BACKGROUND AND AIMS:Frailty is associated with cardiovascular disease (CVD) through shared pathophysiology and risk factors, and frailty is a known modifiable risk factor for CVD. Statins reduce CVD risk and have anti-inflammatory properties that may lower the risk of frailty, though this has not been comprehensively examined. METHODS:Older US veterans (aged ≥67 years) who were statin naïve and received regular care in the Veteran Affairs (VA) medical system from 2002 to 2018 were included. Veterans who were frail at baseline based on a validated 31-item VA-Frailty Index (VA-FI) were excluded (scores >0.2). Data were linked to Medicare and Medicaid. Overlap propensity score weighting (PSW) was used to address confounding by indication. Cox regression models were fit to examine the association of statin use with the composite outcome of incident frailty with censoring at death. Similar analyses were conducted on pre-frail veterans (VA-FI score of 0.1-0.2). RESULTS:Of 987 301 veterans included in the study population (age 72 ± 6 years; 98% men; 87% white), 290 729 initiated statins during the study period. During a mean follow-up of 5.3 (SD 4.1) years, 636 195 incident frailty events occurred, representing unadjusted event rates of 153.1 events per 1000 person-years among statin initiators and 111.4 events per 1000 person-years in non-initiators. After PSW, new statin initiators were less likely to experience incident frailty (hazard ratio 0.76, 95% confidence interval 0.75-0.76) compared to non-initiators. Similar results were seen in pre-frail veterans. CONCLUSIONS:Statin initiation was associated with a significantly lower risk of incident frailty or death among older US veterans including those who were pre-frail at baseline.

BACKGROUND:Persons with CKD are disproportionally affected with cognitive impairment, yet the pathophysiology linking the two conditions is unclear. Because kidney tubule secretion is essential for clearance of medications, uremic toxins, and metabolites, we hypothesized that worse tubular secretion would be associated with reduced cognitive function in CKD. METHODS:The Systolic Blood Pressure Intervention Trial tested a systolic blood pressure target <120 mmHg vs. <140 mmHg in hypertensive individuals at high cardiovascular risk. In paired blood and urine specimens from 1,937 participants with eGFR <60 ml/min/1.73m2, we measured 10 endogenous tubule-secreted metabolites and calculated a urine/plasma ratio for each, then averaged these to generate a summary secretion score. We used unadjusted and multivariable-adjusted linear regression and mixed models to evaluate cross-sectional and longitudinal associations of the secretion score with the Montreal Cognitive Assessment, Digit Symbol Coding, and Logical Memory immediate and delayed tests-measured at baseline and months 24 and 48 of follow-up. Multivariable Cox regression evaluated associations with incident probable dementia and mild cognitive impairment, adjudicated by prespecified criteria. RESULTS:Mean age was 73 ± 9 years, 41% were women, mean eGFR was 48.2 ± 11.4 ml/min/1.73m2, median albuminuria was 14.8 [7.1-48.6] mg/g. Lower secretion score was associated with a 0.06 higher adjusted logical memory delayed score (95% CI: 0.02, 0.11) but not with other cognitive tests at baseline or longitudinal cognitive decline. After a median 4.1 years of follow-up, 118 developed probable dementia and 187 developed mild cognitive impairment. Each 1-SD lower secretion score was associated with lower risk of probable dementia (HR 0.78, 95% CI: 0.63, 0.98) but not mild cognitive impairment. CONCLUSIONS:Among Systolic Blood Pressure Intervention Trial participants with CKD, lower estimated tubular secretion was not associated with worse cognition at baseline or during longitudinal follow-up.

