CHICAGO, March 30 -- The take home message from the ENHANCE trial reported here today is a simple one: it's time for a return to statins.

Harlan M. Krumholz, M.D., of Yale delivered that message as one of a panel of experts asked to interpret the results of the ENHANCE trial, which evaluated the combination of ezetimibe/simvastatin (Vytorin), before a packed house at the American College of Cardiology meeting.

The results of the ENHANCE trial "should change clinical practice" by encouraging physicians to return to "evidence-based medicine," which Dr. Krumholz said means 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 said in an interview.

Dr. Krumholz's verdict was greeted by thunderous and sustained applause, an exceptional reaction to a presentation at a scientific session of the ACC.

Today's presentation of ENHANCE data was the first time that cardiologists had the opportunity to hear a detailed airing of the results, which were first summarized by Merck and Schering-Plough in a press release issued on Jan. 14.

Simultaneously, the study results were also published online by the New England Journal of Medicine along with an analysis of ezetimibe use and two editorials.

At a Merck/Schering-Plough press conference late in the day, Robert J. Spiegel, M.D., chief medical officer and senior vice president at Schering-Plough, said that the drug makers were "very disappointed in the ACC plenary presentation. We had expected a scientific panel discussion and the discussion we got did not serve science well."

Dr. Spiegel said he was particularly disturbed by Dr. Krumholz' comparison of ezetimibe to torcetrapib, an investigational HDL boosting agent that was pulled from development when it was linked to increased cardiovascular deaths.

"There is absolutely no safety signal with [our] drug," Dr. Spiegel said. "We have over 10 million patient-years with this drug and no new safety issue has arisen. So we are very disturbed that this issue was raised. It does not come from data that we have tracked for the FDA."

Today's full-airing of findings of the ENHANCE trial did nothing to blunt the null finding for the combination of ezetimibe/simvastatin, compared with the statin simvastatin alone, that were prefaced in the press release in January.

That press release described a significant reduction in LDL cholesterol with ezetimibe/simvastatin that did not slow progression of atherosclerosis.

To recap the ENHANCE story, the trial found no significant difference in the primary endpoint, mean change in carotid intima-media thickness, between patients randomized to ezetimibe/simvastatin patients versus 360 control patients who received simvastatin alone (P=0.29).

The combination had a significantly greater decrease in LDLs -- a 58% reduction for the ezetimibe/simvastatin group versus 42% for simvastatin controls -- after 24 months (P<0.01), said principal investigator John Kastelein, M.D., of the Academic Medical Center in Amsterdam in Holland.

There were also reductions in triglycerides (6%) and C-reactive protein (25.7%) between the two groups, and those were significant (P<0.01), he said.

Nonetheless, they did not result in significant reductions in the surrogate endpoint of progression in carotid intima-media thickness, which begs two questions. First, is LDL reduction an invalid clinical goal? Second, what is the clinical evidence to support the use of ezetimibe?

The second question becomes especially crucial in light of data reported online today in the NEJM by Cynthia A. Jackevicius, Pharm.D., of the Western Univerisity of Health Sciences in Pomona, Calif., and colleagues, including Yale's Dr. Krumholz, who found that ezetimibe had captured more than 15% of the market for lipid-lowering medications by 2006. This translates to 3.1 million prescriptions for ezetimibe or ezetimibe/simvastatin in December 2006.

Moreover, the increased use of ezetimibe appears to have gained market share by cutting into statin prescriptions, which declined by 6.5% since ezetimibe was introduced in 2006.

Ezetimibe use also increased in Canada but the rise was markedly less, from 0.2% of prescriptions for lipid-lowering drugs in 2003 to 3.4% in 2006.

Two factors, Dr. Jackevicius and colleagues said, may explain the difference between U.S. and Canadian use. The combination of ezetimibe and simvastatin is not approved in Canada, and Canada does not permit direct-to-consumer advertising of prescription drugs.

In the U.S., Merck and Schering-Plough spent $200 million on marketing ezetimibe and the combination product and sales here have "eclipsed $5 billion," Dr. Jackevicius and colleagues said.

Turning to the inherent value of LDL reduction, Robert Bono, M.D., of Northwestern, said there is no question that LDL lowering is beneficial. He pointed out that among patients in the trial -- a difficult-to-treat group who had familial hypercholesterolemia -- the LDL cholesterols were "still more than 141 mg/dL even after 24 months of treatments, [and] with levels that high it is not surprising that there was no reduction in the thickening of the vessel wall."

But Dr. Bono said that it was also likely that ezetimibe was being used as a first-line agent, which he said is probably not the best use for the drug.

Statins, he said, remain the drugs of choice for first-line therapy.

Addressing the issue of the clinical value of LDL cholesterol lowering, two editorials concluded that the ENHANCE data should not be taken as evidence that cholesterol doesn't really matter.

Rather, the editorials hinted, there is a need to broaden the message so that it encompasses both lower is better and how you get there counts.