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.

Multiply robust estimation of principal causal effects with noncompliance and survival outcomes.

Treatment noncompliance and censoring are two common complications in clinical trials. Motivated by the ADAPTABLE pragmatic clinical trial, we develop methods for assessing treatment effects in the presence of treatment noncompliance with a right-censored survival outcome. We classify the participants into principal strata, defined by their joint potential compliance status under treatment and control. We propose a multiply robust estimator for the causal effects on the survival probability scale within each principal stratum. This estimator is consistent even if one, sometimes two, of the four working models-on the treatment assignment, the principal strata, censoring, and the outcome-is misspecified. A sensitivity analysis strategy is developed to address violations of key identification assumptions, the principal ignorability and monotonicity. We apply the proposed approach to the ADAPTABLE trial to study the causal effect of taking low- versus high-dosage aspirin on all-cause mortality and hospitalization from cardiovascular diseases.

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.

Principal stratification analysis of noncompliance with time-to-event outcomes.

Post-randomization events, also known as intercurrent events, such as treatment noncompliance and censoring due to a terminal event, are common in clinical trials. Principal stratification is a framework for causal inference in the presence of intercurrent events. The existing literature on principal stratification lacks generally applicable and accessible methods for time-to-event outcomes. In this paper, we focus on the noncompliance setting. We specify 2 causal estimands for time-to-event outcomes in principal stratification and provide a nonparametric identification formula. For estimation, we adopt the latent mixture modeling approach and illustrate the general strategy with a mixture of Bayesian parametric Weibull-Cox proportional hazards model for the outcome. We utilize the Stan programming language to obtain automatic posterior sampling of the model parameters. We provide analytical forms of the causal estimands as functions of the model parameters and an alternative numerical method when analytical forms are not available. We apply the proposed method to the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) trial to evaluate the causal effect of taking 81 versus 325 mg aspirin on the risk of major adverse cardiovascular events. We develop the corresponding R package PStrata.

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.

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.

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.

Examining COVID-19 testing and vaccination behaviors by heritage and linguistic preferences among Hispanic, Latino, or Spanish RADx-UP participants.

The Hispanic, Latino, or Spanish (hereafter, "Hispanic") populations in the U.S. bear a disproportionate burden of COVID-19-related outcomes, including disease incidence and mortality. Developing culturally appropriate national public health services for Hispanic persons remains a challenge. This study examined the association of heritage and language preference with COVID-19 testing (tested vs. not tested) and vaccination (vaccinated vs. not vaccinated) outcomes among Hispanic participants from 18 Rapid Acceleration of Diagnostics-Underserved Populations (RADx-UP) projects (n = 3308; mean age = 44.1 years [SD = 14.9], 60% women; 83% spoke other than English at home). Generalized estimating equation models adjusted for age, gender, education level, income, insurance coverage, geographic region, comorbidities, and prior infection. Relative to Mexican heritage, individuals identifying as Puerto Rican or Dominican were more likely to test for COVID-19, and South American heritage was associated with higher testing and vaccination rates. Speaking Spanish or another language at home was associated with increased testing compared with speaking English at home for individuals who preferred not to report their heritage, and increased vaccination for those with Mexican, Cuban, or Central American heritage. This study highlights heterogeneity in testing and vaccination behaviors among Hispanic populations based on heritage and language preference, underscoring the diversity within the U.S. Hispanic community. In contrast to other studies on linguistic acculturation and health care utilization, our study found that a language other than English spoken at home was associated with greater vaccine uptake. That is, enculturation - the retention of Spanish language and presumably of Hispanic cultural norms - was linked with being vaccinated.