Importance:Apolipoprotein E ( APOE ) ε4 is the strongest genetic risk factor for sporadic dementia, yet whether the benefits of intensive systolic blood pressure (SBP) control differ by APOE ε4 carrier status remains unknown. This is among the first randomized evaluations of intensive SBP control on all-cause dementia by APOE ε4 status in US adults without diabetes. Objective:To compare effects of intensive vs standard SBP control on incident all-cause probable dementia between APOE ε4 carriers and non-carriers. Design Setting and Participants:Secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), a multicenter randomized trial of adults >50 years with hypertension and increased cardiovascular risk, but without diabetes, prior stroke, or dementia. Primary cognitive follow-up ended July 2018. Participants were further followed with telephone-based outcome assessment from 2019 through 2023. Interventions:Intensive SBP control (goal <120 mm Hg) vs standard SBP control (goal <140 mm Hg). Main Outcomes and Measures:The primary outcome was all-cause probable dementia. Secondary outcomes were mild cognitive impairment (MCI); MCI or dementia; MCI, dementia, or death; and all-cause mortality. APOE ε4 status was the primary effect modifier. Results:Of 9,361 randomized participants, 8,390 (89.6%) had APOE genotyping (29% ε4 carriers); 7,733 (82.6%) had both genotype and outcome data (mean age, 68 years; 36% female; 28% Non-Hispanic Black). Over a median follow-up of 5.1 years, dementia rates (intensive vs standard) were 9.7 vs 13.2 per 1,000 person-years among ε4 carriers (hazard ratio [HR], 0.73; 95% CI, 0.51-1.04) and 6.1 vs 6.7 among non-carriers (HR, 0.91; 95% CI, 0.67-1.23; P-interaction = .35). Four-year risk differences were -1.7% (95% CI, -3.4% to 0%; number needed to treat, 59) among carriers and 0.2% (95% CI, -0.6% to 1%) among non-carriers (P-interaction = .045). Patterns were similar for the composite of MCI or dementia; effects on MCI were similar between APOE ε4 subgroups. Conclusions and Relevance:Among US adults at high cardiovascular risk, intensive SBP control yielded larger absolute risk reduction in dementia among APOE ε4 carriers than non-carriers; relative effects were similar. These findings may inform APOE ε4-stratified blood pressure management for dementia prevention. KEY POINTS:Question: What is the effect of intensive vs standard systolic blood pressure (SBP) control on incident dementia by APOE ε4 status? Findings: In SPRINT, intensive vs standard SBP control yielded a significantly larger 4-year absolute risk reduction in dementia among APOE ε4 carriers (-1.7%) than non-carriers (0.2%; P-interaction = .045); the relative-scale interactions were directionally consistent but not significant. Meaning: Among US adults at high cardiovascular risk, intensive SBP control yielded larger absolute benefit among APOE ε4 carriers than non-carriers; relative benefits were similar. APOE ε4 status may inform risk-stratified blood pressure management for dementia prevention.

BACKGROUND:Current clinical practice guidelines support the long-term use of pharmacotherapy for obesity treatment. Historically, phentermine has been one of the most prescribed obesity medications (OMs), however, its long-term efficacy and safety have never been evaluated in a randomized trial as its market approval predates such requirements. Here we describe the design, rationale, and baseline characteristics for a 24-month, double-blind, randomized controlled trial evaluating the efficacy, cardiovascular risk, and safety of phentermine in adults with overweight or obesity. METHODS:This multicenter trial will compare outcomes among participants randomized to phentermine 24 mg daily versus placebo for 24 months. All participants also receive an online lifestyle intervention. A total of 870 participants with body mass index of 27-44.9 kg/m2 were randomized across six sites in North Carolina (2), Minnesota, Texas, and California (2). Primary outcomes are 24-month mean percent weight loss (efficacy), 24-month mean change in systolic blood pressure (cardiometabolic risk), and overall rates of adverse events and serious adverse events (safety). Secondary outcomes include changes in resting energy expenditure/resting metabolic rate, cardiac autonomic function measured using heart rate variability with electrocardiogram, and a self-reported measure of phentermine dependence. CONCLUSIONS:The safety and efficacy of long-term phentermine remains a pressing, unanswered question, particularly given its low cost and high availability when compared to newer OMs that are highly effective but often associated with significant costs. This study will impact clinical practice regardless of result - either providing evidence to support use of an available low-cost option or prioritizing the use of other OMs. TRIAL REGISTRATION:Clinicaltrials.gov, NCT05176626.

