Phase II study of the safety, tolerability and pilot efficacy of oral factor Xa inhibitor
betrixaban compared with warfarin (2013)


Prevention of stroke in patients with AF 

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To assess the safety and tolerability of betrixaban at 3 different doses compared with dose-adjusted warfarin in patients with AF at risk of stroke

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Trial design

Phase IIb, randomized, dose finding study; open-label for randomization to warfarin vs. betrixaban, blinded for the 3 doses of betrixaban
Active treatment: betrixaban at doses of 40 mg (n=127), 60 mg (n=127) and 80 mg (n=127) given orally once daily for at least 3 months
Control treatment: dose-adjusted warfarin (INR 2.0–3.0) (n=127)

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Primary endpoint: occurrence of major or clinically relevant non-major bleeding
Secondary endpoints: any bleeding, occurrence of death, stroke, myocardial infarction, and systemic embolism

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Trial participants

508 patients (mean age 73 years) with documented AF and at least one additional risk factor for stroke

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Efficacy outcome: The numbers of strokes and deaths were within the range expected for warfarin: one ischemic stroke each in the betrixaban 60 mg and 80 mg groups, and one vascular death each in the betrixaban 40 mg and warfarin groups. There were no myocardial infarctions, systemic embolic events, or pulmonary embolism in any of the 4 dosing groups
Safety outcome: Patients receiving 40 mg betrixaban once daily had significantly less major and clinically relevant non-major bleedings than patients receiving warfarin (incidence 0.8% vs. 5.5%; HR 0.14). The risk of major and clinically relevant non-major bleeding for the 60 mg and 80 mg doses of betrixaban was similar to warfarin (3.9% in both groups). The incidence of any bleeding was significantly lower as compared with warfarin (31.5%) for patients taking betrixaban 40 mg (17.3%) and 80 mg (18.9%); but not for those taking betrixaban 60 mg (25.2%) Betrixaban was as well tolerated as warfarin with similar rates of serious adverse events (9.4, 9.4, 8.7, 9.4% on betrixaban 40, 60, 80 mg, and warfarin, respectively)

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Oral betrixaban at doses of 40–80 mg per day was well tolerated in AF patients at risk for stroke. The rates of major or clinically relevant non-major bleeding were numerically lower with all 3 doses of betrixaban compared with well-managed warfarin; and betrixaban 40 mg daily has a statistically significant lower rate than with warfarin

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(1) Late-breaking clinical trials session at the American College of Cardiology (ACC) 59th Annual Scientific Session in Atlanta, March 15, 2010
(2) Connolly SJ, Eikelboom J, Dorian P, Hohnloser SH, Gretler DD, Sinha U, Ezekowitz MD. Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J 2013;34:1498-505

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Corresponding author

Stuart J. Connolly, MD, Population Health Research Institute, McMaster University, 237 Barton Street East, Hamilton, Canada, ON L8L 2X2, e-mail: stuart.connolly@phri.ca 

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