COmparison of Bleeding Risk Between Rivaroxaban and Apixaban in Patients With Atrial Fibrillation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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COmparison of Bleeding Risk Between Rivaroxaban and Apixaban in Patients With Atrial Fibrillation

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: Apixaban
* Drug: Rivaroxaban


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A pragmatic prospective randomized open blinded endpoint (PROBE) trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Apixaban group<br>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<br>* Refer to Apixaban group<br>* Other names: Eliquis;|
| Active Comparator: Rivaroxaban Group<br>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<br>* Refer to Rivaroxaban group<br>* Other names: Xarelto;|

What is the study measuring?
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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: 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjudicated Major Bleeding events |  | For the duration of the study: 12 months | 
| Adjudicated Clinically Relevant Non-Major Bleeding events |  | For the duration of the study: 12 months | 
| Adjudicated stroke events |  | For the duration of the study: 12 months | 
| All-cause mortality |  | For the duration of the study: 12 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: 12 months | 
| cost per one CRB case prevented |  | For the duration of the study: 12 months | 
| cost per one life year saved |  | For the duration of the study: 12 months | 
| cost per one quality-adjusted life year (QALY) gained |  | For the duration of the study: 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stroke Prevention, Bleed