The results of the 9-year IMPROVE-IT trial are in, and the combo performed better than statin mono therapy in key measures.
In high-risk patients with acute coronary syndromes (ACS), administration of the cholesterol-lowering agent Vytorin, a combination of the non-statin ezetimibe (Zetia) and simvastatin, may be a more useful strategy for lowering LDL cholesterol and reducing the risk of cardiovascular events than statin use alone would be.
This was the conclusion of the nine-year IMPROVE-IT trial, which met its primary and secondary composite efficacy end points, as reported at the American Heart Association’s Scientific Sessions in Chicago, according to a statement by Merck, the manufacturer of the combination drug.
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More than 18,000 patients with ACS were randomized to Vytorin (ezetimibe 10 mg/simvastatin 40 mg) or simvastatin 40 mg and followed for up to nine years. The investigators wanted to determine whether further reduction of LDL-cholesterol below 70 mg/dL with Vytorin could help prevent more cardiovascular events than statin monotherapy.
Patients who took Vytorin at one year had a greater reduction of mean LDL-cholesterol (53 mg/dL) than that experienced by the simvastatin group (70 mg/dL). At the beginning of the study, the average baseline LDL-cholesterol level for patients was about 95 mg/dL, which encompassed approximately two-thirds of the patient population. Treatment-naïve patients had an average baseline LDL-cholesterol level of 101 mg/dL. Patients who had received prior treatment had a mean baseline LDL-cholesterol level of 80 mg/dL.
At the seven-year point, 32.7% of patients receiving Vytorin experienced a primary end-point event, compared to 34.7% of those receiving only simvastatin (hazard ratio of 0.936; P=0.016). A total of 5,314 primary end point events were reported. Patients receiving Vytorin had a 6.4% lower risk of all cardiovascular events such as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, rehospitalization for unstable angina or coronary vascularization, compared with patients who received statin therapy alone.
“In IMPROVE-IT, the addition of ezetimibe to a statin resulted in a further reduction in cardiovascular events compared to statin therapy alone, which is the first time this has been directly shown in a study of a non-statin cholesterol-lowering medicine,” stated the study co-chairs, Drs. Eugene Braunwald of Harvard Medical School and Robert Califf of Duke University. “The IMPROVE-IT data also address an important scientific question about lowering LDL-C to very low levels.”
In terms of safety, patients had similar adverse events, including myopathy (0.2% with Vytorin and 0.1% simvastatin), rhabdomyolysis (0.1% with Vytorin and 0.2% simvastatin), gallbladder problems (3.1% with Vytorin and 3.5% simvastatin), cholecystectomy (1.5% in both groups), ALT and/or AST elevations (2.5% with Vytorin and 2.3% simvastatin). Both groups reported cancer at 10.2%.
Merck announced its plan to submit the IMPROVE-IT trial data to the FDA by mid-2015 to support a new indication for reduction of major cardiovascular events for Vytorin and Zetia.
Approved by the FDA in 2004, Vytorin is a combination agent of a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor (statin) and is indicated as an adjunct to diet to reduce elevated total-cholesterol, LDL-cholesterol, apolipoprotein B, triglycerides, and non-HDL cholesterol. It also is indicated to increase HDL cholesterol in patients with primary hyperlipidemia or mixed hyperlipidemia when diet alone is not enough.