The Women's Health Initiative Randomized Trials and Clinical Practice: A Review.

Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years. Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up. Conclusions and Relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

Systolic Blood Pressure and Survival to Very Old Age: Results From the Women's Health Initiative.

BACKGROUND: The relationship between systolic blood pressure (SBP) and longevity is not fully understood. We aimed to determine which SBP levels in women ≥65 years of age with or without blood pressure medication were associated with the highest probability of surviving to 90 years of age. METHODS: The study population consisted of 16 570 participants enrolled in the Women's Health Initiative who were eligible to survive to 90 years of age by February 28, 2020, without a history of cardiovascular disease, diabetes, or cancer. Blood pressure was measured at baseline (1993 through 1998) and then annually through 2005. The outcome was defined as survival to 90 years of age with follow-up. Absolute probabilities of surviving to 90 years of age were estimated for all combinations of SBP and age using generalized additive logistic regression modeling. The SBP that maximized survival was estimated for each age, and a 95% CI was generated. RESULTS: During a median follow-up of 19.8 years, 9723 of 16 570 women (59%) survived to 90 years of age. Women with an SBP between 110 and 130 mm Hg at attained ages of 65, 70, 75, and 80 years had a 38% (95% CI, 34%-48%), 54% (52%-56%), 66% (64%-67%), or 75% (73%-78%) absolute probability to survive to 90 years of age, respectively. The probability of surviving to 90 years of age was lower for greater SBP levels. Women at the attained age of 80 years with 0%, 20%, 40%, 60%, 80%, or 100% time in therapeutic range (defined as an SBP between 110 and 130 mm Hg) had a 66% (64%-69%), 68% (67%-70%), 71% (69%-72%), 73% (71%-74%), 75% (72%-77%), or 77% (74%-79%) absolute survival probability to 90 years of age. CONCLUSIONS: For women >65 years of age with low cardiovascular disease and other chronic disease risk, an SBP level <130 mm Hg was found to be associated with longevity. These findings reinforce current guidelines targeting an SBP target <130 mm Hg in older women.

Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women : Postintervention Follow-up of a Randomized Clinical Trial.

BACKGROUND: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited. OBJECTIVE: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial. DESIGN: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611). SETTING: A multicenter (n = 40) trial across the United States. PARTICIPANTS: 36 282 postmenopausal women with no history of breast or colorectal cancer. INTERVENTION: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D3 daily or placebo. MEASUREMENTS: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use. RESULTS: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality. LIMITATION: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled. CONCLUSION: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Low physical function following cancer diagnosis is associated with higher mortality risk in postmenopausal women.

BACKGROUND: Postmenopausal women with cancer experience an accelerated physical dysfunction beyond what is expected through aging alone due to cancer and its treatments. The aim of this study was to determine whether declines in physical function after cancer diagnosis are associated with all-cause mortality and cancer-specific mortality. METHODS: This prospective cohort study included 8068 postmenopausal women enrolled in the Women's Health Initiative with a cancer diagnosis and who had physical function assessed within 1 year of that diagnosis. Self-reported physical function was measured using the 10-item physical function subscale of the 36-Item Short Form Health Survey. Cause of death was determined by medical record review, with central adjudication and linkage to the National Death Index. Death was adjudicated through February 2022. RESULTS: Over a median follow-up of 7.7 years from cancer diagnosis, 3316 (41.1%) women died. Our results showed that for every 10% difference in the physical function score after cancer diagnosis versus pre-diagnosis, all-cause mortality and cancer-specific mortality were reduced by 12% (hazard ratio [HR] = 0.88, 95% confidence interval [95% CI] = 0.87 to 0.89 and HR = 0.88, 95% CI = 0.86 to 0.91, respectively). Further categorical analyses showed a significant dose-response relationship between postdiagnosis physical function categories and mortality outcomes (P < .001 for trend), where the median survival time for women in the lowest physical function quartile was 9.1 years (Interquartile range [IQR] = 8.6-10.6 years) compared with 18.4 years (IQR = 15.8-22.0 years) for women in the highest physical function quartile. CONCLUSION: Postmenopausal women with low physical function after cancer diagnosis may be at higher risk of mortality from all causes and cancer-related mortality.

