screening · web viewmajor bleeding, clinically relevant nonmajor bleeding, and all bleeding...

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Supplemental Data

Appendix 1 Search strategies (Page 2-4)

Table S1 Study design of included studies (Page 5-8)Table S2 Baseline characteristics of patients in included studies (Page 9)Table S3 Quality appraisal (0-12)Table S4 Results from included studies (Page 13)Table S5. Efficacy and safety outcomes of extended versus standard-duration thromboprophylaxis. (Page 14)

Figure S1 PRISMA flow diagram (Page 15)Figure S2 Forest plot for efficacy outcomes (Page 16)Figure S3 Forest plot for each types of major bleeding (Page 17)Figure S4 Funnel plots of risk ratio versus standard error of included studies (Page 18)

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Appendix 1. Search strategies.

Database: MEDLINE (PubMed) (From inception to 10/26/2018)Search Strategy:

1. "Extended duration" OR "Extended" OR "Prolonged" (521059)2. "Thromboprophylaxis" OR "Prophylaxis" OR venous thromboembolism[MeSH

Terms] (107604)3. (Direct oral anticoagulants) OR DOAC) OR Novel oral anticoagulants) OR

NOAC) OR Dabigatran) OR Rivaroxaban) OR Apixaban) OR Edoxaban) OR Betrixaban) OR Low-molecular-weight heparin) OR Enoxaparin) OR Tinzaparin) OR Dalteparin) OR Nadroparin) OR Fondaparinux) OR Heparin (105673)

4. "Medical" OR "Medically" (4623033)5. 1 AND 2 AND 3 AND 4 (299)

MEDLINE (PubMed) Query:

(((("Extended duration"[All Fields] OR "Extended"[All Fields]) OR "Prolonged"[All Fields]) AND (("Thromboprophylaxis"[All Fields] OR "Prophylaxis"[All Fields]) OR "venous thromboembolism"[MeSH Terms])) AND ((((((((((((((((Direct[All Fields] AND ("mouth"[MeSH Terms] OR "mouth"[All Fields] OR "oral"[All Fields]) AND ("anticoagulants"[Pharmacological Action] OR "anticoagulants"[MeSH Terms] OR "anticoagulants"[All Fields])) OR DOAC[All Fields]) OR (Novel[All Fields] AND ("mouth"[MeSH Terms] OR "mouth"[All Fields] OR "oral"[All Fields]) AND ("anticoagulants"[Pharmacological Action] OR "anticoagulants"[MeSH Terms] OR "anticoagulants"[All Fields]))) OR ("N(4)-oleylcytosine arabinoside"[Supplementary Concept] OR "N(4)-oleylcytosine arabinoside"[All Fields] OR "noac"[All Fields])) OR ("dabigatran"[MeSH Terms] OR "dabigatran"[All Fields])) OR ("rivaroxaban"[MeSH Terms] OR "rivaroxaban"[All Fields])) OR ("apixaban"[Supplementary Concept] OR "apixaban"[All Fields])) OR ("edoxaban"[Supplementary Concept] OR "edoxaban"[All Fields])) OR ("betrixaban"[Supplementary Concept] OR "betrixaban"[All Fields])) OR ("heparin, low-molecular-weight"[MeSH Terms] OR ("heparin"[All Fields] AND "low-molecular-weight"[All Fields]) OR "low-molecular-weight heparin"[All Fields] OR ("low"[All Fields] AND "molecular"[All Fields] AND "weight"[All Fields] AND "heparin"[All Fields]) OR "low molecular weight heparin"[All Fields])) OR ("enoxaparin"[MeSH Terms] OR "enoxaparin"[All Fields])) OR ("tinzaparin"[Supplementary Concept] OR "tinzaparin"[All Fields])) OR ("dalteparin"[MeSH Terms] OR "dalteparin"[All Fields])) OR ("nadroparin"[MeSH Terms] OR "nadroparin"[All Fields])) OR ("fondaparinux"[Supplementary Concept] OR "fondaparinux"[All Fields])) OR ("heparin"[MeSH Terms] OR "heparin"[All Fields]))) AND ("Medical"[All Fields] OR "Medically"[All Fields])

