Betrixaban Compared With Warfarin in Patients With Atrial Fibrillation: Results of a Phase 2, Randomized, Dose-Ranging Study (Explore-Xa)

Study Questions:

Betrixaban is a novel oral factor Xa inhibitor administered once daily, mostly excreted unchanged in the bile and with low (17%) renal excretion. What is the relative safety and tolerability of betrixaban at three different doses compared to dose-adjusted warfarin in patients with atrial fibrillation (AF) at risk of stroke?

Methods:

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 nonmajor bleeding. The mean follow-up was 147 days.

Results:

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 warfarin. Two ischemic 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 diarrhea than warfarin.

Conclusions:

The authors concluded that 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.

Perspective:

The comparison of major bleeding in this study was 10.3%, which is considerably higher than in clinical practice and other trials. Several factor Xa inhibitors have been shown to be effective and safe in patients with deep-vein thrombosis and AF. A larger and definitive phase 3 trial of betrixaban is indicated.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Vascular Medicine, Lipid Metabolism, Novel Agents

Keywords: Vitamin K, Stroke, Follow-Up Studies, Diarrhea, Warfarin, Pyridines, Risk Factors, Fibrinolytic Agents, International Normalized Ratio, Blood Coagulation, Bile, Venous Thrombosis, Factor Xa, Benzamides, Hemorrhage


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