Introduction: The PREVENT (Predicting Risk of Cardiovascular Disease Events) equations estimate 10-year absolute risks for atherosclerotic CVD (ASCVD), heart failure (HF), and CVD (ASCVD + HF). Of PREVENT inputs, chronological age explains most of the variance in risk estimates. Grim Age acceleration (Grim2AA) is an epigenetic age measure that predicts morbidity and mortality; however, whether it contributes to risk prediction is not known. Hypothesis: Incorporating Grim2AA-adjusted age into PREVENT base equations improves 10-year risk discrimination, calibration, and reclassification. Methods: We analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective, multicenter U.S. cohort. We included participants free of CVD with available clinical and Grim2AA measures in midlife (year 20 visit). Grim2AA-adjusted age (Grim2AA + chronological age) replaced chronological age in PREVENT-CVD, PREVENT-ASCVD, and PREVENT-HF base models. Model performance was assessed using C-statistics and calibration, comparing Grim2AA-adjusted age–based vs. original models. We assessed reclassification using the Partial Likelihood Ratio Test. Results: Among the 2,432 participants included, 42.3% were men and 43.4% were Black, with a mean chronological age of 45.2 ± 3.6 years and a mean Grim2AA of 0.13 ± 5.14 years. During a median follow-up of 17.8 (interquartile range 16.9–18.0) years, 147 ASCVD, 173 CVD, and 42 HF events occurred. In univariate models, predicted risk with original and Grim2AA-adjusted PREVENT measures were each significantly associated with CVD outcomes. Each 1-SD Grim2AA-adjusted PREVENT was associated with ASCVD (1.53 [1.43–1.64]), CVD (1.50 [1.42–1.58]), and HF (1.34 [1.26–1.43]) events. There was no difference in overall predictive utility when Grim2AA-adjusted age was integrated in place of chronological age (C-statistic 0.76 [0.72–0.83] vs 0.76 [0.71–0.82]; Δ<0.01; Figure 1) for PREVENT-CVD. Findings were similar for PREVENT-ASCVD and PREVENT-HF models, with no improvement in calibration or reclassification. Results were similar among the subset of participants with Grim2AA ≥ 2 years. Conclusions: Grim2AA does not improve CVD risk estimation of the PREVENT equations. Further research is needed to determine whether other biological age measures can enhance CVD risk assessment.

BACKGROUND:Guideline-directed medical therapy (GDMT) improves outcomes in heart failure with reduced ejection fraction (HFrEF), but its impact in patients with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF) is less defined. METHODS:We analyzed data from 25,333 adults with ambulatory encounters for heart failure (HF) from February 2022 to February 2024 across >300 clinics in 2 states. Patients were categorized by left ventricular ejection fraction (LVEF) into HFrEF (≤40%), HFmrEF (41-49%), and HFpEF (≥50%), excluding those with improved EF. An electronic health record-embedded GDMT score (range 0-8) was used to quantify therapy with angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blocker (ARB)/angiotensin-receptor neprilysin inhibitor (ARNI), beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors. The primary outcome was a composite of all-cause mortality and hospitalization. RESULTS:The final cohort included 11,810 patients with HFpEF, 2249 patients with HFmrEF, and 6134 patients with HFrEF. GDMT use was highest in HFrEF and lowest in HFpEF. Greater baseline GDMT scores were associated with lower risk of the composite outcome across all EF groups, with the greatest reductions observed at scores ≥6. ACEi/ARB/ARNI and sodium-glucose cotransporter 2 use was associated with lower risk in HFpEF; ACEi/ARB/ARNI, beta-blocker, and mineralocorticoid receptor antagonist use was associated with lower risk in HFmrEF; and all 4 classes were associated with lower risk in HFrEF. ARNI use was associated with better outcomes compared with ACEi/ARB across the EF spectrum. CONCLUSIONS:Comprehensive GDMT was associated with better outcomes across the LVEF spectrum. These findings support the need for prospective evidence to guide medical management in non-HFrEF populations.

