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New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding: A Systematic Review and Meta-analysis

  • I. Lisanne Holster
    Correspondence
    Reprint requests Address requests for reprints to: I. Lisanne Holster, MD, Erasmus MC University Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands. fax: (31) 107034682.
    Affiliations
    Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands
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  • Vera E. Valkhoff
    Affiliations
    Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands
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  • Ernst J. Kuipers
    Affiliations
    Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands

    Department of Internal Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands
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  • Eric T.T.L. Tjwa
    Affiliations
    Department of Gastroenterology and Hepatology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands
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      Background & Aims

      A new generation of oral anticoagulants (nOAC), which includes thrombin and factor Xa inhibitors, has been shown to be effective, but little is known about whether these drugs increase patients’ risk for gastrointestinal bleeding (GIB). Patients who require OAC therapy frequently have significant comorbidities and may also take aspirin and/or thienopyridines. We performed a systematic review and meta-analysis of the risk of GIB and clinically relevant bleeding in patients taking nOAC.

      Methods

      We queried MEDLINE, EMbase, and the Cochrane library (through July 2012) without language restrictions. We analyzed data from 43 randomized controlled trials (151,578 patients) that compared nOAC (regardless of indication) with standard care for risk of bleeding (19 trials on GIB). Odds ratios (ORs) were estimated using a random-effects model. Heterogeneity was assessed with the Cochran Q test and the Higgins I2 test.

      Results

      The overall OR for GIB among patients taking nOAC was 1.45 (95% confidence interval [CI], 1.07−1.97), but there was substantial heterogeneity among studies (I2, 61%). Subgroup analyses showed that the OR for atrial fibrillation was 1.21 (95% CI, 0.91−1.61), for thromboprophylaxis after orthopedic surgery the OR was 0.78 (95% CI, 0.31−1.96), for treatment of venous thrombosis the OR was 1.59 (95% CI, 1.03−2.44), and for acute coronary syndrome the OR was 5.21 (95% CI, 2.58−10.53). Among the drugs studied, the OR for apixaban was 1.23 (95% CI, 0.56−2.73), the OR for dabigatran was 1.58 (95% CI, 1.29−1.93), the OR for edoxaban was 0.31 (95% CI, 0.01−7.69), and the OR for rivaroxaban was 1.48 (95% CI, 1.21−1.82). The overall OR for clinically relevant bleeding in patients taking nOAC was 1.16 (95% CI, 1.00−1.34), with similar trends among subgroups.

      Conclusions

      Studies on treatment of venous thrombosis or acute coronary syndrome have shown that patients treated with nOAC have an increased risk of GIB, compared with those who receive standard care. Better reporting of GIB events in future trials could allow stratification of patients for therapy with gastroprotective agents.

      Keywords

      Abbreviations used in this paper:

      ACS (acute coronary syndrome), AF (atrial fibrillation), CI (confidence interval), DVT (deep vein thrombosis), GIB (gastrointestinal bleeding), LMWH (low-molecular-weight heparin), NNH (number needed to harm), NSAID (nonsteroidal anti-inflammatory drug), nOAC (new oral anticoagulants), OR (odds ratio), OS (orthopedic surgery), PE (pulmonary embolism), PPI (proton pump inhibitor), RCT (randomized controlled trial), VKA (vitamin K antagonist)
      See Covering the Cover synopsis on page 32; see editorial on page 42.
      Gastrointestinal bleeding (GIB) is a serious medical condition that causes considerable morbidity and mortality (5%–15%) and poses an enormous burden on global health care use.
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      The mean hospital costs are reported to range from $2500 to $7300 for upper GIB, $4800 for lower GIB, and around $40,000 for small-bowel bleeding.
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      Antiplatelet agents (eg, aspirin and thienopyridine derivatives) can give rise to GIB by producing ulcers and erosions throughout the gastrointestinal tract. Anticoagulants (ie, vitamin K antagonists [VKA]) and heparins might precipitate bleeding from pre-existing lesions.
      • Sung J.J.
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      and more than 5 for the combination of aspirin and VKA.
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      • Andries A.
      • et al.
      Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study.
      In light of their efficacy, the increased risk of bleeding induced by the therapy is acceptable. Two important limitations of the traditional antithrombotic agents comprise the need for international normalized ratio monitoring with tailored VKA dosing, or subcutaneous administration of low-molecular-weight heparins (LMWH).
      New oral anticoagulants (nOAC) (eg, factor IIa [thrombin] or factor Xa inhibitors) have been developed and theoretically lack these limitations.
      • Turun S.
      • Banghua L.
      • Yuan Y.
      • et al.
      A systematic review of rivaroxaban versus enoxaparin in the prevention of venous thromboembolism after hip or knee replacement.
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      • Claro J.C.
      • et al.
      Oral direct factor Xa inhibitors versus low-molecular-weight heparin to prevent venous thromboembolism in patients undergoing total hip or knee replacement: a systematic review and meta-analysis.
      These drugs are as effective as current therapy. Some randomized controlled trials (RCTs) reported an isolated higher GIB risk,
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      which is potentially fatal, costly, and avoidable. It is therefore important to carefully review the literature on GIB risk attributable to use of nOAC. This is particularly relevant because patients on nOAC often use concomitant low-dose aspirin and/or thienopyridines, which may add substantially to the as yet unknown GIB risk. Furthermore, in contrast with the traditional OAC, no clinically tested antidote is currently available for the novel agents, hampering therapeutic options in case of GIB.
      • Levi M.
      • Eerenberg E.
      • Kamphuisen P.W.
      Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents.
      For these reasons, we conducted a systematic review focusing on the risk of GIB of all nOAC. Because not all trials separately reported GIB risk, we also reviewed the evidence on risk of clinically relevant bleeding associated with nOAC use.

      Materials and Methods

       Study Definitions

      The exposure of interest was defined as the (approximated) indication-specific recommended daily dose of the nOAC either by the European Medicines Agency

      European Medicines Agency, an agency of the European Union. Available: www.ema.europa.eu. Accessed January 24, 2013.

      or the Food and Drug Administration

      U.S. Food and Drug Administration, US Department of Health and Human Services. Available: www.fda.gov. Accessed January 24, 2013.

      for registered nOAC. When nOAC was not registered for the indication for which it was studied, the indication-specific daily dose was defined according to the pharmaceutical manufacturer.
      Standard care was defined as either low-molecular-weight heparin, vitamin K antagonist, antiplatelet therapy, or no (additional) therapy/placebo, depending on the (inter)national guidelines regarding antithrombotic therapy for the concerning indication.
      The primary outcome of this systematic review was the risk of GIB. GIB was considered as at least one episode of clinically apparent hematemesis (frank blood or coffee-ground material that tested positive for blood), melena, or spontaneous rectal bleeding (if more than a few spots) or endoscopically confirmed bleeding, and was judged as major or clinically relevant nonmajor depending on the severity.
      • Gibson C.M.
      • Mega J.L.
      • Burton P.
      • et al.
      Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis in myocardial infarction 51 (ATLAS-ACS 2 TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome.
      The secondary outcome was the risk of clinically relevant bleeding (encompassing both major bleeding and clinically relevant nonmajor bleeding). Major bleeding and clinically relevant nonmajor bleeding in the included studies were defined by the following: (1) the International Society on Thrombosis and Haemostasis,
      • Schulman S.
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      • Bergqvist D.
      • et al.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients.
      • Schulman S.
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      • Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
      • et al.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
      (2) the Thrombolysis In Myocardial Infarction,
      • Rao S.V.
      • Eikelboom J.A.
      • Granger C.B.
      • et al.
      Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes.
      or (3) an adjustment of the International Society on Thrombosis and Haemostasis definition (see Table 1 for exact definitions).
      Table 1Definitions of Bleeding
      End pointSub–end pointDefinition
      Clinically relevant bleedingMajor bleedingAcute, clinically overt bleeding accompanied by ≥1 of the following events: a decrease in hemoglobin level of ≥2 g/dL within a 24-hour period; a transfusion of ≥2 units of packed red cells; bleeding at a critical site (ie, intracranial, intraspinal, intraocular, pericardial, or retroperitoneal bleeding); bleeding into the operated joint (for the studies regarding thromboprophylaxis after surgery), requiring an additional surgery or intervention; intramuscular bleeding with the compartment syndrome; or fatal bleeding
      • Schulman S.
      • Angeras U.
      • Bergqvist D.
      • et al.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients.
      • Schulman S.
      • Kearon C.
      • Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
      • et al.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.


      In addition to the above, when major bleeding occurred in the gastrointestinal tract (defined by at least one episode of clinically apparent hematemesis, melena, spontaneous rectal bleeding) or when a major bleeding was confirmed by endoscopy, it was defined as (major) GIB
      • Gibson C.M.
      • Mega J.L.
      • Burton P.
      • et al.
      Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis in myocardial infarction 51 (ATLAS-ACS 2 TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome.
      Clinically relevant nonmajor bleedingAcute, clinically overt bleeding, such as excessive wound hematoma, bruising or ecchymosis (>25 cm2), gastrointestinal bleeding, hemoptysis, macroscopic hematuria, gingival bleeding (>5 min), epistaxis (>5 min), or any bleeding leading to hospital admission or discontinuation of the study medication, unscheduled contact with a physician, or discomfort or impairment of activities of daily life, that did not meet the other criteria for major bleeding

       Data Sources and Searches

      A comprehensive literature search was conducted to identify RCTs reporting GIB or clinically relevant bleeding in patients receiving nOAC compared with standard treatment. Medline with PubMed as interface, EMbase, and the Cochrane Central Register of Controlled Trials were searched from inception to July 2012. Medical subject heading terms and keywords used to identify RCTs included “apixaban,” “rivaroxaban,” “dabigatran,” “edoxaban,” “betrixaban,” “humans,” and “randomized controlled trial.” No language restrictions were applied. The electronic search strategy was complemented by a manual review of reference lists of included articles. References of recent reviews on nOAC also were examined.
      • Levi M.
      • Eerenberg E.
      • Kamphuisen P.W.
      Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents.
      • Eikelboom J.W.
      • Weitz J.I.
      New anticoagulants.
      • Bauer K.A.
      Recent progress in anticoagulant therapy: oral direct inhibitors of thrombin and factor Xa.
      • Galanis T.
      • Thomson L.
      • Palladino M.
      • et al.
      New oral anticoagulants.
      • Mavrakanas T.
      • Bounameaux H.
      The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism.
      • Deloughery T.G.
      Practical aspects of the oral new anticoagulants.
      • Garcia D.
      • Libby E.
      • Crowther M.A.
      The new oral anticoagulants.

       Study Selection

      Search results were combined and duplicates were removed. Studies were first screened based on title and abstract for relevance, after which the full text was reviewed. This was performed independently by 2 reviewers (I.L.H. and V.E.V.). Inter-rater agreement was assessed using the k statistic. Any discrepancies were resolved by consensus, contacting a third author (E.T.T.L.T.). Studies had to meet the following inclusion criteria: (1) the study compared nOAC with the current standard care in a randomized setting; (2) results included bleeding events as a safety outcome; (3) the study was conducted in the target population of the drug and not in healthy volunteers; and (4) it was published as a full-text article. If any of the 4 criteria were not met, the study was excluded. If data from the same study were published in multiple languages, data from the English article were extracted. In case of suspicion of double reporting of the same patient populations, data from the main publication were extracted.

       Data Extraction

      The included studies were divided by clinical indication of anticoagulant therapy into the following indication groups: (1) prevention of stroke and systemic embolism in patients with atrial fibrillation (AF); (2) prevention of venous thromboembolism after orthopedic surgery (OS); (3) prevention of venous thromboembolism in medically ill patients; (4) treatment of acute deep vein thrombosis (DVT) or pulmonary embolism (PE); and (5) treatment of acute coronary syndrome (ACS). For each included study, we recorded the number of trial participants, follow-up period, and the number of patients who developed the primary safety end points for both treatment arms. The mean age at baseline and the percentage of males were assessed, as well as other characteristics of the study population such as relevant concomitant medications that may affect bleeding risk. This was performed independently by 2 authors (I.L.H. and V.E.V.). Finally, we contacted the main investigator for missing data. Furthermore, given the heterogeneity of the studies, an individual patient data analysis was attempted. All authors were contacted and requested to provide individual patient data. We received responses from 7 of 23 authors (covering 12 of 43 studies). Unfortunately, no one agreed to share this information.

       Quality Assessment

      The quality of included studies was assessed according to the Cochrane Reviewers’ Handbook.

      Higgins J, Green S, eds. Assessment of study quality. In: Cochrane Handbook for systematic reviews of interventions 4.2.6 [updated September 2006]. The Cochrane Library. Chichester, UK: John Wiley & Sons, Ltd, 2006.

      Both manuscript and protocol, if available online, were scanned for relevant information on quality.

       Data Synthesis and Analysis

      Odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated for each RCT and were the bases for the meta-analyses. To include studies with null events in either the active treatment arm or the standard care arm, 0.5 events were added to all cells with study results. In case of null events in both arms, no OR was calculated. To quantify how many patients needed to be exposed to nOAC therapy to cause one additional GIB compared with standard care the number needed to harm (NNH) was assessed.
      To explore between-study variability the Cochran Q test and the Higgins I2 test for heterogeneity were used. Significant heterogeneity was assumed when the Cochran Q P value was less than .10 and the I2 was greater than 50%. To reduce the impact of heterogeneity, we used a random-effects model in these cases.
      To account for possible sources of heterogeneity, we performed prespecified subgroup analyses according to type of nOAC and indication. Heterogeneity between subgroups was evaluated further by a post hoc meta-regression analysis by indication, type of nOAC, and comparator. Comprehensive meta-analysis v2.0 (Biostat, Englewood, NJ) was used to perform the meta-analysis. Meta-regression was performed using PASW statistics 20.0 for Windows (SPSS, IBM, Armonk, New York).
      Sensitivity analysis was performed to exclude studies that compared the bleeding risk of nOAC use with the use of placebo as standard care because this intervention is unlikely to increase bleeding risk. Because we only included published data, publication bias was quantified with the Egger regression test, with the results considered to indicate publication bias when the P value was less than .10. In addition, funnel plots were examined for asymmetry.

