CHEST 203 MMCjournal.chestnet.org/cms/attachment/2088316623/2074923855/mmc1.pdf · e-Table 2: Structured Clinical Questions ... oral rivaroxaban 15 mg twice daily for the first 3

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© 2016 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without writtenpermission from the American College of Chest Physicians. See online for more details. DOI: 10.1016/j.chest.2015.11.026

Antithrombotic Therapy for VTE Disease

CHEST Guideline and Expert Panel Report

Clive Kearon, MD, PhD; Elie A. Akl, MD, MPH, PhD; Joseph Ornelas, PhD; Allen Blaivas, DO, FCCP; David Jimenez, MD, PhD, FCCP; Henri Bounameaux, MD; Menno Huisman, MD, PhD; Christopher S. King, MD, FCCP; Timothy A. Morris, MD, FCCP; Namita Sood, MD, FCCP; Scott M. Stevens, MD; Janine R. E. Vintch, MD, FCCP; Philip Wells, MD; Scott C. Woller, MD; and COL Lisa Moores, MD, FCCP

CHEST 2016; 149(2):315-352


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Online Supplemente-Table 2: Structured Clinical Questions

Topic Population Intervention(s) Comparator(s) Outcome(s) Methodology

Choice of Long-Term (First 3 Months) and Extended (No Scheduled Stop Date) Anticoagulant

Patients with acute DVT of the leg or PE.

LMWH, dabigatran, rivaroxaban, apixaban, edoxaban

VKA Recurrent VTE, major bleeding, mortality, QOL and PTS RCTs

Duration of Anticoagulant Therapy Patients with an acute DVT of the leg or PE Longer duration Shorter duration Recurrent VTE, major bleeding,

mortality, QOL and PTS RCTs

Aspirin for Extended Treatment of Venous Thromboembolism

Patients with DVT of the leg or PE who have completed at last 3 month of initial anticoagulation.

Aspirin No antithrombotic, an anticoagulant

Recurrent VTE, major bleeding, mortality, QOL and PTS RCTs

Whether and How to Prescribe Anticoagulants to Patients with Isolated Distal Deep Vein Thrombosis

Patient with acute isolated distal DVT of the leg Anticoagulation No anticoagulation

DVT extension, PE, major bleeding, mortality, QOL and PTS

RCTs

Catheter-Directed Thrombolysis for Acute Deep Vein Thrombosis of the Leg

Patients with acute proximal DVT of the leg Catheter directed thrombolysis

No active thrombus removal or another method of thrombus removal

Recurrent VTE, major bleeding, mortality, QOL and PTS , shorter ICU and hospital stays, and acute complications

RCTs

Role of Inferior Vena Caval Filter in Addition to Anticoagulation in Patients with Acute Deep Vein Thrombosis or Pulmonary Embolism

Patients with acute DVT of the leg or PE started on anticoagulation

IVC filter No IVC filter Recurrent DVT and PE, major bleeding, mortality, QOL, PTS, and acute complications

RCTs and Cohort Studies

Compression Stocking to Prevent Post-Thrombotic Syndrome

Patients with acute DVT of the leg started on anticoagulant treatment

Compression stocking No compression stocking QOL, PTS and recurrent VTE RCTs

Whether to Treat Subsegmental Pulmonary Embolism

Patient with acute isolated subsegmental PE Anticoagulation No anticoagulation Recurrent VTE, major bleeding,

mortality, QOL and PTS RCTs and Cohort Studies

Treatment of Acute Pulmonary Embolism Out of Hospital Patients with acute PE In hospital treatment At home treatment

Recurrent DVT and PE, major bleeding, mortality, QOL and PTS

RCTs

Systemic Thrombolytic Therapy for Pulmonary Embolism Patients with acute PE Thrombolytic therapy No thrombolytic therapy

Recurrent DVT and PE, major bleeding, mortality, QOL and PTS

RCTs

Catheter-Based Thrombus Removal for the Initial Treatment of Pulmonary Embolism Patients with acute PE Use of catheter-assisted

thrombus removal No use of catheter-assisted thrombus removal

Recurrent DVT and PE, major bleeding, mortality, QOL, and acute complications


Pulmonary Thromboendarterectomy in for the Treatment of Chronic Thromboembolic Pulmonary Hypertension

Patients with chronic thromboembolic pulmonary hypertension

Pulmonary thromboendarterectomy

No pulmonary thromboendarterectomy

Recurrent VTE, major bleeding, mortality, QOL and PTS


Thrombolytic Therapy in Patients with Upper Extremity Deep Vein Thrombosis

Patients with upper extremity DVT Systemic thrombolytic therapy No systemic thrombolytic

therapy

Recurrent VTE, major bleeding, mortality, QOL and PTS , shorter ICU and hospital stays, and acute complications


Management of Recurrent Venous Thromboembolism on Anticoagulant Therapy

Patients with recurrent VTE while on anticoagulant therapy

Higher intensity therapy, alternative anticoagulant, use of IVC filter

No change in anticoagulant therapy

Recurrent VTE, major bleeding, mortality, QOL and PTS



Online Supplemente-Table 3: Evidence Table of Individual Studies and Meta-Analyses Used for Estimates

Study Name Study Design Participants Description Intervention Description Control Description

Outcomes Assessed

Funding and Conflicts of Interest

Risk of Bias Assessment

Agnelli 2001 (WODIT-DVT)1

RCT first episode of symptomatic idiopathic proximal DVT, completed three uninterrupted months of oral anticoagulant therapy without having a recurrence of thromboembolism or bleeding

continuation of oral anticoagulant therapy for nine additional months, dose of warfarin or other oral anticoagulant was adjusted to achieve a target international normalized ratio (INR) between 2.0 and 3.0.