Prevalence of frequent premature ventricular contractions and nonsustained ventricular tachycardia in older women screened for atrial fibrillation in the Women's Health Initiative.

BACKGROUND: Frequent premature ventricular contractions (PVCs) and nonsustained ventricular tachycardia (NSVT) have been associated with cardiovascular disease and mortality. Their prevalence, especially in ambulatory populations, is understudied and limited by few female participants and the use of short-duration (24- to 48-hour) monitoring. OBJECTIVE: The objective of this study was to report the prevalence of frequent PVCs and NSVT in a community-based population of women likely to undergo electrocardiogram (ECG) screening by sequential patch monitoring. METHODS: Participants from the Women's Health Initiative Strong and Healthy (WHISH) trial with no history of atrial fibrillation (AF) but 5-year predicted risk of incident AF ≥5% by CHARGE-AF score were randomly selected to undergo screening with 7-day ECG patch monitors at baseline, 6 months, and 12 months. Recordings were reviewed for PVCs and NSVT (>5 beats); data were analyzed with multivariate regression models. RESULTS: There were 1067 participants who underwent ECG screening at baseline, 866 at 6 months, and 777 at 12 months. Frequent PVCs were found on at least 1 patch from 4.3% of participants, and 1 or more episodes of NSVT were found in 12 (1.1%) women. PVC frequency directly correlated with CHARGE-AF score and NSVT on any patch. Detection of frequent PVCs increased with sequential monitoring. CONCLUSION: In postmenopausal women at high risk for AF, frequent PVCs were relatively common (4.3%) and correlated with higher CHARGE-AF score. As strategies for AF screening continue to evolve, particularly in those individuals at high risk of AF, the prevalence of incidental ventricular arrhythmias is an important benchmark to guide clinical decision-making.

Dietary Intervention Favorably Influences Physical Functioning: The Women's Health Initiative Randomized Dietary Modification Trial.

BACKGROUND: In the Women's Health Initiative Dietary Modification randomized trial, the dietary intervention reduced breast cancer mortality by 21% (P = .02) and increased physical activity as well. OBJECTIVE: Therefore, the aim was to examine whether or not these lifestyle changes attenuated age-related physical functioning decline. DESIGN: In a randomized trial, the influence of 8 years of a low-fat dietary pattern intervention was examined through 20 years of cumulative follow-up. PARTICIPANTS AND SETTING: From 1993 to 1998, 48,835 postmenopausal women, ages 50 to 79 years with no prior breast cancer and negative baseline mammogram were randomized at 40 US clinical centers to dietary intervention or usual diet comparison groups (40 out of 60). The intervention significantly reduced fat intake and increased vegetable, fruit, and grain intake. MAIN OUTCOME MEASURES: In post hoc analyses, physical functioning, assessed using the RAND 36-Item Short Form Health Survey, evaluated quality or limitations of 10 hierarchical physical activities. Longitudinal physical functioning, reported against a disability threshold (when assistance in daily activities is required) was the primary study outcome. STATISTICAL ANALYSES PERFORMED: Semiparametric linear mixed effect models were used to contrast physical functioning trajectories by randomization groups. RESULTS: Physical functioning score, assessed 495,317 times with 11.0 (median) assessments per participant, was significantly higher in the intervention vs comparison groups through 12 years of cumulative follow-up (P = .001), representing a reduction in age-related functional decline. The intervention effect subsequently attenuated and did not delay time to the disability threshold. Among women in the dietary intervention vs comparison groups, aged 50 to 59 years, who were physically inactive at entry, a persistent, statistically significant, favorable influence on physical functioning with associated delay in crossing the disability threshold by approximately a year was seen (P value for interaction = .007). CONCLUSIONS: In the Women's Health Initiative Dietary Modification randomized trial, a dietary intervention that significantly reduced breast cancer mortality also significantly reduced age-related functional decline through 12 years, which was attenuated with longer follow-up.

Traditional Mexican dietary pattern and cancer risk among women of Mexican descent.

