Background The importance of nutritional status is underappreciated in patients with heart failure (HF). This study aimed to describe the range of the prognostic nutrition index (PNI), and the clinical characteristics and outcomes according to PNI, in patients with HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). The primary outcome was the composite of HF hospitalization or cardiovascular death.Methods and Results Individual patient data from the PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in HF) trials were used to examine patient characteristics and outcomes according to quartiles of PNI. Cox regression was used to analyze clinical outcomes, and multivariable fractional polynomial interaction analysis to examine the effects of sacubitril-valsartan, according to PNI. Patients with lower PNI (poorer nutrition) were older, frailer, and had more comorbidities and worse HF status, with greater congestion. Patients with lower PNI had biomarker abnormalities indicating inflammation, bone marrow suppression, and increased collagen turnover, among other physiologic perturbations. Lower PNI was associated with worse outcomes; that is, the rate of the primary end point among patients in the first quartile was 11.31 (10.20-12.54) compared with 7.09 (6.17-8.14) per 100 person-years in the fourth quartile. These associations persisted after adjustment for other prognostic variables. PNI did not modify the effects of sacubitril-valsartan in HFrEF although sacubitril/valsartan seemed to have a greater benefit in patients with HFpEF with a higher PNI.Conclusions Nutritional status, assessed using PNI, is an independent predictor of poor outcomes in HF. Evaluation of nutritional status in clinical practice, the causes of undernutrition, and whether undernutrition should be a therapeutic target, are all worthy of further investigation in HF.

Background An initial decline in estimated glomerular filtration rate (eGFR) often leads to reluctance to continue life-saving therapies in patients with heart failure (HF). Objectives The goal of this study was to describe the association between initial decline in eGFR and subsequent clinical outcomes in patients randomized to placebo or finerenone. Methods In this prespecified analysis of FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure), we examined the association between initial decline in eGFR (≥15%) from randomization to 1 month and subsequent outcomes in patients assigned to finerenone or placebo. The primary outcome was the composite of total HF events and cardiovascular death. Results Among 5,587 patients with an eGFR measurement at both baseline and 1 month, 1,018 (18.2%) experienced a ≥15% decline in eGFR. The proportion of patients experiencing a ≥15% decline in eGFR was 23.0% with finerenone and 13.4% with placebo (OR: 1.95; 95% CI: 1.69-2.24; P < 0.001). After adjustment, an eGFR decline was associated with a higher risk of the primary outcome in patients assigned to placebo (adjusted rate ratio: 1.50; 95% CI: 1.20-1.89) but not in those assigned to finerenone (adjusted rate ratio: 1.07; 95% CI: 0.84-1.35; Pinteraction = 0.04). By contrast, the efficacy of finerenone was consistent across the range of change in eGFR from baseline to 1 month (Pinteraction = 0.50 for percent change in eGFR), and safety, including hyperkalemia, was similar regardless of an early eGFR decline. Conclusions Although an initial decline in eGFR was associated with worse outcomes in patients assigned to placebo, this relationship was not as strong in those treated with finerenone. An early decline in eGFR can be anticipated with finerenone and should not automatically lead to the discontinuation of this disease-modifying therapy (FINEARTS-HF Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure [NCT04435626]; A Multicenter, Randomized, Double-Bline, Parallel-Group, Placebo-Controlled Study to Evaluate the efficacy and safety of finerenone on morbidity and mortality in participants With Heart Failure [NYHA II-IV] and left ventricular ejection fraction ≥40% [EudraCT 2020-000306-29]).

