December 21, 2004
By GARDINER HARRIS
A new study has found that Aleve, a popular over-the-counter painkiller made by Bayer, could increase heart problems, and federal officials are warning patients not to exceed the recommended dose of two 200-milligram pills a day or continue therapy for more than 10 days without consulting a physician. It was the fourth big-selling pain medicine in recent months to be suspected of hurting the heart, and federal drug officials said that similar drugs, like Advil, might also increase heart risks.
The study, sponsored by the National Institutes of Health, was intended to measure whether Aleve and Celebrex, made by Pfizer, might prevent Alzheimer's disease. Nearly 2,500 patients were given one of the two drugs or a placebo and were followed for three years. Those taking Aleve had a 50 percent greater rate of heart problems - including heart attacks and stroke - than those given a placebo. The Celebrex patients saw no increase in heart events. The latest findings follow an announcement Friday that a different national study found that those given high doses of Celebrex had a 240 percent increase in heart problems, including death.
Merck executives withdrew their painkiller Vioxx after a study found that it increased the risk of heart attack and stroke by more than 100 percent. Also, Pfizer announced recently that a study of Bextra found that it increased the risk of heart attacks in those who have had cardiac surgery. "This illustrates the fundamental dynamic that all drugs have risks," said Dr. Steven Galson, acting director of the Food and Drug Administration's center for drug evaluation and research. "All should be taken carefully."
Federal drug officials said that the entire class of painkillers known as nonsteroidal anti-inflammatories - drugs that include Celebrex, Advil and Mobic - could cause worrisome effects on the heart. Sales of Celebrex, along with other anti-inflammatories like Advil and Mobic, are expected to fall as a result.
"We know that there are other phenomena that occur across these class of drugs, including gastrointestinal bleeding," said Dr. Sandra Kweder, deputy director of the F.D.A.'s office of new drugs. Heart problems "may be another class phenomenon." Dr. Kweder said that the agency was studying the results of this latest study and "will be assessing what regulatory actions are appropriate over the next day or two." Researchers stopped the study, but patients will be monitored. Patients taking a prescription form of Aleve known as Naprosyn or naproxen should also consult their physicians, Dr. Galson said. At the very least, the latest results could prove beneficial to Pfizer, which has been arguing that last week's finding about Celebrex should be placed in the context that similar pills may be just as hurtful to the heart and that other studies of Celebrex have shown no such worries.
Indeed, if there is one message from these studies it is that nothing is certain in this science. "This is a very confusing situation," Dr. Kweder said. "Every doctor and patient is going to have to have a conversation about their unique risks." The results surprised many because other studies suggested that naproxen may actually protect the heart. Some said the latest results suggested that many pain pills were far too popular in the United States.
"I've been saying for a long time that over-the-counter Nsaid's are extraordinarily dangerous," said Dr. Mark Fendrick, professor of internal medicine at the University of Michigan. Nsaid refers to nonsteroidal anti-inflammatories, which include Aleve, Advil and Mobic. Many critics of the drug industry say that the industry has used widespread advertising to sell medicines to more patients than need them. Drug makers make more than half of their sales and the majority of their profits in the United States and drug side effects are one of the leading causes of deaths in this country, critics say. The one drug that is known to protect the heart is aspirin, Dr. Fendrick said. All other painkillers are now under suspicion, he said.
But Dr. Garret FitzGerald, chairman of the University of Pennsylvania's pharmacology department and the first to speculate that drugs like Celebrex and Vioxx could be uniquely hurtful to the heart, said he simply did not believe the announcement. The heart problems found in the study have not been examined by a panel of heart experts or statisticians, Dr. FitzGerald noted. Such a vetting could change the results substantially, he said. "It's much too early from the information provided to know if this is a meaningful result or not," he said. Indeed, those making the announcement yesterday cautioned that the results were preliminary. Researchers decided to stop the trial because news of problems with Celebrex had led many of the patients to threaten to drop out. Researchers had long known that those given naproxen in the study had a somewhat increased risk of heart problems, but that increased risk is not what led them to stop the study, said Dr. John Breiten of the University of Washington. "The safety data for some time has been giving a weak signal of possible increased risk of cardiovascular and cerebrovascular problems with naproxen," Dr. Breiten said. A safety committee overseeing the trial met as recently as Dec. 10 and decided that the results were not worrisome enough to stop the trial, Dr. Breiten said. Only when last week's widely publicized test of Celebrex found that that drug could more than triple the risk of heart disease did the researchers decide to end the study and issue their warnings about Aleve, even though Dr. Breiten said that the increase in heart risks may not prove to be statistically significant with further analysis.
A Bayer spokesman had no comment. Dr. Breiten said 70 people experienced heart attacks or strokes, but he would not give numbers for each drug group, saying those numbers would probably change with further vetting. Dr. Elias A. Zerhouni, director of the National Institutes of Health, said that making a decision to suspend a trial is far different and far easier than making regulatory decisions about those drugs. In the case of the Alzheimer's trial, patients were taking the medicines simply in hopes of preventing a disease, not because the medicines were providing a needed benefit. It is very different advising patients who need such medicines to solve their pain, Dr. Zerhouni said.