Cardio-kidney-metabolic syndrome and heart failure remain complex clinical conditions with significant healthcare implications. While therapeutic plans were intended to ensure appropriate prescribing, they often represent bureaucratic barriers. Facilitating or removing such plans could enhance treatment timeliness, therapeutic continuity, and equitable access. This work also includes other widely used cardiovascular drugs such as direct oral anticoagulants, which remain under therapeutic plan requirements despite robust clinical experience and safety data. In light of the recent AIFA resolution of July 4, 2025, abolishing the therapeutic plan for sodium-glucose cotransporter 2 inhibitors, this paper considers such a decision as a major normative and operational breakthrough. The removal of this prescribing barrier reflects both the safety and manageability of these drugs and represents a potential model for broader regulatory simplifications. It is therefore believed that overcoming the prescribing barriers imposed by therapeutic plans is not only a clinical necessity but also an organizational and ethical imperative, in order to avoid delaying or limiting access to care.

Study objective To evaluate the following among new users of vericiguat: up-titration patterns, factors associated with up-titration, occurrence of hypotension/syncope, predictors of hypotension/syncope. Design Retrospective cohort study (linked claims and electronic health record data). Setting US clinical practice. Participants 1361 new users of vericiguat. Interventions N/A. Main outcome measures Vericiguat starting dose, up-titration patterns and predictors, occurrence and predictors of hypotension/syncope, over a 3-month follow-up period. Results Among 1361 new users of vericiguat, 770 (57%) initiated a starting dose of 2.5 mg/day, 330 (24%) initiated a dose of 5 mg/day, and 261 (19%) initiated a dose of 10 mg/day. Over 3-month follow-up, the 10 mg target dose was reached by 349 (26%) patients. Among these patients, the median time to reach the 10 mg dose was 60 days among 2.5 mg/day starters, and 41 days among 5 mg/day starters. Among the 2.5 mg starters, 68% had no up-titration. Among patients initiating either the 2.5 mg/day or 5 mg/day dose, a starting dose of 5 mg (vs. 2.5 mg) was the only significant predictor for reaching the 10 mg dose; adjusted hazard ratio 2.89 (95% CI: 1.86, 4.49, p < 0.0001). Overall, 130 patients (9.6%) had a hypotension event and 67 patients (4.9%) had a syncope event. History of hypotension was the strongest independent predictor of hypotension/syncope events (adj. HR 2.85, 95% CI: 1.96, 4.13, p < 0.0001). A > 2.5 mg/day vericiguat starting dose was not associated with the occurrence of hypotension/syncope (vs. 2.5 mg/day); adj. HR 0.82, 95% C.I. (0.58, 1.16). Conclusion Vericiguat users initiated on the 5 mg/day dose were considerably more likely to reach the target dose of 10 mg/day vs. those started on the recommended 2.5 mg/day dose, without excess risk of hypotension or syncope.

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.

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:Patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) have a high comorbidity burden, which may necessitate numerous medications. Patients and clinicians may be hesitant about initiating another medication, especially among those already experiencing polypharmacy. This pre-specified analysis sought to examine the efficacy and safety of adding finerenone based on the concomitant medication number. METHODS:In the FINEARTS-HF trial, baseline medication use was collected in all 6001 participants with HFmrEF/HFpEF. Clinical outcomes and treatment effects were assessed by the categories of total medication count ('non-polypharmacy': ≤4 medications; 'polypharmacy': 5-9 medications; and 'hyper-polypharmacy': ≥10 medications) and as continuous variables. The primary outcome was a composite of cardiovascular death and total HF events. RESULTS:Overall (age: 72 ± 10 years; 46% women), the total number of medications at baseline ranged from 0 to 29 (mean: 8.4 ± 3.6), with 3588 (60%) meeting polypharmacy and 1878 (31%) meeting hyper-polypharmacy. Incidence rates for the primary outcome increased across medication categories: non-polypharmacy, 10.2; polypharmacy, 12.3; and hyper-polypharmacy, 26.1 per 100 person-years. The treatment benefits of finerenone in reducing the primary outcome were consistent across the spectrum of total medication count (Pinteraction = 0.94). Any serious adverse events and study drug discontinuation were not more frequent with finerenone vs placebo, regardless of polypharmacy categories. CONCLUSION:In FINEARTS-HF, >90% of patients with HFmrEF/HFpEF met the criteria for polypharmacy or hyper-polypharmacy, and these patients faced excess risks of cardiovascular events. Finerenone safely reduced cardiovascular death and total HF events across a broad range of baseline medication use.

Background Patients with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) have a high comorbidity burden, which may require management with numerous medications. Patients and clinicians may be hesitant about initiating another medication, especially among individuals with polypharmacy. Objective This study sought to examine the efficacy and safety of adding finerenone based on the number of concomitant medications in patients with HFmrEF/HFpEF. Methods In this post hoc analysis of the FINEARTS-HF trial, baseline medication use was collected in all 6,001 participants with HFmrEF/HFpEF who were randomized to finerenone or placebo. Clinical outcomes were assessed by medication use categories (“non-polypharmacy”: <5 medications; “polypharmacy”: 5 to 9 medications; and “hyper-polypharmacy”: ≥10 medications) and continuously, adjusted for covariates including age. The primary outcome was a composite of cardiovascular death and total (first and recurrent) HF events. Results Overall (age: 72±10 years; 46% women), the total number of medications at baseline ranged from 0 to 29 and the mean number of medications was 8.4±3.6, with 3,588 (60%) patients met polypharmacy and 1,878 (31%) met hyper-polypharmacy. Patients with higher medication use were older and had a greater burden of comorbidities. Incidence rates for the primary outcome increased across medication categories: non-polypharmacy (10.2 per 100py), polypharmacy (12.3 per 100py), and hyper-polypharmacy (26.1 per 100py) (Figure A). The treatment benefits of finerenone in reducing risks of cardiovascular death and total HF events were consistent across the spectrum of total medication use (P for interaction = 0.94; Figure B). Although adverse events leading to study drug discontinuation increased with the higher number of medications, they were not more frequent with finerenone vs. placebo, regardless of polypharmacy categories. Conclusions In the FINEARTS-HF trial, >90% of patients with HFmrEF/HFpEF met the criteria for polypharmacy and these patients faced excess risks of cardiovascular events. Finerenone safely reduced cardiovascular death and total HF events across a broad range of baseline medication use, including among individuals with polypharmacy.

BACKGROUND:Cardiac amyloidosis (CA) is an increasingly recognized cause of worsening heart failure (WHF) and is associated with poor outcomes, yet patients with CA-related WHF remain poorly characterized in real-world outpatient settings. METHODS:Patients with CA-related WHF, followed in a dedicated WHF Day Hospital clinic, were compared with matched (for age, sex, ejection fraction) non-CA WHF controls. Clinical outcomes included all-cause mortality and HF hospitalization. Frailty was assessed using the Frailty Index (FI) alongside functional and patient-reported measures. Associations with all-cause mortality were evaluated using Kaplan-Meier and Weibull models stratified by CA status. RESULTS:Among 154 WHF patients, 21 had CA and were matched to 42 non-CA controls. Median age was 81 (76-85) years, 23.8% were females. All-cause mortality was significantly higher in the CA-related WHF cohort, with an estimated occurrence of 72.0% vs. 25.9% (95%CI 50.7%-89.9% vs. 14.5%-43.7%) at 120 weeks (log-rank p = 0.001). As expected, in CA patients, the FI ≥ 0.38 and impaired health-related quality of life (EQ-5D) were associated with mortality (log-rank p = 0.002, p = 0.012, respectively). Among biomarkers, natriuretic peptides did not significantly discriminate risk among CA-related WHF, while discriminating in non-CA WHF. sST2 showed a similar prognostic relevance at the upper quartile in CA and non-CA WHF (log-rank p = 0.028, p = 0.009, respectively). CONCLUSIONS:In real-world WHF, despite comparable baseline biomarker profiles and frailty burden, CA identifies a subgroup with an adverse prognosis, worse than comparable patients with a different etiology. Frailty and biomarker profiles show etiology-specific prognostic behavior, supporting a phenotype-driven risk stratification strategy in WHF.

