991; 110:493–499
133 Schwarzbach MH, Schumacher H, Bockler D, et al. Surgicalthrombectomy followed by intraoperative endovascular re-construction for symptomatic ilio-femoral venous thrombo-sis Eur J Vasc Endovasc Surg 2005; 29:58–66
134 Torngren S, Swedenborg J. Thrombectomy and temporaryarterio-venous fistula for ilio-femoral venous thrombosis. IntAngiol 1988; 7:14–18
135 Eight-year follow-up of patients with permanent vena cavafilters in the prevention of pulmonary embolism: the PREPIC(Prevention du Risque d’Embolie Pulmonaire par InterruptionCave) randomized study. Circulation 2005; 112:416–422
136 Streiff MB. Vena caval filters: a comprehensive review.Blood 2000; 95:3669–3677
137 White RH, Zhou H, Kim J, et al. A population-based study ofthe effectiveness of IVC filter use among patients with venousthromboembolism. Arch Intern Med 2000; 160:2033–2041
138 Aschwanden M, Labs KH, Engel H, et al. Acute deep veinthrombosis: early mobilization does not increase the frequencyof pulmonary embolism. Thromb Haemost 2001; 85:42–46
139 Blattler W, Partsch H. Leg compression and ambulation isbetter than bed rest for the treatment of acute deep venousthrombosis. Int Angiol 2003; 22:393–400
140 Junger M, Diehm C, Storiko H, et al. Mobilization versusimmobilization in the treatment of acute proximal deepvenous thrombosis: a prospective, randomized, open, mul-ticentre trial. Curr Med Res Opin 2006; 22:593–602
141 Partsch H, Blattler W. Compression and walking versus bedrest in the treatment of proximal deep venous thrombosis withlow molecular weight heparin. J Vasc Surg 2000; 32:861–869
142 Schellong SM, Schwarz T, Kropp J, et al. Bed rest in deep veinthrombosis and the incidence of scintigraphic pulmonary em-bolism. Thromb Haemost 1999; 82(suppl 1):127–129
143 Partsch H. Therapy of deep vein thrombosis with lowmolecular weight heparin, leg compression and immediateambulation. VASA 2001; 30:195–204
144 Partsch H, Kaulich M, Mayer W. Immediate mobilisation inacute vein thrombosis reduces post-thrombotic syndrome.Int Angiol 2004; 23:206–212
145 Trujillo-Santos J, Perea-Milla E, Jimenez-Puente A, et al. Bedrest or ambulation in the initial treatment of patients with acutedeep vein thrombosis or pulmonary embolism: findings fromthe RIETE registry. Chest 2005; 127:1631–1636
146 Lagerstedt CI, Olsson CG, Fagher BO, et al. Need forlong-term anticoagulant treatment in symptomatic calf-veinthrombosis. Lancet 1985; 515–518
147 Hull R, Delmore T, Genton E, et al. Warfarin sodium versuslow-dose heparin in the long-term treatment of venousthrombosis. The N Engl J Med 1979; 301:855–858
148 Levine MN, Hirsh J, Gent M, et al. Optimal duration of oralanticoagulant therapy: a randomized trial comparing fourweeks with three months of warfarin in patients with proximaldeep vein thrombosis. Thromb Haemost 1995; 74:606–611
149 Optimum duration of anticoagulation for deep-vein throm-bosis and pulmonary embolism. Lancet 1992; 340:873–876
150 Schulman S, Granqvist S, Holmstrom M, et al. The duration oforal anticoagulant therapy after a second episode of venousthromboembolism. N Engl J Med 1997; 336:393–398
151 Douketis JD, Kearon C, Bates S, et al. Risk of fatalpulmonary embolism in patients with treated venous throm-boembolism. JAMA 1998; 279:458–462
152 Linkins LA, Choi PT, Douketis JD. Clinical impact ofbleeding in patients taking oral anticoagulant therapy forvenous thromboembolism: a meta-analysis. Ann Intern Med2003; 139:893–900
153 Agnelli G, Prandoni P, Becattini C, et al. Extended oral
anticoagulant therapy after a first episode of pulmonaryembolism. Ann Intern Med 2003; 139:19–25
154 Agnelli G, Prandoni P, Santamaria MG, et al. Three monthsversus one year of oral anticoagulant therapy for idiopathicdeep vein thrombosis. N Engl J Med 2001; 345:165–169
155 Campbell IA, Bentley DP, Prescott RJ, et al. Anticoagula-tion for three versus six months in patients with deep veinthrombosis or pulmonary embolism, or both: randomisedtrial. BMJ 2007; 334:674–680
156 Kearon C, Gent M, Hirsh J, et al. A comparison of threemonths of anticoagulation with extended anticoagulation fora first episode of idiopathic venous thromboembolism.N Engl J Med 1999; 340:901–907
157 Kearon C, Ginsberg JS, Anderson DR, et al. Comparison of1 month with 3 months of anticoagulation for a first episodeof venous thromboembolism associated with a transient riskfactor. J Thromb Haemost 2004; 2:743–749
158 Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison oflow-intensity warfarin therapy with conventional-intensity war-farin therapy for long-term prevention of recurrent venousthromboembolism. N Engl J Med 2003; 349:631–639
159 Palareti G, Cosmi B, Legnani C, et al. D-dimer testing todetermine the duration of anticoagulation therapy. N EnglJ Med 2006; 355:1780–1789
160 Pinede L, Ninet J, Duhaut P, et al. Comparison of 3 and 6months of oral anticoagulant therapy after a first episode ofproximal deep vein thrombosis or pulmonary embolism andcomparison of 6 and 12 weeks of therapy after isolated calfdeep vein thrombosis. Circulation 2001; 103:2453–2460
161 Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term,low-intensity warfarin therapy for prevention of recurrentvenous thromboembolism. N Engl J Med 2003; 348:1425–1434
162 Schulman S, Rhedin AS, Lindmarker P, et al. A comparisonof six weeks with six months of oral anticoagulant therapyafter a first episode of venous thromboembolism. N EnglJ Med 1995; 332:1661–1665
163 Heit JA, Mohr DN, Silverstein MD, et al. Predictors ofrecurrence after deep vein thrombosis and pulmonary em-bolism: a population-based cohort study. Arch Intern Med2000; 160:761–768
164 Murin S, Romano PS, White RH. Comparison of outcomesafter hospitalization for deep vein thrombosis or pulmonaryembolism. Thromb Haemost 2002; 88:407–414
165 Palareti G, Legnani C, Cosmi B, et al. Risk of venousthromboembolism recurrence: high negative predictivevalue of d-dimer performed after oral anticoagulation isstopped. Thromb Haemost 2002; 87:7–12
166 Prandoni P, Lensing AWA, Cogo A, et al. The long-termclinical course of acute deep venous thrombosis. Ann InternMed 1996; 125:1–7
167 Pini M, Aiello S, Manotti C, et al. Low molecular weightheparin versus warfarin the prevention of recurrence afterdeep vein thrombosis. Thromb Haemost 1994; 72:191–197
168 Baglin T, Luddington R, Brown K, et al. Incidence ofrecurrent venous thromboembolism in relation to clinicaland thrombophilic risk factors: prospective cohort study.Lancet 2003; 362:523–526
169 Christiansen SC, Cannegieter SC, Koster T, et al. Throm-bophilia, clinical factors, and recurrent venous thromboticevents. JAMA 2005; 293:2352–2361
170 Hansson PO, Sorbo J, Eriksson H. Recurrent venous throm-boembolism after deep vein thrombosis: incidence and riskfactors. Arch Intern Med 2000; 160:769–774
171 Schulman S, Wahlander K, Lundstrîm T, et al. Secondaryprevention of venous thromboembolism with the oral directthrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713–1721
