Dataset Information

Impact of cyclooxygenase inhibitors in the Women's Health Initiative hormone trials: secondary analysis of a randomized trial.

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.

SUBMITTER: Hsia J

PROVIDER: S-EPMC1584256 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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Publications

Impact of cyclooxygenase inhibitors in the Women's Health Initiative hormone trials: secondary analysis of a randomized trial.

Hsia Judith J Manson Joann E JE Kuller Lewis L Pettinger Mary M Choe John H JH Langer Robert D RD Limacher Marian M Oberman Albert A Ockene Judith J O'Sullivan Mary Jo MJ Robinson Jennifer G JG

PLoS clinical trials 20060929 5

<h4>Objectives</h4>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.<h4>Design</h4>The hormo ...[more]

PMID: 17016543

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Project description:Importance:Health outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. Objective:To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials. Design, Setting, and Participants:Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014. Interventions:Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n?=?8506) vs placebo (n?=?8102) for 5.6 years (median) or CEE alone (n?=?5310) vs placebo (n?=?5429) for 7.2 years (median). Main Outcomes and Measures:All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization. Results:Among 27?347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. Conclusions and Relevance:Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. Trial Registration:clinicaltrials.gov Identifier: NCT00000611.

Project description:Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention.To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up.A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers.Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n?=?8506) or placebo (n?=?8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n?=?5310) or placebo (n?=?5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010.Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ?65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P?<?.05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials.Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.clinicaltrials.gov Identifier: NCT00000611.

Project description:OBJECTIVE:The Women's Health Initiative hormone trials identified a 44% increase in ischemic stroke risk with combination estrogen plus progestin and a 39% increase with estrogen alone. We undertook a case-control biomarker study to elucidate underlying mechanisms, and to potentially identify women who would be at lower or higher risk for stroke with postmenopausal hormone therapy (HT). DESIGN:The hormone trials were randomized, double-blind, and placebo controlled. SETTING:The Women's Health Initiative trials were conducted at 40 clinical centers 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 placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo. OUTCOME MEASURES:Stroke was 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:No baseline clinical characteristics, including gene polymorphisms, identified women for whom the stroke risk from HT was higher. Paradoxically, women with higher baseline levels of some stroke-associated biomarkers had a lower risk of stroke when assigned to estrogen plus progestin compared to placebo. For example, those with higher IL-6 were not at increased stroke risk when assigned to estrogen plus progestin (odds ratio 1.28) but were when assigned to placebo (odds ratio 3.47; p for difference = 0.02). Similar findings occurred for high baseline PAP, leukocyte count, and D-dimer. However, only an interaction of D-dimer during follow-up interaction with HT and stroke was marginally significant (p = 0.03). CONCLUSIONS:Biomarkers did not identify women at higher stroke risk with postmenopausal HT. Some biomarkers appeared to identify women at lower stroke risk with estrogen plus progestin, but these findings may be due to chance.

Project description:More than two-thirds of US women are overweight or obese, placing them at increased risk for postmenopausal breast cancer.To investigate in this secondary analysis the associations of overweight and obesity with risk of postmenopausal invasive breast cancer after extended follow-up in the Women's Health Initiative (WHI) clinical trials.The WHI clinical trial protocol incorporated measured height and weight, baseline and annual or biennial mammography, and adjudicated breast cancer end points in 67?142 postmenopausal women ages 50 to 79 years at 40 US clinical centers. The women were enrolled from 1993 to 1998 with a median of 13 years of follow-up through 2010; 3388 invasive breast cancers were observed.Height and weight were measured at baseline, and weight was measured annually thereafter. Data were collected on demographic characteristics, personal and family medical history, and personal habits (smoking, physical activity). Women underwent annual or biennial mammograms. Breast cancers were verified by medical records reviewed by physician adjudicators.Women who were overweight and obese had an increased invasive breast cancer risk vs women of normal weight. Risk was greatest for obesity grade 2?plus?3 (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, >35.0) (hazard ratio [HR] for invasive breast cancer, 1.58; 95% CI, 1.40-1.79). A BMI of 35.0 or higher was strongly associated with risk for estrogen receptor-positive and progesterone receptor-positive breast cancers (HR, 1.86; 95% CI, 1.60-2.17) but was not associated with estrogen receptor-negative cancers. Obesity grade 2?plus?3 was also associated with advanced disease, including larger tumor size (HR, 2.12; 95% CI, 1.67-2.69; P?=?.02), positive lymph nodes (HR, 1.89; 95% CI, 1.46-2.45; P?=?.06), regional and/or distant stage (HR, 1.94; 95% CI, 1.52-2.47; P?=?.05), and deaths after breast cancer (HR, 2.11; 95% CI, 1.57-2.84; P?<?.001). Women with a baseline BMI of less than 25.0 who gained more than 5% of body weight over the follow-up period had an increased breast cancer risk (HR, 1.36; 95% CI, 1.1-1.65), but among women already overweight or obese we found no association of weight change (gain or loss) with breast cancer during follow-up. There was no effect modification of the BMI-breast cancer relationship by postmenopausal hormone therapy, and the direction of association across BMI categories was similar for never, past, and current hormone therapy use.Obesity is associated with increased invasive breast cancer risk in postmenopausal women. These clinically meaningful findings should motivate programs for obesity prevention.clinicaltrials.gov Identifier: NCT00000611.

Dataset Information

Impact of cyclooxygenase inhibitors in the Women's Health Initiative hormone trials: secondary analysis of a randomized trial.

Objectives

Design

Setting

Participants

Interventions

Outcome measures

Results

Conclusions

Publications

Impact of cyclooxygenase inhibitors in the Women's Health Initiative hormone trials: secondary analysis of a randomized trial.

Similar Datasets

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