Importance:Patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) or preserved EF (HFpEF) show substantial heterogeneity in prognosis. Objectives:To evaluate the performance of biomarker-driven prognostic models derived from the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved) Trial in the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) and to examine whether baseline risk modified the therapeutic effect of finerenone. Design, Setting, and Participants:This is a prespecified secondary analysis of the FINEARTS-HF trial, which was conducted across 653 sites in 37 countries among adults aged 40 years and older with symptomatic HF and left ventricular EF (LVEF) of 40% or greater. Patients were randomized between September 2020 and January 2023, and data analysis for this study was conducted from September to October 2025. The median (IQR) follow-up period was 32 (23-37) months. Intervention:Finerenone (titrated to 20 mg or 40 mg) or placebo. Main Outcomes and Measures:EMPEROR-Preserved risk scores for the outcomes of first HF hospitalization or cardiovascular death, cardiovascular death, and all-cause death were calculated in FINEARTS-HF using models incorporating N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, New York Heart Association functional class, history of chronic obstructive pulmonary disease and diabetes, insulin use, and-depending on outcome-age, hemoglobin and albumin levels, HF duration, time from prior HF hospitalization, and sodium-glucose transporter 2 inhibitor use. Estimated risks were compared with observed event rates, and model performance was assessed using Harrell C statistic. Treatment effects were evaluated across risk quintiles (Q1 to Q5) and across the continuous risk distribution. Results:Among 6001 patients (mean [SD] age, 72.0 [9.6] years; 2732 [45.5%] women; 3003 randomized to finerenone and 2998 randomized to placebo), the EMPEROR-Preserved risk model estimated risk of outcomes, with Q5 vs Q1 hazard ratios (HRs) of 10.49 (95% CI, 8.14-13.52) for the composite of HF hospitalization or cardiovascular death and 13.47 (95% CI, 8.79-20.64) for cardiovascular death. The model demonstrated good discrimination. The treatment effect of finerenone was consistent across risk quintiles for first HF hospitalization or cardiovascular death (Q1: HR, 0.93 [95% CI, 0.58-1.49]; Q2: HR, 1.04 [95% CI, 0.76-1.43]; Q3: HR, 0.82 [95% CI, 0.62-1.07]; Q4: HR, 0.81 [95% CI, 0.65-1.01]; and Q5: HR, 0.88 [95% CI, 0.74-1.05]; P for interaction = .68) and remained uniform across the continuous risk spectrum. Conclusions and Relevance:The EMPEROR-Preserved risk models demonstrated good performance in FINEARTS-HF. Baseline risk did not modify the relative treatment effect of finerenone. Trial Registration:ClinicalTrials.gov Identifier: NCT04435626.

AIMS:Atrial fibrillation (AF) is a risk factor for respiratory syncytial virus (RSV)-related adverse cardiac events. This prespecified analysis of the DAN-RSV trial investigated RSVpreF vaccine effectiveness (VE) against respiratory and cardiovascular outcomes among older adults with and without AF. METHODS AND RESULTS:DAN-RSV was a pragmatic, open-label, individually randomized trial in Denmark during the 2024/2025 winter season. Adults ≥60 years were randomly assigned 1:1 to RSVpreF vaccine or no vaccine. Baseline and endpoint data were obtained from nationwide health registries. The primary endpoint was hospitalization for RSV-related respiratory tract disease, occurring 14 days after study visit until May 31, 2025. Prespecified respiratory and cardiovascular endpoints were assessed by AF status. Among 131,276 participants, 10,126 (7.7%) had a history of AF (mean age 73.2 ± 6.9 years, 30.4% female). AF participants had higher event rates compared with non-AF participants. RSVpreF vaccine lowered the incidence of the primary endpoint with no evidence of effect modification by AF status (AF: VE 80.6% (95%CI -84.7 to 99.6), no AF: VE 84.6% (95%CI 32.3 to 98.3), p-value for interaction >0.99). RSVpreF vaccine was further associated with a lower incidence of all-cause respiratory tract disease hospitalization (AF: VE 25.7% (95%CI -16.9 to 46.1), no AF: VE 13.0% (95%CI -3.3 to 27.8)) and RSV-related and overall cardio-respiratory disease hospitalization with no evidence of effect modification by AF status (p-value for interaction ≥0.45 for all). RSVpreF vaccine was not significantly associated with AF or stroke hospitalizations regardless of AF status (p-value for interaction≥0.34 for all). CONCLUSIONS:In older adults, RSVpreF vaccine was associated with a lower incidence of RSV-related and all-cause respiratory tract disease hospitalizations, as well as RSV-related and all-cause cardio-respiratory disease hospitalizations, with no evidence of effect modification by AF status.

