Decline in glomerular filtration rate as an endpoint in heart failure clinical trials: challenges and solutions.

Chronic kidney disease (CKD) and cardiovascular disease are tightly interconnected, with common mechanisms that underlie the development and progression of both diseases, recently articulated into the framework of the cardiovascular-kidney-metabolic syndrome. CKD and heart failure commonly coexist in the same individual, with increasing evidence for common therapies in both disease states. It is valuable for patients, clinicians, and regulatory agencies to understand how to best assess CKD progression in patients with heart failure for evaluation of individual patients and as part of an endpoint for outcome trials.

Natriuretic Peptides, Body Mass Index, and Clinical Outcomes in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.

Background: Natriuretic peptides are the primary biomarkers recommended in heart failure (HF) guidelines to risk stratify patients in clinical practice and serve as key eligibility criteria in contemporary clinical trials. However, threshold levels typically do not account for measures of adiposity, such as body mass index (BMI).

Objective: To evaluate the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) with clinical outcomes in individuals with HF and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), stratified according to BMI.

Anthropometric Measures, Cardiovascular Outcomes, and Treatment Effects of Finerenone in Cardiovascular-Kidney-Metabolic Disease: Pooled Participant-Level Analysis of Three Global Trials.

Background: Obesity is a core pathophysiological contributor to cardiovascular, kidney, and metabolic (CKM) conditions. However, the association between different adiposity-related anthropometrics and cardiovascular outcomes in persons with CKM conditions has not been rigorously explored.

Objectives: To examine cardiovascular outcomes and treatment effects of finerenone according to different adiposity-related anthropometrics.

Prioritising the primary prevention of heart failure.

Heart failure remains one of the 21st century's greatest unmet clinical and public health challenges. Heart failure is a highly prevalent chronic condition that affects approximately 55 million people worldwide. Although heart failure can be prevented, the global burden of this condition continues to grow, fuelled by an ageing population, improved survival after myocardial infarction, and increasing prevalence of metabolic and kidney disease.

Prevention of heart failure after acute myocardial infarction.

This Series paper highlights the substantial progress made in understanding and preventing heart failure after acute myocardial infarction. Improving global standards of care for management of acute myocardial infarction with timelier reperfusion has led to stepwise reductions in risk of incident heart failure. Landmark clinical trials have established the role of renin-angiotensin-aldosterone system inhibitors, β blockers, and mineralocorticoid receptor antagonists to specifically reduce the risk of incident heart failure after acute myocardial infarction.

Cardiovascular, kidney, and metabolic health: an actionable vision for heart failure prevention.

The substantial and growing prevalence of heart failure, which remains the leading cause of preventable hospitalisation worldwide, has brought heart failure prevention into sharp focus. Although this condition has historically been characterised by impaired cardiac function, mounting evidence has underscored its complex and multisystem pathobiology. Epidemiological studies have indicated that other forms of cardiovascular disease, along with kidney and metabolic dysfunction, frequently and increasingly contribute to heart failure onset.

Nonsteroidal and Steroidal Mineralocorticoid Antagonists: Rationale, Evidence, and Unanswered Questions.

Steroidal mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone, have demonstrated substantial benefits in randomized controlled trials for patients with heart failure with reduced ejection fraction. However, their effectiveness in heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction remains uncertain, and the implementation of this class has remained low, in part due to its side effects and tolerability profile. Emerging therapies that target the mineralocorticoid receptor and/or the production of aldosterone may offer alternative strategies to treat the aldosterone-mineralocorticoid receptor axis.

Simultaneous initiation of finerenone and empagliflozin across the spectrum of kidney risk in the CONFIDENCE trial.

Background: The CONFIDENCE (COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with CKD and type 2 diabetes using a UACR Endpoint) trial investigated the safety and efficacy of simultaneously initiating finerenone and empagliflozin for patients with chronic kidney disease (CKD) and type 2 diabetes. This prespecified analysis aimed to determine if the predicted risk of kidney disease progression, based on KDIGO risk categories, influenced the benefits and safety of this combination therapy.

Methods: The double-blind, double-dummy trial randomized 818 adults with CKD and type 2 diabetes [urine albumin-creatinine ratio (UACR) ≥100 to <5000 mg/g] to receive once-daily finerenone plus empagliflozin, finerenone alone or empagliflozin alone, all in addition to a renin-angiotensin system inhibitor.

Cardiovascular-Focused Messaging to Improve Influenza Vaccination Rates.

Background: Influenza vaccination rates remain suboptimal despite strong evidence of benefit. Electronic letters emphasizing the cardiovascular benefits of vaccination increased uptake in Denmark; whether this strategy is effective in a diverse U.S.

Benefit of early initiation of disease-modifying therapy in community-based patients with suspected heart failure.

Background And Aims: The initiation of heart failure (HF) therapies at the time of detection of an elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in community-based patients with suspected HF may reduce the risk of early adverse outcomes. The aim of this analysis was to estimate the potential benefit of the early initiation of a sodium-glucose cotransporter 2 inhibitor (SGLT2i) and/or mineralocorticoid receptor antagonist (MRA) in patients with suspected HF and a preexisting non-HF-related indication for treatment.

Methods: A cohort study was performed from 01/01/2015 to 31/03/2023 using linked primary and secondary care data from the Clinical Practice Research Datalink (CPRD).

Adiposity-Related Anthropometrics and Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Participant-Level Pooled Analysis of Randomized Clinical Trials.

Background: Obesity is highly prevalent among individuals with heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) and is associated with increased risk of disability and death.

Objectives: The purpose of this study is to explore the association between different adiposity-related anthropometrics and clinical outcomes in this population.

Methods: In this participant-level pooled analysis of 5 international randomized trials that enrolled adults with HFmrEF/HFpEF, the association between adiposity-related anthropometrics (body mass index [BMI], waist circumference [WC], and waist-to-height ratio [WHtR]) and heart failure (HF) and mortality outcomes was evaluated, overall and by age and sex.

Temporal Changes in Biomarkers, Functional Status, and Quality of Life Prior to Adverse Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction.

Background: Mapping clinical, biomarker, and diuretic dosing trajectories before adverse clinical outcomes in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) may inform population monitoring approaches.

Objectives: We assessed temporal patterns of 2 biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP] and estimated glomerular filtration rate [eGFR]), physician assigned functional status (NYHA functional class), a patient-reported outcome (Kansas City Cardiomyopathy Questionnaire Total Symptom Score [KCCQ-TSS]), and diuretic dosing leading up to a clinical event.

Methods: FINEARTS-HF was a double-blind, randomized clinical trial testing finerenone vs placebo in 6,001 patients with symptomatic HF and a left ventricular ejection fraction of ≥40%.

Sacubitril/valsartan and Quality of Life Assessed Using the EuroQol 5-Dimension 3-Level Questionnaire Level Sum Score (EQ-5D-3L-LSS) in Patients with HFrEF and HFmrEF/HFpEF.

Objectives: To investigate the EQ-5D-3L Level Sum Score (LSS) in patients with heart failure (HF) and reduced (HFrEF) and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) and the effect of sacubitril/valsartan on this score using patient-level data from the PARADIGM-HF and PARAGON-HF trials.

Methods: The LSS was calculated by summating the 3 levels (1-3) for each of the 5 domains (minimum sum score=5; maximum sum score=15). Patient characteristics and outcomes were compared across LSS tertiles (T1-T3) at baseline.

Achieved Ejection Fraction and Effects of Dapagliflozin in Heart Failure With Improved Ejection Fraction.

Background: Patients with heart failure with improved ejection fraction (HFimpEF) remain understudied and face residual risks comparable with those with a left ventricular ejection fraction (LVEF) consistently >40% (no prior heart failure with reduced ejection fraction). The implications of achieved LVEF after improvement on prognosis and treatment response remains unclear.

Objectives: This study examines whether the degree of LVEF improvement influences prognosis and the therapeutic effects of dapagliflozin in HFimpEF.

Efficacy and Tolerability of Finerenone According to the Use and Dosage of Diuretics: A Prespecified Analysis of the FINEARTS-HF Randomized Clinical Trial.

Importance: Given their kidney actions, it is important to evaluate the efficacy and safety of mineralocorticoid receptor antagonists when combined with other diuretics and whether they have a so-called diuretic-sparing effect in patients with heart failure (HF).

Objective: To examine the efficacy and tolerability of finerenone related to background diuretic treatment in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF).

Design, Setting, And Participants: This study is a prespecified secondary analysis of the FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) randomized clinical trial, which was conducted across 653 sites in 37 countries among adults aged 40 years and older with HFmrEF/HFpEF, who were randomized between September 2020 and January 2023.

Electronically delivered, cardiovascular-focused messaging to improve influenza vaccination: Rationale, design, and baseline characteristics of the Kaiser Permanente VACCination Improvement with Nudge-based CardiovAscular Targeted Engagement (KP-VACCINATE) Megatrial.

Background: Despite strong evidence of clinical benefit, influenza vaccination rates remain suboptimal in the United States. Randomized trials suggest that behavioral nudges may improve vaccination rates, particularly when messaging includes language on the potential cardiovascular (CV) benefits of vaccination. Whether these nudges are effective in a diverse US population is unknown.

Heart Failure With Improved Ejection Fraction: Definitions, Epidemiology, and Management.

Heart failure with improved ejection fraction (HFimpEF) has gained increasing recognition as a distinct phenotype within the spectrum of heart failure, characterized by previously reduced left ventricular ejection fraction (≤40%) that subsequently improves to >40%. HFimpEF remains relatively understudied, and uncertainty persists regarding its long-term prognosis and optimal management. Contemporary registries and clinical trials suggest a rising prevalence, likely reflecting both the increased implementation of guideline-directed medical therapy and evolving consensus definitions for its identification.

Finerenone According to Frailty in Heart Failure: A Prespecified Analysis of the FINEARTS-HF Randomized Clinical Trial.

Importance: Patients with frailty are often perceived to have a less favorable benefit-risk profile for novel therapies and therefore may be less likely to receive these.

Objective: To examine the efficacy and safety of finerenone, compared with placebo, according to frailty status in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) or with HF and preserved ejection fraction (HFpEF).

Design, Setting, And Participants: This was a prespecified secondary analysis of a phase 3 randomized clinical trial, the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF), conducted across 653 sites in 37 countries.

Efficacy and Safety of Finerenone in Heart Failure With Preserved Ejection Fraction: A FINE-HEART Analysis.

Background: Pooling data from participants with heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) from all completed outcomes trials evaluating finerenone to date may enhance understanding of its safety and efficacy in this high-risk and heterogeneous population.

Objectives: In this prespecified participant-level pooled analysis of the FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF trials (FINE-HEART), we evaluated the safety and efficacy of finerenone in individuals with HFmrEF/HFpEF.

Methods: The treatment effects of finerenone vs placebo on cardiovascular death or heart failure hospitalization were evaluated using Cox proportional hazards regression models stratified by trial.