Non-Steroidal Anti-Inflammatory Drug-Induced Cardiovascular Adverse Events: A Meta-Analysis

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What is known and objective: Although non-steroidal anti-inflammatory drugs (NSAIDs) have been studied in randomized, controlled trials and meta-analyses in an effort to determine their cardiovascular (CV) risks, no consensus has been reached. These studies continue to raise questions, including whether cyclooxygenase-2 (COX-2) selectivity plays a role in conferring CV risk. We performed a meta-analysis of current literature to determine whether COX-2 selectivity leads to an increased CV risk. Methods: We utilized randomized, controlled trials and prospective cohort studies. We selected eight NSAIDs based on popularity and COX selectivity and conducted a search of the MEDLINE, EMBASE, and Cochrane databases. Primary endpoints included any myocardial infarction (MI), any stroke, CV death, and a combination of all three (composite CV outcomes). Twenty-six studies were found that met inclusion and exclusion criteria. Comparisons were made between all included drugs, against placebo, and against non-selective NSAIDs (nsNSAIDs). Drugs were also compared against COX-2 selective inhibitors (COXIBs) with and without inclusion of rofecoxib. Results and discussion: Incidence of MI was increased by rofecoxib in all comparison categories [all NSAIDs (OR: 1·811, 95% CI: 1·379–2·378), placebo (OR: 1·655: 95% CI: 1·029–2·661), nsNSAIDs (OR: 2·155, 95% CI: 1·146–4·053), and COXIBs (OR: 1·800, 95% CI: 1·217–2·662)], but was decreased by celecoxib and naproxen in the COXIB comparison [(OR: 0·583, 95% CI: 0·396–0·857) and (OR: 0·609, 95% CI: 0·375–0·989, respectively]. Incidence of stroke was increased by rofecoxib in comparisons with all NSAIDs and other COXIBs [(OR: 1·488, 95% CI: 1·027–2·155) and (OR: 1·933, 95% CI: 1·052–3·549), respectively]. Incidence of stroke was decreased by celecoxib when compared with all NSAIDs, nsNSAIDs, and COXIBs [(OR: 0·603, 95% CI: 0·410–0·887), (OR: 0·517, 95% CI: 0·287–0·929), and (OR: 0·509, 95% CI: 0·280–0·925), respectively]. No NSAID reached statistical significance in regard to CV death. Incidence of the composite endpoint was increased by rofecoxib when compared against all NSAIDs, placebo, and other COXIBs [(OR: 1·612, 95% CI: 1·313–1·981), (OR: 1·572, 95% CI: 1·123–2·201) and (OR: 1·838, 95% CI: 1·323–2·554), respectively]. Incidence of composite endpoint was decreased by celecoxib in the all NSAIDs and COXIBs comparisons [(OR: 0·805, 95% CI: 0·658–0·986) and (OR: 0·557, 95% CI: 0.404–0.767), respectively]. When rofecoxib was removed from the COXIBs group, no difference was found with any comparison, suggesting rofecoxib skewed the data. What is new and conclusion: This instead of the meta-analysis suggests that COX-2 selectivity may not play a role in the CV risk of NSAIDs. Rofecoxib was the only drug to demonstrate harm and skewed the data of the COX-2 selective group.