baseline was three months of therapy with warfarin (in 97 percent of the cases) or acenocoumarol; discontinuation of oral anticoagulant therapy was the control

recurrent VTE, major bleeding and death at two years

None Disclosed Low

Agnelli 2003 (WODIT-PE)2

RCT first episode of symptomatic idiopathic proximal DVT, completed three uninterrupted months of oral anticoagulant therapy without having a recurrence of thromboembolism or bleeding

continuation for 3 additional months (PE associated with transient risk factors) or 9 additional months (idiopathic PE), INR between 2.0 and 3.0

baseline was three months of warfarin or acenocoumarol therapy, then discontinuation

recurrent VTE, major bleeding at three months

None Disclosed Low

Agnelli 2013 (AMPLIFY)3 RCT objectively confirmed, symptomatic proximal DVT or PE (with or without DVT)

apixaban 10 mg BID x7 d then 5 mg BID x 6 mo

conventional enoxaparin, followed by warfarin

recurrent VTE, major bleeding and death

Pfizer and Bristol-Myers Squibb

Low

Agnelli 2013 (AMPLIFY-EXT)4

RCT objectively confirmed, symptomatic proximal DVT or PE (with or without DVT)

2.5 mg of apixaban, 5 mg of apixaban, twice daily for was 12 months.

placebo twice daily for 12 months.

recurrent VTE, major bleeding and death

Pfizer and Bristol-Myers Squibb

High

Bauersachs 2010 (EINSTEIN) 5

RCT acute, symptomatic, objectively confirmed proximal DVT, without symptomatic PE

oral rivaroxaban 15 mg twice daily for the first 3 weeks, followed by 20 mg once daily for the intended 3, 6, or 12 months of treatment

subcutaneous enoxaparin, 1.0 mg/kg twice daily, and either warfarin or acenocoumarol

recurrent VTE, major bleeding

Bayer Schering Pharma and Ortho-McNeil

High

Buller 2012 (EINSTEIN–PE) 6

RCT acute, symptomatic pulmonary embolism with objective confirmation, with or without symptomatic DVT

rivaroxaban 15 mg twice daily for the first 3 weeks, followed by 20 mg once daily

enoxaparin 1.0 mg/kg of body weight twice daily and either warfarin or acenocoumarol


Bayer Health- Care and Janssen Pharmaceuticals

Low

Buller 2013 (Hokusai) 7 RCT objectively diagnosed, acute, symptomatic deep-vein thrombosis involving the popliteal, femoral, or iliac veins or acute, symptomatic pulmonary embolism (with or without DVT)

heparin or LMWH followed by edoxaban 60 mg orally once daily, (30 mg once daily in patients with a CC 30-50 ml/min or <=60 kg or potent P-glycoprotein inhibitors)

heparin or LMWH followed by warfarin


Daiichi-Sankyo Low

Campbell 20078 RCT DVT and/or PE six months of anticoagulation with heparin for five days accompanied and followed by warfarin, with a target international normalised ratio of 2.0-3.5.

three months of anticoagulation with heparin for five days accompanied and followed by warfarin, with a target international normalised ratio of 2.0-3.5.

Recurrent VTE, major bleeding and death

Pfizer

Low


Online SupplementChatterjee 20149 SR / MA Diagnosed with PE thrombolytic therapy anticoagulant therapy all-cause mortality

and major bleeding, risk of recurrent embolism and intracranial hemorrhage

AstraZeneca, EKOS Corporation, Embolitech, Boston Scientific, and Cordis Corporation

Low

Couturaud 2015 (PADIS-PE)10

RCT first episode of symptomatic unprovoked PE and having been treated initially for six uninterrupted months with VKA

warfarin for 18 months placebo for 18 months recurrent VTE or major bleeding

French Department of Health, University Hospital of Brest.

Low

Deitcher 2006 (ONCENOX) 11

RCT objective symptomatic VTE, weight less than 120 kg, functional capacity enrolled or randomized within 72 hours of VTE diagnosis, LMWH or UFH had begun

enoxaparin 1.0 mg/kg BID x 5d then enoxaparin 1.0 mg/kg daily x 175d; group, enoxaparin (1.0 mg/kg BID x5d then enoxaparin 1.5 mg/kg daily x175d

enoxaparin 1.0 mg/kg BID x5d with warfarin overlap to a stable INR (2-3) begun day 2 of enoxaparin and continued for a total of 180 days of anticoagulation

recurrent symptomatic VTE

Aventis Pharmaceuticals

High

Eischer 2009 (AUREC-FVIII)12

RCT first DVT and / or PE, VTE objectified by venography or color-coded duplex ultrasound (DVT), perfusion/ventilation lung scan or spiral CT in case of PE

Discontinuation of VKA Continuation of VKA for 2 years

Recurrent VTE, major bleeding, mortality

Kamillo-Eisner-Stiftung Low

Elsharawy 200213 RCT DVT less than 10 days duration

1 million U SK pulse-spray for 1 hour, followed by 100,000 U/hr SK infusion until complete lysis, no change in 12 hrs, or complication, adjunctive therapy of angio/stent

5000 U heparin bolus, followed by heparin adjusted to APTT

Clot lysis, PE, bleeding

Not Reported Low

Enden 2012 (CAVENT)14 RCT iliofemoral DVT less than 21 days duration

tPA 0.01 mg/kg/hr, maximum of 20 mg/24 hour for 4 days

Anticoagulation alone, usual practice, administered locally

post thrombotic syndrome, clot lysis, PE, bleeding

South-Eastern Norway Regional Health Authority; Research Council of Norway; University of Oslo

Low

Hull 2007 (LITE) 15 RCT first or recurrent acute proximal DVT (popliteal, femoral, or iliac v.)

tinzaparin (Innohep) 175 IU/Kg SQ QD

UFH bolus then overlapped with and followed by warfarin (“usual care”-INR range 2-3)

recurrent VTE or death at three months

Canadian Institutes for Health Research, Leo Pharmaceuticals, Pharmion and Dupont Pharmaceuticals

High

Hull 2009 (Home-LITE) 16

RCT first or recurrent acute proximal DVT (popliteal, femoral, iliac v.), objectively documented without condition precluding out-of-hospital treatment

fixed dose of 175 IU/kg SQ QD x 12 weeks

tinzaparin for 5 or more days, overlapped with and followed by warfarin (“usual care”-INR range 2-3)

symptomatic recurrent VTE and death at 12 weeks and 1 year; PTS symptoms; incidence of venous leg ulcers as reported by patients; bleeding at 12 weeks

LEO Pharmacuticals, Watermeadow Medical

High


Online SupplementKahn 2014 (SOX) 17 RCT first symptomatic proximal

DVT compression stockings: below knee 30-40 mm Hg

placebo stockings PTS at 6 -24 months (Ginsberg's criteria); PTS score (Villalta)

Canadian Institutes of Health Research, Sigvaris.

