Adding ezetimibe, a non-statin agent, to statin therapy reduces cardiovascular events in high-risk patients with acute coronary syndrome (ACS), according to results of the IMPROVE-IT Trial presented Nov. 17 at AHA 2014.

The study was led by Christopher P. Cannon, MD, FACC, professor of medicine at Harvard Medical School and physician at Brigham and Women's Hospital, and enrolled 18,144 patients with ACS aged 50 years or older with low-density lipoprotein (LDL) cholesterol levels at or less than 125 or at or less than 100 if they were already using a statin. About 5,000 of patients had suffered a ST-segment elevation myocardial infarction (STEMI), and the remaining 13,000 had suffered a non-STEMI or had unstable angina. Patients also had at least one feature putting them at high risk for a further cardiovascular event, including a previous MI, diabetes, peripheral artery or cerebrovascular disease, coronary disease in multiple arteries, or bypass surgery in the past.

Patients were either given 40 mg of simvastatin or 10/40 mg of ezetimibe/simvastatin, and were followed for an average of six years. The primary endpoint was cardiovascular death, myocardial infarction (MI), hospital admission for unstable angina, coronary revascularization (≥ 30 days after randomization), or stroke.

Results showed that compared to patients given simvastatin plus a placebo, those given both simvastatin and ezetimibe, had a 6.4 percent lower combined risk of subsequent myocardial infarction (MI), stroke, cardiovascular death, rehospitalization for unstable angina and coronary revascularization. MIs alone were reduced by 13 percent, and non-fatal stroke by 20 percent.  Deaths from cardiovascular disease were statistically the same in both groups. Approximately two patients out of every 100 patients treated for seven years avoided a MI or stroke. (Number Needed to Treat (NNT) = 50). Further, the dual therapy reduced patients LDL to an average of 54 mg/dL, compared with 69 for those treated with the statin and placebo.

“The study is the first to show that adding another non-statin drug to a statin to improve cholesterol levels can help patients with specific heart problems do better,” said Cannon. “We took [dual therapy] patients from a clinically appropriate target LDL-C to even lower.  We now have solid evidence that lower is good, and even lower can be even better,” he adds.

“This is the first trial to show that the addition of a nonstatin medication – ezetimibe – to a statin (simvastatin) can reduce cardiovascular events – especially myocardial infarction and ischemic stroke,” said Patrick T. O’Gara, MD, FACC, president of the ACC. “The relative risk reduction was small over a long period of follow up with a large number of high risk patients, but the number of patients needed to treat in order to reduce the incidence of the composite end point by 1 was 50. The trial was designed with simvastatin, a statin of moderate potency, and one used less often now in patients hospitalized with acute coronary syndromes. The trial was not designed to test treatment to specific LDL-cholesterol targets. It was designed to test a single drug strategy (simvastatin) versus a combination drug strategy (simvastatin/ezetimibe) for secondary prevention. It is encouraging to note that there was no important safety signal with the use of ezetimibe in the trial.”

O’Gara adds that, “this is new information that guideline writing committees will take under consideration once it is formally published. The current guidelines already provide clinicians with the flexibility to consider the use of ezetimibe in some patients. The results of this trial should not be extrapolated to low risk patients nor to conversations regarding primary prevention.”

Keywords: Risk, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Cholesterol, LDL, Azetidines, Angina, Unstable, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Diabetes Mellitus, AHA Annual Scientific Sessions

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