American College of Cardiologists report:
ATLANTA -- An investigational, selective factor Xa inhibitor called betrixaban demonstrated apparent safety and efficacy in a phase II trial, making it yet another contender in the race to develop an alternative to warfarin (Coumadin).
At 40 mg, the lowest tested dose, "bleeding was significantly less for betrixaban versus warfarin, while the bleeding rate with the 60 mg and 80 mg doses was comparable to warfarin," said Michael D. Ezekowitz, MD, PhD, vice-president of the Lankenau Institute for Medical Research in Wynnewood, Pa. and a professor of medicine at Jefferson Medical College in Philadelphia.
Ezekowitz reported findings from the late-breaking EXPLORE Xa trial at the American College of Cardiology meeting here.
The drug is not excreted through the kidneys so no dose adjustment is expected for renal impairment.
There was no evidence of liver abnormalities -- a concern with anticoagulants since the FDA refused to approve another investigational Factor Xa inhibitor, ximelagatran, because of hepatoxicity in patients who took the drug for six months.
The most common adverse events in the EXPLORER Xa study were gastrointestinal issues, especially nausea at the 80 mg dose, Ezekowitz said.
The study enrolled 508 patients and evenly randomized them to betrixaban 40, 60, or 80 mg, or to warfarin.
All patients were adults who had atrial fibrillation at the time of enrollment or a least one episode during the previous 12 months. All patients also had at least one additional stroke risk factor.
The average age of patients was 74, and slightly less than half were men. Patients were followed for median of 147 days.
There was no difference in the rate of stroke or death between any of the betrixaban doses and warfarin. But at the 40 mg dose, there was only one major bleeding event with betrixaban versus seven with warfarin (P =0.035). At the 60 mg and 80 mg there were five major bleeding events.
"But none of these events was an intracranial hemorrhage," Ezekowitz said at press conference.
Lars Wallentin, MD, PhD, of the Uppsala Clinical Research Center, in Uppsala, Sweden, said that while the safety of betrixaban was impressive at 40 mg, he questioned the efficacy based on D-dimer data, which showed D-dimer concentration significantly higher (P=0.003) than warfarin.
Ezekowitz agreed that the D-Dimer numbers raised that possibility, but added that clinical experience with a 30 mg dose of the drug found "it was clinically active for treatment of deep vein thrombosis." He said the drug was active at all tested doses.
Wallentin, who served as discussant for the paper, said he was also struck by the fact that most of patients in the U.S. trial were much heavier than patients in European trials. The average weight in the EXPLORE Xa trial was 90 k, "for patients in Europe, the average weight is usually 80 k."
The patients were recruited in North America, and Ezekowitz acknowledged that "patients in the U.S. and Canada tend to be heavier, so this will be consideration when going forward with this drug in international trials."
One unique aspect of the betrixaban development program is that it is being developed with an antidote, which Ezekowitz said would be administered as an injection. He said, however, that the antidote has not yet been tested in humans, and he could not estimate how quickly the antidote would reverse the anticoagulation activity of betrixaban, which is a concern in the event of bleeding.
Ezekowitz has been at the epicenter of the development of warfarin alternatives. Last August he reported the result of a phase III trial of dabigatran, an investigational oral direct thrombin inhibitor.
In that study, dabigatran demonstrated superiority to warfarin for preventing strokes in high-risk patients, and it demonstrated an impressive safety profile.
At the time, Ezekowitz told MedPage Today that if dabigatran were to be approved, "It will become the new standard against which every other [anticoagulant] will need to be compared."
Reminded of those comments today and asked to compare betrixaban to dabigatran, Ezekowitz said he preferred to make comments based on evidence and to date, there "has been no direct comparison between dabigatran and betrixaban."
That said, he noted that betrixaban is taken only once a day, while dabigatran is taken twice, which might be a consideration in patient selection should both drugs come to market.
And in any case, he said that dabigatran had "raised the bar" for anticoagulants and betrixaban looked like it would clear that higher threshold.