PURPOSE: To examine the association of a traditional Mexican diet score with risk of total, breast, and colorectal cancer among women of Mexican ethnic descent in the Women's Health Initiative (WHI). METHODS: Participants were WHI enrollees who self-identified as being of Mexican descent. Data from food frequency questionnaires self-administered at study baseline were used to calculate the MexD score, with higher scores indicating greater adherence to an a priori-defined traditional Mexican diet (high in dietary fiber, vegetables, and legumes). Incident cancers were self-reported by participants from 1993 to 2020 and adjudicated by trained physicians. We used multivariable-adjusted Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 2,343 Mexican descent women (median baseline age: 59 years), a total of 270 cancers (88 breast, 37 colorectal) occurred during a mean follow-up of 14.4 years. The highest tertile of MexD score was associated with a lower risk of all-cancer incidence (HR: 0.67; 95% CI 0.49-0.91; p-trend: 0.01) and colorectal cancer (HR: 0.38; 95% CI 0.14-0.998; p-trend < 0.05), with each unit increase in the MexD score associated with a 6% lower risk of all-cancer incidence (HR: 0.94; 95% CI 0.88-0.99). There was no statistically significant association with risk of breast cancer. CONCLUSION: Consumption of a traditional Mexican diet was associated with a significantly lower risk of all-cancer incidence and colorectal cancer. Confirmation of these findings in future studies is important, given the prevalence of colorectal cancer and a growing U.S. population of women of Mexican descent.

Systolic Blood Pressure and Survival to Very Old Age. Results from the Women's Health Initiative.

Background: The association between systolic blood pressure (SBP) and longevity is not fully understood. We aimed to determine survival probabilities to age 90 for various SBP levels among women aged ≥ 65 years with or without BP medication. Methods: We analyzed blood pressure data from participants in the Women's Health Initiative (n=16,570) who were aged 65 or older and without history of cardiovascular disease, diabetes or cancer. Blood pressure was measured at baseline (1993-1998) and then annually through 2005. The outcome was defined as survival to age 90 with follow-up until February 28, 2020. Results: During a follow-up of 18 years, 9,723 (59%) of 16,570 women survived to age 90. The SBP associated with the highest probability of survival was about 120mmHg regardless of age. Compared to an SBP between 110 and 130 mmHg, women with uncontrolled SBP had a lower survival probability across all age groups and with or without BP medication. A 65-year-old women on BP medication with an interpolated SBP between 110 and 130 mmHg in 80% of the first 5 years of follow-up had a 31% (95% confidence interval, 24%, 38%) absolute survival probability. For those with 20% time in range, the probability was 21% (95% confidence interval, 16%, 26%). Conclusions: An SBP level below 130 mmHg was found to be associated with longevity among older women. The longer SBP was controlled at a level between 110 and 130 mmHg, the higher the survival probability to age 90. Preventing age-related rises in SBP and increasing the time with controlled BP levels constitute important measures for achieving longevity.

Body size over the adult life course and the risk of colorectal cancer among postmenopausal women.

OBJECTIVE: To assess the associations among several anthropometric measures, as well as BMI trajectories and colorectal cancer (CRC) risk in older women. DESIGN: Prospective cohort study. SETTING: Forty clinical centres in the USA. PARTICIPANTS: Totally, 79 034 postmenopausal women in the Women's Health Initiative Observational Study. RESULTS: During an average of 15·8 years of follow-up, 1514 CRC cases were ascertained. Five BMI trajectories over 18-50 years of age were identified using growth mixture model. Compared with women who had a normal BMI at age 18, women with obesity at age 18 had a higher risk of CRC (HR 1·58, 95 % CI 1·02, 2·44). Compared with women who kept relatively low normal body size during adulthood, women who progressed from normal to obesity (HR 1·29, 95 % CI 1·09, 1·53) and women who progressed from overweight to obesity (HR 1·37, 95 % CI 1·13, 1·68) had higher CRC risks. A weight gain > 15 kg from age 18 to 50 (HR 1·20, 95 % CI 1·04, 1·40) and baseline waist circumference > 88 cm (HR 1·33, 95 % CI 1·19, 1·49) were associated with higher CRC risks, compared with stable weight and waist circumference ≤ 88 cm, respectively. CONCLUSION: Women who have a normal weight in early adult life and gain substantial weight later, as well as those who are persistently heavy over adulthood, demonstrated a higher risk of developing CRC. Our study highlights the importance of maintaining a healthy body weight over the life course for reducing the risk of developing CRC in women.

