Finerenone in Patients With a Recent Worsening Heart Failure Event: The FINEARTS-HF Trial.

BACKGROUND: Patients with heart failure (HF) and a recent worsening heart failure (WHF) event are known to be at high risk of recurrent hospitalization and death, regardless of ejection fraction. OBJECTIVES: This study examined the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone in relation to the recency of a WHF event. METHODS: FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure) was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction ≥40%. In this prespecified analysis, we assessed the risk of cardiovascular (CV) events and response to finerenone vs placebo in relation to the time from WHF to randomization (during or within 7 days, 7 days to 3 months, >3 months, or no prior WHF). The primary outcome was a composite of total (first and recurrent) WHF events and CV death, analyzed using a proportional rates method. RESULTS: Of 6,001 patients validly randomized to finerenone or placebo, 1,219 (20.3%) were enrolled during (749 [12.5%]) or within 7 days (470 [7.8%]), 2,028 (33.8%) between 7 days and 3 months, and 937 (15.6%) >3 months from a WHF event; 1,817 (30.3%) had no prior history of WHF. Rates of the primary composite outcome varied inversely with time since WHF, with >2-fold higher risk in those enrolled during or within 7 days of WHF compared with those enrolled >3 months from WHF or without prior WHF (risk ratio [RR]: 2.13; 95% CI: 1.82-2.55). Compared to placebo, finerenone appeared to lower the risk of the primary composite to a greater extent in those enrolled within 7 days of WHF (RR: 0.74; 95% CI: 0.57-0.95) or between 7 days and 3 months of WHF (RR: 0.79; 95% CI: 0.64-0.97) than in those >3 months from WHF or without prior WHF (RR: 0.99; 95% CI: 0.81-1.21); however, no definitive treatment-by-time interaction could be confirmed (P = 0.07). Greater absolute risk reductions with finerenone were accordingly seen in those with recent WHF (Ptrend = 0.011). The risk of adverse events including hyperkalemia and worsening renal function among patients assigned to finerenone was not increased in those with recent WHF. CONCLUSIONS: Compared with those without recent WHF, patients with HF and mildly reduced or preserved ejection fraction who have experienced a recent WHF event are at higher risk for recurrent HF events and CV death; a possible signal of enhanced absolute treatment benefit with finerenone in this population requires further confirmation in future studies. (Study to Evaluate the Efficacy [Effect on Disease] and Safety of Finerenone on Morbidity [Events Indicating Disease Worsening] & Mortality [Death Rate] in Participants With Heart Failure and Left Ventricular Ejection Fraction [Proportion of Blood Expelled Per Heart Stroke] Greater or Equal to 40% [FINEARTS-HF], NCT04435626; A study to gather information on the influence of study drug finerenone on the number of deaths and hospitalizations in participants with heart failure EudraCT 2020-000306-29).

Visit-to-visit changes in heart rate in heart failure: A pooled participant-level analysis of the PARADIGM-HF and PARAGON-HF trials.

AIMS: Resting heart rate (HR) is a strong risk marker in patients with heart failure (HF), but the clinical implications of visit-to-visit changes in HR (ΔHR) are less well established. We aimed to explore the association between ΔHR and subsequent outcomes in a pooled dataset of two well-characterized cohorts of patients with HF across the full range of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: PARADIGM-HF and PARAGON-HF were randomized trials testing sacubitril/valsartan versus enalapril or valsartan, respectively, in patients with HF and LVEF ≤40% (PARADIGM-HF) or LVEF ≥45% (PARAGON-HF). We analysed the association between ΔHR from the preceding visit with the primary endpoint of HF hospitalization (HFH) or cardiovascular death using covariate-adjusted Cox proportional hazards models. A total of 13 194 patients (mean age 67 ± 11 years, 67% men, mean LVEF 40 ± 15%) were included. Over a median follow-up of 2.5 years, 3114 patients experienced a first HFH or cardiovascular death event (10.4 events per 100 patient-years). An increase in HR from the preceding visit, compared with no change, was associated with a higher risk (hazard ratio 1.12; 95% confidence interval [CI] 1.10-1.15; p < 0.001 per 5 bpm increase). Conversely, a drop in HR was associated with a lower risk (hazard ratio 0.97; 95% CI 0.94-1.00; p = 0.044 per 5 bpm drop). The prognostic implications of ΔHR were consistent across the range of LVEF and observed regardless of ß-blocker use or presence of a permanent pacemaker. Visit-to-visit increases in HR were especially prognostic in patients without atrial fibrillation (pinteraction = 0.006). CONCLUSION: Across a broad spectrum of patients with chronic HF, increases in HR from a preceding visit independently predicted clinical outcomes. The detection of notable increases in HR between outpatient visits may help identify patients at heightened risk of adverse events. Clinical Trial Registration; ClinicalTrials.gov NCT01035255 (PARADIGM-HF), NCT01920711 (PARAGON-HF).

