SEPIA-ACS1 TIMI 42

Study Program to Evaluate the Prevention of Ischemia with direct Anti-Xa inhibition
in Acute Coronary Syndromes 1 (2009)

Condition

Prophylaxis for ischemic events in patients with non-ST-elevation acute coronary syndromes

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Objective

To assess the efficacy and safety of different doses of otamixaban compared with UFH plus eptifibatide in patients with high-risk non-ST-elevation acute coronary syndromes and to identify the optimum dose range for further assessment

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Trial design

Randomized, double-blind, triple-dummy, dose-ranging phase II study
Active treatment: otamixaban 0.08 mg/kg i.v. bolus followed by an infusion of 0.035 mg/kg/h (n=125), 0.070 mg/kg/h (n=676), 0.105 mg/kg/h (n=662), 0.140 mg/kg/h (n=658), or 0.175 mg/kg/h; matching placebo (n=671)
Control treatment: UFH 60 IU/kg i.v. bolus followed by an infusion of 1.0–2.0 μg/kg/min plus eptifibatide 180 μg/kg i.v. bolus (maximum 22.6 mg) followed by an infusion of 2.0 μg/kg/min (maximum 15 mg/h); matching placebo (n=449)

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Endpoints

Primary efficacy endpoint: composite of all-cause death, new myocardial infarction, severe recurrent ischemia requiring urgent revascularization and in-hospital bailout use of glycoprotein GPIIb/IIIa inhibitor up to 7 days
Secondary efficacy endpoints: individual components of the composite endpoint, composite endpoint up to 180 days
Primary safety endpoint: composite of TIMI major or minor bleeding up to 7 days
Secondary safety endpoints: TIMI major bleeding, TIMI minor bleeding, stroke

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Trial participants

3241 patients aged ≥18 years with non-ST-elevation acute coronary syndromes at rest of at least 10 minutes duration within 24 hours of randomization who were planned to be treated with an invasive strategy (PCI)

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Results

Efficacy outcome: In the 5 otamixaban groups, the primary efficacy endpoint occurred in 7.2% (9 of 125 patients) with 0.035 mg/kg/h, 4.6% (31/676) with 0.070 mg/kg/h, 3.8% (25/662) with 0.105 mg/kg/h, 3.6% (24/658) with 0.140 mg/kg/h, and 4.3% (29/671) with 0.175 mg/kg/h. In the control group, the rate was 6.2% (28/449). There was no statistically significant trend in the rate of the primary efficacy endpoint across the otamixaban groups (p=0.34). At intermediate doses (0.105 and 0.140 mg/kg/h), treatment with otamixaban resulted in about 40% reductions vs. the control group. These differences were driven by reductions of 45% or more in death or myocardial infarction compared to UFH plus eptifibatide (2.6% and 2.7% vs. 4.9%)
Safety outcome: The rates of the primary safety endpoint in the 5 otamixaban groups showed a significant dose response (p=0.0001 for trend): TIMI major and minor bleedings occurred in 1.6% (2/122) with 0.035 mg/kg/h, 1.6% (11/669) with 0.070 mg/kg/h, 3.1% (20/651) with 0.105 mg/kg/h, 3.4% (22/651) with 0.140 mg/kg/h, and 5.4% (36/664) with 0.175 mg/kg/h. In the control group, the rate was 2.7% (12/448). The difference between the highest otamixaban dose (5.4%) and the controls (2.7%) was statistically significant (p=0.0273)

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Summary

Efficacy: Otamixaban infusions of 0.100–0.140 mg/kg/h were associated with a 40% reduction in death or ischemic complications compared with UFH plus eptifibatide
Safety: Otamixaban infusions of 0.100–0.140 mg/kg/h had a safety profile similar to UFH plus eptifibatide. In summary, otamixaban 0.100–0.140 mg/kg/h seems to be the most reasonable choice for future studies

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Reference

Sabatine MS, Antman EM, Widimsky P, Ebrahim IO, Kiss RG, Saaiman A, Polasek R, Contant CF, McCabe CH, Braunwald E. Otamixaban for the treatment of patients with non-ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind, active-controlled, phase 2 trial. Lancet 2009;374:787-795

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Corresponding author

Marc S. Sabatine, MD, TIMI Study Group, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA, e-mail: msabatine@partners.org

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