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.

INTRODUCTION:Heart failure with preserved or mildly reduced ejection fraction (HFmrEF/HFpEF) is a complex syndrome common in elderly patients with multiple comorbidities. Age and sex affect the clinical phenotypes and outcomes of this condition. This study aimed to identify age- and sex-specific factors influencing prognosis in elderly patients with HFmrEF/HFpEF to improve risk stratification and guide personalized treatment. METHODS:This observational, ambispective study was conducted at Papa Giovanni XXIII Hospital, Bergamo, from June 2017 to August 2022, enrolling patients >65 years with HFmrEF/HFpEF [New York Heart Association (NYHA) Class II-IV] according to ESC guidelines. Data collected included demographics, medical history, echocardiograms, and lab tests. Follow-up lasted at least 1 year, with outcomes defined as a composite of all-cause death, urgent heart transplant, HF hospitalization, and emergency department referral for decompensated HF. Findings were validated using the Swedish HF registry with a similar cohort. RESULTS:Among 2263 HF patients, 971 HFmrEF/HFpEF patients (56.8% males, mean age 79.2 years) were analysed. Males had a higher prevalence of cardiovascular risk factors (e.g. diabetes, obesity, coronary artery disease). The composite outcome occurred more frequently in males (20.6 vs 17.14 per 100 patient years; IRR = 1.20, P = .035). Multivariable analysis identified male sex (HR 1.40, 95% CI 1.13-1.73), age >80 years (HR 1.91, 95% CI 1.22-3.00), higher NYHA class, chronic kidney disease, and severe valvular heart disease as independent predictors of worse outcomes. Males had a 40% higher risk of the outcome compared with women (HR 1.40, 95% CI 1.13-1.73), while patients >80 years old had nearly double the risk compared with those aged 65-70 (HR 1.91, 95% CI 1.22-3.00). The validation analysis in the SwedeHF, adapting the same multiple Cox regression model on 20 950 selected patients, median age 79 years and 57.8% men, and observed between January 2017 and August 2022, showed similar independent risk factors for the composite outcome. CONCLUSION:This study highlights significant sex disparities in elderly HFmrEF/HFpEF patients, with higher age and male sex being an independent predictor for poor outcomes. These findings emphasize the need for personalized treatment strategies based on these demographic factors.

Importance:Sudden death remains a leading cause of mortality in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HF with preserved ejection fraction (HFpEF), but whether these events are preceded by clinical deterioration remains unclear. Objective:To characterize clinical trajectories preceding sudden death in patients with HFmrEF or HFpEF and compare them with trajectories before other modes of death and survival. Design, Setting, and Participants:This was a post hoc analysis of the Finerenone Trial to Investigate the Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF) randomized clinical trial evaluating trajectories of functional status, patient-reported health status, and natriuretic peptide levels preceding adjudicated modes of death. This was a global, event-driven clinical trial. Patients with symptomatic HF, left ventricular EF of 40% or greater, New York Heart Association class (NYHA) II to IV, and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) were enrolled between September 14, 2020, and January 10, 2023. Data analysis was conducted in December 2025. Interventions:Finerenone vs placebo. Main Outcomes and Measures:Longitudinal trajectories of NYHA class, Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS), and NT-proBNP levels preceding sudden death were compared with trajectories in survivors and those who died of HF-related, nonsudden cardiovascular, or noncardiovascular causes, using linear mixed-effects models with restricted cubic splines. Results:Included in this analysis were 6001 patients (mean [SD] age, 72.0 [9.6] years; 3269 male [54%]). Over a median (IQR) follow-up of 2.7 (1.9-3.0) years, 215 sudden deaths occurred. In the 6 months before death, sudden death was preceded by a slight worsening in physician-assigned NYHA class (from approximately 2.3 to 2.4), worsening self-reported health status (an approximately 8-point decline in KCCQ-TSS), and a gradual rise in NT-proBNP levels (from approximately 1800 to 2000 pg/mL). In contrast, among patients who survived, NYHA class improved (from approximately 2.3 to 2.1), KCCQ-TSS increased (from approximately 68 to 77), and NT-proBNP levels declined (from approximately 800 to 650 pg/mL) over the 18 months before the end of follow-up. Comparable patterns of deterioration to those preceding sudden death, often more pronounced, were observed before other modes of death. Conclusions and Relevance:Results of this post hoc analysis of the FINEARTS-HF randomized clinical trial reveal that in this contemporary HFmrEF or HFpEF cohort, sudden death was preceded by modest worsening of symptoms, declining quality of life, and rising natriuretic peptide levels, suggesting many of these events may not have been entirely sudden. However, similar deterioration preceding other modes of death suggests limited specificity for sudden death. Trial Registration:ClinicalTrials.gov Identifier: NCT04435626.

