Lahey Medical Center

Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21-1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97-1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10-0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83-1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04-0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15-0.73]). After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06398366.

Equitable access to clinical studies is essential to ensuring that research findings are generalizable, inclusive, and reflective of all populations. When specific demographic or geographic groups are excluded from participation, the external validity of clinical research is undermined and inequities in treatment access are perpetuated. Autoimmune skin disorders are uncommon and often affect patients living far from major research centers, yet no comprehensive analysis of national clinical study accessibility for these conditions has been conducted. We conducted a retrospective, population-level analysis of study accessibility for autoimmune skin disorders in the United States from 2005 to 2024 using ClinicalTrials.gov and U.S. Census data. Population centers were defined as geographic centroids of ZIP codes, and the distance from each population center to the nearest study site was calculated. Trend analyses assessed changes in accessibility over time and differences across racial and urban–rural categories. Although the number of studies has increased over time (approximately six additional studies annually), travel distances to the nearest study site remain substantial. The average distance has decreased modestly by about 3.4 km per year, but 40% of Americans still live more than 200 km from the closest study site, with the greatest distances observed among rural and American Indian populations. Expanding population coverage requires rapidly increasing travel distances. These findings highlight persistent disparities in access to clinical studies. While decentralization and virtual study models may help reduce these gaps, further research is needed to determine whether such strategies effectively improve participation and representation.

Background and Objectives Observational data can provide evidence of treatment effects in a low-burden, cost-effective manner. Using a causal inference framework to address selection bias, we illustrate the approach in ALS by examining previously researched associations, baseline function and sex, and evaluating metformin’s survival benefits. Methods Data are from the ALS Natural History Study collected in the United States, Israel, and Italy from 2015 to 2025. We employ propensity score matching, two approaches to address loss to follow-up (i.e. a naive exclusion and principal stratification), and randomization-based inference to evaluate difference in 18-month restricted mean survival time. Results For the function investigation, estimated survival is 16.39, 16.14, 16.09, and 16.24 months for the high ALSFRS-R group and 14.04, 14.42, 14.72, and 14.60 months for the low ALSFRS-R group using the non imputed and imputed datasets 1-3, respectively (p<0.0001, N=450; p<0.00001, N=1,485; p<0.00001, N=1,492; p<0.00001, N=1,600). Using principal stratification, estimated survival is 16.38, 16.14, 16.09, and 16.23 months for the high ALSFRS-R group and 14.04, 14.42, 14.72, and 14.59 months for the low ALSFRS-R group with the non imputed and imputed datasets 1-3, respectively (p<0.0001, N=449; p<0.00001, N=1,483; p< 0.00001, N=1,491; p<0.00001, N=1,596). For the sex investigation, estimated survival is 15.20, 15.16, 15.20, and 15.17 months for females and 15.41, 14.84, 14.91, and 14.97 months for males using the non imputed and imputed datasets 1-3, respectively (p≈0.594, N=612; p≈0.155, N=2,081; p≈0.200, N=2,104; p≈0.359, N=2,111). Using principal stratification, estimated survival is 15.20, 15.16, 15.20, and 15.17 months for females and 15.41, 14.83, 14.91, and 14.97 months for males with the non imputed and imputed datasets 1-3, respectively (p≈0.598, N=612; p≈0.146, N=2,079; p≈0.195, N=2,102; p≈0.364, N=2,110). For the metformin investigation, estimated survival is 14.77, 14.87, and 14.57 months for metformin users and 14.59, 14.43, and 13.97 months for non metformin users using imputed datasets 1-3, respectively (p≈0.391, N=289; p≈0.257, N=279; p≈0.191, N=301). Using principal stratification, estimated survival is 14.75, 14.85, and 14.55 months for metformin users and 14.68, 14.58, and 13.97 months for non metformin users with imputed datasets 1-3, respectively (p≈0.458, N=286; p≈0.351, N=275; p≈0.201, N=300). Discussion We reject the sharp null hypothesis for the function investigation and fail to reject it for the sex and metformin investigations. Trial Registration Information ClinicalTrials.gov Identifier: NCT05966038 .