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 539S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
172 Eichinger S, Minar E, Hirschl M, et al. The risk of earlyrecurrent venous thromboembolism after oral anticoagulanttherapy in patients with the G20210A transition in theprothrombin gene. Thromb Haemost 1999; 81:14–17
173 Eichinger S, Pabinger I, Stumpflen A, et al. The risk ofrecurrent venous thromboembolism in patients with and with-out Factor V Leiden. Thromb Haemost 1997; 77:624–628
174 Ho WK, Hankey GJ, Quinlan DJ, et al. Risk of recurrentvenous thromboembolism in patients with common throm-bophilia: a systematic review. Arch Intern Med 2006; 166:729–736
175 Lindmarker P, Schulman S, Sten-Linder M, et al. The risk ofrecurrent venous thromboembolism in carriers and non-carriers of the G1691A Allele in the coagulation factor Vgene and the G20210A Allele in the prothrombin gene.Thromb Haemost 1999; 81:684–689
176 Miles JS, Miletich JP, Goldhaber SZ, et al. G20210A mutationin the prothrombin gene and the risk of recurrent venousthromboembolism. J Am Coll Cardiol 2001; 37:215–218
177 Palareti G, Legnani C, Cosmi B, et al. Predictive value ofd-dimer test for recurrent venous thromboembolism afteranticoagulation withdrawal in subjects with a previous idio-pathic event and in carriers of congenital thrombophilia.Circulation 2003; 108:313–318
178 Ridker PM, Miletich JP, Stampfer MJ, et al. Factor VLeiden and risks of recurrent idiopathic venous thrombo-embolism. Circulation 1995; 92:2800–2802
179 Schulman S, Lindmarker P, Holmstrom M, et al. Post-thrombotic syndrome, recurrence, and death 10 years afterthe first episode of venous thromboembolism treated withwarfarin for 6 weeks or 6 months. J Thromb Haemost 2006;4:734–742
180 Simioni P, Prandoni P, Lensing AW, et al. Risk for subse-quent venous thromboembolic complications in carriers ofthe prothrombin or the factor V gene mutation with a firstepisode of deep-vein thrombosis. Blood 2000; 96:3329–3333
181 Schulman S, Lockner D, Juhlin-Dannfelt A. The duration oforal anticoagulation after deep vein thrombosis. Acta MedScand 1985; 217:547–552
182 Schulman S. Unresolved issues in anticoagulant therapy. JThromb Haemost 2003; 1:1464–1470
183 Holmgren K, Andersson G, Fagrell B, et al. One-monthversus six-month therapy with oral anticoagulants aftersymptomatic deep vein thrombosis. Acta Med Scand 1985;218:279–284
184 Ost D, Tepper J, Mihara H, et al. Duration of anticoagula-tion following venous thromboembolism: a meta-analysis.JAMA 2005; 294:706–715
185 Kearon C. Natural history of venous thromboembolism.Circulation 2003; 107:I-22–I30
186 Locadia M, Bossuyt P, Stalmeier P, et al. Treatment ofvenous thromboembolism with vitamin K antagonists: pa-tients’ health state valuations and treatment preferences.Thromb Haemost 2004; 92:1336–1341
187 Eichinger S, Minar E, Bialonczyk C, et al. D-dimer levelsand risk of recurrent venous thromboembolism. JAMA2003; 290:1071–1074
188 Shrivastava S, Ridker PM, Glynn RJ, et al. D-dimer, factorVIII coagulant activity, low-intensity warfarin and the risk ofrecurrent venous thromboembolism. J Thromb Haemost2006; 4:1208–1214
189 Schulman S, Svenungsson E, Granqvist S. Anticardiolipinantibodies predict early recurrence of thromboembolism anddeath among patients with venous thromboembolism followinganticoagulant therapy. Am J Med 1998; 104:332–338
190 McRae S, Tran H, Schulman S, et al. Effect of patient’s sexon risk of recurrent venous thromboembolism: a meta-
analysis. Lancet 2006; 368:371–378191 White RH, Zhou H, Romano PS. Incidence of idiopathic deep
venous thrombosis and secondary thromboembolism amongethnic groups in California. Ann Intern Med 1998; 128:737–740
192 Cosmi B, Legnani C, Cini M, et al. D-dimer levels in combi-nation with residual venous obstruction and the risk of recur-rence after anticoagulation withdrawal for a first idiopathicdeep vein thrombosis. Thromb Haemost 2005; 94:969–974
193 Piovella F, Crippa L, Barone M, et al. Normalization rates ofcompression ultrasonography in patients with a first episodeof deep vein thrombosis of the lower limbs: association withrecurrence and new thrombosis. Haematologica 2002; 87:515–522
194 Prandoni P, Lensing AW, Prins MH, et al. Residual venousthrombosis as a predictive factor of recurrent venous throm-boembolism. Ann Intern Med 2002; 137:955–960
195 Schulman S, Beyth RJ, Kearon C, et al. Hemorrhagiccomplications of anticoagulant and thrombolytic treatment:American College of Chest Physicians evidence-based clin-ical practice guidelines (8th edition). Chest 2008;133(suppl):257S–298S
196 Beyth RJ, Quinn L, Landefeld CS. A multicomponentintervention to prevent major bleeding complications inolder patients receiving warfarin: a randomized, controlledtrial. Ann Intern Med 2000; 133:687–695
197 Beyth RJ, Quinn LM, Landefeld S. Prospective evaluation ofan index for predicting the risk of major bleeding in outpatientstreated with warfarin. Am J Med 1998; 105:91–99
198 Dentali F, Douketis JD, Lim W, et al. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulanttherapy alone among patients at risk for cardiovasculardisease: a meta-analysis of randomized trials. Arch InternMed 2007; 167:117–124
199 Gage BF, Yan Y, Milligan PE, et al. Clinical classificationschemes for predicting hemorrhage: results from the Na-tional Registry of Atrial Fibrillation (NRAF). Am Heart J2006; 151:713–719
200 Kuijer PMM, Hutten BA, Prins MH, et al. Prediction of therisk of bleeding during anticoagulant treatment for venousthromboembolism. Arch Intern Med 1999; 159:457–460
201 Palareti G, Leali N, Coccheri S, et al. Bleeding complica-tions of oral anticoagulant treatment: an inception-cohort,prospective collaborative study (ISCOAT). Lancet 1996;348:423–428
202 Pengo V, Legnani C, Noventa F, et al. Oral anticoagulanttherapy in patients with nonrheumatic atrial fibrillation andrisk of bleeding: a Multicenter Inception Cohort Study.Thromb Haemost 2001; 85:418–422
203 Crowther MA, Ginsberg JS, Julian J, et al. A comparison oftwo intensities of warfarin for prevention of recurrentthrombosis in patients with antiphospholipid antibody syn-drome. N Engl J Med 2003; 349:1133–1138
204 Finazzi G, Marchioli R, Brancaccio V, et al. A randomizedclinical trial of high-intensity warfarin vs. conventional anti-thrombotic therapy for the prevention of recurrent throm-bosis in patients with the antiphospholipid syndrome(WAPS). J Thromb Haemost 2005; 3:848–853
205 Hull R, Hirsh J, Jay R, et al. Different intensities of oralanticoagulant therapy in the treatment of proximal-veinthrombosis. N Engl J Med 1982; 307:1676–1681
206 Hull R, Delmore T, Carter C, et al. Adjusted subcutaneousheparin versus warfarin sodium in the long-term treatment ofvenous thrombosis. N Engl J Med 1982; 306: 189–194
207 Bynum LJ, Wilson JE. Low-dose heparin therapy in thelong-term management of venous thromboembolism. Am JMed 1979; 67:553–556
208 Monreal M, Lafoz E, Olive A, et al. Comparison of subcu-
540S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