Importance In prior monotherapy studies of patients with hypertension, single subcutaneous doses of zilebesiran, an investigational RNA interference therapeutic, reduced serum angiotensinogen levels and systolic blood pressure (SBP) at 3 and 6 months. Objective To evaluate the efficacy and safety of zilebesiran vs placebo when added to a standard antihypertensive medication. Design, Setting, and Participants This phase 2, randomized, prospective, double-blinded trial enrolled adults with uncontrolled hypertension from 150 sites across 8 countries between January 2022 and June 2023. The final follow-up date was December 11, 2023, and analyses were conducted on March 1, 2024. Interventions Eligible patients were initially randomized in cohorts to receive open-label run-in treatment for at least 4 weeks with indapamide 2.5 mg, amlodipine 5 mg, or olmesartan 40 mg (4:7:10 randomization), each administered once daily. Within cohorts, adherent patients with 24-hour mean ambulatory SBP of 130 mm Hg to 160 mm Hg were subsequently randomized (1:1) to additional blinded treatment to receive single subcutaneous doses of zilebesiran 600 mg or matching placebo. Main Outcomes and Measures The primary end point in each cohort was the difference between zilebesiran and placebo in change from baseline in 24-hour mean ambulatory SBP at 3 months. Results Of 1491 patients entering the run-in phase, 663 (130 receiving indapamide, 240 receiving amlodipine, and 293 receiving olmesartan) were randomized to receive zilebesiran (n = 332) or placebo (n = 331). The least-squares mean difference between zilebesiran and placebo in change from baseline to 3 months in 24-hour mean ambulatory SBP was -12.1 mm Hg (95% CI, -16.5 to -7.6; P < .001) for indapamide, -9.7 mm Hg (95% CI, -12.9 to -6.6; P < .001) for amlodipine, and -4.5 mm Hg (95% CI, -8.2 to -0.8; P = .02) for olmesartan. Across cohorts, more patients who received zilebesiran than placebo experienced hyperkalemia (18 [5.5%] vs 6 [1.8%]), hypotension (14 [4.3%] vs 7 [2.1%]), and acute kidney failure (16 [4.9%] vs 5 [1.5%]) events, but most episodes were mild and resolved without medical intervention. Conclusions and Relevance In patients with uncontrolled hypertension despite treatment with indapamide, amlodipine, or olmesartan, the addition of single-dose zilebesiran resulted in significant SBP reductions compared with placebo at 3 months, with low rates of serious adverse events.

BACKGROUND:Obesity is a core pathophysiologic 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:In this study, the authors sought to examine cardiovascular outcomes and treatment effects of finerenone according to different adiposity-related anthropometrics. METHODS:In this prespecified participant-level pooled analysis of FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF (FINE-HEART), cardiovascular outcomes and treatment effects of finerenone according to baseline body mass index (BMI), waist circumference (WC), waist-height ratio (WHtR), and waist-hip ratio (WHR) were evaluated with the use of multivariable-adjusted Cox proportional hazards regression and Poisson regression. RESULTS:Of 18,759 participants with available data for all anthropometrics, 52% had a BMI ≥30 kg/m2 and 98% had any excess adiposity. Among those with BMI <30 kg/m2, 95% had increased abdominal adiposity, especially women and older individuals. Higher BMI, WC, WHtR, and WHR were each significantly associated with a wide range of cardiovascular outcomes, including cardiovascular death or heart failure (HF) hospitalization and its individual components, major adverse cardiovascular events, new-onset atrial fibrillation, and incident HF hospitalization. BMI-adjusted WHtR and WHtR-adjusted BMI were each associated with a higher rate of cardiovascular death or HF hospitalization, and participants with elevated BMI and WHtR experienced a higher rate of cardiovascular death or HF hospitalization compared with those with elevated BMI or WHtR alone (P < 0.001). Benefits of finerenone on cardiovascular death or HF hospitalization were consistent regardless of baseline BMI (Pinteraction = 0.27) or WHtR (Pinteraction = 0.26), and absolute benefits appeared to be greater among participants with higher adiposity. Serious adverse events were less common with finerenone vs placebo, regardless of baseline BMI category (Pinteraction = 0.08). CONCLUSIONS:These findings suggest that assessment of anthropometrics capturing abdominal adiposity, in addition to BMI, may enhance obesity identification and risk stratification among individuals with CKM conditions. Finerenone consistently reduced adverse cardiovascular outcomes across a wide range of adiposity. (FINE-HEART: An Integrated Pooled Analysis of Finerenone Across 3 Phase III Trials of Heart Failure and Chronic Kidney Disease and Type 2 Diabetes; CRD42024570467).

