Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism
- Conditions
- Venous Thromboembolism
- Interventions
- Registration Number
- NCT03266783
- Lead Sponsor
- Ottawa Hospital Research Institute
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 2760
- 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
-
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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Apixaban group Apixaban 10 mg orally (PO), twice a day (BID) for 1 week, then 5 mg PO BID for 3 months of treatment Rivaroxaban group Rivaroxaban 15 mg orally (PO), twice a day (BID) for 3 weeks, then 20 mg PO once a day (OD) for 3 months of treatment
- Primary Outcome Measures
Name Time Method The rate of adjudicated clinically relevant bleeding (CRB) events For the duration of the study: 3 months CRB events are defined as the composite of major bleeding (MB) events and clinically relevant non-major bleeding (CRNMB) events.
- Secondary Outcome Measures
Name Time Method Adjudicated Major Bleeding events For the duration of the study: 3 months 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.
Adjudicated VTE-related deaths For the duration of the study: 3 months VTE-related death (fatal PE or unexplained deaths) will be confirmed using death certificates and/or autopsy findings.
All-cause mortality For the duration of the study: 3 months Using a binary outcome of an event or no event (Individual rates of death related to VTE, bleeding or other causes).
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 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.
Adjudicated Clinically Relevant Non-Major Bleeding events For the duration of the study: 3 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) evaluationMedication adherence For the duration of the study: 3 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.
Incremental cost-effectiveness ratio For the duration of the study: 3 months 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.
Adjudicated recurrent VTE events For the duration of the study: 3 months 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.
Quality-adjusted life years (QALYs) gained For the duration of the study: 3 months 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.
Trial Locations
- Locations (19)
The University of Sydney
🇦🇺Darlington, New South Wales, Australia
University of Calgary
🇨🇦Calgary, Alberta, Canada
Alberta Health Sciences
🇨🇦Edmonton, Alberta, Canada
St. Paul's Hospital
🇨🇦Vancouver, British Columbia, Canada
QEII Health Science Centre
🇨🇦Halifax, Nova Scotia, Canada
Hamilton General Hospital
🇨🇦Hamilton, Ontario, Canada
Juravinski Hospital
🇨🇦Hamilton, Ontario, Canada
St. Joseph's Healthcare Hamilton
🇨🇦Hamilton, Ontario, Canada
Kingston General Hospital
🇨🇦Kingston, Ontario, Canada
London Health Sciences Center
🇨🇦London, Ontario, Canada
The Ottawa Hospital - General Campus
🇨🇦Ottawa, Ontario, Canada
UHN - Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
Hôpital Sacré-Coeur de Montréal
🇨🇦Montreal, Quebec, Canada
St. Mary's Hospital
🇨🇦Montreal, Quebec, Canada
Jewish General Hospital
🇨🇦Montréal, Quebec, Canada
McGill University Health Center
🇨🇦Montréal, Quebec, Canada
University of Sherbrooke
🇨🇦Sherbrooke, Quebec, Canada
CHU de Québec-Université Laval
🇨🇦Quebec city, Quebec, Canada
The Royal College of Surgeons in Ireland/Mater Misericordiae University Hospital
🇮🇪Dublin, Ireland