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IMPORTANCE: Pragmatic randomized clinical trials (RCTs) often use multiple data sources to examine clinical events, but the relative contribution of data sources to clinical end-point rates is understudied. OBJECTIVE: To assess the contribution of data sources (electronic health records [EHRs], public/private insurance claims, and/or participant-reported data) to clinical end points among ADAPTABLE participants who had available data. DESIGN, SETTING, AND PARTICIPANTS: The ADAPTABLE study was an open-label, pragmatic RCT from April 2016 through June 2019 conducted in research networks within clinical practice. Participants had existing atherosclerotic cardiovascular disease and available data to analyze. The characteristics of patients by combinations of data source availability were compared to examine the contribution of each of the data sources to end-point ascertainment. Data for this prespecified analysis were examined from January 2022 to June 2023. EXPOSURES: Randomized exposure to 81 mg or 325 mg of aspirin daily. MAIN OUTCOMES AND MEASURES: Number of events for the primary end point (composite of death, hospitalization for myocardial infarction, and hospitalization for stroke) that were contributed by EHR or claims data and then number of events contributed by each additional data source. RESULTS: Of 15 006 participants randomized with at least 1 other source of data available beyond participant-reported data, there were 8756 (58.3%) with participant-reported and EHR data; 4291 (28.6%) with participant-reported, EHR, and claims data; 1412 (9.4%) with EHR-only data; 262 (1.7%) with participant-reported and claims data; 202 (1.3%) with EHR and claims data; and 83 (0.6%) with claims-only data. Participants with EHR-only data were younger (median age, 63.7 years; IQR, 55.8-71.4) compared with the other groups (range, 65.6-71.9 years). Among participants with both EHR and claims data, with or without participant-reported data (n = 4493), for each outcome, most events (92%-100%) were identified in the EHR or in claims data. For all clinical end points, participant-reported data contributed less than 10% of events not otherwise available from claims or EHR data. CONCLUSIONS AND RELEVANCE: In this analysis of a pragmatic RCT, claims and EHR data provided the most clinical end-point data when compared with participant-reported events. These findings provide a framework for collecting end points in pragmatic clinical trials. Further work is needed to understand the data source combinations that most effectively provide clinical end-point data in RCTs.

IMPORTANCE: Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in the US. Although aspirin is recommended for secondary prevention of ASCVD, there was no difference in safety and effectiveness of aspirin dosed daily at 81 mg or 325 mg in the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) randomized clinical trial. However, it is unknown whether differences by sex exist in the safety and effectiveness of the different aspirin doses. OBJECTIVE: To evaluate sex-specific differences in the safety and effectiveness of 2 aspirin doses in the ADAPTAPLE trial. DESIGN, SETTING, AND PARTICIPANTS: The ADAPTABLE study was an open-label, pragmatic, randomized clinical trial that randomly assigned participants with chronic, stable ASCVD to 81 mg vs 325 mg of aspirin daily. Using Cox proportional-hazard models, male and female participants were compared for outcomes. In addition, it was assessed whether sex was an effect modifier in the association between aspirin dose and outcomes. The ADAPTABLE trial was conducted at 40 medical centers and 1 health plan. Eligible patients were 18 years and older and had established ASCVD. Study data were analyzed from December 2021 to March 2024. INTERVENTIONS: Patients received 81 mg or 325 mg of aspirin daily for the secondary prevention of ASCVD. MAIN OUTCOMES AND MEASURES: The primary effectiveness outcomes included all-cause death and hospitalization for myocardial infarction (MI) or stroke. The primary safety outcome was hospitalization for major bleeding requiring transfusion. RESULTS: A total of 15 076 patients (median [IQR] age, 67.6 [60.7-73.6] years; 10 352 male [68.7%]) were followed up for a median (IQR) of 26.2 (19.0-34.9) months. Overall, 4724 (31.3%) were female, and 2307 of the female participants (48.8%) received aspirin 81 mg. Compared with males, female participants were younger (median [IQR] age, 66.3 [59.4-72.6] years vs 68.2 (61.4-73.9) years, less likely to self-report White race (3426 [72.5%] vs 8564 [82.7%]), more likely to smoke (564 [12.9%] vs 818 [8.4%]), and more likely to have a history of peripheral arterial disease (1179 [25.7%] vs 2314 [23.0%]). The primary effectiveness outcome of all-cause death and hospitalization for MI or stroke occurred in 379 female participants (8.1%) and 780 male participants (7.1%). There was no significant interaction by sex for the primary effectiveness end point between the 2 aspirin doses (female adjusted hazard ratio [aHR], 1.01; 95% CI, 0.82-1.26 and male aHR, 1.06; 95% CI, 0.91-1.23; P interaction term for sex = .74). During the trial, female participants had fewer revascularization procedures (237 [5.0%] vs 680 [6.6%]; aHR, 0.79; 95% CI, 0.68-0.92; P = .002) but had a higher risk of hospitalization for stroke (aHR, 1.72; 95% CI, 1.27-2.33; P < .001). Among female participants, there was a slightly higher rate of bleeding in the 81-mg aspirin cohort compared with the 325-mg cohort (20 [0.83%] vs 13 [0.52%]; aHR, 2.21; 95% CI, 1.04-4.70; P interaction term for sex = .07). There were no significant differences between female and male participants regarding aspirin dose adherence. CONCLUSIONS AND RELEVANCE: In this secondary analysis of the ADAPTABLE trial, there were no significant sex-specific differences in the effectiveness and safety of 2 aspirin doses for secondary prevention of ASCVD events. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02697916