      Results

       Studies

      Our initial search identified 375 records (Figure 1A). A total of 42 studies were eligible for inclusion. The agreement between reviewers for trial inclusion was excellent (κ, 0.94). The clinical indication comprised AF in 8 studies,
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Ezekowitz M.D.
      • Reilly P.A.
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      Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study).
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      Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation.
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      • Jeon H.K.
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      • et al.
      Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation.
      • Ogawa S.
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      Apixaban in patients with atrial fibrillation.
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      Apixaban versus warfarin in patients with atrial fibrillation.
      OS in 21 studies,
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      A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial.
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      BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study.
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      • Dahl O.E.
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      Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement.
      • Eriksson B.I.
      • Borris L.C.
      • Dahl O.E.
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      A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement.
      • Eriksson B.I.
      • Borris L.C.
      • Dahl O.E.
      • et al.
      Dose-escalation study of rivaroxaban (BAY 59-7939)–an oral, direct Factor Xa inhibitor–for the prevention of venous thromboembolism in patients undergoing total hip replacement.
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      Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial.
      • Eriksson B.I.
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      The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.
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      Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.
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      Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.
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      Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery.
      • Turpie A.G.
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      A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT).
      • Turpie A.G.
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      Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial.
      • Lassen M.R.
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      Apixaban or enoxaparin for thromboprophylaxis after knee replacement.
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      Dabigatran etexilate prevents venous thromboembolism after total knee arthroplasty in Japanese patients with a safety profile comparable to placebo.
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      A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty.
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      Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial.
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      Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study.
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      Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial.
      medically ill patients in 2 studies,
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      • Levine M.N.
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      A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer.
      DVT/PE in 6 studies (reporting on 7 trials),
      • Agnelli G.
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      Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study.
      • Buller H.R.
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      A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study.
      • Botticelli Investigators Writing Committee
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      Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study.
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      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      • EINSTEIN Investigators E
      • Bauersachs R.
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      Oral rivaroxaban for symptomatic venous thromboembolism.
      • EINSTEIN-PE Investigators
      • Buller H.R.
      • Prins M.H.
      • et al.
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      and ACS in 5 studies (Figure 1B).
      • APPRAISE Steering Committee and Investigators
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      Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.
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      Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.
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      Apixaban with antiplatelet therapy after acute coronary syndrome.
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      Rivaroxaban in patients with a recent acute coronary syndrome.
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      Figure thumbnail gr1
      Figure 1(A) Flowchart of included studies. (B) Indications of included studies split by drug. (C) Drugs of included studies split by indication. One of these studies describes 2 subsequent trials, and therefore is mentioned twice in the data extraction. Api, apixaban; ACS, acute coronary syndrome; AF, atrial fibrillation; bet, betrixaban; dab, dabigatran; DVT, deep vein thrombosis; edo, edoxaban; Med ill, medically ill; OS, orthopedic surgery; PE, pulmonary embolism; riv, rivaroxaban.
      To gain insight into the performance per drug, the information on bleeding risk was summarized per individual drug (Figure 1C). Rivaroxaban was studied most frequently (15 studies reporting on 16 trials),
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Turpie A.G.
      • Fisher W.D.
      • Bauer K.A.
      • et al.
      BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study.
      • Eriksson B.I.
      • Borris L.
      • Dahl O.E.
      • et al.
      Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement.
      • Eriksson B.I.
      • Borris L.C.
      • Dahl O.E.
      • et al.
      A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement.
      • Eriksson B.I.
      • Borris L.C.
      • Dahl O.E.
      • et al.
      Dose-escalation study of rivaroxaban (BAY 59-7939)–an oral, direct Factor Xa inhibitor–for the prevention of venous thromboembolism in patients undergoing total hip replacement.
      • Eriksson B.I.
      • Borris L.C.
      • Friedman R.J.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.
      • Lassen M.R.
      • Ageno W.
      • Borris L.C.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.
      • Kakkar A.K.
      • Brenner B.
      • Dahl O.E.
      • et al.
      Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.
      • Turpie A.G.
      • Lassen M.R.
      • Davidson B.L.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial.
      • Agnelli G.
      • Gallus A.
      • Goldhaber S.Z.
      • et al.
      Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study.
      • Buller H.R.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study.
      • EINSTEIN Investigators E
      • Bauersachs R.
      • Berkowitz S.D.
      • et al.
      Oral rivaroxaban for symptomatic venous thromboembolism.
      • EINSTEIN-PE Investigators
      • Buller H.R.
      • Prins M.H.
      • et al.
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      • Mega J.L.
      • Braunwald E.
      • Mohanavelu S.
      • et al.
      Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.
      • Mega J.L.
      • Braunwald E.
      • Wiviott S.D.
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      followed by apixaban (12 trials),
      • Ogawa S.
      • Shinohara Y.
      • Kanmuri K.
      Safety and efficacy of the oral direct factor xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. The ARISTOTLE J study.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Lassen M.R.
      • Davidson B.L.
      • Gallus A.
      • et al.
      The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.
      • Lassen M.R.
      • Raskob G.E.
      • Gallus A.
      • et al.
      Apixaban or enoxaparin for thromboprophylaxis after knee replacement.
      • Lassen M.R.
      • Gallus A.
      • Raskob G.E.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.
      • Lassen M.R.
      • Raskob G.E.
      • Gallus A.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial.
      • Goldhaber S.Z.
      • Leizorovicz A.
      • Kakkar A.K.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients.
      • Levine M.N.
      • Gu C.
      • Liebman H.A.
      • et al.
      A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer.
      • Botticelli Investigators Writing Committee
      • Buller H.
      • Deitchman D.
      • et al.
      Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study.
      • APPRAISE Steering Committee and Investigators
      • Alexander J.H.
      • Becker R.C.
      • et al.
      Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.
      • Alexander J.H.
      • Lopes R.D.
      • James S.
      • et al.
      Apixaban with antiplatelet therapy after acute coronary syndrome.
      dabigatran (10 trials),
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Ezekowitz M.D.
      • Reilly P.A.
      • Nehmiz G.
      • et al.
      Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study).
      • Eriksson B.I.
      • Dahl O.E.
      • Buller H.R.
      • et al.
      A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial.
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial.
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.
      • Committee R.-M.W.
      • Ginsberg J.S.
      • Davidson B.L.
      • et al.
      Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery.
      • Fuji T.
      • Fuijita S.
      • Ujihira T.
      • et al.
      Dabigatran etexilate prevents venous thromboembolism after total knee arthroplasty in Japanese patients with a safety profile comparable to placebo.
      • Eriksson B.I.
      • Dahl O.E.
      • Huo M.H.
      • et al.
      Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial.
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      • Oldgren J.
      • Budaj A.
      • Granger C.B.
      • et al.
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.
      edoxaban (4 trials),
      • Weitz J.I.
      • Connolly S.J.
      • Patel I.
      • et al.
      Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation.
      • Chung N.
      • Jeon H.K.
      • Lien L.M.
      • et al.
      Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation.
      • Fuji T.
      • Fujita S.
      • Tachibana S.
      • et al.
      A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty.
      • Raskob G.
      • Cohen A.T.
      • Eriksson B.I.
      • et al.
      Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study.
      and betrixaban (1 trial).
      • Turpie A.G.
      • Bauer K.A.
      • Davidson B.L.
      • et al.
      A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT).
      The main characteristics of the 43 included trials are summarized in Supplementary Tables 1–5.

       Study Characteristics

      A total of 151,578 patients were included in the 43 trials. Duration of follow-up evaluation ranged from 3 weeks to 31 months, with shorter durations of follow-up evaluation for the OS studies and longer durations for AF studies. Patients with a recent history of peptic ulcer disease or patients with an otherwise increased risk of GIB (eg, patients with a thrombocytopenia or coagulation disorder) were excluded in all 43 trials. Concomitant use of any co-medication affecting coagulation was prohibited in 19% of trials, only low-dose aspirin (<160 mg) was allowed in 14%, only short-acting nonsteroidal anti-inflammatory drugs (NSAIDs) (<17 hours) were allowed in 16%, and short-acting NSAIDs/cyclooxygenase-2 inhibitors and/or low-dose aspirin and/or thienopyridines was allowed in 44%, mostly with the addition that it was discouraged. Information on the allowance of antithrombotic co-medication was absent in 7% of trials (Supplementary Tables 1–5).

       Study Exposure

      First, the risk estimates from each study were pooled by indication because the registered/recommended dose for each individual nOAC differs per indication (Supplementary Table 6). A total of 125,354 patients (83%) were enrolled in the therapeutic arms relevant to this review. Of the 8 trials on AF, 7 trials compared one of the novel agents with dose-adjusted warfarin. Of the 21 trials on thromboprophylaxis after OS, 19 compared a nOAC with LMWH (Supplementary Tables 1–5). All trials, except one trial
      • EINSTEIN Investigators E
      • Bauersachs R.
      • Berkowitz S.D.
      • et al.
      Oral rivaroxaban for symptomatic venous thromboembolism.
      on DVT/PE treatment, compared a nOAC with LMWH followed by VKA. The trials on treatment of ACS compared nOAC with placebo, in addition to standard (double) antiplatelet therapy.

       Publication Bias

      The result of the Egger regression test for publication bias was not significant (intercept, 0.7; 95% CI, –0.4 to 1.7; P = .20) and no funnel plot asymmetry was observed (Supplementary Figure 1), indicating no evidence of publication bias.

       Methodologic Quality of Included Studies

      Supplementary Table 7 presents an overview of the methodologic quality of included RCTs. The majority of trials mentioned the method used for randomization (93%) and adequate concealment of allocation (72%). Seventy percent of studies applied a double-blind design, 23% had a single-blind design, and 7% followed an open-label design. An independent blinded committee identified all suspected outcome events in each study. Ninety-three percent of studies used an intention-to-treat analysis at least for the safety analysis. The number of patients lost to follow-up evaluation varied between 0.1% and 2.5%, but were reported in only 53% of studies.