Importance:Gene-silencing therapies reduce hepatic transthyretin (TTR) production and have been evaluated in phase 3 trials in TTR amyloid cardiomyopathy (ATTR-CM). However, differences in trial design and background therapies have limited assessment of the overall treatment effect and its consistency according to baseline TTR stabilizer use. Objective:To assess the effect of TTR gene-silencing therapies in patients with ATTR-CM. Data Sources and Study Selection:PubMed was searched through June 15, 2026, for randomized, placebo-controlled, phase 3 outcome trials of gene-silencing therapies in ATTR-CM. Data Extraction and Synthesis:Two reviewers independently extracted data, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Fixed-effects meta-analysis estimated rate ratios (RRs) or hazard ratios (HRs) with 95% CIs. Main Outcomes and Measures:The prespecified primary outcome was the composite of all-cause mortality and recurrent cardiovascular events. Secondary outcomes included all-cause mortality, cardiovascular death, time to first primary outcome, functional capacity (6-minute walk distance), and health status (Kansas City Cardiomyopathy Questionnaire-Overall Summary Score). Results:A total of 2 studies (HELIOS-B and CARDIO-TTRansform) met the inclusion criteria and included 2086 patients with ATTR-CM. The studies included 1902 men with a median age of 77 years (range for HELIOS-B, 45-85 years; for CARDIO-TTRansform, 41-91 years). Gene-silencing therapy reduced the primary end point by 20% (RR, 0.80; 95% CI, 0.69-0.94; P = .006), with no heterogeneity between trials (P for heterogeneity = .28). Gene-silencing therapy also reduced the risk of all-cause death (HR, 0.74; 95% CI, 0.61-0.91) and time to first all-cause death or cardiovascular events (HR, 0.77; 95% CI, 0.67-0.89) compared with placebo. Gene silencers preserved 6-minute walk distance (placebo-corrected difference, +22.2 m; 95% CI, 14.3-30.0) and Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (+4.5; 95% CI, 2.7-6.2), with no evidence of between-trial heterogeneity. Treatment effects on primary end points differed according to baseline stabilizer use, with significant benefits observed among patients not receiving background stabilizer therapy (RR, 0.69; 95% CI, 0.57-0.85) and no significant incremental benefit observed for those receiving concomitant stabilizer at baseline (RR, 0.97; 95% CI, 0.77-1.23; P for heterogeneity = .03). Similar heterogeneity was observed for functional capacity and health status. Conclusions and Relevance:The findings from this meta-analysis support TTR gene silencing for ATTR-CM. The attenuated benefit observed for patients receiving concomitant TTR stabilizer therapy may reflect residual differences in case mix, disease duration, or magnitude of TTR suppression or a true ceiling on additional benefit of gene silencing in the setting of background TTR stabilization. Trial Registration:PROSPERO registration: CRD420261421656. ClinicalTrials.gov Identifier: HELIOS-B, NCT04153149; and CARDIO-TTRansform, NCT04136171.