IMPORTANCE: Clinicians recommend enteric-coated aspirin to decrease gastrointestinal bleeding in secondary prevention of coronary artery disease even though studies suggest platelet inhibition is decreased with enteric-coated vs uncoated aspirin formulations. OBJECTIVE: To assess whether receipt of enteric-coated vs uncoated aspirin is associated with effectiveness or safety outcomes. DESIGN, SETTING, AND PARTICIPANTS: This is a post hoc secondary analysis of ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness), a pragmatic study of 15 076 patients with atherosclerotic cardiovascular disease having data in the National Patient-Centered Clinical Research Network. Patients were enrolled from April 19, 2016, through June 30, 2020, and randomly assigned to receive high (325 mg) vs low (81 mg) doses of daily aspirin. The present analysis assessed the effectiveness and safety of enteric-coated vs uncoated aspirin among those participants who reported aspirin formulation at baseline. Data were analyzed from November 11, 2019, to July 3, 2023. INTERVENTION: ADAPTABLE participants were regrouped according to aspirin formulation self-reported at baseline, with a median (IQR) follow-up of 26.2 (19.8-35.4) months. MAIN OUTCOMES AND MEASURES: The primary effectiveness end point was the cumulative incidence of the composite of myocardial infarction, stroke, or death from any cause, and the primary safety end point was major bleeding events (hospitalization for a bleeding event with use of a blood product or intracranial hemorrhage). Cumulative incidence at median follow-up for primary effectiveness and primary safety end points was compared between participants taking enteric-coated or uncoated aspirin using unadjusted and multivariable Cox proportional hazards models. All analyses were conducted for the intention-to-treat population. RESULTS: Baseline aspirin formulation used in ADAPTABLE was self-reported for 10 678 participants (median [IQR] age, 68.0 [61.3-73.7] years; 7285 men [68.2%]), of whom 7366 (69.0%) took enteric-coated aspirin and 3312 (31.0%) took uncoated aspirin. No significant difference in effectiveness (adjusted hazard ratio [AHR], 0.94; 95% CI, 0.80-1.09; P = .40) or safety (AHR, 0.82; 95% CI, 0.49-1.37; P = .46) outcomes between the enteric-coated aspirin and uncoated aspirin cohorts was found. Within enteric-coated aspirin and uncoated aspirin, aspirin dose had no association with effectiveness (enteric-coated aspirin AHR, 1.13; 95% CI, 0.88-1.45 and uncoated aspirin AHR, 0.99; 95% CI, 0.83-1.18; interaction P = .41) or safety (enteric-coated aspirin AHR, 2.37; 95% CI, 1.02-5.50 and uncoated aspirin AHR, 0.89; 95% CI, 0.49-1.64; interaction P = .07). CONCLUSIONS AND RELEVANCE: In this post hoc secondary analysis of the ADAPTABLE randomized clinical trial, enteric-coated aspirin was not associated with significantly higher risk of myocardial infarction, stroke, or death or with lower bleeding risk compared with uncoated aspirin, regardless of dose, although a reduction in bleeding with enteric-coated aspirin cannot be excluded. More research is needed to confirm whether enteric-coated aspirin formulations or newer formulations will improve outcomes in this population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02697916