Low

Kahn 2014 (SOX 2) 18 RCT first symptomatic proximal DVT

compression stockings: below knee 30-40 mm Hg

placebo stockings acute leg pain Canadian Institutes of Health Research, Sigvaris.

Low

Lee 2003 (CLOT) 19 RCT active cancer and newly diagnosed, symptomatic proximal DVT and/or PE

200 IU of dalteparin per kilogram (max daily dose, 18,000 IU) daily for the first month. Then 75-83% of the full dose (~150 IU/kg) x 5mo.

dalteparin initially for 5-7d and a VKA for 6 mo. dose adjusted to target IN 2.5 (range 2-3), dalteparin was d/ced after a >/= 5d and once the INR had remained above 2.0 for two consecutive days

objective symptomatic recurrent VTE, major bleeding and death at six months

Pharmacia High

Lee 2015 (CATCH)20

RCT active cancer and newly diagnosed, symptomatic proximal DVT and/or PE

tinzaparin 175 IU/kg once daily for 6 months

initial tinzaparin 175 IU/kg once daily for 5-10 days overlapped and followed by dose-adjusted warfarin (target INR 2.0-3.0) for 6 months

recurrent VTE and major bleeding

Bayer, Bristol-Myers Low

Lopaciuk 199921 RCT phlebographically proven acute proximal DVT

nadroparin fixed dose 85 anti-Xa IU/kg s.c. BID x 10d then 85 anti-Xa IU/kg sq daily

initial nadroparin fixed dose 85 anti-Xa IU/kg BIX x 10 d then w/ acenocoumarol adjusted to INR 2-3

clinical overt radiographically confirmed DVT

Not Reported High

Lopez-Beret 200122 RCT consecutive symptomatic DVT referred to the vascular laboratory in one hospital in whom lower limb DVT was objectively documented with duplex scan examination

nadroparin adjusted to body weight (0.1 mL/10kg)

acenocoumarol administered daily starting on the 3rd day with an initial dose of 4 mg then adjusted to INR 2-3

recurrent VTE and major bleeding

Not Reported High

Meyer 200223 RCT cancer of any type and PE and/or DVT

enoxaparin 1.5mg/kg SQ daily x 3 mo. w/out dose adjustment

enoxaparin 1.5mg/kg SQ daily + warfarin until INR >2 on 2 consecutive days after at least 4 injections. Target INR 2-3

recurrent VTE, major hemorrhage and death at three months

Aventis Pharmaceuticals

High

Mismetti 2015 (PREPIC 2)24

RCT hospitalized with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least one criterion for severity, scheduled to receive anticoagulant therapy for at least six months

insertion and later withdrawal of a retrievable inferior vena cava filter

no filter symptomatic recurrent PE at three months, recurrent PE at six months, symptomatic DVTs, major bleeding and death at three and six months, and filter complications

University Hospital of Saint-Etienne

Low


Online SupplementPinede 2001 (DOTAVK)25

RCT written informed consent, and symptomatic C-DVT, P-DVT, or PE that was confirmed by positive Doppler ultrasonography or venography

6 weeks for isolated C-DVT with a long course of therapy, 6 months for P-DVT/PE; 12 weeks for C-DVT

short oral anticoagulant course (3 months for proximal DVT and/or PE

recurrences and major, minor, or fatal bleeding complications

French Ministry of Health, Hospices Civils de Lyon, Conseil Régional Rhône-Alpes, and the Association pour la recherche et l’évaluation thérapeutique (APRET)

Low

Piran 201326 SR / MA diagnosed with a PE outpatient antithrombotic treatment

inpatient recurrent VTE, rate of recurrent VTE, major bleeding

American Society of Hematology, Heart and Stroke Foundation of Canada, Heart and Stroke Foundation of Ontario

High

Prins 201327 SR / MA symptomatic DVT and/or PE rivaroxaban 15mg BID x 21d then 20mg daily

enoxaparin plus VKA (INR 2-3)

symptomatic recurrent VTE (composite of fatal or nonfatal PE or DVT), clinically relevant bleeding ( composite of major and non-major clinically relevant bleeding)

Bayer HealthCare and Janssen Pharmaceuticals

Low

Romera 200928 RCT referred to the vascular surgery department with first episode acute proximal leg DVT

tinzaparin SQ in a fixed dose of 175 IU anti-Xa per kg of body weight once daily x 6 mo.

3 mg of acenocoumarol adjusted to (INR 2-3) x 6 mo

first symptomatic DVT or PE at six months and one year, major bleeding at 6-mo

Leo Pharmaceutical Products

High

Schulman 2013 (REMEDY and RESONATE) 29

RCT objectively confirmed, symptomatic, proximal DVT or PE that had already been treated with an approved anticoagulant or if they had received dabigatran in the RE-COVER or RE-COVER II studies

dabigatran at a fixed dose of 150 mg twice daily and warfarin-like placebo

active warfarin titrated to INR 2-3 with a POC device that that provided an encrypted. INR and a dabigatran-like placebo

recurrent symptomatic and objective VTE or death associated with VTE

Boehringer-Ingelheim Low

Schulman 2009 (RECOVER 1)30

RCT acute VTE treated with LMWH or UFH for median of 9 days, objectively diagnosed proximal DVT or PE

dabigatran 150 mg twice daily

warfarin. recurrent symptomatic, objectively confirmed VTE and related deaths at 6 months


Schulman 2014 (RECOVER 2) (Joint Analysis with RECOVER 1) 31

RCT acute VTE treated with LMWH or UFH for 5 to 11 days, objectively diagnosed proximal DVT or PE

dabigatran 150 mg twice daily

warfarin. recurrent symptomatic, objectively confirmed VTE and related deaths at 6 months



Online SupplementSimes 201432 SR / MA first unprovoked VTE aspirin placebo recurrent VTE,

major vascular events (recurrent VTE, MI, stroke and CVD death) and bleeding

National Health and Medical Research Council, New Zealand Health Research Council, New South Wales Health, and Australian Society of Thrombosis and Haemostasis. University of Perugia, Bayer HealthCare

Low

Siragusa 2008 (DACUS)33

RCT With residual vein thrombosis and documented idiopathic and provoked proximal DVT

Oral anticoagulant treatment for 12 months

Oral anticoagulant treatment for 3 months

Recurrence and major bleeding

None Low

Watson 201434 SR / MA acute DVT of lower limb thrombolytic therapy and anticoagulation

anticoagulation alone PE recurrent VTE, major bleeding, post-thrombotic complications, venous patency and venous function

None Low


Online Supplemente-Table 4: Evidence Profile - LMWH vs VKA for long term treatment of VTE 1

Bibliography: Deitcher et al. (ONCENOX)11, Hull et al. (LITE)15, Hull et al. (LITE Home)16, Lee et al. (CLOT)19, Lopaciuk et al.21, Lopez-Beret et al.22, Meyer et al.23, Romera et al.28, Lee et al. (CATCH)20 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias

Inconsistency Indirectness Imprecision Publication bias

Overall quality of evidence

Study event rates (%)

Relative effect (95% CI)2

Anticipated absolute effects

With VKA

With LMWH

Risk with VKA

Risk difference with LMWH (95% CI)

All Cause Mortality (IMPORTANT OUTCOME) 3396 (9 studies) 6 months

Serious3 no serious inconsistency

no serious indirectness

no serious imprecision

undetected ⊕⊕⊕⊝ MODERATE3 due to risk of bias

340/1682 (20.2%)

354/1714 (20.7%)

RR 1.01 (0.89 to 1.14)

Non-Cancer4 17 per 1000

0 more per 1000 (from 2 fewer to 2 more)

Non-Metastatic Cancer4 42 per 1000


Metastatic Cancer4 253 per 1000


Recurrent VTE (CRITICAL OUTCOME) 3627 (9 studies) 6 months

Serious5 no serious inconsistency




150/1800 (8.3%)

98/1827 (5.4%)

RR 0.65 (0.51 to 0.83)

Low6 30 per 1000

11 fewer per 1000 (from 5 fewer to 15 fewer)

Moderate6 80 per 1000


High6 200 per 1000


Major bleeding (CRITICAL OUTCOME) 3637 (9 studies) 6 months

no serious risk of bias

no serious inconsistency


Serious7,8 undetected ⊕⊕⊕⊝ MODERATE7,8 due to imprecision

63/1802 (3.5%)

57/1835 (3.1%)

RR 0.86 (0.56 to 1.32)

Low9 20 per 1000

3 fewer per 1000 (from 9 fewer to 6 more)

High9 80 per 1000


1 The initial parenteral anticoagulation was similar in both arms for all except one study (Hull et al.15) in which patients randomized to LMWH received initially the same LWMH whereas patients randomized to VKA received initially UFH 2 The relative effect (RR; 95% CI) of LMWH versus VKA was assessed, and compared, in the subgroup of trials that enrolled patients without (Hull et al. (LITE)15, Lopez-Beret et al..22) and with (Deitcher et al. (ONCENOX)11, Hull et al. (LITE)15, Lee et al. (CLOT)19, Lee et al. (CATCH)20, Lopez-Beret et al.22, Meyer et al.23) cancer: Recurrent VTE: cancer RR 0.59 (0.44 to 0.78) vs. no cancer RR 0.99 (0.46 to 2.13); P=0.21 for subgroup difference. Major Bleeding: cancer RR 0.96 (0.65 to 1.42) vs. no cancer RR 0.43 (0.17 to 1.17); P=0.14 for subgroup difference. All Cause Mortality: cancer RR 1.00 (0.88 to 1.33) vs. no cancer RR 1.85 (0.59 to 5.77); P=0.29 for subgroup difference. 3 One study did not report deaths, which is unusual and could reflect selective reporting of outcomes.


Online Supplement4 Low corresponds to patients without cancer and patients with non-metastatic cancer. High corresponds to patients with metastatic cancer. These control event rates were derived from the RIETE registry (an ongoing prospective registry of consecutive patients with acute VTE) (Prandoni et al.35) 5 None of the studies was blinded while the diagnosis of recurrent VTE has a subjective component and there could be a lower threshold for diagnosis of recurrent VTE in VKA-treated patients as switching the treatment of such patients to LMWH is widely practiced. At the same time, there is reluctance to diagnose recurrent VTE in patients who are already on LMWH as there is no attractive alternative treatment option. 6 Risk of recurrent VTE: Low corresponds to patients without cancer (3% estimate taken from recent large RCTs of acute treatment), intermediate to patients with local or recently resected cancer (appears to be consistent with Prandoni [particularly if low risk is increased to 4%]), and high to patients with locally advanced or distant metastatic cancer. (Prandoni et al.36) 7 Confidence interval includes both no effect and harm with LMWH

8 95% confidence intervals for the risk ratio for major bleeding includes a potentially clinically important increase or decrease with LMWH, and may also vary with the dose of LMWH used during the extended phase of therapy 9 Risk of bleeding: Low corresponds to patients without risk factor for bleeding (i.e., > 75 years, cancer, metastatic disease; chronic renal or hepatic failure; platelet count <80,0000; requires antiplatelet therapy; history of bleeding without a reversible cause). (Prandoni et al.35, Byeth et al.37)


Online Supplemente-Table 5: Evidence Profile - Dabigatran vs VKA for long-term treatment of VTE 1,2

Bibliography: Schulman et al. (RE-COVER I & II)31 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias



Study event rates (%) Relative effect (95% CI)

Anticipated absolute effects With VKA

With Dabigatran

Risk with VKA

Risk difference with Dabigatran (95% CI)

All Cause Mortality (CRITICAL OUTCOME) 5107 (2 studies)




serious3 undetected ⊕⊕⊕⊝ MODERATE3 due to imprecision

46/2554 (1.8%)4

46/2553 (1.8%)

RR 1.0 (0.67 to 1.5)4

18 per 10004


Recurrent VTE (CRITICAL OUTCOME) 5107 (2 studies)





55/2554 (2.2%)4

60/2553 (2.4%)

RR 1.12 (0.77 to 1.62)4

22 per 10004


Major Bleeding (CRITICAL OUTCOME) 5107 (2 studies)





51/2554 (2%)4

37/2553 (1.4%)

RR 0.73 (0.48 to 1.1)4

20 per 10004


1 Dabigatran 150 mg twice daily vs. warfarin 2 Patients with acute VTE treated initially with low-molecular-weight or unfractionated heparin 3 CI includes values suggesting no effect and values suggesting either benefit or harm

4 Pooled analysis of Schulman et al. (Re-Cover I)30 and Schulman et al. (Re-Cover II)31 performed by Schulman et al.31


Online Supplemente-Table 6: Evidence Profile - Rivaroxaban vs LMWH and VKA for acute and long-term treatment of VTE1,2

Bibliography: Prins et al.27 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias




Anticipated absolute effects With LMWH and VKA

With Rivaroxaban

Risk with LMWH and VKA

Risk difference with Rivaroxaban (95% CI)

All Cause Mortality (CRITICAL OUTCOME) 8281 (2 studies) 3 months





99/4131 (2.4%)4

96/4150 (2.3%)

RR 0.97 (0.73 to 1.27)

24 per 10004


Recurrent VTE (CRITICAL OUTCOME) 8281 (2 studies) 3 months





95/4131 (2.3%)4

86/4150 (2.1%)

RR 0.90 (0.68 to 1.2)

23 per 10004


Major Bleeding (CRITICAL OUTCOME) 8246 (2 studies) 3 months





undetected ⊕⊕⊕⊕ HIGH

72/4116 (1.7%)4

40/4130 (0.97%)

RR 0.55 (0.38 to 0.81)

17 per 10004


1 Rivaroxaban 20 mg daily for 6 or 12 month after initial long-term therapy 2 Included patients had acute, symptomatic, objectively verified proximal deep-vein thrombosis of the legs or PE (unprovoked 73%; cancer 5%; previous VTE 19%) 3 CI includes values suggesting no effect and values suggesting either benefit or harm 4 Pooled analysis of Bauersachs et al. (EINSTEIN-DVT)5 and Buller et al. (EINSTEIN-PE)6 performed by Prins et al.27


Online Supplemente-Table 7: Evidence Profile - Apixaban vs LMWH and VKA for acute and long-term treatment of VTE 1,2

Bibliography: Agnelli et al. (AMPLIFY)3 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias




Anticipated absolute effects With LMWH and VKA

With Apixaban

Risk with LMWH and VKA

Risk difference with Apixaban (95% CI)

All Cause Mortality (CRITICAL OUTCOME) 5365 (1 study)





52/2689 (1.9%)

41/2676 (1.5%)

RR 0.79 (0.53 to 1.19)

19 per 1000


Recurrent VTE (CRITICAL OUTCOME) 5244 (1 study)





71/2635 (2.7%)

59/2609 (2.3%)

RR 0.84 (0.6 to 1.18)

27 per 1000


Major Bleeding (CRITICAL OUTCOME) 5365 (1 study)






49/2689 (1.8%)

15/2676 (0.56%)

RR 0.31 (0.17 to 0.55)

18 per 1000


1 Apixaban 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months 2 Subcutaneous enoxaparin, followed by warfarin 3 CI includes values suggesting no effect and values suggesting either benefit or harm


Online Supplemente-Table 8: Evidence Profile - Edoxaban vs VKA for acute and long-term treatment of VTE 1,2

Bibliography: Buller et al. (Hokusai)7 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias





With Edoxaban

Risk with VKA

Risk difference with Edoxaban (95% CI)






126/4122 (3.1%)4

132/4118 (3.2%)

RR 1.05 (0.82 to 1.33)

31 per 10004





no serious indirectness4

serious3 undetected ⊕⊕⊕⊝ MODERATE3,4 due to imprecision

146/4122 (3.5%)

130/4118 (3.2%)

RR 0.83 (0.57 to 1.21)

35 per 1000







66/4122 (1.6%)

56/4118 (1.4%)

RR 0.85 (0.6 to 1.21)

16 per 1000


1 Edoxaban 60 mg once daily, or 30 mg once daily if patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg

2 Patients with acute VTE who had initially received heparin 3 CI includes values suggesting no effect and values suggesting either benefit or harm 4 Death, with PE not ruled out


Online Supplemente-Table 9: Evidence Profile - Dabigatran vs VKA for extended treatment of VTE 1,2,3,4

Bibliography: Schulman et al. (REMEDY)29 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias





With Dabigatran

Risk with VKA



no serious risk of bias5



serious6 undetected ⊕⊕⊕⊝ MODERATE 5,6 due to imprecision

19/1426 (1.3%)

17/1430 (1.2%)

RR 0.89 (0.47 to 1.71)

13 per 1000






serious6 undetected ⊕⊕⊕⊝ MODERATE5,6,7 due to imprecision

18/1426 (1.3%)

26/1430 (1.8%)

RR 1.44 (0.79 to 2.62)

13 per 1000







25/1426 (1.8%)

13/1430 (0.91%)

RR 0.52 (0.27 to 1.01)

18 per 1000


1 Included patients had acute, symptomatic, objectively verified proximal DVT of the legs or PE 2 Dabigatran 150 mg twice daily taken orally for 6 months after an initial treatment with LMWH or IV UFH 3 Warfarin adjusted to achieve an INR of 2.0 to 3.0 for 6 months after an initial treatment with LMWH or IV UFH 4 Active-Control study outcomes used from Schulman et al. (REMEDY)29 5 Allocation was concealed. Patients, providers, data collectors and outcome adjudicators were blinded. Modified ITT analysis. 1.1% loss to follow-up. Not stopped early for benefit. 6 CI includes values suggesting no effect and values suggesting either benefit or harm 7 Primary end point was composite of recurrent or fatal VTE or unexplained death


Online Supplement e-Table 10: Evidence Profile - Dabigatran vs Placebo for extended treatment of VTE 1,2,3

Bibliography: Schulman et al. (RESONATE)29 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias




Anticipated absolute effects With Placebo

With Dabigatran

Risk with Placebo







2/662 (0.3%)

0/681 (0%)

- - 3 fewer per 1000 (from 11 fewer to 3 more)







37/662 (5.6%)

3/681 (0.44%)

RR 0.08 (0.02 to 0.25)

56 per 1000







0/662 (0%)

2/681 (0.29%)

- - 3 more per 1000 (from 3 fewer to 11 more)

1 Dabigatran 150 mg twice daily 2 Placebo-Control study outcomes used from Schulman et al. (RESONATE)29 3 Patients with VTE who had completed at least 3 initial months of therapy

4 Event rate low in a large sample size.


Online Supplemente-Table 11: Evidence Profile - Rivaroxaban vs Placebo for extended treatment of VTE 1, 2