Objective Despite strong evidence for the benefit of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in heart failure (HF), uptake remains suboptimal. Value-based contracts, such as Accountable Care Organizations (ACOs), often have dedicated patient navigators and pharmacists. To drive high-value care, it is critical to optimize these resources for maximum patient benefit. We sought to evaluate the additive benefit of navigator-based telephone outreach vs patient portal messaging alone among ACO patients with HF. Methods Patients in a Medicare ACO with an ambulatory encounter with a HF diagnosis within 12 months, LVEF within 24 months, eGFR > 30, and not on SGLT2i were eligible for intervention. From 9/2023-2/2024, 100 eligible patients per week were randomly selected to receive a portal message identifying the potential benefit of SGLT2i therapy and a recommendation to schedule a visit with a pharmacist. If no appointment was scheduled within 10 days of the message, a telephonic outreach was performed. Using chi-square analysis, we compared receipt of the message plus telephone call vs message alone on completion of a pharmacist visit. Secondarily, we report frequency of a new SGLT2i prescription between groups, and a review of reasons for SGLT2i declination. Results A total of 1974 patients were messaged. Median age was 77 [74, 83] years, 51.9% were female, 9.2% were Black, and median eGFR was 67 [95% CI 57-75] ml/min/1.73m2. Among patients who were sent a message, 953 (48.3%) were also outreached by telephone as they had not scheduled within 10 days. Of those who were sent a message alone, 81 (8.6%) completed pharmacist visits; subsequent navigator outreach led to an additional 102 (10.7%) visits (p= 0.034). Of the 183 pharmacist visits, 44% originated from messages alone. SGLT2i prescribing was similar between groups (5.1% vs. 4.9%, p=0.64). Completed pharmacist visits increased SGLT2i use (21.9% vs. 3.2%, p <0.001). In patients not taking SGLT2i after a pharmacy visit, 42.0% stated they wanted to speak with their provider (PCP or Specialist) before initiating therapy. Conclusions In a Medicare ACO population, navigator outreach after portal messaging doubled the initial volume of pharmacist visits compared to messaging alone. Pharmacist visits were a modestly successful strategy for SGLT2i initiation, limited by patient acceptance. To increase yield and optimize utilization of our limited resources, future efforts will focus on coupling patient outreach efforts to primary care and cardiology appointments to increase visibility and opportunity for care team collaboration as well as enhancing educational materials delivered through portal messaging.

Background Hyperkalemia is a common and potentially life-threatening electrolyte disorder often associated with chronic kidney disease (CKD) and heart failure (HF). Despite available guidance for acute management, outpatient approaches remain variable across specialties, often resulting in inconsistent treatment and premature discontinuation of guideline-directed medical therapies (GDMTs). A multidisciplinary, consensus-based outpatient hyperkalemia care pathway that integrates identification, risk classification, treatment, and monitoring recommendations across primary care, cardiology, and nephrology care settings was developed to standardize care for patients with hyperkalemia. Methods Two roundtable sessions were conducted to identify key barriers to outpatient hyperkalemia management and subsequently develop the consensus Multidisciplinary Outpatient Hyperkalemia Care Pathway, informed by clinical guidelines. Feedback and perspectives from expert multidisciplinary roundtable clinicians were integrated through iterative rounds of review; the care pathway was further validated via discussion with a primary care physician. Results The consensus-driven Multidisciplinary Outpatient Hyperkalemia Care Pathway outlines a stepwise framework consisting of: (A) a comprehensive assessment and patient work-up, (B) risk classification, (C) individualized dietary and therapeutic management, (D) last-resort GDMT down-titration or discontinuation considerations, (E) GDMT reintroduction recommendations, and (F) long-term monitoring suggestions that integrate referral guidance. Conclusions The Multidisciplinary Outpatient Hyperkalemia Care Pathway provides a structured approach designed to reduce hyperkalemia care variability and support coordinated multidisciplinary care when implemented in clinical practice. Trial Registration Not applicable.

