Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism (COBRRA)

Apixaban and rivaroxaban have been compared to standard therapy for treatment of acute symptomatic venous thromboembolism (VTE) in randomized controlled trials (RCTs), and are both approved by Health Canada. No safety or efficacy data is available from direct head-to-head comparison of these two anticoagulants. Lawsuits in the United States over bleeding events, patient perceptions, and concerns with medication adherence are additional factors highlighting the importance of a comparison trial. This multi-center, pragmatic, prospective, randomized, open-label, blinded end-point (PROBE) trial aims to compare the safety of apixaban and rivaroxaban for the treatment of VTE.

Study Overview

• Status: Completed
• Conditions: Venous Thromboembolism
• Intervention / Treatment: Drug: Apixaban; Drug: Rivaroxaban

Detailed Description

VTE is the third leading cause of mortality by cardiovascular disease. Standard treatment for acute VTE uses a combination of parenteral Low-Molecular-Weight Heparin (LMWH) and oral vitamin K antagonists (VKA) for 3 months, and carries significant bleeding risk. The major and/or clinically-relevant non-major bleeding (CRNMB) event rate is reported between 8.1-9.7% during initial treatment. This treatment is burdensome owing to subcutaneous injections, drug interactions, and laboratory monitoring. Direct oral anticoagulants (DOACs) are simpler to use and do not require laboratory monitoring.

Rivaroxaban and apixaban are two DOACs targeting Factor Xa. Each DOAC was separately proven effective and safe when compared to standard treatment. Comparison of the bleeding rates between studies would favour use of apixaban over rivaroxaban; however, trial limitations and lack of direct comparison between these two agents makes it impossible to draw firm conclusions. This represents a dilemma in clinical practice because the absence of convincing differences in safety has led to genuine uncertainty about which DOAC has the best risk-to-benefit ratio.

To address these limitations, a head-to-head randomized controlled trial (RCT) is needed to determine the safety (i.e. bleeding risk) of twice daily apixaban over once daily rivaroxaban during the first 3 months of acute VTE treatment. Eligibility criteria will be less stringent than the COBRRA pilot study and reflect real-world patients. Cost-effective analysis of apixaban twice daily compared to rivaroxaban once daily will also be performed.

• Study Type: Interventional
• Enrollment (Actual): 2760
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlington, New South Wales, Australia, 200606
      • The University of Sydney
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • University Of Calgary
    • Edmonton, Alberta, Canada
      • Alberta Health Sciences
  • British Columbia
    • Vancouver, British Columbia, Canada
      • St. Paul's Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • QEII Health Science Centre
  • Ontario
    • Hamilton, Ontario, Canada
      • Hamilton General Hospital
    • Hamilton, Ontario, Canada
      • Juravinski Hospital
    • Hamilton, Ontario, Canada
      • St. Joseph's Healthcare Hamilton
    • Kingston, Ontario, Canada
      • Kingston General Hospital
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Center
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital - General Campus
    • Toronto, Ontario, Canada, M5G 2C4
      • UHN - Toronto General Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Health Center
    • Montreal, Quebec, Canada
      • St. Mary's Hospital
    • Montreal, Quebec, Canada
      • Hopital Sacre-Coeur de Montreal
    • Québec, Quebec, Canada
      • CHU de Quebec-Universite Laval
    • Sherbrooke, Quebec, Canada
      • University of Sherbrooke
• Ireland
  • Dublin, Ireland
    • The Royal College of Surgeons in Ireland/Mater Misericordiae University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Confirmed newly diagnosed symptomatic acute venous thromboembolism (VTE) [proximal lower extremity deep vein thrombosis (DVT) or segmental or greater pulmonary embolism (PE)]
• Age ≥ 18 years old
• Informed consent obtained

Exclusion Criteria:

• Have received > 72 hours of therapeutic anticoagulation
• Creatinine clearance < 30 ml/min calculated with the Cockcroft-Gault formula

• Any contraindication for anticoagulation with apixaban or rivaroxaban as determined by the treating physician such as, but not limited to:

