Two US Food and Drug Administration (FDA) panels today jointly voted by a large margin that the cardiovascular (CV) safety of celecoxib (Celebrex, Pfizer) is comparable to naproxen and ibuprofen.
The FDA's Arthritis Advisory Committee (AAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM) voted 15 yes, 5 no, and 1 abstention that the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen (PRECISION) trial demonstrated comparable CV safety for celecoxib with naproxen and ibuprofen.
"I have been convinced by the committee that the trial did add value; I believe there is comparable CV event rate at the 100 mg dose, so my answer was 'yes' in that context," said temporary voting panel member Christianne L. Roumie, MD, MPH, associate professor, internal medicine and pediatrics, Institute for Medicine and Public Health, Vanderbilt University, Nashville, Tennessee.
The panels' vote followed consideration of data from the PRECISION trial — a postmarketing trial requested by the FDA to evaluate the CV thrombotic risk of celecoxib after new data emerged about the risk for CV thromboembolic events connected with the cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs) rofecoxib and celecoxib well over 10 years ago.
The FDA also concluded that the risk for CV thromboembolic events was associated also with nonselective NSAIDs such as ibuprofen and naproxen, but the data were insufficient to allow ranking of the medications in terms of CV risk
PRECISION was a randomized, double-blind, active-controlled, parallel-group study begun in 2006 that included 24,081 individuals. All patients had osteoarthritis or rheumatoid arthritis and had or were at high risk for CV disease.
The study's primary Antiplatelet Trialists' Collaboration (APTC) endpoint was an independently assessed composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. The trial's primary hypothesis was celecoxib's noninferiority to naproxen for the APTC endpoint. Other hypotheses were whether the drug was noninferior to ibuprofen and whether ibuprofen was noninferior to naproxen for the APTC endpoint.
The trial compared CV risk among 8072 celecoxib users with that of 8040 ibuprofen users and 7069 naproxen users. Baseline aspirin use was reported by 3701 (46%) celecoxib users, 3712 (46%) ibuprofen users, and 3652 (46%) naproxen users.
"I agree [that the study] did show that Celebrex is not more dangerous than the other two nonsteroidals…there wasn't a placebo group to show how poor they would do," said voting AAC member Alyce M. Oliver, MD, PhD, professor of medicine, division of rheumatology, Medical College of Georgia at Augusta University.
During the conduct of the PRECISION trial, numerous epidemiological studies and meta-analyses of randomized controlled trials studied the relationship between NSAID use and CV thrombotic risk, including risk factors for CV events such as tobacco smoking.
Current smoking was reported by 1689 (21%) celecoxib users, 1684 (21%) ibuprofen users, and 1631 (21%) naproxen users. Of those who were randomly assigned, 2647 (45%) of celecoxib users, 3652 (45%) of ibuprofen users, and 3657 (46%) of naproxen users were never-smokers; 2729 (34%) of celecoxib users, 2699 (34%) of ibuprofen users, and 2674 (34%) of naproxen users were ex-smokers.
In February 2014, the two FDA committees voted against (9 no, 7 yes) the safety of naproxen in comparison with other NSAIDs.
In July 2015, the FDA required a Safety Labeling Change for the NSAID class to include data from the published epidemiological studies and meta-analyses and the February 2014 advisory committee meeting.
That labeling included warnings about an increased risk for heart attack or stroke that can occur during the first weeks of NSAID use and in people without heart disease or risk factors; that the risk appears higher at greater doses; that the risk may be higher with some NSAIDs than others; and that patients who use NSAIDs during the first year after a first heart attack were more likely to die during that year compared with those who do not take NSAIDs after their first heart attack.
The results of the PRECISION trial were published online November 29, 2016, and Medscape Medical News reported that aspirin appears to limit the safety profile of celecoxib.
The study found that when taken at moderate doses, the CV safety of celecoxib was noninferior to ibuprofen or naproxen.
"I Don't Think This One Trial Answers the Question"
"I voted [that the PRECISION trial did not demonstrate comparable CV safety for celecoxib as compared to naproxen and ibuprofen]. My major concern is the word 'safety'…it perhaps demonstrated noninferiority, but not safety necessarily," said temporary voting member, Neil J. Farber, MD, professor of clinical medicine and medical director, Internal Medicine Group La Jolla, University of California San Diego, La Jolla.
"I voted 'yes' with the caveats that the recommendations are limited to the doses and indications in this trial. I do share the concerns about the design of the study, but I felt that the results were strong enough that the comparability of these particular drugs was probably shown," said voting DSaRM member Christopher H. Schmid, PhD, professor of biostatistics and codirector, Center for Evidence Synthesis in Health, Brown University School of Public Health, Providence, Rhode Island.
" I do want to add that I do believe for the overall question of safety…there needs to be consideration of other studies, whether it's a meta-analyses or something. I don't think this one trial answers the question," Schmid added.
"In terms of the high dropout rate, and the improvement of the visual analog score of only about 10 out of 100, we do a really poor job of controlling our patients' pain — we see that as rheumatologists and as we continue to move away from opioids, it doesn't look like nonsteroidals are doing the trick either, so it is something to look at," Oliver concluded.
Medscape Medical News © 2018
Cite this: CV Safety of Celecoxib Similar to Naproxen, Ibuprofen, FDA Panels Say - Medscape - Apr 25, 2018.
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