Background The HFpEF-ABA score is a simple diagnostic tool developed to estimate the probability of heart failure with preserved ejection fraction (HFpEF) using age, body mass index, and history of atrial fibrillation. Objectives This study aims to evaluate the HFpEF-ABA score in patients with confirmed heart failure (HF) in the FINEARTS-HF trial, its prognostic implications, and the effect of finerenone treatment according to the HFpEF-ABA score. Methods FINEARTS-HF was a randomized, placebo-controlled trial enrolling patients with HF with a left ventricular ejection fraction ≥40%. HFpEF-ABA scores (as a probability between 0% and 100%) were calculated at baseline and categorized as <75%, 75%-90%, or >90%. The association between HFpEF-ABA score and clinical outcomes was examined as well as the effect of finerenone across the range of HFpEF-ABA scores. Results Among 5,988 patients with available HFpEF-ABA scores, 1,940 (32.4%) had a score <75% (low probability), 1,241 (20.7%) had a score 75%-90% (intermediate probability), and 2,807 (46.9%) had a score >90% (high probability). Rates of HF outcomes were higher in patients with higher HFpEF-ABA scores. Examination of HFpEF-ABA score as a continuous variable showed a strikingly nonlinear association with outcomes; the rate of events was similar up to a score of ∼75%, above which there was a steep increase in the event rate. Finerenone reduced events consistently across HFpEF-ABA scores. Conclusions Despite a proven diagnosis of HF with mildly reduced ejection fraction/HFpEF, one-third of participants in FINEARTS-HF had an HFpEF-ABA score <75%, yet the therapeutic effect of finerenone was consistent across the range of HFpEF-ABA scores included. Higher HFpEF-ABA scores were associated with a greater risk of HF events. (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure [FINEARTS-HF]; NCT04435626)

AIMS:Blood pressure (BP) control is a Class I recommendation for the management of heart failure with preserved ejection fraction (HFpEF); however, evidence supporting systolic BP (SBP) targets remains limited. We investigated associations between BP control and subsequent outcomes in patients with HF with mildly reduced EF (HFmrEF)/HFpEF. METHODS:We pooled TOPCAT (Americas), PARAGON-HF, DELIVER, and FINEARTS-HF, which tested spironolactone, sacubitril/valsartan, dapagliflozin, and finerenone, respectively, versus placebo or active control in patients with HF and an LVEF >40% (DELIVER), ≥40% (FINEARTS-HF), or ≥45% (TOPCAT-Americas, PARAGON-HF). Daily BPs were estimated by interpolation from standardized office measurements obtained at randomization and prespecified visits. Time in target range (TIR) was the percentage of the first year after randomization during which SBP was 110-<130 mmHg. Continuous associations between TIR and subsequent risk of HF hospitalization or cardiovascular death, its individual components, and all-cause death was assessed using landmark Cox proportional hazards models with linear splines, adjusted for baseline cardiovascular risk factors. RESULTS:Among 17,788 patients (mean age 72±9 years; 47% women; mean baseline SBP 129±15 mmHg), the median TIR was 38% (≈139 days). Randomization to active therapies increased TIR by 2% (95% CI: -2 to 6) with spironolactone, 7% (5 to 9) with sacubitril/valsartan, 2% (0 to 4) with dapagliflozin, and 3% (1 to 5) with finerenone. Higher TIR was associated with lower subsequent risk of the composite outcome (P=0.021), primarily driven by lower HF hospitalization risk (P=0.007); associations with cardiovascular death and all-cause death were not significant. Sensitivity analyses using stricter (120-<130 mmHg) or more liberal ranges (100-<130 and 120-<140 mmHg) yielded qualitatively similar findings. CONCLUSIONS:In patients with HFmrEF/HFpEF, BP control during the first year was associated with a lower subsequent risk of HF hospitalization. CLINICAL TRIALS REGISTRATION:ClinicalTrials.gov ID NCT00094302 (TOPCAT), NCT01920711 (PARAGON-HF), NCT03619213 (DELIVER), NCT04435626 (FINEARTS-HF).

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and is characterized by phenotypical heterogeneity with a high prevalence of multiple, often overlapping cardiometabolic disorders. Comorbidities such as hypertension, obesity, or diabetes are present in many HFpEF patients and are hypothesized to contribute to adverse cardiac remodelling and myocardial fibrosis through a variety of haemodynamic and metabolic impairments, with nearly half of all HFpEF patients exhibiting left ventricular (LV) hypertrophy or concentric remodelling. Myocardial fibrosis and its surrogate changes in LV structure and geometry lead to functional impairments such as increased diastolic stiffness and elevated filling pressures and are associated with reduced exercise tolerance and poor prognosis in patients with HFpEF. Despite recent therapeutic progress, there are currently no evidence-based therapies mechanistically focusing solely on myocardial fibrosis and LV hypertrophy in HFpEF. Recognizing myocardial fibrosis and LV hypertrophy as key features of the heterogeneous HFpEF pathophysiology may contribute to the development of promising targets for future clinical trials. This review elaborates on the pathophysiological role of fibrotic remodelling and LV hypertrophy in HFpEF, outlines contemporary diagnostic standards, and discusses emerging therapeutic strategies, aiming at directly modulating myocardial fibrosis and hypertrophy in HFpEF.

Background:Patient-reported outcomes (PROs) are increasingly used as endpoints in clinical trials. However, the magnitude of observed changes in control arms attributable to placebo effects, as compared with other benefits of trial participation, has not been described.This study seeks to estimate the magnitude of the placebo effect by calculating changes in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) scores, which quantify the impact of heart failure on patients' symptoms, function, and quality of life, after participants were unblinded to treatment. Methods:REDUCE LAP-HF II randomized participants to atrial shunt or sham procedure, with unblinding after 2 years. The KCCQ was collected at baseline, 2, and 3 years after randomization. KCCQ-OS change from baseline to 2 years (placebo effect plus other benefits from trial participation) and the change from 2 to 3 years (placebo effect loss after unblinding) were calculated in sham-treated patients using mean±SD, as were changes from 2 to 3 years in shunt-treated patients (placebo effect benefit). Results:The analytic cohort included 421 participants (median age 72 years, 65.6% female). Among sham-treated participants (N=182), the mean±SD KCCQ-OS 2-year improvement from baseline was +9.3±22.4 points, with a decrement after unblinding of -1.7±18.2 points from 2 to 3 years. Among shunt-treated patients (N=239), mean±SD KCCQ-OS 2-year improvement was +12.7±22.8 points, with an improvement after unblinding of +1.9±18.2 points. In a hypothetical unblinded trial where placebo effect benefit would be expected in the active intervention arm, and none in the untreated arm, the combined effects would be 3.6 points. Conclusions:In a sham-controlled device trial that collected PRO data during blinded allocation to treatment or sham and after unblinding, the estimated mean placebo effect benefit and loss on the KCCQ-OS were small (≤2 points). Finding a modest placebo effect on PROs may increase confidence in their use as clinical trial outcomes.

Patients with diabetes are at higher risk for respiratory syncytial virus (RSV)-related hospitalization and a more severe disease course.1 Although a bivalent RSV prefusion F protein-based (RSVpreF) vaccine recently demonstrated effectiveness against RSV-related respiratory tract disease in an all-comer, older population,2 it is unknown whether individuals with diabetes derive a different degree of benefit from vaccination. The aim of this prespecified analysis of the DAN-RSV trial was to examine RSVpreF vaccine effectiveness (VE) against respiratory and cardiovascular events among persons with and without diabetes.