A Review of Hormone and Non-Hormonal Therapy Options for the Treatment of Menopause.

Understanding the role of both menopausal hormone therapy (MHT) along with non-hormonal options for the treatment of vasomotor symptoms, sleep disruption, and genitourinary symptoms after menopause is critical to the health of women during middle and later life. Recent updates to the evidence for the treatment of menopausal symptoms pertaining to both hormonal and non-hormonal therapies as well as updated guidance from specialty societies can help guide clinicians in their treatment of women going through natural menopause or with estrogen deficiencies due to primary ovarian insufficiency or induced menopause from surgery or medications. The objective of this narrative review is to provide clinicians with an overview of MHT for the use of menopausal symptoms in women, incorporating updated primary evidence for risk versus benefit profiles, recent specialty society recommendations, and alternative, non-hormonal options. In this review, we summarize literature on the use of MHT for menopause-related symptomatology including options for formulations and dosages of MHT, non-hormonal treatment options, and the risk-benefit profile of MHT including long-term health consequences (eg, cardiovascular disease, cognitive decline, venous thromboembolism, and fracture risk). Finally, we highlight areas in which future research is needed to advance care of women after menopause. In summary, both hormonal (MHT) and non-hormonal options exist to treat symptoms of menopause. There is strong evidence for safety and effectiveness of MHT for the treatment of vasomotor symptoms among women who are less than 60 years of age, less than 10 years since menopause, and without significant cardiometabolic comorbidities. For others, treatment with hormonal versus non-hormonal therapies can be considered based on individual risk profiles, as well as other factors such as drug formulation, therapeutic goals, and symptom severity.

The association of hormone therapy with blood pressure control in postmenopausal women with hypertension: a secondary analysis of the Women's Health Initiative clinical trials.

OBJECTIVE: The objective of this study was to assess the effect of menopausal hormone therapy (HT) on blood pressure control in postmenopausal women with hypertension. METHODS: The Women's Health Initiative HT clinical trials were double-blinded, randomized, placebo-controlled studies of women aged 50 to 79 years testing the effects of HT (conjugated equine estrogens [CEE, 0.625 mg/d] or CEE + medroxyprogesterone acetate [MPA; 2.5 mg/d]) on risks for coronary heart disease and invasive breast cancer, the primary outcomes for efficacy and safety, respectively. This secondary analysis of the Women's Health Initiative HT trials examined a subsample of 9,332 women with hypertension (reported ever taking pills to treat hypertension or were taking antihypertensive medication) at baseline. Blood pressure was measured at baseline and up to 10 annual follow-up visits during the planned study phase. Antihypertensive medications were inventoried at baseline and years 1, 3, 6, and 9 during the study, and self-reported during extended follow-up: 2009-2010 and 2012-2013, which occurred median of 13 and 16 years after randomization, respectively. The intervention effect was estimated through year 6. Cumulative follow-up included all visits. RESULTS: Compared with placebo, CEE-alone had significantly ( P = 0.02) higher systolic blood pressure (SBP) by mean (95% confidene interval [CI]) = 0.9 (0.2-1.5) mm Hg during the intervention phase. For cumulative follow-up, the CEE arm was associated with increased SBP by mean (95% CI) = 0.8 (0.1-1.4) mm Hg ( P = 0.02). Furthermore, CEE + MPA relative to placebo was associated with increased SBP by mean (95% CI) = 1.8 (1.2-2.5) mm Hg during the intervention phase ( P < 0.001). For cumulative follow-up, the CEE + MPA arm was associated with increased SBP by mean (95% CI) = 1.6 (1.0-2.3) mm Hg ( P < 0.001). The mean number of antihypertensive medications taken at each follow-up visit did not differ between randomization groups during the intervention or long-term extended follow-up of 16 years. CONCLUSION: There was a small but statistically significant increase in SBP in both CEE-alone and CEE + MPA arms compared with placebo during both the intervention and cumulative follow-up phases among postmenopausal women with hypertension at baseline. However, this increase in SBP was not associated with an increased antihypertensive medication use over time among women randomized to HT compared with placebo.