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Database: EMBASE (From inception to 10/26/2018)Search Strategy:

1. 'extended duration':ti,ab OR 'extended':ti,ab OR 'prolonged':ti,ab (655842)2. 'thromboprophylaxis'/exp OR 'thromboprophylaxis':ti,ab OR 'prophylaxis'/exp

OR 'prophylaxis':ti,ab OR 'venous thromboembolism'/exp OR 'venous thromboembolism':ti,ab (1080151)

3. 'direct oral anticoagulant'/exp OR 'direct oral anticoagulant' OR 'dabigatran'/exp OR 'dabigatran' OR 'rivaroxaban'/exp OR 'rivaroxaban' OR 'apixaban'/exp OR 'apixaban' OR 'edoxaban'/exp OR 'edoxaban' OR 'betrixaban'/exp OR 'betrixaban' OR 'low molecular weight heparin'/exp OR 'low molecular weight heparin' OR 'enoxaparin'/exp OR 'enoxaparin' OR 'tinzaparin'/exp OR 'tinzaparin' OR 'dalteparin'/exp OR 'dalteparin' OR 'nadroparin'/exp OR 'nadroparin' OR 'fondaparinux'/exp OR 'fondaparinux' OR 'heparin'/exp OR 'heparin' (217398)

4. 'medical' OR 'medically' (8767373)5. #1 AND #2 AND #3 AND #4 (1268)6. random*:ab,ti OR placebo*:de,ab,ti OR ((double NEXT/1 blind*):ab,ti)

(1585572)7. #5 AND #6 (347)

EMBASE Query:

(('extended duration':ti,ab OR 'extended':ti,ab OR 'prolonged':ti,ab) AND ('thromboprophylaxis'/exp OR 'thromboprophylaxis':ti,ab OR 'prophylaxis'/exp OR 'prophylaxis':ti,ab OR 'venous thromboembolism'/exp OR 'venous thromboembolism':ti,ab) AND ('direct oral anticoagulant'/exp OR 'direct oral anticoagulant' OR 'dabigatran'/exp OR 'dabigatran' OR 'rivaroxaban'/exp OR 'rivaroxaban' OR 'apixaban'/exp OR 'apixaban' OR 'edoxaban'/exp OR 'edoxaban' OR 'betrixaban'/exp OR 'betrixaban' OR 'low molecular weight heparin'/exp OR 'low molecular weight heparin' OR 'enoxaparin'/exp OR 'enoxaparin' OR 'tinzaparin'/exp OR 'tinzaparin' OR 'dalteparin'/exp OR 'dalteparin' OR 'nadroparin'/exp OR 'nadroparin' OR 'fondaparinux'/exp OR 'fondaparinux' OR 'heparin'/exp OR 'heparin') AND ('medical' OR 'medically')) AND (random*:ab,ti OR placebo*:de,ab,ti OR ((double NEXT/1 blind*):ab,ti))

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Database: Cochrane Library (From 1946 to 10/26/2018)Search Strategy:

1. ("extended duration" OR "extended" OR "prolonged"):ti,ab,kw (38458)2. thromboprophylaxis OR prophylaxis OR venous thromboembolism (22582)3. Anticoagulants [MeSH](4236)4. “medical” (224607)5. #1 AND #2 AND #3 AND #4 (58)

Database: ClinicalTrials.gov (From inception to 10/26/2018)Search Strategy:

1. Venous thromboembolism2. Prophylaxis3. Medical4. 1 AND 2 AND 3, Filter: interventional studies (106)

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Table S1. Study design of included studies

