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

Date Published: May 22, 2007

Publisher: Public Library of Science

Author(s): Luis Alberto García Rodríguez, Karine Egan, Garret A FitzGerald, Deborah Grady

Abstract: BackgroundSuppression of prostacyclin (PGI2) is implicated in the cardiovascular hazard from inhibitors of cyclooxygenase (COX)-2. Furthermore, estrogen confers atheroprotection via COX-2–dependent PGI2 in mice, raising the possibility that COX inhibitors may undermine the cardioprotection, suggested by observational studies, of endogenous or exogenous estrogens.Methods and FindingsTo 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.ConclusionsWhether 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.

Partial Text: Premenopausal women are less susceptible to myocardial infarction (MI) and stroke than are males of the same age group, an advantage that is lost after menopause [1]. However, the mechanism by which female gender affords cardioprotection is unclear. Despite the cardiovascular advantage of premenopausal women, it has been difficult to identify a cardioprotective effect of hormone therapy (HT) in postmenopausal women [2]. We recently found in mice that estrogen acts via its ERα receptor to up-regulate COX-2–dependent prostacyclin (PGI2) formation which, acting via its receptor (the I prostanoid receptor) constrains both platelet activation and oxidant stress. Indeed, deletion of the I prostanoid receptor undermined substantially the vascular benefit of estrogen therapy in ovariectomized mice rendered prone to atherogenesis by deletion of the low-density lipoprotein receptor [3].

Overall, current use of HT was associated with a reduced risk of MI with an OR of 0.78 (95% CI 0.61–1.00) (Table 1). The corresponding OR among long-term users of HT, defined as exceeding 2 y, was 0.72 (95% CI 0.52–0.99). However, this suggestion of cardioprotection from HT disappeared (Figure 1) in women who were taking tNSAIDS concomitantly (OR 1.50; 95% CI 0.85–2.64). If tNSAIDs had not been used in the preceding month (combining the past users and never users of NSAIDs), use of HT resulted in an OR of 0.66 (95% CI 0.50–0.88). When we performed a standard test of interaction, the level of significance attained was p = 0.0012. The figure also shows that these estimates of risk did not vary by duration of HT. The interaction was apparent in women taking both opposed and unopposed estrogens, with ORs of 1.39 (95% CI 0.65–2.95) and 1.86 (95% CI 0.79–4.42), respectively. Also, the interaction between HT and tNSAIDs was already evident within months of starting the tNSAID and was sustained, irrespective of the duration of tNSAID therapy or HT (Table 2). Menopausal status is often lacking in the General Practice Research Database. A secondary analysis restricted to women older than 55 attained similar results: use of HT in the absence of tNSAIDs resulted in an OR of 0.68 (95% CI 0.50–0.93) among women in this age group. Another subset analysis restricted to women free of CHD yielded an OR of 1.57 (95% CI 0.78–3.18) among long-term users of HT taking tNSAIDs concomitantly.

The results of this study raise the possibility that concomitant medication with NSAIDs might undermine a cardioprotective effect of HT in perimenopausal women. Mechanistically, this might relate particularly to inhibition of COX-2. However, the present study pertained to tNSAIDs, which inhibit COX-2, but vary in their comcomitant inhibtion of COX-1 and did not include NSAIDs designed to attain specific inhibition of COX-2.



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