Impact of aspirin dose according to race in secondary prevention of atherosclerotic cardiovascular disease: a secondary analysis of the ADAPTABLE randomised controlled trial.

OBJECTIVES: To evaluate whether the effectiveness and safety of low (81 mg daily) versus high-dose (325 mg daily) aspirin is consistent across races among patients with established atherosclerotic cardiovascular disease (ASCVD). DESIGN: A secondary analysis of the randomised controlled trial ADAPTABLE was performed. SETTING: The study was conducted in 40 centres and one health plan participating in the National Patient-Centred Clinical Research Network (PCORnet) in the USA. PARTICIPANTS: Among 15 076 participants with established ASCVD, 14 096 had self-reported race available and were included in the analysis. Participants were divided according to self-reported race as Black (n=1311, 9.3%), White (n=11 990, 85.1%) or other race (n=795, 5.6%). INTERVENTIONS: Participants were randomised to open-label daily aspirin doses of 81 mg versus 325 mg in a 1:1 ratio for a median of 26.2 months. PRIMARY AND SECONDARY OUTCOMES MEASURES: The primary effectiveness endpoint was a composite of death from any cause, hospitalisation for myocardial infarction or hospitalisation for stroke. The primary safety endpoint was hospitalisation for bleeding requiring blood product transfusion. RESULTS: Estimated cumulative incidence of the primary effectiveness endpoint at median follow-up with the 81 mg and the 325 mg daily doses were 6.70% and 7.12% in White participants (adjusted HR: 1.00 [95% CI: 0.88 to 1.15]); 12.27% and 10.69% in Black participants (adjusted HR: 1.40 [95% CI: 1.02 to 1.93]); and 6.88% and 7.69% in other participants (adjusted HR: 0.86 [95% CI: 0.54 to 1.39]) (p-interaction=0.12), respectively. There was no significant interaction between self-reported race and assigned aspirin dose regarding the secondary effectiveness and the primary safety endpoints. CONCLUSION: Race is not an effect modifier on the impact of aspirin dosing on effectiveness and safety in patients with established ASCVD. In clinical practice, treatment decisions regarding aspirin dose in secondary prevention of ASCVD should not be influenced by race. TRIAL REGISTRATION NUMBER: NCT02697916.

Aspirin Dosing for Secondary Prevention of Atherosclerotic Cardiovascular Disease in Male and Female Patients: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial.

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.

Contribution of Clinical Trial Event Data by Data Source: A Prespecified Analysis of the ADAPTABLE Randomized Clinical Trial.

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.

Identification of risk factors of Long COVID and predictive modeling in the RECOVER EHR cohorts.

BACKGROUND: SARS-CoV-2-infected patients may develop new conditions in the period after the acute infection. These conditions, the post-acute sequelae of SARS-CoV-2 infection (PASC, or Long COVID), involve a diverse set of organ systems. Limited studies have investigated the predictability of Long COVID development and its associated risk factors. METHODS: In this retrospective cohort study, we used electronic healthcare records from two large-scale PCORnet clinical research networks, INSIGHT (~1.4 million patients from New York) and OneFlorida+ (~0.7 million patients from Florida), to identify factors associated with having Long COVID, and to develop machine learning-based models for predicting Long COVID development. Both SARS-CoV-2-infected and non-infected adults were analysed during the period of March 2020 to November 2021. Factors associated with Long COVID risk were identified by removing background associations and correcting for multiple tests. RESULTS: We observed complex association patterns between baseline factors and a variety of Long COVID conditions, and we highlight that severe acute SARS-CoV-2 infection, being underweight, and having baseline comorbidities (e.g., cancer and cirrhosis) are likely associated with increased risk of developing Long COVID. Several Long COVID conditions, e.g., dementia, malnutrition, chronic obstructive pulmonary disease, heart failure, PASC diagnosis U099, and acute kidney failure are well predicted (C-index > 0.8). Moderately predictable conditions include atelectasis, pulmonary embolism, diabetes, pulmonary fibrosis, and thromboembolic disease (C-index 0.7-0.8). Less predictable conditions include fatigue, anxiety, sleep disorders, and depression (C-index around 0.6). CONCLUSIONS: This observational study suggests that association patterns between investigated factors and Long COVID are complex, and the predictability of different Long COVID conditions varies. However, machine learning-based predictive models can help in identifying patients who are at risk of developing a variety of Long COVID conditions.