EXCLAIM 2010 ADOPT 2011 MAGELLAN 2013 APEX 2016 MARINER 2018Author Hull et al. Goldhaber et al. Cohen et al. Cohen et al. Spyropoulos et al.Year of publication 2010 2011 2013 2016 2018Setting International, multicenter International, multicenter International, multicenter International, multicenter International, multicenterStudy design Randomized, parallel,

placebo-controlled trialRandomized placebo-controlled trial

Randomized active-comparator controlled trial

Randomized active-comparator controlled trial

Randomized placebo-controlled trial

Blinding Double-blind Double-blind, double dummy

Double-blind Double-blind, double dummy

Double-blind

Inclusion criteria 1. Age ≥40 years2. Recent reduced

mobility for up to 3 days3. Life expectancy ≥ 6

months4. Anticipated decreased

level of mobility of 5 ± 2 days and likely to continue at a lower than premorbid activity level after the initial 5 ± 2 day period, and at least one of the following medical conditions: Heart failure, NYHA class III or IV, Acute respiratory insufficiency, Other acute medical conditions including, but not limited to: Post acute ischemic stroke Acute infection without septic shock, Acute rheumatic disorders, Acute episode of inflammatory bowel disease, Active cancer

OrAnticipated decreased level of mobility (total bed

1. Age ≥40 years2. Hospitalized due to

congestive heart failure, acute respiratory failure or with infection (without septic shock), acute rheumatic disorder, or inflammatory bowel disease

3. Except for subjects with congestive heart failure or respiratory failure, subjects must have one additional factor including: age≥75, previous documented VTE or history of VTE for which they received anticoagulation for at least 6 weeks, cancer, BMI ≥ 30, estrogenic hormone therapy, chronic heart or respiratory failure

4. Expected hospitalization of ≥ 3 days after randomization

Severely or moderately restricted mobility

1. Age ≥40 years2. Being hospitalized for

acute medical conditions such as: - Heart failure, NYHA

class III or IV - Active cancer- Acute ischemic

stroke - Acute infection - Acute respiratory

insufficiency - Acute rheumatic

disorders - Acute inflammatory

bowel disease - Diabetes mellitus,

pancreatitis, cholecystitis

- Other 3. Anticipated complete

immobilization during the first day of hospitalization and anticipated decreased level of mobility (bed rest) and hospital stay duration of at least 4 days

Hospitalized <72 hours before randomization

1. Age ≥40 years2. At least one of the

following as the cause of the acute hospitalization: Acutely decompensated heart failure with prior symptomatic chronic heart failure, Acute respiratory failure in patients with chronic symptomatic lung disease, Acute infection without septic shock, Acute rheumatic disorders, Acute ischemic stroke with lower extremity hemiparesis or hemiparalysis, or with immobility of other origin that satisfies protocol immobility requirements.

3. Any one of the following: ≥ 75 years of age, or 60-74 years of age

with D-dimer ≥ 2ULN, or

40-59 years of age with D-dimer ≥

1. Age ≥40 years2. Has been hospitalized

for at least 3 and not more than 10 consecutive days for one of the following medical conditions: CHF, Acute respiratory insufficiency or acute exacerbation of COPD, Acute ischemic stroke, Acute infectious diseases, Inflammatory diseases, including rheumatic disease

3. Meet the following VTE criteria with a total modified IMPROVE VTE Risk Score >3 OR If total modified IMPROVE VTE Risk Score is 2, at least one of the following additional risk factors must be present: History of CHF, History of COPD Recent major

surgery or serious trauma

Severe varicosities

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EXCLAIM 2010 ADOPT 2011 MAGELLAN 2013 APEX 2016 MARINER 2018rest or sedentary patients with bathroom privileges) of 5 ± 2 days and likely to continue at lower than premorbid activity level after the initial 5 ± 2 day period and one of the following: – Age >75 years– Age ≥40 years and a history of VTE– Age ≥40 years and a baseline diagnosis of cancer (active cancer or a history of cancer)

2ULN AND a history of either VTE or cancer

4. Have been severely immobilized for 24 hours or are anticipated to be severely Immobilized for 24 hours, and severely or moderately immobilized for 3 or more days.

5. Hemoglobin- Hb ≥ 10.0 g/dL

during current presentation prior to randomization.

- Hb ≥ 9.5 g/dL from two (2) consecutive blood samples taken on consecutive days with stable or rising values.

