While Merck & Co.’s sudden withdrawal Thursday of the blockbuster pain medication Vioxx may have left millions of patients confused and concerned, doctors and researchers say they aren’t surprised.
For more than four years, they have been keeping wary eyes on studies showing links between Vioxx and heart attacks and strokes – often advising patients with heart conditions to use other arthritis pain drugs instead.
“For many of us doing drug epidemiology, this has been a question that has been in the air since 2000 and it’s taken far too long for it to be resolved,” said Jerry Avorn, associate professor of medicine at Harvard Medical School and drug researcher at Brigham and Women’s Hospital in Boston. “This information was out there, waving in the breeze.”
Even before the drug’s approval in 1999, a University of Pennsylvania study raised questions about whether Vioxx and similar drugs slightly raised the risk of heart attacks or strokes.
Then, a 2000 study sponsored by Merck and published in the New England Journal of Medicine clearly showed an increase in heart attacks, although none were fatal. The study was designed to look at Vioxx’s effect on the stomach, and found it was less likely to cause discomfort and bleeding than similar painkillers.
Ever since then, “I was always using it cautiously,” said Lawrence Leventhal, chief of rheumatology at Graduate Hospital of Philadelphia.
But while he and others steered patients at risk of heart disease toward similar drugs such as Pfizer’s Celebrex, Vioxx still enjoyed huge popularity. By the time of its voluntary withdrawal by Merck, it was being used by 2 million people worldwide; its annual sales in 2003 totaled $2.5 billion.
Some critics were upset that a pain drug linked to severe and fatal heart events remained on the market for years – and in fact continued to be approved for wider and wider uses by the FDA. Three weeks ago the FDA approved the prescription of Vioxx to children as young as 2.
“Red flags right from the beginning were ignored because of business issues,” said Vioxx researcher Eric Topol, chief of cardiovascular medicine at The Cleveland Clinic. “The FDA has never done anything to make Merck or others do the right trials in heart patients.”
Some doctors and researchers said Thursday that despite negative studies in recent years, there remained good reasons for some patients to take the drug. In some cases, it was more effective in relieving pain, or it was a convenient, once-a-day alternative to heavy reliance on over-the-counter pain medications, such as ibuprofen, which can cause stomach bleeding or liver damage.
Vioxx, along with Celebrex and its successor Bextra, are in a class of drugs called COX-2 selective nonsteroidal anti-inflammatory drugs, or COX-2 inhibitors.
They work by inhibiting the COX-2 enzyme, which triggers pain and inflammation in the body. But as Penn researchers reported in 1999, COX-2 inhibitors also appear to suppress prostacyclin, a hormonelike substance that dilates blood vessels and reduces blood clotting.
If that is the case, then Vioxx and presumably other COX-2 inhibitors including Celebrex and Bextra may reduce inflammation, while at the same time raising the risk of serious heart events.
Garret A. FitzGerald, chairman of the Department of Pharmacology at Penn, who did the 1999 study, believes all COX-2 inhibitors may pose the same risk.
“What we’ve said all along is if this is a problem, it’s a class problem and not a (specific) drug problem,” he said Thursday. “Will the FDA have a general warning for the class? I’m in favor of that.”
In fact, the FDA suggested Thursday that it would be taking a wider look at all COX-2 inhibitors. Steven Glason, acting director for the agency’s Center for Drug Evaluation, said, “we are interested in longer-term studies.”