Traditional Nonsteroidal Anti-Inflammatory Drugs and Postmenopausal Hormone Therapy: A Drug–Drug Interaction?

BACKGROUND: Suppression of prostacyclin (PGI(2)) is implicated in the cardiovascular hazard from inhibitors of cyclooxygenase (COX)-2. Furthermore, estrogen confers atheroprotection via COX-2–dependent PGI(2) in mice, raising the possibility that COX inhibitors may undermine the cardioprotection, suggested by observational studies, of endogenous or exogenous estrogens. METHODS AND FINDINGS: To identify an interaction between hormone therapy (HT) and COX inhibition, we measured a priori the association between concomitant nonsteroidal anti-inflammatory drugs (NSAIDs), excluding aspirin, in peri- and postmenopausal women on HT and the incidence of myocardial infarction (MI) in a population-based epidemiological study. The odds ratio (OR) of MI in 1,673 individuals and 7,005 controls was increased from 0.66 (95% confidence interval [CI] 0.50–0.88) when taking HT in the absence of traditional (t)NSAIDs to 1.50 (95% CI 0.85–2.64) when taking the combination of HT and tNSAIDs, resulting in a significant (p < 0.002) interaction. The OR when taking aspirin at doses of 150 mg/d or more was 1.41 (95% CI 0.47–4.22). However, a similar interaction was not observed with other commonly used drugs, including lower doses of aspirin, which target preferentially COX-1. CONCLUSIONS: Whether estrogens confer cardioprotection remains controversial. Such a benefit was observed only in perimenopausal women in the only large randomized trial designed to address this issue. Should such a benefit exist, these results raise the possibility that COX inhibitors may undermine the cardioprotective effects of HT.