Natriuretic Peptides, Kidney Function, and Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: N-terminal pro-B-type natriuretic peptides (NT-proBNPs) are guideline-recommended biomarkers for risk stratification in patients with heart failure. However, NT-proBNP levels are often elevated in chronic kidney disease, introducing uncertainty about their prognostic relevance in persons across a broad range of estimated glomerular filtration rate (eGFR). OBJECTIVES: The aim of this study was to assess the association of NT-proBNP with cardiovascular and mortality outcomes in patients with heart failure and mildly reduced or preserved ejection fraction, stratified by baseline kidney function. METHODS: A pooled analysis was conducted of participants with NT-proBNP and eGFR measured at baseline in the I-PRESERVE (Irbesartan in Heart Failure and Preserved Ejection Fraction), TOPCAT (Americas region) (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function), PARAGON (Prospective Comparison of ARNI with ARB 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. The relationship between NT-proBNP and eGFR was assessed using piecewise linear regression. Using multivariable Cox and Poisson regression models, the association of NT-proBNP with outcomes across a range of eGFR was evaluated. The primary outcome was hospitalization for heart failure or cardiovascular death. RESULTS: Among 14,831 participants (mean age: 72.1 years; 50.3% female; mean eGFR: 63.3 mL/min/1.73 m2, and median NT-proBNP: 840 pg/mL) followed up for a median 33.5 months, there were 3,092 primary outcomes. NT-proBNP levels increased by 9%, 8%, and 23% per 10 mL/min/1.73 m2 lower eGFR in patients with baseline eGFR ≥60, 45-<60, and <45 mL/min/1.73 m2, respectively (P for nonlinearity < 0.001). Each doubling in NT-proBNP was associated with a 37% relative increase in the primary outcome (HR: 1.37; 95% CI: 1.34-1.41), consistent across different eGFR categories (P for interaction = 0.42). For the same incidence of the primary outcome, NT-proBNP levels were approximately 2.5- to 3.5-fold lower in patients with eGFR <45 mL/min/1.73 m2, compared with patients with eGFR ≥60 mL/min/1.73 m2. Similar patterns were observed across all outcomes studied, including cardiovascular and noncardiovascular death. CONCLUSIONS: The same NT-proBNP concentration predicts a substantially higher absolute risk of adverse outcomes for people with heart failure and reduced kidney function, compared with those with preserved kidney function. These data call into question proposals for higher NT-proBNP references ranges in people with CKD, and suggest that reduced kidney function per se should not be a reason to disregard higher NT-proBNP levels.

Electronic Nudges to Increase Influenza Vaccination in Patients With Chronic Diseases: A Randomized Clinical Trial.

Importance: Despite strong worldwide guideline recommendations, influenza vaccination rates remain suboptimal among young and middle-aged patients with chronic diseases. Effective scalable strategies to increase vaccination are needed. Objective: To investigate whether electronically delivered letter-based nudges informed by behavioral science could increase influenza vaccination uptake among patients aged 18 to 64 years with chronic diseases. Design, Setting, and Participants: Nationwide pragmatic registry-based randomized clinical implementation trial conducted between September 24, 2023, and May 31, 2024, enrolling all Danish citizens aged 18 to 64 years who met criteria for free-of-charge influenza vaccination in light of preexisting chronic disease. All trial data were sourced from nationwide administrative health registries. Intervention: Randomized in 2.45:1:1:1:1:1:1 ratio to no letter (usual care) or 6 different behaviorally informed electronic letters. Main Outcomes and Measures: The primary end point was receipt of influenza vaccination on or before January 1, 2024, assessed in 7 prespecified coprimary comparisons (all intervention groups pooled vs usual care and each individual intervention group vs usual care). Absolute risk difference in proportions and a crude relative risk were calculated for each comparison. Results: A total of 299 881 participants (53.2% [159 454] female, median age, 52.0 [IQR, 39.8-59.0] years) were randomized. Compared with usual care, influenza vaccination rates were higher among those receiving any intervention letter (any intervention letter, 39.6% vs usual care, 27.9%; difference, 11.7 percentage points; 99.29% CI, 11.2-12.2 percentage points; P < .001). Each individual letter type significantly increased influenza vaccination with the largest effect sizes observed with a repeated letter sent 10 days after the initial letter (repeated letter, 41.8% vs usual care, 27.9%; difference, 13.9 percentage points; 99.29% CI, 13.1-14.7 percentage points; P < .001) and a letter emphasizing potential cardiovascular benefits of vaccination (cardiovascular gain, 39.8% vs usual care, 27.9%; difference, 11.9 percentage points; 99.29% CI, 11.1-12.7 percentage points; P < .001). Vaccination rates were improved across major subgroups. Conclusions and Relevance: In a nationwide randomized clinical implementation trial, electronically delivered letter-based nudges markedly increased influenza vaccination compared with usual care among young and middle-aged patients with chronic diseases. The results of this study suggest that simple, scalable, and cost-efficient electronic letter strategies may have substantial public health implications. Trial Registration: ClinicalTrials.gov Identifier: NCT06030739.