Aims To characterize adults with obesity in a large integrated health system. Methods We created a cross-sectional cohort of adults with at least one body mass index (BMI) value >=30 kg/m2 in the prior 18 months, a recent in-person outpatient visit, and an assigned primary care provider. Electronic health record data were transformed into a patient-level analytic dataset and linked to neighborhood-level social determinants of health. Diagnoses, laboratory values, vital signs, and prescriptions were curated using reproducible phenotype definitions and internally reviewed vocabularies. Results The registry included 284,143 adults, of whom 48% had class I obesity. The cohort was 63% female, 27% black, and 48% lived in areas with high or very high social vulnerability. Common comorbidities included hypertension, type 2 diabetes, depression, and anxiety. HbA1c and cholesterol measurements were absent in more than 40% of the cohort during the prior two years. Overall, 22% of patients received a prescription for at least one weight loss drug in the past 2 years, including 18% who received a GLP-1 agonist approved for weight management. Conclusions This care-engaged obesity cohort was characterized by high representation of women and socially vulnerable populations, substantial cardiometabolic screening gaps, and broad adoption of GLP-1 agonists.

Background:The benefits of improved systolic blood pressure (SBP) control on stroke, coronary heart disease, and heart failure are well-established, yet its effect on overall cerebral small vessel disease (SVD) burden remains uncharacterized. We examined the association between intensive SBP control and change in SVD burden. Methods:We conducted a post-hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), a multicenter randomized clinical trial. Of 1267 hypertensive individuals aged ≥50 years without diabetes or prior stroke screened for the brain MRI substudy, 663 and 442 participants completed brain MRI that met quality control criteria and had complete data on SVD indicators at baseline and at a median of 3.9 (interquartile range, 3.6-4.1) years after randomization, respectively. From November 2010 to March 2013, participants were randomly assigned to an intensive SBP target of <120 mmHg (n = 348) or a standard target of <140 mmHg (n = 315). Post-hoc outcome was change in a global SVD factor, longitudinally validated using confirmatory factor analysis and designed to capture overall SVD-related vascular brain injury by integrating three complementary imaging endophenotypes: periventricular white matter hyperintensities, white matter free water, and basal ganglia perivascular spaces. This trial is registered with ClinicalTrials.gov (NCT01206062). Findings:Mean [SD] baseline age was 68.1 (8.6) years; 263 [40%] participants were women. Compared with standard SBP treatment, intensive treatment was associated with significantly less SVD progression (standardized mean difference [Cohen's d] = -0.40 [95% CI, -0.62 to -0.17]). We also observed gradually more favorable SVD burden changes with greater attained SBP reductions, demonstrating a clear dose-response relationship: 21.2% (95% CI, 7.4%-35%), 26.3% (13.1%-39.5%), and 39.4% (24.2%-54.5%) less progression relative to baseline SVD burden for SBP reductions of 0-10 mmHg, 10-20 mmHg, and ≥20 mmHg, respectively. Interpretation:Among hypertensive adults, targeting an SBP of <120 mmHg, compared with <140 mmHg, was associated with less progression of SVD burden. Even modest SBP reductions of ≤10 mmHg conferred measurable brain benefits, with larger reductions providing incrementally greater protection against SVD progression. Funding:National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, and National Institute of Neurological Disorders and Stroke.

BACKGROUND AND OBJECTIVES:The Systolic Blood Pressure Intervention Trial suggested that intensive lowering of systolic blood pressure (SBP) decreases the risk of developing dementia. However, an insufficient number of probable dementia cases stemming from the trial's early termination made results inconclusive. The goal of this study was to estimate the effect of intensive vs standard SBP lowering on the longer term incidence of cognitive impairment leveraging extended follow-up for cognitive status. METHODS:This is a prespecified secondary analysis of a randomized clinical trial. Between 2010 and 2013, patients aged 50 years and older with hypertension and increased cardiovascular risk excluding those with diabetes mellitus or history of stroke were recruited from 102 clinics in the United States and Puerto Rico. Participants were randomized to a SBP goal of <120 mm Hg (intensive treatment) or <140 mm Hg (standard treatment) and received treatment for 3.3 years. In-person cognitive assessment follow-up occurred through July 2018. Continued ascertainment of cognitive status by telephone began in December 2019 for participants who had not withdrawn consent or been previously adjudicated with probable dementia, but provided consent for future research. Data were analyzed using survival analyses. RESULTS:Of 9,361 randomized participants, 7,221 (77%) were eligible to be re-contacted. Cognitive status of 4,232 (59%) was ascertained (mean age 67 years, 36% female). We accrued a total of 216 new cases of probable dementia, less than our target of 326. Over a median follow-up of 7 years, 248 participants of the intensive treatment group (8.5 per 1,000 person-years) were adjudicated with probable dementia, compared with 293 participants (10.2 per 1,000 person-years) in the standard treatment group (hazard ratio [HR], 0.86; 95% CI, 0.72-1.02). Consistent with earlier results from the trial, the rate of both mild cognitive impairment (MCI; HR, 0.87 95% CI, 0.76-1.00) and a composite of MCI or probable dementia was lower with intensive treatment (HR, 0.89; 95% CI, 0.79, 0.99). DISCUSSION:Among ambulatory adults with hypertension and high cardiovascular risk, intensive treatment vs standard treatment of SBP for 3.3 years resulted in a lower risk of MCI and cognitive impairment including MCI or probable dementia, but not for probable dementia alone. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that intensively reducing SBP (target <120 mm Hg) decreases the risk of cognitive impairment in individuals aged 50 years and older with hypertension. CLINICAL TRIAL INFORMATION:Clinical trial number NCT01206062.

