CHICAGO — The addition of ezetimibe to simvastatin was associated with better clinical outcomes in high-risk patients with ACS compared with simvastatin alone, according to the results of the IMPROVE-IT trial presented at the American Heart Association Scientific Sessions.
This trial is the first to demonstrate clinical benefit of a lipid-modifying therapy added to statin therapy, Christopher P. Cannon, MD, said here.
Christopher P. Cannon
Cannon and colleagues conducted the randomized, double blind, multicenter IMPROVE-IT trial to investigate whether the addition of ezetimibe (Zetia, Merck) to simvastatin (Zocor, Merck) improved CV outcomes relative to statin monotherapy in patients after ACS. The researchers enrolled 18,144 moderate-to-high risk patients (mean age, 64 years; 25% women) within 10 days of ACS onset at 1,158 centers in 39 countries. All patients were aged 50 years or older and had LDL ≤125 mg/dL if not already on statin therapy, or ≤100 mg/dL if already on statin therapy. Approximately 5,000 of the patients had STEMI and the rest had non-STEMI or unstable angina.
Patients were assigned either 40 mg/day of simvastatin (n=9,077) or 10 mg/day of ezetimibe and 40 mg/day of simvastatin (Vytorin, Merck; n=9,067). The patients were up-titrated to 80 mg/day of simvastatin if they had LDL >79 mg/dL.
The primary endpoint was a composite of CV death, MI, hospitalization for unstable angina, stroke and coronary revascularization at least 30 days after randomization. Patients were followed for a minimum of 2.5 years; average follow-up was approximately 6 years.
Mean LDL in both groups was 95 mg/dL. At 1 year, mean LDL was 69.9 mg/dL in the simvastatin group and 53.2 mg/dL in the simvastatin/ezetimibe group; the difference of 16.7 mg/dL was slightly greater than the anticipated 15 mg/dL difference, Cannon, physician at Brigham and Women’s Hospital, professor of medicine at Harvard Medical School and executive director of cardiometabolic trials at Harvard Clinical Research Institute, said during a press conference.
“Would this … translate into a greater clinical benefit? The answer was yes,” Cannon said.
In the intention-to-treat population, the simvastatin/ezetimibe group had a 32.7% rate of the primary outcome compared with 34.7% for the simvastatin group (HR=0.936; 95% CI, 0.887-0.988; P=.016; number needed to treat=50), Cannon said.
The simvastatin/ezetimibe group also had better outcomes than the simvastatin group for the following prespecified secondary outcomes: all-cause death, MI, hospitalization for unstable angina, coronary revascularization or stroke (40.3% vs. 38.7%; HR=0.948; P=.034); CHD, MI or urgent coronary revascularization (18.9% vs. 17.5%; HR=0.912; P=.034); CVD, MI, unstable angina, all revascularization or cerebrovascular accident (36.2% vs. 34.5%; HR=0.945; P=.035), according to the researchers.
The following endpoints also favored the simvastatin/ezetimibe group over the simvastatin group: MI (14.8% vs. 13.1%; HR=0.87; P=.002); ischemic stroke (4.1% vs. 3.4%; HR=0.79; P=.008); and CVD, MI or stroke (22.2% vs. 20.4%; HR=0.9; 95% CI, 0.84-0.97; P=.003). There was a trend toward favorable rate of all stroke in the simvastatin/ezetimibe group (4.8% vs. 4.2%; HR=0.86; P=.052) and no significant differences between the groups in individual endpoints of all-cause death, CVD, CHD, unstable angina or coronary revascularization at least 30 days after randomization, according to the researchers.
There were no differences between the groups in cancer, muscle-related and gallbladder-related events, or other safety endpoints, Cannon said.
Ezetimibe did not have as strong a recommendation as statins for LDL-lowering therapy in the 2013 American College of Cardiology/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults because clinical outcome data for ezetimibe were unavailable at the time. The guidelines “put an emphasis on statins because that is where the evidence is,” Cannon said at the press conference.
“These findings in well-treated patients reaffirm the LDL hypothesis: Reducing LDL prevents CVD,” Cannon said. “These [data] are the evidence the guidelines are looking for.” – by Erik Swain
For more information:
Cannon CP. LBCT.02: Anti-Lipid Therapy and Prevention of CAD. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.
Disclosure: The study was funded by Merck. Cannon reports receiving research grants from Accumetrics, Arisaph, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen Pharmaceuticals, Merck and Takeda, and honoraria from Bristol-Myers Squibb, CSL, Essentialis, GlaxoSmithKline, LipoMedix, Merck, Pfizer, Regeneron, Sanofi and Takeda.