Healthy Hormones

Doubts Are Raised on the Safety of 2 Popular Arthritis Drugs

By Melody Petersen, New York Times
May 22, 2001

Doctors are beginning to worry that Vioxx and Celebrex, two wildly popular arthritis drugs, may not be as safe as they were initially believed to be.

Research presented to the Food and Drug Administration earlier this year showed that patients taking Vioxx, a Merck & Company drug, had a higher, but still relatively low, risk of heart attacks than patients taking an older pain reliever. The study received little public attention at the time, but the F.D.A. is considering whether to add information on possible cardiovascular side effects to both drugs’ labels.

Now Wall Street is becoming aware of the possible problems, with at least one analyst warning that the problem could particularly affect Merck.

The two drugs, which cause fewer ulcers than many other pain relievers, are among the best-selling medicines in the world. And both Pharmacia, which makes Celebrex, and Merck are heavily dependent on the drugs for the sales growth that Wall Street expects.

Celebrex is Pharmacia’s biggest-selling drug, generating sales of $2.3 billion in the 12 months ending in March, according to IMS Health. Pfizer co-markets Celebrex with Pharmacia. Merck sold $1.7 billion of Vioxx in the same period, making it the company’s second-biggest drug behind the cholesterol medicine Zocor.

Millions of Americans have tried Vioxx or Celebrex, many of them prompted to request them from doctors after seeing television advertisements paid for by the two companies, which are locked in a fierce marketing battle.

While the data is still limited, a large study sponsored by Merck last year showed that patients taking Vioxx had four times the risk of heart attacks of patients taking another pain reliever, naproxen, which is sold both generically and under the brand names Naprosyn or Aleve. The risk, which appears to increase over time, was still low, however, at about 4 heart attacks per 1,000 patients.

Merck says the research does not show a problem with Vioxx. Instead, the company says, naproxen acted to reduce heart attacks by working much like aspirin.

The information from Merck’s study was presented to the Food and Drug Administration in February when the companies asked for changes on their drug labels to reflect data showing that Vioxx and Celebrex caused fewer ulcers than other pain relievers.

In an April 27 report, Richard R. Stover, a pharmaceutical industry analyst at Arnhold & S. Bleichroeder Inc., did his own analysis of what he called “disturbing data” from Merck’s study. In an interview, Mr. Stover said he was warning his clients, many of them institutional investors who hold Merck shares, that they should watch the issue carefully since it could hurt the company’s stock price.

Some doctors, however, say they are worried about both drugs.

“There must be a warning,” said Dr. M. Michael Wolfe, chief of the gastroenterology section at the Boston University School of Medicine and a member of the F.D.A. advisory committee that reviewed the issue earlier this year.

“The marketing of these drugs is unbelievable,” Dr. Wolfe added. “I’m sure there are many people out there who are taking these drugs that should not be.”

Several doctors say they are worried about the possibility of heart attacks because many of the arthritis patients taking the drugs are elderly and have a higher risk of cardiovascular problems to begin with.

The current debate centers on whether the higher heart attack rate found in patients taking Vioxx is a result of the drug’s actually causing damage in some patients or to an absence of the heart-protecting benefits that naproxen may have.

Merck’s scientists say that naproxen appears to help reduce heart attacks by stopping or slowing the production of a substance called thromboxane. Thromboxane is thought to cause platelets in the blood to stick together, leading to blood clots.

“Naproxen had a similar antiplatelet effect to aspirin,” said Dr. Eve E. Slater, senior vice president of external policy for Merck’s research labs, “and those people had fewer heart attacks.”

Neither Vioxx nor Celebrex have been shown to have the same heart- protecting benefit.

Dr. Slater also said that Mr. Stver’s report was flawed and biased in favor of Pharmacia. But regulators and some doctors say they still worry that there may be more of a problem with Vioxx.

And even if Vioxx and Celebrex do not damage the heart, the fact that they do not have the heart-protecting benefits of aspirin reduces the ability of the companies to market them as being significantly safer than other pain relievers.

In letters sent to physicians involved in Vioxx clinical trials, Merck recommended last year that doctors consider prescribing low doses of aspirin to patients taking Vioxx if they are at high risk of heart attacks. But those low doses of aspirin could increase the risk of ulcers — the main side effect that both Vioxx and Celebrex were developed to avoid.

The two drugs, known as Cox-2 inhibitors, have been shown to significantly reduce stomach ulcers compared with pain relievers like aspirin and ibuprofen. In rare cases, serious ulcers can lead to death.

So far, no studies have been done to measure whether patients have fewer ulcers if they take low doses of aspirin with either Vioxx or Celebrex.

At an F.D.A. advisory meeting in February, Dr. Maria Lourdes Villalba, a medical officer at the agency, summed up her analysis of Merck’s study, saying that the company had proved that Vioxx, which is known generically as rofecoxib, caused fewer serious ulcers than naproxen. But she said that in her opinion, the potential safety advantage was offset by a higher risk of heart problems.

“Over all, there was no safety superiority of rofecoxib over naproxen,” Dr. Villalba concluded, “mainly due to an excess of serious cardiovascular events.”

Dr. Villalba said that because there were no studies that proved Merck’s theory that naproxen worked like aspirin to decrease heart attacks, the F.D.A. was concerned that the higher rate of heart attacks found with Vioxx might have been caused by the drug’s producing blood clots.

Both Merck and Pharmacia say that patients taking either Vioxx or Celebrex and low doses of aspirin will still have fewer ulcers than if they were taking a drug combination like ibuprofen and aspirin.

Dr. G. Steven Geis, Pharmacia’s vice president for arthritis and cardiovascular clinical research, said, “We believe that if a patient is on low-dose aspirin and needs a drug for arthritis, celecoxib is a good option.”

Celecoxib is the generic name for Celebrex.

Copyright 2001 The New York Times Company

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