Study characteristics

Methods

Study design: randomised, double‐blind trial
Duration of study: 6 months

Participants

Setting: hospital
Country: multinational (358 centres in 28 countries: United States, Argentina, Australia, Austria, Brazil, Canada, China, Czech Republic, Denmark, France, Germany, Hungary, India, Israel, Italy, Korea, Malaysia, Mexico, Norway, Poland, Portugal, Puerto Rico, Romania, Russia, Singapore, South Africa, Spain, Ukraine)
Number of participants: 5395 (PE 1836, other VTE 3559); apixaban 2691 (PE 930, other VTE 1761), enoxaparin + warfarin 2704 (PE 906, DVT 1798)
Age, mean (SD) years: apixaban 57.2 (16.0) years, enoxaparin + warfarin 56.7 (16.0) years
Sex: apixaban 1569 M/1122 F; enoxaparin + warfarin 1598 M/1106 F
Inclusion criteria: people ≥ 18 years of age with an objectively confirmed, symptomatic proximal DVT or PE (with or without DVT)
Exclusion criteria: active bleeding, a high risk of bleeding, or other contraindications to treatment with enoxaparin and warfarin; if they had cancer and long‐term treatment with LMWH was planned; if their DVT or PE was provoked in the absence of a persistent risk factor for recurrence; if < 6 months of anticoagulant treatment was planned; or if they had another indication for long‐term anticoagulation therapy, dual antiplatelet therapy, treatment with aspirin at a dose > 165 mg daily, or treatment with potent inhibitors of cytochrome P‐450 3A4; if they had received > 2 doses of a once‐daily LMWH regimen, fondaparinux, or a VKA; > 3 doses of a twice daily LMWH regimen; or more than 36 hours of continuous IV heparin. Additional exclusion criteria were a haemoglobin level < 9 mg/dL, a platelet count < 100,000/mm³, a serum creatinine level > 2.5 mg/dL (220 μmol/L), or a calculated creatinine clearance < 25 mL/minute

Interventions

Intervention 1: oral apixaban 10 mg twice daily for the first 7 days, followed by 5 mg twice daily for 6 months
Intervention 2: enoxaparin 1 mg/kg body weight every 12 hours for at least 5 days and warfarin concomitantly for 6 months. Warfarin dose was adjusted to maintain the INR 2.0 to 3.0. Enoxaparin or placebo was discontinued when a blinded INR of ≥ 2.0 was achieved
Follow‐up: weeks 2, 4, 8, 12, 16, 20, and 24 after randomisation and 30 days after the end of the intended treatment period

Outcomes

Primary: composite of recurrent symptomatic VTE (fatal or non‐fatal PE and DVT), and mortality related to VTE; major bleeding
Secondary: recurrent symptomatic VTE, mortality related to VTE, mortality from cardiovascular causes, mortality from any cause and the composite of major bleeding and clinically relevant non‐major bleeding

Funding

Quote: "Supported by Pfizer and Bristol‐Myers Squibb."

Comment: Pfizer Inc and Bristol‐Myers Squibb were the pharmaceutical companies that developed apixaban. It is possible that this may have influenced the report of outcomes.

Declarations of interest

Quote: "Dr. Agnelli reports receiving personal fees from Boehringer Ingelheim, Sanofi, Daiichi‐Sankyo, and Bayer. Dr. Buller reports receiving grant support from Bayer, Sanofi, and Daiichi‐Sankyo. Dr. Cohen reports receiving payment for board membership from Bayer, Bristol‐Myers Squibb, Daiichi‐Sankyo, Johnson & Johnson, Pfizer, Portola Pharmaceuticals, and Sanofi, and consulting fees, lecture fees, travel support, and payment for the development of educational presentations from Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Daiichi‐Sankyo, Glaxo‐SmithKline, Johnson & Johnson, Mitsubishi Pharma, Pfizer, Portola Pharmaceuticals, Sanofi, Schering‐Plough, and Takeda. Drs. Curto, Johnson, Masiukiewicz, Pak, and Thompson report being employees of Pfizer. Dr. Gallus reports receiving consulting fees from Pfizer, Bristol‐Myers Squibb, Daiichi‐Sankyo, Bayer, and Boehringer Ingelheim. Dr. Raskob reports receiving consulting fees and travel support from Bayer, Janssen Pharmaceuticals, Daiichi‐Sankyo, and Quintiles. Dr. Weitz reports receiving consulting fees from Boehringer Ingelheim, Daiichi‐Sankyo, Bayer, Pfizer, Bristol‐Myers Squibb, Merck, Janssen Pharmaceuticals, and Portola Pharmaceuticals. No other potential conflict of interest relevant to this article was reported.

Notes

Results were presented for all participants with a VTE but specific recurrent VTE data for the subset of participants with a PE were available in the supplementary material

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation was performed with the use of an interactive voice‐response system"
Comment: study judged at low risk of selection bias.

Allocation concealment (selection bias)

Low risk

Quote: "Randomisation was performed with the use of an interactive voice‐response system"
Comment: study judged at low risk of selection bias

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Double blind. Patients were assigned to receive apixaban tablets plus placebo enoxaparin injections and placebo warfarin tablets or conventional therapy with enoxaparin injections and warfarin tablets plus placebo apixaban tablets. The study used blinded INR monitoring with a point‐of‐care device that generated an encrypted code for INR results. Investigators reported the code to the interactive voice‐response system and received either an actual INR value (for patients assigned to warfarin) or a sham INR value (for patients receiving apixaban)"
Comment: study judged at low risk of performance bias

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "An independent committee, whose members were unaware of the study‐group assignments, adjudicated the qualifying diagnosis, the anatomical extent of the initial deep vein thrombosis or pulmonary embolism, and all suspected outcomes."
Comment: study judged at low risk of detection bias

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

A number of randomised participants were inappropriately excluded from the ITT analysis. Additionally, 144/377 of apixaban participants and 142/413 participants given conventional treatment were classified as discontinuing for "other reasons", with no explanations given. Therefore we deemed the risk of attrition bias to be unclear.

Selective reporting (reporting bias)

High risk

Study protocol was available. Minor bleeding was a pre‐defined secondary outcome but the data on this outcome were not reported in the paper. Therefore we deemed the risk of reporting bias to be high.

Other bias

Low risk

We did not find any methodological issues that might directly lead to a risk of bias.

Study characteristics

Methods

Study design: a randomised, active‐controlled, open‐label study
Duration of study: 5.5 months

Participants

Setting: hospital
Country: Japan
Number of participants: 80 (PE 35, other VTE 45); apixaban 40 (PE 18, other VTE 22), UFH/warfarin 40 (PE 17, other VTE 23)
Age, mean (SD) years: apixaban 64.3 (13.40) years, UFH/warfarin 66.1 (17.72) years
Sex: apixaban: 22 M/18 F, UFH/warfarin: 17 M/23 F
Inclusion criteria: Japanese patients, ≥ 20 years of age and who had objectively confirmed, symptomatic proximal DVT or PE (with or without DVT). Proximal DVT was defined as thrombosis involving at least the popliteal vein or a more proximal vein.
Exclusion criteria: people were excluded if they had thrombectomy or used fibrinolytic agent, had active bleeding, a high risk of bleeding, or other contraindications to treatment with UFH and warfarin; if they had another indication for long‐term anticoagulation therapy, dual antiplatelet therapy, or treatment with aspirin > 165 mg daily. Other key exclusion criteria were > 2 doses of fondaparinux, or continuous infusion of UFH > 36 hours, and > 2 doses of oral VKA before first administration of the study drug. Additional exclusion criteria were haemoglobin < 9 g/dL, platelet count < 100,000/mm^3, and creatinine clearance < 25 mL/min.