taneous unfractionated heparin with a low molecular weightheparin (fragmin) in patients with venous thromboembolismand contraindications to coumarin. Thromb Haemost 1994;71:7–11
209 Das SK, Cohen AT, Edmondson RA, et al. Low-molecular-weight heparin versus warfarin for prevention of recurrentvenous thromboembolism: a randomized trial. World J Surg1996; 20:521–527
210 Hamann H. Rezidivprophylaxe nach phlebothrombose-oraleantikoagulation oder niedermolelulares heparin subkutan.Vasomed 1998; 10:133–136
211 Lee AY, Levine MN, Baker RI, et al. Low-molecular-weightheparin versus a coumarin for the prevention of recurrentvenous thromboembolism in patients with cancer. N EnglJ Med 2003; 349:146–153
212 Gonzalez-Fajardo JA, Arreba E, Castrodeza J, et al. Veno-graphic comparison of subcutaneous low-molecular weightheparin with oral anticoagulant therapy in the long-term treat-ment of deep venous thrombosis. J Vasc Surg 1999; 30:283–292
213 Meyer G, Marjanovic Z, Valcke J, et al. Comparison oflow-molecular-weight heparin and warfarin for the second-ary prevention of venous thromboembolism in patients withcancer: a randomized controlled study. Arch Intern Med2002; 162:1729–1735
214 Veiga F, Escriba A, Maluenda MP, et al. Low molecularweight heparin (enoxaparin) versus oral anticoagulant ther-apy (acenocoumarol) in the long-term treatment of deepvenous thrombosis in the elderly: a randomized trial.Thromb Haemost 2000; 84:559–564
215 Lopaciuk S, Bielska-Falda H, Noszczyk W, et al. Lowmolecular weight heparin versus acenocoumarol in thesecondary prophylaxis of deep vein thrombosis. ThrombHaemost 1999; 81:26–31
216 Lopez-Beret P, Orgaz A, Fontcuberta J, et al. Low molec-ular weight heparin versus oral anticoagulants in the long-term treatment of deep venous thrombosis. J Vasc Surg2001; 33:77–90
217 Hull R, Pineo G, Mah A, et al. Long-term low molecularweight heparin treatment versus oral anticoagulant therapyfor proximal deep vein thrombosis. Blood 2000; 96:449a
218 Hull RD, Pineo GF, Brant RF, et al. Self-managed long-term low-molecular-weight heparin therapy: the balance ofbenefits and harms. Am J Med 2007; 120:72–82
219 Iorio A, Guercini F, Pini M. Low-molecular-weight heparin forthe long-term treatment of symptomatic venous thromboem-bolism: meta-analysis of the randomized comparisons with oralanticoagulants. J Thromb Haemost 2003; 1:1906–1913
220 van der Heijden JF, Hutten BA, Buller HR, et al. Vitamin Kantagonists or low molecular weight heparin for the longterm treatment of symptomatic venous thromboembolism(Cochrane Review). The Cochrane Library 2002; Issue 4Oxford, UK: Update Software
221 Hull RD, Pineo GF, Brant RF, et al. Long-term low-molecu-lar-weight heparin versus usual care in proximal-vein thrombo-sis patients with cancer. Am J Med 2006; 119:1062–1072
222 Weitz J, Hirsh J, Samama MM. New antithrombotic drugs:American College of Chest Physicians evidence-based clin-ical practice guidelines (8th edition). Chest 2008;133(suppl):234S–256S
223 Buller HR, Cohen AT, Davidson B, et al. Extended prophy-laxis of venous thromboembolism with idraparinux. N EnglJ Med 2007; 357:1105–1112
224 Robinson KS, Anderson DR, Gross M, et al. Ultrasono-graphic screening before hospital discharge for deep venousthrombosis after arthroplasty: the Post-Arthoplasty Screen-ing Study; a randomized, controlled trial. Ann Intern Med1997; 127:439–445
225 Vaitkus PT, Leizorovicz A, Cohen AT, et al. Mortality ratesand risk factors for asymptomatic deep vein thrombosis inmedical patients. Thromb Haemost 2005; 93:76–79
226 Kahn SR, Ginsberg JS. The post-thrombotic syndrome:current knowledge, controversies, and directions for futureresearch. Blood Rev 2002; 16:155–165
227 Brandjes DP, Buller HR, Heijboer H, et al. Randomised trialof effect of compression stockings in patients with symptomaticproximal-vein thrombosis. Lancet 1997; 349:759–762
228 Ginsberg JS, Hirsh J, Julian J, et al. Prevention and treat-ment of postphlebitic syndrome: results of a 3-part study.Arch Intern Med 2001; 161:2105–2109
229 Prandoni P, Lensing AW, Prins MH, et al. Below-kneeelastic compression stockings to prevent the post-thromboticsyndrome: a randomized, controlled trial. Ann Intern Med2004; 141:249–256
230 Kolbach DN, Sandbrink MW, Hamulyak K, et al. Non-pharmaceutical measures for prevention of post-thromboticsyndrome. Cochrane Database Syst Rev 2004; CD004174
231 Kahn SR, Shbaklo H, Shapiro S, et al. Effectiveness ofcompression stockings to prevent the post-thrombotic syn-drome (the SOX Trial and Bio-SOX biomarker substudy): arandomized controlled trial. BMC Cardiovasc Dis 2007; 7:21
232 Ginsberg JS, Magier D, Mackinnon B, et al. Intermittentcompression units for severe post-phlebitic syndrome: arandomized crossover study. Can Med Assoc J 1999; 160:1303–1306
233 Smith PC, Sarin S, Hasty J, et al. Sequential gradientpneumatic compression enhances venous ulcer healing: arandomized trial. Surgery 1990; 108:871–875
234 Kumar S, Samraj K, Nirujogi V, et al. Intermittent pneu-matic compression as an adjuvant therapy in venous ulcerdisease. J Tissue Viability 2002; 12:42–44,46,48
235 Kolari PJ, Pekanmaki K, Pohjola RT. Transcutaneous oxygentension in patients with post-thrombotic leg ulcers: treat-ment with intermittent pneumatic compression. CardiovascRes 1988; 22:138–141
236 Barwell J, Davies CE, Deacon J, et al. Comparison ofsurgery and compression with compression alone in chronicvenous ulceration (ESCHAR study): randomised controlledtrial. Lancet 2004; 363:1854–1859
237 Gohel MS, Barwell JR, Taylor M, et al. Long term results ofcompression therapy alone versus compression plus surgeryin chronic venous ulceration (ESCHAR): randomised con-trolled trial. BMJ 2007; 335:83
238 Hammarlund C, Sundberg T. Hyperbaric oxygen reducedsize of chronic leg ulcers: a randomized double-blind study.Plast Reconstr Surg 1994; 93:829–833
239 Martin M. PHLECO: a multicenter study of the fate of 1647hospital patients treated conservatively without fibrinolysisand surgery. Clin Investig 1993; 71:471–477
240 Arenas R, Atoche C. Postthrombotic leg ulcers: safety andefficacy of treatment with pentoxifylline (double-blind study in30 patients). Dermatologia Revista Mexicana 1988; 32:34–38
241 Barbarino C. Pentoxifylline in the treatment of venous legulcers. Curr Med Res Opin 1992; 12:547–551
242 Colgan MP, Dormandy J, Jones P, et al. The efficacy ofTrental in the tratment of venous ulceration. Phlebologie1989: 1154
243 Dale JJ, Ruckley CV, Harper DR, et al. Randomised, doubleblind placebo controlled trial of pentoxifylline in the treat-ment of venous leg ulcers. BMJ 1999; 319:875–878
244 Falanga V, Fujitani RM, Diaz C, et al. Systemic treatment ofvenous leg ulcers with high doses of pentoxifylline: efficacyin a randomized, placebo-controlled trial. Wound RepairRegen 1999; 7:208–213
245 Herdy WDC, Thomas JB, Souza SR, et al. Efficacy of
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 541S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
