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

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ClinicalTrials.gov Identifier: NCT03266783
Recruitment Status : Recruiting
First Posted : August 30, 2017
Last Update Posted : January 13, 2021
Sponsor:
Collaborators:
Canadian Institutes of Health Research (CIHR)
Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network
Information provided by (Responsible Party):
Ottawa Hospital Research Institute

Study Description
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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.

Condition or disease Intervention/treatment Phase
Venous Thromboembolism Drug: Apixaban Drug: Rivaroxaban Phase 4

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2760 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism
Actual Study Start Date : December 13, 2017
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding

Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Apixaban group
10 mg PO BID for 1 week, then 5 mg PO BID for 3 months of treatment
 Drug: Apixaban
Refer to Apixaban group
Other Name: Eliquis
Active Comparator: Rivaroxaban group
15 mg PO BID for 3 weeks, then 20 mg PO OD for 3 months of treatment
 Drug: Rivaroxaban
Refer to Rivaroxaban group
Other Name: Xarelto


Outcome Measures
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Primary Outcome Measures :
  1. The rate of adjudicated clinically relevant bleeding (CRB) events [ Time Frame: 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 :
  1. Adjudicated Major Bleeding events [ Time Frame: For the duration of the study: 3 months ]
  2. Adjudicated Clinically Relevant Non-Major Bleeding events [ Time Frame: For the duration of the study: 3 months ]
  3. Adjudicated recurrent VTE events [ Time Frame: For the duration of the study: 3 months ]
  4. Adjudicated VTE-related deaths [ Time Frame: For the duration of the study: 3 months ]
  5. All-cause mortality [ Time Frame: For the duration of the study: 3 months ]
  6. Medication adherence [ Time Frame: For the duration of the study: 3 months ]
  7. Quality-adjusted life years (QALYs) gained [ Time Frame: For the duration of the study: 3 months ]
  8. Incremental cost-effectiveness ratio [ Time Frame: For the duration of the study: 3 months ]
  9. Impact of verbal consent on patient participation in comparison with participants from sites using written informed consent [ Time Frame: For the duration of the study: 3 months ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed newly diagnosed symptomatic acute VTE (proximal power extremity DVT or segmental or greater 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)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03266783


Contacts
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Contact: Lana Castellucci, MD, FRCPC 613-737-8899 ext 74641 lcastellucci@toh.ca
Contact: Limmy Lobo, MSc 613-737-8899 ext 72103 llobo@ohri.ca

Locations
Show Show 17 study locations
Sponsors and Collaborators
Ottawa Hospital Research Institute
Canadian Institutes of Health Research (CIHR)
Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network
Investigators
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Principal Investigator: Lana Castellucci, MD, FRCPC Ottawa Hospital Research Institute
More Information
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Responsible Party: Ottawa Hospital Research Institute
ClinicalTrials.gov Identifier: NCT03266783    
Other Study ID Numbers: COBRRA
First Posted: August 30, 2017    Key Record Dates
Last Update Posted: January 13, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Thromboembolism
Venous Thromboembolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Rivaroxaban
Apixaban
 Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants