Clinical trials investigator accuses drug companies of delaying release of study results.

The lead outside investigator on a crucial trial of two widely used heart drugs said in an e-mail message last July that Merck and Schering-Plough, the companies that make the drugs, were deliberately delaying the release of the trial results "to hide something," The New York Times reported April 1.

The companies did not release the preliminary results of the trial, called Enhance, until January, almost two years after the trial was finished. When they were finally released, the trial's results showed that the drugs, Vytorin and Zetia, did not work to reduce plaque in arteries. The results led a panel of cardiologists to recommend on Sunday that the drugs be used only as a last resort.

The new information was contained in e-mail messages to executives at Schering-Plough that were released by Sen. Charles Grassley (R-IA), the ranking Republican on the Senate Finance Committee. The committee has been investigating the delay in the release of the Enhance trial results.

A day earlier, a panel of cardiologists called on physicians at the annual meeting of the American College of Cardiology to sharply curtail their use of Vytorin and Zetia, following a formal presentation of a study that reinforced the case against their widespread use in fighting cardiovascular disease, "The Wall Street Journal" reported.

The Enhance investigator, John Kastelein, M.D., also complained last July that Merck and Schering had not consulted him on the reasons for the delay and he threatened to resign as the main study investigator.

A spokeswoman for Schering-Plough said the messages had been presented out of context and that Kastelein's complaints had been resolved months ago, The Journal reported.

Kastelein is a Dutch cardiologist and scientist whom Merck and Schering hired to conduct the Enhance trial, which consisted of images of the arteries of 720 patients taking either Vytorin--the combination of Zetia and Zocor--or Zocor alone. Because Vytorin lowers cholesterol more than Zocor alone, the companies expected that the trial would show that patients who took Vytorin had less growth of plaque in their arteries than those who took Zocor.

The trial ended in April 2006, and its results were initially expected in late 2006 or early 2007. The companies repeatedly delayed releasing the results of the trial, however, saying publicly that many of the images of the arteries were unclear and might need to be re-examined.

By July, Kastelein was privately furious with the companies for the delays, his messages show. "Is it correct that SP has decided not to present at AHA?" he said July 6 in an e-mail message to Rick Veltri, M.D., a vice president at the Schering-Plough Research Institute, referring to the American Heart Assn. conference in November. "If this is the case, our collaboration is over," he wrote, adding, "This starts smelling like extending the publication for no other [than] political reasons and I cannot live with that."

Harlan Krumholz, M.D., a cardiologist at Yale, said Kastelein's messages raised new concerns over the nearly two-year delay in the release of the Enhance results.

"What raises concerns here is the possibility that the delay was being imposed by the companies against the wishes of the principal investigator, who should be the leader of the study," Krumholz said. "I hope that there was a good scientific explanation, endorsed by a steering committee of credible scientists at the time of the decision to delay, which explains why the public and the profession had to wait so long."

Krumholz and three other cardiologists told an audience of more than 5,000 people at the annual American College of Cardiology scientific convention that Vytorin and Zetia should not be used except as a last resort.

The two major cardiology associations seconded those recommendations the next day. Prescriptions for the medicines have already dipped about 15% since January, when preliminary results from the Enhance trial were first disclosed. Still, the drugs are widely used, with about three million prescriptions written each month in the United States alone.

LDL cholesterol is known as a risk factor for heart disease, so doctors have generally assumed that lowering LDL cholesterol by any means would reduce the risk of heart attacks and strokes.

But proving that a drug actually cuts those risks requires an expensive, multi-year clinical trial enrolling 10,000 or more patients. Those outcomes trials have been conducted for statins, and have proved that patients taking those drugs do have a reduced risk of heart disease. No such outcomes trials exist for Vytorin and Zetia.

In 2006, four years after Zetia reached the market, Merck and Schering began enrolling patients in their own outcomes study, which compares people taking Vytorin with those taking Zocor alone. But the results of the trial are not likely to be available until 2012, or possibly later.