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Cardiovascular Safety of NSAIDs for Arthritis

N Engl J Med; ePub 2016 Nov 13; Nissen, et al

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At moderate doses, celecoxib is noninferior to ibuprofen or naproxen with regard to cardiovascular safety, according to a recent study of patients who required nonsteroidal anti-inflammatory drugs (NSAIDs) for osteoarthritis and rheumatoid arthritis. A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. Researchers found:

• 68.8% of patients stopped taking the study drug, and 27.4% discontinued follow-up.

• A primary outcome event (cardiovascular death, nonfatal MI, or nonfatal stroke) occurred in 188 (2.3%) patients in the celecoxib group, 201 (2.5%) patients in the naproxen group, and 218 (2.7%) patients in the ibuprofen group, in the intention-to-treat analysis.

• In the on-treatment analysis, a primary outcome event occurred in 134 (1.7%) patients in the celecoxib group, 144 (1.8%) patients in the naproxen group, and 155 (1.9%) patients in the ibuprofen group.

• The risk of gastrointestional events was significantly lower with celecoxib compared to naproxen or ibuprofen.

• The risk of renal events was significantly lower with celecoxib than with ibuprofen.

Citation: Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. [Published online ahead of print November 13, 2016]. N Engl J Med. doi:10.1056/NEJMoa1611593.

Commentary: NSAIDs are the most widely prescribed class of medications worldwide.1 NSAIDs have an anti-inflammatory effect due to COX-2 inhibition and decrease the release of gastroprotective prostaglandins due to its COX-1 effect, which leads to gastric ulcers. COX-2 inhibitors were developed in order to have an anti-inflammatory effect, but to decrease the effect on gastrointestinal side effects. In 2004, rofecoxib was withdrawn from the market due to cardiovascular adverse effects.2 The FDA then mandated a large CV safety trial of the remaining COX-2 inhibitor, celecoxib. The trial showed that celecoxib does not present a greater CV safety risk than the traditional NSAIDs, naproxen and ibuprofen. The trial also confirmed, as expected, that celecoxib has fewer GI side effects. It is important to recognize that this trial compared celecoxib to NSAIDs and showed no difference in CV safety, but did not compare either to a placebo group. In July 2015, the FDA issued an update of its 2005 boxed warning on CV safety of NSAIDs stating, “The US Food and Drug Administration (FDA) is strengthening an existing label warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) increase the chance of a heart attack or stroke…. The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID.”2 —Neil Skolnik, MD

1. Food and Drug Administration. FDA public health advisory: safety of Vioxx. September 30, 2004. http://www.fda.gov/Drugs/Drug Safety/Postmarket Drug Safety Information for Patients and Providers/ucm106274.htm. Accessed November 28, 2016.

2. FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm. Accessed November 28, 2016.

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