N Engl J Med 2012;367:1297-1309Background: In patients with acute coronary syndrome, clinical guidelines recommend early angiography particularly in those deemed moderate to high risk. However, a proportion of patients do not undergo revascularization, and these patients have poorer outcomes compared to those who do undergo revascularization.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.The TRITON-TIMI 38 trial demonstrated that prasugrel, when compared to clopidogrel, reduces ischemic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). Notably, in the TRITON-TIMI 38 trial, 99% of the patients underwent PCI at the time of randomization.Expanding upon the findings of TRITON-TIMI 38, the TRILOGY ACS trial sought to test the hypothesis that aspirin plus prasugrel is superior to aspirin plus clopidogrel in patients with acute coronary syndrome, without ST segment elevation, who are managed medically without revascularization.Patients: Patients were enrolled if they had unstable angina or non-ST elevation myocardial infarction and were treated medically without revascularization, within 10 days of the index event. Patients with non-ST elevation myocardial infarction had elevated cardiac biomarkers. Patients with unstable angina had ST-segment depression of more than 1 mm in two or more electrocardiographic leads and negative cardiac biomarkers. Patients had to have one of the following: age of 60 years or older, diabetes mellitus, prior myocardial infarction or prior revascularization with either PCI or coronary-artery bypass grafting (CABG). Main exclusion criteria were history of stroke or TIA (this group had net harm with prasugrel in TRITON-TIMI 38), renal failure requiring dialysis and patients taking oral anticoagulants.Baseline characteristics: The trial enrolled 9,326 patients at 966 sites in 52 countries. The average age of patients was 66 years, with 78% were below 75 years old, and 61% were men. About 70% of the patients had non-ST elevation myocardial infraction as their index event. The average GRACE score was 122. About 82% had hypertension, 59% had hyperlipidemia, 38% had diabetes, 43% had prior myocardial infarction and 20% were current or recent smokers. The majority of patients were stable, with 88% classified as Killip class I.Angiography before randomization was performed in 41% of the patients. Medications at randomization included beta-blockers in 78% of the patients, ACEi or ARB in 75%, statins in 83% and proton pump inhibitors in 25%.Procedures: The trial was conducted as double-blind double-dummy study. Patients who underwent randomization within 72 hours after the first medical contact received a loading dose of 30mg of prasugrel followed by 10mg daily. The maintenance dose of prasugrel was 5mg daily for patients aged 75 years or older or patients who weighed less than 60 kg. Patients who underwent randomization after 72 hours of the first medical contact received open label clopidogrel before randomization and the maintenance study drug after randomization. Clopidogrel was given as a loading dose of 300mg followed by a maintenance dose of 75mg daily. Aspirin was given in all patients and the recommended dose was 100mg per day or less. Study drugs were given for a minimum of 6 months and a maximum of 30 months.Endpoints: The primary efficacy endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke among patients < 75 years old. Safety endpoints were bleeding not related to CABG based on Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria for severe or life-threatening bleeding and Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding, and neoplasms.Analysis was performed based on the intention-to-treat principle. The trial was event-driven. To ensure 90% power