The study called Enhance found no sign of benefit for high- risk heart patients when the results were released today at a medical meeting in Chicago. The finding confirmed an earlier report that Vytorin, prescribed almost 20 million times last year, was no better than Merck's Zocor, a generic pill sold for a fifth of the cost. Vytorin combines Zocor with the companies' other cholesterol drug, Zetia.

The results suggest that Vytorin may not stop damage to the arteries and shouldn't be widely used until a larger study proves whether the pill reduces the risk of heart attacks and deaths, doctors said. Researchers said this week they were expanding this trial, delaying it until about 2012.

``The drug has to be used extremely conservatively,'' said Allen Taylor, chief of cardiology at Walter Reed Army Medical Center in Washington, D.C. ``There are a lot of great cholesterol treatments and among those options this is the one with the least evidence that it does the right things.''

The study was presented at the American College of Cardiology meeting in Chicago and simultaneously released by the New England Journal of Medicine.

Vytorin and Zetia had more than $5 billion in sales last year, making them Schering-Plough's most important product group. The Enhance study was designed to give Schering-Plough and Merck an even greater share of the $35 billion worldwide cholesterol market.

Prescriptions Drop

Vytorin prescriptions, which have fallen 18 percent since partial study results were released January 14, may continue to slide after some of the top heart doctors in the U.S. said the drug should be used only after all other treatments have failed.

``The surprising thing about the results is despite an LDL cholesterol that was 50 points lower in the Vytorin group, there was no evidence for any reduction in the buildup of plaques in the carotid or femoral arteries,'' said Steven Nissen, head of cardiology at the Cleveland Clinic in Ohio. ``There is no positive news here.''

Nissen and other cardiologists criticized Schering-Plough and Merck for not starting definitive studies until years after Zetia and Vytorin were on the market. The newly expanded study, dubbed Improve-It, uses half the dose of Zocor, sold generically as simvastatin, in both groups. Zetia was approved in the U.S. in 2002 and Vytorin was cleared in 2004.

Bigger Trial

On Friday, researchers from Brigham and Women's Hospital in Boston and Duke University in Durham, North Carolina said the trial will be expanded by 80 percent to ensure it has enough patients to get a clear result. The 2 1/2 year study, originally intended to include at least 10,000 patients, will now follow 18,000 patients. Doctors are looking for a 10 percent reduction in complications like heart attacks and deaths.

Robert Califf, one of the lead investigators for the study from Duke University Medical Center, defended expanding the trial. Many patients develop side effects like muscle weakness from taking the older cholesterol drugs, called statins, and need alternatives, he said.

``As a person who can't tolerate high-dose statins, it's very important,'' said Califf, a cardiologist at Duke. ``It's a very well tolerated drug. For me, if it lowers event rates at all, I'll take it.''

Effort to Discredit

Merck and Schering-Plough, who funded and helped design the experiment, have tried to discredit it. The companies wanted to alter the main goal of the trial after it was completed, a scientific faux pas, saying the approach used to measure plaque was too imprecise. They also said years of earlier treatment left patients, who had an inherited condition marked by high cholesterol, with little plaque buildup, making it difficult to detect a benefit from the therapy.

Congress is investigating whether the company intentionally delayed releasing the data and tried to change the study design to cover up the findings.

The unexpectedly low plaque buildup at the start of the study may have been responsible for the result, said the researchers led by John Kastelein, a professor at the Academic Medical Center in Amsterdam. Other possibilities for the failure include lack of benefit from the drug or flaws in the technique to measure plaque, they said.

Cause Unknown

The ultimate cause for the lack of benefit remains unknown, researchers wrote in the New England Journal. The results were particularly surprising since Vytorin reduced levels of bad cholesterol significantly more than Zocor, known generically as simvastatin, alone.

``Every single explanation or attempt to discredit the trial based on the standpoint of the sponsors is completely debunked by the data,'' Taylor said. ``If it is not the investigator, it is not the data, it is not the endpoint, it must be the drug.''

About $49 billion in the companies' combined market value has been wiped out since the preliminary results were reported. Whitehouse Station, New Jersey-based Merck fell 27 cents to $44.51 in New York Stock Exchange composite trading Friday. Kenilworth, New Jersey-based Schering-Plough gained 17 cents to $19.47.

Merck and Schering-Plough have said doctors should focus on Vytorin's ability to lower LDL, or ``bad'' cholesterol, in the blood more than simvastatin can accomplish alone. They also said the results shouldn't be applied to the mainstream population because the study only looked at patients with a rare genetic condition that causes them to produce excess cholesterol.

``We believe Vytorin and Zetia should continue to be therapeutic options,'' said Rick Veltri, vice president of global clinical development for cardiovascular and metabolic disease at Schering-Plough, in an interview today.

`Red Flag'

It is unlikely though that the drug would have a benefit on the heart, even with lowering LDL cholesterol, if it didn't reduce plaque build up, Taylor and B. Greg Brown, a cardiologist at the University of Washington School of Medicine in Seattle, wrote in an editorial accompanying the study.

The chance that the pill provides no benefit ``which is the elephant in the parlor, deserves serious consideration in any discussion of the results of the study,'' they wrote. ``For now, the study's findings are a red flag but not a black box.''

The drug was heavily marketed to doctors and patients, including a $140 million-a-year ad campaign with people dressed to resemble food items to show how Vytorin treats cholesterol from food along with that produced by the body because of genetics. The companies have since halted the advertisements.

Doctors say Vytorin and Zetia became overused given that there are other cholesterol drugs, such as Pfizer Inc.'s Lipitor, with data showing they slash the risk of heart attacks and strokes. No such data exists for Vytorin.