AIMS:The estimated glucose disposal rate (eGDR) is a simple, non-invasive measure of insulin resistance. In this exploratory analysis of FINEARTS-HF, we evaluated whether lower eGDR, reflecting greater insulin resistance, is associated with adverse outcomes in heart failure (HF). METHODS AND RESULTS:The eGDR was calculated at baseline using waist circumference, glycated haemoglobin, and hypertension status. Clinical outcomes and treatment effects of finerenone according to baseline eGDR (<median or ≥median) were evaluated. Among 5851 (98%) participants with a calculable eGDR (median [interquartile range] 5.1 [3.9-6.3] mg/kg/min), lower eGDR was associated with greater albuminuria and worse HF-related health status at baseline. Compared with participants with eGDR ≥5.1 mg/kg/min, those with eGDR <5.1 mg/kg/min experienced a 63% higher rate of cardiovascular death and total HF events (adjusted rate ratio [aRR] 1.63; 95% confidence interval [CI] 1.41-1.87; p < 0.001). Similar findings were observed in participants with diabetes (aRR 1.72; 95% CI 1.40-2.12) and without diabetes (aRR 1.34; 95% CI 1.07-1.68; pinteraction = 0.06). Lower baseline eGDR was additionally associated with a higher rate of vascular events, kidney outcomes, new-onset diabetes, and all-cause death. Treatment benefits of finerenone on cardiovascular death and total HF events (pinteraction = 0.64) and new-onset diabetes (pinteraction = 0.36) appeared consistent irrespective of baseline eGDR category. Baseline eGDR category did not modify the safety profile of finerenone. CONCLUSIONS:The eGDR, a validated measure of insulin resistance, was associated with a wide range of cardiovascular, kidney, and metabolic outcomes in patients with HF, including among those without diabetes. Finerenone reduced risk of cardiovascular outcomes and new-onset diabetes, irrespective of baseline insulin resistance. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT04435626.

Background Mineralocorticoid receptor antagonists (MRA) modulate cardiac and systemic pathways such as fibrosis and inflammation, which may contribute to the onset of atrial fibrillation (AF) or atrial flutter (AFL). Objectives In this participant-level pooled analysis of 3 large clinical trials, the authors evaluated the effect of the nonsteroidal MRA finerenone on incident AF/AFL across the cardio-kidney-metabolic (CKM) spectrum. Methods In this prespecified analysis, we pooled participants from 2 trials of chronic kidney disease and type 2 diabetes (FIDELIO-DKD and FIGARO-DKD) and a trial of heart failure (HF) with mildly reduced or preserved ejection fraction (FINEARTS-HF). Patients were randomized 1:1 to finerenone or placebo. New-onset AF/AFL was prospectively adjudicated in all trials by blinded clinical event committees. The risk of new-onset AF/AFL was evaluated using Cox regression models stratified by region and trial. Results Among 14,581 patients who were free of AF/AFL at trial enrollment, 631 (4.3%) experienced new-onset AF/AFL during follow-up. Predictors of new-onset AF/AFL included older age, history of HF, higher body mass index, geographic region, and higher levels of urine albumin-to-creatinine ratio. During 2.9 years of median follow-up, new-onset AF/AFL occurred in 286 (3.9%) participants receiving finerenone and 345 (4.7%) assigned to placebo (HR: 0.83; 95% CI: 0.71-0.97; P = 0.019). Risk reductions were consistent irrespective of number of CKM conditions (Pinteraction = 0.87) and by trial (Pinteraction = 0.57). Participants with new-onset AF/AFL were at significantly higher subsequent risk of cardiovascular death, HF hospitalization, and adverse kidney outcomes. Conclusions The nonsteroidal MRA finerenone reduced the risk of new-onset AF/AFL across the CKM spectrum.

