The IMPROVE-IT study met its primary and all secondary composite efficacy endpoints. In IMPROVE-IT, patients taking the LDL-cholesterol-lowering medicine Vytorin ( Ezetimibe / Simvastatin ), which combines Simvastatin with the non-statin Ezetimibe ( Zetia ), 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.
The results from this 18,144-patient study of high-risk patients presenting with acute coronary syndromes were presented at the American Heart Association 2014 Scientific Sessions.
Because high-risk patients treated with statins, including those on treatment with low levels of LDL-cholesterol ( LDL-C ), continue to be at increased cardiovascular risk, IMPROVE-IT was designed to address whether lowering LDL-C to well under 70 mg/dL by adding Ezetimibe to a statin further reduced cardiovascular events.
In IMPROVE-IT, at seven years, 32.7% of patients taking Vytorin experienced a primary endpoint event compared to 34.7% of patients taking Simvastatin alone ( hazard ratio of 0.936, p=0.016 ).
Based on the LDL-C range compared in the study’s treatment arms ( at one year, a mean LDL-C of 53 mg/dL versus 70 mg/dL, respectively ), the 6.4% relative risk reduction observed in the Vytorin arm in IMPROVE-IT was consistent with the treatment effect that had been projected based on prior studies of statins.
In IMPROVE-IT ( IMProved Reduction of Outcomes: VYTORIN Efficacy International Trial ), the LDL-C levels compared were very low. At one year, the mean LDL-C level was 53 mg/dL in the Vytorin group and 70 mg/dL in the Simvastatin group, with a between-group difference of 17 mg/dL.
When the IMPROVE-IT study was initiated in 2005, the optional recommended target LDL-C level in the United States for acute coronary syndrome patients and other groups considered to be at very high risk for cardiovascular events was less than 70 mg/dL. Prior cardiovascular outcomes studies of statins have not compared treatments at such low LDL-C levels. At the start of the study, the average baseline LDL-C was approximately 95 mg/dL. Among treatment-naïve patients ( about two-thirds of those in the study ), the mean baseline LDL-C was 101 mg/dL. Among patients on prior lipid lowering therapy at enrollment, the mean baseline LDL-C was 80 mg/dL.
Patients in IMPROVE-IT were initially randomized to treatment with Ezetimibe / Simvastatin 10/40 mg or Simvastatin 40 mg. Patients were followed for up to nine years, with a median clinical follow-up of approximately six years. In this event-driven study, 5,314 primary endpoint events were reported.
In addition to the significant result on the primary composite efficacy endpoint, patients taking Vytorin experienced significant reductions compared to patients taking Simvastatin alone on the three secondary composite efficacy endpoints, as follows:
a) Vytorin reduced the incidence of the composite endpoint of death due to all causes, major coronary events, and non-fatal stroke; this endpoint occurred in 38.7% of patients taking Vytorin and 40.3% of patients taking Simvastatin only ( hazard ratio of 0.948, p=0.034 );
b) Vytorin reduced the incidence of the composite endpoint of death due to coronary heart disease ( CHD ), non-fatal myocardial infarction ( MI ), and urgent coronary revascularization with either percutaneous coronary intervention ( PCI ) or coronary artery bypass graft ( CABG ) occurring at least 30 days after randomization; this endpoint occurred in 17.5% of patients taking Vytorin and 18.9% of patients taking Simvastatin only ( hazard ratio of 0.912, p=0.016 ).
c) Vytorin reduced the incidence of the composite endpoint of cardiovascular death, non-fatal myocardial infarction, documented unstable angina that requires admission into a hospital, all revascularization ( including both coronary and non-coronary ) occurring at least 30 days after randomization, and non-fatal stroke; this endpoint occurred in 34.5% of patients taking Vytorin and 36.2% of patients taking Simvastatin only ( hazard ratio of 0.945, p=0.035 ).
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% vs. 0.1% of patients, respectively; rhabdomyolysis was reported in 0.1% vs. 0.2%; gallbladder-related adverse events were reported in 3.1% vs. 3.5%; cholecystectomy was reported in 1.5% vs. 1.5%; and alanine aminotransferase ( ALT ) and/or aspartate transaminase ( AST ) elevations ( greater than or equal to three times ULN, consecutive ) were reported in 2.5% vs. 2.3% of patients.
Over seven years, cancer was reported in 10.2% 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. ( Xagena )
Source: Merck, 2014