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Dec. 29--One of the first researchers to link the popular prescription painkillers Vioxx and Celebrex to heart problems blamed aggressive advertising for escalating public health risks and called for enabling the government to require better clinical trials to prevent future drug disasters.
Vioxx and Celebrex are two of three drugs known as Cox-2 inhibitors that in recent months have been linked to increased cardiovascular problems. The third, Bextra, has also been tied to increased heart risks.
"These drugs were mass-marketed from the moment they were commercially available in the new world of direct-to-consumer advertising, with unrealistic expectations about pain relief, marked gastrointestinal protection, and safety," Dr. Eric J. Topol wrote in a Journal of the American Medical Association article published online yesterday.
"Rather than a sufficient waiting period after approval to firmly establish safety in the large, representative 'real world' population, the unbridled promotion exacerbated the public health problem," wrote Topol, chairman of the Cleveland Clinic Foundation's department of cardiovascular medicine.
In the first nine months of 2004, Pfizer Inc. spent $77.8 million advertising Celebrex, while Merck & Co. spent $68.5 million to advertise Vioxx, according to Nielsen Monitor-Plus.
Meanwhile, Bayer AG spent $42.9 million advertising its over-the-counter painkiller Aleve, known generically as naproxen.
From September through December, Vioxx, Bextra, Celebrex, and naproxen -- painkillers used by millions of people with arthritis -- one by one were linked to spikes in major cardiovascular problems. Merck yanked Vioxx from the market. Pfizer agreed to stop advertising Celebrex and added a warning of possible heart and blood clotting problems to Bextra's label. Last week, the Food and Drug Administration urged consumers to avoid the new-generation painkillers if they have a risk of heart problems and to keep from using naproxen for more than 10 days unless a doctor approved.
Half of people with arthritis also struggle with cardiovascular disease, Topol noted.
In the JAMA article, Topol blamed the FDA for failing to require a clinical trial specifically designed to tease out cardiovascular risks and benefits with Cox-2 inhibitors. Scientists outside the FDA noted heart risks with Vioxx and Celebrex quickly, and in 2001 Topol and others called such a trial "mandatory."
Had "trials been conducted five years ago in patients with established cardiovascular disease, when the benefit and risk were indeterminate, clinicians would have quickly learned the risk and potentially avoided a major cardiovascular calamity," he wrote.
Even now, cardiovascular risks for the painkillers remain unclear. Three independent trials pointed to heart risks with Vioxx, Topol wrote. But only one suggests a "cardiovascular hazard" with Celebrex, contradicting other studies that indicated that painkiller did not pose heart attack or stroke problems.
FDA warnings for naproxen, associated in one study with a 14 percent reduction in heart attacks, are downright "questionable," Topol said in an interview.
"We're kind of in a post-Vioxx world now where that drug's aftereffects are clearly being felt by other programs and other drugs and, of course, the FDA," he said. "These are some of the aftershocks."
In late January, the FDA will convene a two-day meeting of rheumatologists, cardiologists, and agency scientists to review the cardiovascular risks of the class of painkillers that block chemicals linked to inflammation, said one of the invited experts. On the agenda: how to design a clinical trial to best answer the question of cardiovascular risks.
In mid-February, federal advisers will look specifically at Cox-2 inhibitors, drugs designed to ease pain without adding to gastrointestinal woes, to guide the FDA's decisions on whether to remove Bextra and Celebrex from the market or add new warnings.
A number of FDA overhaul bills are expected to be introduced when Congress reconvenes, including legislation to better fund and make independent the agency's office of drug safety. Other proposals would give the FDA more muscle to require post-marketing clinical trials that many companies now promise but few complete.
Providing "more authority to the FDA to shape and require the execution of vital trials is perhaps the most important lesson," Topol wrote. "Currently, for the FDA to mandate that a trial be performed in the post-approval phase of a drug, it has to confront the manufacturer that the drug in question may be withdrawn from the market. There is hardly a precedent for such a drastic step in the history of the FDA."
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