Peggy Nguyen, MD

Ungprasert P, Matteson EL, and Thongprayoon C. Nonaspirin Nonsteroidal Anti-Inflammatory Drugs and Risk of Hemorrhagic Stroke: A Systematic Review and Meta-Analysis of Observational Studies. Stroke. 2016

The risk of cardiovascular events with NSAIDs has recently been publicized in the general media, with the FDA strengthening its warning on the association of NSAIDs with myocardial infarction and strokes in the past year. The relationship between NSAIDs and stroke risk, however, particularly hemorrhagic stroke, is ill-defined. The authors here performed a comprehensive meta-analysis reviewing the risk of hemorrhagic stroke in patients taking NSAIDs.

This meta-analysis identified 10 studies (7 case-control, 3 cohort studies) encompassing 1,489,120 patients. There was some heterogeneity across the studies, but most studies identified NSAID exposure as use of any NSAIDs until the index date or within 30 days prior to index date. Pertinently, there was a small, but not statistically significant, increased risk of hemorrhagic stroke (RR 1.09, 95% CI 0.98 – 1.22). Statistical analysis was also done for individual NSAIDs when data was available from a minimum of 3 studies, with a statistically significant increase for hemorrhagic stroke with diclofenac (RR 1.27, 95% CI 1.02 – 1.59) and meloxicam (RR 1.27, 95% CI 1.08 – 1.50). The highest risk estimate was seen in rofecoxib users, although it was not statistically significant (RR 1.35, 95% CI 0.88 – 2.06). The statistical significance was not significantly changed with sensitivity analyses, although the relative risk was increased for diclofenac and meloxicam in one analysis to 1.46 and 1.48, respectively.

As the authors point out, the results of the meta-analysis should be interpreted with caution. The lack of a significant association with NSAIDs as a whole may be a function of the reversibility of NSAID inhibition on COX-1. Selection bias may exist; due to the cardiovascular warning associated with NSAIDs, the exposed group may in fact be healthier than the non-exposed group, in which case, the risk of hemorrhagic stroke may actually be underestimated. Nevertheless, the results are at least suggestive that in patients who are at increased risk for hemorrhagic stroke, for example, a patient with amyloid angiopathy, it is not unreasonable that these medications be avoided.