To examine the discrimination, calibration, and algorithmic fairness of the Epic End of Life Care Index (EOL-CI). We assessed the EOL-CI's performance by estimating area under the receiver operating characteristic curve (AUC), sensitivity, and positive and negative predictive values in community-dwelling adults ≥65 years of age in a single health system in the Southeastern United States. Algorithmic fairness was examined by comparing the model's performance across sex, race, and ethnicity subgroups. Using a machine learning approach, we also explored local re-calibration of the EOL-CI considering additional information on past hospitalizations and frailty. Among 215 731 patients (median age = 74 years, 57% female, 12% of Black race), 10% were classified as medium risk (15-44) and 3% as high risk (≥45) by the EOL-CI. The observed 1-year mortality rate was 3%. The EOL-CI had an AUC 0.82 for 1-year mortality, with a positive predictive value of 22%. Predictive performance was generally similar across sex and race subgroups, though the EOL-CI displayed better performance with increasing age and in older adults with 2 or more outpatient encounters in the past 24 months. Local re-calibration of the EOL-CI was required to provide absolute estimates of mortality risk, and calibration was further improved when the EOL-CI was augmented with data on inpatient hospitalizations and frailty. The EOL-CI demonstrates reasonable discrimination, albeit with better performance in older adults and in those with greater health system contact. Local refinement and calibration of the EOL-CI score is required to provide direct estimates of prognosis, with the goal of making the EOL-CI a more a valuable tool at the point of care for identifying patients who would benefit from targeted palliative care interventions and proactive care planning.

Over 9 million Americans are projected to have dementia by 2030, and adults with mild cognitive impairment (MCI), a potential pre-cursor to dementia, will also rise. With recent and emerging clinical trial evidence for interventions to slow the progression of MCI to dementia, identification of persons in primary care with undiagnosed early-stage cognitive impairment may provide opportunity for preventive intervention. A Machine Learning (ML)-based prediction model trained using data from the electronic health record was applied to patients without formal diagnoses of cognitive impairment who were currently seen in selected primary care practices. The ML model is a super learner ensemble of prediction models, combining predictions from boosted trees, oblique random forests, and Cox regression trained using patient records from 2017-01-01 to 2018-12-31. We externally validated the super learner’s discrimination, calibration, and fairness using records from 2019-01-01 to 2020-12-31 (no overlapping patients). Patients for whom the model triggered an alert were recommended by their primary care practitioner to undergo cognitive assessment, consisting of a 30-minute remotely-administered tablet-based cognitive battery. Patients also underwent blood collection for AD biomarkers (ptau217, Ab42, neurofilament light, GFAP), and neuroimaging (MRI, amyloid PET). In the testing cohort, the super learner obtained a concordance statistic (95% confidence interval) of 0.822 (0.810, 0.835), higher than any of the individual ML models (Figure 1), and its predicted risk aligned with observed risk in calibration slope plots (Figure 2). Results of cognitive testing plus expert adjudication of the first 75 patients will be presented by proportion of patients adjudicated as not impaired versus MCI. We will also report categories of therapy such as behavioral (sleep, exercise, etc.), medical (hypertension control, alcohol cessation), or pharmacologic (anti-amyloid therapy) that were recommended based on cognitive, imaging, biomarker, and medical findings. Also reported will be initial feedback on workflow and provider satisfaction with this screening and care model from primary care providers. While predictive models of undiagnosed cognitive impairment are imperfect, they can facilitate scalable and feasible primary care screening models leading to effective care plan design for patients with early cognitive impairment and without adversely affecting workflow.