pentoxifylline in the healing of venous leg ulcers: a clinicalcomparative study. Arquivos Brasileiros de Medicina 1997;71:157–161
246 Schurman W, Eberhardt R. The efficacy of pentoxifyllineadded to topical and compression therapy in patients withvaricose and postthrombotic leg ulcers. Therapiewoche1986; 36:2343–2345
247 Weitgasser H. The use of pentoxifylline (Trental 400) in thetreatment of leg ulcers: results of a double-blind trial.Pharmatherapeutica 1983; 2:143–151
248 Nikolovska S, Pavlova L, Petrova N, et al. Pentoxifylline:efficient in the treatment of venous ulcers in the absence ofcompression? Acta Dermatovenerol Croat 2002; 10:9–13
249 Lyseng-Williamson KA, Perry CM. Micronised purifiedflavonoid fraction: a review of its use in chronic venousinsufficiency, venous ulcers and haemorrhoids. Drugs 2003;63:71–100
250 Shoab SS, Porter J, Scurr JH, et al. Endothelial activationresponse to oral micronised flavonoid therapy in patientswith chronic venous disease: a prospective study. Eur J VascEndovasc Surg 1999; 17:313–318
251 Garner RC, Garner JV, Gregory S, et al. Comparison of theabsorption of micronized (Daflon 500 mg) and nonmicron-ized 14C-diosmin tablets after oral administration to healthyvolunteers by accelerator mass spectrometry and liquidscintillation counting. J Pharm Sci 2002; 91:32–40
252 Coleridge-Smith P, Lok C, Ramelet AA. Venous leg ulcer: ameta-analysis of adjunctive therapy with micronized purifiedflavonoid fraction. Eur J Vasc Endovasc Surg 2005; 30:198–208
253 Coccheri S, Scondotto G, Agnelli G, et al. Randomised,double blind, multicentre, placebo controlled study of sulo-dexide in the treatment of venous leg ulcers. ThrombHaemost 2002; 87:947–952
254 Campbell IA, Yeoh J, Medlicott S. Duration of hospital stayin patients with pulmonary venous thromboembolism: arandomized comparison of unfractionated heparinversus lowmolecular weight heparin [abstract]. Thorax 1998; 53:254
255 Kuijer PM, Gallus AS, Cade J, et al. Randomized compari-son of LMWH versus standard heparin in the initial treat-ment of pulmonary embolism [abstract]. Thromb Haemost1995; 73:974
256 Meyer G, Brenot F, Pacouret G, et al. Subcutaneouslow-molecular-weight heparin fragmin versus intravenousunfractionated heparin in the treatment of acute non mas-sive pulmonary embolism: an open randomized pilot study.Thromb Haemost 1995; 74:1432–1435
257 Perez de Llano LA, Baloira VA, Veres RA, et al. Multicenter,prospective study comparing enoxaparin with unfractionatedheparin in the treatment of submassive pulmonary throm-boembolism. Arch Bronconeumol 2003; 39:341–345
258 Thery C, Simonneau G, Meyer G, et al. Randomized trial ofsubcutaneous low-molecular-weight heparin CY 216 (Fraxi-parine) compared with intravenous unfractionated heparinin the curative treatment of submassive pulmonary embo-lism. Circulation 1992; 85:1380–1389
259 Quinlan DJ, McQuillan A, Eikelboom JW. Low-molecular-weight heparin compared with intravenous unfractionatedheparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med2004; 140:175–183
260 Beer JH, Burger M, Gretener S, et al. Outpatient treatmentof pulmonary embolism is feasible and safe in a substantialproportion of patients. J Thromb Haemost 2003; 1:186–187
261 Kovacs MJ, Anderson D, Morrow B, et al. Outpatienttreatment of pulmonary embolism with dalteparin. ThrombHaemost 2000; 83:209–211
262 Wells PS, Kovacs M, Bormanis J, et al. Expanding eligibility
for outpatient treatment of deep venous thrombosis andpulmonary embolism with low-molecular-weight heparin.Arch Intern Med 1998; 158:1809–1812
263 Wicki J, Perrier A, Perneger TV, et al. Predicting adverseoutcome in patients with acute pulmonary embolism: a riskscore. Thromb Haemost 2000; 84:548–552
264 Aujesky D, Obrosky DS, Stone RA, et al. Derivation andvalidation of a prognostic model for pulmonary embolism.Am J Respir Crit Care Med 2005; 172:1041–1046
265 Jimenez D, Yusen RD, Otero R, et al. Prognostic models forselecting patients with acute pulmonary embolism for initialoutpatient therapy. Chest 2007; 132:24–30
266 Agnelli G, Becattini C, Kirschstein T. Thrombolysis vs heparinin the treatment of pulmonary embolism: a clinical outcome-based meta-analysis. Arch Intern Med 2002; 162:2537–2541
267 Dong B, Jirong Y, Wang Q, et al. Thrombolytic treatment forpulmonary embolism. Cochrane Database Syst Rev 2006; 2;cD004437
268 Wan S, Quinlan DJ, Agnelli G, et al. Thrombolysis com-pared with heparin for the initial treatment of pulmonaryembolism: a meta-analysis of the randomized controlledtrials. Circulation 2004; 110:744–749
269 Urokinase Pulmonary Embolism Trial: a national co-operativestudy. Circulation 1973; 47(suppl II):1
270 Dalla-Volta S, Palla A. PAIMS 2-alteplase combined withheparin versus heparin in the treatment of acute pulmonaryembolism: plasminogen Activator Italian Multicenter Study2. J Am Coll Cardiol 1992; 20:520–526
271 Dotter CT, Seamon AJ, Rosch J, et al. Streptokinase andheparin in the treatment of pulmonary embolism: a random-ized comparison. Vasc Surg 1979; 13 42–52
272 PIOPED Investigators. Tissue plasminogen activator for thetreatment of acute pulmonary embolism. Chest 1990; 97:528–533
273 Jerjes-Sanchez C, Ramirez-Rivera A, de Lourdes Garcia M,et al. Streprokinase and heparin versus heparin alone inmassive pulmonary embolism: a randomized controlled trial.J Thromb Thrombol 1995; 2:227–229
274 Lopaciuk S, Meissner AJ, Ciesielski L, et al. Subcutaneoussodium heparin versus intravenous sodium heparin in thetreatment of deep vein thrombosis: proceedings of the 6thInternational Meeting of the Danubian League AgainstThrombosis and Haemorrhagic Disorders. Vienna, Austria:1989; 389–393
275 Ly B, Arnesen H, Eie H, et al. A controlled clinical trial ofstreptokinse and heparin in the treatment of major pulmo-nary embolism. Acta Med Scand 1978; 203:465–470
276 Marini C, Di Ricco G, Rossi G, et al. Fibrinolytic effects ofurokinase and heparin in acute pulmonary embolism: arandomized clinical trial. Respiration 1988; 54:162–173
277 Tibbutt DA, Davies JA, Anderson JA, et al. Comparison bycontrolled clinical trial of streptokinase and heparin intreatment of life-threatening pulmonary embolism. BMJ1974; 1:343–347
278 Urokinase Pulmonary Embolism Trial Study Group. Uroki-nase pulmonary embolism trial: phase I results. JAMA 1970;214:2163–2172
279 Konstantinides S, Geibel A, Heusel G, et al. Heparin plusalteplase compared with heparin alone in patients withsubmassive pulmonary embolism. N Engl J Med 2002;347:1143–1150
280 Kucher N, Rossi E, De Rosa M, et al. Massive pulmonaryembolism. Circulation 2006; 113:577–582
281 Goldhaber SZ, Visni L, De Rosa M. Acute pulmonaryembolism: clinical outcomes in the International Coopera-tive Pulmonary Embolism Registry (ICOPER). Lancet1999; 353:1386–1389
542S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
282 Douketis JD, Leeuwenkamp O, Grobara P, et al. Theincidence and prognostic significance of elevated cardiactroponins in patients with submassive pulmonary embolism.J Thromb Haemost 2005; 3:508–513
