Safety of All Cox-2 Drugs Questioned

Expert says they work on same heart mechanism as recalled Vioxx

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By
HealthDay Reporter

FRIDAY, Oct. 8, 2004 (HealthDayNews) -- A week after drug giant Merck & Co. withdrew its arthritis drug Vioxx from the market, doubts are being raised about the safety of the two other approved medications in this class, Bextra and Celebrex.

In an article released Thursday by the New England Journal of Medicine, an expert with a long history of research in the cox-2 inhibitor class of medications said cardiovascular problems seen with Vioxx may yet surface with the other two drugs.

The problem, said Dr. Garrett A. FitzGerald, is that all cox-2 inhibitors suppress the production of a heart-protecting fat called prostaglandin I2.

"Vioxx, Celebrex and Bextra all have the same effect on this biochemical system. Therefore, until proven otherwise, evidence would suggest that this mechanism would involve all drugs in this class," explained FitzGerald, who is chairman of pharmacology at the University of Pennsylvania's Institute of Translational Medicine and Therapeutics.

After halting a study suggesting that long-term Vioxx users faced double the risk of heart attack or stroke compared to non-users, Merck announced Sept. 30 it was pulling the drug from markets worldwide.

A day later, Pfizer Inc. -- Merck's main rival in the billion-dollar arthritis medication market -- issued a statement defending its biggest cox-2 drug, Celebrex.

Citing a number of ongoing, long-term studies, Pfizer's president of worldwide development, Dr. Joe Feczko, said, "the data we've accumulated over time demonstrate that Celebrex does not increase the risk of serious cardiovascular events in patients with arthritis and pain, even at higher-than-recommended doses."

One top U.S. Food and Drug Administration official echoed those sentiments. Dr. Steven Galson, acting director of the FDA's Center for Drug Evaluation and Research, told reporters at a press conference last week that cox-2 inhibitors other than Vioxx "do not have this same incidence of heart attack and stroke in clinical trials. There is a real difference in the data."

But FitzGerald said he remains uneasy.

"Back in 1999, we performed studies on Celebrex and Vioxx, and we showed that they had an effect on the same mechanism whereby they relieved pain and inflammation," he explained. That mechanism -- inhibition of an enzyme called cyclooxygenase-2 -- leads to reductions in lipids called prostaglandins.

These prostaglandins "are responsible for pain and inflammation, and they also protect the stomach" so Vioxx users got needed relief without the gastrointestinal upset often associated with other pain relievers, FitzGerald explained.

Unfortunately, prostaglandins, especially prostaglandin I2, "are also responsible for protecting the heart," he added.

The bottom line, according to FitzGerald, is that as cox-2 drugs soothe arthritis pain and reduce risks for gastrointestinal symptoms, they may also raise cardiovascular risks over the long term. That turned out to be the case with Vioxx.

But what about long-term use of Celebrex, or the other Pfizer cox-2 inhibitor, Bextra?

Right now, "we just don't have a handle on 'how long is long'" FitzGerald said. "In the [Vioxx] trial, nothing much happened to patients for a year, and then things started to come apart. But maybe with other drugs, other circumstances, or in other types of patients, it may be two years, three years -- who knows?"

FitzGerald believes that, given the failure of Vioxx, "the burden of proof has now shifted" to Pfizer and the FDA.

He also believes the time has come for the FDA, especially, to take the lead. "I'd really like the FDA, in short order, to give us some advice one way or another, based on their best guess, as to what people at high cardiovascular risk should do," FitzGerald said.

The FDA faced much harsher criticism in a second article released in the same journal. The journal's editors released the articles -- originally scheduled for Oct. 21 publication -- early because of concerns surrounding the use of Vioxx.

In that second report, Dr. Eric J. Topol, a cardiovascular expert at the Cleveland Clinic Foundation, says his team reviewed the available data on Vioxx and Celebrex as far back as 2001, and at that time strongly recommended "a trial specifically assessing [the] cardiovascular risk and benefits of these agents."

He claims that although the FDA had the power to order such a trial, "it never took the initiative," while at the same time letting Merck spend more than $100 million in direct-to-consumer ads promoting Vioxx.

In the meantime, he writes, "tens of thousands" of patients taking Vioxx may have suffered heart attacks or strokes linked to their use of the drug.

And on Thursday, Sen. Charles Grassley (R-Iowa) alleged that the FDA tried to suppress a top safety official in the agency who raised concerns over the safety of Vioxx.

David Graham, associate science director of the Office of Drug Safety, told Grassley that agency officials "ostracized" him and subjected him to "veiled threats" as he tried to have his study cleared for publication, the Washington Post reported. When another top FDA official suggested "watering down" the report, Graham said in an e-mail: "I've gone about as far as I can without compromising my deeply held conclusions about this safety question."

Grassley made the accusations in a press release, which also said, "Instead of acting as a public watchdog, the Food and Drug Administration was busy challenging its own expert and calling his work 'scientific rumor,'" according to the Post account. An FDA spokesman told the paper the allegations were "baloney."

"I believe that there should be a full Congressional review of this case," Topol wrote. "All the facts can and should be scrutinized closely in a Congressional review in order to avert such a catastrophe in the future."

More information

For more on cox-2 inhibitors and other arthritis drugs, go to the Arthritis Foundation.

SOURCES: Garrett A. FitzGerald, M.D., chairman, pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia; Oct. 1, 2004, statement, Pfizer Inc.; Oct. 1, 2004, press conference, U.S. Food and Drug Administration, Rockville, Md.; Oct. 21, 2004, New England Journal of Medicine; Oct. 8, 2004, Washington Post

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