Bibliography: Bauersachs et al. (EINSTEIN-Extension)5 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias





With Rivaroxaban

Risk with Placebo

Risk difference with Rivaroxaban (95% CI)






2/594 (0.34%)

1/602 (0.17%)

RR 0.49 (0.04 to 5.43)

3 per 1000








42/594 (7.1%)

8/602 (1.3%)

RR 0.19 (0.09 to 0.4)

71 per 1000



serious no serious inconsistency



undetected ⊕⊕⊕⊝ MODERATE due to risk of bias

0/590 (0%)

4/598 (0.67%)

- - 4 more per 1000 (from 1 less to 17 more)

1 Rivaroxaban 20mg daily or placebo, specific to the continued treatment study 2 Patients who had completed 6 to 12 months of treatment for VTE 3 CI includes values suggesting no effect and values suggesting either benefit or harm


Online Supplemente-Table 12: Evidence Profile - Apixaban vs Placebo for extended treatment of VTE 1,2

Bibliography: Agnelli et al. (AMPLIFY-EXT)4 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias





With Apixaban

Risk with Placebo

Risk difference with Apixaban (95% CI)

All Cause Mortality (CRITICAL OUTCOME) 1669 (1 study) 12 months




serious3,4 undetected ⊕⊕⊕⊝ MODERATE3,4 due to imprecision

14/829 (1.7%)

7/840 (0.83%)

RR 0.49 (0.2 to 1.22)

17 per 1000


Recurrent VTE (CRITICAL OUTCOME) 1669 (1 study) 12 months






73/829 (8.8%)

14/840 (1.7%)

RR 0.19 (0.11 to 0.33)

88 per 1000


Major Bleeding (CRITICAL OUTCOME) 1669 (1 study) 12 months





4/829 (0.48%)

2/840 (0.24%)

RR 0.49 (0.09 to 2.64)

5 per 1000


1 Apixaban 2.5 mg twice-daily dose vs. placebo 2 Patients with VTE who had completed 6 to 12 months of anticoagulation therapy 3 Significantly wide CIs, including appreciable benefit / harm and no effect line 4 Low number of events


Online Supplemente-Table 13: Evidence Profile - Six, Twelve or Twenty-four Months vs Three or Six Months as minimum duration of anticoagulation for VTE 1,2 Bibliography: Campbell et al.8, Pinede et al. (DOTAVK)25, Agnelli et al. (WODIT-PE Provoked and Unprovoked)2, Agnelli et al. (WODIT-DVT)1, Couturand et al. (PADIS-PE)10, Siragusa et al. (DACUS)33, Eischer et al.(AUREC-FVIII)12 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias




Anticipated absolute effects With No extended

With Extended

Risk with No extended

Risk difference with Extended (95% CI)

Mortality (IMPORTANT OUTCOME) 1736 (7 studies) 1-3 years





51/869 (5.8%)

35/867 (4.0%)

RR 1.39 (0.91 to 2.12)

41 per 1000 16 more per 1000 (from 4 fewer to 46 more)

Recurrent VTE (CRITICAL OUTCOME) 2466 (8 studies) 1-3 years





140/1237 (11.3%)

157/1229 (12.7%)

RR 0.88 (0.71 to 1.09)

128 per 1000


Major Bleeding (CRITICAL OUTCOME) 2466 (8 studies) 1-3 years





31/1237 (2.5%)

14/1229 (1.4%)6

RR 1.78 (0.95 to 3.34)


1 Studies vary in follow-up duration (10 months to 3 years) and in duration of time-limited VKA (3 to 6 months). 2 VKA as NOACs are not included 3 Timing of randomization relative to the start of treatment and length of treatment varied across studies: Pinede et al.25 and Campbell et al.8 randomized at diagnosis; and Agnelli et al.2, Eischer et al.12 and Couturaud et al.10 randomized after the initial 3 mo (Agnelli et al.2) or 6 mo (Eischer et al.12 Couturaud et al.10) of treatment to stop or continued treatment. The longer duration of treatment was 6 mo in Agnelli et al. (provoked PE)2 and Pinede et al.25, 12 months in Agnelli et al. (unprovoked DVT; unprovoked PE)1,2, 24 months in Couturaud et al.10, and 30 months in Eischer et al.12 Generally, study design was strong. No study stopped early for benefit; three stopped early because of slow recruitment (Campbell et al.8, Pinede et al.25, Eischer et al.12) and one because of lack of benefit (Agnelli et al.2). In one study (Campbell et al.8), 20% of VTE outcomes were not objectively confirmed. Patients and caregivers were blinded in Couturaud et al.10, but none of the other studies. Adjudicators of outcomes were blinded in all but one study (Campbell et al.8). All studies used effective randomization concealment, intention-to-treat analysis, and a low unexplained drop-out frequency. 4 Study populations varied across studies: Pinede et al.25 enrolled provoked and unprovoked proximal DVT and PE; Campbell et al.8, enrolled provoked and unprovoked isolated distal DVT, proximal DVT, and PE; Agnelli et al.2 had separate randomizations for provoked PE (3 vs 6 mo) and unprovoked (3 vs 12 mo); Agnelli et al.1 enrolled unprovoked proximal DVT; Eischer et al.12 enrolled unprovoked isolated DVT, proximal DVT and PE with high levels of factor VIII; and Couturaud et al.10 enrolled unprovoked PE. 5 CIs include both values suggesting no effect and values suggesting either benefit or harm.