INTRODUCTION:In heart failure (HF) patients, guidelines recommend scores for assessing outcomes and heart transplant (HTX) eligibility. However, scores use remains limited and cut-off values for HTX listing not well established.Among the available tools, MECKI score is easy to calculate and likely offers the best prognostic accuracy. Compare MECKI score-based survival with that of HTX recipients and identify a MECKI threshold above which survival is inferior to that of HTX recipients at 5-year. METHODS:Consecutive ambulatory HF patients enrolled in MECKI score programme between January 2010 and January 2022 were evaluated. Primary endpoint was a composite of cardiovascular death, HTX, or left ventricular assist device implantation. Heart transplant survival data were obtained from the International Society of Heart and Lung Transplantation registry updated through 2023. To identify the MECKI score threshold beyond which prognosis is worse than that of HTX recipients, patients were stratified by deciles of MECKI score. RESULTS:We analysed 3865 HF patients (mean age 62.4 ± 12.6 years). Peak VO₂ was 58.2 ± 18.3% predicted; VE/VCO₂ slope 33.2 ± 8.2, haemoglobin 13.5 ± 1.7 g/dL, Na⁺ 139 ± 3 mmol/L, LVEF 33.7 ± 10.4%, and eGFR 73 ± 26 mL/min/1.73 m². Periodic breathing occurred in 15.8% of patients. At 5 years, mean survival was 83.7%.The average 5-year survival of HTX recipients (71.2%) lies between the eighth and ninth MECKI score deciles suggesting a MECKI score value ≥0.1368 as the proper cut-off for HTX listing. CONCLUSION:MECKI score ≥0.1368 may warrant HTX listing, while lower scores support clinical deferral.

In the field of heart failure, sodium-glucose cotransporter 2 inhibitors (SGLT2-i) have demonstrated robust efficacy and have received a Class I, Level A recommendation for reducing the risk of heart failure hospitalizations and cardiovascular mortality across the entire spectrum of left ventricular ejection fraction. The therapeutic effect occurs early, with the first statistical significance observed as soon as 12-28 days after treatment initiation. Evidence suggests that early introduction during hospitalization may reduce the short-term risk of cardiovascular death or worsening heart failure. SGLT2 inhibitors display a favourable safety and tolerability profile, without an increased incidence of adverse events compared with placebo. Furthermore, they are indicated for the treatment of type 2 diabetes mellitus and chronic kidney disease, irrespective of the presence of heart failure. Therefore, we propose that in patients presenting with signs and/or symptoms of heart failure and elevated natriuretic peptide levels, SGLT2 inhibitors may be initiated even before echocardiographic confirmation of the diagnosis. Given the favourable risk-benefit profile, this approach may help avoid therapeutic delay, which could otherwise be associated with an increased risk of early adverse events, and may ultimately improve prognosis.