N Engl J Med 2019;381:1524-1534Background Dual antiplatelet therapy after percutaneous coronary intervention had become a standard of care. Both prasugrel and ticagrelor had been shown to provide more rapid and consistent platelet inhibition than clopidogrel. Randomized controlled trials had shown both drugs were superior to clopidogrel in patients with acute coronary syndromes. 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 two drugs have different loading strategies in patients who have acute coronary syndromes without ST-segment elevation. In these patients, ticagrelor is usually administered as pretreatment before diagnostic angiography, but prasugrel is administered only after the coronary anatomy has been assessed by means of diagnostic angiography since no advantage has been observed when prasugrel is used as pretreatment.Before ISAR-REACT 5, there had been no direct comparisons of the two antiplatelet drugs. ISAR-REACT 5 was an investigator-initiated multicenter, non-industry funded RCT to compare the efficacy and safety of the two treatments in patients with acute coronary syndrome. Patients The trial enrolled 4013 patients from 23 centers. Patients were eligible with either STEMI, NSTEMI or unstable angina for which intervention was planned. Exclusion criteria included intolerance of either drugs, history of stroke or intracranial bleeding or any condition that increased the risk of bleeding. Patients could not be on concomitant oral or i.v. therapy with drugs affecting CYP3A4 system. Baseline Characteristics There were 2012 patients assigned to ticagrelor and 2006 patients assigned to prasugrel. The suspected diagnosis at admission was STEMI in 41%, NSTEMI in 46%, and unstable angina in 13% of the patients. The average age was 64 years. Female sex was 24%. Average systolic blood pressure and heart rate was 144 mmHg and 77 bpm. All factors were well balanced. Trial Procedures Therapy with ticagrelor was started at a loading dose of 180 mg and continued at a maintenance dose of 90 mg twice daily. Patients who were assigned to ticagrelor received the loading dose as soon as possible after randomization. Therapy with prasugrel was started at a loading dose of 60 mg and continued at a maintenance dose of 10 mg once per day. A reduced maintenance dose of 5 mg daily was recommended in patients who were 75 years of age or older and in those who had a body weight of less than 60 kg. Prasugrel therapy turned on presentation. STEMI patients were given prasugrel as soon as possible after randomization. In those without STEMI, the loading dose was delayed until knowledge of the coronary anatomy. Prasugrel loading was given before crossing the lesion. In patients with a coronary angiography–confirmed acute coronary syndrome who were not considered to be candidates for PCI but who were considered to be candidates for conservative therapy, dual antiplatelet therapy (aspirin and the randomly assigned trial medication) was recommended. About 83% of patients received PCI, 2% CABG and 13-14% were managed conservatively. Clinical follow-up was scheduled at 30 days, 6 and 12 months.Endpoints The primary end point was a composite of death, MI, or stroke at 1 year after randomization. Secondary end points included the safety end point, which was the incidence of bleeding at 1 year (type 3, 4, or 5 on the Bleeding Academic Research Consortium [BARC] scale, which ranges from 0 to 5, with higher values indicating more severe bleeding), the incidence of the individual components of the primary end point at 1 year, and the incidence of definite or probable stent thrombosis at 1 year.The sample-size calculation assumed a primary endpoint would occur in 10% in the ticagrelor group vs 12.9% in the prasugrel group. This led to an estimate of 1900 patients in each group and 80% power to detect a relative risk reduction of 22% in the ticagrelor