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SILVER SPRING, Md. -- An FDA advisory committee voted 15-5 Wednesday, with one abstention, that the PRECISION trial demonstrated that celecoxib (Celebrex) has comparable cardiovascular safety to naproxen and ibuprofen.
Celebrex maker Pfizer has requested an update to the product label to include the PRECISION data. The FDA isn't required to follow the advice of its advisory committees, but it often does.
"I voted 'yes' with the caveat that this recommendation is limited by the doses and indications in the trial," Christopher Schmid, PhD, of the Brown University School of Public Health in Providence Rhode Island, said at a .
"I [have] concerns about the design of the study but I felt the results were strong enough that the comparability of these drugs was probably shown," he said.
Neil Farber, MD, of the University of California San Diego, disagreed and voted 'no.' "My major concern is the word 'safety" and the fact that I don't think [the trial] proved safety; it perhaps demonstrated non-inferiority but not safety necessarily," he said.
Suzanne Robotti, the panel's consumer representative and the executive director of DES Action USA, a group advocating for people injured by diethylstilbestrol, was the lone abstainer. "I objected to the phrasing of the question," she said. "I found the results of [the study] to be reassuring but they didn't demonstrate safety; they [just] showed no increase in harm. A range of doses was not tested with Celebrex, and I'm not confident the medical community will restrain itself when prescribing in real life."
PRECISION randomized 24,000 osteoarthritis (OA) or rheumatoid arthritis patients with a history of, or risk factors for, cardiovascular (CV) disease to treatment of their arthritis pain with celecoxib, ibuprofen, or naproxen. OA patients comprised 90% of the study population; those in the celecoxib arm were assigned to a maximum dose of 100 mg celecoxib bid. The study found noninferiority of celecoxib for the endpoint of death, non-fatal myocardial infarction, or non-fatal stroke compared with both naproxen and ibuprofen.
The issue harkens back to data that began to emerge in the early 2000s on cardiovascular thromboembolic risk with the COX-2 selective NSAIDs and led to withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the market in 2004.
Celecoxib stayed the course, though the FDA warned that this drug increased risk of serious adverse CV events compared with placebo, and required that non-selective NSAIDs carry a black box warning of potential increased risk of serious adverse CV events, too. PRECISION started up in the wake of that debacle and realization that there was little cardiovascular safety data on the NSAIDs.
Several panelists expressed concern about the high rate of participants who either dropped out of the study or switched medications during it. "Non-inferiority trials are susceptible to certain biases, one being non-adherence [as well as] switching back and forth between treatment arms and use of other medications," said Eric Tchetgen Tchetgen, PhD, of the University of Pennsylvania (UPenn) in Philadelphia. "All of these issues were present in the PRECISION trial; I don't think they were addressed to the full extent I'd like to see it."
The other key question at the 2-day meeting was how the trial should influence labeling and contraindications for naproxen, ibuprofen, and aspirin. PRECISION's population was enriched for CV disease, and about 45% were taking cardioprotective doses of aspirin.
Ibuprofen and naproxen are both reversible inhibitors of cyclooxygenase 1 (COX-1), along with cyclooxygenase 2 (COX-2), so they can interfere with aspirin's antiplatelet activity, as seen by the biomarker serum thromboxane.
A majority of the committee -- 12 members -- voted to recommend including a warning on naproxen packages about the interaction between naproxen and aspirin; two other members voted to include a contraindication for aspirin use; while seven voted in favor of no change in labeling.
"I don't think studies address the issue of age, gender, [and] race," said Robert Dubbs of West Palm Beach, Florida, the panel's patient representative, who voted in favor of the warning. "I think the patient should have a discussion [with their doctor] about taking the medication, so a warning would be appropriate."
But Steven Solga, MD, also from UPenn, disagreed. "I think the warnings on the package label are [already] clear, simple, short, and well-established," he said. "I'm not sure adding a warning that's not clearly well-established serves the public at large."
Members also voted 17-4 not to recommend any changes to the labeling for ibuprofen, rather than adding a contraindication for use with aspirin. "The current warning is about as clear as you can get, and allows for additional information to come in that will change the doctor's or pharmacist's suggestions," said Steven Meisel, PharmD, director of medication safety at Fairview Health Services in Minneapolis.
Farber disagreed. "Yes, there's a warning, but I'm concerned about how much information the physician would have to give to the patient, and whether the physician would have enough time to discuss it," he said.
From the American Heart Association: