Contributions of the Women's Health Initiative to Cardiovascular Research: JACC State-of-the-Art Review

Abstract

The WHI (Women's Health Initiative) enrolled 161,808 racially and ethnically diverse postmenopausal women, ages 50-79 years, from 1993 to 1998 at 40 clinical centers across the United States. In its clinical trial component, WHI evaluated 3 randomized interventions (menopausal hormone therapy; diet modification; and calcium/vitamin D supplementation) for the primary prevention of major chronic diseases, including cardiovascular disease, in older women. In the WHI observational study, numerous clinical, behavioral, and social factors have been evaluated as predictors of incident chronic disease and mortality. Although the original interventions have been completed, the WHI data and biomarker resources continue to be leveraged and expanded through ancillary studies to yield novel insights regarding cardiovascular disease prevention and healthy aging in women.

Keywords: cardiovascular disease; epidemiology; menopause; prevention; randomized trial; women’s health.

Figure 1.. Original design of the WHI.

CaD, calcium and vitamin supplementation. WHI enrolled a total of 161,808 postmenopausal women, aged 50–79 years, at 40 clinical centers across the U.S. The randomized clinical trials component included three distinct interventions for primary prevention of major chronic diseases, whereas the observational study established a prospective cohort to evaluate rates and risk factors for aging-related diseases among older women in the community setting.

Figure 2.. Timeline of the WHI studies.

E, estrogen; E+P, estrogen plus progestin; ES, extension study; LLS, long life study; OS, observational study; RCT, randomized clinical trial. Enrollment of the 161,808 women into the WHI was completed between 1993–1998. The main WHI study ended in 2005, with the hormone therapy trials stopping early in 2002 (E+P) and 2004 (E-alone). The diet modification and calcium/vitamin D trials ended in 2005 after the planned follow-up interval. A series of extension studies have continued longer-term annual follow-up for health outcomes and additional data collection, such as the Long Life Study in-home examination, in consenting women.

Figure 3.. Absolute risks for major outcomes in the WHI hormone trials.

Absolute risks and risk differences for major health outcomes in the Women’s Health Initiative estrogen-progestin and estrogen-alone trials, according to age at study entry, intervention phase. Absolute risks calculated as cases per 10,000 person-years for intervention and placebo groups in each trial. CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate. Considerably variability in the absolute risks of trial outcomes was evident when stratified on age at randomization for both the CEE-alone and CEE plus MPA hormone trial. Used with permission from reference .

Figure 4.. Risk of incident AF according to BMI and physical activity.

Multivariable hazard ratios for incident AF according to BMI and self-reported total recreational physical activity at WHI enrollment. BMI, body mass index (<25 [normal], 25–29.9 [overweight], ≥30 kg/m² [obese]); MET-hr/wk, metabolic equivalent-hours per week (>9 achieves current guideline recommendations). Both higher BMI and lower self-reported physical activity were associated with increased risk of incident AF, the highest relative risk seen in women who were both clinically obese and physically inactive. Adapted from reference .

Figure 5.. Dose-response association of SPPB physical function score and CVD incidence.

Dose-response for multivariable-adjusted risks of CVD incidence (MI, stroke, death) and mortality according to SPPB score in 5,043 women aged 61–99 years. Linear trend, P<0.001 each. CVD, cardiovascular disease; SPPB, short physical performance battery. Even after controlling for several CVD risk predictors, including accelerometer-measured physical activity, there is a strong inverse dose-response in CVD event risks across incremental levels of physical functioning measured using the objective SPPB score among ambulatory older women. Nearly a 4-fold higher relative risk of CVD mortality is evident for women whose SPPB score is 4 compared to those whose score is 12 (referent). Adapted from reference .

Figure 6.. DXA-measured body fat and incident CVD in women with normal BMI.

Multivariable-adjusted associations of trunk or leg fat with incident CVD in women with normal BMI. CI, confidence interval; BMI, body mass index; HC, hip circumference; HR, hazard ratio; Q, quartile; WC, waist circumference; WHR, waist-to-hip ratio. When comparing the highest and lowest quartile of DXA measured trunk fat percentage, greater risks of CVD events is evident beyond the influence of commonly used anthropometric measures BMI, waist circumference, hip circumference, and waist-to-hip ratio. Greater DXA measured leg fat percentage appeared to be associated with lower CVD risk except when simultaneously controlling for waist-to-hip ratio. Used with permission from reference .

Central Illustration.. Evolution of the WHI Study Program.

The unique study design of the population-based Women’s Health Initiative (WHI) included a hybrid of three randomized clinical prevention trials in a partial factorial design and a large-scale observational cohort, each component targeting the prevention of major chronic diseases among postmenopausal women ages 50–79 years at enrollment. HT, menopausal hormone therapy; CaD, calcium plus vitamin D trial; E+P, estrogen plus progestin; DMT, diet modification trial; CVD, cardiovascular disease.