乌鸦传媒

CHICAGO -- In high-risk patients, adding ezetimibe to statin therapy reduced LDL cholesterol by an average of 17 mg/dL and reduced cardiovascular events compared with statin therapy alone.

That finding from the 18,000-patient IMPROVE-IT trial marks the first time that adding a nonstatin lipid-lowering therapy to a statin demonstrated a clinical benefit, Christopher Cannon, MD, of Brigham and Women's Hospital, told 乌鸦传媒.

Cannon presented the results from the study in a late-breaking clinical trial presentation at the American Heart Association's Scientific Sessions.

Niacin, fibrates, and CETP inhibitors added to statins have all failed to achieve a benefit. But ezetimibe plus simvastatin reduced the rate of cardiovascular death, myocardial infarction, or stroke by 2 percentage points (34.7% for simvastatin alone versus 32.7% for ezetimibe plus simvastatin) in IMPROVE-IT, which represented 270 fewer events over 7 years of follow-up.

There was no statistically significant difference in cancer, muscle, or gallbladder-related events, which Cannon said confirmed the safety of ezetimibe.

"Treating 100 patients would prevent two events," Cannon, who was principal investigator of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial), said.

At 1 year, the average LDL-C in the simvastatin arm was 69.9 mg/dL versus 53.2 mg/dL in the ezetimibe/simvastatin group. There was no difference in HDL-C, nor was there a difference in highly-sensitive CRP, which is considered a marker for increased risk of cardiovascular events.

The study randomized 18,000 stabilized acute coronary syndrome patients -- about 40% of them from North America -- to either 40 mg simvastatin or 10 mg ezetimibe/40 mg simvastatin. Patients who had LDLs higher than 79 mg/dL were up-titrated to 80 mg simvastatin -- 27% of the simvastatin patients required higher doses as did 6% of the ezetimibe/simvastatin patients.

Patients were followed at 30 days and then every 4 months until the trial had accumulated 5,250 events, defined as MI, stroke, cardiovascular death, revascularization, or hospitalization for unstable angina.

"It took 7 years of follow-up for us to reach that many events, so some investigators were wondering if this would be the eternal trial," Cannon said. "But that was really good news because it meant that the treatment was working: we were actually doing good for our patients."

It should, however, be noted that 42% of patients, regardless of treatment, stopped the study drug before the end of the trial.

The average age of patients was 64 and about a fourth were women. At baseline the average LDL-C was 95 mg/dL.

, director of the Director of Preventive Cardiology at New York-Presbyterian Hospital, and Medical Director, Columbia Center for Heart Disease Prevention, said the IMPROVE-IT results give cardiologists a needed alternative to statin therapy, which is sorely needed for patients who don't tolerate statin therapy.

Mosca also noted that IMPROVE-IT reinforces the need for clinical endpoint trials because when the drug was evaluated by a surrogate endpoint -- carotid intima-media thickness by ultrasound -- "the finding was negative, but when the drug was studied long-term, in a large population, the benefit was confirmed."

Indeed, that earlier finding from the ENHANCE study cast a shadow over ezetimibe and prescriptions for the ezetimibe/simvastatin combination (Vytorin) as well as ezetimibe itself (Zetia) declined by about half.

One of the ezetimibe/simvastatin critics back then was Harlan M. Krumholz, MD, of Yale University, who urged his colleagues to change their practice based on the ENHANCE results and to return to "evidence-based medicine," which he then defined as more statins and much less use of ezetimibe.

"I'm not saying this drug should go away, but it should definitely go to the end of the line," he told 乌鸦传媒 in 2008.

After reviewing the IMPROVE-IT results, Krumholz said the evidence now supports the use of ezetimibe, which he said may prove to be safer than statin therapy. The question now, he said, is how well does the drug work by itself?

Mosca, and other cardiologists interviewed by 乌鸦传媒 applauded the study results as a "proof of the LDL theory" -- that low is good, but lower is better.

For years, many in preventive cardiology believed that meant setting an ever-lower mg/dL goal: less than 100, less than 75 and so on until the treat-to-target movement hit a wall a year ago when new prevention guidelines recommended statin-centric therapy but no specific targets, and stopped short of saying "lower is better."

The release of those guidelines triggered a backlash of criticism from both sides -- the anti-statin adherents as well as those who believed that lower is always better -- as well as those who panned the new risk assessment tool built into the guideline.

The Cleveland Clinic's who was a leader of the anti-guideline camp last year, said the IMPROVE-IT results validate his stance and he called for an immediate re-do of the guidelines. IMPROVE-IT, Nissen said, proves that treating aggressively with all available agents to the lowest possible target does achieve measurable clinical benefits.

Neil Stone, MD, of Northwestern University who served as a discussant for IMPROVE-IT at the AHA meeting, said that if high intensity statins don't achieve the lowest possible goals, then the data now support the use of ezetimibe with a moderate intensity statin.

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