283 Giannitsis E, Katus HA. Risk stratification in pulmonaryembolism based on biomarkers and echocardiography. Cir-culation 2005; 112:1520–1521
284 Konstantinides S, Geibel A, Olschewski M, et al. Importanceof cardiac troponins I and T in risk stratification of patientswith acute pulmonary embolism. Circulation 2002; 106:1263–1268
285 Scridon T, Scridon C, Skali H, et al. Prognostic significanceof troponin elevation and right ventricular enlargement inacute pulmonary embolism. Am J Cardiol 2005; 96:303–305
286 Becattini C, Vedovati M, Agnelli G. Prognostic value oftroponins in acute pulmonary embolism: a meta-analysis.Circulation 2007; 116:427–433
287 Goldhaber SZ. Echocardiography in the management ofpulmonary embolism. Ann Intern Med 2002; 136:691–700
288 Schoepf UJ, Kucher N, Kipfmueller F, et al. Right ventric-ular enlargement on chest computed tomography: a predic-tor of early death in acute pulmonary embolism. Circulation2004; 110:3276–3280
289 Ten Wolde M, Sohne M, Quak E, et al. Prognostic value ofechocardiographically assessed right ventricular dysfunctionin patients with pulmonary embolism. Arch Intern Med2004; 164:1685–1689
290 Fiumara K, Kucher N, Fanikos J, et al. Predictors of majorhemorrhage following fibrinolysis for acute pulmonary em-bolism. Am J Cardiol 2006; 97:127–129
291 Kanter DS, Mikkola KM, Patel SR, et al. Thrombolytictherapy for pulmonary embolism: frequency of intracranialhemorrhage and associated risk factors. Chest 1997; 111:1241–1245
292 Urokinase-streptokinase embolism trial: phase 2 result.JAMA 1974; 229:1606–1613
293 Goldhaber SZ, Agnelli G, Levine MN. Reduced dose bolusalteplase vs conventional alteplase infusion for pulmonaryembolism thrombolysis: an international multicenter ran-domized trial; The Bolus Alteplase Pulmonary EmbolismGroup. Chest 1994; 106:718–724
294 Goldhaber SZ, Kessler CM, Heit J, et al. A randomizedcontrolled trial of recombinant tissue plasminogen activatorversus urokinase in the treatment of acute pulmonaryembolism. Lancet 1988; 2:293–298
295 Goldhaber SZ, Kessler CM, Heit JA, et al. Recombinanttissue-type plasminogen activator versus a novel dosingregimen of urokinase in acute pulmonary embolism: arandomized controlled multicenter trial. J Am Coll Cardiol1992; 20:24–30
296 Meneveau N, Schiele F, Metz D, et al. Comparative efficacyof a two-hour regimen of streptokinase versus alteplase inacute massive pulmonary embolism: immediate clinical andhemodynamic outcome and one-year follow-up. J Am CollCardiol 1998; 31:1057–1063
297 Meneveau N, Schiele F, Vuillemenot A, et al. Streptokinasevs alteplase in massive pulmonary embolism: a randomizedtrial assessing right heart haemodynamics and pulmonaryvascular obstruction. Eur Heart J 1997; 18:1141–1148
298 Meyer G, Sors H, Charbonnier B, et al. Effects of intravenousurokinase versus alteplase on total pulmonary resistance inacute massive pulmonary embolism: a European multicenterdouble-blind trial. J Am Coll Cardiol 1992; 19:239–245
299 Sors H, Pacouret G, Azarian R, et al. Hemodynamic effectsof bolus vs 2-h infusion of alteplase in acute massivepulmonary embolism: a randomized controlled multicentertrial. Chest 1994; 106:712–717
300 Verstraete M, Miller GAH, Bounameaux H, et al. Intrave-nous and intrapulmonary recombinant tissue-type plasmin-ogen activator in the treatment of acute massive pulmonaryembolism. Circulation 1988; 77:353–360
301 Levine M, Hirsh J, Weitz J, et al. A randomized trial of asingle bolus dosage regimen of recombinant tissue plasmin-ogen activator in patients with acute pulmonary embolism.Chest 1990; 98:1473–1479
302 de Gregorio M, Gimeno M, Alfonso R, et al. Mechanicalfragmentation and intrapulmonary fibrinolysis in the treat-ment of massive pulmonary embolism hemodynamic reper-cussions. Arch Bronconeumol 2001; 37:58–64
303 Fava M, Loyola S, Flores P, et al. Mechanical fragmentationand pharmacologic thrombolysis in massive pulmonary em-bolism. J Vasc Interv Radiol 1997; 8:261–266
304 Schmitz-Rode T, Janssens U, Duda SH, et al. Massive pulmo-nary embolism: percutaneous emergency treatment by pigtailrotation catheter. J Am Coll Cardiol 2000; 36:375–380
305 Schmitz-Rode T, Janssens U, Schild HH, et al. Fragmenta-tion of massive pulmonary embolism using a pigtail rotationcatheter. Chest 1998; 114:1427–1436
306 Leacche M, Unic D, Goldhaber SZ, et al. Modern surgicaltreatment of massive pulmonary embolism: results in 47consecutive patients after rapid diagnosis and aggressivesurgical approach. J Thorac Cardiovasc Surg 2005; 129:1018–1023
307 Meneveau N, Seronde MF, Blonde MC, et al. Managementof unsuccessful thrombolysis in acute massive pulmonaryembolism. Chest 2006; 129:1043–1050
308 Sukhija R, Aronow WS, Lee J, et al. Association of rightventricular dysfunction with in-hospital mortality in patientswith acute pulmonary embolism and reduction in mortalityin patients with right ventricular dysfunction by pulmonaryembolectomy. Am J Cardiol 2005; 95:695–696
309 Beckman JA, Dunn K, Sasahara AA, et al. Enoxaparinmonotherapy without oral anticoagulation to treat acutesymptomatic pulmonary embolism. Thromb Haemost 2003;89:953–958
310 Kucher N, Quiroz R, McKean S, et al. Extended enoxaparinmonotherapy for acute symptomatic pulmonary embolism.Vasc Med 2005; 10:251–256
311 Gosselin MV, Rubin GD, Leung AN, et al. Unsuspectedpulmonary embolism: prospective detection on routine he-lical CT scans. Radiology 1998; 208:209–215
312 O’Connell CL, Boswell WD, Duddalwar V, et al. Unsus-pected pulmonary emboli in cancer patients: clinical corre-lates and relevance. J Clin Oncol 2006; 24:4928–4932
313 Sebastian AJ, Paddon AJ. Clinically unsuspected pulmonaryembolism–an important secondary finding in oncology CT.Clin Radiol 2006; 61:81–85
314 Storto ML, Di Credico A, Guido F, et al. Incidentaldetection of pulmonary emboli on routine MDCT of thechest. AJR Am J Roentgenol 2005; 184:264–267
315 Becattini C, Agnelli G, Pesavento R, et al. Incidence of chronicthromboembolic pulmonary hypertension after a first episodeof pulmonary embolism. Chest 2006; 130:172–175
316 Pengo V, Lensing AWA, Prins MH, et al. Incidence ofchronic thromboembolic pulmonary hypertension after pul-monary embolism. N Engl J Med 2004; 350:2257–2264
317 Ribeiro A, Lindmarker P, Johnsson H, et al. Pulmonaryembolism: one year follow-up with echocardiography dopp-ler and five-year survival analysis. Circulation 1999; 99:1325–1330
318 Jamieson SW, Kapelanski DP, Sakakibara N, et al. Pulmo-nary endarterectomy: experience and lessons learned in1,500 cases. Ann Thorac Surg 2003; 76:1457–1462
319 Fedullo PF, Auger WR, Kerr KM, et al. Chronic thrombo-
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 543S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
embolic pulmonary hypertension. N Engl J Med 2001;345:1465–1472
320 Feinstein JA, Goldhaber SZ, Lock JE, et al. Balloon pulmo-nary angioplasty for treatment of chronic thromboembolicpulmonary hypertension. Circulation 2001; 103:10–13
321 Galie N, Kim NH. Pulmonary microvascular disease inchronic thromboembolic pulmonary hypertension. Proc AmThorac Soc 2006; 3:571–576
