FDA Advisory Panel Votes Against CV Safety Claim for Naproxen

February 11, 2014

SILVER SPRING, MD — In a two-day meeting of the Food and Drug Administration (FDA) Arthritis Advisory Committee (AAC) and Drug Safety and Risk Management (DSARM) Advisory Committee, just nine panel members said they believed naproxen has a lower risk of cardiovascular thrombotic events than other available nonsteroidal anti-inflammatory drugs (NSAIDs).

In contrast, 16 of the advisory panel members felt the data were insufficient to say naproxen was safer than other NSAIDs.

The panel grappled with the available evidence, mainly because the data presented over the two days were indirect or observational. While some members, including Dr Brendan Everett (Brigham and Women's Hospital, Boston, MA) and Dr Peter Kaboli (University of Iowa, Iowa City), said the data were strong enough for them to change their clinical practice, which would see them now select naproxen over other available NSAIDs, others, like Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA), argued the evidence was inconclusive to say naproxen posed less cardiovascular risks.

For Kaul, observational studies are important for raising clinical questions, not settling them.

Nearly 10 years ago, rofecoxib (Vioxx, Merck) was pulled from the global market because of a heightened cardiovascular-risk profile. This led to a 2005 meeting of the AAC and DSARM, where the FDA concluded that the three approved COX-2–selective NSAIDs, celecoxib (Celebrex, Pfizer), rofecoxib, and valdecoxib, were associated with an increased risk of serious adverse cardiovascular events compared with placebo. Valdecoxib was eventually withdrawn from the US market and a boxed warning added to all NSAIDs warning of the cardiovascular risk and risk of serious gastrointestinal bleeding.

Celecoxib is still approved for the treatment of osteoarthritis and rheumatoid arthritis. The Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen (PRECISION) trial is currently evaluating the relative safety of celecoxib, ibuprofen, and naproxen. During the two-day meeting, the panel discussed whether PRECISION should continue, as some felt the trial was biased toward a null effect and that the results would not be useful. However, the majority of panelists felt that despite the difficulties with PRECISION, which has been delayed because of slow enrollment, the study should continue, as it could help inform clinical practice.

The 16–9 vote against changing the label to highlight a lower cardiovascular risk profile with naproxen than with other drugs in the class runs somewhat counter to an FDA review. As reported by heartwire , the FDA review suggested the evidence might be sufficient to say naproxen did not pose the same cardiovascular risks as other NSAIDs. The FDA review pointed to a 2013 meta-analysis published in the Lancet that showed the risk for cardiovascular events was present for both nonselective and COX-2–selective NSAIDs, but the risk might be lower for those treated with naproxen.

A slight majority of the AAC and DSARM panel members also felt the weight of clinical evidence supported a reconsideration of the current NSAID labeling. The label implies that cardiovascular thrombotic risk is not "substantial" with short treatment courses, but 14 panel members said this advice should be reconsidered and that there was no latency period with the NSAID class. Eleven panel members did not feel the label needed to be changed, although many of those who voted against the label change said they didn't feel there was any period in which the cardiovascular risks were nonexistent.

Finally, the panel also discussed whether or not changes should be made to the label of over-the-counter NSAIDs at currently available doses, to refine the message about cardiovascular risk, but this was a nonvoting question. No consensus was reached given the absence of data.


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