Race in Heart Failure: A Pooled Participant-Level Analysis of the Global PARADIGM-HF and PARAGON-HF Trials.

BACKGROUND: Mechanisms of disease pathobiology, prognosis, and potentially treatment responses might vary by race in patients with heart failure (HF). OBJECTIVES: The authors aimed to examine the safety and efficacy of sacubitril/valsartan among patients with HF by self-reported race. METHODS: PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) were global, randomized clinical trials testing sacubitril/valsartan against a renin-angiotensin system inhibitor ([RASi], enalapril or valsartan, respectively) in patients with HF and left ventricular ejection fraction ≤40% (PARADIGM-HF) or left ventricular ejection fraction ≥45% (PARAGON-HF). Patients with self-reported race were categorized as White, Asian, or Black. We assessed the composite of first HF hospitalization or cardiovascular death, its components, and angioedema across races. RESULTS: Among 12,097 participants, 9,451 (78.1%) were White, 2,116 (17.5%) were Asian, and 530 (4.4%) were Black. Over a median follow-up of 2.5 years, Black (adjusted HR: 1.68; 95% CI: 1.42-1.98) and Asian patients (adjusted HR: 1.32; 95% CI: 1.18-1.47) experienced higher risks of the primary outcome compared with White patients. Treatment effects of sacubitril/valsartan vs RASi on the primary endpoint were consistent among White (HR: 0.84; 95% CI: 0.77-0.91), Asian (HR: 0.92; 95% CI: 0.78-1.10), and Black patients (HR: 0.79; 95% CI: 0.58-1.07; Pinteraction = 0.58). Rates of severe angioedema were higher with sacubitril/valsartan vs RASi (White: 0.2% vs 0.1%; Black: 1.5% vs 0.0%; Asian: 0.1% vs 0.1%). CONCLUSIONS: In a pooled experience of 2 global trials, Black and Asian patients exhibited a higher risk of cardiovascular events than White patients. The benefits of sacubitril/valsartan were consistent across races. Risks of severe angioedema were low but numerically higher with sacubitril/valsartan. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255; Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Estimated Long-Term Benefits of Finerenone in Heart Failure: A Prespecified Secondary Analysis of the FINEARTS-HF Randomized Clinical Trial.

Importance: People living with heart failure (HF) with mildly reduced or preserved ejection fraction have substantially curtailed life expectancy free from clinical events compared with their peers of comparable age. The nonsteroidal mineralocorticoid receptor antagonist, finerenone, was recently shown to reduce risks of cardiovascular events in this population over a median follow-up of 2.6 years; as patients with HF typically continue treatment beyond this time frame, estimating the potential long-term benefits of finerenone could inform shared clinical decision-making. Objective: To estimate the projected long-term treatment effects of finerenone in patients with HF with mildly reduced or preserved ejection fraction if treated over a patient's lifetime. Design, Setting, and Participants: Prespecified analyses were conducted of the FINEARTS-HF trial, a phase 3 randomized clinical trial conducted across 653 sites in 37 countries. Adults 40 years and older with symptomatic HF and left ventricular ejection fraction of 40% or greater were randomized from September 2020 to January 2023. Median (IQR) follow-up was 2.6 (1.9-3.0) years. Interventions: Finerenone (titrated to either 20 mg or 40 mg) or placebo. Main Outcomes and Measures: The primary composite outcome was time to cardiovascular death or worsening HF event. The long-term gains in survival free from a primary end point with finerenone were iteratively estimated with age-based Kaplan-Meier curves using age at randomization rather than time from randomization. Differences in areas under the survival curves between the finerenone and placebo arms represented event-free survival gains. Results: Among 6001 participants (median [IQR] age, 73 [66-79] years; 3269 male [54.5%]), mean survival free from the primary end point for a 55-year-old participant was 13.6 years (95% CI, 11.9-15.2 years) with finerenone and 10.5 years (95% CI, 6.8-11.3 years) with placebo, representing a gain in event-free survival of 3.1 years (95% CI, 0.8-5.4 years; P = .007). Mean event-free survival for a 65-year-old participant was 11.0 years (95% CI, 10.1-11.9 years) with finerenone and 8.9 years (95% CI, 8.1-9.8 years) with placebo, representing a gain of 2.0 years (95% CI, 0.8-3.3 years; P = .001). Projected mean event-free survival was numerically greater with finerenone than with placebo for every starting age between 50 to 80 years. Lifetime gains in event-free survival were observed even among individuals already treated with a sodium-glucose cotransporter 2 inhibitor (65-year-old participant: 3.1 years; 95% CI, 0.1-6.0 years; P = .04). Conclusions and Relevance: In this prespecified secondary analysis of the FINEARTS-HF randomized clinical trial, long-term treatment with finerenone was estimated to extend event-free survival by up to 3 years among people with HF with mildly reduced or preserved ejection fraction. Trial Registration: ClinicalTrials.gov Identifier: NCT04435626.