Interventions

Intervention 1: received apixaban 10 mg twice daily for 7 days as an initial therapy, followed by apixaban 5 mg twice daily for 23 weeks as long‐term therapy
Intervention 2: given a continuous IV infusion of UFH to maintain the activated partial thromboplastin time in the range 1.5–2.5‐fold the control value. Warfarin was also concomitantly administered. UFH was continuously given until the effect of warfarin was stabilised; after which, participants were given warfarin alone. UFH was given for at least 5 days consecutively and was discontinued at once if the PT‐INR was ≥ 1.5. If PT‐INR exceeded 2.0 within the initial 5 days of administration, UFH could be discontinued based on the investigator’s judgment. The warfarin dose was adjusted to maintain INR between 1.5 and 2.5 in accordance with Japan PE/DVT treatment guidelines. Treatment was administered for 24 weeks (5.5 months).
Follow‐up: 0, 2, 12, 24 and 28 weeks

Outcomes

Primary: the incidence of the adjudicated composite of ISTH‐defined major bleeding and CRNM bleeding during the treatment period.
Secondary:  the incidence of the adjudicated ISTH major bleeding events and all bleeding events (ISTH major, CRNM, and minor) during the treatment period, composite endpoint of adjudicated recurrent symptomatic VTE (non‐fatal DVT or non‐fatal PE) or VTE‐related death during 24 weeks, thrombotic burden deterioration at 2, 12 and 24 weeks

Funding

Quote: "This study was funded by Pfizer Inc and Bristol‐Myers Squibb."

Comment: Pfizer Inc and Bristol‐Myers Squibb were the pharmaceutical companies that developed apixaban, and the results of the primary outcome favoured the apixaban group. It is possible that this may have influenced the report of outcomes. 

Declarations of interest

Quote: "M. Nakamura has received remuneration from Daiichi Sankyo, Bayer Yakuhin. M. Nishikawa has received remuneration and research funds from Daiichi Sankyo. I. Komuro has received remuneration from Daiichi Sankyo, Nippon Boehringer Ingelheim, and scholarship funds from Astellas Pharma, Daiichi Sankyo, Takeda Pharmaceutical, Nippon Boehringer Ingelheim, Bristol‐Myers Squibb. I. Kitajima has received remuneration from Nippon Boehringer Ingelheim. H.O. has received remuneration from AstraZeneca, Bayer Yakuhin, Boehringer Ingelheim Japan, Bristol‐Myers Squibb, Daiichi Sankyo, Mitsubishi Tanabe Pharma, MSD, Pfizer Japan, Sanofi, Takeda Pharmaceutical and Teijin Pharma, and has received research funds from Bayer Yakuhin, Daiichi Sankyo and Novartis Pharma, and has received scholarship funds from Astellas Pharma, AstraZeneca, Bristol‐Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Kowa, MSD, Otsuka Pharmaceutical, Pfizer Japan, Sanofi, Shionogi and Takeda Pharmaceutical. Y.U., T.Y., H.M., R.Y. have no conflict of interest."

Notes

Study characteristics were presented for all participants with a VTE but specific recurrent PE, recurrent VTE, all‐cause mortality, and major bleeding with a PE were available.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "An interactive voice response system was used for randomisation"
Comment: study judged at low risk of selection bias.

Allocation concealment (selection bias)

Low risk

Quote: "An interactive voice response system was used for randomisation"
Comment: study judged at low risk of selection bias.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Open label"
Comment: blinding of participants and personnel was not conducted. However, review authors judged that the lack of blinding was unlikely to have affected the outcome.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "all outcome events were adjudicated by an event adjudication committee in a blinded manner so as to maintain validity of assessment"
Comment: blinding was performed adequately; study judged at low risk of detection bias.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

In the apixaban group, 3 did not complete the overall trial period (2 no longer willing to participant in study, 1 had other reason). In the UFH/warfarin group, 2 did not complete the overall trial period (1 withdrew from the study prior to the initiation of study treatment, 1 had other reason).
Comment: fewer than 20% of participants dropped out or withdrew and the study author performed ITT analysis; study judged at low risk of attrition bias.

Selective reporting (reporting bias)

Low risk

All the study's pre‐specified outcomes were reported in the pre‐specified way. Study judged at low risk of reporting bias.

Other bias

Low risk

We did not find any methodological issues that might directly lead to a risk of bias.

Study characteristics

Methods

Study design: multinational, randomised, controlled, investigator‐initiated, open‐label, non‐inferiority trial
Duration of study: 6 months

Participants

Setting: multicentre
Country: multinational (119 centres in 11 countries: Belgium, France, Germany, Israel, Italy, Poland, Portugal, Spain, the Netherlands, United Kingdom, United States of America)
Number of participants: 1155 (PE 638, other VTE 517); apixaban 576 (PE 304, other VTE 272), dalteparin 579 (PE 334, other VTE 245)
Age, mean (SD) years: apixaban 67.2 (11.3 ) years, dalteparin 67.2 (10.9) years
Sex: apixaban: 292 M/284 F; dalteparin: 276 M/303 F
Inclusion criteria: consecutive adults with cancer who had a newly diagnosed symptomatic or incidental proximal lower‐limb DVT or PE were eligible to participate in the trial. People with confirmed cancer other than basal‐cell or squamous‐cell carcinoma of the skin, primary brain tumour, known intracerebral metastases, or acute leukaemia were eligible to participate in the trial.
Exclusion criteria: patients’ clinical characteristics, issues related to anticoagulant treatment, bleeding risk, and standard issues from clinical trials of anticoagulant agents

Interventions

Intervention 1: apixaban was given orally at a dose of 10 mg twice daily for the first 7 days and 5 mg twice daily thereafter. Treatment was administered for 6 months.
Intervention 2: dalteparin was given subcutaneously at a dose of 200 IU/kg of body weight once daily for the first month, after which the dose was reduced to 150 IU/kg daily. The maximum daily dose allowed for dalteparin was 18,000 IU. Treatment was administered for 6 months
Follow‐up: trial visits were scheduled at enrolment and at 4 weeks, 3 months, 6 months, and 7 months after randomisation

Outcomes

Primary: recurrent VTE, recurrent DVT, recurrent PE, fatal PE, major bleeding, major gastrointestinal bleeding, major non‐gastrointestinal bleeding
Secondary: recurrent VTE or major bleeding, clinically relevant non‐major bleeding, major or clinically relevant non‐major bleeding, death from any cause, event‐free survival

Funding

Quote: "Supported by the Bristol‐Myers Squibb–Pfizer Alliance."

Comment: the study was supported by the Bristol‐Myers Squibb–Pfizer Alliance, the pharmaceutical companies that developed apixaban and dalteparin respectively, and the results of the primary outcome supported the non‐inferiority hypothesis of apixaban. It is possible that this may have influenced the report of outcomes.

Declarations of interest

Quote: "Dr. Agnelli reports receiving lecture fees from Pfizer and Bayer Healthcare and serving as chair of a registry for Daiichi Sankyo; Dr. Becattini, receiving lecture fees and consulting fees from Bayer Healthcare, Bristol‐Myers Squibb, and Daiichi Sankyo; Dr. Meyer, receiving grant support and travel support from Leo Pharma, Bristol‐Myers Squibb–Pfizer, Stago, and Bayer Healthcare; Dr. Muñoz, receiving grant support, consulting fees, lecture fees, advisory board fees, and travel support from Sanofi and Celgene, lecture fees and advisory board fees from AstraZeneca, Servier, Bristol‐Myers Squibb–Pfizer, Daiichi Sankyo, Bayer, and Merck Sharp & Dohme, lecture fees, advisory board fees, and travel support from Roche, grant support, lecture fees, and advisory board fees from Leo Pharma, advisory"

Notes

Results were presented for all participants with a VTE, but specific recurrent VTE and major bleeding data for the subset of participants with a PE were available in the supplementary material.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was centrally performed through an interactive online system"

Comment: study judged at low risk of selection bias.