       Gastrointestinal Bleeding

      Nineteen trials (44%) reported separate data on GIB.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Chung N.
      • Jeon H.K.
      • Lien L.M.
      • et al.
      Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation.
      • Ogawa S.
      • Shinohara Y.
      • Kanmuri K.
      Safety and efficacy of the oral direct factor xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. The ARISTOTLE J study.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Eriksson B.I.
      • Borris L.
      • Dahl O.E.
      • et al.
      Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement.
      • Eriksson B.I.
      • Borris L.C.
      • Dahl O.E.
      • et al.
      Dose-escalation study of rivaroxaban (BAY 59-7939)–an oral, direct Factor Xa inhibitor–for the prevention of venous thromboembolism in patients undergoing total hip replacement.
      • Lassen M.R.
      • Davidson B.L.
      • Gallus A.
      • et al.
      The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.
      • Eriksson B.I.
      • Borris L.C.
      • Friedman R.J.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.
      • Kakkar A.K.
      • Brenner B.
      • Dahl O.E.
      • et al.
      Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.
      • Lassen M.R.
      • Raskob G.E.
      • Gallus A.
      • et al.
      Apixaban or enoxaparin for thromboprophylaxis after knee replacement.
      • Lassen M.R.
      • Gallus A.
      • Raskob G.E.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.
      • Lassen M.R.
      • Raskob G.E.
      • Gallus A.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial.
      • Levine M.N.
      • Gu C.
      • Liebman H.A.
      • et al.
      A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer.
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      • EINSTEIN Investigators E
      • Bauersachs R.
      • Berkowitz S.D.
      • et al.
      Oral rivaroxaban for symptomatic venous thromboembolism.
      • APPRAISE Steering Committee and Investigators
      • Alexander J.H.
      • Becker R.C.
      • et al.
      Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.
      • Oldgren J.
      • Budaj A.
      • Granger C.B.
      • et al.
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.
      Two small trials yielded null events in both groups and therefore were excluded from the GIB analyses.
      • Eriksson B.I.
      • Borris L.C.
      • Dahl O.E.
      • et al.
      Dose-escalation study of rivaroxaban (BAY 59-7939)–an oral, direct Factor Xa inhibitor–for the prevention of venous thromboembolism in patients undergoing total hip replacement.
      • Lassen M.R.
      • Davidson B.L.
      • Gallus A.
      • et al.
      The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.
      A total of 1101 GIB events in 75,081 patients were reported (1.5%) (Supplementary Table 8). These GIBs were predominantly major bleeds (89%). The percentage of GI bleeds per trial in the nOAC group was low in the trials on OS (nOAC, 0.1%; control, 0.2%), intermediate in the trials on AF (nOAC, 2.1%; control, 1.6%) and DVT/PE (nOAC, 3.0%; control, 1.9%), and high in the trials on ACS (nOAC, 5.3%; control, 1.0%). The NNH was 500 (95% CI, -10,000 to 200), meaning that if 1000 patients were treated with the nOAC instead of standard care, this would result in 2 additional GIBs.
      Four of 17 studies showed an increased risk, 12 a comparable risk, and 1 a lower risk of GIB when the nOAC was administered compared with the standard care. After pooling the results of 17 RCTs, the nOAC were found to be associated with a higher risk of GIB compared with standard care (pooled OR, 1.45; 95% CI, 1.07–1.97), but with substantial heterogeneity (I2, 61%). First, a considerable part of the increased risk could be attributed to the 2 trials on ACS (pooled OR, 5.21; 95% CI, 2.58–10.53; I2, 0%). To illustrate, the NNH was 24 (95% CI, 17–42), meaning that per 24 patients treated with the nOAC on top of standard care for ACS, 1 extra GIB would occur. Second, the risk of GIB with nOAC was increased for the 2 trials on DVT/PE (pooled OR, 1.59; 95% CI, 1.03–2.44; I2 27%), but not for other indications for nOAC. The calculated OR (95% CI) of each trial is shown in Figure 2A and 2B. With post hoc meta-regression, we studied the effect of indication of use (therapeutic use of nOAC vs prophylactic use). This showed no difference between therapeutic or prophylactic use when adjusted for comparator (placebo vs antithrombotic agent).
      Figure thumbnail gr2
      Figure 2(A) Forrest plot of GIB with subgroup analysis by indication. (B) Forrest plot of GIB with subgroup analysis by drug. Data are presented as OR (95% CI) using a random-effects model and I2 test for heterogeneity. Api, apixaban; bet, betrixaban; dab, dabigatran; edo, edoxaban; riv, rivaroxaban; ACS, acute coronary syndrome; AF, atrial fibrillation; DVT, deep vein thrombosis; Med ill, medically ill; OS, orthopedic surgery; PE, pulmonary embolism.
      In a subgroup analysis of individual drugs, dabigatran (3 studies
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      • Oldgren J.
      • Budaj A.
      • Granger C.B.
      • et al.
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.
      ; I2, 36%), and rivaroxaban (5 studies
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Eriksson B.I.
      • Borris L.
      • Dahl O.E.
      • et al.
      Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement.
      • Eriksson B.I.
      • Borris L.C.
      • Friedman R.J.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.
      • Kakkar A.K.
      • Brenner B.
      • Dahl O.E.
      • et al.
      Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.
      • EINSTEIN Investigators E
      • Bauersachs R.
      • Berkowitz S.D.
      • et al.
      Oral rivaroxaban for symptomatic venous thromboembolism.
      ; I2, 0%) were associated with a significant increase in risk of GIB, whereas apixaban (8 studies
      • Ogawa S.
      • Shinohara Y.
      • Kanmuri K.
      Safety and efficacy of the oral direct factor xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. The ARISTOTLE J study.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Lassen M.R.
      • Davidson B.L.
      • Gallus A.
      • et al.
      The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.
      • Lassen M.R.
      • Raskob G.E.
      • Gallus A.
      • et al.
      Apixaban or enoxaparin for thromboprophylaxis after knee replacement.
      • Lassen M.R.
      • Gallus A.
      • Raskob G.E.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.
      • Lassen M.R.
      • Raskob G.E.
      • Gallus A.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial.
      • Levine M.N.
      • Gu C.
      • Liebman H.A.
      • et al.
      A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer.
      • APPRAISE Steering Committee and Investigators
      • Alexander J.H.
      • Becker R.C.
      • et al.
      Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.
      ; I2, 0%) and edoxaban (1 study
      • Chung N.
      • Jeon H.K.
      • Lien L.M.
      • et al.
      Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation.
      ) were not. The pooled OR of GIB associated with dabigatran use was 1.58 (95% CI, 1.29–1.93) (Figure 2B). Expressed in terms of NNH: per 83 patients treated with dabigatran compared with standard care, 1 additional GIB would occur (95% CI, 59–143). The GIB risk associated with use of rivaroxaban had an OR of 1.48 (95% CI, 1.21–1.82). When adjusting for indication of use (therapeutic vs prophylactic), the risk of rivaroxaban remained significantly higher than that of apixaban (OR, 1.77; 95% CI, 1.32–2.38). Analysis by comparator, adjusted for indication of use, revealed no significant differences between different comparators.
      In the sensitivity analysis, we excluded studies that compared nOAC with placebo therapy. No major deviations were seen, except for the risk of GIB during DVT/PE treatment, which reduced and became inconclusive (OR, 1.53; 95% CI, 0.99–2.36). Complete results of this sensitivity analysis are shown in Supplementary Table 8.

       Clinically Relevant Bleeding

      Because GIB is a substantial component of clinically relevant bleeding, we also included this in our analysis. All 43 trials reported on clinically relevant bleeding. The overall risk of clinically relevant bleeding was significantly higher with the use of nOAC compared with standard care (OR, 1.16; 95% CI, 1.00–1.34). Considerable overall heterogeneity, however, was observed (I2, 83%).
      In a subgroup analysis in which different indications for nOAC therapy were considered, we found that patients treated for ACS have an increased risk of bleeding (OR, 2.06; I2, 22%) in contrast to patients receiving thromboprophylaxis during OS (OR, 1.05; I2, 36%). The other indications did not show a significantly increased risk, but this may be hampered by the substantial heterogeneity. Subgroup analysis by individual drug showed a slightly increased risk of rivaroxaban compared with standard care (OR, 1.31; 95% CI, 1.04–1.64), but likewise was marked by heterogeneity (I2, 85%), limiting a solid conclusion on the risk of clinically relevant bleeding (Figure 3 and Supplementary Table 8). The risk of clinically relevant bleeding did not differ by drug when adjusted for indication of use.
      Figure thumbnail gr3
      Figure 3Forrest plot of clinically relevant bleeding summarized by indication and by drug. Data are presented as OR (95% CI) using a random effects model and an I2 test for heterogeneity. ACS, acute coronary syndrome; AF, atrial fibrillation; DVT, deep vein thrombosis; Med ill, medically ill; OS, orthopedic surgery; PE, pulmonary embolism.
      In the sensitivity analysis, excluding studies comparing with placebo, the overall clinically relevant bleeding risk was not increased (OR, 0.98; 95% CI, 0.88–1.10; I2, 65%) (Supplementary Table 8).

      Discussion

      This systematic review and meta-analysis on 43 trials shows that the nOACs are associated with a modest, but significantly higher, risk of GIB compared with current standard care. This risk is the highest in patients treated for thrombosis (ACS and DVT/PE). In ACS, nOACs were administered on top of other antithrombotic medication, increasing the well-known cumulative risk of GIB.
      • Lanas A.
      • Wu P.
      • Medin J.
      • et al.
      Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis.
      The risk of GIB in patients treated for DVT/PE or receiving thromboprophylaxis for AF is higher than in patients receiving thromboprophylaxis after OS, this might suggest a dose and/or duration effect on top of difference in risk caused by patient characteristics in the different indication groups. However, within the subgroup of AF patients, only patients treated with dabigatran and rivaroxaban carry a higher GIB risk, but not with apixaban. Because head-to-head studies between nOAC in AF have not been performed, it is not possible to determine the drugs with the lowest GIB risk in AF without applying statistically indirect comparisons. A network meta-analysis on overall safety was conducted by others on OS patients and showed no significant differences.
      • Gomez-Outes A.
      • Terleira-Fernandez A.I.
      • Suarez-Gea M.L.
      • et al.
      Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons.
      The major strength of this meta-analysis was its focus on GIB. We provide a complete review of 43 trials with a total of 151,578 patients. Given the implementation of nOAC on a large scale, all currently available types of nOAC and all present indications were included because GI physicians will have to deal with GIB complications, irrespective of drug or indication. The data conveyed are corroborated by 2 small meta-analyses with GIB as a secondary safety outcome and in which in total only 3 studies for AF were reviewed.
      • Capodanno D.
      • Capranzano P.
      • Giacchi G.
      • et al.
      Novel oral anticoagulants versus warfarin in non-valvular atrial fibrillation: a meta-analysis of 50,578 patients.
      • Miller C.S.
      • Grandi S.M.
      • Shimony A.
      • et al.
      Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation.
      For optimal clinical relevance, we included only data obtained with the indication-specific registered/recommended dose per drug, instead of combining all levels of dosages per trial, which was performed in meta-analyses assessing overall risk/benefit of thromboprophylaxis after OS.
      • Neumann I.
      • Rada G.
      • Claro J.C.
      • et al.
      Oral direct factor Xa inhibitors versus low-molecular-weight heparin to prevent venous thromboembolism in patients undergoing total hip or knee replacement: a systematic review and meta-analysis.
      • Gomez-Outes A.
      • Terleira-Fernandez A.I.
      • Suarez-Gea M.L.
      • et al.
      Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons.
      Two limitations of the current study need to be addressed: (1) study design and GIB report of included studies, and (2) heterogeneity between studies. First, all included studies have been designed for showing noninferior or superior efficacy of nOAC vs current standard care. As a consequence, GIB is not reported as a safety outcome in the majority of studies and will have to be assessed by future studies or by a critical assessment of published studies. A large number of included studies reported only on the composite end point of bleeding outcomes in general. Although the use of this end point has the advantage of increased power, a difference in GIB risk therefore cannot be investigated. However, when studies separately reported on GIB, this was performed for major bleedings, but mostly not for clinically relevant nonmajor bleedings. This led to an underestimation of the risk of all clinically relevant GIBs (ie, composed of both major and clinically relevant nonmajor GIBs). In addition, for GIB there was no standard definition according to a scientific commission, but most trials reported used a uniform definition to identify GIB. Regarding heterogeneity, which is inevitable with current available data, we applied a random-effects model and excluded observational cohorts, healthy volunteer studies, nonregistered drugs, and unpublished data. Furthermore, we addressed all perceived sources of heterogeneity by prespecified subgroup analysis and meta-regression by indication, type of nOAC, and comparator. Analysis by concomitant use of antiplatelet therapy was not feasible owing to lack of stratification of outcome by use of antiplatelet therapy.
      Some statistical issues merit clarification. First, we calculated risk estimates per study by means of ORs. Although it would have been preferable to calculate hazard ratios, the rationale to compute ORs was that the mean follow-up time until GIB was not reported per treatment arm for any study. The OR can be interpreted as an estimate of the relative risk because the overall occurrence of GIB is rare (1.5%). Second, for the analysis on GIB, following standard practice, we excluded 2 studies that had no events in both arms. This exclusion was performed because such studies do not provide any indication of either the direction or magnitude of the relative treatment effect, whereas exclusion of the 2 trials would not affect the point estimate. Both studies were of relatively small size (and thus would have had a low weight in the meta-analyses, together equaling approximately 2%).
      As evidence of the superior efficacy of nOAC accumulates,
      • Neumann I.
      • Rada G.
      • Claro J.C.
      • et al.
      Oral direct factor Xa inhibitors versus low-molecular-weight heparin to prevent venous thromboembolism in patients undergoing total hip or knee replacement: a systematic review and meta-analysis.
      • Gomez-Outes A.
      • Terleira-Fernandez A.I.
      • Suarez-Gea M.L.
      • et al.
      Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons.
      • Miller C.S.
      • Grandi S.M.
      • Shimony A.
      • et al.
      Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation.
      it is important to consider 2 crucial issues. First, most trials used extensive exclusion criteria to enroll only those patients with a presumed low risk of GIB complications attributable to anticoagulants. It is estimated that when these drugs are marketed for daily clinical practice, almost 25%–40% of future users are high-risk patients and the risk of hemorrhage can be as much as 3- to 15-fold increased.
      • Levi M.
      • Hovingh G.K.
      • Cannegieter S.C.
      • et al.
      Bleeding in patients receiving vitamin K antagonists who would have been excluded from trials on which the indication for anticoagulation was based.
      It is tempting to speculate that the balance between efficacy and safety will shift unfavorably in these patients because the bleeding risk increases to a much greater extent than the risk of thromboembolism. Second, data on concomitant proton pump inhibitor (PPI) use was not available, except for one trial.
      • Alexander J.H.
      • Lopes R.D.
      • James S.
      • et al.
      Apixaban with antiplatelet therapy after acute coronary syndrome.
      A recent consensus guideline states that PPIs should be considered in any person with a risk factor for GIB receiving any type of antithrombotic agent
      • Barkun A.N.
      • Bardou M.
      • Kuipers E.J.
      • et al.
      International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding.
      because PPIs have proven to reduce the risk of upper GIB among both traditional NSAID users, low-dose aspirin users, and among patients taking clopidogrel.
      • Lanas A.
      • Garcia-Rodriguez L.A.
      • Arroyo M.T.
      • et al.
      Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants.
      Future trials, investigating whether gastroprotective agents could increase NNH in patients on nOAC, are warranted. This is of importance because many patients may use nOAC for a considerable duration of time and mostly have significant comorbidity.
      In conclusion, we have shown that the gastrointestinal bleeding risk associated with nOAC use might be higher compared with standard care. The current evidence, however, is based on a highly selected patient group with a low bleeding risk, disallowing a true reflection of future patients in daily clinical practice. We recommend that future studies specifically report on the gastrointestinal bleeding risk to further elucidate the true incidence and associated risk. Subsequently, co-administration of gastroprotective agents could be beneficial and warrants further investigations.

      Supplemental Material

      Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at http://dx.doi.org/10.1053/j.gastro.2013.02.041

      Supplemental Material

      Figure thumbnail fx1
      Supplementary Figure 1Funnel plot of publication bias.
      Supplementary Table 1RCTs Studying New Oral Anticoagulants for the Prevention of Stroke and Systemic Embolism in Patients With Atrial Fibrillation
      Study, trial name, yearBaseline conditionExclusion criteria, specified on bleeding riskStudy group (n) vs control group (n)Median age, menConcomitant use of antiplatelet agents (% study/% control)Median use of study medicationMedian follow-up periodMean CHADS2 score study/control
      • Gage B.F.
      • van Walraven C.
      • Pearce L.
      • et al.
      Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin.
      • Gage B.F.
      • Waterman A.D.
      • Shannon W.
      • et al.
      Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
      Major bleeding HR, RR (95% CI) or % study/% control, definition of major bleeding
      According to the International Society on Thrombosis and Haemostasis (ISTH) criteria16/thrombolysis in myocardial infarction criteria,17 or adjusted criteria.
      Clinically relevant bleeding HR, RR (95% CI) or % study/% control, definition of CRB
      According to the standard definition as reported in the Materials and Methods section, or adjusted definition.
      Gastrointestinal bleeding HR, RR (95% CI) or % study/ % controlINR within therapeutic range in warfarin group, median time
      Used the method of Rosendaal.77
      Ezekowitz et al,
      • Ezekowitz M.D.
      • Reilly P.A.
      • Nehmiz G.
      • et al.
      Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study).
      PETRO, 2007
      AF with coronary artery disease plus ≥1 of the following: HT, DM, symptomatic heart failure, LVEF <40%, previous stroke/TIA, or age >75 yMajor hemorrhage in the past 6 mo, any contraindication to anticoagulant therapyDabigatran 50 mg bid (59/21/27), 150 mg bid (100/36/33), or 300 mg bid (105/34/30) without aspirin or with aspirin 81 or 325 mg qd vs warfarin INR 2–3 (70)70 y, 82%ASA: 40.7/0Not reportedNot reported, total follow-up period 3 moNot reported6.3% in dabigatran 300 mg bid + aspirin, no major bleeding in other groups (P < .02)
      Significant difference.