Effects of the Non-Steroidal MRA Finerenone with and without Concomitant SGLT2 Inhibitor Use in Heart Failure.

BACKGROUND: Patients with heart failure (HF) with mildly reduced or preserved ejection fraction face heightened long-term risks of morbidity and mortality. The sodium glucose-co-transporter-2 inhibitors (SGLT2i) and the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone have both been shown to reduce the risk of cardiovascular events in this population, but the effects of their combined use are not known. METHODS: FINEARTS-HF was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction (LVEF) ≥40%. Baseline SGLT2i use was a prespecified subgroup. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. We first assessed for evidence of treatment heterogeneity based on baseline SGLT2i use. We further examined SGLT2i uptake during the trial and evaluated the treatment effects of finerenone accounting for baseline and during trial use of SGLT2i in time-varying analyses. RESULTS: Among 6,001 participants, 817 (13.6%) were treated with an SGLT2i at baseline. During 2.6-years median follow-up, treatment with finerenone similarly reduced the risk of the primary outcome in participants treated with an SGLT2i (rate ratio 0.83; 95% confidence interval 0.60 to 1.16) and without an SGLT2i at baseline (rate ratio 0.85; 95% confidence interval 0.74 to 0.98); Pinteraction=0.76. In follow-up, 980 participants initiated SGLT2i, which was less frequent in the finerenone arm compared with placebo (17.7% vs. 20.1%; hazard ratio 0.86; confidence interval 0.76 to 0.97). Time-updated analyses accounting for baseline and subsequent use of SGLT2i did not meaningfully alter the treatment effects of finerenone on the primary endpoint. CONCLUSIONS: The treatment benefits of the non-steroidal MRA finerenone were observed irrespective of concomitant use of an SGLT2i. These data suggest that the combined use of SGLT2i and a non-steroidal MRA may provide additive protection against cardiovascular events in patients with HF with mildly reduced or preserved ejection fraction.

Efficacy and Safety of Finerenone Across the Ejection Fraction Spectrum in Heart Failure with Mildly Reduced and Preserved Ejection Fraction: a Prespecified Analysis of The FINEARTS-HF Trial.

BACKGROUND: The effect of treatments for heart failure may vary among patients according to left ventricular ejection fraction (LVEF). In the FINEARTS-HF, the nonsteroidal MRA finerenone reduced the risk of cardiovascular death and total worsening heart failure events in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). We examined the effect of finerenone according to LVEF in FINEARTS-HF. METHODS: FINEARTS-HF was a randomized, placebo-controlled trial examining the efficacy and safety of finerenone in patients with heart failure and LVEF �%. The treatment effect of finerenone was examined in prespecified analyses according to LVEF categories (<50%, ≥50 to <60%, and ≥60%) and with LVEF as a continuous variable. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. RESULTS: Baseline LVEF data were available for 5993 of the 6001 participants in FINEARTS-HF. Mean and median LVEF were 53 ± 8% and 53% (IQR 46% -58%), respectively. LVEF was <50% in 2172 (36), between 50 to <60% in 2674 (45%), and ≥60% in 1147 (19%). Patients with a higher LVEF were older, more commonly female, were less likely to have a history of coronary artery disease, and more frequently had a history of hypertension and chronic kidney disease compared to those with a lower LVEF. Finerenone reduced the risk of cardiovascular death and total heart failure events consistently across LVEF categories: LVEF <50% rate ratio (RR) = 0.84 (95% CI 0.68, 1.03), LVEF ≥50 to <60% RR = 0.80 (0.66, 0.97) and LVEF ≥60% RR = 0.94 (0.70, 1.25); p interaction = 0.70. There was no modification of the benefit of finerenone across the range of LVEF when analyzed as a continuous variable (p interaction = 0.28). There was a similar consistent effect of finerenone on reducing the total number of worsening heart failure events (continuous p interaction = 0.26). CONCLUSIONS: In patients with HFmrEF/HFpEF, finerenone reduced the risk of cardiovascular death and worsening heart failure events, irrespective of LVEF.

Aficamten and Cardiopulmonary Exercise Test Performance: A Substudy of the SEQUOIA-HCM Randomized Clinical Trial.

