NSAIDS

Patients tend to underestimate both the effectiveness and the toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs). For acute pain, single full doses of NSAIDs are more effective than acetaminophen, and some have shown an equal or greater analgesic effect compared to oral opioids combined with acetaminophen, or even injected opioids.  However, there is a price to pay. Dyspepsia and GI ulceration, perforation, and bleeding can occur with all NSAIDs, including parenteral formulations, often without warning. High doses, prolonged use, previous peptic ulcer disease, concomitant systemic corticosteroid or aspirin therapy (even 81 mg/day), excessive alcohol intake, and advanced age increase the risk of these complications. NSAIDs are also nephrotoxic, especially in the elderly. And they may be prothrombotic, which is where this story really begins.

The December 19, 2016 issue of The Medical Letter includes an article about the cardiovascular safety of the COX-2 selective NSAID celecoxib (Celebrex; and generics). COX-2 inhibition does not cause GI toxicity, but it can be prothrombotic, and rofecoxib (Vioxx), the first selective COX-2 inhibitor, was associated with an increased risk of myocardial infarction and cardiovascular death, and was removed from the market. Celecoxib is less COX-2 selective than rofecoxib, and the hope was that it would spare the GI tract without causing an unacceptable increase in cardiovascular events. Our article had to sort out 2 different views of whether this hope had been realized.

An article published on November 13, 2016 in The New England Journal of Medicine by Steven E. Nissen et al reported the results of a randomized trial (PRECISION) comparing the cardiovascular safety of 2 nonselective NSAIDs, ibuprofen and naproxen, with that of celecoxib, all used to treat patients with osteoarthritis or rheumatoid arthritis. Celecoxib was found to be noninferior to ibuprofen or naproxen.

An editorial by Garret A. FitzGerald, published online the same day in Circulation, was sharply critical of the PRECISION trial, even in its title: “ImPRECISION: Limitations to Interpretation of a Large Randomized Clinical Trial.” The editorial criticized the level of cardiovascular risk among the patients in the trial, the dosage of celecoxib, the lack of randomization to aspirin use, and other perceived imperfections in the design of the study.

So how did we deal with these conflicting points of view? We did what we always do. We sent a preliminary draft of our article to a panel of appropriate reviewers, to the first authors of all the articles cited in the text, to our contributing editors, and to the FDA, among others. We could not, in our format, include all the points raised by either Nissen et al or FitzGerald, so we focused on those that we thought would be most important to our readers, and emphasized in our conclusion what we considered to be the take-home lesson for prescribers. You can judge for yourself whether we succeeded: Celecoxib Safety Revisited.

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