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IMPORTANCE: Vascular risk factors have been associated with cognitive decline. Midlife exposure to these factors may be most important in conferring late-life risk of cognitive impairment. OBJECTIVES: To examine Atherosclerosis Risk in Communities (ARIC) participants in midlife and to explore associations between midlife vascular risk factors and 25-year dementia incidence. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort investigation of the Atherosclerosis Risk in Communities (ARIC) Study was conducted from 1987-1989 through 2011-2013. The dates of this analysis were April 2015 through August 2016. The setting was ARIC field centers (Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis suburbs, Minnesota). The study comprised 15 744 participants (of whom 27.1% were black and 72.9% white) who were aged 44 to 66 years at baseline. MAIN OUTCOMES AND MEASURES: Demographic and vascular risk factors were measured at baseline (obesity, smoking, diabetes, prehypertension, hypertension, and hypercholesterolemia) as well as presence of the APOE ε4 genotype. After the baseline visit, participants had 4 additional in-person visits, for a total of 5 in-person visits, hospitalization surveillance, telephone calls, and repeated cognitive evaluations. Most recently, in 2011-2013, through the ARIC Neurocognitive Study (ARIC-NCS), participants underwent a detailed neurocognitive battery, informant interviews, and adjudicated review to define dementia cases. Additional cases were identified through the Telephone Interview for Cognitive Status–Modified or informant interview, for participants not attending the ARIC-NCS visit, or by an International Classification of Diseases, Ninth Revision dementia code during a hospitalization. Fully adjusted Cox proportional hazards regression was used to evaluate associations of baseline vascular and demographic risk factors with dementia. RESULTS: In total, 1516 cases of dementia (57.0% female and 34.9% black, with a mean [SD] age at visit 1 of 57.4 [5.2] years) were identified among 15 744 participants. Black race (hazard ratio [HR], 1.36; 95% CI, 1.21-1.54), older age (HR, 8.06; 95% CI, 6.69-9.72 for participants aged 60-66 years), lower educational attainment (HR, 1.61; 95% CI, 1.28-2.03 for less than a high school education), and APOE ε4 genotype (HR, 1.98; 95% CI, 1.78-2.21) were associated with increased risk of dementia, as were midlife smoking (HR, 1.41; 95% CI, 1.23-1.61), diabetes (HR, 1.77; 95% CI, 1.53-2.04), prehypertension (HR, 1.31; 95% CI, 1.14-1.51), and hypertension (HR, 1.39; 95% CI, 1.22-1.59). The HR for dementia for diabetes was almost as high as that for APOE ε4 genotype. CONCLUSIONS AND RELEVANCE: Midlife vascular risk factors are associated with increased risk of dementia in black and white ARIC Study participants. Further studies are needed to evaluate the mechanism of and opportunities for prevention of the cognitive sequelae of these risk factors in midlife.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by impairment in memory, behavioral changes, and gradual loss of autonomy. Since there is a long latent period prior to diagnosis, the aim of this study was to determine whether twenty single nucleotide polymorphisms identified in genome‐wide association analyses of AD are associated with cognitive change in 8,320 white and 2,039 African‐American middle‐aged adults enrolled in the prospective Atherosclerosis Risk in Communities (ARIC) study. Cognition was evaluated using the Delayed Word Recall Test (DWRT; verbal memory), Digit Symbol Substitution Test (DSST; processing speed), and Word Fluency Test (WFT; executive function). General linear models were used to assess mean differences in 6‐year change in test scores among individuals categorized by genotype after adjusting for age, gender, and years of education. Addition of the minor allele for rs670139 (MS4A4E), rs9331896 (CLU), and rs12155159 (NME8) was nominally associated with change on the DWRT, DSST, and WFT, respectively, in whites. The ZCWPW1(rs1476679) and CDS33(rs3865444) variants were nominally associated with change on the DWRT and WFT in African‐Americans. For rs670139 and rs9331896 the association was only significant in individuals bearing at least one APOEϵ4 allele in stratified analyses. An unweighted genetic risk score aggregating the risk alleles for 15 polymorphisms was not associated with change in cognitive function. Although the AD‐associated genetic variants appear to have small effects on early cognitive change, replication will be required to establish whether there is a discernible influence on cognitive status in midlife. © 2016 Wiley Periodicals, Inc.

