COmparison of Bleeding Risk Between Rivaroxaban and Apixaban in Patients With Atrial Fibrillation (COBRRA-AF)

April 17, 2026 updated by: Ottawa Hospital Research Institute

Atrial Fibrillation (AF) affects 200,000 Canadians and increases risk of stroke, morbidity and mortality. Having a stroke can affect a patient's ability to speak, eat, walk, work, care for themselves, and interact with others. Not only can it ruin one's life, but it can also be fatal. A stroke occurs when blood flow to the brain is blocked by a clot, depriving brain cells of oxygen. In people with atrial fibrillation, blood flow is sluggish in the top chambers of the heart, and blood clots can form there. When a piece of a clot breaks off, it can travel to the brain and cause a stroke. That's where blood thinners come in. Blood thinners, or anticoagulants, decrease the chances of blood clots forming in the heart, reducing the risk of stroke. Studies show that blood thinners are highly effective at reducing the risk of stroke by up to 95%.

The conventional blood thinner is warfarin, taken by mouth. Warfarin requires regular blood tests to make sure a patient getting the correct dose. The patient also may have to avoid certain foods since the medication can interact with them. Newer blood thinners, known as direct-oral anticoagulants (DOACs) are available, which do not require regular blood tests and do not interact with foods. Two of the new blood thinners are called rivaroxaban and apixaban. Like warfarin, they can be taken by mouth, and studies have shown them to be as effective as warfarin.

Both rivaroxaban and apixaban have been approved for stroke prevention in AF by Health Canada. However, there have been no direct head-to-head comparisons of these two anticoagulants, meaning comparative safety data is not available. Increasing use of DOACs for stroke prevention in AF and patient values around bleeding highlight the need for a comparison trial to ensure patients receive the anticoagulant with the greatest balance of benefit to potential harm.

The trial is to assess bleeding rates and superiority of using apixaban versus rivaroxaban in patients with non-valvular atrial fibrillation.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Atrial Fibrillation (AF) affects 200,000 Canadians and increases risk of stroke, morbidity and mortality. Oral anticoagulants such as Vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) are highly effective at reducing the risk of stroke by up to 95%. Randomized controlled trials (RCTs) have compared apixaban and rivaroxaban (both DOACs) to VKAs for stroke prevention in AF, and are approved for this use by Health Canada. However, there have been no direct head-to-head comparisons of these two anticoagulants, meaning comparative safety data is not available. Increasing use of DOACs for stroke prevention in AF, patient values around bleeding, and litigation highlight the need for a comparison trial to ensure patients receive the anticoagulant with the greatest balance of benefit to potential harm.

The objective of this RCT is to compare the safety of the first 12 months of apixaban twice daily to rivaroxaban once daily in patients with non-valvular AF (NVAF). Patients will be monitored for the primary outcome of clinically relevant bleeding (CRB; a composite of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) events during follow-up. This trial will directly inform clinical practice and the choice of first-line therapy.

Study Type

Interventional

Enrollment (Estimated)

3018

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Lana Castellucci, MD, FRCPC
  • Phone Number: 74641 613-737-8899
  • Email: lcastellucci@toh.ca

Study Contact Backup

Study Locations

  • Canada
    • British Columbia
      • Victoria, British Columbia, Canada, V8Z 0B9
    • Nova Scotia
      • Halifax, Nova Scotia, Canada
        • Recruiting
        • QEII Health Science Centre
        • Contact:
          • Ratika Parkash, MD
    • Ontario
      • Kingston, Ontario, Canada
        • Recruiting
        • Kingston General Hospital
        • Contact:
          • Kerstin deWit, MD
      • Ottawa, Ontario, Canada, K1H 8L6
        • Recruiting
        • The Ottawa Hospital - General Campus
        • Contact:
        • Contact:
      • Ottawa, Ontario, Canada
        • Recruiting
        • University Ottawa Heart Institute
        • Contact:
          • Daniel Ramirez, MD
    • Quebec

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age ≥ 18 years old
  • Confirmed new diagnosis of AF on ECG with an indication to start anticoagulation according to Canadian Cardiovascular Society guidelines

Exclusion Criteria:

  • Creatinine clearance =<15 ml/min calculated using 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
    • history of mechanical valve
    • other indication for anticoagulation (e.g. mechanical valves, venous thrombosis)
    • dual antiplatelet agent use
    • known liver disease with coagulopathy
    • use of contraindicated medications (strong inducers/inhibitors of CYP 3A4/5, P-glycoprotein)
    • pregnancy or breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Apixaban group

5 mg PO, twice daily for 12 months of treatment. A dose reduction* to 2.5 mg twice daily will apply if patients meet 2 of 3 following criteria: age > 80 years; weight < 60 kg; creatinine >133 micromol/L.

*Patients with AF who are receiving DOAC should have their renal function assessed at baseline and at least annually
Drug: Apixaban
Refer to Apixaban group
Other Names:
  • Eliquis
Active Comparator: Rivaroxaban Group

20 mg PO, once daily for 12 months of treatment. A dose reduction* to 15 mg daily will apply to patients with creatinine clearance <50 ml/min.

*Patients with AF who are receiving DOAC should have their renal function assessed at baseline and at least annually
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
Time Frame: For the duration of the study: 12 months
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: 12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Medication adherence
Time Frame: For the duration of the study: 12 months
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: 12 months
Adjudicated Major Bleeding events
Time Frame: For the duration of the study: 12 months

Major Bleeding includes clinically overt bleeding and is associated with:

  • 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
  • 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: 12 months
Adjudicated Clinically Relevant Non-Major Bleeding events
Time Frame: For the duration of the study: 12 months

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: 12 months
Adjudicated stroke/TIA events
Time Frame: For the duration of the study: 12 months

Stroke is defined as non-traumatic focal neurologic deficit lasting ≥ 24 hours and confirmed on cerebral imaging (computed tomography or magnetic resonance imaging).

Transient ischemic attack (TIA) is defined as a temporary loss of blood flow to a part of the brain with focal neurologic deficit lasting < 24 hours without imaging evidence of acute infarction.

Strokes are to be classified as ischemic, hemorrhagic stroke, or uncertain. Hemorrhagic strokes are considered and will be reported as both bleeding events as well as stroke endpoints. The location of the bleeding can be determined from the diagnostic imaging reports.
For the duration of the study: 12 months
All-cause mortality
Time Frame: For the duration of the study: 12 months
Using a binary outcome of an event or no event (Individual rates of death, all causes).
For the duration of the study: 12 months
Incremental cost-effectiveness ratio
Time Frame: For the duration of the study: 12 months
We will model the prognosis of a cohort of patients receiving rivaroxaban versus apixaban. The results will be presented as incremental cost per QALY gained, incremental costs per one clinically relevant bleeding cases prevented, and incremental cost per one life year saved.
For the duration of the study: 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

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

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 6, 2021

Primary Completion (Estimated)

December 31, 2027

Study Completion (Estimated)

December 31, 2027

Study Registration Dates

First Submitted

November 19, 2020

First Submitted That Met QC Criteria

November 19, 2020

First Posted (Actual)

November 24, 2020

Study Record Updates

Last Update Posted (Actual)

April 22, 2026

Last Update Submitted That Met QC Criteria

April 17, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • COBRRA-AF

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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