SILVER SPRING, Md. — The FDA advisory committee voted last Wednesday, with 15 in favor, 5 against, and 1 abstention, to conclude that the PRECISION study confirmed celecoxib (Celebrex) has cardiovascular safety similar to that of naproxen and ibuprofen.
Pfizer Inc., the manufacturer of celecoxib, has accordingly applied to update its product labeling to include the results of the PRECISION study. Although not required by regulations, the FDA typically adheres to the recommendations put forth by its advisory committees.
At the joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee, Dr. Christopher Schmid of the Brown University School of Public Health in Providence, Rhode Island, stated, “I voted ‘yes,’ but I believe it is important to note that this conclusion is limited to the population included in this clinical trial and the corresponding drug dosages administered.” He further remarked, “Although I have some concerns about the design of this study, I find the results sufficiently compelling to demonstrate the similarity of these drugs.”
Neil Farber, M.D., of the University of California, San Diego, disagreed with the recommendation and cast a “no” vote. Dr. Farber stated, “My primary concern is the term ‘safety.’ I do not believe [the study] demonstrated safety; it may have demonstrated non-inferiority, but it did not establish safety.”
In the PRECISION study, 24,000 patients with osteoarthritis or rheumatoid arthritis who had a history of cardiovascular disease or cardiovascular risk factors were randomly assigned to receive celecoxib, ibuprofen, or naproxen. Patients with osteoarthritis accounted for 90% of the total study population, and those treated with celecoxib received a dosage of 100 mg twice daily. The study found that celecoxib was non-inferior to naproxen and ibuprofen with respect to death, nonfatal myocardial infarction, or nonfatal stroke.
Cyclooxygenase-2 (COX-2) inhibitors, as selective nonsteroidal anti-inflammatory drugs (NSAIDs), were questioned in the early 21st century for potentially increasing the risk of cardiovascular thromboembolic events, leading to the withdrawal of rofecoxib (Vioxx) and valdecoxib from the market in 2004.
In 2005, the FDA convened its first joint hearing on the cardiovascular safety of NSAIDs. At this meeting, the FDA Advisory Committee voted 31:1 in favor of continuing the use of celecoxib, while the FDA required that all NSAID products marketed in the United States include cardiovascular safety warnings in their labeling. Recognizing the severe lack of data on the cardiovascular safety of NSAIDs, the FDA mandated Pfizer to fund a global, multicenter, long-term, double-blind, controlled study on the cardiovascular safety of NSAIDs, conducted by independent researchers and monitored by an oversight committee (the PRECISION trial). The PRECISION trial spanned 10 years. In 2014, during the eighth year of the study, the FDA held its second joint hearing, summarizing all data published since 2005. The committee voted 16:9 to conclude that naproxen did not demonstrate superior cardiovascular safety compared with celecoxib and ibuprofen.
This FDA hearing marks the third joint hearing on the cardiovascular safety of NSAIDs, primarily discussing the results of the PRECISION study to clarify the cardiovascular safety profile of celecoxib and determining whether labeling information for naproxen, ibuprofen, and aspirin needs to be updated. All participants in the PRECISION study were patients with cardiovascular disease or at high risk, with approximately 45% taking cardioprotective doses of aspirin. Both ibuprofen and naproxen are reversible inhibitors of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2); therefore, they can affect the antiplatelet activity of aspirin, a finding corroborated by levels of the biomarker serum thromboxane.
The majority of the committee members (12) voted to recommend adding a warning to the naproxen packaging regarding its drug interaction with aspirin; 2 members voted to recommend adding a contraindication for individuals taking aspirin; and 7 members voted in favor of making no changes to the labeling. Taking into account the警示 effect of the existing warnings, the committee recommended, by a vote of 17 in favor and 4 against, that no changes be made to the ibuprofen labeling.
Accordingly, after ten years of research, it has been confirmed that celecoxib is non-inferior to naproxen and ibuprofen in terms of cardiovascular safety, and the FDA review committee has granted celecoxib a favorable cardiovascular safety rating. Regarding the safety of NSAIDs, particularly their cardiovascular safety when used in combination with aspirin, related research has not ceased, and medical exploration continues.