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

Venous Thromboembolism Clinical Trial

— COBRRA  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03266783
• Other study ID #: COBRRA
• Status: Recruiting
• Phase: Phase 4
• Start date: December 13, 2017
• Est. completion date: December 2024

Study information

• Verified date: April 2024
• Source: Ottawa Hospital Research Institute
• Contact: Lana Castellucci, MD, FRCPC
• Phone: 613-737-8899
• Email: lcastellucci[@]toh.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 2760
• Est. completion date: December 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Thromboembolism
• Venous Thromboembolism

Intervention

Drug:
• Apixaban
Refer to Apixaban group
• Rivaroxaban
Refer to Rivaroxaban group

Locations

Country	Name	City	State
Australia	The University of Sydney	Darlington	New South Wales
Canada	University of Calgary	Calgary	Alberta
Canada	Alberta Health Sciences	Edmonton	Alberta
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	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	The Ottawa Hospital - General Campus	Ottawa	Ontario
Canada	CHU de Québec-Université Laval	Quebec city	Quebec
Canada	University of Sherbrooke	Sherbrooke	Quebec
Canada	UHN - Toronto General Hospital	Toronto	Ontario
Canada	St. Paul's Hospital	Vancouver	British Columbia
Ireland	The Royal College of Surgeons in Ireland/Mater Misericordiae University Hospital	Dublin

Sponsors (3)

Lead Sponsor	Collaborator
Ottawa Hospital Research Institute	Canadian Institutes of Health Research (CIHR), Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network

Countries where clinical trial is conducted

Australia,  Canada,  Ireland, 

Outcome

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