Results of a controversial study assessing ezetimibe's ability to slow atherosclerotic progression, when used in conjunction with a high-dose statin regimen, have cardiologists split on whether the findings signal a flawed study or a flawed drug.
The results were “disappointing, but not surprising because I had a lot of concern that this was not the right patient population and not the right methodology,” said Dr. Michael Davidson, professor of medicine and director of preventive cardiology at the University of Chicago.
But other experts tied the study's negative result to limitations of ezetimibe itself.
“It appears that this method for lowering LDL cholesterol is not beneficial,” said Dr. Steven Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic. “Statins do many other things that ezetimibe does not do: Statins raise HDL cholesterol, lower triglycerides, and reduce inflammation.”
One explanation why ezetimibe plus simvastatin failed to slow atherosclerotic progression better than simvastatin alone “is that there are differences in the drug effects that go beyond their reduction of LDL,” commented Dr. Christie M. Ballantyne, professor of medicine at Baylor College of Medicine, Houston, and chief of the section of atherosclerosis and vascular medicine.
Amid a congressional investigation, results from the Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial were released months before a formal meeting report, in a statement issued by Merck/Schering Plough Pharmaceuticals. The company, which markets ezetimibe as a solo agent (Zetia) and in combination with simvastatin (Vytorin), had been under pressure to release results from the trial, which ended in April 2006. A full report is expected at the annual meeting of the American College of Cardiology in late March. Merck also markets a formulation of simvastatin (Zocor).
ENHANCE was designed to test whether adding a 10-mg/day dosage of ezetimibe to an 80-mg/day dosage of simvastatin led to slower progression of atherosclerosis than use of the statin alone in patients with heterozygous familial hypercholesterolemia. The study randomized about 360 patients into two treatment arms; after washout, the mean baseline LDL cholesterol was about 319 mg/dL. Atherosclerotic burden was measured as intima-media thickness (IMT) using carotid ultrasound. The average baseline IMT in both groups was 0.69 mm.
Treatment with simvastatin alone over 2 years led to an average drop in LDL cholesterol of about 41% (a drop of about 130 mg/dL); the addition of ezetimibe led to a mean LDL decline of 58%, an additional 17% absolute drop that translated into an extra LDL fall of about 50 mg/dL.
Despite this LDL reduction, the average change in IMT was an increase of 0.0058 mm in the simvastatin-alone group, and an increase of 0.0111 mm in those also treated with ezetimibe. This difference in the primary end point was not statistically significant, and thus the findings failed to show a benefit from adding ezetimibe. There was a small increase in atherosclerotic progression with ezetimibe—the rate was almost twice as great as among patients on simvastatin only—but the difference was not statistically significant. The study was not designed to assess clinical events such as cardiovascular deaths or myocardial infarctions. Clinical and adverse events were similar and low in the two arms.
The undeniable fact, however, was that treatment with ezetimibe in this study failed to further slow atherosclerotic progression even though it cut LDL cholesterol levels by a whopping additional 50 mg/dL.
“It's a paradox,” Dr. Nissen said. He cited a similarly designed 2001 study with 330 patients with heterozygous familial hypercholesterolemia that compared the impact of treatment with 80 mg/day of atorvastatin with 40 mg/day of simvastatin. In that study, simvastatin cut serum LDL levels by 41% and atorvastatin cut them by 51%. After 2 years, the simvastatin patients had a mean IMT progression of 0.036 mm, but the atorvastatin group had an average regression of 0.031 mm, a statistically significant difference (Lancet 2001;357:577–81).
Another possible explanation is that “80% of the participants had been on statins prior to the onset of the study. Hence, much of the atherosclerotic preventive effect of LDL lowering could have already happened,” said Dr. Donald A. Smith, director of lipids and metabolism at Mount Sinai Medical Center, New York. Physicians will need to await further study results with ezetimibe “to confirm the 40-year experience that any method of lowering LDL cholesterol will provide preventive atherosclerotic effects,” he said in an interview.
Some experts cited problems with the ENHANCE study's design. “Little imaging studies like this are virtually worthless,” said Dr. Scott Grundy, professor of medicine and chairman of the Center for Human Nutrition at the University of Texas at Dallas. “I'm concerned that the hype generated about this small trial, without a clinical end point, may be enough to knock [ezetimibe] off the list of agents that can help get LDL to very low levels.” Dr. Grundy has received research grants and honoraria from Merck and other pharmaceutical companies.