      ISTH
      1.9%/ 7.7% /10.1%/5.7%

      Standard definition
      Not reported57.2%
      Connolly et al,
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      RE-LY 2009
      AF and at least one of the following: previous stroke/TIA, LVEF <40%, congestive heart failure, age ≥75 y, or age 65–74 y plus DM or HT or coronary artery diseaseConditions that increased the risk of hemorrhageDabigatran 110 mg bid (6015) or 150 mg bid (6076) vs warfarin INR 2–3 (6022)72 y, 64%Aspirin (<100 mg/day) permitted (21.1/19.6/20.8) during treatment period

      Also other antiplatelet agents
      Not reported2.0 y2.1/2.2/2.1RR, 0.80 (0.69–0.93) (110 mg) RR, 0.93 (0.81-1.07) (150 mg) vs control group

      ISTH
      Not reportedRR, 1.1 (0.86–1.41) (110 mg)

      RR 1.5 (1.19–1.89) (150 mg)
      Significant difference.
      vs control group
      64% mean
      Weitz et al,
      • Weitz J.I.
      • Connolly S.J.
      • Patel I.
      • et al.
      Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation.
      not reported, 2010
      AF and age 18–85 y and CHADS2 ≥1Bleeding disorder or recent major bleedingEdoxaban 30 mg qd (235) or 30 mg bid (244), or 60 mg qd (234) or 60 mg bid (180) vs dose-adjusted warfarin (INR 2–3) (250)65 y, 62%Not reportedNot reported84 days% CHADS2 score of 2, 63.3%0/2/0.4/3.3/0.4, P = .023 for 60 mg bid vs warfarin
      Significant difference.


      ISTH
      3.0/7.8/3.8/10.6/3.2

      P = .029 for 30 mg bid vs warfarin

      P = .002 for 60 mg bid vs warfarin
      Significant difference.


      The edoxaban 60-mg bid arm was terminated prematurely because of an excess of bleeding

      Standard definition
      Not reported49.7%
      Chung et al,
      • Chung N.
      • Jeon H.K.
      • Lien L.M.
      • et al.
      Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation.
      not reported, 2011
      NVAF, age 18–80 y, and CHADS2 ≥1Known bleeding disorders and conditions associated with high risk of bleedingEdoxaban 30 mg qd (79) or 60 mg (80) qd vs dose-adjusted warfarin (INR 2–3) (75)65 y, 65%Ongoing treatment with antiplatelet agents not allowed during studyNot reportedNot reported, total follow-up period, 12 wk2.0/1.9/1.80.0/0.0/2.7

      ISTH
      0.0/7.5/6.7

      Standard definition
      0.0/0.0/1.3 (only major GI bleeding reported)45.1% mean
      Ogawa et al,
      • Ogawa S.
      • Shinohara Y.
      • Kanmuri K.
      Safety and efficacy of the oral direct factor xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. The ARISTOTLE J study.
      ARISTOTLE-J, 2011
      NVAF and age ≥20 y and at least one of the following: age ≥75 y, previous stroke/TIA, LVEF ≤40%, DM, HTContraindications for warfarin use (eg, peptic ulcer), current thrombocytopenia, known or suspected hereditary bleeding tendenciesApixaban 2.5 mg bid (74), Apixaban 5 mg bid (74) vs dose-adjusted warfarin (INR 2–3 or 2–2.6 if age >69 y) (74)Mean age, 70 y, 61%Concomitant ASA use during study allowed (20.8/28.2/25.3)85 days/85 days/84 daysNot reportedMean CHADS2, 1.8/2.1/1.90.0/0.0/1.3

      ISTH
      1.4/1.4/5.3

      Standard definition
      0.0/1.4/0.0>60% of patients had INR within range for 60% of the treatment period
      Connolly et al,
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      AVERROES, 2011
      AF, ≥50 y, and at least one of the following: prior stroke/TIA, age ≥75 y, HT, DM, heart failure, LVEF <35%, peripheral artery disease and for whom vitamin K antagonist therapy was expected to be unsuitableA serious bleeding event in the previous 6 mo or a high risk of bleeding Conditions other than AF that required anticoagulationApixaban 5 mg bid and aspirin placebo (2808) vs aspirin 81–324 mg qd and apixaban placebo (2791)70 y, 59%Thienopyridine could be prescribed during the study if an indication emerged; (1%/2%), nonstudy aspirin use was discouraged but aspirin was taken in 9% of patients >50% of study timeNot reported1.1 y2.0/2.1HR, 1.13 (0.74–1.75)

      ISTH
      5.0/4.4 Definition not reportedHR, 0.86 (0.40–1.86)Not applicable
      Patel et al,
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ROCKET-AF, 2011
      NVAF and history of stroke/TIA/systemic embolism, or at least 2 of the following: heart failure or LVEF <35%, HT, age ≥75 y, or DMHistory or condition associated with an increased risk of bleedingRivaroxaban 20 mg qd and warfarin placebo (7131) vs dose-adjusted warfarin (INR 2–3) and rivaroxaban placebo (7133)73 y, 60%Aspirin (≤100 mg/day) (34.9/36.2) or thienopyridine allowed590 days707 days3.5/3.5HR, 1.04 (0.90–1.20)

      ISTH
      HR, 1.03 (0.96–1.11)

      Standard definition
      3.2/ 2.2
      Significant difference.
      (only major GI bleeds)
      58%; mean, 55%
      Granger et al,
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      ARISTOTLE, 2011
      AF and at least one of the following: age >74 y, previous stroke/TIA/systemic embolism, symptomatic heart failure or LVEF <40%, DM, HTConditions other than AF that required anticoagulation, a need for aspirin at a dose of >165 mg/day or for both aspirin and clopidogrelApixaban 5 mg bid and warfarin placebo (9120) vs dose-adjusted warfarin (INR 2–3) and apixaban placebo (9081)70 y, 65%Aspirin <165 mg/day or clopidogrel allowedNot reported1.8 y2.1/2.1HR, 0.69 (0.60–0.80)

      ISTH
      HR, 0.68 (0.61–0.75)

      Standard definition
      HR, 0.89 (0.70–1.15) (only major GI bleeds)66%; mean, 62.2%
      Bid, twice daily; CHADS2, scoring system used to identify patients in need of anticoagulation (congestive heart failure, hypertension, age, diabetes, previous stroke); DM, diabetes mellitus; HR, hazard ratio; HT, hypertension; INR, international normalized ratio; LVEF, left ventricular ejection fraction; qd, once daily; NVAF, nonvalvular AF; RR, relative risk; TIA, transient ischemic attack.
      a According to the International Society on Thrombosis and Haemostasis (ISTH) criteria
      • Schulman S.
      • Kearon C.
      • Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
      • et al.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
      /thrombolysis in myocardial infarction criteria,
      • Rao S.V.
      • Eikelboom J.A.
      • Granger C.B.
      • et al.
      Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes.
      or adjusted criteria.
      b According to the standard definition as reported in the Materials and Methods section, or adjusted definition.
      c Used the method of Rosendaal.
      • Rosendaal F.R.
      • Cannegieter S.C.
      • van der Meer F.J.
      • et al.
      A method to determine the optimal intensity of oral anticoagulant therapy.
      d Significant difference.
      Supplementary Table 2RCTs Studying New Oral Anticoagulants for the Prevention of Venous Thromboembolism After Orthopedic Surgery
      Study, trial name, yearBaseline conditionExclusion criteria, specified on bleeding riskStudy group

      (n) vs control group (n)
      Median age, % menConcomitant use of antiplatelet agents or other anticoagulants (% study /% control)Median use of study medicationMedian follow-up period, yType of surgery, mean durationMajor bleeding, % study/ % control,
      Major postoperative bleeding: starting after the first postoperative dose of study drug, but not >2 days after the last administration of study drug.
      definition of major bleeding
      According to the International Society on Thrombosis and Haemostasis (ISTH) criteria16/thrombolysis in myocardial infarction criteria,17 or adjusted criteria.
      Clinically relevant bleeding, % study/ % control,
      Major postoperative bleeding: starting after the first postoperative dose of study drug, but not >2 days after the last administration of study drug.
      definition of CRB
      According to the standard definition as reported in the Materials and Methods section, or adjusted definition.
      GIB, % study/ % control
      Eriksson et al,
      • Eriksson B.I.
      • Dahl O.E.
      • Buller H.R.
      • et al.
      A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial.
      BISTRO II, 2005
      Age ≥18 y and ≥40 kg and scheduled for primary elective THR or TKRAny bleeding diathesis, coagulation disorders, gastrointestinal bleeding within the past yearDabigatran 50 mg bid (389) or 150 mg bid (390), 300 mg qd (385) or 225 mg bid (393) and matching placebo vs enoxaparin 40 mg sc qd and matching placebo (392)66 y, 39%Short-acting NSAIDs with half-lives of less than 12 h, low-dose aspirin and COX-2 inhibitors were allowed7 daysNot reported, total study time 4–6 wk68% THR, 32% TKR, 1.4 h0.3/4.1/4.7/3.8/2.0
      During treatment period, not during the follow-up period.


      ISTH
      2.6/8.2/8.3/8.4/4.6
      During treatment period, not during the follow-up period.


      Standard definition
      Not reported
      Turpie et al,
      • Turpie A.G.
      • Fisher W.D.
      • Bauer K.A.
      • et al.
      BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study.
      ODIXa-KNEE, 2005
      Male patients age ≥18 y or postmenopausal women scheduled for elective TKRAny bleeding disorderRivaroxaban 2.5 mg bid (100), 5 mg bid (102), 10 mg bid (103), 20 mg bid (98) or 30 mg bid (106) and matching placebo vs enoxaparin 30 mg bid sc (104) and matching placebo67 y, 39%Anticoagulants, platelet aggregation inhibitors, or any other drug influencing coagulation prohibited at inclusion

      NSAIDs with half-life <17 h allowed
      Mean, 7.3 daysNot reported, total follow-up period, 30–60 days100% TKR, 89 min1.0/0.0/1.9/3.1/7.5/1.9
      During treatment period, not during the follow-up period.


      ISTH
      3.0/2.9/2.9/8.2/14.2/4.8
      During treatment period, not during the follow-up period.


      Standard definition
      Not reported
      Eriksson et al,
      • Eriksson B.I.
      • Borris L.
      • Dahl O.E.
      • et al.
      Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement.
      ODIXa-HIP I 2006
      Male patients age ≥18 y or postmenopausal women scheduled for elective THRAny bleeding disorderRivaroxaban 2.5 mg (135) bid, 5 mg bid (139), 10 mg bid (138), 20 mg bid (137), or 30 mg bid (37) and matching placebo vs enoxaparin 40 mg qd sc (136) and matching placebo65 y, 40%Anticoagulants, platelet aggregation inhibitors or any other drug influencing coagulation prohibited at inclusion

      NSAIDs with half-life <17 h allowed
      Mean, 8.3 daysNot reported, total follow-up period, 30–60 days100% THR, 85 min0.8/2.2/2.3/4.5/5.4/1.5
      During treatment period, not during the follow-up period.


      ISTH
      2.3/8.0/4.5/9.0/8.1/1.5
      During treatment period, not during the follow-up period.


      Standard definition
      Major: 0.0/0.0/0.0/0.0/0.0/0.8
      Eriksson et al,
      • Eriksson B.I.
      • Borris L.C.
      • Dahl O.E.
      • et al.
      A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement.
      ODIXa-HIP II, 2006
      Men aged >17 y and postmenopausal women scheduled for elective, primary THRGastrointestinal bleeding in the previous 6 moRivaroxaban 5 mg qd (128),10 mg qd (142), 20 mg qd (140, 30 mg qd (143), or 40 mg (142) qd plus matching placebo vs enoxaparin 40 mg sc qd plus matching placebo (157)65 y, 41%Only NSAIDs with a half-life <17 h allowed7/8 daysNot reported, total follow-up period, 30–60 days100% THR, 87 min2.3/0.7/4.3/4.9/5.1/1.9
      During treatment period, not during the follow-up period.


      ISTH
      3.9/2.8/5.0/7.0/8.0/5.1
      During treatment period, not during the follow-up period.


      Standard definition
      Not reported
      Eriksson et al,
      • Eriksson B.I.
      • Borris L.C.
      • Dahl O.E.
      • et al.
      Dose-escalation study of rivaroxaban (BAY 59-7939)–an oral, direct Factor Xa inhibitor–for the prevention of venous thromboembolism in patients undergoing total hip replacement.
      not reported, 2007
      Men aged ≥18 y and postmenopausal women scheduled for elective, primary THRNo statement about exclusion of patients with higher risk of bleedingRivaroxaban 2.5 mg bid (77), 5 mg bid (84), 10 mg bid (68), 30 mg qd (91), 20 mg bid (79), 30 mg bid (80) vs enoxaparin 40 mg sc qd (162)65 y, 41%Only NSAIDs with a half-life <17 h allowed7/8 daysNot reported, total follow-up period, 30–60 days100% THR, duration, NS0/2.5/2.9/4.5/6.5/10.8
      During treatment period, not during the follow-up period.