322 Hoeper MM, Mayer E, Simonneau G, et al. Chronicthromboembolic pulmonary hypertension. Circulation 2006;113:2011–2020
323 Bresser P, Pepke-Zaba J, Jais X, et al. Medical therapies forchronic thromboembolic pulmonary hypertension: an evolvingtreatment paradigm. Proc Am Thorac Soc 2006; 3:594–600
324 Skoro-Sajer N, Bonderman D, Wiesbauer F, et al. Trepro-stinil for severe inoperable chronic thromboembolic pulmo-nary hypertension. J Thromb Haemost 2007; 5:483–489
325 Hughes RJ, Jais X, Bonderman D, et al. The efficacy ofbosentan in inoperable chronic thromboembolic pulmonaryhypertension: a 1-year follow-up study. Eur Respir J 2006;28:138–143
326 Tagalakis V, Kahn SR, Libman M, et al. The epidemiology ofperipheral vein infusion thrombophlebitis: a critical review.Am J Med 2002; 113:146–151
327 Becherucci A, Bagilet D, Marenghini J, et al. Effect oftopical and oral diclofenac on superficial thrombophlebitiscaused by intravenous infusion. Med Clin (Barc) 2000;114:371–373
328 Vilardell M, Sabat D, Arnaiz JA, et al. Topical heparin forthe treatment of acute superficial phlebitis secondary toindwelling intravenous catheter: a double-blind, random-ized, placebo-controlled trial. Eur J Clin Pharmacol 1999;54:917–921
329 Bergqvist D, Brunkwall J, Jensen N, et al. Treatment ofsuperficial thrombophlebitis: a comparative trial betweenplacebo, Hirudoid cream and piroxicam gel. Ann ChirGynaecol 1990; 79:92–96
330 De Sanctis MT, Cesarone MR, Incandela L, et al. Treat-ment of superficial vein thrombophlebitis of the arm withEssaven gel: a placebo-controlled, randomized study. Angi-ology 2001; 52(suppl 3):S63–S67
331 Decousus H, Epinat M, Guillot K, et al. Superficial veinthrombosis: risk factors, diagnosis, and treatment. Curr OpinPulm Med 2003; 9:393–397
332 Wichers IM, Di Nisio M, Buller HR, et al. Treatment ofsuperficial vein thrombosis to prevent deep vein thrombosisand pulmonary embolism: a systematic review. Haemato-logica 2005; 90:672–677
333 Quenet S, Laporte S, Decousus H, et al. Factors predictiveof venous thrombotic complications in patients with isolatedsuperficial vein thrombosis. J Vasc Surg 2003; 38:944–949
334 Di Nisio M, Wichers IM, Middeldorp S. Treatment forsuperficial thrombophlebitis of the leg. Cochrane DatabaseSyst Rev 2007; CD004982
335 Superficial Thrombophlebitis Treated by Enoxaparin StudyGroup. A pilot randomized double-blind comparison of alow-molecular-weight heparin, a nonsteroidal anti-inflam-matory agent, and placebo in the treatment of superficialvein thrombosis. Arch Intern Med 2003; 163:1657–1663
336 Titon JP, Auger D, Grange P, et al. Therapeutic manage-ment of superficial venous thrombosis with calcium na-droparin: dosage testing and comparison with a non-steroi-dal anti-inflammatory agent. Ann Cardiol Angeiol (Paris)1994; 43:160–166
337 Prandoni P, Tormene D, Pesavento R. High vs. low doses oflow-molecular-weight heparin for the treatment of superfi-cial vein thrombosis of the legs: a double-blind, randomized
trial. J Thromb Haemost 2005; 3:1152–1157338 Marchiori A, Verlato F, Sabbion P, et al. High versus low
doses of unfractionated heparin for the treatment of super-ficial thrombophlebitis of the leg: a prospective, controlled,randomized study. Haematologica 2002; 87:523–527
339 Belcaro G, Nicolaides AN, Errichi BM, et al. Superficialthrombophlebitis of the legs: a randomized, controlled,follow-up study. Angiology 1999; 50:523–529
340 Gorski G, Szopinski P, Michalak J, et al. Liposomal heparinspray: a new formula in adjunctive treatment of superficialvenous thrombosis. Angiology 2005; 56:9–17
341 Andreozzi GM, Signorelli S, Di Pino L, et al. Tolerabilityand clinical efficacy of desmin in the treatment of superficialthrombovaricophlebitis. Angiology 1996; 47:887–894
342 Lozano FS, Almazan A. Low-molecular-weight heparin ver-sus saphenofemoral disconnection for the treatment ofabove-knee greater saphenous thrombophlebitis: a prospec-tive study. Vasc Endovascular Surg 2003; 37:415–420
343 Sullivan V, Denk PM, Sonnad SS, et al. Ligation versusanticoagulation: treatment of above-knee superficial throm-bophlebitis not involving the deep venous system. J Am CollSurg 2001; 193:556–562
344 Becker DM, Philbrick JT, Walker FB. Axillary and subcla-vian venous thrombosis: prognosis and treatment. ArchIntern Med 1991; 151:1934–1943
345 Joffe HV, Kucher N, Tapson VF, et al. Upper-extremitydeep vein thrombosis: a prospective registry of 592 patients.Circulation 2004; 110:1605–1611
346 Prandoni P, Polistena P, Bernardi E, et al. Upper-extremitydeep vein thrombosis: risk factors, diagnosis, and complica-tions. Arch Intern Med 1997; 157:57–62
347 Prandoni P, Bernardi E, Marchiori A, et al. The long termclinical course of acute deep vein thrombosis of the arm:prospective cohort study. BMJ 2004; 329:484–485
348 Elman ER, Kahn SR. The post-thrombotic syndrome afterupper extremity deep venous thrombosis: a systematic re-view. Thromb Res 2006; 117:609–614
349 Savage KJ, Wells PS, Schulz V, et al. Outpatient use of lowmolecular weight heparin (dalteparin) for the treatment ofdeep vein thrombosis of the upper extremity. ThrombHaemost 1999; 82:1008–1010
350 Karabay O, Yetkin U, Onol H. Upper extremity deep veinthrombosis: clinical and treatment characteristics. J Int MedRes 2004; 32:429–435
351 Kovacs MJ, Kahn SR, Rodger M, et al. A pilot study ofcentral venous catheter survival in cancer patients using lowmolecular weight heparin (dalteparin) and warfarin withoutcatheter removal for the treatment of upper extremity deepvein thrombosis (The Catheter Study). J Thromb Haemost2007; 5:1650–1653
352 AbuRahma AF, Short YS, White JF III, et al. Treatmentalternatives for axillary-subclavian vein thrombosis: long-term follow-up. Cardiovasc Surg 1996; 4:783–787
353 Lee JT, Karwowski JK, Harris EJ, et al. Long-term throm-botic recurrence after nonoperative management of Paget-Schroetter syndrome. J Vasc Surg 2006; 43:1236–1243
354 Lokanathan R, Salvian AJ, Chen JC, et al. Outcome afterthrombolysis and selective thoracic outlet decompression forprimary axillary vein thrombosis. J Vasc Surg 2001; 33:783–788
355 Pegis JD, Papon X, Pasco A, et al. In situ thrombolysis in thetreatment of venous thrombosis of effort in the arm. J MalVasc 1997; 22:187–192
356 Petrakis IE, Katsamouris A, Kafassis E, et al. Two differenttherapeutic modalities in the treatment of the upper extrem-ity deep vein thrombosis: preliminary investigation with 20case reports. Int J Angiol 2000; 9:46–50
357 Sabeti S, Schillinger M, Mlekusch W, et al. Treatment of
544S Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
subclavian-axillary vein thrombosis: long-term outcome ofanticoagulation versus systemic thrombolysis. Thromb Res2002; 108:279–285
358 Schindler J, Bona RD, Chen HH, et al. Regional thrombol-ysis with urokinase for central venous catheter-relatedthrombosis in patients undergoing high-dose chemotherapywith autologous blood stem cell rescue. Clin Appl ThrombHaemost 1999; 5:25–29