Introduction:Pragmatic randomized controlled trials (RCT) often use multiple data sources to examine clinical events, but the relative contribution of data sources (patient-reported, electronic health records (EHR), private/public claims data) to clinical endpoint rates is often not examined.Hypothesis:We hypothesized that claims data would contribute the highest number of events relative to other data sources.Methods:The ADAPTABLE study was an open-label, pragmatic RCT that demonstrated no significant difference in major cardiovascular or bleeding events among patients with CV disease randomized to an aspirin dose of 81vs. 325 mg/daily. We assessed the clinical endpoint rates and contribution of clinical endpoints by data source among patients who had EHR, public and private insurance claims data, and/or patient-reported (portal) data.Results:Of 15,076 patients randomized, there were 1,412 patients with EHR-only data; 8,756 with portal and EHR data; and 4,291 patients with portal, EHR, and claims data (Medicare or private). Patients with EHR-only data were younger (63.7 years) compared to the other groups (65.6-71.1 years); and were more likely Black (10.6%) vs. the other groups (6.3%-9.7%), p<0.001. The table demonstrates trial clinical event rates by data source among patients with available portal, EHR, and claims data. Among patients with available portal, EHR, and claims data, Medicare claims data contributed the most events for the composite endpoint (77.5%) and all-cause death (97.3%), while EHR data contributed the most events for MI (74.3%), stroke (74.3%), and major bleed (73.3%).Conclusions:In a large pragmatic trial, Medicare claims data contributed the most clinical events for the primary composite outcome and all-cause death, when compared with other available data sources. Further work is needed to understand the data source combinations that most effectively provide clinical endpoint data in RCTs.

Background:The ADAPTABLE was a pragmatic randomized controlled trial that found no difference between high dose vs low dose aspirin for secondary prevention of ischemic or bleeding events. Whether concomitant P2Y12 inhibitor therapy modifies the effect of aspirin dose on clinical events remains unclear.Methods:Participants in ADAPTABLE were stratified according to baseline use of clopidogrel or prasugrel (P2Y12 group). Ticagrelor was not permitted due to a black box warning with high dose aspirin. The primary effectivenessendpoint was a composite of myocardial infarction, stroke, or death and the primary safetyendpoint was hospitalization for major bleeding. We used multivariable Cox regression to compare the relative effectivenessand safetyof aspirin dose within P2Y12 and non-P2Y12 groups.Results:Of the 13,815 (91.6%) participants with available data, 3,051 (22.1%) were on a P2Y12 inhibitor at baseline (clopidogrel: 93.4%; prasugrel: 6.6%). P2Y12 inhibitor use was associated with higher risk of the primary effectiveness endpoint (10.86% vs. 6.31%; adjusted HR 1.44 95% CI 1.22-1.62) but was not associated with bleeding (0.53% vs. 0.95%; adjusted HR:1.42; 95% CI 0.91, 2.22). We found no interaction in the relative effectiveness and safety of high vs. low dose aspirin by P2Y12 inhibitor use (Table, P interaction0.09 and 0.73 for primary effectiveness and safety endpoint, respectively). Aspirin dose switching and discontinuation occurred in 28.6% of patients. Although this was more common in high dose vs. low dose aspirin, the above rates did not differ between the P2Y12 and non-P2Y12 groups.Conclusion:In this pre-specified subgroup analysis of a large, pragmatic trial, we found that the relative effectiveness and safety of high dose vs. low dose aspirin was not modified by baseline use of P2Y12 inhibitors. Decisions regarding aspirin dosing should be individualized based on clinical factors and patient preference, regardless of P2Y12 inhibitor use.

