Background and Aim: Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most common pain relief medications, but the risk of hemorrhagic stroke in patients taking these medications is unclear. In this study, our aim was to systematically review, synthesize, and critique the epidemiological studies that evaluate the association between NSAIDs and hemorrhagic stroke risk. We therefore assessed the current state of knowledge, filling the gaps in our existing concern, and make a recommendation for future research. Methods: We searched for articles in PubMed, EMBASE, Scopus, and Web of Science between January 1, 1990, and July 30, 2017, which reported on the association between the use of NSAIDs and hemorrhagic stroke. The search was limited to studies published in English. The quality of the included studies was assessed in accordance with the Cochrane guidelines and the Newcastle-Ottawa criteria. Summary risk ratios (RRs) with 95% CI were pooled using a random-effects model. Subgroup and sensitivity analyses were also conducted. Results: We selected 15 out of the 785 unique abstracts for full-text review using our selection criteria, and 13 out of these 15 studies met all of our inclusion criteria. The overall pooled RR of hemorrhagic stroke was 1.332 (95% CI 1.105-1.605, p = 0.003) for the random effect model. In the subgroup analysis, a significant risk was observed among meloxicam, diclofenac, and indomethacin users (RR 1.48; 95% CI 1.149-1.912, RR 1.392; 95% CI 1.107-1.751, and RR 1.363; 95% CI 1.088-1.706). In addition, a greater risk was found in studies from Asia (RR 1.490, 95% CI 1.226-1.811) followed by Europe (RR 1.393, 95% CI 1.104-1.757) and Australia (RR 1.361, 95% CI 0.755-2.452). Conclusion: Our results indicated that the use of NSAIDs is significantly associated with a higher risk of developing hemorrhagic stroke. These results should be interpreted with caution because they may be confounded owing to the observational design of the individual studies. Nevertheless, we recommend that NSAIDs should be used judiciously, and their efficacy and safety should be monitored proactively.
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