Allocation concealment (selection bias)

Low risk

Quote: "Randomization was centrally performed through an interactive online system" 

Comment: study judged at low risk of selection bias.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Open label" 
Comment: blinding of participants and personnel was not conducted. However, review authors judged that the lack of blinding was unlikely to have affected the outcome.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "blinded adjudication of the outcomes"
Comment: blinding was performed adequately, study judged at low risk of detection bias.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

In the apixaban group, 177 did not complete the overall trial period (137 died, 12 were lost to follow‐up, 28 had other reasons). In the dalteparin group, 197 did not complete the overall trial period (149 died, 8 were lost to follow‐up, 40 had other reasons).
Comment: fewer than 20% of participants dropped out or withdrew, and the study author performed ITT analysis. Study judged at low risk of attrition bias.

Selective reporting (reporting bias)

High risk

Study protocol was available. Quality of life was a predefined secondary outcome, but the data on this outcome were not reported in the paper. In addition, it was stated that a "significant interaction was noted between age subgroups and treatment for recurrent venous thromboembolism" but no result was found in the paper and appendix. Therefore, the risk of reporting bias was deemed to be high.

Other bias

Low risk

We did not find any methodological issues that might directly lead to a risk of bias.

Study characteristics

Methods

Study design: randomised, open‐label, event‐driven, non‐inferiority trial
Duration of study: 12 months

Participants

Setting: hospital
Country: multinational (263 centres in 36 countries: Andorra, Australia, Austria, Belgium, Brazil, Canada, China, Czech Republic, Denmark, Estonia, Finland, France, Germany, China Hong Kong, Hungary, India, Indonesia, Ireland, Israel, Italy, Korea, Latvia, Lithuania, Malaysia, the Netherlands, New Zealand, Norway, Philippines, Poland, Singapore, South Africa, Spain, Sweden, Switzerland, China Taiwan, Thailand, United Kingdom, USA)
Number of participants: 4832 (all are PE); rivaroxaban 2419, warfarin 2413
Age, mean (SD) years: rivaroxaban 57.9 (7.3) years, warfarin 57.5 (7.2) years
Sex: rivaroxaban 1309 M/1110 F, warfarin 1247 M/1166 F
Inclusion criteria: aged 18 or older with an acute, symptomatic PE with objective confirmation, with or without symptomatic DVT
Exclusion criteria: contraindications to heparin or warfarin, had received treatment for more than 48 hours with therapeutic doses of heparin, had received more than one dose of a VKA, had cancer for which long‐term treatment with LMWH was anticipated, had another indication for warfarin therapy, continued to receive treatment with aspirin at a dose of more than 100 mg daily or dual antiplatelet therapy, or had a creatinine clearance of less than 30 mL per minute

Interventions

Intervention 1: oral rivaroxaban 15 mg twice daily for the first 3 weeks, followed by 20 mg once daily
Intervention 2: enoxaparin 1.0 mg/kg of body weight twice daily and either warfarin or acenocoumarol, started within 48 hours of randomisation. Enoxaparin was discontinued when the INR was 2.0 or more for 2 consecutive days and the participants had received at least 5 days of enoxaparin treatment. The dose of VKA was adjusted to maintain an INR of 2.0 to 3.0, determined at least once a month
Follow‐up: 3, 6, and 12 months

Outcomes

Primary: "symptomatic recurrent VTE, defined as a composite of DVT or fatal or non‐fatal PE and clinically relevant bleeding, defined as a composite of major or clinically relevant non‐major bleeding. Death was classified as PE, bleeding or other established diagnoses. PE was considered the cause of death if there was objective documentation of the condition or if death could not be attributed to a documented cause and PE could not be confidently ruled out. Bleeding was defined as major if it was clinically overt and associated with a decrease in the haemoglobin level of 2.0 g per decilitre or more, if bleeding led to the transfusion of 2 or more units of red blood cells, or if bleeding was intracranial or retroperitoneal, occurred in another critical site, or contributed to death. CRNM bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of a study drug, or discomfort or impairment of activities of daily life"
Secondary: major bleeding, death from any cause, vascular events (acute coronary syndrome, ischaemic stroke, transient ischaemic attack or systemic embolism) and net clinical benefit (defined as a composite of the primary efficacy outcome and major bleeding, as assessed in the intention‐to‐treat population)

Funding

Quote: "Supported by Bayer HealthCare and Janssen Pharmaceuticals."

Comment: the study was funded by Bayer HealthCare, the pharmaceutical company that developed rivaroxaban. It is possible that this may have influenced the timeframe of reported safety outcomes.

Declarations of interest

"Dr. Agnelli reports receiving consulting fee, travel support, payment for writing or reviewing the manuscript, and lecture fees from Ictom/Bayer Healthcare. Dr. Berkowitz reports receiving travel support and employment from Bayer HealthCare Pharmaceuticals. Dr. Bounameaux reports receiving consulting fee, travel support, fees for participation in review activities, lecture fees and board membership from ICTOM/Bayer Healthcare, Pfizer, sanofi‐aventis, GlaxoSmithKline, Boehringer‐Ingelheim, and Daiichi‐Sankyo. Dr. Buller reports receiving consulting fee, travel support, fees for participation in review activities, payment for writing or reviewing the manuscript, and Board membership from ICTOM/Bayer Healthcare, Pfizer, sanofi‐aventis, GlaxoSmithKline, Boehringer‐Ingelheim, and Daiichi‐Sankyo. Dr. Chlumsky reports receiving consulting fee, travel support, fees for participation in review activities, and other fee  from ICTOM/Bayer Healthcare. Dr. Cohen reports receiving consulting fee, travel support, fees for participation in review activities, payment for writing or reviewing the manuscript, and lecture fees  from ICTOM/Bayer Healthcare, Astellas,AstraZeneca, Daiichi, Johnson and Johnson, Pfizer and other companies. Dr. Davidson reports receiving travel support, and fees for participation in review activities from Bayer. Dr. Decousus reports receiving fees for participation in review activities, payment for writing or reviewing the manuscript from Bayer. Dr. Gallus reports receiving consulting fee, travel support, fees for participation in review activities, payment for writing or reviewing the manuscript, from ICTOM/Bayer Health Care AG. Dr. Gallus reports receiving consulting fee, travel support, fees for participation in review activities, payment for writing or reviewing the manuscript from ICTOM/Bayer Health Care AG. Dr. Jacobson reports receiving consulting fee, travel support, fees for participation in review activities, payment for writing or reviewing the manuscript from Ictom/Bayer HealthCare AG. Dr. Lensing reports receiving travel support and employment from Bayer Healthcare. Dr. Minar reports receiving consulting fee, travel support, fees for participation in review activities, and lecture fees from BayerHealthcare/ ICTOM. Dr. Misselwitz is an employee of Bayer, the sponsor of the trial. Dr. Prins reports receiving consulting fee, travel support, payment for writing or reviewing the manuscript from ICTOM/BayerHeatltcare. Dr. Raskob reports receiving consulting fee, travel support, fees for participation in review activities, payment for writing or reviewing the manuscript, lecture fees, and payment for manuscript preparation from ICTOM/Bayer Healthcare, Daiichi Sankyo, BMS, and Pfizer. Dr. Schellong reports receiving consulting fee, travel support, fees for participation in review activities, payment for writing or reviewing the manuscript, lecture fees, and payment for development of educational presentations from ICTOM/Bayer Healthcare, Boehringer Ingelheim, Daiichi Sankyo, and other companies. Dr. Segers reports receiving consulting fee, travel support, fees for participation in review activities, payment for writing or reviewing the manuscript from Bayer Healthcare. Dr. Verhamme reports receiving consulting fee, travel support, fees for participation in review activities, payment for writing or reviewing the manuscript, lecture fees from ICTOM/Bayer Healthcare, Boehringer Ingelheim, Sanofi‐Aventis, and other companies. Dr. Verhamme reports receiving consulting fee, travel support, fees for participation in review activities, payment for writing or reviewing the manuscript, lecture fees from ICTOM/Bayer Healthcare, Boehringer Ingelheim, Pfizer."

