Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa)

Abstract

Aims: Patients with atrial fibrillation (AF) are at increased risk of stroke. Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion.

Methods and results: Patients with AF and more than one risk factor for stroke were randomized to one of three blinded doses of betrixaban (40, 60, or 80 mg once daily) or unblinded warfarin, adjusted to an international normalized ratio of 2.0-3.0. The primary outcome was major or clinically relevant non-major bleeding. The mean follow-up was 147 days. Among 508 patients randomized, the mean CHADS2 score was 2.2; 87% of patients had previously received vitamin K antagonist therapy. The time in therapeutic range on warfarin was 63.4%. There were one, five, five, and seven patients with a primary outcome on betrixaban 40, 60, 80 mg daily, or warfarin, respectively. The rate of the primary outcome was lowest on betrixaban 40 mg (hazard ratio compared with warfarin = 0.14, exact stratified log-rank P-value 0.04, unadjusted for multiple testing). Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin. Two ischaemic strokes occurred, one each on betrixaban 60 and 80 mg daily. There were two vascular deaths, one each on betrixaban 40 mg and warfarin. Betrixaban was associated with higher rates of diarrhoea than warfarin.

Conclusion: Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke.

Keywords: Atrial fibrillation; Betrixaban; Stroke.

Figure 1

Patient disposition.

Figure 2

Box and whiskers plot of dose responsive effect of betrixaban on thrombin generation in patient plasma at around a median 13 h (2–18 h) post-dose. Thrombin activity is measured following cleavage of a specific fluorogenic substrate for thrombin. The figure depicts the fluorescence signal vs. the range of betrixaban plasma concentrations. The boxes represent first and third quartile of the population and the whiskers extend to 1.5 inter-quartile range. The inset represents the effect of anticoagulation by warfarin (inter-quartile range) on thrombin generation.

Figure 3

Changes in D-dimer levels in the overall patient population (right panel) and warfarin-naïve patients (left panel) after 12 weeks of treatment. Box and whiskers plots represent levels at baseline, 12 weeks, and changes relative to baseline. Each betrixaban group is compared with the warfarin group; P-values were determined by non-parametric test (Kruskal–Wallis).