Importance Patients with chronic heart failure (HF) and left ventricular ejection fraction (LVEF) less than 40% who experience LVEF improvement to 40% or higher (HFimpEF) may still face residual risks. Objective To assess the clinical profiles, risk, and treatment response to finerenone in participants with HFimpEF. Design, Setting, and Participants A total of 6001 patients with HE, LVEF of 40% or higher, New York Heart Association class II to IV symptoms, and elevated natriuretic peptide levels, were enrolled between September 14, 2020, and January 10, 2023. Patients with a prior history of LVEF less than 40% were included. Data analysis was conducted between September 1 to December 10, 2024. Intervention Participants received finerenone (titrated to 20 mg or 40 mg) or placebo. Main Outcomes and Measures The primary end point was the composite of cardiovascular (CV) death and total (first and recurrent) worsening HF events. Results Of the 6001 participants (mean [SD] age, 72 [9.7], years; 3269 male [55%]), 273 (5%) had a prior LVEF less than 40%. Among those with a prior LVEF of less than 40%, the median recorded prior LVEF was 35% [IQR, 30%-37%], with a median improvement of 12% [IQR, 8%-17%]. Over a median follow-up of 2.6 years, those with a history of LVEF of less than 40% experienced higher rates of the primary outcome of a composite of CV death and worsening of HF events (21.4 per 100 patient-years vs 16.0 per 100 patient-years) than did those whose LVEF was consistently 40% or higher. After adjustment for clinically relevant covariates; however, this rate ratio (RR) was not statistically different (absolute RR, 1.13; 95% CI, 0.85-1.49, P = .39). The treatment effect of finerenone on the primary outcome was consistent among those with a history of LVEF less than 40% and those with LVEF that was consistently 40% or higher (P for interaction = .36). Owing to higher baseline risk, the absolute risk reduction was greater among those with HFimpEF (9.2 vs 2.5 per 100 patient-years). Patients with HFimpEF tended to develop more hypotension with finerenone treatment, but otherwise, the safety profile of finerenone was similar in patients with and without previous LVEF less than 40%. Conclusions and Relevance In this prespecified analysis of a randomized clinical trial, patients with HFimpEF remained at high risk of CV events, underscoring the need for continued management despite LVEF improvement. The treatment benefits of finerenone observed among the overall population of patients with HF with preserved EF were consistent among patients with HFimpEF.

Finerenone improved heart failure (HF) outcomes in patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). Clinical decision-making around initiation of mineralocorticoid receptor antagonists often relies on measures of kidney function and serum potassium (K + ) levels. The aim of this study was to evaluate the efficacy and safety of finerenone across categories of serum K + and estimated glomerular filtration rate (eGFR). Four mutually exclusive categories were created: (1) K + ≤4.5 mmol/L and eGFR ≥60 ml/min/1.73 m 2 ; (2) K + >4.5 mmol/L and eGFR ≥60 ml/min/1.73 m 2 ; (3) K + ≤4.5 mmol/L and eGFR <60 ml/min/1.73 m 2 ; and (4) K + >4.5 mmol/L and eGFR <60 ml/min/1.73 m 2 . Outcomes and treatment effects were compared across these categories. The primary outcome was a composite of total HF events and cardiovascular death. The median follow-up was 32 months. A total of 6001 patients were included. Compared to patients with K + ≤4.5 mmol/L and eGFR ≥60 ml/min/1.73 m 2 , those with eGFR <60 ml/min/1.73 m 2 , irrespective of K + levels, had a 1.5- to 2-fold higher risk of experiencing primary outcome and fatal events across treatment groups. No significant interaction was observed on the effects of finerenone (vs. placebo) on the primary outcome across K + /eGFR categories. The respective risk ratios (RR) and 95% confidence intervals (CI) were: (1) K + ≤4.5 mmol/L and eGFR ≥60 ml/min/1.73 m 2 : RR 0.66, 95% CI 0.52–0.85; (2) K + >4.5 mmol/L and eGFR ≥60 ml/min/1.73 m 2 : RR 0.92, 95% CI 0.65–1.30; (3) K + ≤4.5 mmol/L and eGFR <60 ml/min/1.73 m 2 : RR 0.91, 95% CI 0.74–1.13; (4) K + >4.5 mmol/L and eGFR <60 ml/min/1.73 m 2 : RR 0.92, 95% CI 0.72–1.17; p for interaction = 0.20. Patients with low eGFR and/or high K + experienced more frequent adverse events and treatment discontinuation; still, categories of K + /eGFR did not significantly modify the relative risk of adverse events with finerenone versus placebo ( p for interaction > 0.1 for all adverse events). No significant heterogeneity was found on the effect of finerenone to reduce primary outcome events. Still, adverse events and treatment discontinuation were more frequent among patients with low eGFR and/or high K + , suggesting. that such patients may require tailored strategies to mitigate adverse events and avoid treatment discontinuation.