      ISTH
      2.6/3.8/7.3/11.3/11.7/20.3/1.9
      During treatment period, not during the follow-up period.


      Standard definition
      0.0/0.0/0.0/1.1/0.0/0.0/0.0
      During treatment period, not during the follow-up period.
      Eriksson et al,
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial.
      RE-MODEL, 2007
      Patients ≥18 y and >40 g, scheduled for primary elective unilateral TKRAny bleeding diathesis, GIB or ulcer disease within the past 6 moDabigatran etexilate 150 mg qd (679) or 220 mg qd (703) and matching placebo vs enoxaparin 40 mg sc qd (694) and matching placebo68 y, 34%Concomitant treatment with low-dose aspirin (<160 mg) and selective COX2-inhibitors was allowed8/7 daysNot reported100% TKR, 91 min1.3/1.5/1.3
      During treatment period, not during the follow-up period.


      ISTH
      6.8/5.9/5.3
      During treatment period, not during the follow-up period.


      Standard definition
      Not reported
      Lassen et al,
      • Lassen M.R.
      • Davidson B.L.
      • Gallus A.
      • et al.
      The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.
      APROPOS, 2007
      Patients 18–90 y scheduled for TKRBleeding/coagulation disorder, GIB within 90 days of surgery or ulcer disease within 30 days before surgeryApixaban 2.5 mg bid (153), 5 mg qd (157), 5 mg bid (157), 10 mg qd (156), 10 mg bid (154), 20 mg qd (156) and enoxaparin placebo vs warfarin (INR, 1.8–3.0) (153) or enoxaparin 30 mg sc bid (152) and apixaban placebo67 y, 37%No co-use of medications affecting coagulation/platelet function allowedNot reportedNot reported, final evaluation on day 42100% TKR, 1.56 h0/2.6/2.6/0.6/2.6/3.3/0/0
      During treatment period, not during the follow-up period.


      ISTH
      Major and potentially significant nonovert: 0/2.6/2.6/1.2/2.6/3.3/0/1.3
      During treatment period, not during the follow-up period.


      Adjusted definition
      Major bleeding: 0/0/0/0/0.6/0/0/0
      During treatment period, not during the follow-up period.
      Eriksson et al,
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.
      RE-NOVATE, 2007
      Patients ≥18 y and >40 kg scheduled for elective unilateral THRBleeding diathesis, history of GIB or ulcer disease in the past 6 moDabigatran etexilate 150 mg qd (1163) or 220 mg qd (1146) and matching placebo vs enoxaparin 40 mg sc qd (1154) and matching placebo64 y, 44%Concomitant administration of low-dose aspirin (<160 mg) and selective COX-2 inhibitors or short-acting NSAIDs were allowed33 days94 days100% THR, 86 min1.3/2.0/1.6
      During treatment period, not during the follow-up period.


      ISTH
      6.0/6.2/5.1
      During treatment period, not during the follow-up period.


      Standard definition
      1 Fatal event in 150 mg group with septicemia and GIB
      Eriksson et al,
      • Eriksson B.I.
      • Borris L.C.
      • Friedman R.J.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.
      RECORD-I 2008
      Patients ≥18 y and scheduled for elective THRActive bleeding or high risk of bleedingRivaroxaban 10 mg qd (2266) and matching placebo vs enoxaparin 40 mg sc qd (2275) and matching placebo63 y, 45%Other anticoagulant therapy prohibited at inclusion33.4/33.7 daysFollow-up visit 30–35 days after last study drug100% THR, 91 min0.3/0.1
      During treatment period, not during the follow-up period.
      P = .18

      ISTH
      3.2/2.5
      During treatment period, not during the follow-up period.


      No definition reported
      0.1/<0.1
      During treatment period, not during the follow-up period.
      Lassen et al,
      • Lassen M.R.
      • Ageno W.
      • Borris L.C.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.
      RECORD III, 2008
      Patients ≥18 y and scheduled for TKRActive bleeding or high risk of bleeding that contraindicated the use of LMWHRivaroxaban 10 mg qd (1220) and matching placebo vs enoxaparin 40 mg sc qd (1239) and matching placebo68 y, 32%Other anticoagulant therapy prohibited at inclusion11.9/12.5 daysFollow-up visit 30–35 days after last study drug100% TKR, 97 min0.6/0.5
      During treatment period, not during the follow-up period.


      ISTH
      3.3/2.7
      During treatment period, not during the follow-up period.


      No definition reported
      Not reported
      Kakkar et al,
      • Kakkar A.K.
      • Brenner B.
      • Dahl O.E.
      • et al.
      Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.
      RECORD II, 2008
      Patients ≥18 y and scheduled for elective THRActive bleeding or high risk of bleeding that contraindicated the use of LMWHRivaroxaban 10 mg qd (1228) and matching placebo vs enoxaparin 40 mg sc qd (1229) and matching placebo62 y, 46%Other anticoagulant therapy prohibited at inclusion33.5/12.4 daysFollow-up visit 30–35 days after last study drug100% THR, 94 min<0.1/<0.1
      During treatment period, not during the follow-up period.


      ISTH
      3.3/2.8
      During treatment period, not during the follow-up period.


      No definition reported
      <0.1/0.0
      During treatment period, not during the follow-up period.
      Ginsberg et al,
      • Committee R.-M.W.
      • Ginsberg J.S.
      • Davidson B.L.
      • et al.
      Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery.
      RE-MOBILIZE, 2009
      Patients ≥18 y and >40 kg scheduled for primary elective unilateral TKRClinically significant bleeding disorder, GIB, or ulcer disease within the past 6 moDabigatran etexilate 150 mg qd (877) or 220 mg qd (862) and matching placebo vs enoxaparin 30 mg sc bid (876) and matching placebo66 y, 42%Concomitant administration of low-dose aspirin (<160 mg) and selective COX-2 inhibitors or short-acting NSAIDs were allowed14 daysNot reported, 94% were followed up for 3 mo100% TKR, 91 min0.8/0.7/1.4
      During treatment period, not during the follow-up period.


      ISTH
      3.6/4.0/4.1
      During treatment period, not during the follow-up period.


      Standard definition
      Not reported
      Turpie et al,
      • Turpie A.G.
      • Bauer K.A.
      • Davidson B.L.
      • et al.
      A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT).
      EXPERT, 2009
      Patients 18–75 y and 50–120 kg scheduled for primary elective unilateral TKRBleeding disorders, a recent episode of internal bleeding or at high risk of bleedingBetrixaban 15 mg bid (87) or 40 mg bid (84) vs enoxaparin 30 mg sc bid (43)64 y, 40%Use of thrombolytic agents and anticoagulants was prohibited within 7 days before surgery and throughout the treatment period; use of aspirin <325 mg and NSAIDs were allowed but discouraged11/10.3 daysNot reported100% TKR, duration not reported0.0/0.0/2.3
      During treatment period, not during the follow-up period.


      Modified ISTH
      0.0/2.4/7.0
      During treatment period, not during the follow-up period.


      No definition reported
      Not reported
      Turpie et al,
      • Turpie A.G.
      • Lassen M.R.
      • Davidson B.L.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial.
      RECORD IV, 2009
      Patients ≥18 y and scheduled for elective TKRActive bleeding or high risk of bleeding that contraindicated the use of LMWHRivaroxaban 10 mg qd (1584) and matching placebo vs enoxaparin 30 mg sc bid (1564) and matching placebo65 y, 35%Not reported11.7/11.0 daysPatients were followed up for 30–35 days after the last dose100% TKR, 100 min0.7/0.3
      During treatment period, not during the follow-up period.
      P = .11

      ISTH
      3.0 /2.3
      During treatment period, not during the follow-up period.


      Standard definition
      1 fatal UGIB in rivaroxaban arm
      Lassen et al,
      • Lassen M.R.
      • Raskob G.E.
      • Gallus A.
      • et al.
      Apixaban or enoxaparin for thromboprophylaxis after knee replacement.
      ADVANCE I, 2009
      Patients ≥18 y and scheduled for elective TKR or revisionBleeding or coagulation disorder, active bleeding or high risk of bleeding, ongoing need for oral anticoagulant therapyApixaban 2.5 mg bid (1599) and matching placebo vs enoxaparin 30 mg sc bid (1596) and matching placebo66 y, 38%Only NSAIDs with a half-life <17 hours allowed11.7/11.6 daysFollow-up at 30 and 60 days after last dose100% TKR, 1.54 h0.7/1.4
      During treatment period, not during the follow-up period.
      P = .053 ISTH
      2.9/4.3
      During treatment period, not during the follow-up period.
      P = .03

      Standard definition
      <0.1/0.6
      During treatment period, not during the follow-up period.
      Fuji et al,
      • Fuji T.
      • Fuijita S.
      • Ujihira T.
      • et al.
      Dabigatran etexilate prevents venous thromboembolism after total knee arthroplasty in Japanese patients with a safety profile comparable to placebo.
      not reported, 2010
      Patients >19 y and at least 40 kg scheduled for primary unilateral elective total knee replacementAny bleeding diathesis, clinically relevant bleeding, or ulcer bleeding within the past 6 moDabigatran etexilate 110 mg qd (133), 150 mg qd (126), or 220 mg qd (129) vs placebo (124)

      LMWH not yet registered in Japan at this time
      72 y, 17%The concomitant use of anticoagulants and antiplatelet agents was prohibited13 daysFollow-up 7–10 days after last dose100% TKR, 109 min0.8/0.0/2.3/0.8
      During treatment period, not during the follow-up period.


      ISTH
      0.8/0.8/3.9/3.2
      During treatment period, not during the follow-up period.


      Standard definition
      Not reported
      Lassen et al,
      • Lassen M.R.
      • Raskob G.E.
      • Gallus A.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial.
      ADVANCE II, 2010
      Patients scheduled for elective TKRActive bleeding or needed continuing anticoagulant or anti-platelet treatmentApixaban 2.5 mg bid (1528) and matching placebo vs enoxaparin 40 mg sc qd (1529) and matching placebo67 y, 38%Other anticoagulant or antiplatelet therapy prohibited at inclusion12.1/12.1 daysFollow-up at 30 and 60 days after last dose100% TKR, 1.58 h0.6/0.9
      During treatment period, not during the follow-up period.


      ISTH
      3.5/4.8
      During treatment period, not during the follow-up period.


      Standard definition
      0.2/0.3
      During treatment period, not during the follow-up period.
      Raskob et al,
      • Raskob G.
      • Cohen A.T.
      • Eriksson B.I.
      • et al.
      Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study.
      not reported, 2010
      Patients ≥18 y and scheduled for elective THRKnown or suspected bleeding or coagulation disorder or GIB or peptic ulcer within the past 3 moEdoxaban 15 mg qd (193), 30 mg qd (171), 60 mg qd (187), or 90 mg qd (177) and matching placebo vs dalteparin 5000 IU sc qd (175) and matching placebo58 y, 40%Only aspirin <100 mg qd allowedNot reportedFollow-up at 30 and 60 days after last dose100% THR, 1.38 h0.5/0.6/0.5/1.1/0.0
      During treatment period, not during the follow-up period.


      ISTH
      1.6/1.8/2.2/2.3/0.0
      During treatment period, not during the follow-up period.


      Standard definition
      Not reported
      Fuji et al,
      • Fuji T.
      • Fujita S.
      • Tachibana S.
      • et al.
      A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty.
      not reported, 2010
      Patients 20–84 y and scheduled for primary elective TKRHistory of GIB or peptic ulcerEdoxaban 5 mg qd (105), 15 mg qd (106), 30 mg qd (104), 60 mg qd (106) vs placebo (102)

      LMWH not yet registered in Japan at this time
      71 y, 21%Other anticoagulant or antiplatelet therapy prohibited at inclusion

      Use of dextran was allowed
      Not reportedFollow-up 25–35 days after last dose100% TKR, 1.50 h0.0/0.0/0.0/0.9/0.0
      During treatment period, not during the follow-up period.


      ISTH
      1.9/3.8/3.9/4.7/3.9
      During treatment period, not during the follow-up period.


      Adjusted definition
      Not reported
      Lassen et al,
      • Lassen M.R.
      • Gallus A.
      • Raskob G.E.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.
      ADVANCE III, 2010
      Patients scheduled for elective THR or revisionBleeding or coagulation disorder, active bleeding or high risk of bleeding, ongoing need for oral anticoagulant therapyApixaban 2.5 mg bid (2708) and matching placebo vs enoxaparin 40 mg sc qd (2699) and matching placebo61 y, 47%Only NSAIDs with a half-life <17 h allowed34.0/33.9 daysFollow-up 65 and 95 days after last dose100% THR, 1.49 h0.8/0.7
      During treatment period, not during the follow-up period.


      ISTH
      4.8/5.0
      During treatment period, not during the follow-up period.


      Standard definition
      0.1/0.0
      During treatment period, not during the follow-up period.
      Eriksson et al,
      • Eriksson B.I.
      • Dahl O.E.
      • Huo M.H.
      • et al.
      Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial.
      RE-NOVATE-II 2011
      Patients ≥18 y and scheduled for elective THRClinically significant bleeding disorder, GIB or ulcer disease within the past 6 moDabigatran 220 mg qd (1036) and matching placebo vs enoxaparin 40 mg sc qd (1019) and matching placebo62 y, 48 %No co-use of medications affecting coagulation/platelet function allowed

      Concomitant administration of low-dose aspirin (<160 mg) and selective COX-2 inhibitors or short-acting NSAIDs were allowed
      32 days92 days100% THR, 80 min1.4/0.9
      During treatment period, not during the follow-up period.


      ISTH
      3.7/2.9
      During treatment period, not during the follow-up period.