Most people who develop COVID-19 make a full recovery, but some go on to develop post-acute sequelae of SARS-CoV-2 infection, commonly known as Long COVID. Up to now, we did not know why some people are affected by Long COVID whilst others are not. We conducted a study to identify risk factors for Long COVID and developed a mathematical modeling approach to predict those at risk. We find that Long COVID is associated with some factors such as experiencing severe acute COVID-19, being underweight, and having conditions including cancer or cirrhosis. Due to the wide variety of symptoms defined as Long COVID, it may be challenging to come up with a set of risk factors that can predict the whole spectrum of Long COVID. However, our approach could be used to predict a variety of Long COVID conditions.

Excess burden of respiratory and abdominal conditions following COVID-19 infections during the ancestral and Delta variant periods in the United States: An EHR-based cohort study from the RECOVER program.

IMPORTANCE: The frequency and characteristics of post-acute sequelae of SARS-CoV-2 infection (PASC) may vary by SARS-CoV-2 variant. OBJECTIVE: To characterize PASC-related conditions among individuals likely infected by the ancestral strain in 2020 and individuals likely infected by the Delta variant in 2021. DESIGN: Retrospective cohort study of electronic medical record data for approximately 27 million patients from March 1, 2020-November 30, 2021. SETTING: Healthcare facilities in New York and Florida. PARTICIPANTS: Patients who were at least 20 years old and had diagnosis codes that included at least one SARS-CoV-2 viral test during the study period. EXPOSURE: Laboratory-confirmed COVID-19 infection, classified by the most common variant prevalent in those regions at the time. MAIN OUTCOME(S) AND MEASURE(S): Relative risk (estimated by adjusted hazard ratio [aHR]) and absolute risk difference (estimated by adjusted excess burden) of new conditions, defined as new documentation of symptoms or diagnoses, in persons between 31-180 days after a positive COVID-19 test compared to persons without a COVID-19 test or diagnosis during the 31-180 days after the last negative test. RESULTS: We analyzed data from 560,752 patients. The median age was 57 years; 60.3% were female, 20.0% non-Hispanic Black, and 19.6% Hispanic. During the study period, 57,616 patients had a positive SARS-CoV-2 test; 503,136 did not. For infections during the ancestral strain period, pulmonary fibrosis, edema (excess fluid), and inflammation had the largest aHR, comparing those with a positive test to those without a COVID-19 test or diagnosis (aHR 2.32 [95% CI 2.09 2.57]), and dyspnea (shortness of breath) carried the largest excess burden (47.6 more cases per 1,000 persons). For infections during the Delta period, pulmonary embolism had the largest aHR comparing those with a positive test to a negative test (aHR 2.18 [95% CI 1.57, 3.01]), and abdominal pain carried the largest excess burden (85.3 more cases per 1,000 persons). CONCLUSIONS AND RELEVANCE: We documented a substantial relative risk of pulmonary embolism and a large absolute risk difference of abdomen-related symptoms after SARS-CoV-2 infection during the Delta variant period. As new SARS-CoV-2 variants emerge, researchers and clinicians should monitor patients for changing symptoms and conditions that develop after infection.

Effect of Montelukast vs Placebo on Time to Sustained Recovery in Outpatients with COVID-19: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) is uncertain. Objective: To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19. Design Setting and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate the effectiveness of repurposed medications in treating mild to moderate COVID-19. Between January 27, 2023, and June 23, 2023, 1250 participants ≥30 years of age with confirmed SARS-CoV-2 infection and ≥2 acute COVID-19 symptoms for ≤7 days, were included across 104 US sites to evaluate the use of montelukast. Interventions: Participants were randomized to receive montelukast 10 mg once daily or matched placebo for 14 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID clinical progression scale; and difference in mean time unwell. Results: Among participants who were randomized and received study drug, the median age was 53 years (IQR 42-62), 60.2% were female, 64.6% identified as Hispanic/Latino, and 56.3% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR] 1.02; 95% credible interval [CrI] 0.92-1.12; P(efficacy) = 0.63]). Unadjusted median time to sustained recovery was 10 days (95% confidence interval 10-11) in both groups. No deaths were reported and 2 hospitalizations were reported in each group; 36 participants reported healthcare utilization events (a priori defined as death, hospitalization, emergency department/urgent care visit); 18 in the montelukast group compared with 18 in the placebo group (HR 1.01; 95% CrI 0.45-1.84; P(efficacy)=0.48). Five participants experienced serious adverse events (3 with montelukast and 2 with placebo). Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with montelukast does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov ( NCT04885530 ).

Framework of the strengths and challenges of clinically integrated trials: An expert panel report.

The limitations of the explanatory clinical trial framework include the high expense of implementing explanatory trials, restrictive entry criteria for participants, and redundant logistical processes. These limitations can result in slow evidence generation that is not responsive to population health needs, yielding evidence that is not generalizable. Clinically integrated trials, which integrate clinical research into routine care, represent a potential solution to this challenge and an opportunity to support learning health systems. The operational and design features of clinically integrated trials include a focused scope, simplicity in design and requirements, the leveraging of existing data structures, and patient participation in the entire trial process. These features are designed to minimize barriers to participation and trial execution and reduce additional research burdens for participants and clinicians alike. Broad adoption and scalability of clinically integrated trials are dependent, in part, on continuing regulatory, healthcare system, and payer support. This analysis presents a framework of the strengths and challenges of clinically integrated trials and is based on a multidisciplinary expert "Think Tank" panel discussion that included representatives from patient populations, academia, non-profit funding agencies, the U.S. Food and Drug Administration, and industry.

The Effect of an Obesity Prevention Intervention Among Specific Subpopulations: A Heterogeneity of Treatment Effect Analysis of the Greenlight Trial.

Background: Understanding how different populations respond to a childhood obesity intervention could help optimize personalized treatment strategies, especially with the goal to reduce disparities in obesity. Methods: We conducted a secondary analysis of the Greenlight Cluster Randomized Controlled Trial, a health communication focused pediatric obesity prevention trial, to evaluate for heterogeneity of treatment effect (HTE) by child biological sex, caregiver BMI, caregiver reported race and ethnicity, primary language, and health literacy. To examine HTE on BMI z-score from 2 to 24 months of age, we fit linear mixed effects models. Results: We analyzed 802 caregiver-child pairs, of which 52% of children were female, 58% of households reported annual family income of <$20,000, and 83% did not have a college degree. We observed evidence to suggest HTE by primary language (p = 0.047 for Spanish vs. English) and the combination of primary language and health literacy (p = 0.01). There was insufficient evidence to suggest that the Greenlight intervention effect differed by biological sex, caregiver BMI, or by race/ethnicity. Conclusions: This HTE analysis found that the Greenlight obesity prevention intervention had a more beneficial effect on child BMI z-score over 2 years for children of caregivers with limited health literacy and for caregivers for whom Spanish was the primary language.

Patient-reported predictors of postdischarge mortality after cardiac hospitalization.

BACKGROUND: Adults hospitalized for cardiovascular events are at high risk for postdischarge mortality. Screening of psychosocial risk is prioritized by the Joint Commission. We tested whether key patient-reported psychosocial and behavioral measures could predict posthospitalization mortality in a cohort of adults hospitalized for a cardiovascular event. METHODS: We conducted a prospective cohort study to test the prognostic utility of validated patient-reported measures, including health literacy, social support, health behaviors and disease management, and socioeconomic status. Cox survival analyses of mortality were conducted over a median of 3.5 years. RESULTS: Among 2977 adults hospitalized for either acute coronary syndrome or acute decompensated heart failure, the mean age was 53 years, and 60% were male. After adjusting for demographic, clinical, and other psychosocial factors, mortality risk was greatest among patients who reported being unemployed (hazard ratio [HR]: 1.99, 95% confidence interval [CI]): 1.30-3.06), retired (HR: 2.14, 95% CI: 1.60-2.87), or unable to work due to disability (HR: 2.36, 95% CI: 1.73-3.21), as compared to those who were employed. Patient-reported perceived health competence (PHCS-2) and exercise frequency were also associated with mortality risk after adjusting for all other variables (HR: 0.86, 95% CI: 0.73-1.00 per four-point increase in PHCS-2; HR: 0.86, 95% CI: 0.77-0.96 per 3-day increase in exercise frequency, respectively). CONCLUSIONS: Patient-reported measures of employment status, perceived health competence, and exercise frequency independently predict mortality after a cardiac hospitalization. Incorporating these brief, valid measures into hospital-based screening may help with prognostication and targeting patients for resources during post-discharge transitions of care.

The Injury Prevention Program to Reduce Early Childhood Injuries: A Cluster Randomized Trial.

BACKGROUND AND OBJECTIVES: The American Academy of Pediatrics designed The Injury Prevention Program (TIPP) in 1983 to help pediatricians prevent unintentional injuries, but TIPP's effectiveness has never been formally evaluated. We sought to evaluate the impact of TIPP on reported injuries in the first 2 years of life. METHODS: We conducted a stratified, cluster-randomized trial at 4 academic medical centers: 2 centers trained their pediatric residents and implemented TIPP screening and counseling materials at all well-child checks (WCCs) for ages 2 to 24 months, and 2 centers implemented obesity prevention. At each WCC, parents reported the number of child injuries since the previous WCC. Proportional odds logistic regression analyses with generalized estimating equation examined the extent to which the number of injuries reported were reduced at TIPP intervention sites compared with control sites, adjusting for baseline child, parent, and household factors. RESULTS: A total of 781 parent-infant dyads (349 TIPP; 432 control) were enrolled and had sufficient data to qualify for analyses: 51% Hispanic, 28% non-Hispanic Black, and 87% insured by Medicaid. Those at TIPP sites had significant reduction in the adjusted odds of reported injuries compared with non-TIPP sites throughout the follow-up (P = .005), with adjusted odds ratios (95% CI) of 0.77 (0.66-0.91), 0.60 (0.44-0.82), 0.32 (0.16-0.62), 0.26 (0.12-0.53), and 0.27 (0.14-0.52) at 4, 6, 12, 18, and 24 months, respectively. CONCLUSIONS: In this cluster-randomized trial with predominantly low-income, Hispanic, and non-Hispanic Black families, TIPP resulted in a significant reduction in parent-reported injuries. Our study provides evidence for implementing the American Academy of Pediatrics' TIPP in routine well-child care.

Language Disparities in Caregiver Satisfaction with Physician Communication at Well Visits from 0-2 Years.

OBJECTIVE: This study aimed to describe caregiver satisfaction with physician communication over the first two years of life and examine differences by preferred language and the relationship to physician continuity. METHODS: Longitudinal data were collected at well visits (2 months to 2 years) from participants in a randomized controlled trial to prevent childhood obesity. Satisfaction with communication was assessed using the validated Communication Assessment Tool (CAT) questionnaire. Changes in the odds of optimal scores were estimated in mixed-effects logistic regression models to evaluate the associations between satisfaction over time and language, interpreter use, and physician continuity. RESULTS: Of 865 caregivers, 35% were Spanish-speaking. Spanish-speaking caregivers without interpreters had lower odds of an optimal satisfaction score compared with English speakers during the first 2 years, beginning at 2 months [OR 0.64 (95% CI: 0.43, 0.95)]. There was no significant difference in satisfaction between English-speaking caregivers and Spanish-speaking caregivers with an interpreter. The odds of optimal satisfaction scores increased over time for both language groups. For both language groups, odds of an optimal satisfaction score decreased each time a new physician was seen for a visit [OR 0.82 (95% CI: 0.69, 0.97)]. CONCLUSION: Caregiver satisfaction with physician communication improves over the first two years of well-child visits for both English- and Spanish-speakers. A loss of physician continuity over time was also associated with lower satisfaction. Future interventions to ameliorate communication disparities should ensure adequate interpreter use for primarily Spanish-speaking patients and address continuity issues to improve communication satisfaction.

The Patient Perspective on Colectomy for Recurrent Diverticulitis: A Qualitative Study.

OBJECTIVE: Understand the patient's decision-making process regarding colectomy for recurrent diverticulitis. BACKGROUND: The decision to pursue elective colectomy for recurrent diverticulitis is highly preference-sensitive. Little is known about the patient's perspective in this decision-making process. METHODS: We performed a qualitative study utilizing focus groups of patients with recurrent diverticulitis at 3 centers across the United States. Using an iterative inductive/deductive approach, we developed a conceptual framework to capture the major themes identified in the coded data. RESULTS: From March 2019 to July 2020, 39 patients were enrolled across 3 sites and participated in 6 focus groups. After coding the transcripts using a hierarchical coding system, a conceptual framework was developed. Major themes identified included participants' beliefs about surgery, such as normative beliefs (eg, subjective, value placed on surgery), control beliefs (eg, self-efficacy, stage of change), and anticipated outcomes (eg, expectations, anticipated regret); the role of behavioral management strategies (eg, fiber, eliminate bad habits); emotional experiences (eg, depression, embarrassment); current symptoms (eg, severity, timing); and quality of life (eg, cognitive load, psychosocial factors). Three sets of moderating factors influencing patient choice were identified: clinical history (eg, source of diagnosis, multiple surgeries), clinical protocols (eg, pre-op and post-op education), and provider-specific factors (eg, specialty, choice of surgeon). CONCLUSIONS: Patients view the decision to undergo colectomy through 3 major themes: their beliefs about surgery, their psychosocial context, and moderating factors that influence participant choice to undergo surgery. This knowledge is essential both for clinicians counseling patients who are considering colectomy and for researchers studying the process to optimize care for recurrent diverticulitis.

Age and Aspirin Dosing in Secondary Prevention of Atherosclerotic Cardiovascular Disease.

BACKGROUND: In patients with atherosclerotic cardiovascular disease, increasing age is concurrently associated with higher risks of ischemic and bleeding events. The objectives are to determine the impact of aspirin dose on clinical outcomes according to age in atherosclerotic cardiovascular disease. METHODS AND RESULTS: In the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) trial, patients with atherosclerotic cardiovascular disease were randomized to daily aspirin doses of 81 mg or 325 mg. The primary effectiveness end point was death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke. The primary safety end point was hospitalization for bleeding requiring transfusion. A total of 15 076 participants were randomized to aspirin 81 mg (n=7540) or 325 mg (n=7536) daily (median follow-up: 26.2 months; interquartile range: 19.0-34.9 months). Median age was 67.6 years (interquartile range: 60.7-73.6 years). Among participants aged <65 years (n=5841 [38.7%]), a primary end point occurred in 226 (7.54%) in the 81 mg group, and in 191 (6.80%) in the 325 mg group (adjusted hazard ratio [HR], 1.23 [95% CI, 1.01-1.49]). Among participants aged ≥65 years (n=9235 [61.3%]), a primary end point occurred in 364 (7.12%) in the 81 mg group, and in 378 (7.96%) in the 325 mg group (adjusted HR, 0.95 [95% CI, 0.82-1.10]). The age-dose interaction was not significant (P=0.559). There was no significant interaction between age and the randomized aspirin dose for the secondary effectiveness and the primary safety bleeding end points (P>0.05 for all). CONCLUSIONS: Age does not modify the impact of aspirin dosing (81 mg or 325 mg daily) on clinical end points in secondary prevention of atherosclerotic cardiovascular disease.

Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease and Diabetes Mellitus: A Subgroup Analysis of the ADAPTABLE Trial.