Disclosure forms provided by the authors are available at: https://www.nejm.org/doi/suppl/10.1056/NEJMoa1113572/suppl_file/nejmoa1113572_disclosures.pdf 

Notes

—

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation was performed with the use of a computerised voice‐response system"
Comment: study judged at low risk of selection bias.

Allocation concealment (selection bias)

Low risk

Quote: "Randomisation was performed with the use of a computerised voice‐response system"
Comment: study judged to be at a low risk of selection bias.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Open‐label"
Comment: only one dose of rivaroxaban was given and as the comparison was enoxaparin/VKA, blinding of participants and personnel was not possible. However, we judged that the lack of blinding in the control group was unlikely to have affected the outcome.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "A central committee whose members were unaware of the study‐group assignments adjudicated the results of all baseline lung‐imaging tests and all suspected outcome events"
Comment: study judged to be at low risk of detection bias.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

In the rivaroxaban group, 1 was excluded because of invalid informed consent, 7 did not receive rivaroxaban. In the standard therapy group, 8 did not receive standard therapy.
Comment: fewer than 20% of participants dropped out or withdrew, and the study author performed ITT analysis. Study judged at low risk of attrition bias.

Selective reporting (reporting bias)

Low risk

The study protocol is available and all of the study's pre‐specified outcomes have been reported in the pre‐specified way. Study judged at low risk of reporting bias.

Other bias

Low risk

We did not find any methodological issues that might directly lead to a risk of bias.

Study characteristics

Methods

Study design: a multinational, prospective, randomised, open‐label, blinded endpoint, non‐inferiority study
Duration of study: 6 to 12 months

Participants

Setting: multicentre
Country: multinational (114 centres in 13 countries: Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Hungary, Italy, Netherlands, New Zealand, Spain, USA)
Number of participants: 1046 (PE 657, other VTE 389); edoxaban 522 (PE 328, other VTE 194), dalteparin 524 (PE 329, other VTE 195)
Age, mean (SD) years: edoxaban 64.3 (11.0) years, dalteparin 63.7 (11.7) years
Sex: edoxaban: 277 M/245 F, dalteparin: 263 M/261 F
Inclusion criteria: adults with cancer were eligible for inclusion in the trial if they had acute symptomatic or incidentally detected DVT involving the popliteal, femoral, or iliac vein or the inferior vena cava; acute symptomatic PE that was confirmed by means of diagnostic imaging; or incidentally detected PE involving segmental or more proximal pulmonary arteries
Exclusion criteria: people who met any of the following criteria were not eligible for enrolment: thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current (index) episode of DVT and/or PE; more than 72 hours pre‐treatment with therapeutic dosages of anticoagulant treatment (LMWH, UFH, and fondaparinux per local labelling), oral direct anticoagulants or VKA prior to randomisation to treat the current (index) episode; treatment with therapeutic doses of an anticoagulant including dalteparin for an indication other than VTE prior to randomisation; active bleeding or any contraindication for treatment with LMWH/dalteparin or edoxaban; an ECOG Performance Status of 3 or 4 at the time of randomisation; calculated CrCL < 30 mL/min; history of heparin‐associated thrombocytopenia; acute hepatitis, chronic active hepatitis, liver cirrhosis;
hepatocellular injury with concurrent transaminase (ALT/AST > 3 x ULN) and bilirubin (> 2 x ULN) elevations in the absence of a clinical explanation; life expectancy < 3 months; platelet count < 50,000/mL; uncontrolled hypertension as judged by the investigator (e.g. systolic BP > 170 mmHg or diastolic BP > 100 mmHg despite antihypertensive treatment); women of childbearing potential without proper contraceptive measures, and women who are pregnant or breastfeeding.

Interventions

Intervention 1: edoxaban was administered orally at a fixed dose of 60 mg once daily, with or without food. It was administered at a lower dose (30 mg once daily) in participants with a creatinine clearance of 30 mL to 50 mL per minute or a body weight of 60 kg or less or in those receiving concomitant treatment with potent P‐glycoprotein inhibitors. Treatment was administered for 6 to 12 months; median duration was 7 months.
Intervention 2: dalteparin was given subcutaneously at a dose of 200 IU/kg of body weight once daily for 30 days, with a maximum daily dose of 18,000 IU. Thereafter, dalteparin was given at a dose of 150 IU/kg once daily. If the platelet count declined to less than 100,000 per μL during treatment, the dose of dalteparin was temporarily reduced. Treatment was administered for 6 to 12 months; median duration was 6 months.
Follow‐up: participants underwent assessment, in the clinic or by telephone, on day 31 after randomisation and at months 3, 6, 9, and 12.

Outcomes

Primary: a composite of recurrent venous thromboembolism or major bleeding; death

Secondary: recurrent VTE; major bleeding; clinically relevant non‐major (CRNM) bleeding; major + CRNM bleeding; event‐free survival, VTE‐related death, mortality from all causes, recurrent DVT, recurrent PE

Funding

Quote: "Funded by Daiichi Sankyo."

Comment:  this study was funded by Daiichi Sankyo, the pharmaceutical company that developed edoxaban, and the result of the primary outcome supported the non‐inferiority hypothesis of edoxaban. It is possible that this may have influenced the report of outcomes.

