TUESDAY, Feb. 15, 2005 (HealthDay News) -- Much-anticipated data from three new studies on cox-2 inhibitors cast doubt on the future of these already beleaguered medications, which are the focus of government hearings beginning Wednesday.
The studies, which were released Tuesday and will appear in the March 17 issue of the New England Journal of Medicine, found that three cox-2 drugs -- Vioxx, Celebrex and Bextra -- increase the risk of cardiovascular problems, including heart attacks and strokes.
Signs of cardiovascular trouble were evident to the pharmaceutical companies from the beginning, according to Jeffrey Drazen, editor-in-chief of the journal.
"It was very clear that there were more heart attacks," he said. "If you're on the way to work and smell smoke in the kitchen, you look for the fire. These guys left for work, instead of taking that signal very seriously."
According to some, the new data sounds a death knell for the entire class of medications. Originally hailed as a breakthrough when they first appeared on the market in the late 1990s, cox-2 inhibitors have now forced a reappraisal of the entire drug approval and marketing system in this country.
"The cost isn't worth the benefit," said Drazen, who also penned one of two editorials accompanying the studies. "Most people, given their choice between a heart attack or a stroke and a bleeding ulcer, would prefer the bleeding ulcer."
Initially, cox-2 inhibitors were considered an advance because they do not cause the gastrointestinal complications of traditional nonsteroidal anti-inflammatory drugs (NSAIDs). However, gastrointestinal risks associated with traditional NSAIDs can be minimized by taking proton pump inhibitor-type medications, Drazen noted.
The release of the studies comes just one day before the U.S. Food and Drug Administration (FDA) begins three days of public hearings on cox-2 inhibitors. The results will be a focal point of panel deliberations.
The release of the findings also coincides with an announcement Tuesday by the FDA that it will create a Drug Safety Oversight Board, which will monitor approved drugs for unexpected side effects or problems. The board will also set up a drug safety Web page with emerging information for approved drugs that will include side effects, safety risks and steps that can be taken to minimize problems. Another journal editorialist, Dr. Bruce Psaty of the University of Washington in Seattle, called for the creation of just such an entity in his article.
In reality, most of the data from the three studies is not new.
"All three of these we've seen," Drazen said. "It's like going to the movies and seeing the previews. This is the first chance to see the data reviewed in the cold, hard light of day as opposed to what drug companies wanted us to see."
Disturbing results from the first trial prompted Merck to pull Vioxx from the market in September. In this study, which was funded by Merck and originally designed to assess the effect of the drug on recurrent colorectal polyps, patients taking 25 milligrams of Vioxx a day had about double the rate of cardiovascular events as people taking a placebo, although the absolute number was relatively low (46 vs. 26 in a total group of more than 2,500). Oddly, the risk was not seen until about 18 months out, something which has not been found in other, similar trials.
The second study, also designed to look at colorectal cancer prevention originally, found that people taking Celebrex for an average of almost three years had an increased rate of heart attacks, strokes, heart failure and death. That study was partly funded by its maker, Pfizer Inc., which continues to market the drug.
"These were the results that prompted the announcement on Dec. 17 that the study was being stopped," said lead researcher Dr. Scott D. Solomon, director of noninvasive cardiology at Brigham and Women's Hospital, in Boston. "This report is a more detailed description of the data, although there were no major surprises." Solomon and his team were brought in late last year to perform a cardiovascular analysis.
The rate of adverse events was 1 percent among people taking a placebo, 2.3 percent among those taking 200 milligrams of Celebrex twice a day, and 3.4 percent among those taking 400 milligrams of the drug twice a day.
The third study looked at another cox-2 inhibitor, Bextra, and its intravenous counterpart, in individuals undergoing coronary-artery bypass surgery. Again, this study was funded in part by Pfizer, which makes the medication and continues to sell it. Participants taking one or both of the drugs had a 7.4 percent incidence of adverse events vs. 4 percent in the placebo group. The risk difference was greater when assessed in patients taking both drugs consecutively: 2 percent vs. 0.5 percent in the placebo group.
While all this seems to serve as a clear indictment of this particular class of medications, the stakes have grown considerably since the trouble first cropped up.
A drug registry, such as the one that is about to be implemented by the FDA, may have helped avoid such an outcome. "We had no way of knowing that nothing was happening [there were no trials looking at cardiovascular risks] because trials didn't need to be registered," Drazen explained.
But Solomon said the issue was one of weighing risks and benefits, and the full picture on both sides of the equation has yet to emerge.
"We need to be cautious about the use of these agents but, remember, with every drug there are risks and benefits and that's something that people sometimes forget," Solomon said. "All medications have risks and we need to appropriately weight these newfound risks with any potential benefits of these drugs, including the possibility that they might inhibit tumor growth."
The data on cancer prevention, he said, will be available in three to six months.
As to what the FDA will do with all this information, Solomon would not speculate.
"Where they're going to go with this I certainly can't say," he said. "They could go so far as to pull the drugs off the market, or simply decide to add labeling restrictions."
More information
Read more about the advisory panel hearings at the U.S. Food and Drug Administration.