OBJECTIVE:To compare the association of glaucoma and glaucoma suspect diagnoses with frailty, quantified via an electronic frailty index (eFI), and to evaluate whether a glaucoma diagnosis moderates the association between frailty and the cumulative risk of acute healthcare encounters for incident falls or fractures. DESIGN:Retrospective study of electronic health record (EHR) data. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS:Adults ≥65 years old with an ICD-10 diagnosis code for glaucoma or glaucoma suspect who had a calculable eFI score as of 10/1/2017. METHODS:Ordinal logistic regression was used to examine the cross-sectional association between glaucoma (predictor) and frailty status (outcome) based on the eFI. The relationship of glaucoma and frailty with the cumulative incidence of hospital or emergency room visits for injurious falls or fractures over time was modeled using cause-specific recurrent event survival models that account for censoring and the competing risk of death. MAIN OUTCOME MEASURES:Frailty status based on the eFI and cumulative incidence of falls or fractures. RESULTS:Glaucoma patients were significantly more likely to be frail compared to glaucoma suspects (adjusted odds ratio=1.36, 95 % CI(1.16, 1.60)). Both pre-frailty and frailty were associated with an increased risk of incident falls/fractures in older adults: prefrail (hazard ratio=2.07, 95 % CI (1.40, 3.06)), frail (hazard ratio=3.35, 95 % CI (2.24, 5.03)), but there was no interaction of frailty with glaucoma status on falls/fractures risk. Also, the risk of incident falls/fractures did not significantly differ between glaucoma versus glaucoma suspects. CONCLUSIONS:Glaucoma patients were more likely to be frail or pre-frail based on an EHR-derived index than glaucoma suspects. Both pre-frailty and frailty were associated with increased cumulative risk of injurious falls or fractures but there was no interaction of frailty with glaucoma. Frailty based on the eFI was better at discriminating who is at risk of acute healthcare utilization for falls/fractures than a glaucoma diagnosis.

The Systolic Blood Pressure Intervention Trial (SPRINT) showed intensive blood pressure (BP) control, defined by systolic BP goal of < 120 mm Hg, reduced cardiovascular morbidity and mortality. However, a secondary analysis that incorporated approximately 4-years of observational follow-up found that mean BP levels increased after the trial and the benefit of intensive BP control on cardiovascular and all-cause mortality attenuated. We re-examined these findings using an updated version of the observational data that includes approximately 8-years of follow-up. SPRINT included patients 50 years and older with hypertension and increased cardiovascular risk but without diabetes or history of stroke. The SPRINT intervention ended on August 20, 2015, and trial close-out visits occurred through July 2016. Extended observational follow-up for mortality was obtained via the US National Death Index from 2016 through 2023. Among 9361 randomized participants, the mean (standard deviation) age was 67.9 (9.4) years, and 3332 (35.6%) were women. Over a maximum follow-up of 13 years, 2597 all-cause and 907 CVD mortality events occurred ( Figure ). During the trial, intensive treatment was beneficial for both cardiovascular mortality (hazard ratio [HR], 0.66; 95% CI, 0.49-0.89) and all-cause mortality (HR, 0.83; 95% CI, 0.68-1.00). During the 8-year observational period, the benefit of intensive BP control attenuated for both outcomes (CVD mortality HR: 1.02; 95% CI, 0.84-1.24; all-cause mortality HR: 1.08; 95% CI, 0.94-1.23). Overall (i.e., combining trial and observational periods), intensive BP control was beneficial for CVD mortality (HR, 0.84; 95% CI, 0.74-0.96) but not all-cause mortality (HR, 0.96; 95% CI, 0.89-1.04). Intensive BP control reduced CVD mortality risk during the trial and overall, but its benefits were less evident during the observational period. Given increasing BP levels during the observational period, maintaining BP control may be essential for sustaining long-term benefit. Figure: Cumulative incidence of cardiovascular and non-cardiovascular mortality by treatment group

