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Study Program to Evaluate the Prevention of Ischemia with direct Anti-Xa inhibition in Acute Coronary Syndromes 1—Thrombolysis in Myocardial Infarction 42 - SEPIA-ACS1 TIMI 42 — Presented at ESC 2009
Description:
The goal of the trial was to evaluate the efficacy and safety of the novel intravenous direct factor Xa inhibitor otamixaban in a dose-ranging manner and compared with unfractionated heparin (UFH) plus eptifibatide among patients with non-ST-elevation acute coronary syndromes (NSTE-ACS).
Study Design
Study Design:
Patients Enrolled: 3,241
Mean Follow Up: 180 days
Mean Patient Age: 61 years
Female: 31
Patient Populations:
Presentation with an NSTE-ACS within 24 hours of symptom onset (chest pain at rest ≥ 10 min duration suggestive of an ACS; high-risk features consisting of either new or presumably new ST-segment deviation of ≥0.1 mV in ≥2 contiguous ECG leads, or a cardiac biomarker of necrosis >ULN) and were planned to be treated with an early invasive strategy with coronary angiography.
Exclusions:
Treatment with an anticoagulant for the ACS for > 24 h before randomization, requirement for treatment with an oral anticoagulant, contraindications to eptifibatide (including bleeding within the previous 30 days or known bleeding diathesis, severe hypertension defined as systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg, major surgery or trauma in the past 6 weeks, history of stroke in the past 30 days or any history of hemorrhagic stroke, or creatinine clearance <30 mL/min or dependence on renal dialysis), a platelet count <100,000 per μL of blood, an INR of ≥2, previous PCI within 30 days of randomization, or cardiogenic shock.
Primary Endpoints:
Efficacy: Composite of death, MI, urgent revascularisation, or bailout GP IIb/IIIa inhibitor use up to 7 days
Safety: TIMI major or minor bleeding not related to CABG
Drug/Procedures Used:
Patients were randomized in a double-blind manner to one of five doses of otamixaban (0.08 mg/kg bolus followed by infusions of 0.035 [n=125], 0.070 [n=676], 0.105 [n=662], 0.140 [n=658], or 0.175 [n=671] mg/kg/h) or to control of UFH (60 IU/kg IV bolus followed by an infusion of 12 IU/kg/h) plus eptifibatide (180 μg/kg IV bolus followed by an infusion of 1.0–2.0 μg/kg/min [n=449]).
Concomitant Medications:
Clopidogrel (98%), aspirin (98%), statin (87%)
Principal Findings:
Angiography was performed in 99% of patients per the protocol, with approximately two-thirds done on day 1. PCI was performed in 63% of patients. The median duration of treatment with otamixaban or UFH was approximately 5 hours and with eptifibatide or placebo was 21 hours. During the trial, the Data Safety Monitoring Committee recommended that the group receiving the lowest dose of otamixaban (0.035 mg/kg/h) be discontinued due to clinical evidence of inadequate anticoagulation.
The primary efficacy endpoint of death, MI, urgent revascularisation, or bailout GP IIb/IIIa inhibitor use up to 7 days in the five otamixaban doses was 7.2% for 0.035 mg/kg/h, 4.6% for 0.070 mg/kg/h, 3.8% for 0.105 mg/kg/h, 3.6% for 0.140 mg/kg/h, and 4.3% for 0.175 mg/kg/h (p=0.34 for trend). In the UFH + eptifibatide control group, the rate was 6.2%. Compared to the UFH control group, the intermediate doses of otamixaban had relatively lower rates of the primary endpoint (relative risk [RR] 0.61, 95% CI 0.36-1.02 for 0.105 mg/kg/h group; RR 0.58, 95% CI 0.34-1.00 for 0.140 mg/kg/h group). For the endpoint of death or MI by 7 days, the event rates with otamixaban were lower compared with the control group, with the exception of the lowest dose otamixaban group (4.8%, 2.8%, 2.6%, 2.7% and 2.8% for the five otamixaban doses, respectively, vs 4.9% for the UFH control group; RR 0.57, 95% CI 0.31-1.05 for 0.070 mg/kg/h group vs control, RR 0.52, 95% CI 0.28-0.98 for 0.105 mg/kg/h group, RR 0.56, 95% CI 0.30-1.03 for 0.140 mg/kg/h group, RR 0.58, 95% CI 0.32-1.06 for 0.175 mg/kg/h group).
The primary safety endpoint of non-CABG TIMI major or minor bleeding occurred in 1.6% of the 0.0350 mg/kg/h group, 1.6% of the 0.070 mg/kg/h group, 3.1% of the 0.105 mg/kg/h group, 3.4% of the 0.140 mg/kg/h group, 5.4% of the 0.175 mg/kg/h group (p=0.001 for trend) and 2.7% of the UFH control group. Compared to the UFH control group, the relative risk of major bleeding was higher in the highest otamixaban dose group (RR 1.26, 95% CI 1.06-3.85) but similar in the intermediate dose groups (RR 1.15, 95% CI 0.57-2.32 for the 0.105 mg/kg/h group and RR 1.26, 95% CI 0.63-2.52 for the 0.140 mg/kg/h group). Results were similar for total TIMI major bleeding (0.8%, 1.8%, 3.4%, 2.6%, 3.5% for the otamixaban dose groups, respectively and 1.8% for the control group).
Interpretation:
Among patients with non-ST-elevation ACS, treatment with intermediate doses of the novel direct factor Xa inhibitor otamixaban was associated with a reduction in the composite endpoint of death, MI, urgent revascularisation, or bailout GP IIb/IIIa inhibitor use up to 7 days compared with UFH plus eptifibatide in this dose ranging trial.
The SEPIA-PCI trial previously examined different doses of otamixaban compared with UFH in patients undergoing non-urgent PCI and found signs of clinical efficacy with intermediate doses of 0.120 mg/kg/h and 0.160 mg/kg/h. The present study sought to further evaluate otamixaban among non-ST elevation ACS patients, and likewise found the intermediate dose studied optimized the efficacy benefit without large increases in the primary safety endpoint of TIMI major or minor non-CABG bleeding. The lowest dose studied in the present trial clearly provided inadequate anticoagulation and as such was discontinued early, while the highest dose did not offer additional ischemic benefit but did significantly increase the bleeding risk as compared with UFH plus eptifibatide. Further trials of otamixaban will likely focus on the 0.105-0.140 mg/kg/h dose range for comparison with UFH plus GP IIb/IIIa inhibition.
References:
Sabatine MS, Antman EM, Widimsky P, et al. 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;Aug 28:[Epub ahead of print].
Presented by Dr. Marc S. Sabatine at the European Society of Cardiology Congress, Barcelona, Spain, August 2009.
Keywords: Risk, Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Coronary Angiography, Cyclic N-Oxides, Peptides, Heparin, Pyridines, Electrocardiography
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