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Population enrichment designs can play a vital role in detecting treatment benefits, if present, by selecting a study population where the treatment is more likely to show a benefit compared to the unselected population. While population enrichment designs with one primary endpoint have been studied in the current literature, there are limited research on population enrichment with alternative primary endpoints. Many diseases have multiple sequelae and it can be sufficient to show treatment benefits on at least one of these consequences. In this manuscript, we provide the theoretical basis and development of a two-stage adaptive design with two binary alternative primary endpoints that simultaneously evaluates two subgroups for enrichment, selects one or both endpoints for efficacy assessments at the time of the interim analysis using pre-specified decision rules, and maintains an overall type I error rate. Treatment benefits can be declared in one or both endpoints in a selected subgroup or in the overall population at the time of interim or final analyses. We provide stage-wise boundary values for futility and efficacy and rejection probabilities under heterogeneous treatment effects in the subgroups. We further demonstrate the implementation of the proposed design and discuss venues for future development on this topic. [ABSTRACT FROM AUTHOR]

The article discusses aspirin dosing in individuals with both type 2 diabetes and cardiovascular disease, emphasizing the importance of determining the optimal aspirin dose for secondary prevention. It also highlights the Adaptable trial, which compared the effectiveness and safety of aspirin, revealing no significant differences in cardiovascular events or major bleeding in individuals with diabetes.

In modern clinical practice, less than half of new-onset heart failure (HF) patients undergo ischemic evaluation, and only a minority undergo revascularization. We aimed to assess the proportion of the effect of hypertension (antihypertensive treatment) on incident HF to be eliminated by prevention of CHD event treated with or without revascularization, considering possible treatment-mediator interaction. Causal mediation analysis of ALLHAT included 42,418 participants (age 66.9±7.7; 35.6% black, 53.2% men). A new CHD event (myocardial infarction or angina) that occurred after randomization but before the incident HF outcome was the mediator. Incident symptomatic congestive HF (CHF) and hospitalized/fatal HF (HHF) were the primary and secondary outcomes. Logistic regression (for mediator) and Cox proportional hazards regression (for outcome) were adjusted for demographics, cardiovascular disease history, and risk factors. During a median 4.5-year follow-up, 2,785 patients developed CHF, including 2,216 HHF events. Participants who developed CHD events had twice the higher incidence rate of CHF than CHD-free (28.5 vs 13.9 events/ 1,000 person-years). The proportion of reference interaction indicating direct harm due to CHD event for lisinopril (234% for CHF; 355% for HHF) and amlodipine (244% for CHF; 468% for HHF) was greater than for chlorthalidone (143% for CHF; 269% for HHF). In patients with revascularized CHD events, chlorthalidone and amlodipine eliminated 21-24%, and lisinopril - 45% of HHF. Antihypertensive treatment was not able to eliminate harm from CHD events treated without revascularization. In conclusion, the antihypertensive drugs (chlorthalidone, lisinopril, amlodipine) prevent HF not principally by preventing CHD events but via other pathways. HF is moderated but not mediated by CHD events. Revascularization of CHD events is paramount for HF prevention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)