      Adjusted definition
      Not reported
      Bid, twice daily; COX-2, cyclooxygenase 2; HR, hazard ratio; LMWH, low-molecular-weight-heparin; qd, once daily; THR, total hip replacement; TKR, total knee replacement; sc, subcutaneously; UGIB, upper gastrointestinal bleeding.
      a Major postoperative bleeding: starting after the first postoperative dose of study drug, but not >2 days after the last administration of study drug.
      b According to the International Society on Thrombosis and Haemostasis (ISTH) criteria
      • Schulman S.
      • Kearon C.
      • Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
      • et al.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
      /thrombolysis in myocardial infarction criteria,
      • Rao S.V.
      • Eikelboom J.A.
      • Granger C.B.
      • et al.
      Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes.
      or adjusted criteria.
      c According to the standard definition as reported in the Materials and Methods section, or adjusted definition.
      d During treatment period, not during the follow-up period.
      Supplementary Table 3RCTs Studying New Oral Anticoagulants for the Prevention of Venous Thromboembolism in Medically Ill Patients
      Study, trial name, yearBaseline conditionExclusion criteria, specified on bleeding riskStudy group

      (n) vs control group (n)
      Median age, % menConcomitant use of antiplatelet agents or other anticoagulants, % study /% controlMedian use of study medicationMedian follow-up period, yMajor bleeding, RR (95% CI) or % study/ % control
      Major postoperative bleeding: starting after the first postoperative dose of study drug, but not >2 days after the last administration of study drug.
      Definition of major bleeding
      According to the ISTH (International Society on Thrombosis and Haemostasis) criteria16/TIMI (thrombolysis in myocardial infarction) criteria,17 or adjusted criteria.
      Clinically relevant bleeding, RR (95% CI) or % study/% control
      Major postoperative bleeding: starting after the first postoperative dose of study drug, but not >2 days after the last administration of study drug.
      Definition of CRB
      According to the standard definition as reported in the method section, or adjusted definition.
      GIB, % study/ % control
      Goldhaber et al,
      • Goldhaber S.Z.
      • Leizorovicz A.
      • Kakkar A.K.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients.
      ADOPT, 2011
      Patients age ≥40 y hospitalized for CHF, acute respiratory failure or for infection, acute rheumatic disorder, IBD, and at least 1 additional risk factor for VTE and an expected hospital stay of at least 3 days and moderately or severely restricted in mobilityA disease requiring ongoing treatment with parenteral or oral anticoagulant agent, thrombocytopenia, actively bleeding or at high risk for bleedingApixaban 2.5 mg bid and placebo (3255) vs enoxaparin sc 40 mg qd and placebo (3273)68 y, 49%Patients with ≥2 antiplatelet agents or aspirin at a dose >165 mg/day were excludedMean, 24.9/7.3 daysNot reportedRR, 2.58 (1.02–7.24)

      ISTH
      RR, 1.28 (0.93–1.76)

      Standard definition
      Not reported
      Levine et al,
      • Levine M.N.
      • Gu C.
      • Liebman H.A.
      • et al.
      A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer.
      not reported, 2012
      Patients >18 y receiving first-line or second-line chemotherapy for advanced or metastatic lung, breast, GI, bladder, cancer of unknown origin, ovarian or prostate cancer, myeloma or selected lymphomas and if the expected course of chemotherapy was ≥90 daysActive bleeding or high risk for bleeding, presence of a coagulopathy, requiring long-term oral anticoagulant therapyApixaban 5 mg qd (32), 10 mg qd (30), 20 mg qd (33) vs placebo (30)60 y, 50%Aspirin in a dose ≤165 mg allowed, clopidogrel, cilostazol, or aspirin-dipyridamole prohibitedMean 79.2/76.0/ 73.6/69.9 daysTotal, 12 wk, completed by 78%/80%/76%/ 63%0.0/0.0/6.3/3.4 ISTH3.1/3.4/12.5/3.4

      Adjusted definition
      3.1/0/3.1/3.4
      Bid, twice daily; CHF, chronic heart failure; IBD, inflammatory bowel disease; qd, once daily; sc, subcutaneously; RR, risk ratio; VTE, venous thromboembolism.
      a Major postoperative bleeding: starting after the first postoperative dose of study drug, but not >2 days after the last administration of study drug.
      b According to the ISTH (International Society on Thrombosis and Haemostasis) criteria
      • Schulman S.
      • Kearon C.
      • Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
      • et al.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
      /TIMI (thrombolysis in myocardial infarction) criteria,
      • Rao S.V.
      • Eikelboom J.A.
      • Granger C.B.
      • et al.
      Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes.
      or adjusted criteria.
      c According to the standard definition as reported in the method section, or adjusted definition.
      Supplementary Table 4RCTs Studying New Oral Anticoagulants for the Treatment of Acute Symptomatic Deep Vein Thrombosis or Pulmonary Embolism
      Study, yearBaseline conditionExclusion criteria, specified on bleeding riskStudy group

      (n) vs control group (n)
      Median age, % menConcomitant use of antiplatelet agents or other anticoagulants, % study /% controlMean use of study medicationMedian follow-up periodINR within therapeutic range in control group, median time
      Using the method of Rosendaal.
      Major bleeding % study/ % control

      Definition of major bleeding
      According to the International Society on Thrombosis and Haemostasis (ISTH) criteria16/thrombolysis in myocardial infarction criteria,17 or adjusted criteria.
      Clinically relevant bleeding HR, RR (95% CI) or % study/ % control

      Definition of CRB
      According to the standard definition as reported in the Materials and Methods section, or adjusted definition.
      GIB HR, RR (95% CI) or % study/ % control
      Agnelli et al,
      • Agnelli G.
      • Gallus A.
      • Goldhaber S.Z.
      • et al.
      Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study.
      ODIXa-DVT, 2007
      Patients with symptomatic acute thrombosis of the popliteal or more proximal veins and age ≥18 y and no symptoms of PEIntracerebral or gastrointestinal bleeding within the past 6 mo, an active peptic ulcer or known bleeding disorderRivaroxaban 10 mg bid (119), 20 mg bid (117), 30 mg bid (121), 40 mg qd (121) vs enoxaparin
      For at least 5 days until the INR was 2–3 for 2 consecutive days.
      and a VKA for 12 wk (126)
      59 y, 61%Thrombolytic therapy or treatment with antiplatelet agents, NSAIDs with a half-life >17 h are prohibited, short-term analgesia with ASA 500 mg/d permittedNot reportedNot reported; total study time, 12 wk60%1.7/1.7/3.3/1.7/0.0

      ISTH
      Not reportedNot reported
      Buller et al,
      • Botticelli Investigators Writing Committee
      • Buller H.
      • Deitchman D.
      • et al.
      Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study.
      BOTTICELLI 2008
      Patients with acute symptomatic proximal DVT or extensive calf vein thrombosis and no symptoms of PEActive bleeding or high risk of bleedingApixaban 5 mg bid (130), 10 mg bid (134), or 20 mg qd (128) vs tinzaparin, enoxaparin, or fondaparinux
      For at least 5 days until the INR was 2–3 for 2 consecutive days.
      and a VKA (128)
      59 y, 62%ASA <165 mg/day allowed80/81/77/80/82Not reported; total study time, 12 weeks57%0.8/0.0/1.6/0.0

      ISTH
      8.6/4.5/8.9/7.9

      Standard definition
      Not reported
      Buller et al,
      • Buller H.R.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study.
      EINSTEIN-DVT, 2008
      Patients with acute symptomatic proximal DVT or extensive calf vein thrombosis and no symptoms of PEActive bleeding or high risk of bleedingRivaroxaban 20 mg qd (135), 30 mg qd (134), or 40 mg qd (136) vs unfractioned heparin,
      For at least 5 days until the INR was 2–3 for 2 consecutive days.
      tinzaparin, or enoxaparin (137) and VKA
      58 y, 51%Use of NSAIDs and antiplatelet agents was discouraged

      If indicated, aspirin (up to 100 mg/day), clopidogrel (75 mg/day), or both were allowed
      Median, 85 days/not reportedNot reported; end of study, 84 days50.30.7/1.5/0/1.5

      ISTH
      5.9/6.0/2.2/8.8

      Standard definition
      Not reported
      Schulman et al,
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      RE-COVER, 2009
      Patients ≥18 y with acute symptomatic DVT of the legs or PEHigh risk of bleedingDabigatran 150 mg bid (1273) and matching placebo vs parenteral anticoagulation
      For at least 5 days until the INR was 2–3 for 2 consecutive days.
      and warfarin (1266) and matching placebo
      56 y, 58%Not reported163.4/163.9 daysNot reported; total study time, 6 mo59.9HR, 0.82 (0.45–1.48)

      ISTH
      HR, 0.63 (0.47–0.84)
      Significant difference.


      Adjusted definition
      4.2/2.8
      Bauersachs et al,
      • EINSTEIN Investigators E
      • Bauersachs R.
      • Berkowitz S.D.
      • et al.
      Oral rivaroxaban for symptomatic venous thromboembolism.
      EINSTEIN-ACUTE DVT, 2010
      This report consisted of 2 trials; 1 for the treatment of acute DVT and 1 for continued treatment in patients who received treatment for acute DVT or PE.
      Legal age for consent symptomatic DVT, without symptomatic PEActive bleeding or high risk of bleedingRivaroxaban 15 mg bid for 3 wk, followed by 20 mg qd (1731) vs enoxaparin
      For at least 5 days until the INR was 2–3 for 2 consecutive days.
      and VKA (INR, 2.0–3.0) (1718)
      Mean age, 56 y, 57%Use of NSAIDs and antiplatelet agents was discouraged

      If indicated, aspirin (up to 100 mg/day), clopidogrel (75 mg/day), or both were allowed
      Not reported; total, 3–12 mo based on intended treatment durationNot reported; total study time, 3, 6, or 12 moOverall the INR was in the therapeutic range for 57.7% of the timeHR, 0.65 (0.33–1.30)

      ISTH
      8.1/8.1

      Standard definition
      Not reported
      Bauersachs et al,
      • EINSTEIN Investigators E
      • Bauersachs R.
      • Berkowitz S.D.
      • et al.
      Oral rivaroxaban for symptomatic venous thromboembolism.
      EINSTEIN-EXTENSION, 2010
      This report consisted of 2 trials; 1 for the treatment of acute DVT and 1 for continued treatment in patients who received treatment for acute DVT or PE.
      DVT or PE and treated for 6–12 mo with a VKA or rivaroxabanActive bleeding or high risk of bleedingRivaroxaban 20 mg qd (602) vs placebo (595)Mean, 58 y, 58%Use of NSAIDs and antiplatelet agents was discouraged

      If indicated, aspirin (up to 100 mg/day), clopidogrel (75 mg/day), or both were allowed
      Not reported; total, 6–12 moNot reported; total study time, 6–12 moNot applicable0.7/0.0

      ISTH
      HR, 5.19 (2.3–11.7)
      Significant difference.


      Standard definition
      0.7/0.0
      Buller et al,
      • EINSTEIN-PE Investigators
      • Buller H.R.
      • Prins M.H.
      • et al.
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      EINSTEIN-PE, 2012
      This report consisted of 2 trials; 1 for the treatment of acute DVT and 1 for continued treatment in patients who received treatment for acute DVT or PE.
      Acute symptomatic PE, with or without DVTActive bleeding or high risk of bleeding contraindicating anticoagulant treatmentRivaroxaban 15 mg bid first 3 wk, followed by 20 mg qd (2419) vs enoxaparin and VKA (INR, 2.0-3.0) (2413)
      For at least 5 days until the INR was 2–3 for 2 consecutive days.
      Mean, 58 y, 53%The use of NSAIDs and antiplatelet agents was discouraged

      Aspirin <100 mg/day and clopidogrel at a dose of 75 mg/day were allowed
      214/216 days268/263 days62.7%1.1/2.2

      ISTH
      10.5/11.9

      Standard definition
      Not reported
      ASA, acetylsalicylic acid; bid, twice daily; HR, hazard ratio; INR, international normalized ratio; qd, once daily; RR, risk ratio.
      a Using the method of Rosendaal.
      b According to the International Society on Thrombosis and Haemostasis (ISTH) criteria
      • Schulman S.
      • Kearon C.
      • Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
      • et al.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
      /thrombolysis in myocardial infarction criteria,
      • Rao S.V.
      • Eikelboom J.A.
      • Granger C.B.
      • et al.
      Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes.
      or adjusted criteria.
      c According to the standard definition as reported in the Materials and Methods section, or adjusted definition.
      d For at least 5 days until the INR was 2–3 for 2 consecutive days.
      e Significant difference.
      f This report consisted of 2 trials; 1 for the treatment of acute DVT and 1 for continued treatment in patients who received treatment for acute DVT or PE.
      Supplementary Table 5RCTs Studying New Oral Anticoagulants for the Treatment of Acute Coronary Syndrome
      Study, trial name, yearBaseline conditionExclusion criteria, specified on bleeding riskStudy group

      (n) vs control group (n)
      Median age, % menConcomitant use of antiplatelet agents or other anticoagulants, % study /% controlMedian use of study medicationMedian follow-up periodMajor bleeding, % study/ % control

      Definition of major bleeding
      According to the International Society on Thrombosis and Haemostasis (ISTH) criteria16/thrombolysis in myocardial infarction (TIMI) criteria,17 or adjusted criteria.
      Clinically relevant bleeding, RR or HR (95% CI) or % study/% control Definition of clinically relevant bleeding
      According to the standard definition as reported in the Materials and Methods section, or adjusted definition.
      GIB HR, RR or % study/ % control
      APPRAISE Steering Committee and Investigators,
      • APPRAISE Steering Committee and Investigators
      • Alexander J.H.
      • Becker R.C.
      • et al.
      Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.
      APPRAISE, 2009
      Patients 18–90 y with a recent ACS, and at least 1 additional risk factor for recurrent ischemic eventsCoagulopathy, active bleeding, or high risk of bleedingPhase A: apixaban 2.5 mg bid (179), 10 mg qd (184)

      Phase B: apixaban 2.5 mg bid (138), 10 mg qd (134), 10 mg bid (248), or 20 mg qd (221) vs Phase A: placebo (184), Phase B: placebo (427)
      61 y, 76%All patients were to receive aspirin <165 mg/day (99.7/99.7/100/100/100)

      The use of clopidogrel was left to the discretion of the treating physician >75% received dual antiplatelet therapy
      22.1/21.5/12.7/10.9/ 21.7/ wkNot reported, total follow-up period of study, 6 moPhase A and B: 2.5 mg bid and 10 mg qd: 1.6/1.9/0.8

      The 2 higher-dose apixaban arms were discontinued because of excess total bleeding

      Phase B: 0.8/0.0/2.9/4.1/0.0

      ISTH
      Phase A and B: 2.5 mg bid and 10 mg qd: 5.7/7.9/3.0

      HR, 2.5 mg bid: 1.78 (0.91–3.48)

      HR, 10 mg qd: 2.45 (1.31–4.61)
      Statistically significant.


