Trial DesignRationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): Comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes
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Study design and objectives
The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is a randomized, double-blind, active-control, multicenter, clinical trial designed to examine whether the use of the combination of ezetimibe and simvastatin, with its greater reductions in LDL-C, translates into clinical benefit on CV outcomes compared with simvastatin monotherapy in up to 18,000 patients stabilized after an ACS. We hypothesize that ezetimibe/simvastatin will reduce the incidence of the
Study population
The trial is enrolling men and women who have been hospitalized for ST-segment elevation myocardial infarction (STEMI) or non–ST-segment elevation myocardial infarction (NSTEMI) or unstable angina (UA) within the previous 10 days. To be eligible, patients must have high-risk features (see below), meet lipid criteria, and be stabilized for at least 24 hours before randomization. Patients with STEMI must have electrocardiographic changes (persistent ST-segment elevation ≥0.1 mV, new Q waves, or
Randomization and treatment protocol
Participants are to be recruited at approximately 1,200 sites worldwide, including >400 within North America. During screening visits, informed consent is obtained and baseline medical history, examination, and laboratory testing are performed. Subjects entered into the study receive randomized, double-blind treatment assignment in a 1:1 ratio to either ezetimibe/simvastatin 10/40 mg or simvastatin 40 mg once daily. Randomized treatment assignment is stratified by 3 factors: (1) the randomized
End points
The primary efficacy end point is the time from randomization until the first occurrence of one of the following: CV death, major coronary events (nonfatal MI, documented unstable angina requiring hospital admission, all coronary revascularization with either percutaneous coronary intervention [PCI] or CABG occurring at least 30 days after randomization), or nonfatal stroke.
The secondary efficacy end-point measures are time from randomization until the first occurrence of (1) death due to any
Statistical design and analysis
The trial was designed based on information available as of spring 2005. An initial sample size of 10,000 patients was selected to afford 90% power to detect a 10% relative risk reduction in the primary end point at a significance level of .05. The trial is an event-driven trial and originally was planned to continue until a minimum of 2,955 primary end point events had occurred and each patient completed a minimum 2.5 years of study exposure. The sample size was based on anticipated event
Study organization
The executive committee is responsible for the overall design, conduct, and supervision of the study, including the development of any protocol amendments. It adjudicates policy among the various constituencies of the study and is responsible for reviewing the progress of the study at regular intervals to ensure patient safety and study integrity. The executive committee is composed of representatives from the TIMI Study Group (Boston, MA), Duke Clinical Research Institute (Durham, NC), and the
Current status
Recruitment began in October 2005. As of June 2008, there are >800 participating sites in 30 countries with study drug. Recruitment is ongoing and >11,000 patients have been enrolled. Baseline characteristics of the first 10,000 patients enrolled are shown in Table I.
Context
The IMPROVE-IT trial has become even more important since the release of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial results,24 which compared the effects the combination of ezetimibe and high-dose simvastatin with high-dose simvastatin alone on carotid intima-media thickness (IMT) in patients with heterozygous familial hypercholesterolemia. At 2 years, there was no significant difference between the 2 arms with respect to the
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Cited by (0)
Trial Registration Number: NCT00202878
Dr. Eric Bates served as the guest editor for this manuscript.
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See Appendix A for the IMPROVE-IT Investigators.