Cardiovascular Risk of Nonsteroidal Anti‐inflammatory Drugs and Classical and Selective Cyclooxygenase‐2 Inhibitors: A Meta‐analysis of Observational Studies

The purpose of this study was to review the published evidence on the clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) and to assess the cardiovascular risk (CVR) of cyclooxygenase-2 inhibitors (coxibs), excluding aspirin, by means of a meta-analytic procedure. A search was conducted on MEDLINE and EMBASE databases between October 1999 and June 2018. Cohort and case-control studies showing CVR as relative risk (RR), odds ratio, hazard ratio, or incidence rate ratio associated with NSAIDs versus no treatment were selected. We estimated the pooled RR and the 95% confidence interval (CI) for all NSAIDs as a whole and individually. Eighty-seven studies met the inclusion criteria. Overall, NSAIDs were found to be associated with a statistically significantly increased CVR (RR, 1.24 [95%CI, 1.19-1.28]). The risk was slightly higher for coxibs (RR, 1.22 [95%CI, 1.17-1.28]) as compared with nonselective NSAIDs (RR, 1.18 [95%CI, 1.12-1.24]). Data analysis by drug disclosed that rofecoxib (RR, 1.39 [95%CI, 1.31-1.47]), followed by diclofenac (RR, 1.34 [95%CI, 1.26-1.42]) and etoricoxib (RR, 1.27 [95%CI, 1.12-1.43]) were the NSAIDs associated with the highest CVR. Analysis by type of event showed that the highest risk corresponded to vascular events for both coxibs (RR, 2.18 [95%CI, 1.72-2.78]) and nonselective NSAIDs (RR, 2.46 [95%CI, 2.00-3.02]). The meta-analysis results suggest that the use of the marketed coxibs celecoxib and etoricoxib would be related to a statistically significant CVR increase. Etoricoxib CVR could be higher than that for celecoxib. This increment would be similar to classical NSAID CVR.