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Vioxx Case Illustrates Dual Nature of Drugs Researchers Also Discover Positive Side

Posted on: Thursday, 23 December 2004, 06:00 CST

In one of the great examples of the mixed messages of science, the same study that killed the blockbuster arthritis drug Vioxx after showing that it had heart risks also found that the drug had a significant benefit: It prevented precancerous colon polyps in some patients, one of the study's principal researchers said.

But the drug's maker, Merck, and the researcher, Dr. Robert Bresalier, said that neither Merck nor the researchers had known that Vioxx prevented polyps when Merck stopped the study and withdrew the drug from the market.

"At the time we made our decision to voluntarily withdraw Vioxx, the study had not yet been completed, and efficacy results had not been disclosed to Merck by the study's steering committee," Christopher Loder, a Merck spokesman, said.

Instead, because an independent board overseeing the study had reported that Vioxx, whose generic name is rofecoxib, was associated with a twofold increase in heart attacks and strokes, an unacceptable risk for otherwise healthy people, Merck announced on Sept. 30 that it was halting the 2,000-patient study. It withdrew Vioxx from the market and stopped all other studies that asked if the drug could prevent cancer.

The company says it has no plans to bring the drug back.

Bresalier, a professor and chairman of the department of gastrointestinal medicine and nutrition at M.D. Anderson Cancer Center in Houston, explained the polyp results had emerged in data analyses only a few weeks ago, showing the study was "substantially positive." He has not yet presented the results to other scientists for review. The study was paid for by Merck.

The company declined to comment on the polyp data except to say that they would be presented at the American Gasteroenterological Association's meeting in May and would be published.

But Bresalier said that, while the final analyses were not in, markedly fewer patients got precancerous polyps while taking Vioxx and that no other study had shown such pronounced effects in patients like those in this study, who previously had such polyps and were at risk for getting more. Most colon cancer starts with polyps, although most polyps do not become cancers.

Now, the mixed news about Vioxx raises questions of risk and benefit that science simply cannot answer.

There is increasing evidence that not just Vioxx but similar drugs, like Celebrex, or celecoxib; and Bextra, or valdecoxib, both made by Pfizer, might increase the risk of heart problems. But the risks of Vioxx and Celebrex came to light only because they were tested in long-term studies to see if they could prevent cancer. And if drugs like this do prevent cancer, which risk is worse, cancer if you do not take them, or heart attacks if you do? Who decides?

In the meantime, scientists say they are reeling from the discouraging news about drugs once thought to hold so much promise.

First Vioxx was withdrawn from the market. Then, last week, Celebrex turned out to increase the risk of heart attacks in a similar colon polyp prevention study. (Those polyp data have not yet been analyzed.) Bextra, it turned out, increased heart attack risk in patients who had had heart surgery. And on Monday, even Aleve, or naproxen, the over-the-counter pain reliever, fell under suspicion. In a study asking whether it or Celebrex could prevent Alzheimer's disease, Aleve patients had a 50 percent greater rate of heart problems, which is a small increase that may not be statistically significant. The study was halted anyway. All this points to troubling realities in the calculus of risk versus benefit.

What if you are at high risk of colon cancer? Do you take Celebrex? Or what if you have arthritis and end up with a choice of a drug that can cause ulcers and heart attacks or one that confers a greater risk of heart attacks, but does not cause ulcers?

"This is where it all becomes murky," said Dr. Daniel Simmons, the director of the Cancer Research Center at Brigham Young University and a discoverer of the COX-2 enzyme. The discovery led to the development of Vioxx, Celebrex and Bextra, the drugs that block the enzyme.

And what if you are a drug company, wondering whether to pour money into a long study of a drug that might prevent cancer? The Vioxx and Celebrex stories illustrate the chance a company takes. Pfizer still sells Celebrex, but stock prices in both companies plummeted with the news of their drugs' risks, and Merck faces a raft of patients' lawsuits.

Yet cancer prevention trials take years and involve healthy people, magnifying the risk that some drug dangers will emerge, scientists say.

"If you are talking about treating otherwise healthy people for years and years and years with drugs, it is almost impossible to be sure that in some relatively small fraction of patients, there won't be side effects, even severe side effects," said Dr. Bert Vogelstein, a colon cancer researcher and Howard Hughes investigator at Johns Hopkins University.

Now, Pfizer and Merck have seen what the consequences can be. "I hope it doesn't prevent companies from trying to develop anticancer drugs," Vogelstein said. "But I fear it will."

Celebrex is known to prevent polyps in patients with familial adenomatous polyposis, a genetic condition that makes it inevitable that one day they will get colon cancer. But even these patients are asking their doctors if they should still take Celebrex. Or should they give it to their children, who inherited the condition?

"I have patients right now who are struggling with this," said Dr. Raymond DuBois, a colon cancer specialist at Vanderbilt University School of Medicine in Nashville, Tennessee, who has been a consultant to Merck and Pharmacia, a previous maker of Celebrex.

Many scientists say that the fate of the so-called COX-2 inhibitors is particularly poignant since these were drugs that once seemed to be the perfect marriage of science and clinical medicine.

Source: International Herald Tribune

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