Promising trial on statin add-in falls flat; studies continue

Washington -- The Jan. 14 announcement of findings from the Enhance trial, which compared patients on the cholesterol-lowering drug Vytorin -- a combination of ezetimibe and simvastatin -- with a statin alone, sent shockwaves through the medical community. After all, many physicians viewed this as a promising approach in reducing heart disease risk because the drugs it combined work differently to reduce LDL cholesterol.

However, the study results showed no real difference between the two treatment groups in the two-year, randomized trial -- at least when it came to measuring plaque buildup in carotid arteries.

The initial response was to question whether the drug still had a place in physicians' medicine chests. But physician groups, including the American College of Cardiology and the American Heart Assn., soon adopted more measured positions, weighing in to say physicians should stay the course in prescribing Vytorin, and patients now taking the drug should not panic.

The study also found that patients using the combination drug experienced a 58% drop in LDL cholesterol, while those on the statin alone had a 41% drop. Overall, the safety profiles of the drugs were similar.

The data were released by the pharmaceutical companies Merck and Schering-Plough, which make the drugs. They also have been submitted for presentation at the American College of Cardiology's Annual Scientific Session this spring.

"Obviously a positive study would have been more favorable," said Skip Irvine, a spokesman for Merck/Schering Plough Joint Ventures. "This was a very challenging study, given the high hurdle [it] set, the population [people with heterozygous familial hypercholesterolemia], and their very high LDL levels at baseline."

Given the study's two-year duration and doses -- 10 mg of ezetimibe and 80 mg of simvastatin -- "we were very pleased to see that overall the safety profiles of ezetimibe/simvastatin and simvastatin alone were similar and generally consistent with their product labels," he said.

But the study created a stir for another reason. Although the trial concluded in April 2006, Merck and Schering-Plough did not release the results until mid-January -- a span that drew the attention of congressional committees.

The House Committee on Energy and Commerce began an investigation into the trial Dec. 11, 2007. Committee Chair John Dingell (D, Mich.) said in a Jan. 14 statement that the inquiry would continue despite the data's release. The announcement that the study "failed to find any positive benefit from the addition of Zetia to a common, inexpensive, generic therapy raises concerns that attempts were made to mask the minimal value of this new drug," said Dingell.

Irvine said the companies are "fully cooperating with the committee and are in the process of responding to requests for information."

Wait and see

The focus is now shifting to large, ongoing comparison studies of the drugs. Those trials are testing whether the use of the combination simvastatin and ezetimibe will reduce heart attacks or deaths more than the use of simvastatin alone. Results aren't expected for two to three years.

"It will be very important for those larger studies, directed at assessing cardiac outcomes, to be completed so we can fairly assess the potential of ezetimibe," said Daniel W. Jones, MD, the heart association's president.

An American College of Cardiology statement recommends that major clinical decisions not be made on the basis of the Enhance study alone and adds "there should be no reason for patients to panic."

Steven Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic and immediate past president of the ACC, cautioned that ezetimibe should be used only if a statin fails to reduce cholesterol adequately, since the combination drug demonstrated no added benefit and patients would still be exposed to side effects.

Ezetimibe "is still recommended for patients who cannot meet their cholesterol goals when they are on the highest statin dose they are able to take," said Lisa Martin, MD, director of the Lipid Research Clinic at George Washington University Medical Center in Washington, D.C. "The good news was there were very few cardiac events in either group."

But the whole issue of LDL-cholesterol lowering may need to be reconsidered. "Maybe it's not just lowering LDL," she said, since the lowered cholesterol did not result in lowered arterial plaque. "That's something we will have to find out in the future."

The end point of the Enhance trial, also known as the Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia trial, was the change in intima-media thickness measured in three sites in the carotid arteries.

The measures showed no statistically significant change.

Thomas Weida, MD, a family physician in Hershey, Pa., is interested in knowing how the difference in intima thickness translates clinically. "That's going to need a bigger study," said Dr. Weida, who is a board member of the American Academy of Family Physicians.

Dr. Weida also questioned the study population. The 720 people enrolled all had heterozygous familial hypercholesterolemia, a genetic condition that causes high cholesterol at young ages. "They tested this on a fairly rare group, so does their experience translate over to the vast majority of people with high cholesterol that we see?" asked Dr. Weida.

The study really didn't change anything, said James M. Wilson, MD, Hall chair in cardiology at St. Luke's Episcopal Hospital/Texas Heart Institute in Houston. "What we need to say is: It's a negative study. It's not particularly meaningful just yet, but let's see what happens in the clinical trial. Let's see if it shows itself to be a benefit, as we all think it will."