359 Caparrelli DJ, Freischlag J. A unified approach to axillosub-clavian venous thrombosis in a single hospital admission.Semin Vasc Surg 2005; 18:153–157
360 Thomas IH, Zierler BK. An integrative review of outcomesin patients with acute primary upper extremity deep venousthrombosis following no treatment or treatment with anti-coagulation, thrombolysis, or surgical algorithms. Vasc En-dovascular Surg 2005; 39:163–174
361 Machleder HI. Evaluation of a new treatment strategy forPaget-Schroetter syndrome: spontaneous thrombosis of theaxillary-subclavian vein. J Vasc Surg 1993; 17:305–315
362 Schneider DB, Dimuzio PJ, Martin ND, et al. Combinationtreatment of venous thoracic outlet syndrome: open surgicaldecompression and intraoperative angioplasty. J Vasc Surg2004; 40:599–603
363 Spence LD, Gironta MG, Malde HM, et al. Acute upperextremity deep venous thrombosis: safety and effectivenessof superior vena caval filters. Radiology 1999; 210:53–58
364 Ascher E, Hingorani A, Tsemekhin B, et al. Lessons learnedfrom a 6-year clinical experience with superior vena cavaGreenfield filters. J Vasc Surg 2000; 32:881–887
365 Feugier P, Aleksic I, Salari R, et al. Long-term results ofvenous revascularization for Paget-Schroetter syndrome inathletes. Ann Vasc Surg 2001; 15:212–218
366 Lee MC, Grassi CJ, Belkin M, et al. Early operativeintervention after thrombolytic therapy for primary subcla-vian vein thrombosis: an effective treatment approach. JVasc Surg 1998; 27:1101–1107
367 Malcynski J, O’Donnell TF Jr, Mackey WC, et al. Long-termresults of treatment for axillary subclavian vein thrombosis.Can J Surg 1993; 36:365–371
368 Meier GH, Pollak JS, Rosenblatt M, et al. Initial experiencewith venous stents in exertional axillary-subclavian veinthrombosis. J Vasc Surg 1996; 24:974–981
369 Sanders RJ, Cooper MA. Surgical management of subclavianvein obstruction, including six cases of subclavian veinbypass. Surgery 1995; 118:856–863
370 Sheeran SR, Hallisey MJ, Murphy TP, et al. Local throm-bolytic therapy as part of a multidisciplinary approach toacute axillosubclavian vein thrombosis (Paget-Schroettersyndrome). J Vasc Interv Radiol 1997; 8:253–260
371 Urschel HC Jr, Patel AN. Paget-Schroetter syndrome ther-apy: failure of intravenous stents. Ann Thorac Surg 2003;75:1693–1696
372 Yilmaz EN, Vahl AC, Heek van NT, et al. Long-term resultsof local thrombolysis followed by first rib resection: anencouraging clinical experience in treatment of subclavianvein thrombosis. Vasc Surg 2000; 34:17–23
373 Marie I, Levesque H, Cailleux N, et al. Deep venousthrombosis of the upper limbs: apropos of 49 cases [inFrench]. Rev Med Interne 1998; 19:399–408
374 Baarslag HJ, Koopman MM, Reekers JA, et al. Diagnosisand management of deep vein thrombosis of the upperextremity: a review. Eur Radiol 2004; 14:1263–1274
375 Buller HR, Agnelli G, Hull RD, et al. Antithrombotictherapy for venous thromboembolic disease: the SeventhACCP Conference on Antithrombotic and Thrombolytic
Therapy. Chest 2004; 126(suppl):401S–428S376 Elliott G. Upper-extremity deep vein thrombosis. Lancet
1997; 349:1188–1189377 Joffe HV, Goldhaber SZ. Upper-extremity deep vein throm-
bosis. Circulation 2002; 106:1874–1880378 Martinelli I, Battaglioli T, Bucciarelli P, et al. Risk factors
and recurrence rate of primary deep vein thrombosis of theupper extremities. Circulation 2004; 110:566–570
379 Burihan E, de Figueiredo LF, Francisco JJ, et al. Upper-extremity deep venous thrombosis: analysis of 52 cases.Cardiovasc Surg 1993; 1:19–22
380 Hingorani A, Ascher E, Lorenson E, et al. Upper extremitydeep venous thrombosis and its impact on morbidity andmortality rates in a hospital-based population. J Vasc Surg1997; 26:853–860
381 Hingorani A, Ascher E, Ward M, et al. Combined upper andlower extremity deep venous thrombosis. Cardiovasc Surg2001; 9:472–477
382 Lindblad B, Tengborn L, Bergqvist D. Deep vein thrombo-sis of the axillary-subclavian veins: epidemiologic data, ef-fects of different types of treatment and late sequelae. EurJ Vasc Surg 1988; 2:161–165
383 Marinella MA, Kathula SK, Markert RJ. Spectrum of upper-extremity deep venous thrombosis in a community teachinghospital. Heart Lung 2000; 29:113–117
384 Kahn SR, Elman EA, Bornais C, et al. Post-thromboticsyndrome, functional disability and quality of life after upperextremity deep venous thrombosis in adults. Thromb Hae-most 2005; 93:499–502
385 Apollonio A, Angeletti R. Conservative treatment of venousleg ulcers (pentoxifylline vs defibrotide) [in Italian]. Gior-nale Italiano di Angiologia 1992; 12:151–156
386 Belcaro G, Cesarone MR, Nicolaides AN, et al. Treatmentof venous ulcers with pentoxifylline: a 6-month randomized,double-blind, placebo controlled trial. Angiology 2002;53(suppl 1):S45–S47
387 De Sanctis MT, Belcaro G, Cesarone MR, et al. Treatmentof venous ulcers with pentoxifylline: a 12-month, double-blind, placebo controlled trial. Microcirculation and healing.Angiology 2002; 53(suppl 1):S49–S51
388 Guilhou JJ, Fevrier F, Debure C, et al. Benefit of a 2-monthtreatment with a micronized, purified flavonoidic fraction onvenous ulcer healing: a randomized, double-blind, con-trolled versus placebo trial. Int J Microcirc Clin Exp 1997;17(suppl 1):21–26
389 Glinski W, Chodynicka B, Roszkiewicz J, et al. Effectivenessof a micronized purified flavonoid fraction (MPFF) in thehealing process of lower limb ulcers: an open multicentrestudy, controlled and randomized [in Italian]. MinervaCardioangiol 2001; 49:107–114
390 Roztocil K, Stvrtinova V, Strejcek J. Efficacy of a 6-monthtreatment with Daflon 500 mg in patients with venous legulcers associated with chronic venous insufficiency. IntAngiol 2003; 22:24–31
391 Goldhaber SZ, Haire WD, Feldstein ML, et al. Aleptaseversus heparin in acute pulmonary embolism: randomizedtrial assessing right-ventricular function and pulmonary per-fusion. Lancet 1993; 341:507–511
392 Massoure PL, Constans J, Caudry M, et al. Upper extremitydeep venous thrombosis: 40 hospitalized patients [inFrench]. J Mal Vasc 2000; 25:250–255
393 Persson LM, Arnhjort T, Larfars G, et al. Hemodynamic andmorphologic evaluation of sequelae of primary upper ex-tremity deep venous thromboses treated with anticoagula-tion. J Vasc Surg 2006; 43:1230–1235
www.chestjournal.org CHEST / 133 / 6 / JUNE, 2008 SUPPLEMENT 545S
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
Errata
In the June 2008 supplement, in the article by Hirsh et al,“Executive Summary: American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines (8th Edition)”(Chest 2008; 133[suppl]:71S–109S), on page 99S, in column one,Recommendation 2.5.2, the text should read “For patients withacute ST-segment elevation myocardial infarction receiving fi-bronolytic therapy who have preserved renal function (� 2.5mg/dL [220 �mol/L] in males and � 2.0 mg/dL [175 �mol/L] infemales), we recommend the use of enoxaparin over UFH,continued up to 8 days (Grade 2A).” The online version has beencorrected, and that version should be used.
