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IMPROVE-IT published: Adding ezetimibe to simvastatin lowers LDL, improves CV outcomes
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Confirming findings previously presented, adding ezetimibe to statin therapy lowered LDL levels and improved CV outcomes in patients with ACS, according to the results of the IMPROVE-IT study published in The New England Journal of Medicine.
The researchers conducted a randomized, double blind trial of 18,144 patients hospitalized for ACS in the past 10 days who had LDL 50 mg/dL to 100 mg/dL if receiving lipid-lowering therapy or 50 mg/dL to 125 mg/dL if not receiving lipid-lowering therapy. Results were initially presented at the American Heart Association Scientific Sessions in November 2014.
Patients were assigned 40 mg simvastatin (Zocor, Merck) plus 10 mg ezetimibe (Zetia, Merck) or 40 mg simvastatin plus placebo.
The primary endpoint was a composite of CV death, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization 30 days or more after randomization and nonfatal stroke. Median follow-up was 6 years.
According to the results, the median time-weighted average LDL level was 53.7 mg/dL in the simvastatin-ezetimibe (Vytorin, Merck) group compared with 69.5 mg/dL in the simvastatin monotherapy group (P < .001).
Fewer events when ezetimibe added
The event rate for the primary endpoint at 7 years was 32.7% in the simvastatin-ezetimibe group vs. 34.7% in the simvastatin monotherapy group (absolute risk difference, 2 percentage points; HR = 0.936; 95% CI, 0.89-0.99).
“This finding is notable in that several previous trials have failed to show a significant benefit of nonstatin lipid-modifying agents when added to statins,” Christopher P. Cannon, MD, 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, and colleagues wrote.
Christopher P. Cannon
The following secondary endpoints also occurred less frequently at 7 years in the simvastatin-ezetimibe group:
- Death from any cause, major coronary event or nonfatal stroke: 38.7% vs. 40.3%; HR = 0.95; 95% CI, 0.9-1).
- Death from CHD, nonfatal MI or urgent coronary revascularization after 30 or more days: 17.5% vs. 18.9%; HR = 0.91; 95% CI, 0.85-0.98).
- Death from CV causes, nonfatal MI, hospitalization for unstable angina, all revascularization after 30 or more days or nonfatal stroke: 34.5% to 36.2%; HR = 0.95; 95% CI, 0.9-1.
Cannon and colleagues detected no significant differences between the groups in rates of prespecified muscle, gallbladder and hepatic disease adverse events and cancer.
LDL hypothesis supported
“The observation that a nonstatin lipid-lowering agent can also reduce [CV] risk does indirectly support the LDL hypothesis (ie, that lowering LDL leads to a reduction in [CV] events), but most importantly it undercuts the `statin hypothesis,’ that somehow only statins are beneficial,” Cannon and colleagues wrote.
“This trial cannot prove that the effect was mediated by the lowering of LDL levels alone, since changes and other lipoproteins and high-sensitivity C-reactive protein may have played a role,” they added. “However, the consistency with expectations from the [Cholesterol Treatment Trialists] analysis, in which a different class of drug was used, provides further evidence for a relationship between lipid lowering and improved outcomes.” – by Erik Swain
Disclosure: The study was funded by Merck. Cannon reports receiving grant support from Accumetrics, Arisaph, AstraZeneca and Janssen Pharmaceuticals; grant support and personal fees from Boehringer Ingelheim, GlaxoSmithKline, Merck and Takeda; and personal fees from Bristol-Myers Squibb, CSL Behring, Essentialis, Kowa, Lipimedix, Pfizer, Regeneron and Sanofi. Please see the full study for a list of the other researchers’ relevant financial disclosures.
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