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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism

Conditions
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Venous Thromboembolism

Intervention / Treatment
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* Drug: Apixaban
* Drug: Rivaroxaban


Participation Criteria
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Eligibility Criteria
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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)

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Apixaban group<br>10 mg orally (PO), twice a day (BID) for 1 week, then 5 mg PO BID for 3 months of treatment | Drug: Apixaban<br>* Refer to Apixaban group<br>* Other names: Eliquis;|
| Active Comparator: Rivaroxaban group<br>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<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: 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjudicated Major Bleeding events |  | For the duration of the study: 3 months | 
| Adjudicated Clinically Relevant Non-Major Bleeding events |  | For the duration of the study: 3 months | 
| Adjudicated recurrent VTE events |  | For the duration of the study: 3 months | 
| Adjudicated VTE-related deaths |  | For the duration of the study: 3 months | 
| All-cause mortality |  | For the duration of the study: 3 months | 
| Medication adherence |  | For the duration of the study: 3 months | 
| Quality-adjusted life years (QALYs) gained |  | For the duration of the study: 3 months | 
| Incremental cost-effectiveness ratio |  | 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 |  | For the duration of the study: 3 months |