Reorganization of H3K9me heterochromatin leads to neuronal impairment via the cascading destruction of the KDM3B-centered epigenomic network.

Histone H3K9 methylated heterochromatin silences repetitive non-coding sequences and lineage-specific genes during development, but how tissue-specific genes escape from heterochromatin in differentiated cells is unclear. Here, we examine age-dependent transcriptomic profiling of terminally differentiated mouse retina to identify epigenetic regulators involved in heterochromatin reorganization. The single-cell RNA sequencing analysis reveals a gradual downregulation of Kdm3b in cone photoreceptors during aging. Disruption of Kdm3b (Kdm3b +/- ) of 12-month-old mouse retina leads to the decreasing number of cones via apoptosis, and it changes the morphology of cone ribbon synapses. Integration of the transcriptome with epigenomic analysis in Kdm3b +/- retinas demonstrates gains of heterochromatin features in synapse assembly and vesicle transport genes that are downregulated via the accumulation of H3K9me1/2. Contrarily, losses of heterochromatin in apoptotic genes exacerbated retinal neurodegeneration. We propose that the KDM3B-centered epigenomic network is crucial for balancing of cone photoreceptor homeostasis via the modulation of gene set-specific heterochromatin features during aging.

Validation of Claims-Based Frailty Index for Identifying Moderate-to-Severe Dementia in Medicare Beneficiaries.

OBJECTIVE: Previous research using the National Health and Aging Trends Study showed that a claims-based frailty index (CFI) could be useful for identifying moderate-to-severe dementia in Medicare claims data. This study aims to validate the findings in an independent cohort. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: The study included 658 fee-for-service beneficiaries with dementia who participated in the 2016-2020 Medicare Current Beneficiary Survey in the community-dwelling. METHODS: We operationalized the Functional Assessment Staging Test (FAST) scale (range: 1-7, stages 5-7 indicate moderate-to-severe dementia) using survey information. CFI (range: 0-1, higher scores indicate greater frailty) was calculated using Medicare claims 12 months before the participants' interview date. Using the previously proposed cut point of 0.280, we calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for identifying moderate-to-severe dementia. Survey procedures were used to account for survey design and weighted to reflect national estimates. RESULTS: The population had a mean age (SD) of 80.7 (8.9) years, 58.5% female, and 101 beneficiaries (14.8%) had moderate-to-severe dementia. The CFI cut point of 0.280 demonstrated sensitivity 0.49 (95% CI, 0.38-0.59), specificity 0.80 (0.77-0.84), PPV 0.30 (0.23-0.38), and NPV 0.90 (0.87-0.93). Compared with those with a CFI <0.280, beneficiaries with a CFI ≥0.280 had an elevated risk of mortality (2.9% vs 4.1%) over 1 year. CONCLUSIONS AND IMPLICATIONS: These results confirm our previous findings that CFI among beneficiaries with a dementia diagnosis is a useful measure of moderate-to-severe dementia for Medicare claims data.

Pre-procedural nursing home length of stay and outcomes of transcatheter aortic valve replacement.

BACKGROUND: Older adults with severe aortic stenosis (AS) may receive care in a nursing home (NH) prior to undergoing transcatheter aortic valve replacement (TAVR). NH level of care can be used to stabilize medical conditions, to provide rehabilitation services, or for long-term care services. Our primary objective is to determine whether NH utilization pre-TAVR can be used to stratify patients at risk for higher mortality and poor disposition outcomes at 30 and 365 days post-TAVR. METHODS: We conducted a retrospective cohort study among Medicare beneficiaries who spent ≥1 day in an NH 6 months before TAVR (2011-2019). The intensity of NH utilization was categorized as low users (1-30 days), medium users (31-89 days), long-stay NH residents (≥ 100 days, with no more than a 10-day gap in care), and high post-acute rehabilitation patients (≥90 days, with more than a 10-day gap in care). The probabilities of death and disposition were estimated using multinomial logistic regression, adjusting for age, sex, and race. RESULTS: Among 15,581 patients, 9908 (63.6%) were low users, 4312 (27.7%) were medium users, 663 (4.3%) were high post-acute care rehab users, and 698 (4.4%) were long-stay NH residents before TAVR. High post-acute care rehabilitation patients were more likely to have dementia, weight loss, falls, and extensive dependence of activities of daily living (ADLs) as compared with low NH users. Mortality was the greatest in high post-acute care rehab users: 5.5% at 30 days, and 36.4% at 365 days. In contrast, low NH users had similar mortality rates compared with long-stay NH residents: 4.8% versus 4.8% at 30 days, and 24.9% versus 27.0% at 365 days. CONCLUSION: Frequent bouts of post-acute rehabilitation before TAVR were associated with adverse outcomes, yet this metric may be helpful to determine which patients with severe AS could benefit from palliative and geriatric services.

Impact of COVID-19 on brain connectivity and rehabilitation outcome after stroke.

Background: Coronavirus disease (COVID-19) may induce neurological issues, impacting brain structure and stroke recovery. Limited studies have explored its effects on post-stroke rehabilitation. Our study compares brain structure and connectivity, assessing rehabilitation outcomes based on pre-stroke COVID-19 infection. Methods: A retrospective analysis of 299 post-stroke rehabilitation cases from May 2021 to January 2023 included two groups: those diagnosed with COVID-19 at least two weeks before stroke onset (COVID group) and those without (control group). Criteria involved first unilateral supratentorial stroke, <3 months post-onset, initial MR imaging, and pre- and post-rehabilitation clinical assessments. Propensity score matching ensured age, sex, and initial clinical assessment similarities. Using lesion mapping, tract-based statistical analysis, and group-independent component analysis MRI scans were assessed for structural and functional differences. Results: After propensity score matching, 12 patients were included in each group. Patient demographics showed no significant differences. Analyses of MR imaging revealed no significant differences between COVID and control groups. Post-rehabilitation clinical assessments improved notably in both groups, however the intergroup analysis showed no significant difference. Conclusions: Previous COVID-19 infection did not affect brain structure or connectivity nor outcomes after rehabilitation.

Efficacy of personalized repetitive transcranial magnetic stimulation based on functional reserve to enhance ambulatory function in patients with Parkinson's disease: study protocol for a randomized controlled trial.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is one of the non-invasive brain stimulations that modulate cortical excitability through magnetic pulses. However, the effects of rTMS on Parkinson's disease (PD) have yielded mixed results, influenced by factors including various rTMS stimulation parameters as well as the clinical characteristics of patients with PD. There is no clear evidence regarding which patients should be applied with which parameters of rTMS. The study aims to investigate the efficacy and safety of personalized rTMS in patients with PD, focusing on individual functional reserves to improve ambulatory function. METHODS: This is a prospective, exploratory, multi-center, single-blind, parallel-group, randomized controlled trial. Sixty patients with PD will be recruited for this study. This study comprises two sub-studies, each structured as a two-arm trial. Participants are classified into sub-studies based on their functional reserves for ambulatory function, into either the motor or cognitive priority group. The Timed-Up and Go (TUG) test is employed under both single and cognitive dual-task conditions (serial 3 subtraction). The motor dual-task effect, using stride length, and the cognitive dual-task effect, using the correct response rate of subtraction, are calculated. In the motor priority group, high-frequency rTMS targets the primary motor cortex of the lower limb, whereas the cognitive priority group receives rTMS over the left dorsolateral prefrontal cortex. The active comparator for each sub-study is bilateral rTMS of the primary motor cortex of the upper limb. Over 4 weeks, the participants will undergo 10 rTMS sessions, with evaluations conducted pre-intervention, mid-intervention, immediately post-intervention, and at 2-month follow-up. The primary outcome is a change in TUG time between the pre- and immediate post-intervention evaluations. The secondary outcome variables are the TUG under cognitive dual-task conditions, Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III, New Freezing of Gait Questionnaire, Digit Span, trail-making test, transcranial magnetic stimulation-induced motor-evoked potentials, diffusion tensor imaging, and resting state functional magnetic resonance imaging. DISCUSSION: The study will reveal the effect of personalized rTMS based on functional reserve compared to the conventional rTMS approach in PD. Furthermore, the findings of this study may provide empirical evidence for an rTMS protocol tailored to individual functional reserves to enhance ambulatory function in patients with PD. TRIAL REGISTRATION: ClinicalTrials.gov NCT06350617. Registered on 5 April 2024.

Antiplatelet and Anticoagulant Use in Nursing Home Residents With Atrial Fibrillation.

This cross-sectional study evaluates the use of oral anticoagulants and antiplatelets, including aspirin, among nursing home residents with atrial fibrillation.

Evolving role of the health system CIO: perspectives from 33 health systems.

OBJECTIVES: This study explores the evolving position of the health system chief information officer (CIO) by identifying new core roles for success. METHODS: An advisory board of industry executives and system leaders guided the study. Purposeful sampling was used to invite chief executive officer and CIOs from 65 not-for-profit US health systems to participate. Interviews were conducted with 51 executives from 33 different systems, using a comprehensive interview topic guide. Interview transcripts were analysed using NVivo software, focusing on themes related to the evolving role of the health system CIO. RESULTS: Analyses revealed three main themes, with the CIO as (1) enabler of strategic change and transformation, (2) strategic developer of technology and leadership talent and (3) driver of organisational culture. DISCUSSION: The role of CIO has undergone transformation from technology and information system management to strategic leadership within the broader health system context. It highlights the importance of comprehensive business knowledge for CIOs and the need for other C-suite executives to have a deeper understanding of information and technology. CONCLUSION: As healthcare continues to evolve, the role of the CIO is expected to expand further, requiring a blend of technical and strategic business skills. This evolution presents opportunities for health systems to enhance their leadership development programmes, preparing leaders for the complexities of the contemporary health system sector.

Leadership to Accelerate Healthcare's Digital Transformation: Evidence From 33 Health Systems.

GOAL: The COVID-19 pandemic, healthcare market disruptors, and new digital healthcare technologies have made a substantial impact on the delivery of healthcare services, highlighting the critical roles of leaders in hospitals and health systems. This study sought to understand the evolving roles of CEOs, CIOs, and other executive leaders in the postpandemic era and highlight the adaptability and strategic vision of executives in shaping the future of healthcare delivery. METHODS: Between October 2022 and May 2023, 51 interviews were conducted with CEOs, CIOs, and other executives responsible for delivering technology solutions for 33 nonprofit health systems in the United States. They were asked to describe their backgrounds; how information solutions and technologies were viewed within their organizations' strategy, operations, and governance; and the key characteristics of executive leaders. PRINCIPAL FINDINGS: The study has found that effective CEOs have an authentic belief in technology's role in achieving their organization's mission and that contemporary CIOs are strategic executive partners who align strategy with culture to improve care. This study examines how healthcare systems are creating digitally savvy executive leadership teams that operate in a new, integrated model that unites previously siloed functions. PRACTICAL APPLICATIONS: Some healthcare CIOs are unprepared for current and future business challenges, and some CEOs are unsure how to leverage digital technologies and C-suite expertise to transform their organizations. This research provides insights into how the nation's health systems are building and sustaining leadership teams capable of adapting to the healthcare environment and accelerating organizational transformation.

Effects of oridonin on sperm function and the PI3K/PDK1/AKT signaling pathway: Implications for reproductive toxicity.

Oridonin, a natural terpenoid isolated from the leaves of Isodon rubescens (Hemsley) H.Hara, is widely used in oriental medicine for its anticancer properties across various cancer types. Despite its prevalent use, the toxic effects of oridonin on male reproduction, particularly its impact on sperm functions and the mechanisms involved, are not well understood. This study aimed to explore the effects and underlying mechanisms of oridonin on sperm functions. We initially treated Duroc boar spermatozoa with varying concentrations of oridonin (0, 5, 50, 75, 100, and 150 µM) and incubated them to induce capacitation. We then assessed cell viability and several sperm functions, including sperm motility and motion kinematics, capacitation status, and ATP levels. We also analyzed the expression levels of proteins associated with the phosphatidylinositol 3-kinase (PI3K)/phosphoinositide-dependent kinase-1 (PDK1)/protein kinase B (AKT) signaling pathway and phosphotyrosine proteins. Our results indicate that oridonin adversely affects most sperm functions in a dose-dependent manner. We observed significant decreases in AKT, p-AKT (Thr308), phosphatase and tensin homolog (PTEN), p-PDK1, and p-PI3K levels following oridonin treatment, alongside an abnormal increase in phosphotyrosine proteins. These findings suggest that oridonin may disrupt normal levels of tyrosine-phosphorylated proteins by inhibiting the PI3K/PDK1/AKT signaling pathway, which is crucial for cell proliferation, metabolism, and apoptosis, thus potentially harming sperm functions. Consequently, we recommend considering the reproductive toxicity of oridonin when using it as a therapeutic agent.

Accounting for taste: preferences mediate the relationship between documentation time and ambulatory physician burnout.

OBJECTIVES: Physician burnout in the US has reached crisis levels, with one source identified as extensive after-hours documentation work in the electronic health record (EHR). Evidence has illustrated that physician preferences for after-hours work vary, such that after-hours work may not be universally burdensome. Our objectives were to analyze variation in preferences for after-hours documentation and assess if preferences mediate the relationship between after-hours documentation time and burnout. MATERIALS AND METHODS: We combined EHR active use data capturing physicians' hourly documentation work with survey data capturing documentation preferences and burnout. Our sample included 318 ambulatory physicians at MedStar Health. We conducted a mediation analysis to estimate if and how preferences mediated the relationship between after-hours documentation time and burnout. Our primary outcome was physician-reported burnout. We measured preferences for after-hours documentation work via a novel survey instrument (Burden Scenarios Assessment). We measured after-hours documentation time in the EHR as the total active time respondents spent documenting between 7 pm and 3 am. RESULTS: Physician preferences varied, with completing clinical documentation after clinic hours while at home the scenario rated most burdensome (52.8% of physicians), followed by dealing with prior authorization (49.5% of physicians). In mediation analyses, preferences partially mediated the relationship between after-hours documentation time and burnout. DISCUSSION: Physician preferences regarding EHR-based work play an important role in the relationship between after-hours documentation time and burnout. CONCLUSION: Studies of EHR work and burnout should incorporate preferences, and operational leaders should assess preferences to better target interventions aimed at EHR-based contributors to burnout.

Efficacy of personalized rTMS to enhance upper limb function in subacute stroke patients: a protocol for a multi-center, randomized controlled study.

Background: Repetitive transcranial magnetic stimulation (rTMS) is widely used therapy to enhance motor deficit in stroke patients. To date, rTMS protocols used in stroke patients are relatively unified. However, as the pathophysiology of stroke is diverse and individual functional deficits are distinctive, more precise application of rTMS is warranted. Therefore, the objective of this study was to determine the effects of personalized protocols of rTMS therapy based on the functional reserve of each stroke patient in subacute phase. Methods: This study will recruit 120 patients with stroke in subacute phase suffering from the upper extremity motor impairment, from five different hospitals in Korea. The participants will be allocated into three different study conditions based on the functional reserve of each participant, measured by the results of TMS-induced motor evoked potentials (MEPs), and brain MRI with diffusion tensor imaging (DTI) evaluations. The participants of the intervention-group in the three study conditions will receive different protocols of rTMS intervention, a total of 10 sessions for 2 weeks: high-frequency rTMS on ipsilesional primary motor cortex (M1), high-frequency rTMS on ipsilesional ventral premotor cortex, and high-frequency rTMS on contralesional M1. The participants of the control-group in all three study conditions will receive the same rTMS protocol: low-frequency rTMS on contralesional M1. For outcome measures, the following assessments will be performed at baseline (T0), during-intervention (T1), post-intervention (T2), and follow-up (T3) periods: Fugl-Meyer Assessment (FMA), Box-and-block test, Action Research Arm Test, Jebsen-Taylor hand function test, hand grip strength, Functional Ambulatory Category, fractional anisotropy measured by the DTI, and brain network connectivity obtained from MRI. The primary outcome will be the difference of upper limb function, as measured by FMA from T0 to T2. The secondary outcomes will be the differences of other assessments. Discussion: This study will determine the effects of applying different protocols of rTMS therapy based on the functional reserve of each patient. In addition, this methodology may prove to be more efficient than conventional rTMS protocols. Therefore, effective personalized application of rTMS to stroke patients can be achieved based on their severity, predicted mechanism of motor recovery, or functional reserves. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT06270238.

Assessing the Benefits and Harms of Pharmacotherapy in Older Adults with Frailty: Insights from Pharmacoepidemiologic Studies of Routine Health Care Data.