Associations of Biomarker-Calibrated Healthy Eating Index-2010 Scores with Chronic Disease Risk and Their Dependency on Energy Intake and Body Mass Index in Postmenopausal Women.

BACKGROUND: Prior studies examined associations between the Healthy Eating Index (HEI) and chronic disease risk based on self-reported diet without measurement error correction. OBJECTIVE: Our objective was to test associations between biomarker calibration of the food-frequency questionnaire (FFQ)-derived HEI-2010 with incident cardiovascular disease (CVD), cancer, and type 2 diabetes (T2D) among Women's Health Initiative (WHI) participants. METHODS: Data were derived from WHI postmenopausal women (n = 100,374) aged 50-79 y at enrollment (1993-1998) at 40 US clinical centers, linked to nutritional biomarker substudies and outcomes over subsequent decades of follow-up. Baseline or year 1 FFQ-derived HEI-2010 scores were calibrated with nutritional biomarkers and participant characteristics (e.g., BMI) for systematic measurement error correction. Calibrated data were then used in HR models examining associations with incidence of CVD (total, subtypes, mortality), cancer (total, subtypes, mortality), and T2D in WHI participants with approximately 2 decades of follow-up. Models were multivariable-adjusted with further adjustment for BMI and doubly labeled water (DLW)-calibrated energy. RESULTS: Multivariable-adjusted HRs modeled a 20% increment in HEI-2010 score in relation to outcomes. HRs were modest using uncalibrated HEI-2010 scores (HRs = 0.91-1.09). Using biomarker-calibrated HEI-2010, 20% increments in scores yielded multivariable-adjusted HRs (95% CIs) of 0.75 (0.60, 0.93) for coronary heart disease; 0.75 (0.61, 0.91) for myocardial infarction; 0.96 (0.92, 1.01) for stroke; 0.88 (0.75, 1.02) for CVD mortality; 0.81 (0.70, 0.94) for colorectal cancer; 0.81 (0.74, 0.88) for breast cancer; 0.79 (0.73, 0.87) for cancer mortality; and 0.45 (0.36-0.55) for T2D. Except for cancer mortality and T2D incidence, results became null when adjusted for DLW-calibrated energy intake and BMI. CONCLUSIONS: Biomarker calibration of FFQ-derived HEI-2010 was associated with lower CVD and cancer incidence and mortality and lower T2D incidence in postmenopausal women. Attenuation after adjustment with BMI and DLW-calibrated energy suggests that energy intake and/or obesity are strong drivers of diet-related chronic disease risk in postmenopausal women. The Women's Health Initiative is registered at clinicaltrials.gov at NCT00000611.

Genetic evidence for causal relationships between age at natural menopause and the risk of ageing-associated adverse health outcomes.

BACKGROUND: A later age at natural menopause (ANM) has been linked to several ageing-associated traits including an increased risk of breast and endometrial cancer and a decreased risk of lung cancer, osteoporosis and Alzheimer disease. However, ANM is also related to several proxies for overall health that may confound these associations. METHODS: We investigated the causal association of ANM with these clinical outcomes using Mendelian randomization (MR). Participants and outcomes analysed were restricted to post-menopausal females. We conducted a one-sample MR analysis in both the Women's Health Initiative and UK Biobank. We further analysed and integrated several additional data sets of post-menopausal women using a two-sample MR design. We used ≤55 genetic variants previously discovered to be associated with ANM as our instrumental variable. RESULTS: A 5-year increase in ANM was causally associated with a decreased risk of osteoporosis [odds ratio (OR) = 0.80, 95% CI (0.70-0.92)] and fractures (OR = 0.76, 95% CI, 0.62-0.94) as well as an increased risk of lung cancer (OR = 1.35, 95% CI, 1.06-1.71). Other associations including atherosclerosis-related outcomes were null. CONCLUSIONS: Our study confirms that the decline in bone density with menopause causally translates into fractures and osteoporosis. Additionally, this is the first causal epidemiological analysis to our knowledge to find an increased risk of lung cancer with increasing ANM. This finding is consistent with molecular and epidemiological studies suggesting oestrogen-dependent growth of lung tumours.