      Phase B: 5.0/5.6/7.8/7.3/0.8

      Standard definition
      Phase A and B: 2.5 mg bid and 10 mg qd

      5.7/2.5/0.8
      Mega et al,
      • Mega J.L.
      • Braunwald E.
      • Mohanavelu S.
      • et al.
      Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.
      ATLAS ACS-TIMI 46, 2009
      Patients >17 y with ACS and at least 1 extra risk factorA hemoglobin concentration <100 g/L, a platelet count <90,000 per uL of blood, or a history of any intracranial hemorrhageRivaroxaban 5 mg qd (231), 10 mg qd (294), 20 mg qd (236) with aspirin only or 5 mg qd (228), 10 mg qd (1288), 15 mg qd (534), 20 mg qd (680) with aspirin and thienopyridine vs placebo (1160)57 y, 77%Warfarin prohibited at inclusion

      Aspirin: ASA/ASA + thienopyridine/ placebo: 99.2/98.9/99.0

      Thienopyridine: 80.8 (baseline)
      Not reportedNot reported; total follow-up period of study, 6 moWith aspirin only:

      0.0/2.2/0.0/0.0

      With aspirin + thienopyridine: 0.7/1.5/1.8/1.8/0.1

      TIMI
      5 mg: HR, 2.21 (1.25–3.91)
      Statistically significant.


      10 mg: HR, 3.35 (2.31–4.87)
      Statistically significant.


      15 mg: HR, 3.60 (2.32–5.58)
      Statistically significant.


      20 mg: HR, 5.06 (3.45–7.42)
      Statistically significant.


      TIMI clinically significant
      0.8/1.2 needed colonoscopy or upper endoscopy because of bleeding
      Alexander et al,
      • Alexander J.H.
      • Lopes R.D.
      • James S.
      • et al.
      Apixaban with antiplatelet therapy after acute coronary syndrome.
      APPRAISE-II, 2011
      Patients with a recent ACS and at least 2 additional high-risk characteristicsCoagulopathy, active bleeding, or high risk of bleedingApixaban 5 mg bid (3705) vs placebo (3687)67 y, 68%Parenteral or oral anticoagulants or high-dose aspirin (>325 mg/day) prohibited at inclusion

      The use, choice, and duration of antiplatelet therapy and other medical therapy were left to the discretion of the treating physician
      175/185 days240/242 days2.7/1.1 HR 2.48 (1.72–3.58)#

      After recruitment of about 7000 patients the trial was stopped, owing to an excess of clinically important bleeding events with apixaban in the absence of a counterbalancing reduction in ischemic events

      ISTH
      3.2/1.2; HR, 2.64 (1.87–3.72)
      Statistically significant.


      Standard definition
      Not reported
      Oldgren et al,
      • Oldgren J.
      • Budaj A.
      • Granger C.B.
      • et al.
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.
      RE-DEEM, 2011
      Patients ≥ 18 y hospitalized with MI within the past 14 days receiving dual antiplatelet therapy and at least 1 risk factor for subsequent cardiovascular complicationsOngoing or planned treatment with VKA, conditions associated with an increased risk of bleeding such as history of severe bleeding, GI hemorrhage within the past year, PUD in the previous 30 daysDabigatran 50 mg bid (372), 75 mg bid (371), 110 mg bid (411), or 150 mg bid (351) vs placebo (373)Mean, 62 y, 76%The daily aspirin dose was strongly advised to be ≤100 mg, but higher doses were permitted according to local practice

      The recommended daily dose of clopidogrel was 75 mg, although loading doses of 300–600 mg were allowed for PCI procedures (aspirin and clopidogrel at randomization, 99.2%; aspirin only, 0.4%; aspirin and clopidogrel at 26 weeks, 83.8; aspirin only, 14.2%)
      Range, 158.9–164.4 days for the dabigatran groups and 164.7 days for the placebo groupTotal, 28 wk0.8/0.3/2.0/1.2/0.5

      ISTH
      50 mg: HR, 1.77 (0.70–4.50), 75 mg: HR, 2.17 (0.88–5.31), 110 mg: HR, 3.92 (1.72–8.95), 150 mg: 4.27 (1.86–9.81)
      Statistically significant.


      Standard definition
      2.4/3.0/4.9/

      3.2/1.3
      Mega et al,
      • Mega J.L.
      • Braunwald E.
      • Wiviott S.D.
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      ATLAS ACS 2-TIMI 51, 2012
      Patients ≥18 y with MI or unstable angina Patients <55 y had in addition either DM or a previous MIClinically significant GIB within 12 mo before randomizationRivaroxaban 2.5 mg qd (5174), 5 mg qd (5176) vs placebo (5176)Mean, 62 y, 75%All patients were to receive low-dose aspirin; they were to receive a thienopyridine according to the national guidelines13.1 moNot reported; maximum, 31 mo1.8/2.4/0.6

      TIMI
      11.5/15.0/6.3

      TIMI clinically significant
      Not reported
      ASA, acetylsalicylic acid; bid, twice daily; HR, hazard ratio; MI, myocardial infarction; PCI, percutaneous coronary intervention; PUD, peptic ulcer disease; RR, relative risk.
      a According to the International Society on Thrombosis and Haemostasis (ISTH) criteria
      • Schulman S.
      • Kearon C.
      • Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
      • et al.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
      /thrombolysis in myocardial infarction (TIMI) criteria,
      • Rao S.V.
      • Eikelboom J.A.
      • Granger C.B.
      • et al.
      Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes.
      or adjusted criteria.
      b According to the standard definition as reported in the Materials and Methods section, or adjusted definition.
      c Statistically significant.
      Supplementary Table 6Registered/Recommended Dose per Indication
      RivaroxabanApixabanDabigatranEdoxabanBetrixaban
      AF20 mg qd
      Registered dose at the European Medicines Agency.
      ,
      Registered dose at the Food and Drug Administration.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      5 mg bid
      Registered dose at the Food and Drug Administration.
      ,
      By request of the pharmaceutical company.
      • Ogawa S.
      • Shinohara Y.
      • Kanmuri K.
      Safety and efficacy of the oral direct factor xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. The ARISTOTLE J study.
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      150 mg bid
      Registered dose at the European Medicines Agency.
      ,
      Registered dose at the Food and Drug Administration.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Ezekowitz M.D.
      • Reilly P.A.
      • Nehmiz G.
      • et al.
      Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study).
      60 mg qd
      By request of the pharmaceutical company.
      • Weitz J.I.
      • Connolly S.J.
      • Patel I.
      • et al.
      Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation.
      • Chung N.
      • Jeon H.K.
      • Lien L.M.
      • et al.
      Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation.
      -
      OS10 mg qd
      Registered dose at the European Medicines Agency.
      ,
      Registered dose at the Food and Drug Administration.
      • Eriksson B.I.
      • Borris L.C.
      • Dahl O.E.
      • et al.
      A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement.
      • Eriksson B.I.
      • Borris L.C.
      • Friedman R.J.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.
      • Lassen M.R.
      • Ageno W.
      • Borris L.C.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.
      • Kakkar A.K.
      • Brenner B.
      • Dahl O.E.
      • et al.
      Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.
      • Turpie A.G.
      • Lassen M.R.
      • Davidson B.L.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial.
      or 5 mg bid
      The lowest studied effective dose or the dose most comparable with the registered dose.
      • Turpie A.G.
      • Fisher W.D.
      • Bauer K.A.
      • et al.
      BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study.
      • Eriksson B.I.
      • Borris L.
      • Dahl O.E.
      • et al.
      Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement.
      • Eriksson B.I.
      • Borris L.C.
      • Dahl O.E.
      • et al.
      Dose-escalation study of rivaroxaban (BAY 59-7939)–an oral, direct Factor Xa inhibitor–for the prevention of venous thromboembolism in patients undergoing total hip replacement.
      2.5 mg bid
      Registered dose at the European Medicines Agency.
      • Lassen M.R.
      • Davidson B.L.
      • Gallus A.
      • et al.
      The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.
      • Lassen M.R.
      • Raskob G.E.
      • Gallus A.
      • et al.
      Apixaban or enoxaparin for thromboprophylaxis after knee replacement.
      • Lassen M.R.
      • Gallus A.
      • Raskob G.E.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.
      • Lassen M.R.
      • Raskob G.E.
      • Gallus A.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial.
      220 mg qd
      Registered dose at the European Medicines Agency.
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial.
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.
      • Committee R.-M.W.
      • Ginsberg J.S.
      • Davidson B.L.
      • et al.
      Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery.
      • Fuji T.
      • Fuijita S.
      • Ujihira T.
      • et al.
      Dabigatran etexilate prevents venous thromboembolism after total knee arthroplasty in Japanese patients with a safety profile comparable to placebo.
      • Eriksson B.I.
      • Dahl O.E.
      • Huo M.H.
      • et al.
      Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial.


      or 300 mg qd
      The lowest studied effective dose or the dose most comparable with the registered dose.
      • Eriksson B.I.
      • Dahl O.E.
      • Buller H.R.
      • et al.
      A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial.
      30 mg qd
      By request of the pharmaceutical company.
      • Fuji T.
      • Fujita S.
      • Tachibana S.
      • et al.
      A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty.
      • Raskob G.
      • Cohen A.T.
      • Eriksson B.I.
      • et al.
      Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study.
      40 mg bid
      The lowest studied effective dose or the dose most comparable with the registered dose.
      • Turpie A.G.
      • Bauer K.A.
      • Davidson B.L.
      • et al.
      A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT).
      ACS5 mg
      The lowest studied effective dose or the dose most comparable with the registered dose.
      • Mega J.L.
      • Braunwald E.
      • Mohanavelu S.
      • et al.
      Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.
      • Mega J.L.
      • Braunwald E.
      • Wiviott S.D.
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      5 mg bid
      The lowest studied effective dose or the dose most comparable with the registered dose.
      • APPRAISE Steering Committee and Investigators
      • Alexander J.H.
      • Becker R.C.
      • et al.
      Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.
      or

      2.5 mg bid
      The lowest studied effective dose or the dose most comparable with the registered dose.
      • Alexander J.H.
      • Lopes R.D.
      • James S.
      • et al.
      Apixaban with antiplatelet therapy after acute coronary syndrome.
      110 mg bid
      The lowest studied effective dose or the dose most comparable with the registered dose.
      • Oldgren J.
      • Budaj A.
      • Granger C.B.
      • et al.
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.
      --
      DVT/PE15 mg bid 3 weeks followed by 20 mg qd
      Registered dose at the European Medicines Agency.
      ,
      Registered dose at the Food and Drug Administration.
      • EINSTEIN Investigators E
      • Bauersachs R.
      • Berkowitz S.D.
      • et al.
      Oral rivaroxaban for symptomatic venous thromboembolism.
      • EINSTEIN-PE Investigators
      • Buller H.R.
      • Prins M.H.
      • et al.
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.


