The New York Times  July 22, 2008

By Alex Berenson

In a clinical trial, the cholesterol-lowering drug Vytorin did not help people with heart-valve disease avoid further heart problems but did appear to increase their risk of cancer, scientists reported Monday.

The scientists who reported on the trial, called Seas, cautioned against panicking over the cancer findings, saying that even well-designed clinical trials sometimes produce chance results. A review of two other, much larger trials did not find a similar risk, they said.

Vytorin and Zetia, a companion drug, are prescribed each month to almost three million people worldwide and are among the world’s top-selling medicines.

But other cardiologists and epidemiologists said that the cancer risk could not be so easily dismissed.

The findings of the Seas trial will heighten concerns about Vytorin’s safety and effectiveness, said Dr. Steven Nissen, a former president of the American College of Cardiology and a longtime critic of Vytorin. Six months ago, a fourth clinical trial, called Enhance, also failed to show that Vytorin benefited patients, leading a panel of top cardiologists to recommend using Vytorin and Zetia only as a last resort.

Since that recommendation, Vytorin and Zetia prescriptions have plunged, though the drugs remain among the largest sellers for Merck and Schering- Plough, which jointly sell them. The drugs had combined sales of $5 billion last year.

Shares of Merck and Schering skidded Monday after the Seas trial results were reported, with Merck shares down 6 percent and Schering down 12 percent. After the close of trading, both companies reported second-quarter earnings that were slightly ahead of analysts’ estimates.

Vytorin is a single pill that combines two cholesterol-lowering medicines — Zocor, or simvastatin, and Zetia, or ezetimibe. Both Zocor and Zetia are also available as single pills. Zocor is a statin. Because two decades of research have proven that statins reduce the risk of heart attacks and do not raise the risk of cancer, the new safety concerns center around ezetimibe. In the United States, about two million prescriptions a month are written for ezetimibe, either independently as Zetia or in the Vytorin combination pill.

In the Seas trial, which involved nearly 1,900 patients whose heart valves were partially blocked, participants were given either Vytorin or a placebo pill that contained no medicine. Scientists hoped that the trial would show that patients taking Vytorin would have a lower risk of needing valve replacement surgery or having heart failure. But the drug did not show those benefits.

“No significant difference was observed between the treatment groups for the combined primary endpoint,” Dr. Terje Pedersen, the principal investigator for the study and a professor medicine at Ulleval University Hospital in Norway, said. The primary endpoint is the result that scientists hope to prove when they conduct a clinical trial.

However, patients taking Vytorin in the Seas trial did have a sharply higher risk of developing and dying from cancer. In the trial 102 patients taking Vytorin developed cancer, compared with 67 taking the placebo. Of those, 39 people taking Vytorin died from their cancer, compared with 23 taking placebo.

The absolute numbers of cancer cases were relatively small. But they reached statistical significance, meaning the odds were less than 5 percent that they were the result of chance.

To evaluate the cancer findings, Richard Peto, professor of medical statistics and epidemiology at the University of Oxford, examined the interim results of two other clinical trials of Vytorin — called Sharp and Improve-It. The University of Oxford is leading the Sharp trial, which is sponsored by Merck and Schering-Plough but run independently by the university’s Clinical Trial Service Unit.

The Improve-It trial is being led by investigators by Harvard and Duke University.

Both Sharp and Improve-It are comparing Vytorin with simvastatin — Zocor — alone.

Neither trial has yet been completed, but the two trials combined have about 20,000 patients, nearly 10 times as many as the Seas trial.

So far, about the same number of patients taking Vytorin in Sharp and Improve-It have developed cancer as those taking simvastatin alone, Mr. Peto said in London on Monday. That fact strongly suggests that the finding in Seas is due to chance, Mr. Peto said.

“I think we should not be diverted by fears of cancer,” he said.

Mr. Peto also noted that the increase in cancers was not clustered around a single type of malignancy, but occurred widely. If ezetimibe did cause cancer, it would be more likely to cause a single type than many types, he said.

But other doctors said the data from Improve-It and Sharp were not definitive. The patients in those trials have generally been followed for one to two years, while the Seas trial followed patients for four years. Because cancer generally takes years to develop, it may take some time for Vytorin’s risks — if they are real — to become evident in patients.

“I don’t know that you have much information about the cancer risk from the other two trials,” said Dr. Bruce Psaty, professor of epidemiology at the University of Washington.

In addition, the other two trials contain a puzzling finding. While the number of cancer cases is similar in those trials among patients taking Vytorin and those who were not, the number of cancer deaths is approximately one-third higher among those taking Vytorin. In all, 136 people taking Vytorin have died of cancer in the three trials, compared with 95 taking other medicines or a sugar placebo pill.