Online Supplemente-Table 14: Evidence Profile - Aspirin vs Placebo for extended treatment of VTE

Bibliography: Simes et al. (INSPIRE)32 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias



Study event rates (%)

Relative effect (95% CI)

Anticipated absolute effects

With Control

With Aspirin

Risk with Control

Risk difference with Aspirin (95% CI)

All Cause Mortality (CRITICAL OUTCOME) 1224 (2 studies) up to 4 years




very serious2,3

undetected ⊕⊕⊝⊝ LOW1,2,3 due to imprecision

23/608 (3.8%)

20/616 (3.2%)

HR 0.82 (0.45 to 1.52)4

Moderate risk population5 5 per 1000


Recurrent VTE (CRITICAL OUTCOME) 1224 (2 studies) up to 4 years





112/608 (18.4%)

81/616 (13.1%)

HR 0.65 (0.49 to 0.86)4

184 per 1000


Major Bleeding (CRITICAL OUTCOME) 1224 (2 studies) up to 4 years





7/608 (1.2%)

9/616 (1.5%)

HR 1.31 (0.48 to 3.53)4

12 per 1000


1 Both of the included studies were stopped early with knowledge of overall rates of VTE. Decision to stop was not made with unblinded data. Only 1/3 of the intended patients in the study 2 CI includes values suggesting no effect and values suggesting either benefit or harm 3 Greater than 50% change in risk reduction 4 Estimate based on Simes et al. (INSPIRE)32 of synthesis of Brighton et al. (ASPIRE)38 and Becattini et al. (WARFASA)39 5 Estimate taken from Douketis et al.40


Online Supplement e-Table 15: Evidence Profile - Catheter assisted thrombus removal vs anticoagulation alone for acute leg DVT

Bibliography: Watson et al.34 used for all outcomes except Patency and QoL. Enden et al.14 used for Patency estimates. Enden et al.41 used for QoL estimates. Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias




Anticipated absolute effects With Anticoagulation alone

With Catheter assisted thrombus removal

Risk with Anticoagulation alone

Risk difference with Catheter assisted thrombus removal (95% CI)





very serious1,2

undetected ⊕⊕⊝⊝ LOW1,2 due to imprecision

5/108 (4.6%)3

2/101 (2%)

RR 0.43 (0.08 to 2.16)

46 per 10003 26 fewer per 1000 (from 43 fewer to 54 more)

Recurrent VTE (IMPORTANT OUTCOME) 189 (1 study) 3 months




very serious1,2


18/99 (18.2%)

10/90 (11.1%)

RR 0.61 (0.3 to 1.25)4

Moderate risk population5 48 per 1000 19 fewer per

1000 (from 34 fewer to 12 more)

Major bleeding (CRITICAL OUTCOME) 224 (2 studies) 3 months




very serious1,2


0/116 (0%)

3/108 (2.8%)

RR 7.69 (0.4 to 146.9)4

Moderate risk population5,7 29 per 1000 194 more per


Postthrombotic syndrome (CRITICAL OUTCOME) 189 (1 study) 2 years





55/99 (55.6%)

37/90 (41.1%)

RR 0.74 (0.55 to 1)6

Moderate risk population9 588 per 1000 153 fewer

per 1000 (from 265 fewer to 0 more)8

Patency (IMPORTANT OUTCOME) 189 (1 study) 6 months





45/99 (45.5%)10

58/90 (64.4%)

RR 1.42 (1.09 to 1.85)

455 per 100010 191 more per 1000 (from 41 more to 386 more)

Quality of Life (CRITICAL OUTCOME; Better indicated by higher values) 189 (1 study) 24 months

serious12 no serious inconsistency




99 90 - The mean quality of life in the intervention groups was 0.2 higher (2.8 lower to 3 higher)12, 13

1 Confidence interval includes values suggesting both benefit and harm 2 Low number of events 3 Reported deaths from Enden et al. (CAVENT)14


Online Supplement4 Estimate taken from Watson et al.34. The one study included for this outcome was Enden et al. (CAVENT)14 5 Baseline risks for non-fatal recurrent VTE and for major bleeding derived from Douketis et al.42 6 This estimate is based on the Watson et al.34. The one study included for this outcome was Enden et al. (CAVENT).14 For PTS at 6 months, published data from Enden et al. (CAVENT)14 provides an estimate RR of 0.93 (0.61, 1.42) via Watson et al.34 7 Most of bleeding events occur during the first 7 days 8 For severe PTS, assuming the same RR of 0.46 and a baseline risk of 13.8%43, the absolute reduction is 75 fewer severe PTS per 1000 (from 29 fewer to 138 fewer) over 2 years 9 This estimate is based on the findings of the VETO study.43 10 Reported patency from Enden et al. (CAVENT)14 11 Open-label 12 Disease-specific QOL (VEINES-QOL) estimate used at 24 months according to treatment allocation 13 Generic QoL (EQ-5D) at 24 months according to treatment allocation estimate is MD 0.04 (-0.01 to 0.17)


Online Supplemente-Table 16: Evidence Profile - Temporary Inferior Vena Caval Filter vs No Temporary Inferior Vena Caval Filter in addition to anticoagulation for acute DVT or PE 1,2

Bibliography: Mismetti et al. (PREPIC 2)24 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias




Anticipated absolute effects With No Temporary Inferior Vena Caval Filter in addition to anticoagulation

With Temporary Inferior Vena Caval Filter

Risk with No Temporary Inferior Vena Caval Filter in addition to anticoagulation

Risk difference with Temporary Inferior Vena Caval Filter (95% CI)






12/199 (6%)

15/200 (7.5%)

RR 1.25 (0.6 to 2.6)


Recurrent PE (CRITICAL OUTCOME) 399 (1 study) 3 months





3/199 (1.5%)

6/200 (3%)

RR 2.00 (0.51 to 7.89)


Major Bleeding (CRITICAL OUTCOME) 399 (1 study) 3 months





10/199 (5%)

8/200 (4%)

RR 0.80 (0.32 to 1.98)

50 per 1000 10 fewer per 1000 (from 34 fewer to 49 more)

1 All patients received full-dose anticoagulant therapy according to guidelines for at least 6 months 2 Filter removal was attempted in 164 patients and successful for 153 (93.3%) 3 CI includes values suggesting no effect and values suggesting either benefit or harm 4 Small number of events


Online Supplemente-Table 17: Evidence Profile - Elastic Compression Stockings vs No Elastic Compression Stockings to Prevent PTS of the leg

Bibliography: Kahn et al. (SOX)17 for PTS and recurrent VTE; Kahn et al.18 for acute leg pain Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias




Anticipated absolute effects With No elastic compression stockings

With Elastic compression stockings

Risk with No elastic compression stockings

Risk difference with Elastic compression stockings (95% CI)

PTS (CRITICAL OUTCOME; assessed with: Villalta Score1) 803 (1 study) 6 months





168/394 (42.6%)

176/409 (43%)

RR 1.01 (0.86 to 1.18)3

Moderate risk population4 479 per 1000 5 more per


Recurrent VTE (CRITICAL OUTCOME) 803 (1 study) 6 months





38/394 (9.6%)

