A long-awaited study of analgesics called non-steroidal anti-inflammatory drugs, the most prescribed class of drugs in the world, has concluded that the three most commonly used drugs have a similar risk of cardiovascular complications. However, critics say the study was too flawed to compare.
Concerns about a type of NSAID called COX-2 inhibitors peaked in 2004 when the drug Vioxx was withdrawn from the market, a decision stalled because the manufacturer Merck & Co had initially concealed data that would reveal cardiovascular risks Of the drug. A second COX-2 inhibitor, Celebrex from Pfizer Inc., was allowed to remain on the market with the condition that Pfizer carry out a study to show that Celebrex was no worse than two old NSAIDs, naproxen and ibuprofen.
The study lasted 10 years and enrolled more than 24,000 patients, but faced challenges. Doctors from EU countries would not participate because they were concerned about the safety of Celebrex. In addition, scientists expected patients with high-risk arthritis of heart disease to volunteer. But the study was eventually dominated by the low-risk ones. And before it was over, about two-thirds of the participants quit because their assigned medication did not control their pain.
A final analysis was presented Nov. 13 during the annual American Scientific Sessions of the American Heart Association, and published online in the New England Journal of Medicine. After taking the drug at recommended doses for at least 18 months, 4.2 percent of Celebrex patients had a major cardiac event, such as a heart attack or stroke, compared with 4.3 percent Of those taking naproxen and 4.8 percent with ibuprofen. The percentage of people who died of cardiovascular disease was higher for those taking naproxen by 1.1 percent, although differences between the three drugs were not statistically significant, said Steven Nissen, president of cardiovascular medicine at the Cleveland Clinic Who led the study.
Renal problems, a known risk of taking NSAIDs, occurred in 0.7 percent of the Celebrex group, 0.9 percent of the naproxen group and 1.1 percent of those taking ibuprofen. Of the three NSAIDs, Celebrex had the lowest risk of gastrointestinal complications, not a surprise because avoidance of such complications was one of the key reasons the drug was developed.
Given the dangers of Vioxx, many doctors had dismissed Celebrex even before the Pfizer-funded study began, Nissen said. “Everyone thought I knew the answer.” And she was even surprised when Celebrex improved cardiovascular risk than the other two, and said the results should be reassuring for patients taking the drug, which is now available as a generic.
But the study has its skeptics. “Does it give us answers? No, and that’s the tragedy,” said Garret FitzGerald of the Institute of Translational and Therapeutic Medicine at the University of Pennsylvania. Critical to the design of the study since its inception, FitzGerald wrote a commentary on the trial, published online on November 13 in Circulation.
FitzGerald anticipated that, given concerns about cardiovascular side effects, physicians would hesitate to enroll their high-risk patients in the study, and that they would have to go longer to gather enough data. “This is a trial that most people abandoned before it ended,” he said. In addition, physicians were allowed to increase doses of naproxen and ibuprofen if patients needed it for pain control, but the amount of Celebrex remained fixed. “It was not a fair comparison,” he said.
The data also do not explain patients taking aspirin when the study began, said Elliott Antman, a cardiologist at Brigham and Women’s Hospital in Boston. Aspirin, which acts as an anticoagulant, may reduce the risk of heart attack. Due to the way the drugs work, naproxen and ibuprofen – but not Celebrex – can interfere with the benefits of aspirin. Having more patients at high risk of heart attack would have increased the study’s ability to detect risk, he adds. “This was a trial that was supposed to compare the results in high-risk cardiovascular patients, but they actually still have that question,” Antman said. And given the time and expense of this trial, it is unlikely to be another. New, less problematic pain medications, he said, are “an urgent clinical need.”