Nonsteroidal Anti-Inflammatory Drugs and Cardiovascular Outcomes in Women: Results From the Women’s Health Initiative

Study Questions:

Is regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) associated with increased risk for cardiovascular events among postmenopausal women?


Postmenopausal women enrolled in the Women’s Health Initiative (WHI) were classified as regular users or nonusers of nonaspirin NSAIDs. Cox regression examined NSAID use as a time-varying covariate and its association with the primary outcome of total cardiovascular disease defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary analyses considered the association of selective cyclooxygenase (cox)-2 inhibitors (e.g., celecoxib), nonselective agents with cox-2>cox-1 inhibition (e.g., naproxen), and nonselective agents with cox-1>cox-2 inhibition (e.g., ibuprofen) with the primary outcome. Data from the WHI study were used for the present analysis. WHI enrolled postmenopausal women ages 50-79 years from the United States into randomized clinical trials (n = 68,132) or an observational study (n = 93,676). Enrollment was from October 1, 1993 to December 31, 1998.


Overall, 160,801 participants were available for analysis (mean follow-up, 11.2 years). Regular NSAID use at some point in time was reported by 53,142 participants. At baseline, the 31,433 NSAID users were more likely to be white, overweight, or obese, and with higher blood pressure. Regular NSAID use was associated with an increased risk for cardiovascular events versus no NSAID use (hazard ratio [HR], 1.10; 95% confidence interval, 1.06-1.15; p < 0.001). Selective cox-2 inhibitors were associated with a modest increased hazard for cardiovascular events (HR, 1.13; 95% CI, 1.04-1.23; p = 0.004 and celecoxib only: HR, 1.13; 95% CI, 1.01-1.27; p = 0.031). Among aspirin users, concomitant selective cox-2 inhibitor use was no longer associated with increased hazard for cardiovascular events. There was an increased risk for agents with cox-2>cox-1 inhibition (HR, 1.17; 95% CI, 1.10-1.24; p < 0.001 and naproxen only: HR, 1.22; 95% CI, 1.12-1.34; p < 0.001). This harmful association remained among concomitant aspirin users. We did not observe a risk elevation for agents with cox-1>cox-2 inhibition (HR, 1.01; 95% CI, 0.95-1.07; p = 0.884 and ibuprofen only: HR, 1.00; 95% CI, 0.93-1.07; p = 0.996).


The investigators concluded that regular use of selective cox-2 inhibitors and nonselective NSAIDs with cox-2>cox-1 inhibition showed a modestly increased risk for cardiovascular events. Nonselective agents with cox-1>cox-2 inhibition were not associated with increased cardiovascular risk.


Although not a randomized controlled trial of NSAIDs, these data suggest that regular use of selective cox-2 inhibitors and nonselective NSAIDs with cox-2>cox-1 inhibition may not be recommended in particular for women at increased risk for cardiovascular events, and if used, concomitant aspirin may reduce cardiovascular risk.

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