Phase 3 Trial Update of Effient for UA/NSTEMI Patients Managed Medically without Revascularization

Daiichi Sankyo and Lilly announced data from the TRILOGY ACS study, a Phase 3 trial comparing prasugrel (Effient) plus aspirin to clopidogrel (Plavix; BMS/Sanofi Pharmaceuticals Partnership) plus aspirin in patients with unstable angina (UA) or non-ST elevation myocardial infarction (NSTEMI), who were managed medically without revascularization (percutaneous coronary intervention (PCI) or coronary artery bypass graft [CABG] surgery).

TRILOGY ACS (TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes) was a multi-center, double-blind, randomized, controlled trial. The primary endpoint was the time to occurrence of the first instance of the composite endpoint of CV death, heart attack or stroke. The sample size in the trial was selected to detect a 22% relative risk reduction in patients treated for up to 30 months with prasugrel compared with clopidogrel. Inclusion criteria for the study included at least one of the following high-risk features in UA/NSTEMI patients: age >60 years, prior myocardial infarction, diabetes mellitus and/or prior revascularization (PCI or CABG). Exclusion criteria included planned PCI or CABG, STEMI as the initial event, and medical management decision >72 hours after onset of event without clopidogrel treatment.

Prasugrel loading and maintenance dosages in TRILOGY ACS were adjusted for the medically managed patient population enrolled and differ from the current indicated dosages for ACS-PCI patients. Patients <75 years and weighing >60 kg received a 10mg maintenance dose of prasugrel. Prasugrel dosage adjustments (5mg) were made for very elderly patients (≥75 years of age) and for those <60 kg; patients with prior TIA/stroke were excluded. More than 90% of the patients in the study were treated with clopidogrel prior to randomization, per the guidelines for secondary prevention. Although all patients in the study were committed to be treated medically without revascularization for the index event, a small percentage of patients <75 years of age underwent revascularization (7.9%) after randomization.

At 30 months, 13.9% of prasugrel patients vs. 16% of clopidogrel patients experienced the combined primary endpoint of heart attack, stroke or cardiovascular (CV) death in patients <75 years of age, the primary analysis population (HR=0.91; 95% CI: 0.79–1.05).(1) This outcome was not statistically significant (P=0.21).

From a safety perspective, TRILOGY ACS showed that rates of TIMI major bleeding events (including life-threatening or fatal bleeds) did not differ significantly between the prasugrel plus aspirin and clopidogrel plus aspirin treatment groups in patients <75 years of age or in the overall study population. In patients <75 years of age, non-CABG TIMI major bleeding occurred in 2.1% of prasugrel patients vs. 1.5% of clopidogrel patients (HR=1.31, 95% CI: 0.81–2.11, P=0.27). However, the rates of TIMI major or minor bleeding were higher in patients treated with prasugrel (3.3% of prasugrel patients vs. 2.1% of clopidogrel patients; HR=1.54; 95% CI: 1.06–2.23; P=0.02).

An analysis performed to account for multiple recurrent ischemic events suggested a lower risk among participants <75 years treated with prasugrel (HR=0.85; 95% CI: 0.72–1.00; P=0.044). A post-hoc exploratory analysis observed a trend for a lower risk in heart attack, stroke and death among patients treated with prasugrel beyond one year; HRs and 95% CIs for the time period of <12 months versus the time period of >12 months comparing prasugrel vs. clopidogrel for the primary efficacy endpoint were 0.99 (0.84–1.16) vs. 0.72 (0.54–0.97) (interaction P=0.07).

Prasugrel (Effient) is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic CV events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with an artery-opening procedure called PCI as follows: [1] patients with unstable angina (UA) or non–ST-elevation myocardial infarction (NSTEMI); [2] patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI. 

Clopidogrel (Plavix) is a P2Y12 platelet inhibitor indicated in reduction of atherosclerotic events in: recent myocardial infarction (MI) or stroke, established peripheral arterial disease; non-ST-segment elevation acute coronary syndrome (unstable angina/non-ST-elevation MI) or ST-elevation MI.

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