BACKGROUND:Midlife hypertension is linked to white matter injury and dementia, partly through cerebral small vessel disease. We examined how age and systolic blood pressure (SBP) affect progression of 2 cerebral small vessel disease markers, white matter hyperintensity volume (WMHv), and peak width of skeletonized mean diffusivity, in the SPRINT (Systolic Blood Pressure Intervention) and ACCORD (Action to Control Cardiovascular Risk in Diabetes) trials. METHODS:We assessed age modification of intensive (<120 mm Hg) versus standard (<140 mm Hg) SBP treatment on peak width of skeletonized mean diffusivity (n=440) and asinh transformed WMHv (n=449) progression using linear mixed models in SPRINT using age as a continuous variable and by age group (≤65, 66-75, and >75 years). We performed similar analyses in ACCORD (n=172) on WMHv progression, continuously and in 2 age groups (≤65, 65-79 years). RESULTS:In SPRINT, the overall interaction between age and SBP on WMHv change was not statistically significant (P=0.18). However, intensive SBP treatment demonstrated a stepwise greater longitudinal WMHv reduction with younger age ≤65 years (-0.19 [95% CI, -0.28 to -0.11]), 66 to 75 years (-0.11 [95% CI, -0.19 to -0.02]), >75 years (-0.06 [95% CI, -0.20 to 0.09]), corresponding to respective reductions of 75%, 34%, and 19%. Intensive treatment produced a similar pattern in peak width of skeletonized mean diffusivity progression, with a significant treatment effect in those ≤65 only (P=0.15 for overall treatment by age interaction). In ACCORD, intensive SBP-lowering was associated with reduced WMHv progression in the younger (≤65) compared with the older age group (P=0.038). CONCLUSIONS:Intensive SBP control may be more effective in reducing white matter injury at younger compared with older ages.

Background Missing data in electronic health records are highly prevalent and result in analytical concerns such as heterogeneous sources of bias and loss of statistical power. One simple analytic method for addressing missing or unknown covariate values is to treat missingness for a particular variable as a category onto itself, which we refer to as the missing indicator method. For cross-sectional analyses, recent work suggested that there was minimal benefit to the missing indicator method; however, it is unclear how this approach performs in the setting of longitudinal data, in which correlation among clustered repeated measures may be leveraged for potentially improved model performance. Objectives This study aims to conduct a simulation study to evaluate whether the missing indicator method improved model performance and imputation accuracy for longitudinal data mimicking an application of developing a clinical prediction model for falls in older adults based on electronic health record data. Methods We simulated a longitudinal binary outcome using mixed effects logistic regression that emulated a falls assessment at annual follow-up visits. Using multivariate imputation by chained equations, we simulated time-invariant predictors such as sex and medical history, as well as dynamic predictors such as physical function, BMI, and medication use. We induced missing data in predictors under scenarios that had both random (missing at random) and dependent missingness (missing not at random). We evaluated aggregate performance using the area under the receiver operating characteristic curve (AUROC) for models with and with no missing indicators as predictors, as well as complete case analysis, across simulation replicates. We evaluated imputation quality using normalized root-mean-square error for continuous variables and percent falsely classified for categorical variables. Results Independent of the mechanism used to simulate missing data (missing at random or missing not at random), overall model performance via AUROC was similar regardless of whether missing indicators were included in the model. The root-mean-square error and percent falsely classified measures were similar for models including missing indicators versus those with no missing indicators. Model performance and imputation quality were similar regardless of whether the outcome was related to missingness. Imputation with or with no missing indicators had similar mean values of AUROC compared with complete case analysis, although complete case analysis had the largest range of values. Conclusions The results of this study suggest that the inclusion of missing indicators in longitudinal data modeling neither improves nor worsens overall performance or imputation accuracy. Future research is needed to address whether the inclusion of missing indicators is useful in prediction modeling with longitudinal data in different settings, such as high dimensional data analysis.