Introduction:Many clinicians recommend enteric coated aspirin (EC-ASA) to decrease gastrointestinal bleeding (GIB) in secondary cardiovascular (CV) protection even though studies suggest decreased platelet inhibition with EC-ASA compared to uncoated “plain” formulations (P-ASA). ADAPTABLE was a large, pragmatic study, showing no difference in ischemic events or bleeding between 81-mg and 325-mg ASA and provides a large population to assess effectiveness and safety of EC-ASA versus P-ASA in CV patients.Methods:Participants (pts) from ADAPTABLE were re-grouped according to type and dose of reported ASA use at baseline. The primary effectiveness endpoint was the composite of myocardial infarction (MI), stroke, or death from any cause and the primary safety endpoint was major bleeding events (hospitalization for a bleeding event with use of a blood product or intracranial hemorrhage) analyzed between groups by ASA type and within groups by dose using multivariable Cox proportional hazards.Results:15,076 pts were randomized to 81-mg or 325 -mg ASA were followed for a median of 26.2 months of whom 10,678 reported ASA type at baseline. Of pts reporting ASA type used, 69% used EC-ASA and were slightly older, more likely to be in the 81-mg cohort, be nonsmokers, have slightly more coronary artery disease, and have a slightly lower prior MI rate (Table). No other significant differences between the 2 cohorts were noted. There was no significant difference in the effectiveness or safety outcomes between the EC-ASA and P-ASA cohorts (Table). Within EC-ASA and P-ASA, ASA dose had no effect on effectiveness (interaction p = 0.41) or safety (interaction p = 0.07).Conclusion:Enteric coating did not significantly affect the primary effectiveness or safety endpoints in ADAPTABLE, regardless of ASA dose. More research is needed to confirm whether enteric coated aspirin formulations or newer formulations will improve ischemic and bleeding outcomes in patients with CV disease.

Prospective data evaluating abnormal sleep quality and quantity with cognitive decline are limited because most studies used subjective data and/or had short follow-up. We hypothesized that, over 15 y of follow-up, participants with objectively measured obstructive sleep apnea (OSA) and other indices of poor sleep quantity and quality would experience greater decline in cognitive functioning than participants with normal sleep patterns.