6. Expected total length of current hospitalization ≥ 3 days and enrollment occurs < 96 hours after hospitalization/presentation.

and/ or chronic venous insufficiency*

D dimer > 2x ULN during index hospital admission

Obesity, defined as body mass index ≥35 kg/m2

3. Life expectancy of at least 3 months post discharge

4. Hospitalization and prophylactic treatment with LMWH or heparin for at least 3 days to a maximum of 14 days

Subjects with spinal cord infarction can be included unless there is evidence of intramedullary, subdural or epidural hemorrhage

Exclusion criteria High bleeding risk, history of HIT or thrombosis, renal failure, anemia, thrombocytopenia, or pregnancy

Confirmed VTE, disease requiring anticoagulation, high bleeding risk, liver disease, anemia or thrombocytopenia, severe renal disease (CrCl<30), prior HIT, concomitant dual anti-platelet or aspirin >165 mg/day, or pregnancy

High bleeding risk, liver disease, severe renal insufficiency, HIV infection, or use of mechanical thromboprophylaxis

High bleeding risk, thrombocytopenia, liver disease, severe renal insufficiency, uncontrolled HIV infection, or concomitant dual anti-platelet, life expectancy <8 weeks

High bleeding risk, thrombocytopenia, active cancer, liver disease, severe renal insufficiency (CrCl<30), HIV infection, concomitant dual anti-platelet, aspirin >165 mg/day, or clopidogrel >75 mg/day, presence of IVC filter, or pregnancy

Method of randomization

Computer-generated in permuted block of four

Central telephone system with the use of a computer-generated randomization

Permuted block stratified by center

Permuted block stratified by region, entry criteria, anticoagulants dose, and

Permuted block of four stratified by country and creatinine clearance

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EXCLAIM 2010 ADOPT 2011 MAGELLAN 2013 APEX 2016 MARINER 2018list concomitant strong P-

glycoprotein inhibitorsTime of randomization

After open-label prophylaxis with enoxaparin 40 mg SC QD for 10 ±4 days

Up to 72 hours from hospitalization



Within 24 hours of hospital discharge (Had been hospitalized for at least 3 days prior)

Intervention Enoxaparin 40 mg SC QD for 10 ±4 days then enoxaparin 40 mg SC QD for an additional 28 ±4 days

Apixaban 2.5 mg PO BID for 30 days

Rivaroxaban 10 mg QD for 35 ±4 days

Betrixaban 80 mg PO QD for 35-42 days (loading dose of 160 mg)

Note: Reduced-dose betrixaban (40 mg) for patients with severe renal insufficiency or receiving concomitant P-glycoprotein inhibitor

Rivaroxaban 10 mg QD for 45 days

Control Enoxaparin 40 mg SC QD for 10 ±4 days then placebo for an additional 28 ±4 days

Enoxaparin 40 mg SC QD during hospitalization and for a minimum of 6 days

Enoxaparin 40 mg SC QD for 10 ±4 days

Enoxaparin 40 mg SC QD for 10 ± 4 days

Placebo for 45 days

Primary efficacy outcome

A composite of symptomatic or asymptomatic proximal DVT, symptomatic PE, or fatal PE, during the double-blind treatment period (28 ±4 days after random assignment)

A composite during the 30-day treatment period of death related to VTE, fatal or nonfatal PE, symptomatic DVT, or asymptomatic proximal-leg DVT

A composite of asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic nonfatal PE, or death related to venous thromboembolism from day 1 to day 10 and day 1 to day 35

A composite of asymptomatic proximal DVT between day 32 and day 47, symptomatic proximal or distal DVT, symptomatic nonfatal PE, or death from VTE between day 1 and day 42

A composite of any symptomatic VTE or death related to VTE

Safety outcome Primary The incidence of major hemorrhagic complications during and up to 48 hours after the treatment periodSecondary 1. The incidence of major

and minor hemorrhagic complications

2. Serious adverse events

Major bleeding, clinically relevant nonmajor bleeding, and all bleeding reported by investigators; myocardial infarction; stroke; thrombocytopenia; and death from any cause