BACKGROUND AND HYPOTHESIS:Finerenone reduces cardiovascular events in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The cardiovascular benefit emerges within months, before measurable kidney protection, but the early pathways carrying it are not comprehensively quantified. We hypothesized that early reductions in urine albumin-to-creatinine ratio (UACR) and systolic blood pressure (SBP) jointly mediate a substantial proportion of finerenone's long-term cardiovascular benefit, whereas changes in body weight and serum potassium do not. METHODS:We performed causal mediation analysis using individual patient data from FIDELITY (pooled FIDELIO-DKD and FIGARO-DKD; n = 12,143). Mediators were change from baseline to month 4 in log urine albumin-to-creatinine ratio (UACR), systolic blood pressure (SBP), body weight, and serum potassium. The outcome was time from month 4 to first cardiovascular event (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization). Outcome models used parametric accelerated failure time regression with Weibull distribution. Joint mediation by UACR and SBP was estimated by bootstrapping. RESULTS:At month 4, finerenone reduced UACR by 32.2% (95% CI 30.3 to 34.2), SBP by 3.6 mmHg (3.1 to 4.1), and body weight by 0.23 kg (0.13 to 0.32), and increased serum potassium by 0.19 mEq/L (0.17 to 0.20). Although all four biomarkers changed significantly, only UACR and SBP mediated cardiovascular outcomes: UACR mediated 39% (95% CI 7 to 71) and SBP mediated 21% (3 to 40); body weight and potassium did not. Jointly, UACR and SBP mediated 50% (95% CI 21 to 100) of the cardiovascular benefit. CONCLUSIONS:In T2D and CKD, early reductions in UACR and SBP jointly account for half of finerenone's long-term cardiovascular benefit. Body weight and potassium changes do not mediate the benefit, supporting UACR and SBP as complementary indicators of cardiovascular efficacy.

Importance:Cardiovascular-kidney-metabolic (CKM) syndrome reflects the interplay of obesity, diabetes, chronic kidney disease (CKD), and cardiovascular disease. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has improved outcomes in type 2 diabetes (T2D) and CKD. Objective:To evaluate the efficacy and safety of finerenone across CKM stages, and to examine the effects of finerenone on CKM syndrome progression and regression over time. Design, Setting, and Participants:This study is a post hoc pooled analysis of 2 randomized, double-blind, placebo-controlled, phase 3 multinational, multicenter clinical trials (FIDELITY) and was conducted across 48 countries. Patients with T2D and CKD with estimated glomerular filtration rate (eGFR) 25 mL/min/1.73 m2 or higher, serum potassium 4.8 mmol/L or less, and taking maximally tolerated renin angiotensin system inhibitor therapy were included and classified into CKM syndrome stages, using American Heart Association criteria. These data were analyzed from September 2025 and March 2026. Intervention:Participants in the pooled trials were randomly assigned to either finerenone or placebo. Main Outcomes and Measures:Cardiovascular composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization and a kidney composite outcome of kidney failure, a sustained 57% or more decrease in eGFR from baseline over 4 weeks or more, or death from kidney failure. Results:Among 12 990 participants (mean [SD] age, 64.8 [9.5] years; 3932 women [30%] and 9058 men [70%]) in FIDELITY, 3864 were classified as CKM stage 2 (30%), 3275 stage 3 (25%), and 5851 stage 4 (45%). After a median follow-up of 3 years, stage 4 was associated with a higher incidence of cardiovascular events (adjusted hazard ratio [aHR], 1.87; 95% CI, 1.56-2.24) and kidney events (aHR, 1.96; 95% CI, 1.43-2.69) when compared with stage 2. Finerenone consistently reduced cardiovascular (P for interaction = .86) and kidney (P for interaction = .65) events, irrespective of baseline CKM stage. Absolute rate reductions for the composite cardiovascular outcome were -1.1 per 100 person-years for stage 4 and -0.4 per 100 person-years for stage 2. After 3 years, participants randomized to finerenone were more likely to experience CKM syndrome regression (11.4% vs 7.4%; adjusted odds ratio [aOR], 1.66; 95% CI, 1.30-2.13; P < .001) and less likely to experience CKM syndrome progression (aOR, 0.89; 95% CI, 0.79, 1.00; P = .05) vs placebo. Conclusions and Relevance:Among patients with T2D and CKD in this study, finerenone reduced risks of cardiovascular and kidney events across CKM stages and led to greater CKM syndrome regression, and lesser CKM syndrome progression, over time. Trial Registration:ClinicalTrials.gov Identifier: NCT02540993 and NCT02545049.

