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Betrixaban, the latest anticoagulant to make its debut, is well tolerated and does not lead to excess bleeding compared with warfarin in patients with atrial fibrillation (A-fib) at risk for stroke, according to a study published online March 13, 2013, ahead of print in the European Heart Journal.
Betrixaban (Portola Pharmaceuticals, San Francisco, CA), an oral factor Xa inhibitor administered once daily, has been previously studied in the phase II EXPERT trial, which found similar efficacy and safety compared with enoxaparin.
For the international Explore-Xa study, Stuart J. Connolly, MD, of Population Health Research Institute (Hamilton, Canada), and colleagues randomized 508 patients with nonvalvular A-fib to warfarin or 1 of 3 different betrixaban doses: 40 mg (n = 127), 60 mg (n = 127), or 80 mg (n = 127).
Lowest Dose Performs Best
After a mean follow-up of 147 days, major or clinically relevant non-major bleeding (primary outcome) had occurred in:
The lowest betrixaban dose was associated with less risk of the primary outcome compared with warfarin, while the 60- and 80-mg doses had risk levels similar to that of warfarin. Looking at any bleeding event, betrixaban 40 mg and 80 mg each reduced risk compared with warfarin (table 1).
Table 1. Bleeding Outcomes vs. Warfarin
Betrixaban 40 mg HR (95% CI)
Betrixaban 60 mg HR (95% CI)
Betrixaban 80 mg HR (95% CI)
Major or Clinically Relevant Non-Major Bleeding
a Exact stratified log-rank P value = 0.04.b Exact stratified log-rank P value = 0.01.c Exact stratified log-rank P value = 0.02.
Two strokes were reported: 1 in the betrixaban 60-mg arm and 1 in the 80-mg arm. Also, 1 patient in each of the betrixaban 40-mg and warfarin arms died of vascular causes within the study period.
Rates of serious adverse events ranged between 8.7% and 9.4% among the 4 treatment groups. However, higher rates of diarrhea were reported in the pooled betrixaban group compared with patients treated with warfarin (6.0% vs. 8.0%), and betrixaban-treated patients were more likely to prematurely discontinue their assigned study drug for any cause (8.9% vs. 6.3%).
Direct Comparisons Needed
“The main limitation of this study is its small size,” Dr. Connolly and colleagues write. “Hence, it was statistically underpowered to provide definitive conclusions regarding the safety or efficacy of any particular betrixaban dose vs. warfarin.”
Even so, the data provide guidance as to the optimal betrixaban dose to use in future clinical trials. “A larger and definitive phase 3 trial of betrixaban is indicated,” they conclude.
In a telephone interview with TCTMD, Larry B. Goldstein, MD, of Duke University Medical Center (Durham, NC), said clinicians have been struggling with how to best incorporate the other new anticoagulants into routine practice. Betrixaban, if approved, will go through a similar process, he added.
“We’re just beginning to gather information on clinical effectiveness in real-world settings,” he said. “Apixaban was the most recently approved, and we basically have virtually no routine clinical experience with that yet. Dabigatran has been approved for the longest, so we have relatively more information about that. And rivaroxaban is sort of in between. There are positive things with these new agents, but there are some areas of caution as well. I think we’re just trying to sort through those now.”
Because no direct head-to-head comparison studies have been conducted with the newer anticoagulants, Dr. Goldstein said it is difficult to know which is “best.” However, in reading the study’s description of betrixaban, “the pharmacology seems to be not all that different [from other factor Xa inhibitors,” he noted.
“I think having choices is a good thing, mainly for patients,” Dr. Goldstein concluded. “As for any new approach or any new drug, it’s taking us a little bit of time to determine which patients under which circumstances [are appropriate for choosing a novel anticoagulant over warfarin], and then among them, which one to choose.”