CV effects of NSAIDs

CV effects of NSAIDs

Nonselective NSAIDs inhibit COX-1 and COX-2 enzymes to varying degrees. However, even among those offering significant levels of COX-1 inhibition, none have consistently shown the same level of cardioprotection afforded by ASA. This may stem from concurrent inhibition of the COX-2 enzyme, unsustained COX-1 inhibition due to the reversible nature of NSAID binding, or inability of NSAIDs to form protective mediators (lipoxins, resolvins) as occurs with ASA. In addition, NSAIDs have been associated with sodium and fluid retention in susceptible patients (see Question 19), loss of hypotensive effects of several blood pressure medications (see Question 33), and interference with the effects of ASA (see Question 26), all of which could serve to increase the risk of MI, stroke, and thromboembolism.

Evidence of potential CV risk with NSAIDs was first identified shortly after the development of COX-2-specific inhibitors. Secondary analysis of a large multicenter trial (VIGOR trial) identified a significant increase in nonfatal MI in patients on rofecoxib compared with naproxen. A second trial examining the role of rofecoxib in the prevention of adenomatous polyps in the colon (APPROVe) demonstrated an increased risk of CV events in patients taking rofecoxib compared with placebo. These studies eventually led to the withdrawal of the drug from the market. Valdecoxib and parecoxib have been studied in high-risk populations as well (patients undergoing coronary artery bypass grafting); the combined incidence of MI and stroke in patients taking these medications was significantly increased, despite small study sizes and short trial duration, leading to drug withdrawal from the market.

CV risk with COX-2 inhibitors and nonselective NSAIDs has now been evaluated through RCTs and observational studies. These have demonstrated an increased CV risk among several nonselective NSAIDs, suggesting that this risk is not specific to COX-2-selective inhibitors.

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