Venous Thromboembolism
Conditions
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.
Interventions
DRUGApixaban
Refer to Apixaban group
DRUGRivaroxaban
Refer to Rivaroxaban group
Sponsors
Ottawa Hospital Research Institute
Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network
Canadian Institutes of Health Research (CIHR)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With 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. |
| Number of Participants With 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 International Society on Thrombosis and Haemostasis (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) evaluation |
| Number of Participants With Adjudicated Recurrent Venous Thromboembolism (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 Deep Vein Thrombosis (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 Pulmonary Embolism (PE) will be diagnosed if the Ventilation-Perfusion (VQ) scan is non-normal and a new unmatched segmental or greater perfusion defect is documented, or an intraluminal filling defect is seen on Computed Tomography Pulmonary Angiogram (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. |
| Number of Participants With 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). |
| Medication Adherence | For the duration of the study: 3 months | Reported as the number of patients self-reporting full medication adherence. |
| Quality-Adjusted Life Years (QALYs) Gained | For the duration of the study: 3 months | We will measure health utility values using the EQ-5D-5L (EuroQoL-5 Dimension-5 Level) Questionnaire 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. |
| 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. |
| 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. |
Countries
Australia, Canada, Ireland
Contacts
PRINCIPAL_INVESTIGATORLana Castellucci, MD, FRCPC
Ottawa Hospital Research Institute
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 58.0 years |
| Body Mass Index | 29 kg/m^2 |
| Body Weight | 85.2 kg |
| Continued Antiplatelet Use | 71 Participants |
| Creatinine Clearance | 105.6 ml/min |
| History of Venous Thromboembolism | 210 Participants |
| Provoked or Unprovoked Venous Thromboembolism Provoked | 612 Participants |
| Provoked or Unprovoked Venous Thromboembolism Unknown | 1 Participants |
| Provoked or Unprovoked Venous Thromboembolism Unprovoked | 1022 Participants |
| Qualifying Venous Thromboembolism diagnosis Deep vein thrombosis alone | 691 Participants |
| Qualifying Venous Thromboembolism diagnosis Pulmonary embolism with or without deep vein thrombosis | 637 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 8 Participants |
| Race (NIH/OMB) Asian | 67 Participants |
| Race (NIH/OMB) Black or African American | 95 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 64 Participants |
| Race (NIH/OMB) White | 2400 Participants |
| Region of Enrollment Australia | 100 participants |
| Region of Enrollment Canada | 2498 participants |
| Region of Enrollment Ireland | 4 participants |
| Sex: Female, Male Female | 578 Participants |
| Sex: Female, Male Male | 748 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 1,345 | 4 / 1,355 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 36 / 1,345 | 30 / 1,355 |
Outcome results
None listed