TAO

Treatment of Acute coronary syndrome with Otamixaban (2013)

Condition

Treatment of acute coronary syndrome

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Objective

To compare the clinical efficacy and safety of otamixaban with that of unfractionated heparin (UFH) plus downstream eptifibatide in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) undergoing early invasive strategy

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Trial design

Randomized, double-blind, triple-dummy, placebo-controlled phase III study with 2 phases:

Phase 1: from randomization until the end of PCI (or, if no PCI, up to day 4 or hospital discharge, whichever came first):

Active treatment:

  • Arm 1: otamixaban – dose 1: i.v. bolus of 0.080 mg/kg followed by continuous infusion of 0.100 mg/kg per hour; UFH matching placebo (n = 2657)
  • Arm 2: otamixaban – dose 2: i.v. bolus of 0.080 mg/kg followed by continuous infusion of 0.140 mg/kg per hour; UFH matching placebo (n = 5106)

Control treatment:

  • Arm 3: UFH i.v. bolus of 60 IU/kg (maximum 4000 IU) followed by continuous infusion of 12 IU/kg per hour (maximum 1000 IU/h) to maintain an activated partial thromboplastin time at 1.5–2.0 times the control group; at the time of PCI, additional UFH boluses could be administered if the activated clotting time was not in the 200- to 250-seconds range; otamixaban matching placebo (n = 5466)

Phase 2: from PCI (downstream use) until 18–24 hours post PCI or hospital discharge:

Active treatment:

  • Arm 1: eptifibatide matching placebo
  • Arm 2: eptifibatide matching placebo

Control treatment:

  • Arm 3: eptifibatide i.v. bolus of 180 μg/kg immediately before PCI, followed by a continuous infusion of 2.0 μg/kg per minute, and a second 180-μg/kg bolus 10 minutes later (for patients with a creatinine clearance <50 ml/min, the infusion rate was reduced to 1 μg/kg per minute); otamixaban matching placebo

An interim analysis, to be performed after at least 1969 patients had been randomized in each group and had completed a 7-day follow-up allowed the data monitoring committee to choose the optimal otamixaban-dose group to continue until study end

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Endpoints

Primary efficacy endpoint: composite of all-cause death and new myocardial infarction from randomization to day 7
Secondary efficacy endpoints: primary efficacy outcome up to day 30; composite of all-cause death, new myocardial infarction, and any stroke (days 1–7); rehospitalization or prolongation of hospitalization due to a new episode of myocardial ischemia/myocardial infarction (days 1–30); all-cause death (days 1–7); procedural thrombotic complications during the index PCI
Primary safety endpoints: composite of TIMI major and minor bleeding (days 1–7)
Secondary safety endpoints: CABG-related and non-CABG-related bleedings

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Trial participants

13229 patients with non-ST-segment elevation acute coronary syndrome with ischemic symptoms at rest ≥10 minutes within 24 hours of randomization, scheduled to undergo a coronary angiography (followed, when indicated, by PCI) to be performed within 36 hours of randomization and at the latest on day 3. Angiography was performed in 13125 patients (99.2%) and led to PCI in 8656 patients (65.4%) and to CABG surgery in 682 patients (5.2%)

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Results

Efficacy outcome: The primary outcome of death or myocardial infarction through day 7 occurred in 5.5% of the patients treated with otamixaban 0.140 mg/kg per hour vs. 5.7% of the patients treated with UFH plus eptifibatide (RR 0.99). In the lower-dose otamixaban group, discontinued by the data monitoring committee, the rate of the primary outcome at day 7 was 6.3%. Otamixaban 0.140 mg/kg per hour did not significantly reduce the risk of any of the components of the secondary efficacy outcomes. The rate of thrombotic procedural complications was 4.0% in patients treated with otamixaban vs. 4.6% in those receiving UFH plus eptifibatide (RR 0.88), in particular, the rates of stent thrombosis were 1.3% vs. 1.6% and the rates of catheter or guidewire thrombus were less than 0.1% vs. 0.3%. Analysis of the primary outcome by 30 days confirmed the absence of a reduction with otamixaban
Safety outcome: Patients in the otamixaban group had an increased rate of the primary safety outcome of TIMI major or minor bleeding at day 7 compared with patients in the combination of UFH-plus-eptifibatide group (3.1% vs. 1.5%; RR 2.13). There were marked increases in CABG-related and non-CABG-related bleedings with otamixaban (0.8% vs. 0.4% and 0.9% vs. 0.4%, respectively)

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Summary

Efficacy: Otamixaban did not reduce ischemic events compared with UFH plus eptifibatide in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and a planned invasive strategy
Safety: The risk of major or minor bleeding was approximately doubled with otamixaban

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Reference

Steg PG, Mehta SR, Pollack CV Jr, Bode C, Cohen M, French WJ, Hoekstra J, Rao SV, Ruzyllo W, Ruiz-Nodar JM, Sabaté M, Widimsky P, Kiss RG, Navarro Estrada JL, Hod H, Kerkar P, Guneri S, Sezer M, Ruda M, Nicolau JC, Cavallini C, Ebrahim I, Petrov I, Kim JH, Jeong MH, Ramos Lopez GA, Laanmets P, Kovar F, Gaudin C, Fanouillere KC, Minini P, Hoffman EB, Moryusef A, Wiviott SD, Sabatine MS; TAO Investigators. Anticoagulation with otamixaban and ischemic events in non-ST-segment elevation acute coronary syndromes: the TAO randomized clinical trial. J Am Med Ass 2013;310:1145-1455

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Corresponding author

Philippe Gabriel Steg, MD, Université Paris-Diderot, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, 46 Rue Henri Huchard, 75018 Paris, France, e-mail: gabriel.steg@bch.aphp.fr

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