TAO: Otamixaban Fails to Outshine Heparin Plus Eptifibatide in NSTE-ACS

AMSTERDAM, The Netherlands—In patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) slated for invasive treatment, otamixaban does not offer superior efficacy over the combination of unfractionated heparin (UFH) and eptifibatide. Moreover, the novel anticoagulant doubles the risk of bleeding, according to late breaking findings presented September 1, 2013, at the European Society of Cardiology Congress and simultaneously published online ahead of print in the Lancet.

Philippe G. Steg, MD, of Hôpital Bichat (Paris, France), shared final results from the TAO (Treatment of Acute Coronary Syndromes with Otamixaban) trial, which have inspired otamixaban’s manufacturer (Sanofi; Paris, France) to halt development of the drug.

Similar Efficacy with More Bleeding

In the double-blind, triple-dummy study, a total of 13,229 NSTE-ACS patients scheduled to undergo early invasive treatment within 3 days were randomized to 1 of 2 otamixaban doses (IV bolus of 0.080 mg/kg followed by infusions of 0.100 or 0.140 mg/kg/hr) or UFH plus eptifibatide. The lower otamixaban dose was discontinued after a planned interim analysis indicated futility.

The composite of all-cause death or new MI at 7 days (primary efficacy outcome) occurred at similar rates in patients receiving the higher otamixaban dose compared with UFH and eptifibatide, as did procedural thrombotic complications (composite of stroke and stent thrombosis). However, TIMI major/minor bleeding through day 7 was twice as high with otamixaban. While intracranial bleeding was sharply increased with otamixaban, events were rare (table 1).

Table 1. TAO Trial: Outcomes at 7 Days

^a P = 0.93

^b P < 0.001

Results were “remarkably robust and consistent across subgroups,” Dr. Steg noted, including those defined by baseline characteristics, medical history, prior use of antithrombotic agents, disease characteristics, patient management, TIMI and GRACE risk scores, and duration of study drug.

Due to bleeding, the study anticoagulant was discontinued in 4.7% of otamixaban patients and 1.7% of UFH/eptifibatide patients (P < 0.001). Levels of other serious adverse events and liver-function abnormalities were similar between the 2 groups.

Additional findings suggested “slightly worse” efficacy at the lower dose and continued risk of bleeding, Dr. Steg commented. “Therefore, . . . a lower dose would not have achieved better results.”

In summary, he concluded, “Although I will not hide that we’re highly disappointed by the trial results as investigators [as was] the sponsor, we were also disappointed that we were not able to improve upon the anticoagulation therapy for our patients.”

No Need for Disappointment

Discussant Christian W. Hamm, MD, PhD, of Kerckhoff Heart and Thorax Center (Bad Nauheim, Germany), commended the TAO investigators for their “well conducted” trial. “You should not be disappointed and frustrated, because I think we can learn very important lessons for the management of patients with acute coronary syndromes,” he added.

The results apply specifically to the acute phase, he stressed, during which “platelet inhibition is the key problem,” making it is difficult to directly replace a GPI with an anticoagulant.

Moreover, the field may simply have “reached the limits,” Dr. Hamm noted. “We need to think of other pathways, maybe not [looking at] anticoagulation or antiplatelet drugs to improve the outcomes. . . . There is still room left to improve the outcome of these patients.” Heparin, whether unfractionated or low molecular weight, paired with a GPI remains, at this stage, the best treatment for patients undergoing PCI in the acute phase,” he advised.

TAO Differs from Earlier Dose-Finding Trial

“Otamixaban is theoretically attractive as an 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,” the JAMA paper notes.

The authors outline several reasons why otamixaban showed such promise in the dose-finding SEPIA-ACS1 trial, published in the Lancet in 2009, which found lower risk of combined death and MI with the new drug. Event rates varied between the 2 trials, which could have affected statistical significance. More sensitive biomarkers used in TAO may have uncovered an increase in periprocedural MI for otamixaban. SEPIA-ACS1 involved only single bolus of eptifibatide, whereas TAO had a double bolus; the difference may have contributed toward the excess bleeding seen for otamixaban in the latter trial, they suggest.

Study Details

Unfractionated heparin was given as a 60-IU/g IV bolus (maximum of 4,000 IU) followed by infusion of 12 IU/kg/hr (maximum of 1,000 IU/hr) to maintain an activated partial thromboplastin time at 1.5-2.0 times the control group. Treatment began as soon as possible after randomization and continued until the end of PCI.

Eptifibatide was administered as an 180-µg/kg bolus immediately before PCI followed by continue infusion of 2.0 µg/kg/min and a second bolus of 180-µg/kg 10 minutes later. Patients with creatinine clearance < 50 mL/min received a reduced infusion of 1 µg/kg/minute. Eptifibatide treatment continued for 18 to 24 hours after PCI or until hospital discharge.

All patients also received aspirin and either clopidogrel, prasugrel, or ticagrelor. More than 99% of patients underwent angiography, and approximately 65% were treated with PCI. Fewer than half of PCIs were performed via femoral access.

Source:

Steg PG, Mehta SR, Pollack CV Jr, et al. Anticoagulation with otamixaban and ischemic events in non-ST-segment elevation acute coronary syndromes: The TAO randomized clinical trial. JAMA. 2013;Epub ahead of print.

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