September 01, 2013

AMSTERDAM — The new intravenous direct factor Xa inhibitor otamixaban (Sanofi) did not reduce ischemic events compared with unfractionated heparin plus eptifibatide but increased bleeding among patients with non-ST-segment-elevation ACS (NSTE-ACS) and a planned invasive strategy in the TAO study [1].

The study was presented September 1, 2013 at the European Society of Cardiology (ESC) 2013 Congress and published simultaneously in the Journal of the American Medical Association. The authors, led by Dr Gabriel Steg (Hôpital Bichat, Paris, France), conclude that the results "do not support the use of otamixaban for patients with NSTE-ACS undergoing planned early PCI."

In June, after these results were first discovered, Sanofi made the decision to discontinue development of otamixaban "due to lower efficacy than expected."

At the ESC press conference on the study, Steg said this was the first IV factor Xa inhibitor to be studied in the acute setting but that these results suggest that these agents have an "unfavorable efficacy/safety balance in the modern era of dual antiplatelet therapy and routine intervention in ACS."

Focus on Antiplatelets Rather Than Anticoagulants

Chair of the press conference, Dr Keith Fox (University of Edinburgh, Scotland), said the study had highlighted some important messages over mechanisms. Steg elaborated: "In this modern era of quick intervention, it appears that anticoagulation is not so important, with several trials of new anticoagulants having failed to show better efficacy but increased bleeding. In contrast, it is the antiplatelet drugs that appear to be key in this area, with trials of agents with improved antiplatelet activity having more success."

The results of the TAO trial contrast with those of the smaller phase 2, dose-ranging SEPIA-ACS1 TIMI 42 study, which suggested a reduction in death/MI with otamixaban without an increase in bleeding compared with heparin plus eptifibatide in a similar population. But the authors note that the phase 2 trial had few events and very wide confidence intervals. Steg said this was "another lesson highlighting that we need to beware of the results of phase 2 trials."

In the paper, Steg et al point out that with its rapid onset and offset, intravenous administration, and predictable anticoagulant response that does not require monitoring, otamixaban was considered to be an attractive single anticoagulant to be used across the continuum of care for NSTE-ACS, from emergency care through intervention.

The TAO trial was a double-blind superiority trial that enrolled 13 229 patients with NSTE-ACS and a planned early invasive strategy who were randomized to otamixaban (bolus and infusion, at one of two doses) or unfractionated heparin plus, at the time of PCI, eptifibatide. A planned interim analysis was conducted for otamixaban dose selection, and the higher dose (0.080 mg/kg bolus followed by an infusion of 0.140 mg/kg per hour) was chosen for the rest of the trial.

Results showed that the primary efficacy outcome--the composite of all-cause death or new MI through day 7--was not significantly different between groups. There were also no differences for the secondary end points, including procedural thrombotic complications, which were a problem with the previous factor Xa inhibitor, fondaparinux, in the OASIS-5 study. But the primary safety outcome of TIMI major or minor bleeding through day 7 was increased with otamixaban.

TAO: Primary End Points at Seven Days

End point Otamixaban (%) Heparin/eptifibatide (%) RR (95% CI) p
Death/MI 5.5 5.7 0.99 (0.85–1.16) 0.93
TIMI major or minor bleeding 3.1 1.5 2.13 (1.63–2.78) <0.001

 

The results were consistent across patient subgroups.

Steg said the obvious question was whether a lower dose might have been better, but data on the lower dose of otamixaban used in TAO (same bolus but infusion of 0.1 mg/kg) did not suggest that to be the case. This dose actually showed slightly worse efficacy than heparin/eptifibatide and still increased bleeding.

The authors conclude that these results suggest a narrow therapeutic window for acute Xa inhibition and that increasing the intensity of anticoagulation via this mechanism is unlikely to achieve a superior efficacy-safety balance in ACS in the modern era of intervention, when patients are receiving combined injectable anticoagulation, dual antiplatelet therapy, and routine early intervention.

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