Based on findings of the TAO randomized trial, otamixaban should not be used to manage patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) who are scheduled to undergo angiography and PCI. The findings were presented Sept. 1 at the European Society of Cardiology Congress 2013 in Amsterdam and simultaneously published online in JAMA.
TAO (Treatment of Acute Coronary Syndromes with Otamixaban) is a randomized double-blind controlled clinical trial that compared the novel intravenous direct factor Xa inhibitor otamixaban with unfractionated heparin plus downstream eptifibatide in patients with NSTE-ACS who were to undergo a planned invasive strategy. The trial was designed as a superiority study with efficacy and safety outcomes.
The primary efficacy outcome was the composite of all-cause mortality or new MI from the time of randomization to day seven. The primary safety outcome was the composite of Thrombosis in MI (TIMI) major and minor bleeding through day seven.
The trial enrolled 13,229 patients from 568 facilities in 55 countries between April 2010 and February 2013, randomized to one of two otamixaban dosing groups (both with an intravenous bolus 0.08 mg/kg) or unfractionated heparin plus downstream eptifibatide. Almost all (99.2 percent) received angiography, which was followed by PCI in 65.4 percent and CABG in 5.2 percent. Radial was the dominant PCI approach.
At day seven, the rate of death or MI was 5.5 percent in the group treated with the higher dose otamixaban (0.14 mg/kg per hour) vs. 5.7 percent in the heparin/eptifibatide group. The rate in the lower dose otamixaban group (0.1 mg/kg per hour, discontinued after an interim analysis) was 6.3 percent at seven days. At 30 days, there was no reduction of risk with otamixaban.
Major and minor bleeding rates at day seven were higher in the otamixaban group, at 3.1 percent vs. 1.5 percent in the heparin/eptifibatide group.
“Otamixaban is theoretically attractive as anticoagulant for NSTE-ACS: it is an injectable agent with rapid onset and offset, modest renal elimination, and predictable anticoagulant effect that obviates the need for monitoring,” wrote Philippe Gabriel Steg, MD, of the Université Paris-Diderot in Paris, and colleagues. “The TAO results, however, demonstrate lack of efficacy benefit but marked increases in bleeding when compared with UFH [unfractionated heparin] plus a glycoprotein IIb/IIIa receptor inhibitor, even with the majority of patients undergoing transradial PCI.”
The results run counter to a Phase II trial, the SEPIA-ACS1 TIMI 42 study. In that study, all but one of the otamixaban dosage groups had lower rates of death, second MI or additional coronary complications than the heparin/eptifibatide group. Steg et al detailed a number of differences between the trials that might explain the apparent discrepancies.
They suggested that had TAO been a noninferiority trial, then otamixaban might have been even with the heparin plus eptifibatide approach, but the almost double bleeding risk “makes otamixaban a nonviable clinical option.”
The study was funded by Sanofi.