Serial 7-Day Electrocardiogram Patch Screening for AF in High-Risk Older Women by the CHARGE-AF Score.

BACKGROUND: Asymptomatic atrial fibrillation (AF) is associated with an increased risk of stroke. The yield of serial electrocardiographic (ECG) screening for AF is unknown. OBJECTIVES: The aim of this study was to determine the frequency of AF detected by serial, 7-day ECG patch screenings in older women identified as having an elevated risk of AF according to the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology)-AF clinical prediction score. METHODS: Postmenopausal women with a 5-year predicted risk of new-onset AF ≥5% according to CHARGE-AF were recruited from the ongoing WHISH (Women's Health Initiative Strong and Healthy) randomized trial of a physical activity intervention. Participants with AF at baseline by self-report or medical records review were excluded. Screening with 7-day ECG patch monitors was performed at baseline, 6 months, and 12 months from study enrollment. RESULTS: On baseline monitoring, 2.5% of the cohort had AF detected, increasing to 3.7% by 6 months and 4.9% cumulatively by 12 months. Yield of patch screening was higher among participants with a higher (≥10%) CHARGE-AF score: 4.2% had AF detected at baseline, 5.9% at 6 months, and 7.2% at 12 months. Most participants with patch-identified AF never had a clinical diagnosis of AF (36 of 46 [78%]). CONCLUSIONS: Older women with an elevated CHARGE-AF score had a high prevalence of AF on 7-day ECG patch screening. Serial screening over 12 months substantially increased the detection of AF. These data can be useful in helping identify high-risk participants for enrollment in future studies of the management of asymptomatic AF.(Women's Health Initiative Silent Atrial Fibrillation Recording Study [WHISH STAR]; NCT05366803.).

Physical function trends and their association with mortality in postmenopausal women.

OBJECTIVE: Research is limited regarding the predictive utility of the RAND-36 questionnaire and physical performance tests in relation to all-cause, cardiovascular disease (CVD), and total-cancer mortality in older women. METHODS: Data on the RAND-36 questionnaire, gait speed, and chair stand performance were assessed in 5,534 women aged ≥65 years at baseline. A subset (n = 298) had physical function assessments additionally at follow-up (years 1, 3, or 6). Multivariable Cox proportional hazards regression models estimated associations (HR) for a 1-standard deviation (SD) difference in baseline RAND-36 scores and performance tests (alone and combined) with mortality outcomes in the overall cohort and in models stratified by enrollment age (<70 and ≥ 70 y). The relative prognostic value of each physical function exposure was assessed using the Uno concordance statistic. RESULTS: A total of 1,186 deaths from any cause, 402 deaths from CVD, and 382 deaths from total-cancer were identified during a mean follow-up of 12.6 years. Overall, each 1-SD unit higher baseline RAND-36 score was associated with significantly lower all-cause mortality (HR =0.90) and discriminatory capacity (Uno = 0.65) that was comparable to each performance exposure (HRs 0.88-0.91; Uno = 0.65). These findings were consistent in women aged <70 and ≥ 70 years. The associations of RAND-36 and performance measures with CVD mortality and total-cancer mortality were not significant in multivariable models nor in age-stratified models. CONCLUSIONS: The RAND-36 questionnaire is a reasonable substitute for tracking physical functioning and estimating its association with all-cause mortality in older adults when clinical performance testing is not feasible.

Adverse Pregnancy Outcomes and Incident Heart Failure in the Women's Health Initiative.

