Vytorin, which combines the unique cholesterol drug Zetia with the traditional statin drug simvastatin, was found to be no better than simvastatin alone for reducing plaque buildup in the carotid arteries. The carotid arteries run through both sides of the neck to the brain.
In fact, patients taking Vytorin actually had slightly more plaque buildup during the trial than those taking simvastatin alone.
The findings were revealed Monday morning in a news release issued by the drug companies Merck and Schering-Plough, which jointly market Vytorin and Zetia.
In an interview with WebMD, cardiologist Steven E. Nissen, MD, called the results "a stunning reversal for Zetia and Vytorin."
Nissen is chairman of the department of cardiovascular medicine at the Cleveland Clinic, and is a past president of the American College of Cardiology.
"Zetia works only by blocking the absorption of cholesterol, but it has not been shown to produce any health benefits," he says. "I have been skeptical of these drugs from the beginning because I wasn't sure that Zetia's mechanism of cholesterol lowering would produce the same benefits that we see with statins."
But P.K. Shah, MD, who directs the cardiology department at Cedars-Sinai Medical Center in Los Angeles, tells WebMD that the trial results do not mean that the millions of patients taking Zetia or Vytorin derive no benefit from the drugs.
"I don't think this is a call for a moratorium on Zetia. That would be overreaching," he says. "This was a small study and it is not the last word."
Congressional Probe of Zetia, Vytorin Research
The release of the results came just weeks after the announcement of a congressional investigation into the drug companies' actions surrounding the study, which ended nearly two years ago.
In addition to delays in presenting the results, critics had accused the companies of attempting to change the endpoints of the study, known as the ENHANCE trial, in an effort to present the results in a more favorable light.
In a news release issued Monday afternoon, the two congressmen leading the investigation had harsh words for Merck and Schering-Plough.
"Today's announcement that the ENHANCE study failed to find any positive benefit from the addition of Zetia to a common, inexpensive, generic therapy raised concerns that attempts were made to mask the minimal value of this new drug," Committee on Energy and Commerce chairman John Dingell, D-Mich., charged.
Rep. Bart Stupak, D-Mich., who chairs the oversight subcommittee, said the investigation will continue.
"In light of today's results, which were released nearly two years after the ENHANCE trial ended, it is easy to conclude that Merck and Schering-Plough intentionally sought to delay the release of this data," Stupak said. "It's currently unclear whether these companies knew that adding a new expensive drug accomplished nothing more than an established cheaper generic. But it is clear that our investigation is far from over."
A spokesman for Schering-Plough tells WebMD that the timing of the trial results release had nothing to do with the congressional investigation.
Lee Davies blamed the delay in presenting the findings on the complexity of interpreting the data, which included some 40,000 visual images that had to be analyzed.
Davies pointed out that the study was designed to assess plaque buildup in the arteries in a very high-risk patient population. The trial was not designed to look at outcomes such as heart attack, stroke, and death.
The trial included 720 patients with a rare genetic condition predisposing them to very high cholesterol.
During the two-year study, patients were treated with either high doses of simvastatin alone or Vytorin, which combines Zetia and simvastatin.
The side effect profile for the two treatments was similar, and was consistent with the labeling for Vytorin, Davies says.
But Vytorin users had slightly more plaque buildup in their carotid arteries, although the difference was not statistically significant and could have been due to chance.
Davies says three larger ongoing trials, involving some 20,000 patients, should answer questions about whether Zetia and Vytorin prevent more adverse events and deaths than statins alone.
He questions the reaction to the ENHANCE results, which he called a "small, academic trial."
"The implications drawn from the findings in terms of clinical use seem out of proportion to what the trial was designed to demonstrate," he says. "One should keep in mind that while statins are the first-line therapy for most people, they are not enough for many people and are not appropriate for some. There is a need for viable alternatives, and Zetia and Vytorin have proven to be very effective for lowering LDL levels."
Combined quarterly sales of Zetia and Vytorin reached $1.3 billion in the second quarter of 2007, with Vytorin sales growing by 30% and Zetia sales increasing by 21%, according to the Dow Jones news service MarketWatch.
Docs Weigh in
A statement released Tuesday afternoon by the American College of Cardiology (ACC) urged patients taking Zetia or Vytorin to remain calm in the wake of the ENHANCE findings.
The statement made it clear that ACC still considers Zetia a reasonable option for patients who cannot tolerate statin drugs or can only tolerate low-dose statins.
"There is no reason for patients to panic," the statement read. "Concerned patients using these drugs should talk to their health care professional. This is not an urgent situation and patients should never stop taking any prescribed medications without first discussing the issue with their health care professional."
Michael Blazing, MD, of Duke University Medical Center, is lead investigator of the largest ongoing trial of Zetia, sponsored by Merck and Schering-Plough.
Patients will be followed to record the incidence of major cardiovascular events, including heart attacks or strokes.
Blazing tells WebMD that study should be completed by 2012.
"In order to really answer the questions about the safety and efficacy, we need much bigger trials like ours with these major events as the endpoints," he says.
Shah agrees, adding that he sees no reason why anyone taking Zetia and Vytorin should stop taking the drugs based on the ENHANCE results.
"Do (Zetia and Vytorin) save more lives? Do people who take them have fewer heart attacks and strokes?" he asks. "The answer to these questions will tell us if these drugs are useful, and we don't yet know the answers."
But Nissen says it's wrong for the drug companies to continue to make billions of dollars a year from the sale of Zetia and Vytorin when there is no evidence that they work any better than generic statins, which cost much less.
"We are supposed to continue giving these drugs on faith for the next four or five years in the hope that they work," he says. "That makes no sense. We practice evidence-based medicine, and right now the only evidence we have suggests that (Zetia and Vytorin) add nothing in terms of health benefits."