BACKGROUND:Recent trials of new heart failure (HF) treatments suggest the effect of therapy may vary by N-terminal pro-B type natriuretic peptide (NT-proBNP) level. OBJECTIVES:The authors examined the efficacy of sacubitril/valsartan according to NT-proBNP levels in patients with reduced, mildly reduced, and preserved left ventricular ejection fraction (LVEF) enrolled in PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) and PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Receptor Blockers Global Outcomes in HF with Preserved Ejection Fraction). METHODS:Individual patient data from PARADIGM-HF and PARAGON-HF were pooled and participants were divided into categories defined by quintiles of NT-proBNP level. The primary outcome examined was the composite of HF hospitalization or cardiovascular death. RESULTS:Among the 13,195 patients enrolled in both trials, 13,142 (99.6%) had a baseline NT-proBNP level measured. The rate of the primary outcome (per 100 person-years) increased with NT-proBNP levels: quintile 1, 5.9 (95% CI: 5.3-6.5); quintile 2, 7.5 (95% CI: 6.9-8.2); quintile 3, 9.0 (95% CI: 8.2-9.7); quintile 4, 12.0 (95% CI: 11.1-12.9); and quintile 5, 20.8 (95% CI: 19.6-22.2). The relative risk reduction in the primary outcome with sacubitril/valsartan was consistent across NT-proBNP levels: the HR in quintile 1 was 0.79 (95% CI: 0.65-0.96); quintile 2, 0.87 (95% CI: 0.72-1.04); quintile 3, 0.79 (95% CI: 0.66-0.93); quintile 4, 0.85 (95% CI: 0.73-0.99); and quintile 5, 0.86 (95% CI: 0.76-0.97; P for interaction = 0.86). The absolute risk reduction was greatest in NT-proBNP quintile 5; the number needed to treat for the primary outcome over the median follow-up of 31 months was 16 in quintile 5 vs 37 in quintile 1. CONCLUSIONS:The relative risk reductions with sacubitril/valsartan were consistent irrespective of NT-proBNP level in HF patients across the range of LVEF. Consequently, the absolute risk reductions were greatest in patients with higher NT-proBNP levels. (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial]; NCT01035255; and PARAGON-HF [Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Receptor Blockers Global Outcomes in HF with Preserved Ejection Fraction]; NCT01920711).

Importance:Worsening heart failure (HF) is commonly managed in the outpatient setting with adjustments in oral diuretic therapy. The effect of the nonsteroidal mineralocorticoid receptor antagonist finerenone on outpatient worsening HF events in patients with mildly reduced or preserved ejection fraction is unknown. Objective:To evaluate the effect of finerenone on outpatient worsening HF events requiring oral diuretic intensification among patients with HF with mildly reduced or preserved ejection fraction. Design, Setting, and Participants:This is a secondary analysis of the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF), a global, multicenter randomized clinical trial. Patients had HF and an ejection fraction of 40% or greater. Data analysis was conducted from September 1 to December 10, 2024. Intervention:Participants were randomized 1:1 to finerenone or placebo. Main Outcomes and Measures:Primary outcome events (cardiovascular death, HF hospitalization, and outpatient urgent HF visit requiring intravenous diuretic therapy) were centrally adjudicated. In this prespecified analysis, outpatient oral diuretic intensification events were defined as initiations of loop or thiazide diuretic or increases in loop diuretic dosage. The risk of all-cause death following each type of worsening HF event (HF hospitalization, urgent HF visit, or outpatient oral diuretic intensification) and the effect of finerenone on outpatient oral diuretic intensification alone or as part of an extended composite outcome with primary outcome events were evaluated. Results:A total of 6001 participants (mean [SD] age, 72.0 [9.6] years; 2732 [46%] female) were enrolled. First worsening HF events included 664 HF hospitalizations, 87 urgent HF visits, and 1250 oral diuretic intensifications. Rates of death were higher following worsening HF: 27.7 (95% CI, 24.3-31.5) per 100 patient-years after HF hospitalization, 13.6 (95% CI, 8.8-21.1) per 100 patient-years after urgent HF visit, and 11.6 (95% CI, 10.2-13.1) per 100 patient-years after outpatient oral diuretic intensification compared with 4.5 (95% CI, 4.2-4.9) per 100 patient-years for patients without worsening HF. Adding outpatient oral diuretic intensification to the primary outcome increased the number of patients experiencing events from 1343 to 2238. Finerenone reduced outpatient oral diuretic intensification alone (hazard ratio [HR], 0.89 [95% CI, 0.80-0.98]; P = .02) and in an extended composite outcome that further included cardiovascular death, HF hospitalization, and urgent HF visit (HR, 0.85 [95% CI, 0.78-0.92]; P < .001). Conclusions and Relevance:Outpatient worsening HF events requiring oral diuretic intensification were common, associated with poor prognosis, and reduced by finerenone in patients with HF with mildly reduced or preserved ejection fraction. Trial Registration:ClinicalTrials.gov Identifier: NCT04435626.