ABSTRACT BACKGROUND Peak oxygen uptake (pVO 2 ) is a strong, independent predictor of adverse cardiovascular outcomes, supporting cardiopulmonary exercise testing as a primary end point assessing efficacy of novel drug therapies in obstructive hypertrophic cardiomyopathy (oHCM) clinical trials. However, characterizing changes in pVO 2 that patients perceive as beneficial or meaningful (ie, minimal important difference [MID]) has not been determined. METHODS Data from patients with symptomatic oHCM enrolled in SEQUOIA-HCM and MAPLE-HCM were pooled. A total of 282 patients were randomized 1:1 to aficamten (5–20 mg daily) or matching placebo in SEQUOIA-HCM, and 175 patients were randomized 1:1 to aficamten (5-20mg daily) or to metoprolol (50–200 mg) in MAPLE-HCM; follow-up in both trials was 24 weeks. Primary outcome was change from baseline to week 24 (Δ) in pVO 2 using Patient Global Impression of Change with anchor-based analysis to define MID. RESULTS At week 24, ΔpVO 2 (mL/kg/min) that corresponded to no change, one-category improvement, and one-category worsening were –0.05 (95% CI, –0.58 to 0.48), +0.35 (95% CI, –0.22 to 0.91), and –0.61 (95% CI, –1.36 to 0.13), respectively. Similarly, minute ventilation to carbon dioxide production ratio (VE/VCO 2 ) slope that corresponded to no change, one-category improvement, and one-category worsening were 0.16 (95% CI, –0.59 to 0.90), –1.15 (95% CI, – 1.89 to –0.42), and 0.88 (95% CI, –0.42 to 2.19), respectively. In a responder analysis using this new threshold for pVO 2 , 60% of patients receiving aficamten achieved a ΔpVO 2 ≥0.35 versus 31% of patients on placebo or metoprolol (odds ratio, 3.4 [95% CI, 2.3–4.9], P <0.001). Consistent findings were seen with VE/VCO 2 responder analysis. CONCLUSIONS Changes in pVO 2 of +0.35 and –0.61 mL/kg/min were associated with a small but perceptible clinical improvement and worsening, respectively, in patients with oHCM. Applying this newly defined threshold resulted in excellent differentiation of treatment effect in a clinical trial. These novel data provide a measure of clarity to patients and clinicians regarding the interpretation of changes in pVO 2 following therapeutic interventions, with potential impact on HCM management strategies and future clinical trials. Clinical Trial Registration SEQUOIA-HCM ( NCT05186818 ; https://clinicaltrials.gov/study/NCT05186818?term=sequoia-hcm&rank=1 ); MAPLE-HCM ( NCT05767346 ; https://clinicaltrials.gov/study/NCT05767346?term=maple-hcm&rank=1 ) Clinical Perspective What Is New? Using pooled data from over 440 patients with symptomatic obstructive hypertrophic cardiomyopathy enrolled in two phase 3 clinical trials, we define, for the first time, the minimally important difference for peak oxygen uptake (pVO 2 ) and ventilatory efficiency (VE/VCO 2 ) using patient-anchored and distribution-based methodologies. A change in pVO 2 of +0.35 mL/kg/min and a change in VE/VCO 2 of –1.15 represent the minimal thresholds associated with patient-perceived clinical improvement. Responder analyses using these thresholds demonstrated robust differentiation between aficamten and placebo/metoprolol, with an odds ratio exceeding 3 for achieving a meaningful improvement in pVO 2 . What Are the Clinical Implications? These newly defined thresholds bridge the gap between statistically significant changes in cardiopulmonary exercise testing measures and clinically meaningful benefit as perceived by patients with obstructive hypertrophic cardiomyopathy. Clinicians can use these benchmarks to contextualize individual patient responses to medical therapy, informing shared decision-making regarding treatment continuation or modification. These data provide a standardized, patient-centered framework for designing and interpreting primary end points in future hypertrophic cardiomyopathy clinical trials.