BACKGROUND:Transthyretin amyloidosis with cardiomyopathy is a progressive, fatal disease characterized by deposition of extracellular misfolded transthyretin (TTR) in the myocardium. Eplontersen is an N-acetylgalactosamine ligand-conjugated antisense oligonucleotide targeting hepatocyte TTR messenger RNA to reduce the production of circulating TTR. METHODS:CARDIO-TTRansform is a Phase 3, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of eplontersen in transthyretin amyloidosis with cardiomyopathy. Key inclusion criteria include histological evidence of amyloid deposits or grade 2 to 3 cardiac uptake on cardiac scintigraphy in the absence of plasma cell dyscrasia, New York Heart Association class I-III, and end-diastolic interventricular septum thickness >12 millimeters. Participants were randomized 1:1 to receive eplontersen 45 mg or placebo, administered subcutaneously every 4 weeks for up to 140 weeks, followed by a 20-week post-treatment evaluation period or open-label extension. Participants received locally available standard of care, including unrestricted use of TTR stabilizers. The primary end point is a composite of cardiovascular mortality and recurrent clinical cardiovascular events through 140 weeks. Secondary end points, in order of testing hierarchy, include changes from baseline in 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire overall summary score, recurrent cardiovascular events, all-cause mortality, the primary end point in the patient subgroup receiving stabilizers at baseline, and cardiovascular mortality. Echocardiography was performed in all participants, with cardiovascular magnetic resonance imaging and technetium scintigraphy in a subset. CONCLUSIONS:CARDIO-TTRansform is fully enrolled, with 1432 randomized participants who were dosed with study drug or placebo. As the largest transthyretin amyloidosis with cardiomyopathy study to date, it will evaluate whether eplontersen improves cardiovascular outcomes in patients receiving locally available standard of care, including TTR stabilizers.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04136171. URL: http://ClinicalTrialsRegister.eu; Unique identifier: EudraCT number 2019-002835-27.

BACKGROUND AND AIMS:It remains unclear what the safe serum potassium range is in heart failure (HF) and whether it is the same in HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). METHODS:A patient-level pooled analysis from 12 randomized controlled trials including 32 346 HFrEF and 13 723 HFpEF patients was performed. Baseline serum potassium level was categorized into six groups (<3.5, ≥3.5-<4.0, ≥4.0-<4.5, ≥4.5-<5.0, ≥5.0-<5.5, and ≥5.5 mmol/L) and serum potassium level at baseline was also analysed as a continuous variable using restricted cubic splines. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular death, sudden death, pump failure death, first HF hospitalization, and composites of HF hospitalization and cardiovascular or all-cause death. RESULTS:The median follow-up was 24.2 and 36.8 months in HFrEF and HFpEF trials, respectively. In HFrEF, serum potassium levels showed a reverse J-shaped association with outcomes. Compared with ≥4.0-4.5 mmol/L (reference), potassium <3.5 mmol/L was associated with higher risks of all-cause mortality (adjusted hazard ratio 1.49; 95% confidence interval, 1.27-1.76), as well as cardiovascular, sudden, and pump failure death. The lowest risk for all outcomes was observed within the baseline serum potassium range of 4.2-5.0 mmol/L, but even 'mild hyperkalaemia' (5.0-5.5 mmol/L) was not associated with worse outcomes in HFrEF. Although the risk curve was U-shaped and flatter in HFpEF, the lowest incidence of all outcomes was observed over the same potassium range as HFrEF. CONCLUSION:In HFrEF, hypokalaemia is strongly associated with worse outcomes and should be avoided. In terms of safety, the optimal serum potassium concentration in both HFrEF and HFpEF appears to be in the range 4.2-5.0 mmol/L.

