Amsterdam, The Netherlands , Sunday 1 September 2013 – The investigational anticoagulant otamixaban significantly increased bleeding without reducing mortality or new heart attacks compared to currently recommended therapy among patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS) who were scheduled for an early invasive strategy, according to results of the Treatment of Acute Coronary Syndromes with Otamixaban (TAO) trial.
The TAO study failed to meet its primary endpoint showing superiority of otamixaban, an injectable factor Xa inhibitor, over a combination of unfractionated heparin (UFH) and eptifibatide in moderate- to high-risk NSTE-ACS patients scheduled to undergo angiography and potentially percutaneous coronary intervention (PCI) within 3 days of randomization.
“The risk of major or minor bleeding was approximately doubled with otamixaban across all patient subgroups, and a lower dose did not achieve better results,” said the study’s lead investigator Philippe Gabriel Steg, MD, from the Hôpital Bichat, Assistance Publique - Hôpitaux de Paris.
The findings “suggest a narrow therapeutic window for acute injectable Xa inhibition in the setting of ACS treated with modern antiplatelet therapy and routine early intervention, and that raising the intensity of anticoagulation via this mechanism will not achieve a superior efficacy/safety balance in ACS in the modern era of intervention,” said Professor Steg.
In June, the developer, Sanofi, announced its decision to discontinue the investigational program with the drug “due to efficacy lower than expected”.
The multicenter, phase 3 TAO study randomized 13,229 patients to either standard treatment consisting of UFH plus downstream eptifibatide (started only for PCI patients and discontinued 18 to 24 h after PCI ) or otamixaban (0.08 mg/kg intravenous bolus at randomization then 0.100 or 0.140 mg/kg per hour intravenous infusion). UFH and otamixaban (and their placebos) were started and stopped usually at the end of PCI unless patients required continued anticoagulation for a medical reason.
In addition to the study medication all patients received both aspirin and an oral adenosine diphosphate receptor antagonist.
Rates for the primary outcome, a composite of all-cause death or new myocardial infarction from randomization to day 7, were not significantly different between the two groups (5.5% with otamixaban vs 5.7% with controls, adjusted relative risk 0.99, P =.93).
However, the primary safety outcome, the rate of major or minor bleeding according to Thrombolysis in Myocardial Infarction (TIMI) criteria through day 7 was more than doubled with otamixaban (3.1% vs 1.5%, relative risk 2.13, P<.001).
Unfractionated heparin (UFH), particularly when combined with a glycoprotein IIb/IIIa inhibitor (GPI) such as eptifibatide at the time of percutaneous coronary intervention (PCI), “remains an effective and widely used therapy, and its use is supported by US and European guidelines,” said Professor Steg.
“However, UFH has limitations, such as a narrow therapeutic window, a somewhat unpredictable anticoagulant response, and activation of the PF4 platelet receptor,” he explained.
Theoretically, otamixaban, seemed an attractive anticoagulant for this patient population because it is an injectable agent with rapid onset and offset, modest renal elimination, and predictable anticoagulant effect that obviates the need for monitoring.
Although a previous phase 2 trial (SEPIA-ACS1 TIMI 42) had suggested a clinical benefit of otamixaban, it was a dose-ranging trial, with an overall low event rate, making risk estimates less accurate. The dosing of eptifibatide was also slightly different.