Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most highly prescribed medications in the world, a fact that probably reflects aging populations in developed countries and the increasing prevalence of musculoskeletal diseases. Conventional NSAIDs target both cyclo-oxygenase (COX) -1 and COX-2 and blockade of COX-1 can increase the risk for gastrointestinal adverse events, including bleeding. Increased understanding of the functions of COX-1 and -2 resulted in the development and marketing of selective COX-2 inhibitors (coxibs) at the end of the 1990‘s and early 2000‘s. Not long after the approval of these drugs, results from large-scale clinical trials suggested that rofecoxib and possibly also celecoxib may be associated with increased risk for myocardial infarction vs conventional NSAIDs, particularly naproxen. This result, and other similar findings prompted a meeting of the United States Food and Drug Administration (FDA) in 2005 and a determination that all NSAIDs were associated with increased risk for cardiovascular events, and withdrawal of rofecoxib from the market. The uncertainty about the cardiovascular safety of NSAIDs and coxibs also prompted the initiation of the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen (PRECISION) trial that aimed to directly compare the risks associated with these medications in a cohort of >20,000 patients.
NSAID safety regained the spotlight in 2014 with the publication of a very large-scale meta-analysis indicating that naproxen had a lower risk for cardiovascular adverse events than other conventional NSAIDs or coxibs. The FDA met again and decided that these results did not warrant a change in labelling for naproxen vs other NSAIDs/coxibs.
The results of PRECISION were published at the end of 2016 and, somewhat surprisingly in view of prior results, it indicated no significant differences in the cardiovascular safety of celecoxib, ibuprofen, and naproxen. While results from this study might seem to have resolved the issue of whether there are differences in the cardiovascular risks associated with two commonly used NSAIDs and a coxib, they have been widely criticized for several important reasons. It has been noted that the cardiac event rate in PRECISION was about 1% per year and that it was not a study of patients at high cardiovascular risk. In addition, of about 8000 patients randomized to each treatment, approximately 5,000 had discontinued assigned therapy by the end of the trial. Many patients were also completely lost to follow-up. While PRECISION was an ambitious trial aimed at answering a very important question and required more than a decade of effort, it has not completely closed the gap between what we know and what we need to learn to advise patients about the most widely used class of pain medications.