Importance: Some prior evidence suggests that adverse pregnancy outcomes (APOs) may be associated with heart failure (HF). Identifying unique factors associated with the risk of HF and studying HF subtypes are important next steps. Objective: To investigate the association of APOs with incident HF overall and stratified by HF subtype (preserved vs reduced ejection fraction) among postmenopausal women in the Women's Health Initiative (WHI). Design, Setting, and Participants: In 2017, an APO history survey was administered in the WHI study, a large multiethnic cohort of postmenopausal women. The associations of 5 APOs (gestational diabetes, hypertensive disorders of pregnancy [HDP], low birth weight, high birth weight, and preterm delivery) with incident adjudicated HF were analyzed. In this cohort study, the association of each APO with HF was assessed using logistic regression models and with HF subtypes using multinomial regression, adjusting for age, sociodemographic characteristics, smoking, randomization status, reproductive history, and other APOs. Data analysis was performed from January 2020 to September 2021. Exposures: APOs (gestational diabetes, HDP, low birth weight, high birth weight, and preterm delivery). Main Outcomes and Measures: All confirmed cases of women hospitalized with HF and HF subtype were adjudicated by trained physicians using standardized methods. Results: Of 10 292 women (median [IQR] age, 60 [55-64] years), 3185 (31.0%) reported 1 or more APO and 336 (3.3%) had a diagnosis of HF. Women with a history of any APO had a higher prevalence of hypertension, diabetes, coronary heart disease, or smoking. Of the APOs studied, only HDP was significantly associated with HF with a fully adjusted odds ratio (OR) of 1.75 (95% CI, 1.22-2.50), and with HF with preserved ejection fraction in fully adjusted models (OR, 2.06; 95% CI, 1.29-3.27). In mediation analyses, hypertension explained 24% (95% CI, 12%-73%), coronary heart disease 23% (95% CI, 11%-68%), and body mass index 20% (95% CI, 10%-64%) of the association between HDP and HF. Conclusions and Relevance: In this large cohort of postmenopausal women, HDP was independently associated with incident HF, particularly HF with preserved ejection fraction, and this association was mediated by subsequent hypertension, coronary heart disease, and obesity. These findings suggest that monitoring and modifying these factors early in women presenting with HDP may be associated with reduced long-term risk of HF.

The short physical performance battery and incident heart failure among older women: the OPACH study.

OBJECTIVE: Reduced functional capacity is a hallmark of early pre-clinical stages of heart failure (HF). The Short Physical Performance Battery (SPPB) is a valid measure of lower extremity physical function, has relatively low implementation burden, and is associated with cardiovascular disease and mortality. However, the SPPB-HF association is understudied in older women among whom HF burden is high. METHODS: Women (n = 5325; mean age 79 ± 7 years; 34% Black, 18% Hispanic, and 49% White) without prior HF completed the SPPB consisting of standing balance, strength, and walking tests that were summarized as a composite score from 0 (lowest) to 12 (highest), categorized as very low (0-3), low (4-6), medium (7-9), or high (10-12). Participants were followed for up to 8 years for incident HF (306 cases identified). Cox proportional hazards regression estimated hazard ratios (HR) adjusting for age, race/ethnicity, education, smoking, alcohol, diabetes, hypertension, COPD, osteoarthritis, depression, BMI, systolic blood pressure, lipids, glucose, and accelerometer-measured moderate-vigorous physical activity (MVPA) and sedentary time. RESULTS: Incident HF cases (crude rate per 1000 person-years) in the four SPPB categories (very low to high) were 34 (26.0), 79 (14.5), 128 (9.3), and 65 (5.6). Corresponding multivariable-adjusted HRs (95% CIs) were 2.22 (1.34-3.66), 1.63 (1.11-2.38), 1.39 (1.00-1.94), and 1.00 (referent; P-trend<0.001). Higher HF risk was associated with lower SPPB in women with major modifiable HF risk factors including obesity (HR per 3-unit SPPB decrement: present HR = 1.41, absent HR = 1.41), hypertension (present HR = 1.45, absent HR = 1.30), diabetes (present HR = 1.32, absent HR = 1.44), and lower accelerometer-measured MVPA (<45 min/day HR = 1.29, ≥45 min/day HR = 1.60); all P-interaction>0.10. CONCLUSION: Lower SPPB scores were associated with greater risk of incident HF in older women even after accounting for differences in HF risk factors and objectively measured PA. Implementing the SPPB in clinical settings could potentially enhance individual-level HF risk assessment, which should be further explored.

