AS360 - Physical activity to improve cardiovascular health in women: a pragmatic trial (WHISH) CCC

Investigator Names and Contact Information

Marcia Stefanick (stefanick@stanford.edu)

Introduction/Intent

AS360: Physical activity to improve cardiovascular health in women: a pragmatic trial (WHISH) CCC Grant Period 2015-2021

SPECIFIC AIMS Between 2010 and 2050, the United States is projected to experience rapid growth in its older population, with the number of Americans aged 65 and older projected to be 88.5 million (55% women).3 These dramatic demographic changes create a public health mandate to identify effective interventions that will preserve the health and independence of older women. Compelling evidence supports the importance of physical activity (PA) for reducing the risk of cardiovascular disease (CVD), e.g., fatal and non-fatal myocardial infarction (MI), and ischemic stroke,4-7 as well as preserving physical and cognitive health and reducing functional limitations such as impaired mobility,8 in older adults. In nearly 74,000 Women’s Health Initiative (WHI) Observational Study participants, initially aged 50-79 years, both walking and vigorous exercise were associated with substantially lower CVD rates during a mean 3.2 years of follow-up, irrespective of race/ethnicity group, age, and body-mass index.9 Prolonged sedentary time also predicted CVD risk9 independent of leisure-time PA, and the combination of low PA and prolonged sitting (≥10 hours/day) augmented CV risk.10 Despite the steady emergence of evidence-based interventions for increasing PA in older adults that can be delivered on a large scale, we still lack adequate randomized trial data demonstrating that these interventions prevent clinical events, improve functional status (and independence), or impact public health.11 To address this critical gap, we propose a large-scale pragmatic, randomized controlled trial, the Women’s Health Initiative Strong & Healthy (WHISH) trial. To maximize efficiencies of study design and implementation, this multi-site clinical trial will be embedded in the ongoing WHI Extension cohort of women, now aged 63-99 years. The WHISH trial will test the hypothesis that a centralized, public health intervention designed to increase and/or maintain PA levels in older women will reduce major CV events (MI, stroke, and CVD death) in older women over an approximate 4-year period. CVD outcomes will be ascertained using established pre-existing methods and the infrastructure in place in the WHI Extension Study, including annual mailings with centralized physician adjudication of CV events in a Medical Records Cohort of ~20,000 women and use of Centers of Medicare & Medicaid Services (CMS) records for an additional ~32,500 women, supplemented by National Death Index data for all. The WHI infrastructure, combined with innovative, evidence-based means to deliver the PA intervention to community-dwelling older women, provides a unique opportunity to extend the generalizability of PA benefits. Demonstrating that a cost- and resource-efficient PA intervention can reduce the CV health burden of older women has major public health significance. We propose to apply state-of-the science behavioral approaches and currently available though under-utilized technologies to deliver a PA intervention in a highly efficient manner without the need for major direct human contact to ~21,000 WHI participants expected to consent after being randomized to the PA intervention. We will use an algorithm-driven interactive voice response (IVR) system, built to complement National Institute on Aging (NIA) Go4Life® Exercise & Physical Activity materials, to provide tailored advice on how to achieve nationally recommended levels of PA and overcome barriers to exercise, with a means for self-monitoring (IVR-based logging activity) and setting personal goals with feedback. The PA intervention builds on evidence-based behavioral science principles and program components that have proven to be effective in increasing PA in older women, with innovative adaptive approaches to tailoring the delivery to meet individual needs. Specific Aims:

Primary Aim: Conduct a pragmatic, randomized controlled trial in 50,500 older women enrolled in the WHI Extension Study by allocating women to a tailored physical activity (PA) intervention or “usual activity” (observational study comparison group) and following them for CVD outcomes over approximately 4 years.

Primary hypothesis: A tailored PA intervention designed to improve levels of aerobic PA, combined with muscle strengthening, balance and flexibility exercises, and reduced sedentary behavior, will reduce major CV events (defined as a composite outcome of MI, stroke, and CV death), compared to the “usual activity” group.

Safety Aims: Evaluate whether the tailored PA intervention increases the individual risks of total clinical fracture, hip fracture, falls, and non-CVD mortality over the follow-up period.

Secondary Aim: Evaluate whether the tailored PA intervention reduces risk of selected PA-linked secondary outcomes of substantial importance to maintaining independence in older women and potentially ameliorable through regular physical activity participation.

Secondary hypotheses: Women randomized to the intervention (compared to “usual activity”) will have: a. Lower rates of venous thromboembolic events (VTE) and peripheral artery disease (PAD). b. Less loss of physical function and higher rates of ongoing mobility.

Secondary Safety Aim: Evaluate whether increased PA increases coronary revascularization (CABG or PCI).