Declarations of interest

Quote: "Dr. Buller reports personal fees from Daiichi‐Sankyo, during the conduct of the study; personal fees from Bayer Healthcare, personal fees from BMS/Pfizer, personal fees from Boehringer‐Ingelheim, personal fees from Portola, personal fees from Medscape, personal fees from Eli Lilly, personal fees from Sanofi Aventis, and personal fees from Ionis outside the submitted work. Dr. Carrier reports personal fees from Daiichi Sankyo during the conduct of the study; grants and personal fees from BMS, grants and personal fees from LEO Pharma, personal fees from Pfizer, personal fees from Sanofi, and personal fees from Bayer outside the submitted work. Dr. Di Nisio reports personal fees from Daiichi Sankyo outside the submitted work. Dr. Garcia reports grants and personal fees from Daiichi Sankyo during the conduct of the study; personal fees from BMS, personal fees from Boehringer‐Ingelheim, grants and personal fees from Janssen, personal fees from Pfizer, personal fees from Medscape, and grants and personal fees from Incyte outside the submitted work. Dr. Garcia reports grants and personal fees from Daiichi Sankyo during the conduct of the study; personal fees from BMS, personal fees from Boehringer‐Ingelheim, grants and personal fees from Janssen, personal fees from Pfizer, personal fees from Medscape, and grants and personal fees from Incyte outside the submitted work. Dr. Kakkar reports personal fees from Daiichi Sankyo during the conduct of the study; grants and personal fees from Bayer AG, personal fees from Boehringer‐Ingelheim, personal fees from Janssen Pharma, personal fees from Sanofi SA, and personal fees from Verseon outside the submitted work. Dr. Kovacs reports grants and personal fees from Pfizer, grants and personal fees from Bayer, grants from Daiichi Sankyo Pharma, and grants from Bristol Meyers Squibb outside the submitted work. Dr. Mercuri reports personal fees from Daiichi‐Sankyo, outside the submitted work. Dr. Meyer reports non‐financial support from Leo Pharma, grants and non‐financial support from BMS‐Pfizer, non‐financial support from Stago, and non‐financial support from Bayer Healthcare outside the submitted work. Dr. Raskob reports personal fees from Daiichi Sankyo during the conduct of the study; personal fees from Bayer Healthcare, personal fees from BMS, personal fees from Boehringer‐Ingelheim, personal fees from Eli Lilly, personal fees from Janssen, personal fees from Johnson and Johnson, personal fees from Pfizer, personal fees from Portola, personal fees from Merck, and personal fees from Medscape outside the submitted work. Dr. Segers reports grants from Daiichi Sankyo during the conduct of the study; grants from IONIS Pharmaceuticals, grants from Daiichi Sankyo, and grants from Janssen Pharmaceuticals outside the submitted work. Dr. Shi reports personal fees from Daiichi Sankyo outside the submitted work. Dr. Verhamme reports grants and personal fees from Daiichi Sankyo, during the conduct of the study; grants and personal fees from Bayer Healthcare, personal fees from BMS, grants and personal fees from Boehringer‐Ingelheim, personal fees from Portola, personal fees from Medscape, grants and personal fees from LeoPharma, grants from Sanofi, personal fees from Medtronic, personal fees from Pfizer, outside the submitted work. Dr. Wang reports non‐financial support from Daiichi Sankyo during the conduct of the study. Dr. Weitz reports personal fees from Daiichi‐Sankyo, during the conduct of the study; personal fees from Bayer Healthcare, personal fees from BMS, personal fees from Boehringer‐Ingelheim, personal fees from Ionis Pharmaceuticals, personal fees from Janssen, personal fees from Johnson and Johnson, personal fees from Pfizer, personal fees from Portola, personal fees from Medscape, personal fees from Novartis outside the submitted work. Dr. Yeo reports grants and personal fees from Daiichi Sankyo during the conduct of the study; personal fees from Bayer Healthcare, personal fees from Pfizer, personal fees from Boerhringer Ingelheim, personal fees from Sanofi, and personal fees from Leo Pharma outside the submitted work. Dr. Zhang reports personal fees from Daiichi Sankyo outside the submitted work. Dr. Zhang reports personal fees from Daiichi Sankyo outside the submitted work."

Disclosure forms provided by the authors are available at: www.nejm.org/doi/suppl/10.1056/NEJMoa1711948/suppl_file/nejmoa1711948_disclosures.pdf  

Notes

Study characteristics were presented for all participants with a VTE, but specific recurrent VTE and major bleeding with a PE were available.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was performed with the use of an interactive Web‐based system"
Comment: study judged at low risk of selection bias.

Allocation concealment (selection bias)

Low risk

Quote: "Randomization was performed with the use of an interactive Web‐based system"
Comment: study judged at low risk of selection bias.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Open label"
Comment: blinding of participants and personnel was not conducted. However, review authors judged that the lack of blinding was unlikely to have affected the objective outcome.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "all events were adjudicated by a committee whose members were unaware of the treatment assignments"
Comment: blinding was performed adequately; study judged at low risk of detection bias.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

In the edoxaban group, 16 did not complete the overall trial period (3 did not receive the assigned treatment, 10 withdrew consent, 3 were lost to follow‐up). In the dalteparin group, 18 did not complete the overall trial period (1 did not receive the assigned treatment, 12 withdrew consent, 5 were lost to follow‐up).
Comment: fewer than 20% of participants dropped out or withdrew, and the study author performed ITT analysis. Study judged at low risk of attrition bias.

Selective reporting (reporting bias)

Low risk

All of the study's pre‐specified outcomes were reported in the pre‐specified way. Study judged at low risk of reporting bias.

Other bias

Low risk

We did not find any methodological issues that might directly lead to a risk of bias.

Study characteristics

Methods

Study design: randomised, double‐blind, non‐inferiority study
Duration of study: 12 months

Participants

Setting: multicentre
Country: multinational (439 centres in 36 countries: Argentina, Australia, Austria, Belarus, Belgium, Brazil, Canada, China, Czech Republic, Denmark, Estonia, France, Germany, Hungary, India, Israel, Italy, Japan, Korea, Mexico, the Netherlands, New Zealand, Norway, Philippines, Poland, Russia, Singapore, South Africa, Spain, Sweden, Switzerland, China Taiwan, Thailand, Turkey, Ukraine, United Kingdom, USA) 
Number of participants: 3319 (all are PE); edoxaban 1650, warfarin 1669
Age, mean (SD) years: edoxaban 57.1 (16.6) years, warfarin 57.4 (16.5) years
Sex: edoxaban 863 M/787 F, warfarin 875 M/794 F
Inclusion criteria: people aged 18 or older who had objectively diagnosed, acute, symptomatic DVT involving the popliteal, femoral or iliac veins or acute, symptomatic PE (with or without DVT)
Exclusion criteria: contraindications to heparin or warfarin, had received treatment for more than 48 hours with therapeutic doses of heparin, had received more than one dose of a VKA, had cancer for which long‐term treatment with LMWH was anticipated, had another indication for warfarin therapy, continued to receive treatment with aspirin at a dose of more than 100 mg daily or dual antiplatelet therapy, or had a creatinine clearance of less than 30 mL per minute

Interventions

Intervention 1: oral edoxaban 60 mg once daily or 30 mg once daily in participants with a creatinine clearance of 30 mL to 50 mL per minute or a body weight of 60 kg or less or in participants who were receiving concomitant treatment with potent P‐glycoprotein inhibitors
Intervention 2: dose‐adjusted warfarin therapy to achieve an INR of 2.0 to 3.0 and edoxaban‐like placebo
Follow‐up: days 5, 12, 30, and 60 after randomisation, monthly while on study drug or every 3 months after discontinuing the study drug and finally at 12 months

Outcomes

Primary: incidence of symptomatic recurrent VTE (DVT and fatal or non‐fatal PE), clinically relevant bleeding (major or clinically relevant non major)
Secondary: none

Funding

Quote: "Funded by Daiichi‐Sankyo."

Comment: the study was funded by Daiichi‐Sankyo, the pharmaceutical company that developed edoxaban. It is possible that this may have influenced the timeframe of reported safety outcomes.

Declarations of interest

Quote: "Dr. Büller reports receiving consulting fees from Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Isis Pharmaceuticals, and ThromboGenics, and grant support from Bayer and Pfizer. Dr. Decousus reports receiving fees for board membership from Bayer and Daiichi Sankyo, lecture fees from GlaxoSmithKline, and grant support from Bayer, Bristol‐Myers Squibb–Pfizer, Boehringer Ingelheim, and Portola. Drs. Grosso, Mercuri, Schwocho, and Shi report being employees of Daiichi Sankyo. Dr. Middeldorp reports receiving consulting fees from Bayer and Bristol‐Myers Squibb–Pfizer, lecture fees from Bayer, GlaxoSmithKline, Bristol‐Myers Squibb–Pfizer, and Boehringer Ingelheim, and grant support from GlaxoSmithKline, Bristol‐Myers Squibb–Pfizer, and Sanquin. Dr. Prins reports receiving consulting fees from Bayer, Pfizer, and Boehringer Ingelheim, and lecture fees from Bayer. Dr. Raskob reports receiving consulting fees and travel support from Bayer, Bristol‐Myers Squibb, Janssen, Johnson & Johnson, Pfizer, Sanofi‐Aventis, and Takeda. Dr. Schellong reports receiving consulting fees from Bayer and Boehringer Ingelheim, and lecture fees from Bayer, Boehringer Ingelheim, and Bristol‐Myers Squibb–Pfizer. Dr. Segers reports receiving fees for the scientific management of the studies as director of the International Clinical Trial Organization and Management (ICTOM) academic research organization from Bayer, Isis Pharmaceuticals, and Pfizer. Dr. Verhamme reports receiving consulting fees from Bayer, Boehringer Ingelheim, ThromboGenics, and Pfizer, lecture fees from Bayer, Boehringer Ingelheim, Leo Pharma, Sanofi‐Aventis, and Pfizer, and grant support from Bayer, Boehringer Ingelheim, Leo Pharma, and Sanofi‐Aventis. Dr. Wells reports receiving lecture fees from Bayer, Boehringer Ingelheim, Biomerieux, and Bristol‐Myers Squibb–Pfizer. No other potential conflict of interest relevant to this article was reported."

