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The results of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) were recently presented by Christopher Cannon, MD at the American Heart Association Scientific Sessions. The trial followed 18,144 high-risk patients, who were within 10 days of a coronary event such as myocardial infarction (MI), with a view to enhancing clinical outcomes with lipomodulatory therapy. Patients were randomised to receive a moderate dose of simvastatin, a drug belonging to a commonly prescribed cholesterol-lowering class of drugs called statins, or simvastatin in combination with ezetimibe (Vytorin), a non-statin cholesterol-lowering drug with mixed evidence of efficacy to date.

Patient outcomes were recorded over seven years and the trial ended when 5,250 primary endpoint events had been recorded, including myocardial infarction, cardiovascular death, stroke, unstable angina or coronary revascularisation within a month of randomisation. Patients treated with combination therapy demonstrated a modest though statistically significant reduction in the manifestation of endpoint events (34.7% for simvastatin alone versus 32.7% for ezetimibe plus simvastatin). In addition, patients treated with combination therapy had lower low-density lipoprotein (LDL) levels (69.9 mg/dL for simvastin alone versus 53.2 mg/dL for combination therapy). LDL are complex particles which transport fats such as cholesterol around the body. The LDL hypothesis of cardiovascular disease states that reductions in LDL will result less atherosclerosis and related cardiovascular diseases such as MI or stroke. This trial provides further validation of that hypothesis.

The reduction in cardiovascular risk produced by ezetimibe co-therapy was modest, however, prevention of just one endpoint event required the treatment of 50 patients for seven years, casting doubts on the cost-effectiveness of this approach, although a robust analysis of these economic issues has yet to be published. Indeed, both clinical and economic data must be treated as preliminary until publication of peer-reviewed manuscripts.

Some commentators have lauded the results as hopeful for patients who do not tolerate statins. However, these results cannot be extrapolated to ezetimibe treatment without statins, or in patients who take ezetimibe as a primary preventative. The IMPROVE-IT trial is only applicable to patients who have had a recent coronary event, a relatively small subset of those at overall risk for disease. Combination therapy may be of benefit to those who will not tolerate higher doses of statins, but the trial did not examine that specifically. The trial design and scope is to be applauded, both in terms of patient numbers and duration. Rather than utilise surrogate endpoints, such as the 2008 ENHANCE trial which showed no benefit in simvastin/ezetimibe combination therapy, IMPROVE-IT strove for a clinically relevant endpoint – patient outcomes.

In summation, IMPROVE-IT has demonstrated a tangible, albeit incremental success in preventative therapy for cardiovascular disease.