AS450 WHISH renewal

SPECIFIC AIMS This is a competitive renewal application for the Women’s Health Initiative Strong & Healthy (WHISH) trial. America’s 65-and-older population is projected to nearly double in size from 49 million today to 95 million by 2060, with women far outnumbering men, particularly among adults aged 85-and-older.1 Compelling evidence supports the importance of physical activity (PA) for reducing cardiovascular disease (CVD) risk,5, 6 including WHI findings,7-11 and for preserving physical and cognitive health12 and reducing functional limitations and impaired mobility13 in older adults. Despite the steady emergence of evidence-based interventions for increasing PA in older adults that could be delivered on a large scale, we still lack adequate randomized trial data demonstrating that such interventions prevent clinical CVD events.5, 6 The long-term objective of the WHISH trial is to address this critical question by conducting a large-scale pragmatic, randomized controlled trial embedded in the large and race/ethnicity diverse ongoing WHI Extension Study of older women. The WHISH trial is testing the hypothesis that a centralized, public health intervention designed to increase and/or maintain PA levels and reduce sedentary behavior will reduce major CV events (MI, stroke, CV death) in older women. To simulate real-world programmatic implementation, WHISH randomized 49,333 eligible participants in the WHI Extension Study which has ongoing outcomes and data collection, to a behavioral intervention vs. usual follow-up in May 2015. A passive consent process in the Intervention group (n=24,663) resulted in <4% of women “opting out” of the intervention. WHISH delivers a targeted, adaptive, instructional intervention, based on 2008 and 2018 DHHS PA guidelines2, 3 and designed to complement the National Institute on Aging’s (NIA) Go4Life® campaign,4 using seasonal newsletters, manuals, pedometers, resistance bands, telephone and e-mail motivational messages, and a website designed specifically for older women. The intervention adapts to participant feedback from annual surveys and other input regarding activity preferences and is customized and targeted to their current PF and PA levels. Primary effectiveness and safety outcomes (CVD, fracture) are evaluated using intention-to-treat in the entire randomized population. The outcomes of WHISH could have immense translational impact on the future of physical activity dissemination programs for healthy CV aging. Therefore, continued intervention with additional follow-up and outcomes ascertainment are needed for WHISH to provide definitive answers for the following reasons: 1) At the end of this grant period (February 2020), only 4 years of follow-up will be available. Using rigorous observed trial metrics now available, longer follow-up is needed to ensure adequate power to evaluate impacts on hard CVD events; 2) long-term changes in PA are needed to influence clinical outcomes, which is why short-term trials have not been able to evaluate incident CVD events; and 3) the impacts of the WHISH intervention, regardless of effects on hard CVD endpoints, could be beneficial for other relevant markers of healthy CV aging including physical function (PF), biomarkers of myocardial and vascular health, sleep problems, and depressive symptoms, outcomes of major public health importance that we cannot adequately assess with currently available data. This application proposes to evaluate these outcomes in WHISH participants by leveraging a NHLBI-sponsored WHI Extension through 2027 with a planned “Long Life Study 2” home visit for biospecimen collection and phenotypic evaluation of healthy aging parameters. Thus, we propose the following specific aims to provide definitive answers from the WHISH Trial: Primary Aim: Continue the centralized, adaptive, targeted PA intervention and ascertainment of adjudicated CVD, fracture and non-CVD death endpoints in WHISH women retaining their randomized treatment assignment to provide a minimum of 8 years of follow-up for surviving participants. Primary hypothesis: The WHISH targeted PA intervention designed to increase aerobic PA combined with muscle strengthening, balance and flexibility exercises, and to reduce sedentary behavior, will reduce major CVD clinical events (composite of MI, stroke, and CV death), compared to the “usual follow-up” group. Secondary Aim: Determine WHISH intervention effects on measures of healthy CV aging including PF measured using the Short Physical Performance Battery (SPPB), sleep disturbances, and depressive symptoms. This Aim will use data collected in the LLS2 funded by the WHI Extension Study 2020-2027. Hypothesis: The WHISH intervention will result in higher SPPB scores, improved sleep parameters, and lower levels of depressive symptoms compared to the “usual activity” group. Exploratory Aim: Create an experimental framework within WHISH and conduct pilot studies to determine whether the WHISH PA intervention influenced levels of novel biomarkers indicative of healthy CV aging and/or occult myocardial injury, such as N-terminal pro-brain natriuretic peptide (NT-proBNP) and high sensitivity cardiac Troponin T (hsTnT). A WHISH Biomarker Advisory Group involving US experts will vet the most promising biomarkers for pilot testing. This aim will facilitate future WHISH/WHI Ancillary Studies and will utilize biospecimens collected in the LLS2 of the next WHI Extension Study, 2020-2027. Hypothesis: WHISH Intervention women will have more favorable levels of CVD biomarkersSPECIFIC AIMS This is a competitive renewal application for the Women’s Health Initiative Strong & Healthy (WHISH) trial. America’s 65-and-older population is projected to nearly double in size from 49 million today to 95 million by 2060, with women far outnumbering men, particularly among adults aged 85-and-older.1 Compelling evidence supports the importance of physical activity (PA) for reducing cardiovascular disease (CVD) risk,5, 6 including WHI findings,7-11 and for preserving physical and cognitive health12 and reducing functional limitations and impaired mobility13 in older adults. Despite the steady emergence of evidence-based interventions for increasing PA in older adults that could be delivered on a large scale, we still lack adequate randomized trial data demonstrating that such interventions prevent clinical CVD events.5, 6 The long-term objective of the WHISH trial is to address this critical question by conducting a large-scale pragmatic, randomized controlled trial embedded in the large and race/ethnicity diverse ongoing WHI Extension Study of older women. The WHISH trial is testing the hypothesis that a centralized, public health intervention designed to increase and/or maintain PA levels and reduce sedentary behavior will reduce major CV events (MI, stroke, CV death) in older women. To simulate real-world programmatic implementation, WHISH randomized 49,333 eligible participants in the WHI Extension Study which has ongoing outcomes and data collection, to a behavioral intervention vs. usual follow-up in May 2015. A passive consent process in the Intervention group (n=24,663) resulted in <4% of women “opting out” of the intervention. WHISH delivers a targeted, adaptive, instructional intervention, based on 2008 and 2018 DHHS PA guidelines2, 3 and designed to complement the National Institute on Aging’s (NIA) Go4Life® campaign,4 using seasonal newsletters, manuals, pedometers, resistance bands, telephone and e-mail motivational messages, and a website designed specifically for older women. The intervention adapts to participant feedback from annual surveys and other input regarding activity preferences and is customized and targeted to their current PF and PA levels. Primary effectiveness and safety outcomes (CVD, fracture) are evaluated using intention-to-treat in the entire randomized population. The outcomes of WHISH could have immense translational impact on the future of physical activity dissemination programs for healthy CV aging. Therefore, continued intervention with additional follow-up and outcomes ascertainment are needed for WHISH to provide definitive answers for the following reasons: 1) At the end of this grant period (February 2020), only 4 years of follow-up will be available. Using rigorous observed trial metrics now available, longer follow-up is needed to ensure adequate power to evaluate impacts on hard CVD events; 2) long-term changes in PA are needed to influence clinical outcomes, which is why short-term trials have not been able to evaluate incident CVD events; and 3) the impacts of the WHISH intervention, regardless of effects on hard CVD endpoints, could be beneficial for other relevant markers of healthy CV aging including physical function (PF), biomarkers of myocardial and vascular health, sleep problems, and depressive symptoms, outcomes of major public health importance that we cannot adequately assess with currently available data. This application proposes to evaluate these outcomes in WHISH participants by leveraging a NHLBI-sponsored WHI Extension through 2027 with a planned “Long Life Study 2” home visit for biospecimen collection and phenotypic evaluation of healthy aging parameters. Thus, we propose the following specific aims to provide definitive answers from the WHISH Trial:

Primary Aim: Continue the centralized, adaptive, targeted PA intervention and ascertainment of adjudicated CVD, fracture and non-CVD death endpoints in WHISH women retaining their randomized treatment assignment to provide a minimum of 8 years of follow-up for surviving participants.

Primary hypothesis: The WHISH targeted PA intervention designed to increase aerobic PA combined with muscle strengthening, balance and flexibility exercises, and to reduce sedentary behavior, will reduce major CVD clinical events (composite of MI, stroke, and CV death), compared to the “usual follow-up” group.

Secondary Aim: Determine WHISH intervention effects on measures of healthy CV aging including PF measured using the Short Physical Performance Battery (SPPB), sleep disturbances, and depressive symptoms. This Aim will use data collected in the LLS2 funded by the WHI Extension Study 2020-2027.

Hypothesis: The WHISH intervention will result in higher SPPB scores, improved sleep parameters, and lower levels of depressive symptoms compared to the “usual activity” group.

Exploratory Aim: Create an experimental framework within WHISH and conduct pilot studies to determine whether the WHISH PA intervention influenced levels of novel biomarkers indicative of healthy CV aging and/or occult myocardial injury, such as N-terminal pro-brain natriuretic peptide (NT-proBNP) and high sensitivity cardiac Troponin T (hsTnT). A WHISH Biomarker Advisory Group involving US experts will vet the most promising biomarkers for pilot testing. This aim will facilitate future WHISH/WHI Ancillary Studies and will utilize biospecimens collected in the LLS2 of the next WHI Extension Study, 2020-2027.

Hypothesis: WHISH Intervention women will have more favorable levels of CVD biomarkers