Clinical trial NCT03266783: Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism
Official title: Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Venous Thromboembolism
Lead sponsor: Ottawa Hospital Research Institute
Sponsor class: OTHER
Collaborators: name: Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network
name: Canadian Institutes of Health Research (CIHR)
First posted: 2017-08-30
Enrollment: 2760
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: The rate of adjudicated clinically relevant bleeding (CRB) events
timeFrame: For the duration of the study: 3 months
Secondary outcomes:
measure: Adjudicated Major Bleeding events
timeFrame: For the duration of the study: 3 months
measure: Adjudicated Clinically Relevant Non-Major Bleeding events
timeFrame: For the duration of the study: 3 months
measure: Adjudicated recurrent VTE events
timeFrame: For the duration of the study: 3 months
measure: Adjudicated VTE-related deaths
timeFrame: For the duration of the study: 3 months
measure: All-cause mortality
timeFrame: For the duration of the study: 3 months
measure: Medication adherence
timeFrame: For the duration of the study: 3 months
measure: Quality-adjusted life years (QALYs) gained
timeFrame: For the duration of the study: 3 months
measure: Incremental cost-effectiveness ratio
timeFrame: For the duration of the study: 3 months
measure: Impact of verbal consent on patient participation in comparison with participants from sites using written informed consent
timeFrame: For the duration of the study: 3 months
Other outcomes:
Locations:
city: Darlington
country: Australia
facility: The University of Sydney
state: New South Wales
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: Alberta Health Sciences
state: Alberta
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Halifax
country: Canada
facility: QEII Health Science Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Hospital
state: Ontario
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Hamilton
state: Ontario
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Center
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital - General Campus
state: Ontario
city: Toronto
country: Canada
facility: UHN - Toronto General Hospital
state: Ontario
city: Montreal
country: Canada
facility: Hôpital Sacré-Coeur de Montréal
state: Quebec
city: Montreal
country: Canada
facility: St. Mary's Hospital
state: Quebec
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Montréal
country: Canada
facility: McGill University Health Center
state: Quebec
city: Quebec city
country: Canada
facility: CHU de Québec-Université Laval
state: Quebec
city: Sherbrooke
country: Canada
facility: University of Sherbrooke
state: Quebec
city: Dublin
country: Ireland
facility: The Royal College of Surgeons in Ireland/Mater Misericordiae University Hospital
Study officials:
affiliation: Ottawa Hospital Research Institute
name: Lana Castellucci, MD, FRCPC
role: PRINCIPAL_INVESTIGATOR
References: