Research Centers Collaborative Network Workshop on Digital Health Approaches to Research in Aging.

Digital health technologies are ubiquitous in the healthcare landscape. Older adults represent an important user group who may benefit from improved monitoring of physical and cognitive health and in-home access to care, but there remain many barriers to widespread use of digital health technologies in gerontology and geriatric medicine. The National Institute on Aging Research Centers Collaborative Network convened a workshop wherein geriatricians and gerontological researchers with expertise related to mHealth and digital health applications shared opportunities and challenges in the application of digital health technologies in aging. Discussion broadly centered on 2 themes: promises and challenges in (i) the use of ecological momentary assessment methodologies in gerontology and geriatric medicine, and (ii) the development of health promotion programs delivered via digital health technologies. Herein, we summarize this discussion and outline several promising areas for future research.

New horizons in frailty identification via electronic frailty indices: early implementation lessons from experiences in England and the United States.

Frailty represents an integrative prognostic marker of risk that associates with a myriad of age-related adverse outcomes in older adults. As a concept, frailty can help to target scarce resources and identify subgroups of vulnerable older adults that may benefit from interventions or changes in medical management, such as pursing less aggressive glycaemic targets for frail older adults with diabetes. In practice, however, there are several operational challenges to implementing frailty screening outside the confines of geriatric medicine. Electronic frailty indices (eFIs) based on the theory of deficit accumulation, derived from routine data housed in the electronic health record, have emerged as a rapid, feasible and valid approach to screen for frailty at scale. The goal of this paper is to describe the early experience of three diverse groups in developing, implementing and adopting eFIs (The English National Health Service, US Department of Veterans Affairs and Atrium Health-Wake Forest Baptist). These groups span different countries and organisational complexity, using eFIs for both research and clinical care, and represent different levels of progress with clinical implementation. Using an implementation science framework, we describe common elements of successful implementation in these settings and set an agenda for future research and expansion of eFI-informed initiatives.

Intensive Blood Pressure Treatment and Subclinical Brain Infarcts: A Secondary Analysis of SPRINT (Systolic Pressure Intervention Trial).

OBJECTIVE: Subclinical brain infarcts (SBI) increase the risk for stroke and dementia, but whether they should be considered equivalent to symptomatic stroke when determining blood pressure targets remains unclear. We tested whether intensive systolic blood pressure (SBP) treatment reduced the risk of new SBI or stroke and determined the association between SBI and cognitive impairment. METHODS: In this secondary analysis of SPRINT (Systolic Pressure Intervention Trial), participants ≥50 years old, with SBP 130-180mmHg and elevated cardiovascular risk but without known clinical stroke, dementia, or diabetes, were randomized to intensive (<120mmHg) or standard (<140mmHg) SBP treatment. Brain magnetic resonance images collected at baseline and follow-up were read for SBI. The occurrence of mild cognitive impairment (MCI) or probable dementia (PD) was evaluated. RESULTS: For 667 participants at baseline, SBI were identified in 75 (11%). At median 3.9 years follow-up, 12 of 457 had new SBI on magnetic resonance imaging (5 intensive, 7 standard), whereas 8 had clinical stroke (4 per group). Baseline SBI (subhazard ratio [sHR] = 3.90; 95% CI 1.49 to 10.24; p = 0.006), but not treatment group, was associated with new SBI or stroke. For participants with baseline SBI, intensive treatment reduced their risk for recurrent SBI or stroke (sHR = 0.050; 95% CI 0.0031 to 0.79; p = 0.033). Baseline SBI also increased risk for MCI or PD during follow-up (sHR = 2.38; 95% CI 1.23 to 4.61; p = 0.010). INTERPRETATION: New cerebral ischemic events were infrequent, but intensive treatment mitigated the increased risk for participants with baseline SBI, indicating primary prevention SBP goals are still appropriate when SBI are present. ANN NEUROL 2024.

Ascertainment and Statistical Issues for Randomized Trials of Cardiovascular Interventions for Cognitive Impairment and Dementia.

There has been considerable progress in the prevention and treatment of cardiovascular disease, reducing the population burden of cardiovascular morbidity and mortality. Recently, some randomized trials, including the SPRINT (Systolic Blood Pressure Intervention Trial), have suggested that improvements in cardiovascular risk factors may also slow cognitive decline and reduce the eventual development of dementia. Unfortunately, the randomized trial template that has been used repeatedly to successfully demonstrate reductions in major adverse cardiac events faces several design and analytic obstacles when applied in the context of cognitive decline and dementia. Here, we review these obstacles, motivated by SPRINT and the context of selecting an appropriate cognitive end point for future preventive randomized trials. A few options are available, spanning neuropsychological test scores or composites reflecting specific domains of cognitive function, adjudicated cognitive impairment, or potentially physiological biomarkers. This choice entails considerations around statistical power, modes of ascertainment, the clinical relevance of treatment effects, a myriad of statistical issues (interval censoring, missing data, the competing risk of death, practice effects, etc), as well as ethical considerations around equipoise. Collectively, these considerations indicate that trials aiming to mitigate the cardiovascular contribution to cognitive decline and dementia will generally need to be large, inclusive of a wide age range of older adults, and with multiple years of follow-up.

Cerebrovascular reactivity in Alzheimer's disease signature regions is associated with mild cognitive impairment in adults with hypertension.

INTRODUCTION: Vascular risk factors contribute to cognitive decline suggesting that maintaining cerebrovascular health could reduce dementia risk. The objective of this study is to evaluate the association of cerebrovascular reactivity (CVR), a measure of brain blood vessel elasticity, with mild cognitive impairment (MCI) and dementia. METHODS: Participants were enrolled in the Systolic Blood Pressure Intervention Trial Memory and Cognition in Decreased Hypertension (SPRINT-MIND) magnetic resonance imaging substudy. Baseline CVR in Alzheimer's disease (AD) signature regions were primary variables of interest. The occipital pole and postcentral gyrus were included as control regions. RESULTS: Higher AD composite CVR was associated with lower MCI risk. No significant associations between inferior temporal gyrus, occipital pole, or postcentral gyrus CVR and MCI risk, or any regional CVR-combined risk associations were observed. DISCUSSION: CVR in AD signature regions is negatively associated with occurrence of MCI, implicating CVR in AD signature regions as a potential mechanism leading to cognitive impairment.

The Association of Frailty and Neighborhood Disadvantage with Emergency Department Visits and Hospitalizations in Older Adults.

BACKGROUND: Risk stratification and population management strategies are critical for providing effective and equitable care for the growing population of older adults in the USA. Both frailty and neighborhood disadvantage are constructs that independently identify populations with higher healthcare utilization and risk of adverse outcomes. OBJECTIVE: To examine the joint association of these factors on acute healthcare utilization using two pragmatic measures based on structured data available in the electronic health record (EHR). DESIGN: In this retrospective observational study, we used EHR data to identify patients aged ≥ 65 years at Atrium Health Wake Forest Baptist on January 1, 2019, who were attributed to affiliated Accountable Care Organizations. Frailty was categorized through an EHR-derived electronic Frailty Index (eFI), while neighborhood disadvantage was quantified through linkage to the area deprivation index (ADI). We used a recurrent time-to-event model within a Cox proportional hazards framework to examine the joint association of eFI and ADI categories with healthcare utilization comprising emergency visits, observation stays, and inpatient hospitalizations over one year of follow-up. KEY RESULTS: We identified a cohort of 47,566 older adults (median age = 73, 60% female, 12% Black). There was an interaction between frailty and area disadvantage (P = 0.023). Each factor was associated with utilization across categories of the other. The magnitude of frailty's association was larger than living in a disadvantaged area. The highest-risk group comprised frail adults living in areas of high disadvantage (HR 3.23, 95% CI 2.99-3.49; P < 0.001). We observed additive effects between frailty and living in areas of mid- (RERI 0.29; 95% CI 0.13-0.45; P < 0.001) and high (RERI 0.62, 95% CI 0.41-0.83; P < 0.001) neighborhood disadvantage. CONCLUSIONS: Considering both frailty and neighborhood disadvantage may assist healthcare organizations in effectively risk-stratifying vulnerable older adults and informing population management strategies. These constructs can be readily assessed at-scale using routinely collected structured EHR data.

Automated Electronic Frailty Index-Identified Frailty Status and Associated Postsurgical Adverse Events.

Importance: Electronic frailty index (eFI) is an automated electronic health record (EHR)-based tool that uses a combination of clinical encounters, diagnosis codes, laboratory workups, medications, and Medicare annual wellness visit data as markers of frailty status. The association of eFI with postanesthesia adverse outcomes has not been evaluated. Objective: To examine the association of frailty, calculated as eFI at the time of the surgical procedure and categorized as fit, prefrail, or frail, with adverse events after elective noncardiac surgery. Design, Setting, and Participants: This cohort study was conducted at a tertiary care academic medical center in Winston-Salem, North Carolina. The cohort included patients 55 years or older who underwent noncardiac surgery of at least 1 hour in duration between October 1, 2017, and June 30, 2021. Exposure: Frailty calculated by the eFI tool. Preoperative eFI scores were calculated based on available data 1 day prior to the procedure and categorized as fit (eFI score: ≤0.10), prefrail (eFI score: >0.10 to ≤0.21), or frail (eFI score: >0.21). Main Outcomes and Measures: The primary outcome was a composite of the following 8 adverse component events: 90-item Patient Safety Indicators (PSI 90) score, hospital-acquired conditions, in-hospital mortality, 30-day mortality, 30-day readmission, 30-day emergency department visit after surgery, transfer to a skilled nursing facility after surgery, or unexpected intensive care unit admission after surgery. Secondary outcomes were each of the component events of the composite. Results: Of the 33 449 patients (median [IQR] age, 67 [61-74] years; 17 618 females [52.7%]) included, 11 563 (34.6%) were classified as fit, 15 928 (47.6%) as prefrail, and 5958 (17.8%) as frail. Using logistic regression models that were adjusted for age, sex, race and ethnicity, and comorbidity burden, patients with prefrail (odds ratio [OR], 1.24; 95% CI, 1.18-1.30; P < .001) and frail (OR, 1.71; 95% CI, 1.58-1.82; P < .001) statuses were more likely to experience postoperative adverse events compared with patients with a fit status. Subsequent adjustment for all other potential confounders or covariates did not alter this association. For every increase in eFI of 0.03 units, the odds of a composite of postoperative adverse events increased by 1.06 (95% CI, 1.03-1.13; P < .001). Conclusions and Relevance: This cohort study found that frailty, as measured by an automatically calculated index integrated within the EHR, was associated with increased risk of adverse events after noncardiac surgery. Deployment of eFI tools may support screening and possible risk modification, especially in patients who undergo high-risk surgery.

Effect of Intensive Blood Pressure Control on Kidney Outcomes: Long-Term Electronic Health Record-Based Post-Trial Follow-Up of SPRINT.

BACKGROUND: Intensive BP lowering in the Systolic Blood Pressure Intervention Trial (SPRINT) produced acute decreases in kidney function and higher risk for AKI. We evaluated the effect of intensive BP lowering on long-term changes in kidney function using trial and outpatient electronic health record (EHR) creatinine values. METHODS: SPRINT data were linked with EHR data from 49 (of 102) study sites. The primary outcome was the total slope of decline in eGFR for the intervention phase and the post-trial slope of decline during the observation phase using trial and outpatient EHR values. Secondary outcomes included a ≥30% decline in eGFR to <60 ml/min per 1.73 m 2 and a ≥50% decline in eGFR or kidney failure among participants with baseline eGFR ≥60 and <60 ml/min per 1.73 m 2 , respectively. RESULTS: EHR creatinine values were available for a median of 8.3 years for 3041 participants. The total slope of decline in eGFR during the intervention phase was -0.67 ml/min per 1.73 m 2 per year (95% confidence interval [CI], -0.79 to -0.56) in the standard treatment group and -0.96 ml/min per 1.73 m 2 per year (95% CI, -1.08 to -0.85) in the intensive treatment group ( P < 0.001). The slopes were not significantly different during the observation phase: -1.02 ml/min per 1.73 m 2 per year (95% CI, -1.24 to -0.81) in the standard group and -0.85 ml/min per 1.73 m 2 per year (95% CI, -1.07 to -0.64) in the intensive group. Among participants without CKD at baseline, intensive treatment was associated with higher risk of a ≥30% decline in eGFR during the intervention (hazard ratio, 3.27; 95% CI, 2.43 to 4.40), but not during the postintervention observation phase. In those with CKD at baseline, intensive treatment was associated with a higher hazard of eGFR decline only during the intervention phase (hazard ratio, 1.95; 95% CI, 1.03 to 3.70). CONCLUSIONS: Intensive BP lowering was associated with a steeper total slope of decline in eGFR and higher risk for kidney events during the intervention phase of the trial, but not during the postintervention observation phase.

Association of Intensive Lifestyle Intervention for Type 2 Diabetes With Labor Market Outcomes.

Importance: An intensive lifestyle intervention (ILI) has been shown to improve diabetes management and physical function. These benefits could lead to better labor market outcomes, but this has not been previously studied. Objective: To estimate the association of an ILI for weight loss in type 2 diabetes with employment, earnings, and disability benefit receipt during and after the intervention. Design, Setting, and Participants: This cohort study included participants with type 2 diabetes and overweight or obesity and compared an ILI with a control condition of diabetes support and education. Data for the original trial were accrued from August 22, 2001, to September 14, 2012. Trial data were linked with Social Security Administration records to investigate whether, relative to the control group, the ILI was associated with improvements in labor market outcomes during and after the intervention period. Difference-in-differences models estimating relative changes in employment, earnings, and disability benefit receipt between the ILI and control groups were used, accounting for prerandomization differences in outcomes for linked participants. Outcome data were analyzed from July 13, 2020, to May 17, 2023. Exposure: The ILI consisted of sessions with lifestyle counselors, dieticians, exercise specialists, and behavioral therapists on a weekly basis in the first 6 months, decreasing to a monthly basis by the fourth year, designed to achieve and maintain at least 7% weight loss. The control group received group-based diabetes education sessions 3 times annually during the first 4 years, with 1 annual session thereafter. Main Outcomes and Measures: Employment and receipt of federal disability benefits (Supplemental Security Income and Social Security Disability Insurance), earnings, and disability benefit payments from 1994 through 2018. Results: A total of 3091 trial participants were linked with Social Security Administration data (60.1% of 5145 participants initially randomized and 97.0% of 3188 of participants consenting to linkage). Among the 3091 with fully linked data, 1836 (59.4%) were women, and mean (SD) age was 58.4 (6.5) years. Baseline clinical and demographic characteristics were similar between linked participants in the ILI and control groups. Employment increased by 2.9 (95% CI, 0.3-5.5) percentage points for the ILI group relative to controls (P = .03) with no significant relative change in disability benefit receipt (-0.9 [95% CI, -2.1 to 0.3] percentage points; P = .13). Conclusions and Relevance: The findings of this cohort study suggest that an ILI to prevent the progression and complications of type 2 diabetes was associated with higher levels of employment. Labor market productivity should be considered when evaluating interventions to manage chronic diseases.

Assessment of an embedded primary care-derived electronic health record (EHR) frailty index (eFI) in older adults with acute myeloid leukemia.

INTRODUCTION: Assessing frailty is integral to treatment decision-making for older adults with acute myeloid leukemia (AML). Prior electronic frailty indices (eFI) derive from an accumulated-deficit model and are associated with mortality in older primary care populations. We evaluated use of an embedded eFI in AML by describing baseline eFI categories by treatment type and exploring associations between eFI categories, survival, and treatment received. MATERIALS AND METHODS: This was a retrospective study of subjects ≥60 years old with new AML treated at an academic medical center from 1/2018-10/2020. The eFI requires ≥2 ambulatory visits over two years and uses demographics, vitals, ICD-10 codes, outpatient labs, and available functional information from Medicare Annual Wellness Visits. Frailty was defined as fit (eFI ≤ 0.10), pre-frail (0.10 < eFI ≤ 0.21), and frail (eFI > 0.21). Chemotherapy was intensive (anthracycline-based) or less-intensive (hypomethylating agent, low dose cytarabine +/- venetoclax). Therapy type, pre-treatment characteristics, and chemotherapy cycles were compared by eFI category using chi-square and Fisher's exact tests and ANOVA. Median survival was compared by eFI category using log-rank tests stratified by therapy type. RESULTS: Among 166 older adults treated for AML (mean age 74 years, 61% male, 85% Caucasian), only 79 (48%) had a calculable eFI score before treatment. Of these, baseline eFI category was associated with treatment received (fit (n = 31): 68% intensive, 32% less intensive; pre-frail (n = 38): 37% intensive, 63% less intensive; frail (n = 10): 0% intensive, 100% less intensive; not calculable (n = 87): 48% intensive, 52% less-intensive; p < 0.01). The prevalence of congestive heart failure and secondary AML differed by frailty status (p < 0.01). Median survival did not differ between eFI categories for intensively (p = 0.48) or less-intensively (p = 0.09) treated patients. For those with less-intensive therapy who lived ≥6 months, eFI category was not associated with the number of chemotherapy cycles received (p = 0.97). The main reason for an incalculable eFI was a lack of outpatient visits in our health system prior to AML diagnosis. DISCUSSION: A primary care-derived eFI was incalculable for half of older adults with AML at an academic medical center. Frailty was associated with chemotherapy intensity but not survival or treatment duration. Next steps include testing adaptations of the eFI to the AML setting.

Clinical trials in vascular cognitive impairment following SPRINT-MIND: An international perspective.

A large interventional trial, the Systolic Blood Pressure Intervention Trial sub-study termed Memory and Cognition in Decreased Hypertension (SPRINT-MIND), found reduced risk of cognitive impairment in older adults with intensive, relative to standard, blood-pressure-lowering targets (systolic BP < 120 vs. <140 mm Hg). In this perspective, we discuss key questions and make recommendations for clinical practice and for clinical trials, following SPRINT-MIND. Future trials should embody cognitive endpoints appropriate to the participant group, ideally with adaptive designs that ensure robust answers for cognitive and cardiovascular endpoints. Reliable data from diverse populations, including the oldest-old (age > 80 years), will maximize external validity and global implementation of trial findings. New biomarkers will improve phenotyping to stratify patients to optimal treatments. Currently no antihypertensive drug class stands out for dementia risk reduction. Multi-domain interventions, incorporating lifestyle change (exercise, diet) alongside medications, may maximize global impact. Given the low cost and wide availability of antihypertensive drugs, intensive BP reduction may be a cost-effective means to reduce dementia risk in diverse, aging populations worldwide.

Identifying Patients for Intensive Blood Pressure Treatment Based on Cognitive Benefit: A Secondary Analysis of the SPRINT Randomized Clinical Trial.

Importance: Intensive vs standard treatment to lower systolic blood pressure (SBP) reduces risk of mild cognitive impairment (MCI) or dementia; however, the magnitude of cognitive benefit likely varies among patients. Objective: To estimate the magnitude of cognitive benefit of intensive vs standard systolic BP (SBP) treatment. Design, Setting, and Participants: In this ad hoc secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), 9361 randomized clinical trial participants 50 years or older with high cardiovascular risk but without a history of diabetes, stroke, or dementia were followed up. The SPRINT trial was conducted between November 1, 2010, and August 31, 2016, and the present analysis was completed on October 31, 2022. Intervention: Systolic blood pressure treatment to an intensive (<120 mm Hg) vs standard (<140 mm Hg) target. Main Outcomes and Measures: The primary outcome was a composite of adjudicated probable dementia or amnestic MCI. Results: A total of 7918 SPRINT participants were included in the analysis; 3989 were in the intensive treatment group (mean [SD] age, 67.9 [9.2] years; 2570 [64.4%] men; 1212 [30.4%] non-Hispanic Black) and 3929 were in the standard treatment group (mean [SD] age, 67.9 [9.4] years; 2570 [65.4%] men; 1249 [31.8%] non-Hispanic Black). Over a median follow-up of 4.13 (IQR, 3.50-5.88) years, there were 765 and 828 primary outcome events in the intensive treatment group and standard treatment group, respectively. Older age (hazard ratio [HR] per 1 SD, 1.87 [95% CI, 1.78-1.96]), Medicare enrollment (HR per 1 SD, 1.42 [95% CI, 1.35-1.49]), and higher baseline serum creatinine level (HR per 1 SD, 1.24 [95% CI, 1.19-1.29]) were associated with higher risk of the primary outcome, while better baseline cognitive functioning (HR per 1 SD, 0.43 [95% CI, 0.41-0.44]) and active employment status (HR per 1 SD, 0.44 [95% CI, 0.42-0.46]) were associated with lower risk of the primary outcome. Risk of the primary outcome by treatment goal was estimated accurately based on similar projected and observed absolute risk differences (C statistic = 0.79). Higher baseline risk for the primary outcome was associated with greater benefit (ie, larger absolute reduction of probable dementia or amnestic MCI) of intensive vs standard treatment across the full range of estimated baseline risk. Conclusions and Relevance: In this secondary analysis of the SPRINT trial, participants with higher baseline projected risk of probable dementia or amnestic MCI gained greater absolute cognitive benefit from intensive vs standard SBP treatment in a monotonic fashion. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Evidence for Age Bias Contributing to Therapeutic Inertia in Blood Pressure Management: A Secondary Analysis of SPRINT.