In the Systolic Blood Pressure Intervention Trial (SPRINT), intensive systolic blood pressure (SBP) lowering slowed progression of white matter injury (WMI) on MRI. We hypothesized that intensive lowering would be equally as effective and may confer greater benefits for brain health at younger ages compared to older ages. We tested whether the relative effects of intensive lowering on WMI differed by age using 2 MRI measures: white matter hyperintensity volume (WMHv) and peak-width skeletonized mean diffusivity (PSMD) in SPRINT. Participants were age ≥50 with cardiovascular risk and randomized to intensive (SBP goal <120 mm Hg) or standard treatment (SBP goal <140 mm Hg). We calculated WMHv and PSMD in a subgroup of participants who had a baseline and follow-up MRI. WMHv were inverse-hyperbolic sine-transformed, and the ratio of follow-up to baseline used to quantify progression. PSMD progression was quantified as a difference. Using mixed-effects linear models, we estimated the effects of age on relative progression in MRI markers between groups. Age effects were investigated as categorical (<65, 65-75, or ≥75 years) or continuous. For participants in the intensive group (n=251 with follow-up), mean SBP was 122 mmHg versus 135 mmHg in the standard group (n=201) over a median 3.9-year MRI interval. The largest treatment effect on WMHv progression was found in the <65 age group (i.e. greatest relative reduction with intensive treatment): -0.19, 95%CI [-0.27, -0.11]), followed by the 65-75 age group (-0.11, [-0.21, -0.01]), and least in the >75 age group (-0.06, [-0.20, -0.08]) (Figure 1). Intensive treatment resulted in a 73%, 52%, and 20% reduction in WMHv progression respectively, although this was not statistically significant (p=0.21). Analyses of PSMD progression produced similar results (Figure 2). When using age as a continuous measure, the beneficial effect of intensive treatment waned with increasing age (Figure 3) without reaching statistical significance (p=0.19). Intensive SBP lowering was equally as effective and may have a greater relative effect on reducing WMI when implemented at younger ages compared to older ages. Large prospective interventional studies that include younger individuals are needed to determine the effects of SBP on white matter integrity across the lifespan.

OBJECTIVE:This study aimed to apply The Lancet Diabetes & Endocrinology criteria for diagnosing obesity among clinical trial participants and understand participants' characteristics by obesity status. METHODS:The criteria were operationalized and applied to baseline data from the Long-term Effectiveness of the Anti-obesity medication Phentermine (LEAP) trial (NCT05176626). Excess adiposity, organ and tissue dysfunction, and limitations to daily activities were assessed. We examined differences between participants with "no obesity," "pre-clinical obesity," and "clinical obesity." RESULTS:Among the 860 participants, 0.8% had no obesity (mean BMI 29.0 kg/m2 [SD 0.6]), 18.7% had pre-clinical obesity (mean BMI 35.2 kg/m2 [SD 3.5]), and 80.5% had clinical obesity (mean BMI 35.9 kg/m2 [SD 4.3]). Participants with no/pre-clinical obesity had lower mean SF-12 mental component scores and greater baseline engagement with weight control strategies compared to those with clinical obesity. Participants with clinical obesity were older and, by definition, had a greater burden of cardiometabolic risk factors. CONCLUSIONS:Among clinical trial participants eligible for obesity pharmacotherapy, 19.5% were classified as having no/pre-clinical obesity using the Lancet criteria. Applying the criteria was complicated in a well-resourced trial setting, which suggests potential challenges in implementing these guidelines in real-world practice.

OBJECTIVES:The safety of intensive blood pressure lowering in patients with preexisting cerebral small vessel disease (CSVD) remains unclear. METHODS:We used data from 759 participants in Systolic Blood Pressure Intervention Trial (SPRINT) who completed a baseline MRI, and categorized participants by the median abnormal white matter hyperintensity volume (WMHv, <3.2 cm 3 versus ≥3.2 cm 3 ). We estimated the association of the baseline WMHv with cardiovascular outcomes and adverse events using Cox proportional hazards models adjusted for treatment assignment, age, sex, MRI scanner, and intracranial volume. We used stratified analysis to determine the effect of intensive versus standard treatment by the baseline WMHv. RESULTS:The mean age of the participants was 68 ± 9 years and 39% were female. In adjusted models, adults with WMHv above the median had an increased risk of the primary cardiovascular composite outcome [hazard ratio (HR) 2.59, 95% confidence interval (CI) 1.39, 4.81], all-cause mortality (HR 2.06, 95% CI 0.97, 4.37), and mild cognitive impairment or probable dementia (HR 1.76, 95% CI 0.99, 3.13). While the effects of intensive versus standard blood pressure treatment were similar for most outcomes by WMHv, intensive treatment was associated with a higher risk for mild cognitive impairment or probable dementia among adults with a WMHv above the median (HR 2.36, 95% CI 1.20, 4.66), but not among adults with a WMHv below the median (p-value for interaction = 0.09). CONCLUSIONS:In this posthoc analysis of SPRINT, adults with a higher WMHv were at a higher risk for adverse cardiovascular and cognitive outcomes. Among these adults, intensive blood pressure treatment reduced cardiovascular events, while its effects on the risk of cognitive impairment or dementia in this subgroup merit further study.