Notes

We successfully contacted study authors for outcome data, including the rate of recurrent pulmonary embolism, deep vein thrombosis, and major bleeding.  

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation was performed with the use of an interactive Web‐base system"
Comment: study judged at low risk of selection bias.

Allocation concealment (selection bias)

Low risk

Quote: "Randomisation was performed with the use of an interactive Web‐base system"
Comment: study judged to be at a low risk of selection bias.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Edoxaban or warfarin was administered in a double‐blind fashion"
Comment: study judged to be at a low risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "An independent committee, whose members were unaware of the study‐group assignments, adjudicated all suspected outcome and the results of baseline imaging tests and assessed the anatomical extent of thrombosis"
Comment: study judged to be at a low risk of performance bias.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

In the edoxaban group, 25 did not receive heparin–edoxaban, 181 did not complete the overall study period, 132 died, 36 withdrew consent, 7 were lost to follow‐up, 6 had other reasons. In the warfarin group, 27 did not receive heparin–warfarin, 167 did not complete the overall study period, 126 died, 34 withdrew consent, 4 were lost to follow‐up, 3 had other reasons.
Comment: fewer than 20% of participants dropped out or withdrew, and the study author performed ITT analysis. Study judged at low risk of attrition bias.

Selective reporting (reporting bias)

Low risk

The study protocol is available and all of the study's pre‐specified outcomes have been reported in the pre‐specified way. Study judged at low risk of reporting bias.

Other bias

Low risk

We did not find any methodological issues that might directly lead to a risk of bias.

Study characteristics

Methods

Study design: an open‐label, randomised trial
Duration of study: 6.5 months

Participants

Setting: multicentre 
Country: Japan (30 centres)
Number of participants: 97 (PE 40, other VTE 57); rivaroxaban 78 (PE 33, other VTE 45), UFH (UFH)/warfarin 19 (PE 7, other VTE 12)
Age, mean (SD) years: rivaroxaban (10 mg twice daily/15 mg once daily): 65.0 (9.9) years; rivaroxaban (15 mg twice daily/15 mg once daily): 68.8 (12.2) years; UFH/warfarin: 63.4 (18.3) years
Sex: rivaroxaban (10 mg twice daily/15 mg once daily): 16 M/7 F; rivaroxaban (15 mg twice daily/15 mg once daily): 25 M/30 F; UFH/warfarin: 10 M/9 F
Inclusion criteria: people older than 20 years who had acute, objectively confirmed symptomatic proximal DVT and/or PE
Exclusion criteria: people were excluded if they had received heparin or fondaparinux treatment for longer than 48 hours or more than a single dose of warfarin. Other exclusion criteria were: thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent for the current episode; any contraindication listed in the local labelling of UFH or warfarin or another indication for the use of UFH or warfarin; a creatinine clearance < 30 mL/min; significant hepatic disease or ALT > 3 times ULN; bacterial endocarditis; active bleeding or a high risk of bleeding contraindicating treatment with UFH or warfarin; a systolic BP of more than 180 mm Hg or a diastolic BP of more than 110 mm Hg; childbearing potential without proper contraceptive measures, pregnancy, or breast‐feeding; concomitant use of strong cytochrome P450 3A4 inhibitors (i.e. azole‐antimycotics or HIV protease inhibitors); and a life expectancy of fewer than 3 months.

Interventions

Intervention 1: participants received rivaroxaban 15 mg twice daily for a total of 3 weeks in a double‐blind fashion, followed by open‐label rivaroxaban 15 mg once daily. Treatment was continued for 3, 6, or 12 months, as decided by the treating physician. The mean treatment duration was 195 days.
Intervention 2: participants assigned to control treatment received IV UFH, with the dose adjusted to prolong the APPT to 1.5–2.5‐fold that of controls, for at least 5 days, overlapping with and followed by INR (range 1.5–2.5)‐titrated warfarin. UFH was discontinued when the INR was 1.5 or more for 2 consecutive measurements at least 24 hours apart. Initially, the INR was measured every 2 to 3 days and, when stable, at least once per month. Treatment was continued for 3, 6, or 12 months, as decided by the treating physician. The mean treatment duration was 200 days.
Follow‐up: day 22 and at the end of the 3, 6, or 12 months' intended treatment period.

Outcomes

Primary: the occurrence of symptomatic recurrent VTE or asymptomatic deterioration
Secondary: venous ultrasound and spiral CT, major bleeding, CRNM bleeding

Funding

Quote: "The program was sponsored by Bayer Yakuhin Ltd."

Comment: Bayer Yakuhin Ltd, Japan developed rivaroxaban. Some authors received funding from some pharmaceutical companies. The results showed a similar efficacy and safety profile with rivaroxaban and control treatment. It is possible that this may have influenced the report of outcomes.

Declarations of interest

Quote: "Bayer Yakuhin supported this study, was involved in the design of the trial, and collected and analysed the data. MHP has received research support and honoraria, and has participated in advisory boards for Bayer HealthCare, Sanofi‐Aventis, Boehringer Ingelheim, GlaxoSmithKline, Daiichi Sankyo, LEO Pharma, ThromboGenics, and Pfizer. AWAL, MKato, JO, YM, KI, and MKajikawa are employees of Bayer HealthCare Pharmaceuticals. NY has received honoraria for oral presentations from Daiichi Sankyo. AH has received research grants from Astellas Pharmaceuticals, AstraZeneka, MSD, Otsuka Pharmaceutical, Kissei Pharmaceutical, Kyowa Hakko Kirin, Kowa Pharmaceuticals, Sanofi, Daiichi Sankyo, Takeda Pharmaceuticals, Mitsubishi Tanabe Pharma, Boehringer Ingelheim, Nihon Medi‐Physics, and Bayer Yakuhin, and has received funding from Sanofi, Daiichi Sankyo, Toa Eiyo, Novartis, and Bayer Yakuhin for participation in clinical trials. AH has received funding for endowed courses from Otsuka Pharmaceutical, Fukuda Denshi, Hokushin Medical, Boston Scientific, and Vega Life Corporation. SS has received funding from Bayer Yakuhin, Daiichi Sankyo, Takeda Pharmaceuticals, Otsuka Pharmaceutical, Novartis Pharma, and Boehringer Ingelheim for participation in clinical trials. The other authors declare that they have no competing interests."

Notes

Results were presented for all participants with a VTE but specific recurrent VTE data for the subset of participants with a PE were available.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization was done centrally, using an interactive web response system"
Comment: study judged at low risk of selection bias.

Allocation concealment (selection bias)

Low risk

Quote: "Randomization was done centrally, using an interactive web response system"
Comment: study judged at low risk of selection bias.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Open label"
Comment: blinding of participants and personnel was not conducted. However, review authors judged that the lack of blinding was unlikely to have affected the objective outcome.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "use objective and validated tests to confirm suspected recurrent VTE and the use of an independent committee, whose members were blinded to treatment assignment to adjudicate outcome events"
Comment: blinding was performed adequately; study judged at low risk of detection bias.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Three participants from a single site were excluded from all analyses because of serious non‐compliance with the protocol/Good Clinical Practice guidelines.
Comment: fewer than 20% of participants dropped out or withdrew, and the study author performed ITT analysis. Study judged at low risk of attrition bias.

