ESC: Otamixaban Fails in ACS
AMSTERDAM — The novel intravenous direct factor Xa inhibitor otamixaban failed to make a difference in preventing ischemic events among patients with non-ST-segment elevation myocardial infarction when compared with heparin and eptifibatide (Integrilin) — and caused excess bleeding, researchers reported here.
In the massive TAO (Treatment of Acute Coronary Syndromes with Otamixaban Trial), 5.5% (279) of 5,150 patients on otamixaban experienced the primary endpoint compared with 5.7% (310) of 5,466 patients on heparin with downstream eptifibatide (P=0.93), said Philippe Steg, MD, of the University of Paris-Diderot, at the annual meeting of the European Society of Cardiology.
Major bleeding at 7 days, as defined by the Thrombolysis In Myocardial Infarction (TIMI) bleeding criteria, occurred in 89 (1.7%) of the otamixaban patients and in 41 (0.8%) of the heparin/eptifibatide patients — a more than doubling of the risk (OR 2.32, 95%CI 1.61-3.36), Steg said. A similar pattern was seen for major bleeding not related to a coronary artery bypass graft (CABG), CABG-related major bleeding, and TIMI minor bleeding.
Overall, 3.1% of otamixaban patients experienced bleeding episodes, compared with 1.5% of the patients taking heparin/eptifibatide to prevent clotting in the coronary arteries (OR 2.13, 95%CI 1.63-2.78, P<0.001). The results were consistent across pre-specified subgroups, Steg said.
Freek Verheugt, MD, professor of cardiology at the University of Nijmegen, the Netherlands, told MedPage Today, “We see that in the TAO study otamixaban was not more effective than the comparator treatment — so it is neutral in that respect. But treatment with otamixaban was associated with a doubling of bleeding risk in all major and minor bleeding categories. While the numbers of intracranial hemorrhage were small, there were still five cases with otamixaban and one with heparin/eptifibatide.”
“When you see that there was a worse outcome in safety with otamixaban, it means this entire trial is negative,” he said. “I do not think there is a future for this intravenous drug.” In fact, Steg said that Sanofi, the developer of drug, has ended development of otamixaban based on the “disappointing” results from the trial.
The experience with anti-coagulants is such that “we have to find a dose that represents a sweet spot – when the anti-coagulation prevents unwanted clotting and does not cause excess bleeding,” Verheugt added.
In the trial, Steg and colleagues enrolled patients with non-ST-segment elevation myocardial infarction-acute coronary syndromes. Patients were treated with either unfractionated heparin and eptifibatide administered at the time of percutaneous coronary interventions, or an intravenous bolus of 0.08 mg/kg of otamixaban followed by an infusion of 0.14 mg/kg per hour. The time from the onset of the last symptom until randomization was about 15 hours.
The study patients were about 62 years of age; about 30% were women; about 87% were white; their median body weight was about 80 kg (176 pounds). The median body mass index was 27.7. The largest number of patients — about 33% — were from Eastern Europe; about 28% of all the patients in the study were diabetic; about 71% had hypertension; about 33% were current smokers; and approximately 19% had experienced previous myocardial infarcts.
At discharge from the hospital, 97% of the patients were on aspirin and 91% were on clopidogrel or similar drugs.
Of the patients in the study, 99% underwent coronary angiography, 65% underwent a percutaneous coronary intervention, and about 5% had CABG surgery.
The study was funded by sanofi.
Steg disclosed commercial interests with Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline; Lilly, Merck-Sharpe-Dohme, Otsuka, Pfizer, Roche, The Medicines Company, sanofi, Servier and Vivius. Other researchers also disclosed commercial interests with a number of companies, including Boston Scientific, Janssen, Lutipold Pharma, Novartis, Medtronic, Eisai, Genzyme, Takeda, Abbott Pharmaceutics, Accumetrics, Amgen, diaDexus, Ortho-Clinical Dianostics, Roche Diagnostics, Sezer, Ruda, Ebrahim, Petrov, and Kovar.
Verheugt disclosed commercial relationships with Bayer, Boehringer Ingelheim, Daiichi-Sankyo and sanofi.