External Control Arms in Idiopathic Pulmonary Fibrosis Using Clinical Trial and Real-World Data Sources.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which novel therapies are needed. External controls (ECs) could enhance IPF trial efficiency, but the direct comparability of ECs versus concurrent controls is unknown. Objectives: To develop IPF ECs by fit-for-purpose data standards to historical randomized clinical trial (RCT), multicenter registry (Pulmonary Fibrosis Foundation Patient Registry), and electronic health record (EHR) data and to evaluate endpoint comparability among ECs and the phase II RCT of BMS-986020. Methods: After data curation, the rate of change in FVC from baseline to 26 weeks among participants receiving BMS-986020 600 mg twice daily was compared with the BMS-placebo arm and ECs using mixed-effects models with inverse probability weights. Measurements and Main Results: At 26 weeks, the rates of change in FVC were -32.71 ml for BMS-986020 and -130.09 ml for BMS-placebo (difference, 97.4 ml; 95% confidence interval [CI], 24.6-170.2), replicating the original BMS-986020 RCT. RCT ECs showed treatment effect point estimates within the 95% CI of the original BMS-986020 RCT. Pulmonary Fibrosis Foundation Patient Registry ECs and EHR ECs experienced a slower rate of FVC decline compared with the BMS-placebo arm, resulting in treatment-effect point estimates outside of the 95% CI of the original BMS-986020 RCT. Conclusions: IPF ECs generated from historical RCT placebo arms result in comparable primary treatment effects to that of the original clinical trial, whereas ECs from real-world data sources, including registry or EHR data, do not. RCT ECs may serve as a potentially useful supplement to future IPF RCTs.

Internet Versus Noninternet Participation in a Decentralized Clinical Trial: Lessons From the ADAPTABLE Study.

Background Internet-based participation has the potential to enhance pragmatic and decentralized trials, where representative study populations and generalizability to clinical practice are key. We aimed to study the differences between internet and noninternet/telephone participants in a large remote, pragmatic trial. Methods and Results In a subanalysis of the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) study, we compared internet participants with those who opted for noninternet participation. Study process measures examined included participant characteristics at consent, study medication adherence, and study retention. The clinical outcome examined was a composite of all-cause mortality, hospitalization for myocardial infarction, or hospitalization for stroke. Noninternet participants were older (mean 69.4 versus 67.4 years), more likely to be female (38.9% versus 30.2%), more likely to be Black (27.3% versus 6.0%) or Hispanic (11.1% versus 2.0%), and had a higher number of comorbid conditions. The composite clinical outcome was more than twice as high in noninternet participants. The hazard of nonadherence to the assigned aspirin dosage was 46% higher in noninternet participants than internet participants. Conclusions Noninternet participants differed from internet participants in notable demographic characteristics while having poorer baseline health. Over the course of ADAPTABLE, they also had worse clinical outcomes and greater likelihood of study drug nonadherence. These results suggest that trials focused on internet participation select for younger, healthier participants with a higher proportion of traditionally overrepresented patients. Allowing noninternet participation enhances diversity; however, additional steps may be needed to promote study retention and study medication adherence. Registration Information clinicaltrials.gov. Identifier: NCT02697916.

Comparison of the effectiveness and safety of 2 aspirin doses in secondary prevention of cardiovascular outcomes in patients with chronic kidney disease: A subgroup analysis of ADAPTABLE.

BACKGROUND: Among patients with established cardiovascular disease, the ADAPTABLE trial found no significant differences in cardiovascular events and bleeding rates between 81 mg and 325 mg of aspirin (ASA) daily. In this secondary analysis from the ADAPTABLE trial, we studied the effectiveness and safety of ASA dosing in patients with a history of chronic kidney disease (CKD). METHODS: ADAPTABLE participants were stratified based on the presence or absence of CKD, defined using ICD-9/10-CM codes. Within the CKD group, we compared outcomes between patients taking ASA 81 mg and 325 mg. The primary effectiveness outcome was defined as a composite of all cause death, myocardial infarction, or stroke and the primary safety outcome was hospitalization for major bleeding. Adjusted Cox proportional hazard models were utilized to report differences between the groups. RESULTS: After excluding 414 (2.7%) patients due to missing medical history, a total of 14,662 patients were included from the ADAPTABLE cohort, of whom 2,648 (18%) patients had CKD. Patients with CKD were older (median age 69.4 vs 67.1 years; P < .0001) and less likely to be white (71.5% vs 81.7%; P < .0001) when compared to those without CKD. At a median follow-up of 26.2 months, CKD was associated with an increased risk of both the primary effectiveness outcome (adjusted HR 1.79 [1.57, 2.05] P < .001 and the primary safety outcome (adjusted HR 4.64 (2.98, 7.21), P < .001 and P < .05, respectively) regardless of ASA dose. There was no significant difference in effectiveness (adjusted HR 1.01 95% CI 0.82, 1.23; P = .95) or safety (adjusted HR 0.93; 95% CI 0.52, 1.64; P = .79) between ASA groups. CONCLUSIONS: Patients with CKD were more likely than those without CKD to have adverse cardiovascular events or death and were also more likely to have major bleeding requiring hospitalization. However, there was no association between ASA dose and study outcomes among these patients with CKD.

Electronic health record characterization and outcomes of heart failure with preserved ejection fraction.

BACKGROUND: Electronic health record (EHR)-based identification of heart failure with preserved ejection fraction (HFpEF) in the clinical setting may facilitate screening for clinical trials by improving the understanding of its epidemiology and outcomes; yet, previous data have yielded variable results. We sought to characterize groups identified with HFpEF by different EHR screening strategies and their associated long-term outcomes across a large and diverse population. METHODS: We retrospectively analyzed 116,499 consecutive patients from an academic referral center who underwent echocardiography, and 9,263 patients who underwent echocardiography within 6 months of right heart catheterization (RHC), between 2008 and 2018. EHR-based screening strategies identified patients with HFpEF using 1) International Classification of Diseases (ICD)-9/10 codes, 2) H2FpEF score ≥6 and ejection fraction (EF) ≥50%, or 3) RHC wedge pressure ≥15 mmHg and EF ≥50%, when available. Primary outcomes were 1) cumulative incident heart failure hospitalization (HFH), and 2) death, over 10 years. RESULTS: There were 33,461 (29%) patients who met either ICD or H2FpEF-HFpEF definition, of whom 5,310 (16%) met both criteria. Compared to ICD-HFpEF, patients with H2FpEF-HFpEF were more likely older (median age 72 vs 67), White (78% vs 64%), and had atrial fibrillation (97% vs 41%). Among those also with RHC, 6,353 (69%) patients met any HFpEF criteria, of whom only 783 (12%) satisfied all three criteria. Female sex was more common among RHC-HFpEF (55%) compared to other methods (H2FpEF-HFpEF, 47%; ICD-HFpEF, 43%). Atrial fibrillation was substantially higher among HFpEF identified by the H2FpEF score (97%) compared to other methods (49% for ICD and 47% for RHC). Across HFpEF screening methods, 10-year cumulative incidence rates for HFH was 32% to 45% for echocardiography only and 43% to 52% for echocardiography and RHC populations; 10-year risk of death was 54% to 56% for echocardiography only and 52% to 57% for echocardiography and RHC populations. CONCLUSIONS: Different EHR-based HFpEF definitions identified cohorts with modest overlap and varying baseline characteristics. Yet, long-term risk for HFH and death were similarly high for cohorts identified among both populations undergoing echocardiography only or echocardiography and RHC. These data aid in identifying relevant subgroups in clinical trials of HFpEF.

Outcomes among patients with peripheral artery disease in the Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness (ADAPTABLE) study.