  • active bleeding,
  • active malignancy, defined as a) diagnosed with cancer within the past 6 months; or b) recurrent, regionally advanced or metastatic disease; or c) currently receiving treatment or have received any treatment for cancer during the 6 months prior to randomization; or d) a hematologic malignancy not in complete remission,
  • weight > 120 kg,
  • liver disease (Child-Pugh Class B or C),
  • use of contraindicated medications
  • another indication for long-term anticoagulation (e.g. atrial fibrillation)
  • pregnant (note below) or breastfeeding (Note: as reported by the patient or a pregnancy test will be ordered at the discretion of the treating physician for women of childbearing potential as per standard of care)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Apixaban group; 10 mg orally (PO), twice a day (BID) for 1 week, then 5 mg PO BID for 3 months of treatment	Drug: Apixaban; Refer to Apixaban group; Other Names: Eliquis
Active Comparator: Rivaroxaban group; 15 mg orally (PO), twice a day (BID) for 3 weeks, then 20 mg PO once a day (OD) for 3 months of treatment	Drug: Rivaroxaban; Refer to Rivaroxaban group; Other Names: Xarelto

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The rate of adjudicated clinically relevant bleeding (CRB) events	CRB events are defined as the composite of major bleeding (MB) events and clinically relevant non-major bleeding (CRNMB) events.	For the duration of the study: 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjudicated Major Bleeding events	Major bleeding will be defined as fatal bleeding, and/or, Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or bleeding causing a fall in hemoglobin of ≥20 g/L, or leading to transfusion of ≥2 units of whole blood or red cells.	For the duration of the study: 3 months
Adjudicated Clinically Relevant Non-Major Bleeding events	Clinically relevant non-major bleeding will be defined as any sign or symptom of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for the ISTH definition of major bleeding but does meet at least one of the following criteria: Requiring medical intervention by a healthcare professional; Leading to hospitalization or increased level of care; Prompting a face to face (i.e., not just a telephone or electronic communication) evaluation	For the duration of the study: 3 months
Adjudicated recurrent VTE events	Recurrent VTE will be confirmed with investigational reports including clinic notes, D-dimer results and imaging as per standard of care. Recurrent DVT will be confirmed by compression ultrasound revealing a new (compared to baseline/index ultrasound) area of non-compressibility in the popliteal vein or more proximal vein, or venography demonstrating a constant intraluminal filling defect in the popliteal vein or more proximal veins. Recurrent PE will be diagnosed if the V/Q scan is non-normal and a new unmatched segmental or greater perfusion defect is documented, or an intraluminal filling defect is seen on CTPA in a segmental or greater vessel that was previously free of thrombus, or pulmonary angiography demonstrating a constant intraluminal filling defect or a cutoff of a vessel >2.5 mm in diameter will be considered diagnostic for PE.	For the duration of the study: 3 months
Adjudicated VTE-related deaths	VTE-related death (fatal PE or unexplained deaths) will be confirmed using death certificates and/or autopsy findings.	For the duration of the study: 3 months
All-cause mortality	Using a binary outcome of an event or no event (Individual rates of death related to VTE, bleeding or other causes).	For the duration of the study: 3 months
Medication adherence	Reported as the number of patients self-reporting "all assigned medications were taken" "missing at least one dose of study medication", or "not able to take all of the study medications" out of the total number of medication compliance assessments done respectively.	For the duration of the study: 3 months
Quality-adjusted life years (QALYs) gained	We will measure health utility values using the EuroQoL-5D-5L 51 at baseline, 2 week (± 7 days), and 90 days (+14 days). We will model the prognosis of a cohort of patients receiving rivaroxaban as a baseline against the potential impact of apixaban. The results will be presented as incremental cost per QALY gained, incremental costs per one CRB cases prevented, and incremental cost per one life year saved.	For the duration of the study: 3 months
Incremental cost-effectiveness ratio	Incremental cost-effectiveness ratios including cost per one CRB case prevented, cost per one life year saved, cost per one quality-adjusted life year (QALY) gained, which will be analyzed as part of the health economic analysis plan.	For the duration of the study: 3 months
Impact of verbal consent on patient participation in comparison with participants from sites using written informed consent	Impact of verbal consent on patient participation in comparison with participants from sites using written informed consent. Due to the qualitative nature of this outcome, it will be presented descriptively.	For the duration of the study: 3 months

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: Canadian Institutes of Health Research (CIHR); Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network
• Investigators: Principal Investigator: Lana Castellucci, MD, FRCPC, Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2017
• Primary Completion (Actual): April 30, 2025
• Study Completion (Actual): September 8, 2025

Study Registration Dates

• First Submitted: August 10, 2017
• First Submitted That Met QC Criteria: August 28, 2017
• First Posted (Actual): August 30, 2017

Study Record Updates

• Last Update Posted (Estimated): November 17, 2025
• Last Update Submitted That Met QC Criteria: November 14, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Embolism and Thrombosis; Thromboembolism; Venous Thromboembolism; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Morpholines; Oxazines; Thiophenes; Rivaroxaban; apixaban
• Other Study ID Numbers: COBRRA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No