A composite of major bleeding or clinically relevant nonmajor bleeding events observed no later than 2 days after administration of the last dose of double-blind study medication

Major bleeding at any point until 7 days after the discontinuation of all study medications

Major bleeding, nonmajor clinically relevant bleeding, other bleeding, and adverse events

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EXCLAIM 2010 ADOPT 2011 MAGELLAN 2013 APEX 2016 MARINER 20183. Thrombocytopenia

Definition of major bleeding

Bleeding associated with - Death- Decrease in Hb of ≥30

g/L- A transfusion of ≥2 units

of packed red blood cells or whole blood

- Surgical interventionOr, retroperitoneal, intracranial, or intraocular bleeding

*A threshold decrease of 2 g/dL was used in a post-hoc analysis.

- Fatal or overt bleeding- Bleeding accompanied

by decrease in Hb of ≥2 g/dL over 24-hour period, or transfusion of ≥2 units of packed red blood cells

- Intracranial, intraspinal, intraocular, pericardial, or retroperitoneal bleeding

- Bleeding in an operated joint that required reoperation or intervention

- Intramuscular bleeding with the compartment syndrome

- Bleeding leading to a ≥2 g/dl fall in hemoglobin or a transfusion of ≥2 units of packed red blood cells or whole blood

- Bleeding into a critical site (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome), or

- Bleeding leading to death







Diagnosis of DVT Bilateral compression ultrasonography or venography

Compression ultrasonography

Ultrasonography or other vascular imaging techniques

Ultrasonography or other vascular imaging techniques

Ultrasonography or venography

Diagnosis of PE CT or ventilation–perfusion lung scanning

Spiral CT or ventilation–perfusion lung scanning

Thoracic spiral CT, ventilation–perfusion lung scanning with chest radiography, or pulmonary angiography

CT, ventilation–perfusion lung scanning, pulmonary angiography, or autopsy

CT angiography or spiral CT, pulmonary angiography, or ventilation–perfusion lung scanning, or autopsy

Outcome assessment Blinded central adjudication

Blinded central adjudication



Blinded central adjudication with prespecified criteria

Mandatory bilateral compression USG in asymptomatic subjects (Day after randomization)

Day 28 ±4 Between Day 5 and Day 14

Day 35 ±4 Day 35 to 42 Not required

Patients excluded due to missing outcome data

Intervention group: 16%Control group: 16%




All randomized patients were analyzed

Follow up duration 180 days 90 days 35 days 42 days 45 days

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VTE, venous thromboembolism; NYHA, New York Heart Association; ULN, upper limit of normal; BMI, body mass index, CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; Hb, hemoglobin; LMWH, low molecular weight heparin; HIT, heparin-induced thrombocytopenia; CrCl, creatinine clearance; HIV, human immunodeficiency virus; IVC, inferior vena cava; DVT, deep vein thrombosis; PE, pulmonary embolism; CT, computed tomography.Table S2. Baseline characteristics of patients in included studies

EXCLAIM 2010 ADOPT 2011 MAGELLAN 2013 APEX 2016 MARINER 2018

Enoxaparin Placebo Apixaban Enoxaparin Rivaroxaban Enoxaparin Betrixaban Enoxaparin Rivaroxaban EnoxaparinNumber of participants 2975 2988 3255 3273 4050 4051 3759 3754 6007 6012Mean age (SD), year 67.9 (12.1) 67.5 (12.5) 66.8 (12.0) 66.7 (12.0) Median: 71 Median: 71 76.7 (8.5) 76.2 (8.3) 69.7 69.7Male sex, % 49.3 49.4 50 48.2 55.6 52.7 45.4 45.8 52.1 52.5White race, % 74.8 74.8 76 75.6 68.7 67.7 93.2 93.7 96.3 96.6Mean body mass index, kg/m2

28.7 28.7 NR NR 28.2 28.2 29.2 29.5 29.0 28.8

Median duration of hospitalization, days

NR NR NR(Mean exposure duration of apixaban: 25 ±10 days)