Performance of the IBIS/Tyrer-Cuzick model of breast cancer risk by race and ethnicity in the Women's Health Initiative.

BACKGROUND: The IBIS/Tyrer-Cuzick model is used clinically to guide breast cancer screening and prevention, but was developed primarily in non-Hispanic White women. Little is known about its long-term performance in a racially/ethnically diverse population. METHODS: The Women's Health Initiative study enrolled postmenopausal women from 1993-1998. Women were included who were aged <80 years at enrollment with no prior breast cancer or mastectomy and with data required for IBIS/Tyrer-Cuzick calculation (weight; height; ages at menarche, first birth, and menopause; menopausal hormone therapy use; and family history of breast or ovarian cancer). Calibration was assessed by the ratio of observed breast cancer cases to the number expected by the IBIS/Tyrer-Cuzick model (O/E; calculated as the sum of cumulative hazards). Differential discrimination was tested for by self-reported race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, Asian or Pacific Islander, and American Indian or Alaskan Native) using Cox regression. Exploratory analyses, including simulation of a protective single-nucleotide polymorphism (SNP), rs140068132 at 6q25, were performed. RESULTS: During follow-up (median 18.9 years, maximum 23.4 years), 6783 breast cancer cases occurred among 90,967 women. IBIS/Tyrer-Cuzick was well calibrated overall (O/E ratio = 0.95; 95% CI, 0.93-0.97) and in most racial/ethnic groups, but overestimated risk for Hispanic women (O/E ratio = 0.75; 95% CI, 0.62-0.90). Discrimination did not differ by race/ethnicity. Exploratory simulation of the protective SNP suggested improved IBIS/Tyrer-Cuzick calibration for Hispanic women (O/E ratio = 0.80; 95% CI, 0.66-0.96). CONCLUSIONS: The IBIS/Tyrer-Cuzick model is well calibrated for several racial/ethnic groups over 2 decades of follow-up. Studies that incorporate genetic and other risk factors, particularly among Hispanic women, are essential to improve breast cancer-risk prediction.

Nutritional epidemiology and the Women's Health Initiative: a review.

The dietary modification (DM) clinical trial, within the Women's Health Initiative (WHI), studied a low-fat dietary pattern intervention that included guidance to increase vegetables, fruit, and grains. This study was motivated in part from uncertainty about the reliability of observational studies examining the association between dietary fat and chronic disease risk by using self-reported dietary data. In addition to this large trial, which had breast and colorectal cancer as its primary outcomes, a substantial biomarker research effort was initiated midway in the WHI program to contribute to nutritional epidemiology research more broadly. Here we review and update findings from the DM trial and from the WHI nutritional biomarker studies and examine implications for future nutritional epidemiology research. The WHI included the randomized controlled DM trial (n = 48,835) and a prospective cohort observational (OS) study (n = 93,676), both among postmenopausal US women, aged 50-79 y when enrolled during 1993-1998. Also reviewed is a nutrition and physical activity assessment study in a subset of 450 OS participants (2007-2009) and a related controlled feeding study among 153 WHI participants (2010-2014). Long-term follow-up in the DM trial provides evidence for intervention-related reductions in breast cancer mortality, diabetes requiring insulin, and coronary artery disease in the subset of normotensive healthy women, without observed adverse effects or changes in all-cause mortality. Studies of intake biomarkers, and of biomarker-calibrated intake, suggest important associations of total energy intake and macronutrient dietary composition with the risk for major chronic diseases among postmenopausal women. Collectively these studies argue for a nutrition epidemiology research agenda that includes major efforts in nutritional biomarker development, and in the application of biomarkers combined with self-reported dietary data in disease association analyses. We expect such efforts to yield novel disease association findings and to inform disease prevention approaches for potential testing in dietary intervention trials. This trial was registered at clinicaltrials.gov as NCT00000611.