Clinical Trial of Vytorin Raises Questions

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Milwaukee Journal Sentinel (WI)

April 1, 2008

Nearly two years ago James Stein, a cardiologist at the University of Wisconsin-Madison, got an unusual call. Researchers for Merck/Schering Plough Pharmaceuticals, who were conducting a clinical trial of the blockbuster cholesterol drug Vytorin, wanted him to look at ultrasound images of the carotid arteries of a few people in the trial, which had just finished enrolling patients.

Stein, an expert on the use of carotid ultrasound to detect heart disease, looked at a few of the ultrasounds and didn?t hear much from Merck/Schering-Plough for nearly a year and a half.

In the two years after Stein was contacted, Vytorin, which had already received approval from the U.S. Food and Drug Administration, was heavily promoted in TV ads, and its sales skyrocketed, though the results of the trial had not been released. When they were finally released in January, they showed that the drug did not limit the buildup of plaque in arteries.

Not until Sunday were the full results of the trial published, in the New England Journal of Medicine, and presented at the American College of Cardiology meeting in Chicago.

Stein and several other experts eventually would be enlisted by Merck/Schering-Plough to form an advisory panel for the trial, and more unusual events would occur. ?This wasn?t the standard way clinical trials are done in the U.S.,? Stein said. ?I think lots of things about this study were irregular.?

So irregular, in fact, that in December, the House Committee on Energy and Commerce launched an investigation looking into whether there was a delay in revealing the results of the trial until Jan. 14, 2008, nearly a year and a half after the trial ended.

Officials with Merck/Schering-Plough maintain that the trial remained blinded, and that neither the researchers conducting it nor the companies knew which group of patients received Vytorin until Dec. 31, 2007.

?We conducted this trial with the utmost scientific integrity,? said Rick Veltri, group vice president with the Schering-Plough Research Institute. ?There is no doubt that this trial took longer to do (than anticipated). The delay was about honest scientific discussion.?

John Kastelein, the study?s lead author and a researcher at the Academic Medical Center in Amsterdam, said he, too, did not know the results of the study until January. ?I don?t know what the drug company knew,? he said. ?If there is anyone in the world who could find out, it?s the U.S. House of Representatives, because they have subpoena powers.?

Vytorin combines the drugs ezetimibe (Zetia) and simvastatin (Zocor), two drugs that work in different ways to lower cholesterol.

The results presented Sunday in Chicago show that while the combined drug, Vytorin, reduced cholesterol about 17% more than just Zocor, there was no significant difference in the plaque thickness found in the carotid arteries of the 720 patients in the trial, who were about equally divided between Zocor and Vytorin. In other words, Vytorin did no more for artery health than Zocor alone.

A separate, independent analysis published Sunday found that Zetia was heavily promoted in the United States despite no data showing it had any clinical benefit. More than $200 million was spent on direct-to-consumer advertising for Vytorin in the United States during 2007, resulting in sales that exceeded $5 billion, according to a special article published in the New England Journal of Medicine.

The article compared sales of Zetia in Canada, where such promotion is not allowed, to U.S. sales. It said sales of traditional cholesterol-lowering statin drugs, which have proven benefits in reducing heart attacks and stroke, were displaced by Zetia, followed by rapid growth of Vytorin. The development markedly altered the approach of treating high cholesterol in the United States and increased the cost of drugs, the authors concluded.

The companies continue to market Vytorin in newspaper ads. They also promoted the drug at the cardiology meeting in Chicago, passing out free pens, fresh-squeezed orange juice and a combination clock/USB port docking station to anyone willing to listen to a personal pitch about how it lowered cholesterol more than other drugs.

But doctors say the drug is being overprescribed, given that there is no data showing that it offers any clinical benefit. Harlan Krumholz, senior author of the article on the analysis of Zetia and Vytorin sales, said only a small portion of people with high cholesterol should be taking Zetia or Vytorin.

He said many people might be taking Zetia without optimizing their use of statin drugs, which have proven clinical benefits. As a result, it could mean they are more likely to suffer a heart attack, he said. ?It could be harmful,? said Krumholz, of the Yale University School of Medicine. ?People need to turn back to statins.?

Indeed, many doctors mistakenly believe that using a drug like Vytorin is better because they believe it lowers cholesterol in two ways instead of one, said Raymond Gibbons, a cardiologist with the Mayo Clinic and a former president of the American Heart Association. ?Where does that come from?? said Gibbons, who was not a part of the trial. ?I think it comes from the ads.?

Gibbons and other doctors said statins should be the first line of treatment for high cholesterol. Then other drugs, such as niacin, can be used if cholesterol levels still are too high. After that, a drug like Zetia can be tried.

But in 2006, 34 million prescriptions were written for Zetia. ?How did we get to the point of having a drug with no (clinical) outcome data being used by 34 million people?? asked Steven Nissen, a cardiologist with the Cleveland Clinic, who was not a part of the trial.

Nissen said he can?t say whether the results of the trial were delayed on purpose, but it was not conducted like a standard clinical trial. He noted that the trial had no steering committee and no committee to monitor the safety of the trial. ?That?s irregular,? he said, adding that it will be up to Congress and other government investigators to find out why there was a delay in releasing the results.

Stein, the UW cardiologist, said he has turned over all his correspondence with the trial?s investigators and Merck/Schering-Plough to the House committee. ?They are very interested in who knew what and when,? he said.

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