Nonsteroidal anti-inflammatory drugs and cardiovascular outcomes in women: results from the women's health initiative

Abstract

Background: Conclusive data about cardiovascular toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) are sparse. We hypothesized that regular NSAID use is associated with increased risk for cardiovascular events in postmenopausal women, and that this association is stronger with greater cyclooxygenase (cox)-2 when compared with cox-1 inhibition.

Methods and results: Postmenopausal women enrolled in the Women's Health Initiative 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 cox-2 inhibitors (eg, celecoxib), nonselective agents with cox-2>cox-1 inhibition (eg, naproxen), and nonselective agents with cox-1>cox-2 inhibition (eg, ibuprofen) with the primary outcome. 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. Regular NSAID use was associated with an increased hazard 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 (hazard ratio, 1.13; 1.04-1.23; P=0.004 and celecoxib only: HR, 1.13; 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; 1.10-1.24; P<0.001 and naproxen only: HR, 1.22; 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; 0.95-1.07; P=0.884 and ibuprofen only: HR, 1.00; 0.93-1.07; P=0.996).

Conclusions: Regular use of selective cox-2 inhibitors and nonselective NSAIDs with cox-2>cox-1 inhibition showed a modestly increased hazard for cardiovascular events. Nonselective agents with cox-1>cox-2 inhibition were not associated with increased cardiovascular risk.

Clinical trial registration url: www.clinicaltrials.gov. Unique identifier: NCT00000611.

Keywords: anti-inflammatory agents, non-steroidal; coronary artery disease; myocardial infarction; stroke.

Conflict of interest statement

Disclosures

Dr Bavry is a contractor for the American College of Cardiology's Cardiosource. The other authors report no conflicts.

© 2014 American Heart Association, Inc.

Figures

Figure 1

Of all 161,808 Women Health Initiative (WHI) enrollees, 160,801 were utilized in the analysis. Women were only excluded due to missing baseline covariates (n = 311) if the number of women with that missing variable was small. Otherwise, a separate factor level “missing” was maintained in categorical variables.

Figure 2

Adjusted hazard ratios for the primary outcome (cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke) and secondary outcomes for regular NSAID use versus no NSAID use. Group 1=cox-2 selective agents, group 2=non-selective agents with cox-2>cox-1 inhibition, group 3=non-selective agents with cox-1>cox-2 inhibition.