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SEPIA-PCI - SEPIA-PCI
Description:
The goal of the trial was to evaluate the effect of otamixaban, a selective and direct inhibitor of factor Xa, among patients undergoing nonurgent percutaneous coronary intervention (PCI).
Study Design
Study Design:
Patients Enrolled: 947
Mean Follow Up: 30 days
Mean Patient Age: Median age, 63 years
Female: 22
Patient Populations:
Age ≥18 years undergoing nonurgent PCI of a native coronary vessel with a femoral approach
Exclusions:
Pregnancy, treatment with other investigational drugs or devices within 30 days before enrollment or planned use of investigational drugs or devices during the study, recent ACS (within 48 hours), New York Heart Association class III or IV congestive heart failure, hemodynamic instability, significant valvular disease, active or recent significant bleeding, bleeding disorder, ischemic stroke within 12 months or history of hemorrhagic stroke, international normalized ratio >1.2, and creatinine clearance ≤30 ml/min
Primary Endpoints:
Change in prothrombin fragments 1+2 (F1+2), and anti-factor Xa activity
Secondary Endpoints:
TIMI bleeding at day 3 or hospital discharge (whichever came first) and 30-day ischemic events
Drug/Procedures Used:
Patients were randomized in a double-blind, double-dummy manner to one of five ascending doses of otamixaban (n = 787) or unfractionated heparin (UFH; 50-70 U/kg bolus; n = 160). The five weight-adjusted doses of otamixaban were given as an intravenous bolus and a 3-hour infusion, as follows: dose 1 = 0.025 mg/kg bolus and 0.035 mg/kg/h; dose 2 = 0.045 mg/kg bolus and 0.065 mg/kg/h; dose 3 = 0.080 mg/kg bolus and 0.120 mg/kg/h; dose 4 = 0.120 mg/kg bolus and 0.160 mg/kg/h; and dose 5 = 0.140 mg/kg bolus and 0.200 mg/kg/h.
Principal Findings:
A small percentage of patients had a recent acute coronary syndrome (ACS) event (13%). Stents were used in 94.4% of patients during the PCI. Creatinine clearance between 30 and 60 ml/min was present in 12% of patients. During PCI, thrombus was observed in a coronary artery or catheter or adherent to the guidewire in 1.0% of the otamixaban groups and 1.3% of the UFH group; two of the catheter/guidewire-related thromboses were considered serious, both of whom were in the otamixaban dose 1 group.
Compared with UFH, the coprimary endpoint of reduction from baseline to end of infusion in F1+2 was larger with the highest dose of otamixaban (median -0.3 vs. -0.2 ng/ml, p = 0.008); median change in doses 1-4 was -0.2, -0.3, -0.2, and -0.2, respectively. Anti-factor Xa levels increased across the dose groups (65, 155, 393, 571, and 691 ng/ml for otamixaban doses 1-5, respectively; p < 0.001 for trend).
TIMI major or minor bleeding through discharge or day 3 did not have a dose-response for the otamixaban groups (2.0%, 1.9%, 3.8%, 3.9%, and 2.6% for doses 1-5, respectively); the rate in the UFH group was 3.8%. However, when adding in minimal bleeding to the composite endpoint, a dose response was observed (24.8%, 42.2%, 41.8%, 49.7%, and 55.1% for doses 1-5, respectively; p < 0.001 for trend); the rate in the UFH group was 37.3%.
The composite of death, MI, or target-vessel revascularization by 30 days occurred in 5.8%, 7.1%, 3.8%, 2.5%, and 5.1% of doses 1-5 of the otamixaban groups compared with 5.6% of the UFH group (all p = NS vs. UFH).
Interpretation:
Among patients undergoing nonurgent PCI, use of the highest dose of the selective and direct inhibitor of factor Xa otamixaban was associated with a larger reduction in F1+2 compared with UFH, along with a stepwise increase in anti-factor Xa levels across the otamixaban dose groups.
While TIMI major or minor bleeding was not increased across the otamixaban dose groups, minimal bleeding did increase in a dose escalation manner, particularly at the highest two doses. The overall rate of thrombus was low for both the otamixaban and UFH groups, but there were two cases of serious catheter/guidewire thrombus in the lowest dose group, suggesting that dose may not be adequate in the PCI setting when glycoprotein IIb/IIIa inhibitors are not used concomitantly.
There was no difference in clinical events, although the trial was not powered for clinical events. Further large-scale trials would be required to more fully evaluate the safety and efficacy of otamixaban.
References:
Cohen M, Bhatt DL, Alexander JH, et al. Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI trial. Circulation 2007;115:2642-51.
Keywords: Acute Coronary Syndrome, Cyclic N-Oxides, Thrombosis, Heparin, Pyridines, Coronary Vessels, Creatinine, Stents, Percutaneous Coronary Intervention
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