Merck Announces Results from Investigational IMPROVE-IT Study of VYTORIN Published in NEJoM

Merck

, known as MSD outside the United States and Canada, today announced that the New England Journal of Medicine published the results of the IMPROVE-IT trial, an investigational study comparing treatment with VYTORIN® (ezetimibe and simvastatin) to treatment with simvastatin alone in more than 18,000 patients presenting with acute coronary syndromes. The results of IMPROVE-IT were first presented at the American Heart Association Scientific Sessions in November, 2014. In IMPROVE-IT, patients taking the LDL-cholesterol-lowering medicine VYTORIN— which combines simvastatin with the non-statin ZETIA® (ezetimibe)—experienced significantly fewer major cardiovascular events (as measured by a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, re-hospitalization for unstable angina or coronary revascularization occurring at least 30 days after randomization) than patients treated with simvastatin alone. "IMPROVE-IT was designed to answer a very important scientific question about the relationship between cardiovascular risk and lowering LDL-C to very low levels with ezetimibe in combination with a statin, and we are pleased that the results are now being published in NEJM," said Eugene Braunwald, M.D., study co-chair, founding chair of the TIMI Study Group at Brigham and Women's Hospital. "We are very grateful to our investigators and to the participating patients for their commitment to completion of this complex, nine-year study. The analyses of the 18,000 patient IMPROVE-IT study are a robust addition to the many other important studies on the importance of lowering LDL-C." VYTORIN and ZETIA are currently indicated for use along with a healthy diet to reduce elevated LDL cholesterol in patients with hyperlipidemia. The current U.S. Prescribing Information for both products states that the effect of ezetimibe on cardiovascular morbidity and mortality, alone or incremental to statin therapy, has not been determined. Merck has submitted the data from the IMPROVE-IT study to the U.S. Food and Drug Administration to support a new indication for reduction of cardiovascular events for ZETIA (ezetimibe) and VYTORIN (ezetimibe and simvastatin). In November 2014, Merck announced IMPROVE-IT met its primary and all secondary composite efficacy endpoints. In IMPROVE-IT, at seven years, 32.7 percent of patients taking VYTORIN experienced a first primary endpoint event (major cardiovascular event) compared to 34.7 percent of patients taking simvastatin alone, corresponding to a 6.4% relative risk reduction (absolute risk reduction 2%, hazard ratio of 0.936, 95% CI 0.887 to 0.988, p=0.016). The mean LDL-C in the study at one year was 53 mg/dl in the VYTORIN arm and 70 mg/dl in the simvastatin arm. In a separate exploratory analysis of major vascular events, the risk reduction in the VYTORIN arm compared to the simvastatin alone arm was consistent with the treatment effect that had been projected based on prior studies of statins. There were no significant differences between treatment groups in adverse events of special interest, which included myopathy and rhabdomyolysis, gallbladder adverse events, liver enzyme elevations greater than or equal to three times the upper limit of normal (ULN) and cancer. These safety findings from IMPROVE-IT were generally consistent with current labeling for ezetimibe. Among 9,067 patients in the ezetimibe/simvastatin group vs. 9,077 patients in the simvastatin group, myopathy was reported in 0.2 percent vs. 0.1 percent of patients, respectively; rhabdomyolysis was reported in 0.1 percent vs. 0.2 percent; gallbladder-related adverse events were reported in 3.1 percent vs. 3.5 percent; cholecystectomy was reported in 1.5 percent vs. 1.5 percent; and alanine aminotransferase (ALT) and/or aspartate transaminase (AST) elevations (greater than or equal to three times ULN, consecutive) were reported in 2.5 percent vs. 2.3 percent of patients. Over seven years, new, relapsing or progressing cancer was reported in 10.2 percent of patients in both treatment groups. VYTORIN should not be taken with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products); or with gemfibrozil, cyclosporine, or danazol. VYTORIN also should not be taken by anyone with active liver disease, unexplained persistent elevations of hepatic transaminase levels, or hypersensitivity to the product; or by women who are pregnant, nursing or may become pregnant. ZETIA should not be taken by people with hypersensitivity to any component of the medication. Statin contraindications also apply when ZETIA is used with these drugs: statins are contraindicated in patients with active liver disease, unexplained persistent elevations in hepatic transaminase levels and in pregnant and nursing women. Refer to individual statin labels for details about who should not take that statin.