Importance:Statin nonadherence is a leading, addressable driver of preventable cardiovascular events. Although health systems routinely use outreach to promote preventive care, most strategies are static and lack evidence from randomized clinical trials. Objective:To determine whether an adaptive, sequential digital outreach strategy improves short-term statin refill vs usual communication among adults with established atherosclerotic cardiovascular disease (ASCVD) or high ASCVD risk and recent nonadherence within a rapidly implemented, health system-embedded randomized clinical trial. Design, Setting, and Participants:Pragmatic, health system-embedded, prospective randomized open blinded end point (PROBE) clinical trial using a 2-stage sequential, multiple assignment, randomized trial (SMART) design. The trial was conducted via Kaiser Permanente Northern California, an integrated health care delivery system serving more than 4.6 million members. Eligible participants were adults 18 years or older with established ASCVD or high ASCVD risk, recent statin nonadherence, and eligibility for all study communication modalities. Interventions:Participants were randomized 1:1:1:1 to receive secure portal messaging, SMS/text messaging, nonsecure email, or usual communication. Initial nonresponders within 14 days underwent prespecified second-stage randomization to repeat the same outreach, switch communication modality, or receive usual communication. Main Outcomes and Measures:Rates of 14-day statin refill following each randomization, with 28-day follow-up. Results:Among 20 604 participants (mean [SD] age, 54.8 [9.0] years; 40.9% female; 27.8% Asian, 10.9% Black, 33.6% Hispanic; 15.3% with established ASCVD), initial digital outreach increased 14-day statin refill vs usual communication (14.4% vs 12.0%; adjusted risk difference, 2.3 percentage points [95% CI, 1.3-3.4]; adjusted risk ratio, 1.20 [95% CI, 1.10-1.30]). Among initial nonresponders, second-stage outreach further increased refill (13.0% vs 10.4%; adjusted risk difference, 2.5 percentage points [95% CI, 1.3-3.7]; adjusted risk ratio, 1.25 [95% CI, 1.11-1.39]). Switching communication modalities did not improve refill vs repeating the same modality (13.2% vs 12.5%; adjusted risk ratio, 1.06 [95% CI, 0.94-1.17]). Cumulative statin refill through 28 days was higher in those receiving any digital outreach vs usual communication (24.9% vs 21.2%; adjusted hazard ratio, 1.21 [95% CI, 1.13-1.30]). Results were consistent across prespecified subgroups. Conclusions and Relevance:Among adults with a statin indication and recent statin nonadherence, adaptive outreach improved short-term refill vs usual communication. A second outreach produced additional gains among initial nonresponders, although switching communication modalities provided no additional benefit. These findings support adaptive, sequential health system outreach strategies to improve cardiovascular prevention when integrated into population health programs. Trial Registration:ClinicalTrials.gov Identifier: NCT07522645.

AIMS:Clinicians may be less inclined to consider new therapies in patients with long-standing heart failure (HF) due in part to clinical inertia. Whether the treatment effects of the non-steroidal mineralocorticoid receptor antagonist finerenone vary according to HF duration remains uncertain. METHODS:In this prespecified analysis of the FINEARTS-HF trial, HF duration (defined as the time from diagnosis) was categorized into four groups: <3 months, ≥3 months to 2 years, ≥2 to 5 years, or ≥5 years. The primary outcome was a composite of cardiovascular death and total HF events. The efficacy and safety of finerenone were analyzed across the duration of HF. RESULTS:Among 5,977 participants with available data (age: 72±10 years; 46% female), those with longer duration HF were older and had a higher comorbidity burden, while most patients, irrespective of HF duration, had NYHA class II functional status. Compared with HF duration <3 months, longer HF duration experienced a significantly higher adjusted risk of the primary outcome. The benefit of finerenone was consistent across HF duration categories: the rate ratio (95%CI) for the primary outcome in the <3-month group was 0.84 (0.61-1.16); ≥3 months to 2 years, 0.95 (0.74-1.23); ≥2 to 5 years, 0.77 (0.61-0.98); and ≥5 years, 0.81 (0.64-1.02) (Pinteraction=0.46). Drug discontinuation due to serious adverse events was similar between finerenone and placebo, regardless of HF duration. CONCLUSIONS:These findings suggest that even patients with long-standing HF with only mild functional status limitation may still benefit from further therapeutic optimization with therapies such as finerenone.