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TAO: Otamixaban in non-ST-segment elevation acute coronary syndrome patients undergoing a planned invasive strategy

Acute Coronary Syndromes (ACS)


 Presenter abstract | Discussant report | All the Scientific resources on ESC Congress 365

Presentation

By Philippe Gabriel Steg
Other authors: Dr Shamir R. Mehta, Canada; Professor Charles V. Pollack Jr, USA; Dr Christoph Bode, Germany; Dr Christophe Gaudin, France; Ms Karen Fanouillere, France; Dr Angele Moryusef, USA; Dr Stephen D. Wiviott, USA; Dr Marc Cohen, USA; Dr Witold Ruzyllo, Poland; Dr Manel Sabaté Tenas, Spain; Professor Petr Widimsky, Czech Republic; Professor Róbert Gábor Kiss, Hungary; Dr Marc S. Sabatine, USA for the TAO Investigators 
Background:
In the management of non–ST-segment elevation acute coronary syndromes (NSTE-ACS), there remains a risk of short-term death and morbidity despite guideline-based antithrombotic therapy and interventions. In those guidelines, there is no consensus on a single optimal anticoagulant that can be used across the continuum of care in ACS between first evaluation and post-intervention settings.
Unfractionated heparin (UFH), particularly when combined with a glycoprotein IIb/IIIa inhibitor at the time of percutaneous coronary intervention (PCI), remains an effective and widely used therapy but has limitations including a narrow therapeutic window and an inconsistent and somewhat unpredictable anticoagulant response. The synthetic intravenous direct factor Xa inhibitor, otamixaban, has a rapid onset and offset of action, linear kinetics, and limited renal elimination.
A phase II trial in patients with NSTE-ACS showed a marked reduction in the combined outcome of death or myocardial infarction and similar bleeding rates with otamixaban at mid-range doses, compared with UFH and eptifibatide.
Design:
The Treatment of Acute Coronary Syndromes with Otamixaban (TAO) trial is a phase III, randomized, double-blind, triple-dummy controlled trial testing the efficacy and safety of otamixaban compared with UFH plus eptifibatide in moderate-to-high risk patients with NSTE-ACS pretreated with dual oral antiplatelet therapy planned for an early invasive strategy.
A total of 13,220 patients in 55 countries were to be randomized (1:1:1 ratio) to receive UFH plus downstream eptifibatide (started immediately pre-PCI and continued per label), or otamixaban (0.08 mg/kg intravenous bolus at randomization followed by 0.100 or 0.140 mg/kg per hour intravenous infusion until the end of PCI or up to day 4 maximum if no PCI was performed). An interim analysis was performed after ≥1969 patients per arm completed 7 days of follow-up and the Data Monitoring Committee selected one otamixaban dose (blinded to investigators, Executive Committee, and sponsor) to be carried forward using a prespecified algorithm based on superior efficacy and optimal safety.
The primary efficacy outcome is the composite of all-cause death or new myocardial infarction by day 7. The primary safety outcome is Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding from randomization to day 7. Components of primary and secondary efficacy and safety endpoints were to be adjudicated.
The results will be available for presentation in August 2013.

Conclusions:
The results from the TAO study will provide insights into the clinical efficacy and safety of otamixaban in patients with NSTE-ACS planned to undergo an early invasive strategy.

 

Discussant Report

Christian W Hamm
Antithrombotics are the cornerstones of treatment of patients presenting with an acute coronary syndrome (ACS). The choice of the best antiplatelet and anticoagulation regimen is still debated with new agents that have emerged. The role of anticoagulation, particularly in the framework of PCI, remains an unresolved issue.
Currently, unfractionated heparin or low molecular weight heparins are the most widely used compounds in Europe, although there are convincing data for the direct thrombin inhibitor bivalirudin. In a conservative strategy the factor Xa inhibitor fondaparinux is the preferred choice, whereas in an invasive approach this was not demonstrated.


Now, otamixaban which is an intravenous factor Xa inhibitor with rapid onset and offset of action was tested in the large randomized TAO trial against the standard concept with unfractionated heparin in combination with the glycoprotein IIb/IIIa inhibitor eptifibatide. The targeted anticoagulation with otamixaban did not reduce adverse events, but only doubled the bleeding rates. Although this trial is negative, there are important lessons to learn for the management of patients undergoing PCI in ACS.
It seems that in the acute phase of ACS anticoagulation plays a less important role than effective platelet inhibition and results only in higher bleeding complications.


This may be different when in the long term secondary events may be prevented as demonstrated in the ATLAS trial for rivaroxaban as an oral factor Xa inhibitor. Accordingly, the pathophysiologic mechanisms in the acute and chronic phase seem to differ, requiring distinct treatment concepts.

References


Session Title: TAO: Otamixaban in non-ST-segment elevation acute coronary syndrome patients undergoing a planned invasive strategy 706

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.