N Engl J Med 2015;372:2387-2397Background: Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, effectively lower low-density lipoprotein (LDL) and improve cardiovascular outcomes across different populations. High-intensity statins exhibit greater efficacy in lowering LDL and decreasing non-fatal cardiac events compared to moderate-intensity statins. Nonetheless, due to the residual risk of cardiac events, and concerns about the safety and tolerability of high intensity statins, there is a growing demand for newer therapeutic options.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.Ezetimibe acts on the Niemann–Pick C1–like 1 (NPC1L1) protein, inhibiting cholesterol absorption from the intestine. When combined with statins, ezetimibe further decreases LDL levels by an average of 23 to 24%.The IMPROVE-IT trial sought to test the hypothesis that adding ezetimibe to simvastatin is superior to simvastatin alone in reducing cardiovascular events in patients with recent acute coronary syndrome.Patients: Patients were enrolled if they had acute coronary syndrome (STEMI, NSTEMI or high-risk unstable angina) in the preceding 10 days, and were at least 50 years old. LDL levels within 24 hours of the acute coronary syndrome (ACS) had to be at least 50 mg/dL but less than or equal to 125 mg/dL in lipid-therapy naïve patients or less than or equal to 100 mg/dL in patients receiving lipid lowering therapy. Patients were excluded if they had hemodynamic or electrical instability following the ACS event, planned CABG, active liver disease, creatinine clearance< 30 ml/min, or they had chronic lipid lowering therapy of simvastatin> 40mg, atorvastatin 40mg or more, any dose of rosuvastatin, or any ezetimibe/simvastatin combination.Baseline characteristics: The average age of patients was 64 years with 76% being men. The average weight was 83 kg. About 27% had diabetes, 61% had hypertension, 21% had prior myocardial infarction, 4% had congestive heart failure and 33% were current smokers. The median creatinine clearance was 85 ml/ min. The index event was STEMI in 29% of the patients, NSTEMI in 47% and unstable angina in the rest. Coronary angiogram was performed in 88% of the patients and percutaneous coronary intervention was performed in 70%. The mean LDL was 94 mg/dL and was similar in both groups.Procedures: Patients were randomized 1:1 in a double blinded fashion to receive simvastatin 40mg daily plus ezetimibe 10mg daily or simvastatin 40mg daily plus placebo. Patients had follow-up visits at 30 days, 4 months, and every 4 months thereafter.In both study groups, if LDL level was higher than 79 mg/dL on two consecutive measurements, the simvastatin dose was increased to 80 mg per day. This practice continued until June 2011, approximately one year after the study's randomization concluded, when the Food and Drug Administration advised limiting new prescriptions of simvastatin 80 mg daily. If LDL levels were higher than 100 mg/dL on the new regimen, the study drug could be discontinued, and more potent therapy could be initiated. Patients were followed for at least 2.5 years and for up to 7 years.Endpoints: The primary efficacy end point was a composite endpoint of death from cardiovascular disease, a major coronary event (defined as nonfatal myocardial infarction, unstable angina requiring hospital admission, or coronary revascularization occurring at least 30 days after randomization), or nonfatal stroke. The trial also reported death from any cause as part of one of the secondary composite endpoints. Safety variables included liver enzymes and creatine kinase levels, myopathy or rhabdomyolysis, gallbladder-related adverse events or cancer.Statistical analysis was performed based on the intention-to-treat principle. To achieve 90% power for detecting 9.375% lower relative risk for the primary end point with simvastatin–ez