33/409 (8.1%)

RR 0.84 (0.54 to 1.31)6

Moderate risk population7 210 per 1000 34 fewer per


Acute Leg Pain (IMPORTANT OUTCOME; Better indicated by lower values) 742 (1 study) 60 days





365 377 - The mean acute leg pain in the control groups was 1.13 leg pain severity assessed on an 11-point numerical pain rating scale9

The mean acute leg pain in the intervention groups was 0.26 higher (0.03 lower to 0.55 higher)9

Quality of Life (CRITICAL OUTCOME; Better indicated by higher values) 803 (1 study)






394 409 - The mean quality of life in the intervention groups was 0.12 lower (1.11 lower to 0.86 higher)10,11

1 For included studies, number of post-thrombotic syndrome events as assessed by Villalta’s criteria 2 Low number of events 3 There were three studies originally included for this outcome (Brandjes et al.44, Prandoni et al.45 and Kahn et al. (SOX).17) There was very high heterogeneity between the three studies, I2 =92% (p<0.01). The pooled effect of the three studies was RR 0.63 (0.35 to 1.13). Yet, because of the high risk of bias associated with Brandjes et al.44 and Prandoni et al.45, it was decided to focus on the estimate of the low risk trial, Kahn et al. (SOX)17, which is used here 4 This estimate is based on the findings of the VETO study43 5 CI includes values suggesting no effect and values suggesting either benefit or harm 6 There were three studies originally included for this outcome (Brandjes et al.44, Prandoni et al.45 and Kahn et al. (SOX).17). The pooled effect of the three studies was RR 0.91 (0.65 to 1.27). Yet, because of the high risk of bias associated with Brandjes et al.44 and Prandoni et al.45, it was decided to focus on the estimate of the low risk trial, Kahn et al. (SOX)17, which is used here 7 This estimate is the mean of two estimates derived from two studies: 12.4% probable/definite VTE46 and 29.1% confirmed VTE.47 8 Wide CI that includes no effect 9 Estimate derived from Kahn et al.18 10 Estimate based on VEINES-QOL score improvement of 5.8 points (SD 7.5) for active ECS versus 5.9 (SD 7.1) for placebo ECS 11 SF-36 physical component score improved by 8.4 points (SD 13.6) for active ECS versus 9.9 (SD 13.2) for placebo ECS (difference between groups of -1.53 points, 95% CI -3.44 to 0.39; p=0.12)


Online Supplemente-Table 18: Evidence Profile - Systemic thrombolytic therapy vs. anticoagulation alone for acute PE Bibliography: Chatterjee et al.9 Quality assessment Summary of Findings Participants (studies) Follow up

Risk of bias Inconsistency Indirectness Imprecision Publication bias



Anticipated absolute effects With Anticoagulation alone

With Systemic thrombolytic therapy

Risk with Anticoagulation alone

Risk difference with Systemic thrombolytic therapy (95% CI)

All Cause Mortality (CRITICAL OUTCOME) 2115 (17 studies)





41/1054 (3.9%)2

23/1061 (2.2%)2

OR 0.53 (0.32 to 0.88)3

39 per 10002 18 fewer per 1000 (from 5 fewer to 26 fewer)

Recurrent PE (CRITICAL OUTCOME) 2043 (15 studies)





31/1019 (3%)2

12/1024 (1.2%)2

OR 0.40 (0.22 to 0.74)4

30 per 10002 18 fewer per 1000 (from 8 fewer to 24 fewer)

Major bleeding (CRITICAL OUTCOME) 2115 (16 studies)






36/1054 (3.4%)2

98/1061 (9.2%)2

OR 2.73 (1.91 to 3.91)5


Intracranial Hemorrhage (CRITICAL OUTCOME) 2043 (15 studies)





2/1019 (0.2%)2

15/1024 (1.5%)2

OR 4.63 (1.78 to 12.04)6


1 Low number of events 2 Majority (83%) of participants in Chatterjee et al.9 were "moderate" risk. 3 Estimate from Chatterjee et al.9. Other estimates from meta-analyses on this topic include: Dong et al.48 - OR 0.89 (0.45, 1.78) Cao et al.49 - RR 0.64 (0.29, 1.40) Marti et al.50 - OR 0.59 (0.36 - 0.96) Nakamura et al.51 - RR 0.72 (0.39, 1.31) Chatterjee et al. (Intermediate-Risk PE Only)9 - OR 0.46 (0.25 - 0.92) Marti et al. (Intermediate-Risk PE Only)50 - OR 0.42 (0.17 - 1.03) 4 Estimate from Chatterjee et al.9. Other estimates from meta-analyses on this topic include: Dong et al.48- OR 0.63 (0.33, 1.20) Cao et al.49 - RR 0.44 (0.19, 1.05) Marti et al.50 - OR 0.50 (0.27 - 0.94) Nakamura et al.51 - RR 0.60 (0.21, 1.69) 5 Estimate from Chatterjee et al.9. Other estimates from meta-analyses on this topic include: Dong et al.48 - OR 1.61 (0.91, 2.86) Cao et al.49 - RR 1.16 (0.51, 2.60) Marti et al.50 - OR 2.91 (1.95 - 4.36) Nakamura et al.51 - RR 2.07 (0.58, 7.35) 6 Estimate from Chatterjee et al.9


Online Supplemente-Figure 1: PRISMA Diagram - Choice of long-term (first 3 months) and extended (no scheduled stop date) anticoagulant


Online Supplemente-Figure 2: PRISMA Diagram - Duration of anticoagulant therapy


Online Supplemente-Figure 3: PRISMA Flow Diagram - Role of inferior vena caval (IVC) filter in addition to anticoagulation in patients with acute DVT or PE


Online Supplemente-Figure 4: PRISMA Flow Diagram - Compression stocking to prevent post thrombotic syndrome (PTS)


Online Supplemente-Figure 5: Forest Plots of Pooled Estimates: Six, Twelve or Twenty-four Months vs Three or Six Months as minimum duration of anticoagulation for VTE1

1 Review Manager (RevMan) [Computer program]. Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.


Online Supplemente-Figure 6: Forest Plots of Pooled Estimates: LMWH vs. VKA for long term treatment of VTE1

1 Review Manager (RevMan) [Computer program]. Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.


Online Supplement

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