Patients taking Plavix, a popular and expensive antistroke drug, experience more than 12 times as many ulcers as patients who take aspirin plus a heartburn pill, a study to be published today in The New England Journal of Medicine found.

Up to half of those now taking Plavix do so because their doctors assume that Plavix is safer on the stomach than aspirin, said Dr. Francis K. L. Chan, the study's lead author. Both the American College of Cardiology and the American Heart Association recommend that heart and stroke patients at risk of developing ulcers be given Plavix instead of aspirin.

The new study suggests that the guidelines should be changed, and that many of those who are taking Plavix should consider switching to aspirin plus a heartburn pill because it is not only safer but cheaper, Dr. Chan said.

"Plavix might really damage the stomach," Dr. Chan said.

Dr. Rose Marie Robertson, chief science officer at the American Heart Association, said, "The A.C.C/A.H.A. guidelines always examine all the available literature in reaching a decision. We are eager to analyze this important new study in the context of available data on Plavix, even though it was not a study of patients with cardiovascular disease."

The study is bad news for both Sanofi-Aventis and Bristol-Myers Squibb, based in New York, which co-market Plavix. Plavix had $2.8 billion in sales in during the first half of 2004 and is on track to become one of the three top-selling drugs in the world. It is by far the companies' biggest seller. Plavix was a major reason for Sanofi's hostile takeover battle last year for Aventis, which ended with a friendly merger of the two French drug companies.

For Bristol-Myers, the drug has been one of its lone bright spots as it loses exclusive rights to other big sellers and struggles to overcome an accounting scandal that resulted last year in a $300 million fine, one of the biggest levied by the Securities and Exchange Commission.

Generic drug makers are also challenging Plavix's patent, and some analysts believe that the generics may win that battle this year or next.

A spokeswoman for Sanofi-Aventis, based in Paris, did not return calls for comment. Rob Hutchison, a spokesman for Bristol-Myers, said that the study did not directly compare aspirin and Plavix. Instead, the difference in ulcers could be entirely a result of the heartburn pill, which has long been known to prevent ulcers. He said the study should have included a group of patients who got Plavix plus a heartburn pill.

Dr. Chan said he decided against that, because there was little point. Plavix is prescribed for many patients because it is believed to safe for the stomach. There's little reason not to substitute aspirin, a widely available and very cheap drug, for Plavix, a very expensive one, if Plavix is not safe to the stomach, he said.

Aspirin sells for less than 10 cents a pill. Plavix sells for between $3 and $4 a pill. Tests underwritten by Sanofi-Aventis suggest that Plavix may be slightly better than aspirin at preventing strokes. But the huge popularity of Plavix has also resulted, in part, because it has long been considered safer on the stomach than aspirin.

Dr. Chan said he was surprised to find that almost no studies had been done to confirm whether this assumption was true. He found 320 patients whose ulcers had healed and gave half of them Plavix and half of them aspirin plus Nexium, a heartburn pill. He followed them for a year.

Thirteen of the patients taking Plavix, or 8.6 percent, experienced renewed ulcer bleeding during the year while just one, or 0.7 percent, of those taking aspirin and Nexium had an ulcer bleed.

"That's an astonishingly high rate of bleeding ulcers" in the Plavix group, said Dr. Bryon Cryer, associate professor of medicine at the University of Texas Southwestern Medical School and author of an editorial on the Chan study in tomorrow's Journal.

"This observation is astonishing enough to lead physicians to rethink their preferred treatment strategies to prevent cardiovascular disease in patients with histories of previous ulcers," Dr. Cryer said.

There is no need for patients to limit their choice of heartburn pills to Nexium, Dr. Chan said. Nexium is also expensive and there is almost no evidence that it is any more effective than Prilosec, a similar pill. Both medicines are made by AstraZeneca, based in London.

Dr. Chan said he used Nexium simply because the drug was the only such heartburn pill on his hospital's list of preferred medicines. Dr. Chan said that most gastroenterologists believed Nexium, Prilosec, Aciphex and Prevacid all worked equally well.

Dr. Cryer recommended that doctors consider using aspirin and Nexium or any of its cousins in place of Plavix.

But Dr. Irwin Grosman, chief of gastroenterology at the Long Island College Hospital in Brooklyn, said he was not certain that any other drug beside Nexium would work as well. "You don't have the evidence to support that," he said.

Still, he said, Plavix alone was clearly not the right therapy for these patients.

The Plavix study comes in the wake of safety problems with other drugs, like Vioxx, made by Merck, which was withdrawn in September after it proved to double the risk of heart attack and stroke. Studies of Celebrex and Bextra, similar medicines made by Pfizer, also showed increased risks. But Dr. Chan said he was not suggesting that Plavix be withdrawn or that it was particularly dangerous.

Representatives for the American College of Cardiology did not return calls for comment.