In the June 2008 supplement, in the article by Goodman et al,“Acute ST-Segment Elevation Myocardial Infarction: AmericanCollege of Chest Physicians Evidence-Based Clinical PracticeGuidelines (8th Edition)” (Chest 2008; 133[suppl]:708S–775S),on page 710S, in column one, Recommendation 2.5.2 (and onpage 739S column one), the text should read “For patients withacute ST-segment elevation myocardial infarction receiving fi-bronolytic therapy who have preserved renal function (� 2.5mg/dL [220 �mol/L] in males and � 2.0 mg/dL [175 �mol/L] infemales), we recommend the use of enoxaparin over UFH,continued up to 8 days (Grade 2A).” The online version has beencorrected and that version should be used.
In the June 2008 supplement, in the article by Kearon et al,“Antithrombotic Therapy for Venous Thromboemobolic Disease:American College of Chest Physicians Evidence-Based ClinicalPractice Guidelines (8th Edition)” (Chest 2008; 133[suppl]:454S–545S), the conflict of interest disclosures from the authorswere inadvertently left out. They are as follows: Dr. Kearondiscloses that he has received grant monies from the CanadianInstitutes for Health Research and the Heart and Stroke Foun-dation of Canada. He is also on an advisory committee forGlaxoSmithKline and Boehringer Ingelheim. Dr. Agnelli revealsno real or potential conflicts of interest or commitment. Dr.Goldhaber discloses that he has received grant monies fromMitsubishi, Boehringer Ingelheim, Sanofi-Aventis, Eisai, Glaxo-SmithKline, and AstraZeneca. He has also received consultantfees from Sanofi-Aventis, Eisai, Bristol-Myers Squibb, andBoehringer Ingelheim. Dr. Raskob discloses that he has servedon the speaker bureau and advisory committees and has received
consultant fees from Bayer, BMS, Daiichi-Sankyo, Pfizer, Sanofi-Aventis, Takedo and Boehringer Ingelheim. Dr. Comerottadiscloses that he is on the speaker bureaus of Sanofi-Aventis,Bristol-Myers Squibb, and GlaxoSmithKline and serves on anadvisory committee for ConvaTec, and Bacchus Vascular. He isalso a shareholder of LeMaitre Vascular.
In the September 2008 supplement by Tarlo et al, “Diagnosis andManagement of Work-Related Asthma: American College of ChestPhysicians Consensus Statement” (Chest 2008; 134:1S–41S), someof the subheadings are misleading in the print version. The onlineversion has been corrected and should be used. There is no changeto the text, but the level of headings shown on pages 7S–9S, 17S, and31S–32S is more clear in the corrected online edition. Also, on theTable of Contents pages the Endorsements should read “TheCanadian Society of Allergy and Clinical Immunology and TheCanadian Thoracic Society”.
In the July 2008 issue, in the correspondence by BaHammamet al, “Positive Airway Pressure Therapy and Daytime Hypercap-nia in Patients With Sleep-Disordered Breathing” (Chest 2008;134:218–219), the first author’s surname was misspelled. It isBaHammam. It has been corrected in the online edition.
Correction
I have come to realize that I neglected to provide as full apotential conflict of interest statement as I could have in myreview article, “Update on the Management of COPD” (Chest2008; 133:1451–1462). I wish to disclose the following: Bar-tolome R. Celli has been reimbursed by GSK, BI, Pfizer, AZ,Almirall, and Esteve for participating in advisory boards andspoken at different meetings. The division that Dr. Celli headshas been awarded research grants for different medication trialsby the same companies and for the discovery of new biomarkersin COPD, and has received grants for the participation in thedevelopment of biological lung volume reduction surgery fromthe company AERIS. Bartolome R. Celli, MD, FCCP, Pulmo-nary and Critical Care Medicine, Caritas St. Elizabeth’s MedicalCenter, Boston, MA.
CHEST Errata
892 Errata
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from
DOI 10.1378/chest.08-0658 2008;133; 454S-545SChest
Raskob and Anthony J. ComerotaClive Kearon, Susan R. Kahn, Giancarlo Agnelli, Samuel Goldhaber, Gary E.
Practice Guidelines (8th Edition)American College of Chest Physicians Evidence-Based Clinical
:*Antithrombotic Therapy for Venous Thromboembolic Disease
October 14, 2011This information is current as of
http://chestjournal.chestpubs.org/content/suppl/2008/06/23/133.6_suppl.454S.DC1.html View e-supplements related to this article at:
Supplementary Material
http://chestjournal.chestpubs.org/content/133/6_suppl/454S.full.htmlUpdated Information and services can be found at:
Updated Information & Services
http://chestjournal.chestpubs.org/content/133/6_suppl/454S.full.html#ref-list-1This article cites 383 articles, 116 of which can be accessed free at:
References
http://chestjournal.chestpubs.org/content/133/6_suppl/454S.full.html#related-urlsThis article has been cited by 100 HighWire-hosted articles:
Cited Bys
http://www.chestpubs.org/site/misc/reprints.xhtmlfound online at: Information about reproducing this article in parts (figures, tables) or in its entirety can bePermissions & Licensing
http://www.chestpubs.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:
Reprints
"Services" link to the right of the online article.Receive free e-mail alerts when new articles cite this article. To sign up, select the
Citation Alerts
PowerPoint slide format. See any online figure for directions. articles can be downloaded for teaching purposes inCHESTFigures that appear in Images in PowerPoint format
© 2008 American College of Chest Physicians by guest on October 14, 2011chestjournal.chestpubs.orgDownloaded from