OBJECTIVE: Patients with diabetes mellitus (DM) and concomitant atherosclerotic cardiovascular disease (ASCVD) must be on the most effective dose of aspirin to mitigate risk of future adverse cardiovascular events. RESEARCH DESIGN AND METHODS: ADAPTABLE, an open-label, pragmatic study, randomized patients with stable, chronic ASCVD to 81 mg or 325 mg of daily aspirin. The effects of aspirin dosing was assessed on the primary effectiveness outcome, a composite of all-cause death, hospitalization for myocardial infarction, or hospitalization for stroke, and the primary safety outcome of hospitalization for major bleeding. In this prespecified analysis, we used Cox proportional hazards models to compare aspirin dosing in patients with and without DM for the primary effectiveness and safety outcome. RESULTS: Of 15,076 patients, 5,676 (39%) had DM of whom 2,820 (49.7%) were assigned to 81 mg aspirin and 2,856 (50.3%) to 325 mg aspirin. Patients with versus without DM had higher rates of the composite cardiovascular outcome (9.6% vs. 5.9%; P < 0.001) and bleeding events (0.78% vs. 0.50%; P < 0.001). When comparing 81 mg vs. 325 mg of aspirin, patients with DM had no difference in the primary effectiveness outcome (9.3% vs. 10.0%; hazard ratio [HR] 0.98 [95% CI 0.83-1.16]; P = 0.265) or safety outcome (0.87% vs. 0.69%; subdistribution HR 1.25 [95% CI 0.72-2.16]; P = 0.772). CONCLUSIONS: This study confirms the inherently higher risk of patients with DM irrespective of aspirin dosing. Our findings suggest that a higher dose of aspirin yields no added clinical benefit, even in a more vulnerable population.

Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain. Objective: To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19. Design, Setting, and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less. Interventions: Participants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607). Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28. Results: Among 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy = .40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit): 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy = .86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Avenues for Strengthening PCORnet's Capacity to Advance Patient-Centered Economic Outcomes in Patient-Centered Outcomes Research (PCOR).

PCORnet, the National Patient-Centered Clinical Research Network, provides the ability to conduct prospective and observational pragmatic research by leveraging standardized, curated electronic health records data together with patient and stakeholder engagement. PCORnet is funded by the Patient-Centered Outcomes Research Institute (PCORI) and is composed of 8 Clinical Research Networks that incorporate at total of 79 health system "sites." As the network developed, linkage to commercial health plans, federal insurance claims, disease registries, and other data resources demonstrated the value in extending the networks infrastructure to provide a more complete representation of patient's health and lived experiences. Initially, PCORnet studies avoided direct economic comparative effectiveness as a topic. However, PCORI's authorizing law was amended in 2019 to allow studies to incorporate patient-centered economic outcomes in primary research aims. With PCORI's expanded scope and PCORnet's phase 3 beginning in January 2022, there are opportunities to strengthen the network's ability to support economic patient-centered outcomes research. This commentary will discuss approaches that have been incorporated to date by the network and point to opportunities for the network to incorporate economic variables for analysis, informed by patient and stakeholder perspectives. Topics addressed include: (1) data linkage infrastructure; (2) commercial health plan partnerships; (3) Medicare and Medicaid linkage; (4) health system billing-based benchmarking; (5) area-level measures; (6) individual-level measures; (7) pharmacy benefits and retail pharmacy data; and (8) the importance of transparency and engagement while addressing the biases inherent in linking real-world data sources.

Feeding, television, and sleep behaviors at one year of age in a diverse sample.

Background: Healthy lifestyle behaviors that can prevent adverse health outcomes, including obesity, are formed in early childhood. This study describes feeding, television, and sleep behaviors among one-year-old infants and examines differences by sociodemographic factors. Methods: Caregivers of one-year-olds presenting for well care at two clinics, control sites for the Greenlight Study, were queried about feeding, television time, and sleep. Adjusted associations between sociodemographic factors and behaviors were performed by modified Poisson (binary), multinomial logistic (multi-category), or linear (continuous) regression models. Results: Of 235 one-year-olds enrolled, 81% had Medicaid, and 45% were Hispanic, 36% non-Hispanic Black, 19% non-Hispanic White. Common behaviors included 20% exclusive bottle use, 32% put to bed with bottle, mean daily juice intake of 4.1 ± 4.6 ounces, and active television time 45 ± 73 min. In adjusted analyses compared to Hispanic caregivers, non-Hispanic Black caregivers were less likely to report exclusive bottle use (odds ratio: 0.11, 95% confidence interval [CI] 0.03-0.39), reported 2.4 ounces more juice (95% CI 1.0-3.9), 124 min more passive television time (95% CI 60-188), and 37 min more active television time (95% CI 10-64). Increased caregiver education and higher income were associated with 0.4 (95% CI 0.13-0.66) and 0.3 (95% CI 0.06-0.55) more servings of fruits and vegetables per day, respectively. Conclusion: In a diverse sample of one-year-olds, caregivers reported few protective behaviors that reduce the risk for adverse health outcomes including obesity. Differences in behavior by race/ethnicity, income, and education can inform future interventions and policies. Future interventions should strive to create culturally effective messaging to address common adverse health behaviors.