BACKGROUND: Despite evidence supporting the cardiovascular and cognitive benefits of intensive blood pressure management, older adults have the lowest rates of blood pressure control. We determined the association between age and therapeutic inertia (TI) in SPRINT (Systolic Blood Pressure Intervention Trial), and whether frailty, cognitive function, or gait speed moderate or mediate these associations. METHODS: We performed a secondary analysis of SPRINT of participant visits with blood pressure above randomized treatment goal. We categorized baseline age as <60, 60 to <70, 70 to <80, and ≥80 years and TI as no antihypertensive medication intensification per participant visit. Generalized estimating equations generated odds ratios for TI associated with age, stratified by treatment group based on nested models adjusted for baseline frailty index score (fit [frailty index, ≤0.10], less fit [0.100.10). CONCLUSIONS: Older age is associated with greater TI independent of physical or cognitive function, implying age bias in hypertension management.

Performance of Cox regression models for composite time-to-event endpoints with component-wise censoring in randomized trials.

BACKGROUND: Composite time-to-event endpoints are beneficial for assessing related outcomes jointly in clinical trials, but components of the endpoint may have different censoring mechanisms. For example, in the PRagmatic EValuation of evENTs And Benefits of Lipid-lowering in oldEr adults (PREVENTABLE) trial, the composite outcome contains one endpoint that is right censored (all-cause mortality) and two endpoints that are interval censored (dementia and persistent disability). Although Cox regression is an established method for time-to-event outcomes, it is unclear how models perform under differing component-wise censoring schemes for large clinical trial data. The goal of this article is to conduct a simulation study to investigate the performance of Cox models under different scenarios for composite endpoints with component-wise censoring. METHODS: We simulated data by varying the strength and direction of the association between treatment and outcome for the two component types, the proportion of events arising from the components of the outcome (right censored and interval censored), and the method for including the interval-censored component in the Cox model (upper value and midpoint of the interval). Under these scenarios, we compared the treatment effect estimate bias, confidence interval coverage, and power. RESULTS: Based on the simulation study, Cox models generally have adequate power to achieve statistical significance for comparing treatments for composite outcomes with component-wise censoring. In our simulation study, we did not observe substantive bias for scenarios under the null hypothesis or when the treatment has a similar relative effect on each component outcome. Performance was similar regardless of if the upper value or midpoint of the interval-censored part of the composite outcome was used. CONCLUSION: Cox regression is a suitable method for analysis of clinical trial data with composite time-to-event endpoints subject to different component-wise censoring mechanisms.

Concordance between clinical outcomes in the Systolic Blood Pressure Intervention Trial and in the electronic health record.

BACKGROUND: Randomized trials are the gold standard for generating clinical practice evidence, but follow-up and outcome ascertainment are resource-intensive. Electronic health record (EHR) data from routine care can be a cost-effective means of follow-up, but concordance with trial-ascertained outcomes is less well-studied. METHODS: We linked EHR and trial data for participants of the Systolic Blood Pressure Intervention Trial (SPRINT), a randomized trial comparing intensive and standard blood pressure targets. Among participants with available EHR data concurrent to trial-ascertained outcomes, we calculated sensitivity, specificity, positive predictive value, and negative predictive value for EHR-recorded cardiovascular disease (CVD) events, using the gold standard of SPRINT-adjudicated outcomes (myocardial infarction (MI)/acute coronary syndrome (ACS), heart failure, stroke, and composite CVD events). We additionally compared the incidence of non-CVD adverse events (hyponatremia, hypernatremia, hypokalemia, hyperkalemia, bradycardia, and hypotension) in trial versus EHR data. RESULTS: 2468 SPRINT participants were included (mean age 68 (SD 9) years; 26% female). EHR data demonstrated ≥80% sensitivity and specificity, and ≥ 99% negative predictive value for MI/ACS, heart failure, stroke, and composite CVD events. Positive predictive value ranged from 26% (95% CI; 16%, 38%) for heart failure to 52% (95% CI; 37%, 67%) for MI/ACS. EHR data uniformly identified more non-CVD adverse events and higher incidence rates compared with trial ascertainment. CONCLUSIONS: These results support a role for EHR data collection in clinical trials, particularly for capturing laboratory-based adverse events. EHR data may be an efficient source for CVD outcome ascertainment, though there is clear benefit from adjudication to avoid false positives.