      10 mg bid,
      The lowest studied effective dose or the dose most comparable with the registered dose.
      • Agnelli G.
      • Gallus A.
      • Goldhaber S.Z.
      • et al.
      Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study.
      or 30 mg qd
      The lowest studied effective dose or the dose most comparable with the registered dose.
      • Buller H.R.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study.
      10 mg bid
      By request of the pharmaceutical company.
      • Botticelli Investigators Writing Committee
      • Buller H.
      • Deitchman D.
      • et al.
      Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study.
      150 mg bid
      The lowest studied effective dose or the dose most comparable with the registered dose.
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      --
      Medically ill-5 mg qd
      The lowest studied effective dose or the dose most comparable with the registered dose.
      • Levine M.N.
      • Gu C.
      • Liebman H.A.
      • et al.
      A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer.
      or 2.5 mg bid
      The lowest studied effective dose or the dose most comparable with the registered dose.
      • Goldhaber S.Z.
      • Leizorovicz A.
      • Kakkar A.K.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients.
      ---
      Bid, twice daily; qd, once daily.
      a Registered dose at the European Medicines Agency.
      b Registered dose at the Food and Drug Administration.
      c By request of the pharmaceutical company.
      d The lowest studied effective dose or the dose most comparable with the registered dose.
      Supplementary Table 7Methodologic Quality of Included Studies According to the Cochrane Reviewers’ Handbook
      StudyMethod of randomization

      (A/B/C)
      Concealment of allocation

      (A/B/C)
      Blinding for treatment

      (A/B/C/D)
      Independent clinical end point committee

      (A/B/C)
      Lost to follow-up evaluation of total study population (%)Intention-to-treat analysis (A/B/C/D)
      Ezekowitz et al,
      • Ezekowitz M.D.
      • Reilly P.A.
      • Nehmiz G.
      • et al.
      Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study).
      2007 PETRO
      CCBANot reportedC
      Connolly et al,
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Ezekowitz M.D.
      • Connolly S.
      • Parekh A.
      • et al.
      Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran.
      2009 RELY
      AABA20/18,113 = 0.1%A
      Weitz et al,
      • Weitz J.I.
      • Connolly S.J.
      • Patel I.
      • et al.
      Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation.
      2010
      AABA3/1146 = 0.3%A
      Chung et al,
      • Chung N.
      • Jeon H.K.
      • Lien L.M.
      • et al.
      Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation.
      2011
      AABA2/235 = 0.9%A
      Ogawa et al,
      • Ogawa S.
      • Shinohara Y.
      • Kanmuri K.
      Safety and efficacy of the oral direct factor xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. The ARISTOTLE J study.
      2011
      ACBA4/222 = 1.8%A
      Connolly et al,
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      • Eikelboom J.W.
      • O'Donnell M.
      • Yusuf S.
      • et al.
      Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment.
      2011 AVERROES
      AAAANot reportedA
      Patel et al,
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • ROCKET AF Study Investigators
      Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study.
      2011 ROCKET AF
      AAAA32/14,264 = 0.2%A
      Granger et al,
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Lopes R.D.
      • Alexander J.H.
      • Al-Khatib S.M.
      • et al.
      Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale.
      2011 ARISTOTLE
      ACAA69/18,201 = 0.4%A
      Eriksson et al,
      • Eriksson B.I.
      • Dahl O.E.
      • Buller H.R.
      • et al.
      A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial.
      2005, BISTRO II
      ACAA12/1969 = 0.6%A
      Turpie et al,
      • Turpie A.G.
      • Fisher W.D.
      • Bauer K.A.
      • et al.
      BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study.
      2005, ODIXa-KNEE
      AAAA3/621 = 0.5%A
      Eriksson et al,
      • Eriksson B.I.
      • Borris L.
      • Dahl O.E.
      • et al.
      Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement.
      2006, ODIXa-HIP I
      CCAANot reportedA
      Eriksson et al,
      • Eriksson B.I.
      • Borris L.C.
      • Dahl O.E.
      • et al.
      A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement.
      2006, ODIXa-HIP II
      CCAANot reportedA
      Eriksson et al,
      • Eriksson B.I.
      • Borris L.C.
      • Dahl O.E.
      • et al.
      Dose-escalation study of rivaroxaban (BAY 59-7939)–an oral, direct Factor Xa inhibitor–for the prevention of venous thromboembolism in patients undergoing total hip replacement.
      2007
      ACCANot reportedA
      Eriksson et al,
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial.
      2007, RE-MODEL
      AAAANot reportedA
      Lassen et al,
      • Lassen M.R.
      • Davidson B.L.
      • Gallus A.
      • et al.
      The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.
      2007, APROPOS
      AABANot reportedA
      Eriksson et al,
      • Eriksson B.I.
      • Dahl O.E.
      • Rosencher N.
      • et al.
      Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.
      2007, RE-NOVATE
      AAAANot reportedA
      Eriksson et al,
      • Eriksson B.I.
      • Borris L.C.
      • Friedman R.J.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.
      2008, RECORD1
      AAAANot reportedA
      Lassen et al,
      • Lassen M.R.
      • Ageno W.
      • Borris L.C.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.
      2008, RECORD3
      AAAANot reportedA
      Kakkar et al,
      • Kakkar A.K.
      • Brenner B.
      • Dahl O.E.
      • et al.
      Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.
      2008, RECORD2
      AAAANot reportedA
      Ginsberg et al,
      • Committee R.-M.W.
      • Ginsberg J.S.
      • Davidson B.L.
      • et al.
      Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery.
      2009, RE-MOBILIZE
      AAAANot reportedA
      Turpie et al,
      • Turpie A.G.
      • Bauer K.A.
      • Davidson B.L.
      • et al.
      A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT).
      2009, EXPERT
      AABA1/215 = 0.4%A
      Turpie et al,
      • Turpie A.G.
      • Lassen M.R.
      • Davidson B.L.
      • et al.
      Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial.
      2009, RECORD4
      AAAANot reportedA
      Lassen et al,
      • Lassen M.R.
      • Raskob G.E.
      • Gallus A.
      • et al.
      Apixaban or enoxaparin for thromboprophylaxis after knee replacement.
      2009, ADVANCE-1
      ACAA79/3195 = 2.5%A
      Fuji et al,
      • Fuji T.
      • Fuijita S.
      • Ujihira T.
      • et al.
      Dabigatran etexilate prevents venous thromboembolism after total knee arthroplasty in Japanese patients with a safety profile comparable to placebo.
      2010
      ACAANot reportedA
      Lassen,
      • Lassen M.R.
      • Raskob G.E.
      • Gallus A.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial.
      2010, ADVANCE-2
      AAAANot reportedA
      Raskob,
      • Raskob G.
      • Cohen A.T.
      • Eriksson B.I.
      • et al.
      Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement. A randomised double-blind dose-response study.
      2010
      AAAANot reportedA
      Fuji et al,
      • Fuji T.
      • Fujita S.
      • Tachibana S.
      • et al.
      A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty.
      2010
      ACAANot reportedA
      Lassen et al,
      • Lassen M.R.
      • Gallus A.
      • Raskob G.E.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.
      2010, ADVANCE-3
      AAAANot reportedA
      Eriksson et al,
      • Eriksson B.I.
      • Dahl O.E.
      • Huo M.H.
      • et al.
      Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial.
      2011, RE-NOVATE II
      AAAA2/2055 = 0.1%A
      Goldhaber et al,
      • Goldhaber S.Z.
      • Leizorovicz A.
      • Kakkar A.K.
      • et al.
      Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients.
      2011 ADOPT
      AAAANot reportedA
      Levine et al,
      • Levine M.N.
      • Gu C.
      • Liebman H.A.
      • et al.
      A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer.
      2012
      AAAA0/125 = 0%A
      Agnelli et al,
      • Agnelli G.
      • Gallus A.
      • Goldhaber S.Z.
      • et al.
      Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study.
      2007
      AABA1/613 = 0.2%A
      Buller et al,
      • Botticelli Investigators Writing Committee
      • Buller H.
      • Deitchman D.
      • et al.
      Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study.
      2008, BOTTICELLI
      AABANot reportedA
      Buller et al,
      • Buller H.R.
      • Lensing A.W.
      • Prins M.H.
      • et al.
      A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study.
      2008 Einstein-DVT
      AABA1/542 = 0.2%A
      Schulman et al,
      • Schulman S.
      • Kearon C.
      • Kakkar A.K.
      • et al.
      Dabigatran versus warfarin in the treatment of acute venous thromboembolism.
      2009 RE-COVER
      AAAA15/2564 = 0.6%B
      Bauersachs et al,
      • EINSTEIN Investigators E
      • Bauersachs R.
      • Berkowitz S.D.
      • et al.
      Oral rivaroxaban for symptomatic venous thromboembolism.
      2010 EINSTEIN-ACUTE DVT
      AACA33/3449 = 1.0%B
      Bauersachs et al,
      • EINSTEIN Investigators E
      • Bauersachs R.
      • Berkowitz S.D.
      • et al.
      Oral rivaroxaban for symptomatic venous thromboembolism.
      2010 EINSTEIN-ExTENSION
      AAAA2/1196 = 0.2 %.A
      Buller et al,
      • EINSTEIN-PE Investigators
      • Buller H.R.
      • Prins M.H.
      • et al.
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      2012, EINSTEIN-PE
      AACA18/4832 = 0.4%A
      Appraise Steering Committee and Investigators,
      • APPRAISE Steering Committee and Investigators
      • Alexander J.H.
      • Becker R.C.
      • et al.
      Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.
      2009, APPRAISE
      AAAA25/1715 = 1.5%A
      Mega et al,
      • Mega J.L.
      • Braunwald E.
      • Mohanavelu S.
      • et al.
      Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.
      2009 ATLAS ACS-TIMI 46
      ACAA22/3491 = 0.6%A
      Alexander et al,
      • Alexander J.H.
      • Lopes R.D.
      • James S.
      • et al.
      Apixaban with antiplatelet therapy after acute coronary syndrome.
      2011, APPRAISE-2
      AAAA50/7392 = 0.7%A
      Oldgren et al,
      • Oldgren J.
      • Budaj A.
      • Granger C.B.
      • et al.
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.
      2011, RE-DEEM
      AAAA12/1878 = 0.6%A
      Mega et al,
      • Mega J.L.
      • Braunwald E.
      • Wiviott S.D.
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      2012, ATLAS ACS 2-TIMI 51
      ACAA0.3%A
      NOTE. The quality assessment criteria include: (1) method of randomization: A, truly random: computer-generated random numbers, coin toss, and so forth; B, quasirandom: birth-date, patient registration-number, and so forth; C, not stated/unclear; (2) allocation concealment: A, adequate: trialist unaware of each participant's allocation, by, for instance, central randomization systems or serially numbered opaque envelopes, and so forth; B, inadequate: trialist aware of allocations at recruitment; C, not stated/unclear; (3) blinding for treatment: A, double blind; B, double-blind for dose of NOAC, but not for NOAC vs control; C, unblinded; D, not stated/unclear; (4) blinding of outcome assessment: A, blinded; B, unblinded; C, not stated/unclear; (5) participant flow: loss to follow-up of total study population described; (6) intention-to-treat analysis (all subjects who received at least one dose are considered to be part of the trial, regardless of completion of treatment): A, yes at least for safety analysis; B, only for efficacy analysis; C, no; D, not stated/unclear.
      Supplementary Table 8Gastrointestinal and Clinically Relevant Bleeding by Indication and by Drug Including Sensitivity Analyses
      SubgroupsStudies,
      The number in parentheses shows the number of excluded studies in the sensitivity analysis.
      n
      N events/N total nOACN events/ N total controlOR (95% CI)P for heterogeneityI2

      (%)
      Gastrointestinal bleeding
       All studies17631/37,201470/37,3351.45 (1.07–1.97).00161
       By indication
      Atrial fibrillation6524/25,234408/25,1401.21 (0.91–1.61).01764
      Orthopedic surgery611/934316/93400.78 (0.31–1.96).14939
      Medically ill11/321/290.91 (0.05–15.13)1.0000
      DVT/PE257/187135/18561.59 (1.03–2.44).24127
      ACS238/72110/9705.21 (2.58–10.53).3720
       By drug
      Apixaban8145/18,084153/18,3011.23 (0.56–2.73).00170
      Betrixaban0-----
      Dabigatran3255/7755160/76591.58 (1.29–1.93).20836
      Edoxaban10/801/750.31 (0.01–7.69)1.0000
      Rivaroxaban5231/11,282156/11,3001.48 (1.21–1.82).6310
      Sensitivity analysis of GIB
       All studies13 (-4)588/35,850459/35,7461.29 (1.14–1.46).02249
       By indication
      Atrial fibrillation6 (idem)524/25,234408/25,1401.21 (0.91–1.61).01764
      Orthopedic surgery6 (idem)11/934316/93400.78 (0.31–1.96).14939
      Medically ill(-1)-----
      DVT/PE1 (-1)53/127335/12661.53 (0.99–2.36)1.0000
      ACS(-2)-----
       By drug
      Apixaban6 (-2)126/17,737147/17,6730.87 (0.68–1.10).19232
      Betrixaban0-----
      Dabigatran2 (-1)235/7349155/72881.52 (1.24–1.87).9810
      Edoxaban1 (idem)0/801/750.31 (0.01–7.69)1.0000
      Rivaroxaban4 (-1)227/10,684156/10,7101.47 (1.20–1.81).7720
      Clinically relevant bleeding
       All studies434690/62,1864582/63,1681.16 (1.00–1.34)<.00178
       By indication
      Atrial fibrillation82632/25,6372867/25,4600.93 (0.75–1.16)<.00184
      Orthopedic surgery21681/17,130652/17,2111.05 (0.94–1.17).05236
      Medically ill286/321668/32461.28 (0.93–1.77).8060
      DVT/PE7517/6387566/63610.98 (0.68–1.43)<.00178
      ACS5774/9816429/10,8902.06 (1.82–2.33).39622
       By drug
      Apixaban121211/25,2281426/25,4350.99 (0.74–1.35)<.00187
      Betrixaban12/843/430.33 (0.05–2.03)1.0000
      Dabigatran10714/12,130708/11,9641.15 (0.89–1.48).00170
      Edoxaban422/58717/5991.24 (0.65–2.39).6900
      Rivaroxaban162741/24,1572428/25,1271.31 (1.04–1.64)<.00185
      Sensitivity analysis of clinically relevant bleeding
       All studies34 (-9)3870/51,5084137/51,4330.98 (0.88–1.10)<.00165
       By indication
      Atrial fibrillation8 (idem)2632/25,6372867/25,4600.93 (0.75–1.16)<.00184
      Orthopedic surgery19 (-2)672/16,898644/16,9851.05 (0.94–1.17).02742
      Medically ill1 (-1)85/318467/32171.29 (0.93–1.78)1.0000
      DVT/PE6 (-1)481/5789559/57710.85 (0.74–0.96).13541
      ACS(-5)-----
       By drug
      Apixaban9 (-3)1075/21,2081362/21,1650.84 (0.67–1.06)<.00174
      Betrixaban12/843/430.33 (0.05–2.03)1.0000
      Dabigatran8 (-2)677/11,595696/11,4691.03 (0.83–1.28).01460
      Edoxaban3 (-1)18/48413/4971.32 (0.63–2.76).5110
      Rivaroxaban13 (-3)2098/18,1372063/18,2591.04 (0.93–1.18).17327
      NOTE. In case of I2 > 50%, significant heterogeneity was assumed and a random-effects model was used.
      a The number in parentheses shows the number of excluded studies in the sensitivity analysis.

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