The objective of this review is to summarize and appraise the research methodology, emerging findings, and future directions in pharmacoepidemiologic studies assessing the benefits and harms of pharmacotherapies in older adults with different levels of frailty. Older adults living with frailty are at elevated risk for poor health outcomes and adverse effects from pharmacotherapy. However, current evidence is limited due to the under-enrollment of frail older adults and the lack of validated frailty assessments in clinical trials. Recent advancements in measuring frailty in administrative claims and electronic health records (database-derived frailty scores) have enabled researchers to identify patients with frailty and to evaluate the heterogeneity of treatment effects by patients' frailty levels using routine health care data. When selecting a database-derived frailty score, researchers must consider the type of data (e.g., different coding systems), the length of the predictor assessment period, the extent of validation against clinically validated frailty measures, and the possibility of surveillance bias arising from unequal access to care. We reviewed 13 pharmacoepidemiologic studies published on PubMed from 2013 to 2023 that evaluated the benefits and harms of cardiovascular medications, diabetes medications, anti-neoplastic agents, antipsychotic medications, and vaccines by frailty levels. These studies suggest that, while greater frailty is positively associated with adverse treatment outcomes, older adults with frailty can still benefit from pharmacotherapy. Therefore, we recommend routine frailty subgroup analyses in pharmacoepidemiologic studies. Despite data and design limitations, the findings from such studies may be informative to tailor pharmacotherapy for older adults across the frailty spectrum.

Use of chronic care management service among Medicare beneficiaries in 2015-2019.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) introduced chronic care management (CCM) services in 2015 for patients with multiple chronic diseases. Few studies examine the utilization of CCM services by geographic region, sociodemographic, and clinical characteristics. METHODS: We used 2014-2019 Medicare claims data from a 5% random sample of fee-for-service beneficiaries aged 65 years or over. We included beneficiaries potentially eligible for CCM services because they had multiple chronic conditions (1,073,729 in 2015 and 1,130,523 in 2019). We calculated the proportion of potentially eligible beneficiaries receiving CCM service each year for the total population and by geographic region, sociodemographic, and clinical characteristics. RESULTS: The proportion of beneficiaries with two or more chronic conditions receiving CCM services increased from 1.1% in 2015 to 3.4% in 2019. The increase in CCM use was higher in the southern region, among dually eligible beneficiaries and beneficiaries with a greater burden of chronic conditions (2-5 conditions vs ≥10 conditions: 0.7% vs 2.0% in 2015; 2.1% vs 7.0% in 2019) and frailty (robust vs severely frail: 0.6% vs 3.3% in 2015; 1.9% vs 9.4% in 2019). Nearly one out of five recipients did not continue CCM service after the initial service. CONCLUSION: We found that CCM service is being used by a very small fraction of eligible patients. Barriers and facilitators to more effective CCM adoption should be identified and incorporated into strategies that encourage more widespread use of this Medicare benefit.

Automated segmentation of MRI white matter hyperintensities in 8,421 patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: To date, only a few small studies have attempted deep learning-based automatic segmentation of white matter hyperintensity (WMH) lesions in patients with cerebral infarction, which is complicated because stroke-related lesions can obscure WMH borders. We developed and validated deep learning algorithms to segment WMH lesions accurately in patients with cerebral infarction, using multisite datasets involving 8,421 patients with acute ischemic stroke. MATERIALS AND METHODS: We included 8,421 stroke patients from 9 centers in Korea. 2D UNet and SE-Unet models were trained using 2,408 FLAIR MRI from 3 hospitals and validated using 6,013 FLAIR MRIs from 6 hospitals. WMH segmentation performance was assessed by calculating DSC, correlation coefficient, and concordance correlation coefficient compared to a human-segmented gold standard. In addition, we obtained an uncertainty index that represents overall ambiguity in the voxel classification for WMH segmentation in each patient based on the Kullback-Leibler divergence. RESULTS: In the training dataset, the mean age was 67.4±13.0 years and 60.4% were men. The mean (95% CI) DSCs for Unet in internal testing and external validation were respectively 0.659 (0.649-0.669) and 0.710 (0.707-0.714), which were slightly lower than the reliability between humans (DSC=0.744; 95% CI=0.738-0.751; P=.031). Compared with the Unet, the SE-Unet demonstrated better performance, achieving a mean DSC of 0.675 (0.666-0.685; P<.001) in the internal testing and 0.722 (0.719-0.726; P<.001) in the external validation; moreover, it achieved high DSC values (ranging from 0.672 to 0.744) across multiple validation datasets. We observed a significant correlation between WMH volumes that were segmented automatically and manually for the Unet (r=0.917, P<.0001) and even stronger for the SE-Unet (r=0.933, P<.0001). The SE-Unet also attained a high concordance correlation coefficient (ranging from 0.841 to 0.956) in external test datasets. In addition, the uncertainty indices in the majority of patients (86%) in the external datasets were below 0.35, with an average DSC of 0.744 in these patients. CONCLUSIONS: We developed and validated deep learning algorithms to segment WMH in patients with acute cerebral infarction using the largest-ever MRI datasets. In addition, we showed that the uncertainty index can be used to identify cases where automatic WMH segmentation is less accurate and requires human review. ABBREVIATIONS: WMH = white matter hyperintensity; CNN = convolutional neural networks; SE = squeeze-and-excitation; KL = Kullback-Leibler; ReLU = rectified linear unit; LKW = last known well; mRS = modified Rankin Scale; NIHSS = National Institute of Health Stroke Scale; LAA = large artery atherosclerosis; SVO = small vessel occlusion; CE = cardioembolism.