NR(Mean exposure duration of enoxaparin: 7 ±4 days)

11.0 11.0 10 10 Mean: 6.7 Mean: 6.7

Acute medical condition, %Heart failure 18.4 18.9 39.0 38.1 32.3 32.4 44.6 44.5 40.6 39.9Respiratory failure 30.4 30.1 37.1 37.1 27.3 28.7 11.9 12.6 26.2 26.8Infection 32.8 33.6 21.5 22.8 45.8 45.1 29.6 28.2 17.5 17.4Ischemic stroke 6.7 6.4 NR NR 17.3 17.3 10.9 11.5 14.3 14.4Inflammatory or rheumatic disease

2.7 3.1 2.0 1.8 3.8 3.7 2.9 3.1 1.4 1.5

Active cancer 1.7 1.5 3.5 3.0 7.3 7.3 NR NR Excluded ExcludedVTE risk factors, % Age ≥75 year 29.5 30.2 29.6 29.9 38.3 38.6 68.5 67.0 35.9 35.6History of VTE 6.7 6.8 4.3 3.8 5.0 4.4 8.3 7.9 12.7 12.4History of cancer 13.3 14.1 9.6 9.8 17.3 16.7 12.4 11.8 8.1 8.9Hormone therapy 2.3 2.1 1.5 0.8 1.2 1.2 1.1 0.8 NR NRHistory of heart failure(NYHA class III or IV)

25.3 25.8 37.9 38.1 34.8 34.1 22.7 23.0 NR NR

Hereditary or acquired thrombophilia

0.1 0.1 NR NR 0.4 0.2 <0.1 0.1 NR NR

Elevated D-dimer (≥2 NR NR NR NR NR NR 62.3 62.1 70.4 70.5

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Enoxaparin Placebo Apixaban Enoxaparin Rivaroxaban Enoxaparin Betrixaban Enoxaparin Rivaroxaban Enoxaparinx ULN)Obesity (BMI ≥30) 34.2 33.7 44.5 44.3 NR NR NR NR NR NRObesity (BMI ≥35) NR NR NR NR 15.1 15.3 NR NR NR NR

NR, not reported; VTE, venous thromboembolism; NYHA, New York Heart Association; ULN, upper limit of normal; BMI, body mass index.

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Table S3. Quality appraisal

EXCLAIM 2010 ADOPT 2011 MAGELLAN 2013

APEX 2016 MARINER 2018

Domain 1: Risk of bias arising from the randomization process1.1 Was the allocation sequence random?

Yes Yes Yes Yes Yes

1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?

Yes Yes Yes Yes Yes

1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?

No No No No No

Risk-of-bias judgement

Low Low Low Low Low

Domain 2: Risk of bias due to deviations from the intended interventions (effect of assignment to intervention)2.1. Were participants aware of their assigned intervention during the trial?

No No No No No

2.2. Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?

No No No No No

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2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?

- - - - -

2.4. If Y/PY to 2.3: Were these deviations from intended intervention balanced between groups?

- - - - -

2.5 If N/PN/NI to 2.4: Were these deviations likely to have affected the outcome?

- - - - -

2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?

Yes Yes Yes Yes Yes

2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?

- - - - -


Low Low Low Low Low

Domain 3: Missing outcome data

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3.1 Were data for this outcome available for all, or nearly all, participants randomized?

Probably no No No Probably no Yes

3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?

Yes No No Yes -

3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?

- No No - -

3.4 If Y/PY/NI to 3.3: Do the proportions of missing outcome data differ between intervention groups?

- - - - -

3.5 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?

- - - - -


Low Low Low Low Low

Domain 4: Risk of bias in measurement of the outcome -

4.1 Was the method of measuring the outcome inappropriate?

No No No No No

4.2 Could measurement or

No No No No No

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ascertainment of the outcome have differed between intervention groups ?4.3 If N/PN/NI to 4.1 and 4.2: Were outcome assessors aware of the intervention received by study participants ?

