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Published: Feb 11, 2014
By John Gever, Deputy Managing Editor, MedPage Toda
In 16-9 vote, the FDA advisory committee assessing NSAID safety said the warning label on naproxen should not be changed to suggest it has a better cardiovascular risk profile than other drugs in this class.
Those voting “No” on the question indicated that the current evidence on naproxen’s safety — much of which was indirect, coming from studies in which it served as a comparator to a coxib drug — did not meet the standards necessary to support label statements.
The panel — comprising members of FDA’s arthritis and risk management committees — split more closely on a question about label information on the duration of NSAID treatment that raises cardiovascular safety risks.
Currently, labels for these drugs say that short-term treatment is relatively safe; however, some recent studies have sown doubt. A total of 14 panel members said the current statement should be reconsidered, while 11 voted No. However, most of those in the latter camp indicated in postvote discussion that they believed there is no completely safe dosing period.
The meeting represents the latest chapter in the story of the cardiovascular risks of NSAIDs that began when data started to emerge in the early 2000s raising questions about the COX-2 inhibitors, including rofecoxib (Vioxx) and celecoxib. In 2001, a study in the Journal of the American Medical Association linked those two drugs to elevated risks of thrombotic events compared with other NSAIDs.
FDA officials said they called the meeting to help them decide whether it should revisit decisions on labeling made nearly 10 years ago, in light of analyses published following the Vioxx brouhaha.
In 2005, the agency put a boxed warning on all NSAIDs discussing cardiovascular and gastrointestinal risks after concluding that differences between the drugs could not be discerned. But since then evidence has been accumulating that the risks are not consistent across the class. A key analysis published last year in The Lancet, for example, showed that all NSAIDs carry some degree of cardiovascular risk, but that naproxen appears to be the safest.
In 2006, Pfizer started the PRECISION trial to evaluate the relative safety of celecoxib versus naproxen or ibuprofen in patients with osteoarthritis or rheumatoid arthritis who had or were at high risk for cardiovascular disease. That trial is still ongoing. However, in light of the other studies suggesting greater safety with naproxen, the FDA is considering whether to stop it or at least require that participants undergo a new consent process.
Multiple studies — including a meta-analysis in BMJ, another meta-analysis in PLOS Medicine, and the more recent meta-analysis in The Lancet — have found that naproxen carries a lower cardiovascular risk compared with other drugs in the class.
After evaluating the evidence, an FDA analysis released prior to the meeting concluded: “To reduce the population burden of drug-related deaths from NSAID toxicity, naproxen should be considered first-line treatment in patients for whom the risk of cardiovascular adverse events is relevant. Accordingly, the class NSAID labeling should be amended to reflect the more favorable cardiovascular risk profile of naproxen. The labeling can also note that naproxen had a less favorable gastrointestinal risk, but that GI events were less likely to be fatal than cardiovascular events.”
At least one FDA staff member has called for the PRECISION trial to be halted because of the evidence of naproxen’s superior safety.
“Randomization of subjects is no longer reasonable because of the recently delineated difference in cardiovascular risk among the treatments, and significant difficulties with interpretation of the results will compromise the trial’s ability to meet its scientific objective,” the staffer wrote. “If a clinical hold is not imposed, subjects should be re-consented so that they can be informed of the findings of the [Lancet] meta-analysis regarding the PRECISION study drugs, and can have the option of withdrawing.”
The literature also questions another of the FDA’s conclusions from 2005, that short-term use of NSAIDs avoids the cardiovascular risks. A 2011 study, for example, showed that patients with a history of myocardial infarction had an increased risk of death or a recurrent event even during the first week of NSAID exposure.
“It could be clarified that the advice to use an NSAID for the shortest duration possible is not based on the absence of a cardiovascular risk during a short latency period, but is simply a prudent way to limit patient exposure,” according to the FDA review documents.