BACKGROUND: We aimed to understand the effects of aspirin dose on outcomes in patients with peripheral artery disease (PAD) as well as their participation in a pragmatic randomized controlled trial. METHODS: In a subanalysis of the Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness (ADAPTABLE) study, we compared aspirin doses (81 vs 325 mg) among participants with PAD and study participation metrics in patients with and without PAD. The primary outcome composite was all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke. RESULTS: Among 14,662 participants enrolled in ADAPTABLE with PAD status available, 3493 (23.8%) had PAD. Participants with PAD were more likely to experience the primary composite (13.76% vs 5.31%, p < 0.001), all-cause mortality (7.55% vs 3.01%, p < 0.001), myocardial infarction (5.71% vs 2.09%, p < 0.001), stroke (2.45% vs 0.86%, p < 0.001), and major bleeding (1.19% vs 0.44%, p < 0.001). A higher aspirin dose did not reduce the primary outcome in patients with PAD (13.68% vs 13.84% in 81 mg and 325 mg groups; OR 1.05, 95% CI 0.88-1.25). Participants with PAD were less likely to enroll via email (33.0% vs 41.9%, p < 0.0001), less likely to choose internet follow-up (79.2% vs 89.5%, p < 0.0001), and were more likely to change their aspirin doses (39.7% vs 30.7%, p < 0.0001). CONCLUSIONS: ADAPTABLE participants with PAD did not benefit from a higher dose of aspirin and participated in the study differently from those without PAD. These results reinforce the need for additional PAD-specific research and suggest that different trial strategies may be needed for optimal engagement of patients with PAD. (ClinicalTrials.gov Identifier: NCT02697916).

Looking for opportunities to co-enroll: The DISCOVERY study experience.

BACKGROUND: Conducting high-quality stroke trials is complex and costly. Often these trials compete for the attention of researchers and the availability of patients. Enrolling patients in more than one study concurrently has the potential to accelerate recruitment into individual studies. DISCOVERY is a multicenter, inception cohort study of cognitive impairment and dementia following ischemic or hemorrhagic stroke. At the request of site investigators, a DISCOVERY committee reviews individual studies for approval of possible concurrent co-enrollment into DISCOVERY. The purpose of this report is to summarize the characteristics and outcomes of studies reviewed by committee for possible co-enrollment. METHODS: This analysis covers studies reviewed from 07/01/2020 to 04/26/2022 by the Site Management Committee (SMC) of the DISCOVERY Recruitment and Retention Core. Characterization of each study included study type, number and length of follow-up visits, and whether there were protocol-required blood draws, brain imaging studies, or cognitive tests. Studies were scored for patient burden and scientific overlap with Discovery. The primary outcome was SMC approval to co-enroll. RESULTS: 59 studies were reviewed, and 69.5% (n = 41, 21 clinical trials; 20 observational studies) were found by the SMC to be appropriate for co-enrollment. Higher patient burden and greater scientific overlap with DISCOVERY reduced the rates of approval for co-enrollment. CONCLUSION: A large number of diverse stroke studies are being run concurrently across the DISCOVERY study network, however, about two-thirds of the studies were considered appropriate for consideration of co-enrollment. Future studies should study how co-enrollment might improve trial network efficiency.

Increasing access and uptake of SARS-CoV-2 at-home tests using a community-engaged approach.

Inequalities around COVID-19 testing and vaccination persist in the U.S. health system. We investigated whether a community-engaged approach could be used to distribute free, at-home, rapid SARS-CoV-2 tests to underserved populations. Between November 18-December 31, 2021, 400,000 tests were successfully distributed via 67 community partners and a mobile unit to a majority Hispanic/Latino/Spanish population in Merced County, California. Testing before gathering (59 %) was the most common testing reason. Asians versus Whites were more likely to test for COVID-19 if they had close contact with someone who may have been positive (odds ratio [OR] = 3.4, 95 % confidence interval [CI] = 1.7-6.7). Minors versus adults were more likely to test if they had close contact with someone who was confirmed positive (OR = 1.7, 95 % CI = 1.0-3.0), whereas Asian (OR = 4.1, 95 % CI = 1.2-13.7) and Hispanic/Latino/Spanish (OR = 2.5, 95 % CI = 1.0-6.6) versus White individuals were more likely to test if they had a positive household member. Asians versus Whites were more likely to receive a positive test result. Minors were less likely than adults to have been vaccinated (OR = 0.2, 95 % CI = 0.1-0.3). Among unvaccinated individuals, those who completed the survey in English versus Spanish indicated they were more likely to get vaccinated in the future (OR = 8.2, 95 % CI = 1.5-44.4). Asians versus Whites were less likely to prefer accessing oral COVID medications from a pharmacy/drug store only compared with a doctor's office or community setting (OR = 0.3, 95 % CI = 0.2-0.6). Study findings reinforce the need for replicable and scalable community-engaged strategies for reducing COVID-19 disparities by increasing SARS-CoV-2 test and vaccine access and uptake.