BACKGROUND:Post-acute care (PAC) is designed to help older adults recover functional independence following hospitalization. Frailty is a predictor of adverse health outcomes in hospitalized older adults, but the impact on PAC remains unclear. The objective of this study was to investigate whether (1) frailty is associated with hospital discharge location and (2) the impact of frailty and discharge location on health outcomes. METHODS:We conducted a retrospective cohort study from a single US-based healthcare system from January 2021 to September 2023 of adults aged ≥ 65 years with an electronic frailty index (eFI) frailty score and hospital admission for at least 24 h. We evaluated the odds of hospital discharge location (home, home health services [HHS], and skilled nursing facility [SNF]) and health outcomes including hospital readmission and mortality, using logistic regression and Cox-regression models adjusted for demographics and healthcare system factors. RESULTS:A cohort of 23,407 older adult patients was included, with a mean age of 76.7 years (SD 7.7), 53% female sex, and 19% non-White race/ethnicity. Participant frailty was categorized as 22% non-frail, 46% pre-frail, 23% frail, and 8% severely frail. Patients with a higher degree of frailty were more likely to discharge with PAC (SNF or HHS) compared to home, adjusted odds ratio OR [95% CI], frail: OR 1.20 [1.09-1.33]. Frailty was a risk factor for 90-day hospital readmissions (OR 1.91 [1.67-2.20], p < 0.001) and mortality (HR 2.56 [2.10-3.13], p < 0.001) compared to non-frail individuals. In addition, patients discharged to SNF had higher mortality (HR 5.46 [4.43-6.73], p < 0.001), but did not have increased readmissions compared to individuals discharged home without HHS. CONCLUSIONS:Frailty in older adults was a risk factor for discharge to PAC, higher mortality, and readmissions. Automated frailty assessment can be used to identify high-risk patients, facilitating targeted interventions across the PAC continuum.

Importance Frailty assessed at a single time point is associated with mortality in older women with breast cancer. Little is known about how changes in frailty following cancer treatment initiation affect mortality. Objective To evaluate the association between claims-based frailty trajectories following adjuvant chemotherapy initiation and 5-year mortality in older women with stage I to III breast cancer. Design, Setting, and Participants This longitudinal cohort study used the Surveillance, Epidemiology, and End Results cancer registries linked to Medicare claims data (claims from 2003-2019). Women aged 65 years or older with stage I to III breast cancer diagnosed from 2004 to 2017 were included. Eligible women underwent breast surgery followed by adjuvant chemotherapy as initial treatment. A landmark design was used to identify frailty trajectories during the year following chemotherapy initiation. Continuous enrollment in Medicare fee-for-service from 180 days before cancer diagnosis through 360 days following chemotherapy initiation (landmark) was required. Women who died or disenrolled before the landmark were excluded. Analyses were conducted between September 2022 and March 2024. Exposures Claims-based frailty trajectories during the 360 days following chemotherapy initiation were identified using the Faurot frailty index, a validated claims-based proxy for frailty based on demographics and diagnosis, procedure, and durable medical equipment claims. The Faurot frailty index was calculated every 30 days from chemotherapy initiation through the landmark (360 days after chemotherapy initiation). Claims-based frailty trajectory clusters were identified using longitudinal K-means clustering. Main Outcomes and Measures Associations between the claims-based frailty trajectory clusters and 5-year mortality from the landmark were estimated using Kaplan-Meier analysis. Results In total, 20 292 women with breast cancer (median [IQR] age, 70 [67-74] years) were identified. The K-means analysis resulted in 6 trajectory clusters: 3 robust (16 120 women [79.4%]) or resilient (3259 [16.1%]) trajectories and 3 nonresilient trajectories (913 women [4.5%]). Five-year mortality was higher in women belonging to the 3 nonresilient trajectories compared with those belonging to the 3 resilient trajectories (52.1% vs 20.3%; difference, 31.8%; 95% CI, 29.0%-36.2%). Conclusions and Relevance In this cohort study of women with stage I to III breast cancer, frailty changes following chemotherapy initiation were associated with long-term survival. Future research should assess the association of frailty interventions following cancer treatment initiation with survival and patient-centered outcomes in this population.