Importance: Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures. Objective: To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates. Design, Setting, and Participants: This was a prespecified analysis from SEQUOIA-HCM, a double-blind, placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO2] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024. Interventions: Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks. Main Outcomes and Measures: The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-component z score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed. Results: Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory-validated exercise testing at baseline and week 24. Integrated composite exercise performance improved in the aficamten group (mean [SD] z score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z score, -0.19 [0.45]), yielding a placebo-corrected improvement of 0.35 (95% CI, 0.25-0.46; P <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold (all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO2 were more common than large reductions (32% and 2%, respectively) compared with placebo (16% and 11%, respectively). Improvements in both components of the primary outcome, pVO2 and VE/VCO2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05). Conclusions and Relevance: This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten. Trial Registration: ClinicalTrials.gov Identifier: NCT05186818.

Finerenone Improves Outcomes in Patients with Heart Failure with Mildly Reduced or Preserved Ejection Fraction Irrespective of Age: A Prespecified Analysis of FINEARTS-HF.

Background: Finerenone improves outcomes in patients with HF and mildly reduced or preserved ejection fraction (HFmrHF/HFpEF). It is important to understand the efficacy and safety of finerenone in these patients according to age. Methods: The aim of this analysis was to evaluate the interaction between age and the efficacy and safety of finerenone in the FINEARTS-HF trial (Finerenone trial to investigate efficacy and safety compared to placebo in patients with heart failure). A total of 6,001 patients aged 40-97 years were stratified by quartile (Q 1-4) of baseline age: Q1 40-66 years (n=1,581), Q2 67-73 years (n=1,587), Q 3 74-79 years (n=1,421), and Q4 ≧ 80 years (n=1,412). FINEARTS-HF evaluated the impact of age on the efficacy of finerenone with respect to the primary composite outcome of cardiovascular death and total (first and recurrent) HF events, including HF hospitalization or urgent HF event, along with secondary efficacy and safety outcomes. Results: The incidence of primary outcome increased with age. Finerenone reduced the risk of the primary outcome consistently across all age categories: RR (95% CI) Q1 0.70 (0.53- 0.92), Q2 0.83 (0.64-1.07), Q3 0.98 (0.76-1.26), and Q4 0.85 (0.67-1.07); p for interaction =0.27. Similarly, a consistent effect was observed for the components of the primary outcome. The mean increase in Kansas City Cardiomyopathy Questionnaire-total symptom score from baseline to 12 months was greater with finerenone than placebo, with a consistent effect across all age categories: mean placebo-corrected change (95% CI) Q1 2.87 (1.09-4.66), Q2 1.24 (-0.59-3.07), Q3 0.94 (-0.98-2.86), and Q4 1.24 (-0.90-3.38); P-interaction=0.50. Adverse events were similar across all age categories. The odds of experiencing hypotension, elevated creatinine, or hyperkalemia (increased) or hypokalemia (decreased) related to finerenone did not differ by age. Conclusions: In the FINEARTS-HF trial, finerenone reduced the primary outcome and components of the primary outcome, and improved symptoms across a wide age spectrum. In addition, finerenone was safe and well-tolerated, irrespective of age. Trial Registration: URL: https://clinicaltrials.gov Unique Identifiers: NCT04435626 and EudraCT 2020-000306-29.

In-hospital course of patients with heart failure with improved ejection fraction in the DELIVER trial.

AIMS: Patients with heart failure (HF) with improved ejection fraction (HFimpEF) may face residual risks of clinical events that are comparable to those experienced by patients with HF whose left ventricular ejection fraction (LVEF) has consistently been above 40%. However, little is known about the clinical course of patients with HFimpEF during hospitalization for HF. METHODS AND RESULTS: DELIVER randomized patients with HF and LVEF >40% to dapagliflozin or placebo, including HFimpEF (LVEF previously ≤40%). We evaluated all HF hospitalizations adjudicated by the clinical endpoints committee with available data for determination of in-hospital course. Complicated hospitalization was defined as any hospitalization requiring intensive care unit stay, intravenous vasopressors/inotropes/vasodilators, invasive or non-invasive ventilation, mechanical fluid removal, ultrafiltration, or mechanical circulatory support. LVEF changes were extracted using a validated GPT-3.5, a large language model, via a secure private endpoint. Of the 6263 patients enrolled in DELIVER, 1151 (18%) had HFimpEF. During a median follow-up of 2.3 years, there were 224 total HF hospitalizations in 144 patients with HFimpEF and 985 in 603 patients with LVEF consistently >40%. Patients with HFimpEF experienced higher rates of complicated HF hospitalization as compared with patients with LVEF consistently >40% (39% vs. 27%; p < 0.001). Among those who experienced a first HF hospitalization, there was no significant difference in length of stay or in-hospital mortality between patients with HFimpEF versus LVEF consistently >40%. In a subset of participants who had at least one LVEF measurement available during HF hospitalization, 66% of those with HFimpEF and 29% of patients with LVEF consistently >40% experienced a reduction in their LVEF to ≤40% from the time of enrolment (p < 0.001). In the entire DELIVER cohort, dapagliflozin reduced total uncomplicated and complicated HF hospitalizations, irrespective of HFimpEF status (pinteraction ≥0.30). CONCLUSIONS: Among patients hospitalized for HF in DELIVER, those with HFimpEF experienced a more adverse in-hospital clinical course, necessitating higher resource utilization beyond standard diuretic therapy compared with patients with HF and LVEF consistently >40%, but had similar in-hospital mortality. Treatment benefits of dapagliflozin were not modified by hospitalization type.

