March 19, 2010 – An experimental factor Xa inhibitor given to patients with non-valvular atrial fibrillation (AF) or atrial flutter and at least one risk factor for stroke, reduced the incidence of major and clinically relevant non-major (CRNM) bleeds compared to dose-adjusted warfarin.
The data were presented during a late-breaking clinical trials session this week at the American College of Cardiology (ACC) 59th Annual Scientific Session in Atlanta. The results were from EXPLORE-Xa, a phase two exploratory dose finding study of betrixaban, an investigational oral direct factor Xa inhibitor.
"Given that bleeding can be a significant safety issue for patients who take warfarin, there is a critical unmet need for anticoagulant therapy options," said U.S. national coordinator in the study, Michael Ezekowitz, MB, ChB, DPhil, vice president of the Lankenau Institute for Medical Research and professor at Jefferson Medical College. "The EXPLORE-Xa study accomplished its objective of providing important information to guide the betrixaban dosing strategy for future investigational studies."
In this multinational, dose-finding study of 508 patients with non-valvular AF or atrial flutter and at least one risk factor for stroke, a once daily dose of betrixaban 40 mg (n=127) demonstrated significantly less major and CRNM bleeding than open label warfarin (n=127). The risk of major and CRNM bleeding for the 60 mg (n=127) and 80 mg (n=127) doses of betrixaban was similar to warfarin.
About the EXPLORE-Xa Study
The phase 2b randomized, parallel group study examined three blinded doses of betrixaban compared with open-label, dose-adjusted warfarin in 508 patients. Patients ranged from ages 46 to 91 and a total of 87 percent previously received a vitamin K antagonist. Participants were not excluded for severe renal impairment, except those on dialysis. One hundred and twenty-seven patients were randomized to each of four treatment groups: betrixaban 40, 60 or 80 mg or open-label warfarin (INR 2-3), the current standard of care. The study was conducted in 35 centers in the U.S., Canada and Germany with a minimum follow-up of three months and a maximum of 12 months. The goal of the study was to assess the safety and tolerability of betrixaban compared to warfarin to provide information to guide further clinical development.
The primary study endpoint was the time to occurrence of major or CRNM bleeding. The incidence (crude rates) of major or CRNM bleeding was 0.8 percent, 3.9 percent, 3.9 percent and 5.5 percent for the betrixaban 40 mg, 60 mg, and 80 mg and warfarin groups, respectively.
The secondary endpoints included the time to occurrence of any bleeding (major, CRNM, and minimal) and the time to occurrence of death, stroke (ischemic or hemorrhagic), myocardial infarction, or other systemic embolism. The incidence (crude rates) of any bleeding was significantly lower compared to warfarin (31.5 percent) for patients taking betrixaban 40 mg (17.3 percent) and 80 mg (18.9 percent); but not those taking betrixaban 60 mg (25.2 percent). The number of events in the secondary composite endpoint of death, stroke, myocardial infarction or other systemic embolism ranged from zero to one in each of the four dosing groups, which was the expected stroke/embolic event rate for the warfarin control group. There was one stroke each in the betrixaban 60 mg and 80 mg groups, and one death each in the betrixaban 40 mg and warfarin groups. There were no myocardial infarctions or other systemic emboli in any of the four dosing groups.
The most common adverse events in the betrixaban groups combined (n=381) were diarrhea (6 percent versus 0.8 percent on warfarin); nausea (5.5 vs. 1.6 percent on warfarin); constipation (5.2 vs. 2.4 percent on warfarin); headache (5.2 vs. 2.4 percent on warfarin) and peripheral edema (6.8 vs. 7.9 percent on warfarin). A numerically higher percentage of patient discontinuations occurred in each of the three betrixaban groups than in the open label warfarin group (8.7-9.4 vs. 6.3 percent).
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