Suppression 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 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.
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.
It is controversial whether estrogens confer cardioprotection. This study suggests that even should such a benefit exist, COX inhibitors may undermine cardioprotective effects of hormone therapy.
There is currently a great deal of uncertainty regarding the effect of postmenopausal hormone therapy on heart disease in women. Premenopausal women are much less likely to experience heart attacks and strokes than men, a difference that does not exist between postmenopausal women and men. One mechanism that might explain these observations relates to the effect of estrogen, which is thought to have a protective effect on the heart. Hormone replacement therapy (HT) consisting of replacement estrogen, and sometimes progesterone as well, is often taken by women experiencing symptoms of menopause. Evidence from observational studies and the Womens' Health Initiative (WHI) trial has suggested that HT protects against heart disease in perimenopausal women. However, researchers have suggested that any beneficial effect of hormone replacement therapy on the heart might be counteracted by the effects of certain types of painkillers also being taken by women involved in the studies. These painkillers, nonsteroidal anti inflammatory drugs ( NSAIDs), prevent production of a molecule called prostacyclin. Prostacyclin plays a role in preventing blood clotting and is therefore thought to be important in protecting the heart. Estrogen, however, acts to increase production of prostacyclin, and it is therefore theoretically possible that hormone replacement therapy does have a beneficial effect on heart health, but which is counteracted by the negative effects of NSAIDs.
Why Was This Study Done?
In this study, the researchers wanted to find out whether there was any evidence for an interaction between NSAID use, hormone replacement therapy, and heart disease. Such understanding in turn might help to identify more clearly whether hormone replacement therapy protects against heart disease in specific subgroups of postmenopausal women.
What Did the Researchers Do and Find?
This study was carried out using information from the UK's General Practice Research Database, which is the largest computer database of anonymous medical records from primary care anywhere in the world. It contains information entered by UK general practitioners on their patients' drug prescriptions, diagnoses, referrals to hospital, and other data. The researchers here searched for all individuals from the database who were aged between 50 and 84 years on 1 January 1997, and then followed them up through the database for four years, or until the individual died, reached 85 years of age, or was diagnosed with a heart attack or cancer. From this search, the researchers found 1,673 women who had heart attacks or who died from coronary heart disease; these were considered “cases.” Then, these 1,673 women were matched against 20,000 “control” women of similar age. Information was pulled out for each case or control on their use of hormone replacement therapy, NSAIDs (covering 21 different drugs, but most commonly diclofenac, ibuprofen, and naproxen), and various risk factors for heart disease. The researchers then compared use of hormone replacement therapy and NSAIDs between the cases and controls, while making statistical adjustments for other risk factors (such as diabetes and smoking, for example).
The researchers found that current use of hormone replacement therapy was associated with a lower risk of heart attack than non-use. The odds ratio (chance of a heart attack among HT users compared to the chance among non-users of HT) was 0.78. However, when looking at women who used NSAIDs at the same time as hormone replacement therapy, the researchers found no suggestion of a reduction in risk of heart attack: the odds ratio for the chance of heart attack among this group of women, as compared to nonusers of both NSAIDs and hormone replacement therapy, was 1.50.
What Do These Findings Mean?
These findings suggest that hormone replacement therapy and NSAIDs might interact, with NSAIDs acting against a role for hormone replacement therapy in preventing heart attacks. At face value, these results are in conflict with the findings of one large trial, the WHI trial, which failed to find a benefit of HT in preventing heart attacks. However, a recent analysis of WHI suggests cardioprotective effects of HT in women close to the time of the menopause and this coincides with the younger age of women in the observational studies such as the present one rather than in the WHI overall. Observational research studies, such as the present one, are often difficult to interpret because the groups being compared are not necessarily equivalent. It's possible that women who take hormone replacement therapy, or NSAIDs, are in some way different from women who do not, which will bias the findings. Determination of the clinical implications of these findings would most appropriately be resolved in future trials, designed to address the question of interest.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040157.
Resources from the US National Institutes of Health on menopausal hormone therapy, including links to information about the Women's Health Initiative trials, information about managing menopausal symptoms, and more
Resources from the US National Institutes of Health (MedlinePlus) about heart disease in women
Information from NHS Direct, the UK National Health Service, about hormone replacement therapy
The UK General Practice Research Database is the database utilized in this article
Wikipedia entry on nonsteroidal anti-inflammatory drugs (NSAIDs) (note: Wikipedia is an internet encyclopedia anyone can edit)