Novel Oral Anticoagulant May Be Alternative to Warfarin in AF

Atlanta—Betrixaban, an investigational oral factor Xa inhibitor, was safe and well tolerated, with a similar or lower risk of major bleeding compared with warfarin in patients with nonvalvular atrial fibrillation (AF) or atrial flutter who were at risk for stroke.

“In the diverse patient population included in our study, a dose- and concentration-dependent effect of betrixaban was observed on the primary end point of major and clinically relevant nonmajor bleeding,” said Michael D. Ezekowitz, MD, vice president of the Lankenau Institute for Medical Research and professor of medicine at Jefferson Medical College in Philadelphia, Pennsylvania. Dr. Ezekowitz presented results of the EXPLORE Xa (a randomized clinical trial of 3 doses of a long-acting oral direct factor Xa inhibitor betrixaban in patients with AF) phase 2 pilot, dose-finding study of betrixaban at a late-breaking clinical trials session.

“It is important to keep in mind that this is a preliminary study. A definitive evaluation can only be accomplished through a large, phase 2 clinical trial,” he added.

Warfarin, the current standard of care for AF, is challenging for both patients and physicians to manage. The dose must be individualized for each patient. Identifying the right dose in the therapeutic range requires constant monitoring and frequent dose adjustments to avoid either blood clots (too low a dose) or dangerous bleeding (too high a dose), Dr. Ezekowitz explained. “Given that bleeding can be a significant safety issue for patients who take warfarin, there is a critical unmet need for anticoagulant therapy options,” he added.

Oral betrixaban has a rapid onset of action, can be taken once a day, and does not require constant monitoring. Unlike other novel anticoagulants, the drug is not cleared primarily in the kidney, so it may be safer in people with severe renal disease, Dr. Ezekowitz commented. Another unique factor is that betrixaban is being codeveloped with an antidote, he added.

The study enrolled 508 patients with AF or atrial flutter and at least 1 additional risk factor for stroke, such as older age, diabetes, or hypertension.  “The study was unusual in that it enrolled a wide variety of patients with AF, regardless of renal function, age, weight, or need for other medications,” Dr. Ezekowitz told the audience.

Patients were randomized to receive 1 of 3 blinded doses of the investigation agent (40, 60, and 80 mg once a day) or open-label dose-adjusted warfarin. Age range was 46 to 91 years, and about 87% had previously received a vitamin K antagonist. The study was conducted at 35 centers in the United States, Canada, and Germany. Follow-up ranged from 3 to 12 months.

At 12 months, the incidence of major or clinically relevant nonmajor bleeding was 0.8%, 3.9%, 3.9%, and 5.5% for the betrixaban 40 mg, 60 mg, 80 mg, and warfarin groups, respectively. The incidence of any bleeding was significantly lower for betrixaban 40 mg versus warfarin (P=.011) and 80 mg versus warfarin (P=.022), but not for those taking betrixaban 60 mg.

“The number of strokes in each group was within the range expected for warfarin—0 to 1 per treatment arm,” Dr. Ezekowitz said. No myocardial infarctions or other systemic emboli were reported in any of the 4 groups.

When asked during an official press conference how betrixaban stacks up against dabigatran, another novel anticoagulant proven noninferior to warfarin with less bleeding in the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial last year, Dr. Ezekowitz said that although the RE-LY trial “raised the bar,” it did not “reach perfection.” He noted that betrixaban has some novel properties, including once-daily dosing, whereas dabigatran requires twice-daily dosing. Additionally, codevelopment with an antidote is another advantage.—Alice Goodman