Cardiac biomarkers and effects of aficamten in obstructive hypertrophic cardiomyopathy: the SEQUOIA-HCM trial.

BACKGROUND AND AIMS: The role of biomarker testing in the management of obstructive hypertrophic cardiomyopathy (oHCM) is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI), and to evaluate effect of treatment with aficamten on biomarker concentrations. METHODS: Cardiac biomarkers were measured at baseline and serially throughout the study. Regression analyses determined predictors of baseline NT-proBNP and hs-cTnI concentrations, and to evaluate whether early changes in these biomarkers relate to later changes in left ventricular outflow tract gradient (LVOT-G), other echocardiographic measures, health status, and functional capacity. RESULTS: Baseline concentration of NT-proBNP was associated with LVOT-G and measures of diastolic function, while hs-cTnI was associated with left ventricular thickness. Within 8 weeks of treatment with aficamten, NT-proBNP was reduced by 79% (95% CI 83%-76%, P < .001) and hs-cTnI by 41% (95% CI 49%-32%, P < .001); both biomarkers reverted to baseline after washout. Reductions in NT-proBNP and hs-cTnI by 24 weeks were strongly associated with a lowering of LVOT-G, improvement in health status, and increased peak oxygen uptake. NT-proBNP reduction strongly correlated with the majority of improvements in exercise capacity. Furthermore, the change in NT-proBNP by Week 2 was associated with the 24-week change in key endpoints. CONCLUSIONS: NT-proBNP and hs-cTnI concentrations are associated with key variables in oHCM. Serial measurement of NT-proBNP and hs-cTnI appears to reflect clinical response to aficamten therapy.

Therapeutic Effects of Heart Failure Medical Therapies on Standardized Kidney Outcomes: Comprehensive Individual Participant-Level Analysis of 6 Randomized Clinical Trials.

Background: Kidney outcomes have been variably defined using non-standardized composite endpoints in key heart failure (HF) trials, thus introducing complexity in their interpretation and cross-trial comparability. We examined the effects of steroidal mineralocorticoid receptor antagonists (MRAs), the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, and sodium-glucose cotransporter-2 (SGLT2) inhibitors on composite kidney endpoints using uniform definitions in 6 contemporary HF trials. Methods: Individual participant-level data from trials of steroidal MRAs (EMPHASIS-HF, TOPCAT Americas), ARNI (PARADIGM-HF, PARAGON-HF), and SGLT2 inhibitors (DAPA-HF, DELIVER) were included. The standardized composite kidney endpoint was defined as a sustained decline (a reduction in estimated glomerular filtration rate (eGFR) confirmed by a subsequent measurement at least 30 days later) in eGFR by 40%, 50%, or 57%, end-stage kidney disease, or renal death. eGFR was recalculated in a standardized manner using the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Results: Among 28,690 participants across the 6 trials (median age 69 years [IQR, 62-76]; 9,656 [33.7% ] women), the proportion experiencing the composite kidney endpoint with a more stringent definition of a sustained decline in kidney function (eGFR threshold of 57%) ranged from 0.3% to 3.3%. The proportion of patients experiencing this endpoint with a less stringent definition (eGFR threshold of 40%) ranged from 1.0% and 10.0%. The steroidal MRAs doubled the risk of the composite kidney endpoint when applying the least stringent definition compared with placebo, but these effects were less apparent and no longer significant with application of more stringent definitions. ARNI appeared to consistently reduce the occurrence of the composite kidney endpoints irrespective of specific eGFR threshold applied. The potential benefits of SGLT2-inhibitors on the composite kidney endpoints appeared more apparent when defined by more stringent eGFR thresholds, although none of these effects individually were statistically significant. Conclusions: When applying standardized stringent kidney endpoint definitions, steroidal MRAs, ARNI, and SGLT2-inhibitors have either neutral or beneficial effects on kidney outcomes in HF. Applying less stringent definitions increased event rates but included acute declines in eGFR that might not ultimately reflect long-term effects on kidney disease progression.

Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Aficamten, a next-in-class cardiac myosin inhibitor, improved peak oxygen uptake (pVO2) and lowered resting and Valsalva left ventricular outflow (LVOT) gradients in adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM), a phase 3, multicenter, randomized, double-blinded, placebo-controlled study. OBJECTIVES: The authors sought to evaluate the effect of aficamten on echocardiographic measures of cardiac structure and function in SEQUOIA-HCM. METHODS: Serial echocardiograms were performed over 28 weeks in patients randomized to receive placebo or aficamten in up to 4 individually titrated escalating doses (5-20 mg daily) over 24 weeks based on Valsalva LVOT gradients and left ventricular ejection fraction (LVEF). RESULTS: Among 282 patients (mean age 59 ± 13 years; 41% female, 79% White, 19% Asian), mean LVEF was 75% ± 6% with resting and Valsalva LVOT gradients of 55 ± 30 mm Hg and 83 ± 32 mm Hg, respectively. Over 24 weeks, aficamten significantly lowered resting and Valsalva LVOT gradients, and improved left atrial volume index, lateral and septal e' velocities, and lateral and septal E/e' (all P ≤ 0.001). LV end-systolic volume increased and wall thickness decreased (all P ≤ 0.003). Aficamten resulted in a mild reversible decrease in LVEF (-4.8% [95% CI: -6.4 to -3.3]; P < 0.001) and absolute LV global circumferential strain (-3.7% [95% CI: 1.8-5.6]; P < 0.0010), whereas LV global longitudinal strain was unchanged. Several measures, including LVEF, LVOT gradients, and E/e' returned to baseline following washout. Among those treated with aficamten, improved pVO2 and reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) were associated with improvement in lateral e' velocity and septal and lateral E/e' (all P < 0.03), whereas improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (KCCQ-CSS) was associated with a decrease in both LVOT gradients (all P < 0.001). CONCLUSIONS: Compared with placebo, patients receiving aficamten demonstrated significant improvement in LVOT gradients and measures of LV diastolic function, and several of these measures were associated with improvements in pVO2, KCCQ-CSS, and NT-proBNP. A modest decrease in LVEF occurred yet remained within normal range. These findings suggest aficamten improved multiple structural and physiological parameters in oHCM without significant adverse changes in LV systolic function. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).

Effect of Aficamten on Cardiac Structure and Function in Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM CMR Substudy.

BACKGROUND: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) hypertrophy, LV outflow tract obstruction, and left atrial dilation, which can be associated with progressive heart failure, atrial fibrillation, and stroke. Aficamten is a next-in-class cardiac myosin inhibitor that reduces outflow tract obstruction by modulating cardiac contractility, with the potential to reverse pathological remodeling and, in turn, reduce cardiovascular events. OBJECTIVES: This study sought to investigate the effect of aficamten on cardiac remodeling compared with placebo using cardiovascular magnetic resonance (CMR) and its association with key clinical endpoints in the SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) CMR substudy. METHODS: SEQUOIA-HCM was a phase 3 double-blind, placebo-controlled trial for adults with symptomatic oHCM who were randomized 1:1 to 24 weeks of aficamten (dose range: 5-20 mg) or placebo. Eligible participants were offered enrollment in the CMR substudy with studies performed at baseline and week 24. Image analysis was performed in a blinded fashion by a core laboratory. RESULTS: Of the 282 randomized patients, 57 (20%) participated in the substudy, and of those, 50 (88%) completed both baseline and week 24 CMR. Baseline characteristics of the CMR cohort were similar to the overall study population. Of these 50 patients, 21 received aficamten and 29 received placebo. Relative to placebo, patients receiving aficamten demonstrated significant reductions (Δ least-squares mean) in LV mass index (-15 g/m2; 95% CI: -25 to -6 g/m2; P = 0.001), maximal LV wall thickness (-2.1 mm; 95% CI: -3.1 to -1.1 mm; P < 0.001), left atrial volume index (-13 mL/m2; 95% CI: -19 to -7 mL/m2; P < 0.001), native T1 relaxation time (-37 ms; 95% CI: -69 to -5 ms; P = 0.026), indexed extracellular volume fraction (-3.9 g/m2; 95% CI: -7.0 to -0.9 g/m2; P = 0.014), and indexed myocyte mass (-14 g/m2; 95% CI: -23 to -4 g/m2; P = 0.004), while there were no significant changes in LV chamber volumes, LV replacement fibrosis (late gadolinium enhancement mass -0.7 g; 95% CI: -2.9 to 1.6 g; P = 0.54), or extracellular volume (0.7%; 95% CI: -2.2% to 3.6%; P = 0.61). CONCLUSIONS: The CMR substudy of SEQUOIA-HCM demonstrated that treatment with aficamten relative to placebo for 24 weeks resulted in favorable cardiac remodeling. These changes, particularly with regard to LV mass, wall thickness, and left atrial size, could potentially lead to reduced cardiovascular events including heart failure and atrial fibrillation with longer follow-up. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).