Background Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging is commonly used to facilitate diagnosis in suspected cardiac sarcoidosis (CS). However, there is a gap in evidence regarding the diagnoses and outcomes of patients who undergo FDG PET/CT. Objectives Evaluate the diagnoses and outcomes of patients referred for FDG PET/CT imaging for suspected CS. Methods We studied all consecutive patients referred to our center for FDG PET/CT for suspected CS from June 2006 to November 2023. Patients were characterized by their final clinical diagnosis and followed to a composite outcome of left ventricular assist device placement, heart transplant, or death. Results A total of 1646 patients (mean age 58.4 ± 12.4 years; 66 % male) met inclusion criteria: 285 (17.3 %) with Heart Rhythm Society (HRS) criteria positive CS, 83 (5.0 %) with probable CS, 237 (14.4 %) with sarcoidosis but without HRS criteria for CS, and 1041 (63.2 %) with other diagnoses. 227 patients (13.8 %) underwent genetic testing, of whom 32 (14.1 %) were found to have a pathogenic/likely pathogenic variant. Over a median follow up of 4.4 years, 327 patients (19.9 %) met the primary outcome. There was no significant difference in outcomes by diagnosis (log-rank p = 0.4936). Conclusions Most patients referred for FDG PET/CT for suspected CS were not found to have CS in follow up. However, they are at similar risk for the need for advanced therapies and many are found to have genetic CMP. These data highlight the importance of advanced heart disease consultation and referral for genetic testing in this population.

The value of generic quality of life (QoL) instruments in heart failure (HF) is uncertain. In this study, the authors sought to quantify individual dimension scores and the EuroQol 5-Dimension questionnaire (EQ-5D) Level Sum Score (LSS) in patients with HF with reduced, mildly reduced, or preserved ejection fraction, the association between those scores and outcomes, and the impact of treatment with dapagliflozin on the scores. Analyses were conducted using patient-level data from DAPA-HF and DELIVER trials. Cox proportional hazards regression models were used to assess the association between EQ-5D scores (each dimension and LSS) and clinical outcomes. Sankey diagrams were used to illustrate changes in individual patient EQ-5D dimensions from baseline to 8 months' follow-up. Of the 11,007 patients randomized in DAPA-HF and DELIVER, 10,135 (92.1%) completed the instrument at baseline. Scores varied markedly by question with 37%, 30%, and 33% of patients reporting no, slight, or moderate or greater problem, respectively for mobility; 67%, 20%, and 13% for self-care; 40%, 33%, and 27% for usual activities; 45%, 32%, and 23% for pain/discomfort; and 57%, 27%, and 16% for anxiety/depression. Patients with higher (worse) EQ-5D-LSS were more frequently female, had more comorbidities, and had worse HF status. Compared with patients free from any problem across all dimensions (ie, an EQ-5D-LSS of 5), the HRs for the composite outcome of time to first cardiovascular death or worsening HF were 1.27 (95% CI: 1.10-1.47), 1.70 (95% CI: 1.46-1.98), and 2.31 (95% CI: 1.88-2.85) in patients with EQ-5D-LSS of 6-10, 11-15, and 16-25 points, respectively. Dapagliflozin led to greater improvement and less worsening in mobility (OR: 1.13 [95% CI: 1.04-1.23]; P = 0.004), self-care (OR: 1.13 [95% CI: 1.02-1.24]; P = 0.016), usual activities (OR: 1.11 [95% CI: 1.02-1.21]; P = 0.015), and anxiety/depression (OR: 1.10 [95% CI: 1.01-1.21]; P = 0.034) after 8 months. The number needed to treat for 1 patient to report improvement in EQ-5D-LSS was 31 (95% CI: 20-72). The EQ-5D revealed problems not often associated (eg, pain) with HF or commonly quantified in HF (eg, anxiety/depression). Dapagliflozin improved multiple QoL dimensions, and possibly anxiety/depression. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

BACKGROUND Hypertension is common in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), and current guidelines recommend treating systolic blood pressure (SBP) to a target <130 mm Hg. However, data supporting treatment to this target are limited. Additionally, pulse pressure (PP), a marker of aortic stiffness, has been associated with increased risk of cardiovascular events, but its prognostic impact in HFpEF has not been extensively studied. OBJECTIVES This study aimed to explore the impact of baseline SBP and PP on cardiovascular outcomes in patients with HFmrEF or HFpEF. METHODS The I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction), TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist)-Americas, PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blocker Global Outcomes in HF With Preserved Ejection Fraction), and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials were global, randomized clinical trials testing irbesartan, spironolactone, sacubitril/ valsartan, and dapagliflozin, respectively, against either a placebo or an active comparator (valsartan, in PARAGON-HF), in patients with heart failure and a left ventricular ejection fraction >= 40% (in DELIVER) or >= 45% (in the other trials). The relationship between continuous baseline SBP and PP, and the primary endpoint (first heart failure hospitalization or cardiovascular death) was analyzed with restricted cubic splines. We further evaluated the prognostic impact of SBP categories (<120, 120-129, 130-139, and >= 140 mm Hg) and PP quartiles on the primary endpoint. RESULTS A total of 16,950 patients (mean age 71 f 9 years; 49% male; mean SBP 131 f 15 mm Hg; mean PP 55 f 14 mm Hg) were included. The relationship between SBP and the primary endpoint was J-shaped, with the lowest risk at 120 to 130 mm Hg. A similar pattern was found for PP, with the lowest risk at 50 to 60 mm Hg. The highest SBP category (reference: 120-129 mm Hg) and PP quartile (reference: 46-54 mm Hg) were associated with a higher risk of the primary outcome (HR: 1.22; 95% CI: 1.10-1.34 and HR: 1.22; 95% CI: 1.11-1.34, respectively). Higher PP was associated with greater cardiovascular risk, regardless of SBP. CONCLUSIONS Our analysis of a large pooled dataset from 4 clinical trials, including >16,900 patients with HFmrEF/ HFpEF, indicates a J-shaped relationship between both SBP and PP and cardiovascular risk. The lowest risk was observed at SBP levels between 120 and 130 mm Hg and PP values between 50 and 60 mm Hg (I-PRESERVE [Irbesartan in Heart Failure With Preserved Systolic Function], NCT00095238; TOPCAT [Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist], NCT00094302; PARAGON-HF [Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction], NCT01920711; DELIVER [Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure], NCT03619213) (JACC. 2025;85:710-722) (c) 2025 Published by Elsevier on behalf of the American College of Cardiology Foundation.

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. Patients with HF with New York Heart Association functional class II through IV, a left ventricular ejection fraction of 40% or higher, evidence of structural heart disease, and elevated natriuretic peptide levels were randomized between September 2020 and January 2023. Data analysis was conducted from October 1 to November 30, 2024. Intervention Addition of once-daily finerenone or placebo to usual therapy. Main Outcomes and Measures The primary outcome was a composite of cardiovascular death and total worsening HF events. Frailty was measured using the Rockwood cumulative deficit approach. Results Of the 6001 patients randomized in FINEARTS-HF, a frailty index (FI) was calculable in 5952 patients (mean [SD] age, 72.0 [9.6] years; 3241 [54.4%] male). In total, 1588 patients (26.7%) had class I frailty (FI <= 0.210 [not frail]), 2141 (36.0%) had class II frailty (FI 0.211-0.310 [more frail]), and 2223 (37.3%) had class III frailty (FI >= 0.311 [most frail]). Compared with patients with class I frailty, those with class II and III frailty had a higher risk of the primary outcome (unadjusted rate ratio [RR], 1.88 [95% CI, 1.54-2.28] for class II and 3.86 [95% CI, 3.22-4.64] for class III). The effect of finerenone on the primary outcome did not vary significantly by frailty class (class I: RR, 1.07 [95% CI, 0.77-1.49]; class II: RR, 0.66 [95% CI, 0.52-0.83]; class III: RR, 0.91 [95% CI, 0.76-1.07]; P for interaction = .77). Frailty class did not modify the effects of finerenone on the components of the primary outcome, all-cause death, or improvement in the Kansas City Cardiomyopathy Questionnaire total symptom score. The effects of finerenone, compared with placebo, on experiencing hypotension, elevated creatinine level, hyperkalemia, or hypokalemia did not differ by frailty class. Conclusions and Relevance In FINEARTS-HF, finerenone reduced the risk of total worsening HF events and cardiovascular death, and it improved symptoms; these effects were not modified by frailty status. In addition, the effects of finerenone on experiencing hypotension, elevated creatinine level, hyperkalemia, or hypokalemia did not differ by frailty status.