IMPROVE-IT: Adding Ezetimibe to Statins Yields Cardiovascular Benefit

IMPROVE-IT: Adding Ezetimibe to Statins Yields Cardiovascular Benefit
IMPROVE-IT: Adding Ezetimibe to Statins Yields Cardiovascular Benefit
Adding ezetimibe to statin therapy may further lower the risk for cardiovascular events in high-risk acute coronary syndrome patients.

The addition of ezetimibe to statin therapy was associated with significant clinical benefit in high-risk patients with acute coronary syndrome (ACS), according to data presented at the American Heart Association’s Scientific Sessions 2014.

The study, called IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), was conducted at 1,158 centers in 39 countries. A total of 18,144 patients aged 50 years or older with ACS and LDL cholesterol levels at or less than 125 mg/dL or at or less than 100 mg/dL if they were already using a statin were enrolled in the study.

Patients were enrolled within 10 days of hospitalization for an MI or unstable angina, and all were considered high risk. Patients were then randomly assigned to simvastatin 40 mg or ezetimibe 10 mg/simvastatin 40 mg (Vytorin, Merck) daily. Uptitration to simvastatin 80 mg occurred if LDL cholesterol was greater than 79 mg/dL. Mean follow-up was 5.68 years.

Over a 7-year period, event rates of the primary outcome — a composite of subsequent myocardial infarction (MI), stroke, cardiovascular (CV) death, rehospitalization for unstable angina and coronary revascularization — were lower in patients taking simvastatin plus ezetimibe vs. those taking simvastatin plus placebo (32.7% vs. 34.7%). Results indicated that risk for the primary outcome was 6.4% lower in the combination therapy group vs. the simvastatin monotherapy group (P=.016).

The number needed to treat for the primary outcome was 50, according to the data.

The researchers also noted reductions in several secondary endpoints with ezetimibe plus simvastatin vs. simvastatin alone. This was most pronounced for the combined endpoint of coronary heart disease (CHD), MI and urgent coronary revascularization, with event rates of 17.5% for the combination therapy group vs. 18.9% for the simvastatin alone group (P=.016).

Cardiovascular disease (CVD)-related death was statistically similar between groups.

Is Lower Better?

In addition to improvements in CV events, the researchers sought to assess whether lower LDL cholesterol targets may be beneficial.

“We conducted this trial primarily to learn whether ezetimibe could reduce cardiovascular clinical events when added to statin therapy. In addition, we wanted to know whether ‘even lower was even better,’ meaning, could we improve outcomes by driving the LDL cholesterol below 70 mg/dL, which has been the target in prior guidelines,” said study investigator Robert Giugliano, MD, Associate Professor of Medicine at Harvard Medical School in Boston.

Results indicated that ezetimibe plus simvastatin reduced patients’ LDL to an average of 54 mg/dL compared with 69 mg/dL for those treated with simvastatin plus placebo. 

“Endocrinologists will want to know about these landmark results because this is the only trial that has answers to these two questions: the clinical efficacy of ezetimibe when added to statin therapy, and what happens when the LDL cholesterol is pushed below 70 mg/dL,” Dr. Giugliano told Endocrinology Advisor.

Clinical Implications

Lori Mosca, MD, MPH, PhD, Professor of Medicine at Columbia University Medical Center and Director of Preventive Cardiology at New York-Presbyterian Hospital, said these study results will help expand treatment options for high-risk patients with ACS, especially among those who are intolerant of or who do not achieve desired results with intense statin therapy. 

She said the results also suggest that it may be optimal to push the LDL cholesterol bar even lower among high-risk patients to achieve maximum benefit to prevent recurrent heart disease and stroke.

“I do think it will change clinical practice. They highlight the importance of lowering LDL cholesterol and the importance of lowering it in those with the highest levels. We have known for a long time that this was a good approach, but this shows us that even lower is even better,” Dr. Mosca said in an interview with Endocrinology Advisor.


  1. Cannon CP et al. LBCT.02 – Anti-Lipid Therapy and Prevention of CAD. IMPROVE-IT Trial: A Comparison of Ezetimibe/Simvastatin versus Simvastatin Monotherapy on Cardiovascular Outcomes After Acute Coronary Syndromes. Presented at: American Heart Association’s Scientific Sessions 2014; Nov. 15-19, 2014; Chicago