SILVER SPRING, MD. – Manufacturers of prescription and over-the-counter nonsteroidal anti-inflammatory medications said at a joint meeting of two Food and Drug Administration advisory committees that there is not enough evidence to increase warnings about potential risk for cardiovascular events.
Not surprisingly, Pfizer, Novartis, and Johnson & Johnson’s McNeil Consumer Healthcare division all argued that there are also not enough data to suggest that Bayer’s naproxen has any less risk of CV events than other NSAIDs – as has been suggested by many studies.
The FDA’s Arthritis Advisory Committee (AAC) and the Drug Safety and Risk Management Advisory Committee are due to vote on Feb. 11 on whether there should be more warnings for prescription and over-the-counter (OTC) versions of NSAIDs on the potential for cardiovascular events, especially in patients at higher risk for heart attack, heart failure, or stroke. They also are being asked to consider if the risk changes with duration of treatment and whether naproxen might be safer than other NSAIDs. Finally, the panels are being asked to assess whether an ongoing study of NSAID safety – Pfizer’s PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen) – should continue.
The new review of NSAID safety was prompted in large part by a meta-analysis from the Coxib and traditional NSAID Trialists’ (CNT) Collaboration at Oxford University. The meta-analysis assessed both the gastrointestinal and cardiovascular risks of nonselective NSAIDs. It concluded that naproxen had a lower risk of CV thromboembolic events than celecoxib and ibuprofen (Lancet 2013;382:769-79).
The stakes are high. According to the FDA and manufacturers who spoke at the advisory committee meeting on Feb. 10, there are some 100 million prescriptions written for NSAIDs each year, and 29 million Americans are regular users of NSAIDs.
The Oxford meta-analysis honed in on 639 trials that involved a selective NSAID (collectively known as coxibs) and nonselective NSAIDs, including naproxen, diclofenac, and ibuprofen, Dr. Colin Baigent, professor of epidemiology at the University of Oxford (England), told the panelists. For coxibs, there was a 37% increase in cardiovascular events, mostly from myocardial infarction or coronary heart disease. There also was a 37% increase in major vascular events but no evidence of increased stroke risk. Naproxen had a better safety profile, but "we can’t say there is no risk," Dr. Baigent said. There was a doubling of risk for heart failure with all NSAIDs.
Analyses of various registries in Denmark reached similar conclusions, said Dr. Gunnar H. Gislason, professor of cardiology at the University of Copenhagen’s Hospital Gentofte. There was an increased risk of cardiovascular events and death, and the risk increased with higher doses with most NSAIDs, he noted.
The risk began with starting doses and persisted, but naproxen had a much lower risk. Even so, Dr. Gislason said he believed that "use of NSAIDs should be limited, especially among high-risk individuals and patients with established cardiovascular disease." He also recommended avoiding diclofenac and cyclooxygenase-2 (COX-2) inhibitors, which had the highest risk in the Danish studies.
Pfizer, which has seven NSAIDs approved in the United States, said that the Oxford analysis did not provide sufficient evidence for strengthening or changing current class-wide warnings about cardiovascular events. The trial relied on indirect comparisons and studies of products like diclofenac that are not widely used in the United States, said Dr. Milton L. Pressler, Pfizer’s vice president for clinical sciences.
Novartis, which makes diclofenac, also said that the evidence was not sufficient to make any major changes. The company, however, did propose in October to strengthen warnings for diclofenac that would caution against using more than 150 mg daily or using it for longer than 4 weeks in patients at high risk for CV events.
Naproxen may be safer in part because it acts more like aspirin, inhibiting platelet aggregation, and thus is less likely to trigger thrombotic events, said Irene Laurora, Pharm.D., vice president of medical affairs at Bayer Healthcare, which makes Aleve, the OTC formulation of naproxen. The product should be labeled as having less potential for causing CV events, said Leonard Baum, vice president of regulatory affairs for Bayer.
Labeling for OTC products is sufficient to warn consumers about the dangers of high doses or longer use, said Dr. Ed Kuffner, McNeil’s vice president of medical affairs and clinical research. McNeil makes the OTC ibuprofen product Motrin. He also noted that current labels also urge higher-risk patients, such as those with hypertension or underlying heart disease, to consult a physician before using ibuprofen.
Many of the panelists were interested in learning more about the PRECISION trial. Principal investigator Steven E. Nissen said that the study is 95% enrolled, with 22,621 patients randomized at 486 sites. Dr. Nissen, chair of cardiovascular medicine at the Cleveland Clinic, said PRECISION offers a real-world trial that, when completed in late 2015, will answer many outstanding questions. The study is still blinded, but Dr. Nissen said that several analyses are completed, including an ambulatory blood pressure substudy, a comparative renal safety analysis, a comparative gastrointestinal safety analysis, and comparative effects on symptoms and quality of life.