This review highlights the barriers and facilitators that implementation science studies face in the institutional review board (IRB) approval pathway and provides recommendations on how to potentially streamline this process. Significant gaps persist between evidence-based recommendations and real-world clinical practice. Implementation science projects investigate how to promote uptake of evidence-based and guideline-recommended practices. Regulatory ambiguity may arise because implementation science involves aspects of traditional research and quality improvement. Currently, there is a lack of well-delineated processes to determine the optimal review pathway for implementation science projects. Current research review pathways do not facilitate efficient approval for implementation science projects due to ambiguous IRB submission guidelines, limited exposure to implementation science, and recent integration of digital tools. In this review, we suggest further development of expedited review pathways for low-risk projects, creation of tools for researchers to determine IRB application category, and further investment in digital health-focused implementation science projects and approval pathways to prepare for the emerging wave of implementation science and maximize the positive impact on patient health outcomes.

Background/Objectives: Chronic kidney disease (CKD) and cardiovascular disease (CVD) confer a substantial, interrelated health burden. CKD markedly increases cardiovascular risk and premature mortality, while CVD accelerates kidney disease progression. Despite the availability of simple diagnostic tests and validated CVD risk tools, CKD screening remains inconsistent, kidney measures are under-integrated into CVD risk stratification, and guideline-recommended screening is variably adopted due to system-, clinician-, and patient-level barriers. This initiative aimed to develop a consensus-based, practical algorithm to integrate CKD screening into CVD risk management. Methods: A structured Delphi process was used to develop an evidence-informed, consensus-based screening algorithm. In Phase 1, a multidisciplinary expert panel completed iterative surveys to identify and prioritize key screening components and achieve preliminary consensus. Participants received a landscape assessment summarizing current practices, evidence, and implementation gaps. A roundtable discussion reviewed clinical guidelines, published evidence, and survey findings, informing the development of an initial algorithm draft. In Phase 2, a follow-up roundtable refined the algorithm, assessed feasibility within real-world clinical workflows, and confirmed consensus on priority elements. Agreement was finalized through structured group discussion and survey-based validation. Results: Panel discussions identified optimal CKD screening triggers, key gaps in current practice, and opportunities to promote earlier identification of at-risk patients. Refinement during the second roundtable resulted in consensus on algorithm structure, content, and applicability across settings. The final algorithm reflects a streamlined, implementation-focused approach to support consistent and earlier identification of at-risk patients. Conclusions: The algorithm, labeled the Primary Care Cardio-Kidney Risk Navigator, provides a practical, flexible framework that integrates and operationalizes existing guideline recommendations into a unified, workflow-oriented approach for primary care that supports consistent real-world implementation. It supports earlier identification, referral, and prevention strategies for at-risk populations and can be implemented within electronic health records or as a standalone clinical decision support tool.

Background: The prevalence and prognostic impact of metabolic dysfunction-associated steatotic liver disease (MASLD), overall and across the cardiovascular-kidney-metabolic (CKM) spectrum, is uncertain. Methods: In the prospective Coronary Artery Risk Development in Young Adults (CARDIA) study, abdominal computed tomography was performed at a follow-up examination in 2010. MASLD was defined as hepatic steatosis (≤51 Hounsfield units) and ≥1 cardiometabolic criteria, without other causes of hepatic steatosis. The association between MASLD (vs. no MASLD) and clinical outcomes was evaluated. Subgroup analyses were repeated by CKM stage. Results: Among 2,600 participants with sufficient data (mean age, 50±10 years), 89% had CKM syndrome stage ≥1 ( Figure, A ); 24% had MASLD, with higher prevalence at higher CKM syndrome stages ( Figure, B ). After covariate adjustment, MASLD was associated with a higher rate of all-cause death (aHR, 1.90; 95% CI, 1.22-2.98), without heterogeneity across CKM stages ( P interaction =0.78) ( Figure, C ). MASLD was associated with a higher rate of incident cardiovascular events (aHR, 1.81; 95% CI, 1.23-2.65), observed primarily in those with CKM stages 0-1 ( P interaction =0.032) ( Figure, C ). Conclusions: MASLD impacted 1 in 4 middle-aged adults and was associated with cardiovascular and mortality events, particularly at earlier CKM stages. These findings suggest early MASLD recognition and intervention across the CKM spectrum may reduce long-term adverse outcomes.

