Ezetimibe’s Rapid U.S. Adoption Called Flawed

By Mitchel L. Zoler

CHICAGO -- When data on ezetimibe's missing antiatherosclerotic effect finally received its first airing at a scientific meeting, the consensus conclusion from a panel of cardiologists was that it was a case of a new-drug introduction run amok.

"Amid an aggressive marketing campaign, ezetimibe was rapidly adopted into practice," Dr. Harlan M. Krumholtz said at the annual meeting of the American College of Cardiology. Following ezetimibe's entry onto the U.S. market in late 2002, its use "skyrocketed." By 2006, 15% of all prescriptions for lipid-lowering drugs in the United States were either for ezetimibe alone (Zetia) or for the combination of ezetimibe and simvastatin (Vytorin), Dr. Krumholtz said in his talk, and in a report that he coauthored in the April New England Journal of Medicine (N. Engl. J. Med. 2008;358:1819-28.).

"In the United States, ezetimibe supplanted statins to some extent, and this led to reduced use of statins and reduced statin doses," said Dr. Krumholtz, professor of medicine, epidemiology, and public health at Yale University, New Haven, Conn. Ezetimibe "was the next new thing. There was a wave of enthusiasm," with physicians "not thinking critically enough" about its proper role.

"The strongest recommendation we can make is turn back to statins," he said, a message that had unanimous support from the three other experts chosen by the ACC to review and comment on the ezetimibe data at the meeting.

"We underscore optimizing doses of statins," agreed Dr. Patrick T. O'Gara, director of clinical cardiology at Brigham and Women's Hospital, Boston, and another member of the review panel. "Many of us have patients in our practices who started treatment with a lower dose of a statin plus ezetimibe to spare them from taking higher doses of statin that are perhaps much more effective."

"We thought that we could get a lower cholesterol level by adding ezetimibe rather than doubling the statin dose, which was well received by our patients who felt that increasing statin doses increased their risk of severe complications," said Dr. Joseph V. Messer, professor of medicine at Rush University, Chicago, a third member of the ACC's comment panel.

Trouble for ezetimibe began Jan. 14, when Merck/Schering Plough Pharmaceuticals, which markets the drug, issued a press release with the essential findings from the study it sponsored, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial.

The full results were published online the same day as the ACC session (N. Engl. J. Med. 2008 March 30 [Epub doi: 10.1056/NEJMoa0800742]), and were also summarized at the meeting by senior author Dr. John J. P. Kastelein, professor of medicine and chairman of vascular medicine at the Academic Medical Centre in Amsterdam.

The core findings remained as first announced more than 2 months before: Although treatment of patients with heterozygous familial hypercholesterolemia with a combination of 10 mg ezetimibe and 80 mg simvastatin was substantially more potent than 80 mg of simvastatin alone for reducing blood levels of LDL cholesterol and also high sensitivity C-reactive protein, the combination had absolutely no advantage over the statin alone for slowing the progression of carotid atherosclerosis as measured by ultrasound during 2 years of follow-up of the 720 patients in the study.

The ACC review panel was assembled to go over all of the data starting a few weeks before the meeting, and by the time their assessment was done "the most likely explanation [for the results] that we kept coming back to was that in this study ezetimibe did not work," Dr. Krumholtz said.

"It lowered LDL, but it did not retard atherosclerosis." The panel members stressed that they had reached a consensus, and that their individual statements on the implications of the results represented the opinion of all four of them.

"Ezetimibe is a new drug, a first-in-its-class, with a novel mechanism of action. It was approved only on the basis of lowering LDL. We didn't have results from any clinical outcomes studies. Until we are shown some data that can give us confidence that there is net benefit [from ezetimibe treatment] we need to use it very judiciously. It should have been tested this way early, but it got a pass. It should be profound evidence that moves us away from using statins." he said.

Both Dr. Krumholtz and Dr. O'Gara cited niacin, fibrates, and resins as better-proven agents that can be used first if treatment with a statin isn't tolerated or is inadequate. For the time being, ezetimibe use should be limited to the relatively small number of patients who still need LDL lowering despite use of all of these other agents.

Another concern of the ACC's panel was ezetimibe's safety, although results from the ENHANCE study and other investigations have so far indicated that the drug is well tolerated and safe. In addition, the panelists noted that a major 18,000-patient trial of ezetimibe now underway and using clinical end points was reviewed at the meeting by the study's data and safety monitoring board, and a decision was made to proceed with the study, an indication that no unexpected excess of adverse events was occurring in the trial. Results of this study are expected in 2012.

The results reported last year from a clinical outcomes trial of torcetrapib "really chastened me," Dr. Krumholtz said. Torcetrapib had shown potent, positive effects for raising levels of HDL cholesterol while also lowering LDL cholesterol and seemed safe and well tolerated. But then the results from a clinical end points study showed that torcetrapib raised blood pressure in many patients and boosted the study group's mortality rate, and led to premature stopping of the study in late 2006.

The fourth panel member was Dr. Rick A. Nishimura, professor of medicine at the Mayo Clinic, Rochester, Minn., and a member of the guidelines task force for the ACC and American Heart Association.

Dr. Nishimura said that revised lipid-management guidelines that reflect the new findings on ezetimibe could be released before the end of this year.