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IMPORTANCE: Hypertension is a treatable potential cause of cognitive decline and dementia, but its greatest influence on cognition may occur in middle age. OBJECTIVE: To evaluate the association between midlife (48-67 years of age) hypertension and the 20-year change in cognitive performance. DESIGN, SETTING, AND PARTICIPANTS: The Atherosclerosis Risk in Communities cohort (1990-1992 through 2011-2013) underwent evaluation at field centers in Washington County, Maryland, Forsyth County, North Carolina, Jackson, Mississippi, and the Minneapolis, Minnesota, suburbs. Of 13 476 African American and white participants with baseline cognitive data, 58.0% of living participants completed the 20-year cognitive follow-up. EXPOSURES: Hypertension, prehypertension, or normal blood pressure (BP) at visit 2 (1990-1992) constituted the primary exposure. Systolic BP at visit 2 or 5 (2011-2013) and indication for treatment at visit 2 based on the Eighth Joint National Committee (JNC-8) hypertension guidelines constituted the secondary exposures. MAIN OUTCOMES AND MEASURES: Prespecified outcomes included the 20-year change in scores on the Delayed Word Recall Test, Digit Symbol Substitution Test, and Word Fluency Test and in global cognition. RESULTS: During 20 years, baseline hypertension was associated with an additional decline of 0.056 global z score points (95% CI, −0.100 to −0.012) and prehypertension was associated nonsignificantly with 0.040 more global z score points of decline (95% CI, −0.085 to 0.005) compared with normal BP. Individuals with hypertension who used antihypertensives had less decline during the 20 years than untreated individuals with hypertension (−0.050 [95% CI, −0.003 to −0.097] vs −0.079 [95% CI, −0.156 to −0.002] global z score points). Having a JNC-8–specified indication for initiating antihypertensive treatment at baseline was associated with a greater 20-year decline (−0.044 [95% CI, −0.085 to −0.003] global z score points) than not having an indication. We observed effect modification by race for the continuous systolic BP analyses (P = .01), with each 20–mm Hg increment at baseline associated with an additional decline of 0.048 (95% CI, −0.074 to −0.022) points in global cognitive z score in whites but not in African Americans (decline, −0.020 [95% CI, −0.026 to 0.066] points). Systolic BP at the end of follow-up was not associated with the preceding 20 years of cognitive change in either group. Methods to account for bias owing to attrition strengthened the magnitude of some associations. CONCLUSIONS AND RELEVANCE: Midlife hypertension and elevated midlife but not late-life systolic BP was associated with more cognitive decline during the 20 years of the study. Greater decline is found with higher midlife BP in whites than in African Americans.

An algorithm to classify heart failure (HF) end points inclusive of contemporary measures of biomarkers and echocardiography was recently proposed by an international expert panel. Our objective was to assess agreement of HF classification by this contemporaneous algorithm with that by a standardized physician reviewer panel, when applied to data abstracted from community-based hospital records.

Background:Ischemic Stroke (IS) is associated with an increased risk of dementia, but the relative contribution of IS severity or recurrence to cognition is not known. We aimed to determine the risk of dementia after incident IS and how it varies by stroke severity and recurrence in the Atherosclerosis Risk in Communities (ARIC) study.Methods:15,405 ARIC participants free of stroke and dementia at baseline (1987-9) were followed for IS and dementia through 2019. Incident and recurrent IS were classified by expert review of hospital records, with stroke severity by the National Institutes of Health Stroke Scale (NIHSS) classified as NIHSS≤5, 6-10, 11-15, ≥16. Dementia cases were adjudicated through expert review of in-person evaluations, informant interviews, phone assessments, hospitalization code or death certificates. Poisson regression models with robust error variance were used to estimate dementia incidence in participants with and without IS, and associations between time-dependent IS incidence (excluding dementia in the first year after stroke), frequency and severity, and dementia were studied with Cox proportional hazards models, adjusting for demographics, APOEε4 and vascular risk factors.Results:1151 IS (970 incident) and 2807 dementia cases were identified. NIHSS was available for 877 IS (76%). Adjusted incidence rates (95% CI) of dementia per 100 person-years were 0.45 (0.42-0.49) in participants without IS vs. 1.33 (1.15-1.55) in those with IS. Compared to no IS, risk of dementia (adjusted HR, 95% CI) increased with IS number and severity from 1.71 (1.47-1.99) for participants with one IS to 6.68 (3.58-12.46) for those with ≥3 events, and from 1.64 (1.36-1.98) for NIHSS≤5 to 4.43 (1.84-10.68) for NIHSS≥16 (Table).Conclusion:Risk of dementia is significantly increased after stroke, independent of vascular risk factors. These data suggest a dose-response relationship between number of stroke events and stroke severity, and risk of dementia.

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