Pragmatic evaluation of events and benefits of lipid lowering in older adults (PREVENTABLE): Trial design and rationale.

Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double-blind, placebo-controlled randomized pragmatic clinical trial, will compare high-intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community-dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site-reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co-secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults.

Association of Intensive vs Standard Blood Pressure Control With Regional Changes in Cerebral Small Vessel Disease Biomarkers: Post Hoc Secondary Analysis of the SPRINT MIND Randomized Clinical Trial.

Importance: Little is known about the associations of strict blood pressure (BP) control with microstructural changes in small vessel disease markers. Objective: To investigate the regional associations of intensive vs standard BP control with small vessel disease biomarkers, such as white matter lesions (WMLs), fractional anisotropy (FA), mean diffusivity (MD), and cerebral blood flow (CBF). Design, Setting, and Participants: The Systolic Blood Pressure Intervention Trial (SPRINT) is a multicenter randomized clinical trial that compared intensive systolic BP (SBP) control (SBP target <120 mm Hg) vs standard control (SBP target <140 mm Hg) among participants aged 50 years or older with hypertension and without diabetes or a history of stroke. The study began randomization on November 8, 2010, and stopped July 1, 2016, with a follow-up duration of approximately 4 years. A total of 670 and 458 participants completed brain magnetic resonance imaging at baseline and follow-up, respectively, and comprise the cohort for this post hoc analysis. Statistical analyses for this post hoc analysis were performed between August 2020 and October 2022. Interventions: At baseline, 355 participants received intensive SBP treatment and 315 participants received standard SBP treatment. Main Outcomes and Measures: The main outcomes were regional changes in WMLs, FA, MD (in white matter regions of interest), and CBF (in gray matter regions of interest). Results: At baseline, 355 participants (mean [SD] age, 67.7 [8.0] years; 200 men [56.3%]) received intensive BP treatment and 315 participants (mean [SD] age, 67.0 [8.4] years; 199 men [63.2%]) received standard BP treatment. Intensive treatment was associated with smaller mean increases in WML volume compared with standard treatment (644.5 mm3 vs 1258.1 mm3). The smaller mean increases were observed specifically in the deep white matter regions of the left anterior corona radiata (intensive treatment, 30.3 mm3 [95% CI, 16.0-44.5 mm3]; standard treatment, 80.5 mm3 [95% CI, 53.8-107.2 mm3]), left tapetum (intensive treatment, 11.8 mm3 [95% CI, 4.4-19.2 mm3]; standard treatment, 27.2 mm3 [95% CI, 19.4-35.0 mm3]), left superior fronto-occipital fasciculus (intensive treatment, 3.2 mm3 [95% CI, 0.7-5.8 mm3]; standard treatment, 9.4 mm3 [95% CI, 5.5-13.4 mm3]), left posterior corona radiata (intensive treatment, 26.0 mm3 [95% CI, 12.9-39.1 mm3]; standard treatment, 52.3 mm3 [95% CI, 34.8-69.8 mm3]), left splenium of the corpus callosum (intensive treatment, 45.4 mm3 [95% CI, 25.1-65.7 mm3]; standard treatment, 83.0 mm3 [95% CI, 58.7-107.2 mm3]), left posterior thalamic radiation (intensive treatment, 53.0 mm3 [95% CI, 29.8-76.2 mm3]; standard treatment, 106.9 mm3 [95% CI, 73.4-140.3 mm3]), and right posterior thalamic radiation (intensive treatment, 49.5 mm3 [95% CI, 24.3-74.7 mm3]; standard treatment, 102.6 mm3 [95% CI, 71.0-134.2 mm3]). Conclusions and Relevance: This study suggests that intensive BP treatment, compared with standard treatment, was associated with a slower increase of WMLs, improved diffusion tensor imaging, and FA and CBF changes in several brain regions that represent vulnerable areas that may benefit from more strict BP control. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.