Abstract
Objectives:We evaluated the hypothesis that cyclooxygenase (COX) inhibitor use might have counteracted a beneficial effect of postmenopausal hormone therapy, and account for the absence of cardioprotection in the Women's Health Initiative hormone trials. Estrogen increases COX expression, and inhibitors of COX such as nonsteroidal anti-inflammatory agents appear to increase coronary risk, raising the possibility of a clinically important interaction in the trials.Design:The hormone trials were randomized, double-blind, and placebo-controlled. Use of nonsteroidal anti-inflammatory drugs was assessed at baseline and at years 1, 3, and 6.Setting:The Women's Health Initiative hormone trials were conducted at 40 clinical sites in the United States.Participants:The trials enrolled 27,347 postmenopausal women, aged 50–79 y.Interventions:We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo.Outcome Measures:Myocardial infarction, coronary death, and coronary revascularization were ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial.Results:Hazard ratios with 95% confidence intervals were calculated from Cox proportional hazard models stratified by COX inhibitor use. The hazard ratio for myocardial infarction/coronary death with estrogen plus progestin was 1.13 (95% confidence interval 0.68–1.89) among non-users of COX inhibitors, and 1.35 (95% confidence interval 0.86–2.10) among continuous users. The hazard ratio with estrogen alone was 0.92 (95% confidence interval 0.57–1.48) among non-users of COX inhibitors, and 1.08 (95% confidence interval 0.69–1.70) among continuous users. In a second analytic approach, hazard ratios were calculated from Cox models that included hormone trial assignment as well as a time-dependent covariate for medication use, and an interaction term. No significant interaction was identified.Conclusions:Use of COX inhibitors did not significantly affect the Women's Health Initiative hormone trial results.
Highlights
The relationship between cyclooxygenase (COX) inhibition and coronary heart disease (CHD) risk is currently the focus of intense scrutiny [1,2]
The putative increase in CHD risk with selective COX-2 inhibitors has been attributed to reduction in atheroprotective prostacyclin I2 levels [3]
The second set of models included a main effect for randomization assignment in the hormone trial and use of aspirin !80 mg daily, other nonsteroidal anti-inflammatory drug (NSAID), and selective COX-2 inhibitors as time-dependent covariates, and an interaction term
Summary
The relationship between cyclooxygenase (COX) inhibition and coronary heart disease (CHD) risk is currently the focus of intense scrutiny [1,2]. Estrogen activates COX-2 in female mice through an estrogen-receptor-mediated mechanism, thereby increasing levels of prostacyclin [4] This observation has raised concern that COX inhibition might counteract a beneficial effect of estrogen on prostacyclin levels and, account for the absence of cardioprotection with estrogen in recent randomized trials [5]. There was a concern that medication use outside the trial with nonsteroidal antiinflammatory drugs (NSAIDs), and the type of NSAID known as COX-2 inhibitors, could have affected the findings. This concern arose because it is known that COX-2 inhibition lowers levels of prostacyclin, a molecule thought to be beneficial to cardiovascular health, whereas estrogen increases prostacyclin levels. The authors of this paper aimed to do a statistical exploration of the data from the Women’s Health Initiative hormone trials, to find out whether NSAID use by participants in the trials could have affected the trials’ main findings
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