- - - - -

4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?

- - - - -

4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?

- - - - -


Low Low Low Low Low

Domain 5: Risk of bias in selection of the reported result

5.1 Was the trial analysed in accordance with a pre-specified plan that was finalized before unblinded outcome data were available for analysis ?

Yes Yes Yes Yes Yes

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Is the numerical result being assessed likely to have been selected, on the basis of the results, from...5.2. ... multiple outcome measurements (e.g. scales, definitions, time points) within the outcome domain?

No No No No No

5.3 ... multiple analyses of the data?

No No No No No


Low Low Low Low Low

Overall risk of biasRisk-of-bias judgement

Low Low Low Low Low

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Table S4. Results from included studies


Efficacy outcomesSymptomatic VTE or VTE-related death

Enoxaparin: 5/2485 (0.2)Placebo: 25/2510 (1.0)

Apixaban: 14/3255 (0.43)Enoxaparin: 27/3273 (0.82)

Rivaroxaban: 42/2967 (1.4)Enoxaparin: 59/3057 (1.9)

Betrixaban: 35/3721 (0.9)Enoxaparin: 54/3720(1.5)RR (95%CI) 0.64 (0.42-0.98)

Rivaroxaban: 50/6007 (0.83)Enoxaparin: 66/6012 (1.10)HR (95%CI) 0.76 (0.52-1.09)

Symptomatic VTE Enoxaparin: 5/2485 (0.2)Placebo: 24/2510 (1.0)ARD (95%CI) -0.75 (-1.19--0.32)



Betrixaban: 23/3112 (0.7)Enoxaparin: 40/3174 (1.2)


VTE-related death Enoxaparin: 0/2485 (0)Placebo: 1/2510 (<0.01)ARD (95%CI) -0.04 (-0.12-0.04)





Symptomatic proximal or distal DVT Enoxaparin: 5/2485 (0.2)Placebo: 20/2510 (0.8)ARD (95%CI) -0.60 (-1.00--0.19)*Distal DVT not reported





Asymptomatic proximal DVT Enoxaparin: 55/2485 (2.2)Placebo: 75/2510 (3.0)ARD (95%CI) -0.77 (-1.69-0.14)




NR

Symptomatic non-fatal PE Enoxaparin: 0/2485 (0)Placebo: 4/2510 (0.2)





Total VTE or VTE-related death Enoxaparin: 61/2485 (2.5)Placebo: 100/2510 (4.0)




NR

All-cause mortality Enoxaparin: 60/2975 (2.1)Placebo: 65/2988 (2.2)HR (95%CI) 0.93 (0.65-1.32)





Safety outcomesAll bleeding Enoxaparin: 186/2975 (6.3)

Placebo: 116/2988 (3.9)ARD (95%CI) 2.37 (1.26-3.48)

Apixaban: 246/3184 (7.73)Enoxaparin: 219/3217 (6.81)RR (95%CI) 1.13 (0.95-1.34)

NR NR NR

Major bleeding Enoxaparin: 25/2975 (0.8)Placebo: 10/2988 (0.3)ARD (95%CI) 0.51 (0.12-0.89)

Apixaban: 15/3184 (0.47)Enoxaparin: 6/3217 (0.19)RR (95%CI) 2.58 (1.02-7.24)

Rivaroxaban: 43/3997 (1.1)Enoxaparin: 15/4001(0.4)RR (95%CI) 2.9 (1.60-5.15)

Betrixaban: 25/3716 (0.7)Enoxaparin: 21/3716 (0.6)RR (95%CI) 1.19 (0.67-2.12)


Clinically-relevant non-major bleeding

NR Apixaban: 70/3184 (2.20)Enoxaparin: 61/3217 (1.90)

Rivaroxaban: 121/3997 (3.0)Enoxaparin: 52/4001(1.3)

Betrixaban: 116/3716 (3.1)Enoxaparin: 59/3716 (1.6)RR (95%CI) 1.97 (1.44-2.68)