Real World-Evidence for Regulatory Use Decision Aid: An Interactive Tool To Inform Clinical Development and Regulatory Strategies.

Real-world evidence (RWE) is increasingly used to complement clinical trial data for regulatory decision-making and in certain cases utilized to establish the clinical effectiveness of a therapy. However, the use of RWE is not applicable for all regulatory submissions, and it can be challenging to identify appropriate use cases. An interactive tool was developed ("Decision Aid," https://sn.pub/TpDjZx ) to assist researchers, industry, and other stakeholders in identifying regulatory situations that can benefit from leveraging RWE by organizing precedent cases based on a given regulatory objective (new product approval, labeling expansion for new indication or additional clinical data, post-marketing requirement) and type of RWE study design (external control, observational study, pragmatic trial). Key success factors ensuring fit-for-purpose data and rigorous methods (e.g., clear endpoints, minimizing bias, data completeness) are also described. The tool allows the user to navigate through the precedent cases by selecting certain regulatory objectives and/or study designs. The Decision Aid supports regulatory activities in the RWE space and encourages further use of RWE in regulatory decision-making.

Standardizing, harmonizing, and protecting data collection to broaden the impact of COVID-19 research: the rapid acceleration of diagnostics-underserved populations (RADx-UP) initiative.

OBJECTIVE: The Rapid Acceleration of Diagnostics-Underserved Populations (RADx-UP) program is a consortium of community-engaged research projects with the goal of increasing access to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) tests in underserved populations. To accelerate clinical research, common data elements (CDEs) were selected and refined to standardize data collection and enhance cross-consortium analysis. MATERIALS AND METHODS: The RADx-UP consortium began with more than 700 CDEs from the National Institutes of Health (NIH) CDE Repository, Disaster Research Response (DR2) guidelines, and the PHENotypes and eXposures (PhenX) Toolkit. Following a review of initial CDEs, we made selections and further refinements through an iterative process that included live forums, consultations, and surveys completed by the first 69 RADx-UP projects. RESULTS: Following a multistep CDE development process, we decreased the number of CDEs, modified the question types, and changed the CDE wording. Most research projects were willing to collect and share demographic NIH Tier 1 CDEs, with the top exception reason being a lack of CDE applicability to the project. The NIH RADx-UP Tier 1 CDE with the lowest frequency of collection and sharing was sexual orientation. DISCUSSION: We engaged a wide range of projects and solicited bidirectional input to create CDEs. These RADx-UP CDEs could serve as the foundation for a patient-centered informatics architecture allowing the integration of disease-specific databases to support hypothesis-driven clinical research in underserved populations. CONCLUSION: A community-engaged approach using bidirectional feedback can lead to the better development and implementation of CDEs in underserved populations during public health emergencies.

Iterative approaches to the use of electronic health records data for large pragmatic studies.

Randomized controlled trials (RCT) are the gold standard for evaluating the effectiveness and safety of interventions and treatments, yet traditional clinical trials have relied on cumbersome and redundant processes such as electronic data entry which involves manual abstraction of already available electronic health record (EHR) data. This review focuses on the opportunities to expand the use of EHR data for pragmatic clinical trials using methods and lessons learned from the Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness (ADAPTABLE) study, the demonstration project from PCORnet® (the National Patient-Centered Clinical Research Network).