BACKGROUND:Chronic kidney disease (CKD) is a major risk factor for heart failure (HF). However, the burden of worsening HF (WHF) events among adults with mild-to-moderate CKD has not been well described. OBJECTIVES:This study assessed the burden of WHF in a contemporary cohort of adults with mild-to-moderate CKD. METHODS:We identified adults with mild-to-moderate CKD (eGFR 30-59 mL/min/1.73m² or eGFR ≥60 mL/min/1.73m² with albuminuria) within a large, integrated healthcare delivery system from 2012 to 2021. Outcomes included hospitalizations, emergency department visits, and outpatient encounters for WHF, stratified by HF status and level of CKD. RESULTS:Among 375,495 adults with mild-to-moderate CKD, mean age was 64 ± 16 years, 54% were women, mean eGFR was 76 ± 26 mL/min/1.73m², and 6.5% had prior known HF. CKD stages G1A2 (31.6%), G2A2 (24.9%), and G3aA1 (25.1%) were most prevalent. Rates (95% CI) per 100 person-years for WHF events were 1.85 (1.83-1.87) for hospitalizations, 0.85 (0.84-0.86) for emergency department visits, and 0.83 (0.81-0.84) for outpatient encounters, resulting in a cumulative rate of 2.42 (2.40-2.44). Event rates were higher at lower eGFR and higher albuminuria levels. CONCLUSIONS:WHF is a common source of morbidity in adults with earlier stage CKD, and particularly high in those with lower eGFR and greater albuminuria. These findings underscore the importance of implementing available and emerging cardioprotective and renoprotective therapies in this high-risk population.

Background: Given the dynamic and increasingly modifiable nature of LVEF, static, cross-sectional LVEF-based classification alone is incomplete. Recognizing this, the 2022 AHA/ACC HF Guidelines introduced a new classification of HF with improved EF (HFimpEF). Understanding factors associated with HFimpEF may have implications for drug and device intensification; however, limited contemporary data with modern GDMT use exist to inform this question. Objective: To describe patient characteristics associated with incident HFimpEF across a large, diverse, multisite integrated healthcare delivery system. Methods: We identified patients who were diagnosed with incident HFrEF between January 2013-December 2023 across Kaiser Permanente Northern California, a large integrated healthcare delivery system. We defined incident HFimpEF as a follow-up LVEF >40% within 12 months of HFrEF diagnosis. Patients who died, disenrolled from the health plan, or did not receive a follow-up LVEF were classified as having persistent HFrEF. Regularized logistic regression was used to identify predictors of incident HFimpEF. To examine the importance of post-diagnosis guideline directed medical therapy (GDMT) use in predicting HFimpEF, we re-indexed the cohort at 90 days post-HFrEF and added GDMT change from time of incident HFrEF and the new index date as new covariates. We then re-trained models to examine the relative importance of GDMT use compared to characteristics at the time of HFrEF diagnosis. Results: Among 33,163 adults with newly diagnosed HFrEF [mean (SD) LVEF 31% (7.5%)], 13,117 (39.6%) experienced HFimpEF within 12 months. In multivariable models, potential reversible forms of cardiomyopathy (e.g. atrial fibrillation, alcohol use), higher baseline LVEF, lower BNP and smaller LV volumes, and lower burden of cardiovascular-kidney-metabolic (CKM) comorbidities (lower history of MI, lower HbA1c) were among the top predictors of incident HFimpEF ( Figure, Panel A ). After accounting for GDMT initiation between incident HFrEF and 90 days post- HFrEF, we found that all GDMT medications initiated were positively associated with developing incident HFimpEF and were included among the top predictors of incident HFimpEF ( Figure, Panel B ). Conclusion: Early GDMT initiation is strongly associated with HFimpEF, particularly in patients with fewer CKM comorbidities. Future research should explore tailored treatment strategies for patients most likely to benefit from early intervention.