Critical-site bleeding Enoxaparin: 5/2975 (0.8)Placebo: 0/2988 (0.3)

Apixaban: 1/3184 (<0.1)Enoxaparin: 2/3217 (<0.1)

Rivaroxaban: 9/3997 (0.2)Enoxaparin: 4/4001(0.1)

Betrixaban: 3/3716 (<0.1)Enoxaparin: 9/3716 (0.2)

Rivaroxaban: 3/5982 (<0.1)Enoxaparin: 2/5980 (<0.1)HR (95%CI) 1.50 (0.25-8.97)

Fatal bleeding Enoxaparin: 1/2975 (<0.1)Placebo: 0/2988 (0)ARD (95%CI) 0.03 (-0.03-0.10)

Apixaban: 0/3184 (0)Enoxaparin: 2/3217 (0.06)

Rivaroxaban: 7/3997 (0.2)Enoxaparin: 1/4001(<0.1)

Betrixaban: 1/3716 (<0.1)Enoxaparin: 1/3716 (<0.1)

Rivaroxaban: 2/5982 (<0.1)Enoxaparin: 0/5980 (0)

Minor bleeding Enoxaparin: 164/2975 (5.5)Placebo: 106/2988 (3.5)ARD (95%CI) 1.97 (0.91-3.02)

NR NR NR NR

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NR, not reported. VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; ARD, absolute risk difference; RR, relative risk; HR, hazard ratio.

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Outcome Pooled

RR

95% CI I2

(%)

ARR/ ARI

(%)

NNT/

NNH

Symptomatic VTE or VTE-related

death

0.62 0.46-0.83 45 0.4 250

Symptomatic VTE 0.52 0.36-0.76 38 0.4 268

Symptomatic DVT 0.47 0.29-0.78 38 0.2 405

Non-fatal PE 0.59 0.38-0.91 0 0.1 703

VTE-related death 0.80 0.70-1.09 0 0.1 942

Total VTE or VTE-related death 0.75 0.66-0.85 0 1.3 78

Major bleeding 2.04 1.42-2.91 23 0.3 333

Fall in hemoglobin of ≥2 g/dL 2.52 1.72-3.70 0 0.29 342

Transfusion of ≥2 units of

blood

2.70 1.62-4.48 0 0.21 468

Fatal bleeding 2.24 0.64-7.83 4 0.04 2832

Critical site bleeding 1.20 0.41-3.51 48 0.02 4913

All-cause mortality 0.97 0.87-1.08 0 0.1 935

Composite of non-fatal PE or VTE-

related death

0.73 0.57-0.93 0 0.25 403

Composite of fatal or critical-site

bleeding

1.42 0.41-4.91 67 0.06 1785

Table S5. Efficacy and safety outcomes of extended versus standard-duration thromboprophylaxis.

RR, risk ratio; CI, confidence interval; ARR, absolute risk reduction; ARI, absolute risk increase; NNT, number needed to treat; NNH, number needed to harm; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism.

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Figure S1. PRISMA flow diagram

Figure S2. Forest plot for efficacy outcomes

Studies included in quantitative synthesis

(n = 5)

Studies included in qualitative synthesis

(n = 5)

Full-text articles excluded, with reasons(n = 77)

Duplicates of the same study = 7 Not an RCT = 41 Is a study protocol = 3 Is a substudy = 23 Did not directly compare standard-duration

with extended-duration prophylaxis = 2 Study in secondary prophylaxis = 1

Full-text articles assessed for eligibility

(n = 82)

Records excluded(n = 495)

Records screened(n = 577)

Records after duplicates removed(n = 577)

Additional records identified through other sources

(Cliniicaltrials.gov n = 4)

Identification

Eligibility

Included

Screening

Records identified through database searching(n = 701)

(PubMed =296, EMBASE = 347, Cochrane = 58)

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Figure S3. Forest plot for each types of major bleeding

22

Figure S4. Funnel plots of risk ratio versus standard error of included studies.

screening · web viewmajor bleeding, clinically relevant nonmajor bleeding, and all bleeding...

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