Title: A Randomized Clinical Trial of Three Doses of a Long-Acting Oral Direct Factor Xa Inhibitor Betrixaban in Patients With Atrial Fibrillation (EXPLORE-Xa)
Trial Sponsor: Portola Pharmaceuticals and Merck
Year Presented: 2010
Topic(s): Arrhythmias, Congenital Heart Disease, Prevention/Vascular
Summary Posted: 3/15/2010 10:00:00 AM
Writer: Anthony A. Bavry, M.D., M.P.H., F.A.C.C.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., M.P.H., F.A.C.C.
Author Disclosure: Research/Research Grants: Astra Zeneca; Consultant Fees/Honoraria: Duke Clinical Research Institute; Research/Research Grants: Heartscape; Research/Research Grants: PLx Pharma; Research/Research Grants: Cogentus; Research/Research Grants: Sanofi Aventis; Data Safety Monitoring Board (Gov’t/Nonprofit): Duke Clinical Research Institute; Research/Research Grants: Bristol Myers Squibb; Research/Research Grants: Eisai; Research/Research Grants: Takeda; Research/Research Grants: The Medicines Company; Research/Research Grants: Ethicon
Related Resources
Presentation Slides: EXPLORE-Xa
Description
The goal of the phase 2 trial was to evaluate treatment with three doses of the long-acting oral direct factor Xa inhibitor betrixaban compared with warfarin among patients with nonvalvular atrial fibrillation.
Hypothesis
Betrixaban would be superior in preventing significant bleeding events.
Drugs/Procedures Used
Patients with nonvalvular atrial fibrillation were randomized to one of three doses of betrixaban (40 mg, n = 127; 60 mg, n = 127; 80 mg, n = 127) versus warfarin, with goal international normalized ratio (INR) 2-3 (n = 127).
Principal Findings
Overall, 508 patients were randomized. The median age was 74 years, 54% had an estimated glomerular filtration rate >70 ml/min, mean CHADS2 score was 2.2, and 33% were women.
At 3 months, the number of major or clinically relevant nonmajor bleeds was one in the betrixaban 40 mg group, four in the betrixaban 60 mg group, five in the betrixaban 80 mg group, and four in the warfarin group. The number of strokes was 0, 1, 1, and 0 and the number of deaths was 1, 0, 0, 1, respectively, for the four groups.
Considering the extent of follow-up, the lowest hazard for the primary outcome was in the betrixaban 40 mg group, intermediate in the 60 mg and 80 mg groups, and highest in the warfarin group (p = 0.35, for betrixaban groups compared with warfarin).
Alanine aminotransferase (ALT) >2x ULN was 2.4% in the betrixaban groups and 2.4% in the warfarin group. Vomiting, nausea, and diarrhea were more common with betrixaban.
Interpretation
Among patients with atrial fibrillation, the three tested doses of betrixaban appeared to be well-tolerated. Bleeding seemed to be lowest with the betrixaban 40 mg group, compared with higher-dose betrixaban or warfarin. Larger clinical trials are warranted to determine the efficacy and safety of betrixaban.
Conditions
• Arrhythmias / Atrial fibrillation
Therapies
• Anticoagulant
• Medical
Study Design
Randomized. Blinded. Parallel.
Patients Screened: 561
Patients Enrolled: 508
Mean Follow-Up: 3-12 months
Mean Patient Age: 73 years
% Female: 33%
Primary Endpoints
Time to occurrence of major or clinically relevant nonmajor bleeding
Secondary Endpoints
Time to occurrence of any bleeding (major, clinically relevant nonmajor, and minimal)
Time to occurrence of death, stroke, myocardial infarction, or other systemic embolism
Patient Population
Patients with nonvalvular atrial fibrillation with at least one risk factor for stroke
Age at least 18 years of age
No uncontrolled hypertension
Aspirin ≤162 mg daily
INR ≤2.2 at randomization or unable to comply with INR monitoring
Exclusions:
Weight <40 kg
Hemodialysis withing the last year
Atrial fibrillation due to reversible cause
Mechanical prosthetic valve
Condition other than atrial fibrillation requiring anticoagulation
Systolic blood pressure >160 mm Hg
Active endocarditis
Scheduled major surgery or pulmonary vein isolation procedure
Stroke, systemic embolic event, or acute coronary syndrome within 30 days
Limited life expectancy
Thrombocytopenia
Elevated liver transaminases
History of long QT syndrome
Use of aspirin >162 mg daily
Use of verapamil
Use of an investigational drug or device within 30 days
Noncompliance with INR monitoring
Inability to provide informed consent
References: Presented by Dr. Michael Ezekowitz at the ACC.10/i2 Summit, Atlanta, GA, March 2010.