Aspirin Dosing for Secondary Prevention of Atherosclerotic Cardiovascular Disease in Patients Treated With P2Y12 Inhibitors.

Background The ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) was a large, pragmatic, randomized controlled trial that found no difference between high- versus low-dose aspirin for secondary prevention of atherosclerotic cardiovascular disease. Whether concomitant P2Y12 inhibitor therapy modifies the effect of aspirin dose on clinical events remains unclear. Methods and Results Participants in ADAPTABLE were stratified according to baseline use of clopidogrel or prasugrel (P2Y12 group). The primary effectiveness end point was a composite of death, myocardial infarction, or stroke; and the primary safety end point was major bleeding requiring blood transfusions. We used multivariable Cox regression to compare the relative effectiveness and safety of aspirin dose within P2Y12 and non-P2Y12 groups. Of 13 815 (91.6%) participants with available data, 3051 (22.1%) were receiving clopidogrel (2849 [93.4%]) or prasugrel (203 [6.7%]) at baseline. P2Y12 inhibitor use was associated with higher risk of the primary effectiveness end point (10.86% versus 6.31%; adjusted hazard ratio [HR], 1.40 [95% CI, 1.22-1.62]) but was not associated with bleeding (0.95% versus 0.53%; adjusted HR, 1.42 [95% CI, 0.91-2.22]). We found no interaction in the relative effectiveness and safety of high- versus low-dose aspirin by P2Y12 inhibitor use. Overall, dose switching or discontinuation was more common in the high-dose compared with low-dose aspirin group, but the pattern was not modified by P2Y12 inhibitor use. Conclusions In this prespecified analysis of ADAPTABLE, we found that the relative effectiveness and safety of high- versus low-dose aspirin was not modified by baseline P2Y12 inhibitor use. Registration https://www.clinical.trials.gov. Unique identifier: NCT02697916.

TV Time, Especially During Meals, is Associated with Less Healthy Dietary Practices in Toddlers.

BACKGROUND: While several studies examine the relationship between screen time and dietary practices in children and teenagers, there is limited research in toddlers. This study evaluates the association between television (TV) exposure and dietary practices in two-year-old children. METHODS: We conducted a cross-sectional, secondary data analysis from the Greenlight Intervention Study. Toddlers' daily TV watching time, mealtime TV, and dietary practices were assessed by caregiver report at the 24-month well child visit. Separate regression models were used and adjusted for sociodemographic/household characteristics and clinic site. RESULTS: 532 toddlers were included (51% Latino; 30% non-Latino Black; 59% ≤$20,000 annual household income). Median daily TV watching time was 42 minutes [IQR: 25, 60]; 25% reported the TV was "usually on" during mealtimes. After adjustment, toddlers who watched more TV daily had higher odds of consuming sugar-sweetened beverages (SSB), fast food, and more junk food; those watching less TV had higher odds of consuming more fruits/vegetables. Those with the TV "usually on" during mealtimes were more likely to consume SSB [aOR 3.72 (95%CI 2.16-6.43)], fast food [aOR 2.83 (95%CI 1.54-5.20)], and more junk food [aOR 4.25 (95%CI 2.71-6.65)]. CONCLUSIONS: Among toddlers from primarily minoritized populations and of lower socioeconomic status, those who watched more TV daily and usually had the TV on during meals had significantly less healthy dietary practices, even after adjusting for known covariates. This study supports the current American Academy of Pediatrics screen time guidelines and underscores the importance of early counseling on general and mealtime TV.

Effectiveness and Safety of Enteric-Coated vs Uncoated Aspirin in Patients With Cardiovascular Disease: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial.

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.