Background: Persistent racial and ethnic disparities exist in influenza vaccination coverage. Increasing uptake in this population could potentially reduce influenza infection and associated complications in a at-risk population. Purpose: To explore differences in the effectiveness of behavioral nudges on influenza vaccination rates according to ethnicity. Methods: We conducted a secondary analysis of the nationwide, pragmatic, registry-based, randomized, implementation trial NUDGE-FLU-CHRONIC, which evaluated the effect of 6 different electronic nudging letter strategies on influenza uptake compared with usual care among persons aged 18-64 years, with a chronic disease associated with an increased risk of adverse influenza-related outcomes. Ethnicity was categorized into two groups, white or non-white. Effect modification by ethnicity was tested on the absolute scale. Absolute differences and relative risks (RR) for each comparison were calculated at a significance level of 0.0071. Results: Of 299,881 participants (53.2% female, median age 52.0 years [IQR, 39.8-59.0]) randomized, 90.4% were white. Vaccination uptake was significantly lower compared with non-whites (22.0% vs. 37.7%, p<0.001). White residents were older (median [IQR] age: 52.5 [40.5, 59.2] vs. 46.6 [36.0, 55.8]), and had a higher prevalence of heart failure (4.0% vs 2.7%, p<0.001), atrial fibrillation (6.9% vs 3.2%, p<0.001, and hypertension (36.2% vs 28.9, p<0.001), whereas non-whites had a higher prevalence of ischemic heart disease (10.5% vs. 8.9%, p<0.001), and diabetes (24.6% vs. 18.7%, p<0.001). White residents were more likely to be educated, be employed, and had higher income (all p<0.001). Each letter successfully increased influenza vaccination irrespective of ethnicity; however, the magnitude of effectiveness of each letter was significantly modified by ethnicity (Figure 1; all p<0.001), such that effectiveness was less pronounced among non-whites with the largest difference in effect size observed with the repeated letter and the smallest difference in effect size observed with the cardiovascular gain letter. Conclusion: Electronic nudging letters consistently led to clinically relevant relative gains in vaccine uptake, irrespective of ethnicity. However, absolute gains from these nudging strategies were somewhat attenuated in non-white residents. These results highlight the need for greater emphasis on vaccine implementation strategies tailored according to ethnicity.

Background: Previous studies have shown dapagliflozin, a sodium-glucose co-transporter-2 inhibitor (SGLT2i), to be a cost-effective treatment option for patients with heart failure (HF) with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF) in multiple European settings. Research question: Is the cost-effectiveness of dapagliflozin treatment in HFpEF/HFmrEF modified by either the time since HFpEF/HFmrEF diagnosis or the time since the last hospitalization for heart failure (HHF) event? Methods: A Markov cohort transition model was built for the UK setting, informed by patient-level data from the randomized, placebo-controlled DELIVER trial. The patient population was subset according to categories of time since last HHF event (including no prior HHF) and time since HF diagnosis (further subset to those with no prior HHF). For each subgroup, disease evolution was characterized by transitions among health states defined by quartiles of the Kansas City Cardiomyopathy Questionnaire Total Symptom Scale. The risk of fatal (cardiovascular and non-cardiovascular) and non-fatal events of worsening HF were modelled, adjusting for baseline characteristics and time-updating health state. Incremental costs and quality-adjusted life-years (QALYs) were calculated for each subgroup to yield incremental cost-effectiveness ratios (ICERs). Results: The lowest ICERs were observed for subgroups with the shortest time from HF diagnosis (with and without prior HHF) or last HHF event (Figure 1). Across all subgroups, the calculated ICERs were below the UK willingness-to-pay (WTP) threshold of £20,000/QALY gained. Conclusions: In patients with HFpEF/HFmrEF, the cost-effectiveness of dapagliflozin improved (via lower ICERs) in the subgroups corresponding to earliest disease (least time since an HHF event or HF diagnosis) compared with groups of later disease and potentially delayed treatment initiation. These findings suggest early optimization of HF therapy with implementation of guideline-directed medical therapy, including SGLT2is, may improve economic value.