Acute coronary syndrome patients at high risk from heart disease and stroke may benefit from taking the non-statin drug ezetimibe in combination with statin therapy, according to the results of a large, global study reported at the American Heart Association’s annual meeting.
Lead author Dr. Christopher P. Cannon, a professor of medicine at Harvard Medical School and physician at Brigham and Women’s Hospital – both in Boston, MA – says their study “is the first to show that adding a non-statin drug to a statin to improve cholesterol levels can help patients with specific heart problems do better.”
Called IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial), the study involved 1,158 centers across 39 countries and enrolled a total of 18,144 participants who were followed for an average of 6 years.
All of the participants were at least 50 years old and had acute coronary syndrome (ACS), with low-density lipoprotein (LDL) cholesterol levels at 125 or lower, or at 100 or lower if the patient was already using a statin.
“The patients, enrolled within 10 days of hospitalization for a heart attack or unstable angina, were high risk,” Dr. Cannon says.
About 5,000 of the patients were hospitalized with a “full-thickness” heart attack, known as an ST-segment elevation myocardial infarction (STEMI). The remaining patients were hospitalized with either a non-STEMI heart attack or unstable angina.
The participants in the study also had at least one feature characteristic of high risk for a future cardiovascular event. These factors included a previous heart attack, diabetes, peripheral artery or cerebrovascular disease, coronary disease in multiple arteries or previous bypass surgery.
Previous studies conducted at Brigham and Women’s Hospital have been unable to answer whether further reducing cholesterol beyond the effects offered by high-dose statins provided better clinical outcomes for patients. The IMPROVE-IT researchers believe they have now answered this question.
Statins work by blocking cholesterol production in the liver. Ezetimibe, however, works by reducing the absorption of cholesterol in the intestine. In the IMPROVE-IT study, the combination of ezetimibe and a statin – simvastatin – reduced patients’ LDL levels to an average of 54 mg/dL.
By contrast, a control group that was administered simvastatin and a placebo had an average LDL level of 69 mg/dL.
Compared with the placebo group, patients who received the dual therapy also had a 6.4% lower risk of all cardiovascular events, 14% lower risk of all heart attacks, 14% lower risk of stroke and 21% lower risk of ischemic stroke.
About 2 out of every 100 dual therapy patients treated for 7 years avoided having a heart attack or stroke. Deaths from cardiovascular disease, however, were about the same in both groups.
“We took those patients from a clinically appropriate target LDL-C to even lower,” says Dr. Cannon. “We now have solid evidence that lower is good, and even lower can be even better.”
He adds that the inclusion of ezetimibe in the patients’ treatment regime did not raise their risk of liver or muscle problems, cancer or other side effects.
Study co-chairs, Drs. Eugene Braunwald of Harvard Medical School and Robert Califf of Duke University in Durham, NC, say:
“In IMPROVE-IT, the addition of ezetimibe to a statin resulted in a further reduction in cardiovascular events compared to statin therapy alone, which is the first time this has been directly shown in a study of a non-statin cholesterol-lowering medicine.
The IMPROVE-IT data also address an important scientific question about lowering LDL-C to very low levels.”
However, the simvastatin and ezetimibe combination drug Vytorin has a controversial history. Last year, Vytorin’s manufacturer, Merck, agreed to pay $688 million to settle lawsuits making the claim that the company had harmed investors by delaying the release of unfavorable results from trials of the drug.
The company now considers that the IMPROVE-IT data has vindicated its position on simvastatin and ezetimibe combination therapy.