Selective reporting (reporting bias)

Low risk

All the study's pre‐specified outcomes were reported in the pre‐specified way. Study judged at low risk of reporting bias.

Other bias

Low risk

We did not find any methodological issues that might directly lead to a risk of bias.

Study characteristics

Methods

Study design: randomised, open‐label, parallel‐group, multicenter study
Duration of study: 3 months

Participants

Setting: multicentre (35 hospitals)
Country: USA
Number of participants: 114 (all were PE); rivaroxaban 51, standard of care 63
Age, mean (SD) years: rivaroxaban 49.14 (13.3) years, standard of care 47.56 (17.2) years
Sex: rivaroxaban 24M/27F, standard of care 31M/32F
Inclusion criteria: adults presenting to the emergency department (ED) with objectively confirmed, low‐risk PE were eligible for enrolment. Low‐risk PE was defined by the absence of any Hestia criteria, adapted for emergency medicine by removing 24‐hour requirements.
Exclusion criteria: people were excluded for a troponin level above the institutional upper reference level, contraindications to anticoagulation, or by investigator determination of barriers to treatment or follow‐up. Although the Hestia criteria exclude haemodynamically unstable patients, instability is not defined and was determined per the physician's judgment. 

Interventions

Intervention 1: participants randomised to early discharge on rivaroxaban were discharged within 24 hours of ED triage and were instructed to take rivaroxaban with food, 15 mg twice daily for 21 days and then 20 mg once daily to study completion. Treatment for 3 months
Intervention 2: standard of care participants were treated per local protocol, which could include hospitalisation and any Food and Drug Administration (FDA)‐approved anticoagulant strategy, including rivaroxaban. If receiving warfarin, the target INR was 2.0 to 3.0, with testing per local protocol.
Follow‐up: 30 days, 90 days

Outcomes

Primary: total amount of time spent in the hospital, expressed in hours for venous thromboembolic or bleeding events, in the 30 days after randomisation. The primary safety outcome was major bleeding within 90 days.
Secondary: prespecified secondary efficacy endpoints included 90‐day rates of new/recurrent VTE, VTE‐related death, unplanned hospital or physician office visits for VTE

Funding

Quote: "Funding for this research was provided by Janssen Pharmaceuticals, Raritan, NJ"

Comment: Janssen Pharmaceuticals, Raritan, NJ, manufactures rivaroxaban. The results showed a similar efficacy and safety profile with rivaroxaban and control treatment. It is possible that this may have influenced the report of outcomes.

Declarations of interest

Quote: "Consulting for commercial interests, including advisory board work‐WFP, CC, DD, and AS have received funding personally from Janssen for consulting. WFP, and CC have received funding personally from Bayer, AG. JK has received grant funding from Janssen for a separate study. Payment for writing independent of grant funding—No author received payment from for writing any part of this manuscript. Employment—PW and JX are employed by Janssen, which manufactures rivaroxaban. Institutional Grant Receipt—WFP, CC, DD, SF, CKa, CKe, JM, and AS’s institution has received funding from Janssen for this investigator‐initiated research. Miscellaneous—DD has been a member of the SAEM board of directors. Author Contributions: WFP—study concept and design, acquisition of the data, analysis and interpretation of the data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical expertise, and acquisition of funding. CC—acquisition of the data, analysis and interpretation of the data, critical revision of the manuscript for important intellectual content, and statistical expertise. DD—study concept and design, acquisition of the data, and critical revision of the manuscript for important intellectual content. SK—acquisition of the data and critical revision of the manuscript for important intellectual content. CKa—study concept and design, analysis and interpretation of the data, and critical revision of the manuscript for important intellectual content. CKe—acquisition of the data and critical revision of the manuscript for important intellectual content. JK—study concept and design and critical revision of the manuscript for important intellectual content. JM—acquisition of the data and critical revision of the manuscript for important intellectual content. PW—study concept and design, analysis and interpretation of the data, critical revision of the manuscript for important intellectual content, statistical expertise, and acquisition of funding. JX—analysis and interpretation of the data, critical revision of the manuscript for important intellectual content, and statistical expertise. AS—study concept and design, acquisition of the data, analysis and interpretation of the data, critical revision of the manuscript for important intellectual content, statistical expertise, and acquisition of funding."

Notes

—

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly assigned in a 1:1 ratio to emergency department discharge on open‐label rivaroxaban or standard care (as determined by the attending physician) by an interactive Web within 12 hours of diagnosis."
Comment: study judged at low risk of selection bias.

Allocation concealment (selection bias)

Low risk

Quote: "Randomization was centrally performed through an interactive online system."
Comment: study judged at low risk of selection bias.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Open label, as participants could not be blinded to their own hospitalisation, to reduce observer bias clinical and safety endpoints were adjudicated by a panel blinded to treatment allocation."
Comment: lack of blinding was unlikely to have affected the outcome.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "As participants could not be blinded to their own hospitalisation, to reduce observer bias clinical and safety endpoints were adjudicated by a panel blinded to treatment allocation."
Comment: blinding was performed adequately; study judged at low risk of detection bias.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

In the rivaroxaban group, 7 dropouts (3 lost to follow‐up, 0 withdrew consent, 4 other reasons). In the standard of care group: 8 dropouts (4 lost to follow‐up, 2 withdrew consent, 2 other reasons).
Comment: fewer than 20% of participants dropped out or withdrew, and the study author performed ITT analysis. Study judged at low risk of attrition bias.

Selective reporting (reporting bias)

Low risk

All of the study's pre‐specified outcomes were reported in the pre‐specified way. Study judged at low risk of reporting bias.

Other bias

Low risk

We did not find any methodological issues that might directly lead to a risk of bias.

Study characteristics

Methods

Study design: randomised, double‐blind, double‐dummy non‐inferiority trial
Duration of study: 6 months

Participants

Setting: multicentre
Country: multinational (228 clinical centres in 29 countries: USA, Argentina, Australia, Austria, Belgium, Brazil, Canada, Czech Republic, Denmark, France, Germany, Greece, Hungary, India, Israel, Italy, Mexico, the Netherlands, New Zealand, Norway, Portugal, Russian Federation, Slovakia, South Africa, Spain, Sweden, Turkey, Ukraine, United Kingdom)
Number of participants: 2539 (PE 786, other VTE 1753); dabigatran 1273 (PE 391, other VTE 882), warfarin 1266 (PE 395, other VTE 871)
Age, mean (range) years: dabigatran 55 (15.8) years, warfarin 54.4 (16.2) years
Sex: dabigatran 738 M/535 F, warfarin 746 M/520 F
Inclusion criteria: people aged ≥ 18 years who had acute, symptomatic, objectively verified proximal DVT of the legs or PE and for whom 6 months of anticoagulant therapy was considered an appropriate treatment
Exclusion criteria: duration of symptoms > 14 days, PE with haemodynamic instability or requiring thrombolytic therapy, another indication for warfarin therapy, recent unstable cardiovascular disease, a high risk of bleeding, liver disease with an ALT level that was 2 x ULN range, an estimated creatinine clearance < 20 mL/minute, a life expectancy < 6 months, contraindication to heparin or to radiographic contrast material, pregnancy or risk of becoming pregnant, requirement for long‐term anticoagulant therapy

Interventions

Intervention 1: oral dabigatran 150 mg twice daily and warfarin‐like placebo
Intervention 2: dose‐adjusted warfarin therapy to achieve an INR of 2.0 to 3.0 and dabigatran‐like placebo
Follow‐up: 6 months

Outcomes

Primary: recurrent VTE evaluated using the same diagnostic methods used for the initial diagnosis
Secondary: bleeding that was defined as major if it was clinically overt and if it was associated with a fall in the haemoglobin level ≥ 20 g/L, resulted in the need for transfusion of ≥ 2 units of red cells, involved a critical site, or was fatal.

