Is the CV risk associated with NSAIDs specific to certain drugs?
Observational and RCT data suggest that all NSAIDs are associated with some level of CV risk, especially in high-risk populations (e.g., prior CV event or calculated CV risk score >20%). Some studies have shown that naproxen has a neutral or even mildly protective effect on CV outcomes. This has been theorized to occur because of the strong inhibition of platelet COX-1 by naproxen (>95% reduction of COX-1-dependent TXA 2 , resulting in functional platelet suppression) as well as its long half-life (>12 hours). However, the data on naproxen in regards to CV risk is inconsistent. In addition, a recent RCT (PRECISION trial) demonstrated similar rates of CV endpoints among users of naproxen, ibuprofen, and celecoxib, suggesting equivalent CV risk among these NSAIDs. As such, ASA should be considered the only proven cardioprotective agent.
CV risk was first identified in studies of COX-2-selective inhibitors, and several aspects of COX-2 biology may explain some of the risk associated with its inhibition by both selective and nonselective NSAIDs. COX-2 activity in the endothelium serves as the main source of prostacyclin (PGI 2 ) production. In vitro studies have shown that COX-2 expression is turned on in response to shear stress, suggesting that expression occurs constitutively in response to laminar blood flow in the physiologic state. In the pathologic state (e.g., severe atherosclerosis, unstable MI), PGI 2 levels are further increased in an effort to inhibit vessel constriction and platelet aggregation. Inhibition of this enzyme by selective or nonselective NSAIDs, especially in high-risk patients, could lead to subsequent CV events. In addition, COX-2 specific inhibitors such as celecoxib have been shown to have effect on neither in vitro platelet function nor bleeding time, perhaps serving as a “second hit” for the development of CV disease. Given these findings, one may expect RRs for particular NSAIDs to separate according to their inhibition of the COX-2 enzyme, but data is inconsistent in this regard as well. Furthermore, the PRECISION trial included nearly 25,000 patients (with a mean follow-up period of approximately 3 years) and did not show a differing CV risk among regular users of naproxen, ibuprofen, and celecoxib. In 2015 the FDA updated its label warning for NSAIDs and advised against “ranking” NSAID medications according to CV risk; this decision was based on the absence of conclusive data supporting differential risk among available options.