Effect of Aficamten on Health Status Outcomes in Obstructive Hypertrophic Cardiomyopathy: Results from SEQUOIA-HCM.

BACKGROUND: A primary goal in treating obstructive hypertrophic cardiomyopathy (oHCM) is to improve patients' health status: their symptoms, function, and quality of life. The health status benefits of aficamten, a novel cardiac myosin inhibitor, have not been comprehensively described. OBJECTIVES: This study sought to determine the effect of aficamten on patient-reported health status, including symptoms of fatigue, shortness of breath, chest pain, physical and social limitations, and quality of life. METHODS: SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) randomized symptomatic adults with oHCM to 24 weeks of aficamten (n = 142) or placebo (n = 140), followed by a 4-week washout. The Kansas City Cardiomyopathy Questionnaire (KCCQ) and Seattle Angina Questionnaire 7-item (SAQ7) were serially administered. Changes in mean KCCQ-Overall Summary Score (KCCQ-OSS) and SAQ7-Summary Score (SAQ7-SS) from baseline to 24 weeks and following treatment withdrawal were compared using linear regression adjusted for baseline scores and randomization strata. Proportions of patients with clinically important changes were compared. RESULTS: Among 282 participants, the mean age was 59 ± 13 years, 115 (41%) were female, and 223 (79%) were White. Baseline KCCQ-OSS (69.3 ± 20.1 vs 67.3 ± 18.8) and SAQ7-SS (72.0 ± 21.0 vs 72.4 ± 18.3) were similar between aficamten and placebo groups. Treatment with aficamten, compared with placebo, improved both the mean KCCQ-OSS (13.3 ± 16.3 vs 6.1 ± 12.6; mean difference: 7.9; 95% CI: 4.8-11.0; P < 0.001) and SAQ7-SS (11.6 ± 17.4 vs 3.8 ± 14.4; mean difference: 7.8; 95% CI: 4.7-11.0; P < 0.001) at 24 weeks, with benefits emerging within 4 weeks. No heterogeneity in treatment effect was found across subgroups. A much larger proportion of participants experienced a very large health status improvement (≥20 points) with aficamten vs placebo (KCCQ-OSS: 29.7% vs 12.4%, number needed to treat: 5.8; SAQ7-SS: 31.2% vs 13.9%, number needed to treat: 5.8). Participants' health status worsened significantly more after withdrawal from aficamten than placebo (KCCQ-OSS: -16.2 ± 19.0 vs -3.0 ± 9.6; P < 0.001; SAQ7-SS: -17.4 ± 21.4 vs -2.5 ± 13.3), further confirming a causal effect of aficamten. CONCLUSIONS: In patients with symptomatic oHCM, treatment with aficamten resulted in markedly improved health status, including significant improvement in chest pain-related health status, than placebo. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).

Sacubitril/valsartan reduces incident anaemia and iron therapy utilization in heart failure: The PARAGON-HF trial.

AIMS: Renin-angiotensin system inhibitors (RASi) have been shown to lower haemoglobin levels, potentially related to reductions in erythropoietin levels and haematopoiesis. We examined whether sacubitril/valsartan might attenuate this effect of RASi alone on incident anaemia in patients with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). METHODS AND RESULTS: PARAGON-HF was a global, multicentre randomized clinical trial of sacubitril/valsartan versus the RASi valsartan in patients with HF and left ventricular ejection fraction ≥45%. We evaluated haemoglobin trajectory and risks of incident anaemia and new iron therapy initiation during follow-up. Among 4795 participants, 1111 (23.2%) had anaemia at randomization and 5.6% were treated with iron at baseline. Over a median follow-up of 2.9 years, patients with anaemia were at significantly higher risk for total HF hospitalizations and cardiovascular death, compared with those without anaemia (21.6 vs. 11.5 per 100 patient-years; adjusted rate ratio 1.31; 95% confidence interval [CI] 1.12-1.54; p = 0.001). Sacubitril/valsartan slightly slowed the decline in haemoglobin levels by 0.1 g/dl (95% CI 0.0-0.2 g/dl; p = 0.005). Participants treated with sacubitril/valsartan were at significantly lower risk of developing anaemia (30.3% vs. 37.6%; hazard ratio [HR] 0.76; 95% CI 0.68-0.85; p < 0.001) and starting iron therapy (8.1% vs. 10.0%; HR 0.81; 95% CI 0.67-0.97; p = 0.026). Treatment effects of sacubitril/valsartan versus valsartan on total HF hospitalizations and cardiovascular death were consistent among patients across the haemoglobin spectrum (pinteraction = 0.60). CONCLUSIONS: Among patients with HFmrEF/HFpEF, treatment with sacubitril/valsartan resulted in modestly smaller declines in haemoglobin, lower rates of incident anaemia, and fewer new initiations of iron therapy compared with RASi. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01920711.