Funding

Quote: "Supported by Boehringer Ingelheim."

Comment: the study was funded by Boehringer‐Ingelheim, the pharmaceutical company that developed dabigatran. It is possible that this may have influenced the timeframe of reported safety outcomes.

Declarations of interest

Quote: "Dr. Schulman reports receiving consulting fees from AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, GlaxoSmithKline, and Sanofi‐Aventis, lecture fees from LEO Pharma, Sanofi‐Aventis, and Boehringer Ingelheim, and grant support from Bayer HealthCare; Dr. Kearon, consulting fees from Boehringer Ingelheim; Dr. Kakkar, consulting fees and honoraria from Boehringer Ingelheim, Bayer Schering Pharma, Sanofi‐Aventis, Bristol‐Myers Squibb, Pfizer, ARYx Therapeutics, Canyon Pharmaceuticals, and Eisai, lecture fees from Sanofi‐Aventis, Bayer Schering Pharma, Boehringer Ingelheim, GlaxoSmithKline, Eisai, and Pfizer, and grant support from Sanofi‐Aventis, Boehringer Ingelheim, Pfizer, and Bayer Schering Pharma; Dr. Mismetti, consulting fees and lecture fees from Boehringer Ingelheim, Sanofi‐Aventis, and GlaxoSmithKline; Dr. Schellong, lecture fees and consulting fees from Bayer HealthCare, Boehringer Ingelheim, and GlaxoSmithKline and consulting fees from Sanofi‐Aventis; Dr. Eriksson, consulting fees and lecture fees from Boehringer Ingelheim, Pfizer, AstraZeneca, Bayer HealthCare, LEO Pharma, and Sanofi‐Aventis; and Dr. Goldhaber, clinical research support from Sanofi‐Aventis, Bristol‐Myers Squibb, and Boehringer Ingelheim, and consulting fees from Sanofi‐Aventis, Boehringer Ingelheim, Merck, MEDRAD Interventional/Possis, Bristol‐Myers Squibb, Genentech, and Medscape. Mr. Baanstra and Dr. Schnee report being employees of Boehringer Ingelheim. No other potential conflict of interest relevant to this article was reported."

Notes

2539 participants were recruited into the trial but only 1602 had a PE and were included in the analysis of this review.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Computer generated randomisation scheme"
Comment: study judged at low risk of selection bias.

Allocation concealment (selection bias)

Low risk

Quote: "Staff members at the clinical centres called an interactive voice‐response system that randomly assigned subjects to one of the supplied medication kits. The treatment‐group assignment was concealed from all the investigators and their staff at the coordinating centre and the clinical centres and from the clinical monitors"
Comment: study judged to be at low risk of selection bias.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Double blind. The treatment‐group assignment was concealed from all the investigators and their staff at the coordinating centre and the clinical centres and from the clinical monitors. Warfarin or a placebo that looked identical to warfarin.... Administration of dabigatran or a placebo that looked identical to dabigatran"
Comment: study judged to be at low risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "All suspected outcome events and deaths were classified by central adjudication committees, whose members were unaware of the treatment assignments"
Comment: study judged to be at low risk of detection bias.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

The study drug was stopped before 6 months in 204 participants (16%) in the dabigatran group (126 because of an adverse event, 21 because of non‐adherence, 9 because of loss to follow‐up, 39 because of withdrawal of consent, and 9 for other reasons) and in 183 participants (14.5%) in the warfarin group (102 because of an adverse event, 35 because of non‐adherence, 6 because of loss to follow‐up, 36 because of withdrawal of consent, and 4 for other reasons).
Comment: fewer than 20% of participants dropped out or withdrew, and the study author performed ITT analysis. Study judged at low risk of attrition bias.

Selective reporting (reporting bias)

Low risk

All of the study's pre‐specified outcomes have been reported in the pre‐specified way. Study judged at low risk of reporting bias.

Other bias

Low risk

We did not find any methodological issues that might directly lead to a risk of bias.

Study characteristics

Methods

Study design: randomised, double‐blind, double‐dummy trial
Duration of study: 6 months

Participants

Setting: 208 study sites
Country: multinational (228 clinical centres in 30 countries: USA, Australia, Brazil, Bulgaria, Canada, China, Czech Republic, Denmark, France, Hungary, India, Israel, Italy, Korea, Malaysia, the Netherlands, New Zealand, Norway, Philippines, Poland, Russian Federation, Singapore, Slovakia, South Africa, Spain, Sweden, China Taiwan, Thailand, Turkey, Ukraine, United Kingdom) 
Number of participants: 2568 (PE 816, other VTE 1752): dabigatran 1280 (PE 402, other VTE 878), warfarin 1288 (PE 414, other VTE 874)
Age, mean (SD) years: dabigatran 54.7 (16.2) years, warfarin 55.1 (16.3) years
Sex: dabigatran 781 M/499 F, warfarin 776 M/512 F
Inclusion criteria: people aged 18 or older who had acute, symptomatic, objectively verified proximal DVT of the legs or PE and for whom 6 months of anticoagulant therapy was considered to be an appropriate treatment
Exclusion criteria: duration of symptoms longer than 14 days; PE with haemodynamic instability or requiring thrombolytic therapy; another indication for warfarin therapy; recent unstable cardiovascular disease; a high risk of bleeding; liver disease with an aminotransferase level that was 3 times the ULN range; an estimated creatinine clearance of less than 20 mL per minute; a life expectancy of less than 6 months; a contraindication to heparin or to radiographic contrast material; pregnancy or risk of becoming pregnant; requirement for long‐term anticoagulant therapy

Interventions

Intervention 1: oral dabigatran 150 mg twice daily and warfarin‐like placebo for 6 months
Intervention 2: active warfarin adjusted to achieve an INR of 2.0 to 3.0 and dabigatran‐like placebo for 6 months

Outcomes

Primary: recurrent VTE objectively verified, preferably with the same method as for the index event
Secondary: major bleeding defined according to the ISTH criteria

Funding

Quote: "The study was funded by Boehringer‐Ingelheim."
Comment: Boehringer‐Ingelheim is the pharmaceutical company that developed dabigatran. It is possible that this may have influenced the timeframe of reported safety outcomes.

Declarations of interest

None

Notes

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Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomised by use of an interactive voice response system and a computer‐generated randomisation scheme in blocks of 4"
Comment: study judged at low risk of selection bias.

Allocation concealment (selection bias)

Low risk

Comment: no information given about how treatment allocation was concealed but study authors state that "the design of the trial was essentially identical to that of the first study with dabigatran for the treatment of acute VTE" (RE‐COVER 2009), which we judged to be at low risk of selection bias.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Double‐blind"
Comment: stated as double‐blind. No other information given about how blinding was maintained but study authors state that "the design of the trial was essentially identical to that of the first study with dabigatran for the treatment of acute VTE", which we judged to be at low risk of performance bias.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "A central adjudication committee, the members of which were unaware of the treatment assignments, classified all suspected outcome events, bleeding events, and deaths"
Comment: study judged to be at low risk of detection bias.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

14 participants in the dabigatran group and 7 in the warfarin group did not receive any study medication (10 did not meet the inclusion criteria or met the exclusion criteria, 9 withdrew consent, and 2 had an adverse event).
Comment: fewer than 20% of participants dropped out or withdrew, and the study author performed ITT analysis. Study judged at low risk of attrition bias.

Selective reporting (reporting bias)

Low risk

All of the study's pre‐specified outcomes have been reported in the pre‐specified way. Study judged at low risk of reporting bias.

Other bias

Low risk

We did not find any methodological issues that might directly lead to a risk of bias.