Published: Feb 9, 2014 | Updated: Feb 9, 2014
By Todd Neale, Senior Staff Writer, MedPage Today
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Two FDA advisory committees will meet Monday and Tuesday to consider the significance of recent evidence surrounding the cardiovascular risks of nonsteroidal anti-inflammatory drugs (NSAIDs), including studies pointing to lower risks with naproxen.
The FDA put a boxed warning discussing cardiovascular and gastrointestinal risks on all NSAIDs in 2005 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 a 2-day joint meeting, the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee will try to sort out what that and other studies should mean in terms of labeling, and what they mean for the completion of an ongoing trial evaluating the relative risks of celecoxib (Celebrex), naproxen, and ibuprofen.
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.
In 2004, Merck pulled rofecoxib from the market because of evidence pointing to greater risks of myocardial infarction and stroke with long-term use. Similar concerns soon spread to the other COX-2 inhibitors, prompting a February 2005 joint meeting of two FDA advisory committees to discuss risks of thrombotic events with all NSAIDs.
Based on those discussions, the FDA concluded that all NSAIDs carried a risk of a thrombotic events, that there was not enough information to differentiate risks between NSAIDs, that short-term use appeared to avoid that risk, that all NSAIDs should carry a similar boxed warning, and that valdecoxib (Bextra) should be removed from the market. Celecoxib was not pulled.
The next year, 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.
Since then, numerous observational studies and meta-analyses have delved into the cardiovascular risks of individual NSAIDs, and briefing documents released by the FDA in advance of the upcoming meeting indicate that labeling might be changed to reflect differences in risk between various agents. The briefing documents also indicated that the PRECISION trial could be stopped based on the findings.
Multiple studies — including a meta-analysis in BMJ, a 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, FDA staff members 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.
The members of the two FDA advisory committees will discuss all of these issues and vote on whether the evidence supports a lower cardiovascular risk for naproxen compared with other NSAIDs, as well as whether advice regarding the lack of risk with short-term use should be modified.
From the American Heart Association: