November 25, 2004

Merck Resisted Tests on Vioxx-Aspirin Mix

For all the risks associated with Merck's arthritis and pain drug Vioxx, the company has always pointed to one virtue: Vioxx was less likely to cause ulcers or stomach bleeding than cheaper, over-the- counter medications like ibuprofen, sold under names like Advil, or naproxen, sold under names like Aleve.

But as far back as 2001, Merck executives had evidence, based on the company's own research, that this might not be true for hundreds of thousands of Vioxx users who regularly took low doses of aspirin to reduce their risk of heart attack or stroke.

In 2001, Vioxx's label stated that its combination with low-dose aspirin "may result in an increased rate" of gastrointestinal complications compared to Vioxx alone. By then, Merck already had a test under way to answer the aspirin question, and its interim findings were not promising.

A report from November 2001 showed that Merck scientists had expected to find that the combination of low-dose aspirin and Vioxx would produce fewer ulcers than ibuprofen. But the study showed the number was the same. The company noted in the drug's label in 2003 that patients who took Vioxx and low-dose aspirin together did not have fewer signs of ulcers than those taking ibuprofen alone. But the company never followed up on a plan in 2001 to run a conclusive test to establish the drug's advantages, if any, to aspirin users.

It is not known how many of the two million or so people who were taking Vioxx when it was pulled off the market in late September for increased heart risks were also on an aspirin regimen.

But executives at two other drug makers, which ran clinical trials of medicines similar to Vioxx, a class of drugs known as COX- 2 inhibitors, said that those tests assumed that about one out of every five patients also used low-dose aspirin, a known stomach irritant. That estimate, if applied to Vioxx, would mean that last year alone some 400,000 users would have been affected.

The aspirin issue is emblematic of a broader question: whether many patients and their insurers are spending hundreds of millions of dollars annually on COX-2 drugs when they could get similar benefits from older, cheaper painkillers like ibuprofen.

Two other top sellers in the class, Celebrex and Bextra, both made by Pfizer, have not been shown to have significant gastrointestinal advantages for any group of users. Yet COX-2 drugs often cost more than $2.50 a pill, compared with pennies for older painkillers.

There is no question that for some people Vioxx did offer better protection against bleeding ulcers and intestinal perforations than many traditional painkillers. That protection can be lifesaving; it is estimated that thousands of patients, particularly older ones, die annually because of gastrointestinal complications associated with the use of over-the-counter painkillers.

Such improved gastrointestinal safety was the major promise of both Vioxx and Celebrex when they were first sold in the late 1990s. And many doctors began to prescribe them instead of older drugs precisely for that reason.

Joan Wainwright, a Merck spokeswoman, said the follow-up trial planned in 2001 was not done, in part because it was unclear how many patients would be needed to run such a test.

The absence of conclusive information about the interaction between COX-2 drugs and aspirin has hovered over medications like Vioxx since their introduction.

"These are very important questions, and no one knows the answers to them," said Dr. M. Michael Wolfe, a professor at Boston University Medical School who served on an advisory panel for the Food and Drug Administration in 2001 that looked at the heart risks of Vioxx. Merck executives said they had decided not to include aspirin-taking patients in their major study of Vioxx, which was called the Vigor trial. Their reasoning was that aspirin, which irritates the intestinal lining, might cloud how the drug fared from an ulcer standpoint against naproxen, which was used as the comparison drug in the study. The Vigor study found that patients taking Vioxx had about 50 percent fewer gastrointestinal problems than those taking naproxen. But it also indicated a fivefold risk of heart attacks compared with naproxen users.