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The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) reduces both low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events in patients with and those without cardiovascular disease.1–4 Intensive statin therapy, as compared with moderate-dose statin therapy, incrementally lowers LDL cholesterol levels and rates of nonfatal cardiovascular events.5–9 Because of the residual risk of recurrent cardiovascular events and safety concerns associated with high-dose statin therapy,10 additional lipid-modifying therapies have been sought.11–14
Ezetimibe targets the Niemann–Pick C1–like 1 (NPC1L1) protein, thereby reducing absorption of cholesterol from the intestine.15,16 When added to statins, ezetimibe reduces LDL cholesterol levels by an additional 23 to 24%, on average.17,18 Polymorphisms affecting NPC1L1 are associated with both lower levels of LDL cholesterol and a lower risk of cardiovascular events.19 Whether further lowering of LDL cholesterol levels achieved with the addition of ezetimibe to statin therapy leads to a benefit in clinical outcomes is unknown. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) evaluated the effect of ezetimibe combined with simvastatin, as compared with that of simvastatin alone, in stable patients who had had an acute coronary syndrome and whose LDL cholesterol values were within guideline recommendations.20–24
Methods
Study Oversight
The trial was designed and led by an executive committee that included representatives from the Thrombolysis in Myocardial Infarction (TIMI) Study Group, the Duke Clinical Research Institute (DCRI), and the study sponsor (Merck), in collaboration with an international steering committee (see the Supplementary Appendix, available with the full text of this article at NEJM.org).22–24 The ethics committee at each participating center approved the protocol and amendments. A data and safety monitoring board oversaw the study. DCRI managed the database and performed the primary analyses independently using raw data; TIMI and the sponsor verified the analyses. All the authors vouch for the completeness and accuracy of the data and all analyses, as well as for the fidelity of this report to the trial protocol, which is available at NEJM.org.
Patient Population
Men and women who were at least 50 years of age were eligible for inclusion if they had been hospitalized within the preceding 10 days for...