A Randomized Clinical Trial of Three Doses of a Long-Acting Oral Direct Factor Xa Inhibitor Betrixaban in Patients With Atrial Fibrillation - EXPLORE-Xa

Mar 15, 2010
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Portola Pharmaceuticals and Merck
Date Presented:
01/01/2010
Date Updated:
03/15/2010
Original Posted Date:
03/15/2010
References

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.

Study Design

  • Parallel

Patients Screened: 561
Patients Enrolled: 508
Mean Follow Up: 3-12 months
Mean Patient Age: 73 years
Female: 33%

Patient Populations:

  • 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

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

Drug/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 upper limit of normal (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.

References:

Presented by Dr. Michael Ezekowitz at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

Keywords: Nausea, Vomiting, Stroke, Follow-Up Studies, Diarrhea, Warfarin, Pyridines, Risk Factors, International Normalized Ratio, Glomerular Filtration Rate, Factor Xa, Benzamides, Hypertension


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