Longitudinal Changes in a Claims-Based Frailty Proxy Measure Compared to Concurrent Changes in the Fried Frailty Phenotype.

BACKGROUND: Frailty is a dynamic aging-related syndrome, but measuring frailty transitions is challenging. The Faurot frailty index is a validated Medicare claims-based frailty proxy based on demographic and billing information. We evaluated whether 3-year changes in the Faurot frailty index were consistent with concurrent changes in the frailty phenotype in a cohort of older adults. METHODS: We used longitudinal data from the National Health and Aging Trends Study (NHATS) with Medicare claims linkage (2010-2018). We identified older adults (66+ years) in the 2011 and 2015 NHATS cohorts with at least 1 year of Medicare fee-for-service continuous enrollment (N = 6 951). We described annual changes in mean claims-based frailty for up to 3 years, based on concurrent transitions in the frailty phenotype. RESULTS: At baseline, 32% were robust, 48% prefrail, and 19% frail based on the frailty phenotype. Mean claims-based frailty for older adults who were robust at baseline and worsened to frail increased over 3 years (0.09-0.25). Similarly, those who worsened from prefrail to frail experienced an increase in mean claims-based frailty (0.14-0.26). Improvements in the frailty phenotype did not correspond to decreases in claims-based frailty. Older adults whose frailty phenotype improved over time had a lower baseline claims-based frailty score than those who experienced stable or worsening frailty. CONCLUSIONS: Older adults who experienced a frailty phenotype worsening over 3 years experienced concurrent increases in the Faurot frailty index. Our results suggest that claims data may be used to identify clinically meaningful worsening in frailty.

Frailty and Clinical Outcomes of Ticagrelor Versus Clopidogrel in Older Adults With Acute Myocardial Infarction.

BACKGROUND: Ticagrelor is recommended over clopidogrel in acute coronary syndrome based on the results of the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial. We aimed to emulate PLATO in older adults with and without frailty and with acute coronary syndrome treated with percutaneous coronary intervention. METHODS AND RESULTS: We created a new-user cohort of Medicare fee-for-service beneficiaries aged ≥65 years hospitalized for acute coronary syndrome from 2014 to 2018 and initiated ticagrelor or clopidogrel following percutaneous coronary intervention. Frailty was defined using a validated claims-based frailty index ≥0.25. Coprimary outcomes were major adverse cardiovascular events and major bleeding. Follow-up began on the date of first outpatient prescription for ticagrelor or clopidogrel and ended on the earliest date for an outcome event, death, discontinuation of the index drug, or disenrollment from Medicare. The study included 42 843 older adults; 23% were frail. After propensity score matching, the rates of major adverse cardiovascular events per 100 person-years comparing ticagrelor versus clopidogrel groups were 7.8 and 7.3 in the frail cohort (hazard ratio [HR], 1.07 [95% CI, 0.84-1.36]) and 3.7 and 4.2 in the nonfrail cohort (HR, 0.87 [95% CI, 0.75-1.02]). The corresponding rates of major bleeding were 4.3 and 3.8 in the frail cohort (HR, 1.12 95% CI, [0.80-1.56]) and 2.2 and 1.8 in the nonfrail cohort (HR, 1.22 [95% CI, 0.98-1.51]). CONCLUSIONS: There was a trend toward a modest reduction in risk of major adverse cardiovascular events and a trend toward a modest increase in risk of major bleeding with ticagrelor compared with clopidogrel in the nonfrail cohort. There was insufficient evidence for the benefit of ticagrelor in frail older adults.