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FDA Says “No” to New Indication for Ezetimibe (Zetia) and Ezetimibe/Simvastatin (Vytorin)
The FDA has issued a complete response letter regarding supplemental new drug applications for ezetimibe (Zetia) and ezetimibe/simvastatin (Vytorin) for reducing the risk of cardiovascular events (i.e., cardiovascular [CV] death, nonfatal myocardial infarction [MI], nonfatal stroke, hospitalization for unstable angina, or the need for revascularization) in patients with coronary heart disease. The applications were based on results from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). Both treatments are marketed by Merck, who didn’t give a reason for the agency’s decision in a published statement.
Ezetimibe and ezetimibe/simvastatin are approved for use along with a healthy diet to reduce elevated low-density lipoprotein (LDL) cholesterol in patients with hyperlipidemia. The effect of ezetimibe on cardiovascular morbidity and mortality has not been determined. Moreover, no incremental benefit of ezetimibe/simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.
Ezetimibe, administered alone or in combination with a statin, is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, apolipoprotein B, and non–high-density lipoprotein (HDL) cholesterol in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia when diet alone is not enough.
Ezetimibe/simvastatin is indicated to reduce elevated total cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and non-HDL cholesterol, and to increase HDL cholesterol in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia when diet alone is not enough.
IMPROVE-IT was an international, randomized, double-blind, active-comparator study involving 18,144 high-risk patients with an acute coronary syndrome (ACS), including unstable angina, non–ST-segment elevation acute MI (NSTEMI), and ST-segment elevation acute MI (STEMI). The study assessed the incidence of major CV events, as measured by a composite of CV death, nonfatal MI, nonfatal stroke, rehospitalization for ACS, or coronary revascularization (occurring 30 days or more after the initial event), in patients treated with ezetimibe/simvastatin compared with patients treated with simvastatin alone.
All of the patients were started at doses of ezetimibe/simvastatin 10/40 mg or simvastatin 40 mg. Before a 2011 protocol amendment, the dose could be titrated to ezetimibe/simvastatin 10/80 mg or simvastatin 80 mg if successive LDL-C values exceeded 79 mg/dL. The study enrolled patients within 10 days of ACS hospitalization who had sufficient risk, as defined in the protocol, and who had an initial LDL-C less than or equal to 125 mg/dL if lipid-lowering drug naïve or less than 100 mg/dL if on a prior prescription lipid-lowering therapy identified as no more potent than simvastatin 40 mg/day. The LDL-C entry limitations were designed to enroll patients who were reasonably anticipated to achieve LDL-C levels of 70 mg/dL or less in the simvastatin-only cohort, which was the optional recommended target set in the 2004 update to the Adult Treatment Panel (ATP) III guidelines.
IMPROVE-IT met its primary and all secondary composite efficacy endpoints. At seven years, 33% of patients treated with taking ezetimibe/simvastatin experienced a first primary endpoint event (a major cardiovascular event) compared with 35% of patients receiving simvastatin alone, which corresponded to a 6.4% relative risk reduction and a 2.0% absolute risk reduction (hazard ratio, 0.936; P = 0.016). The mean LDL-C levels at one year were 53 mg/dL in the ezetimibe/simvastatin arm and 70 mg/dL in the simvastatin monotherapy arm.