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Cardiac resynchronization therapy (CRT) improves survival, symptoms, quality of life, exercise capacity, and cardiac structure and function in patients with New York Heart Association (NYHA) functional class II or ambulatory class IV heart failure (HF) with wide QRS complex. The totality of evidence supports the use of CRT in patients with less severe HF symptoms. CRT is recommended for patients in sinus rhythm with a widened QRS interval (>=150 ms) not due to right bundle branch block (RBBB) who have severe left ventricular (LV) systolic dysfunction and persistent NYHA functional class II-III symptoms despite optimal medical therapy (strength of evidence A). CRT may be considered for several other patient groups for whom evidence of benefit is clinically significant but less substantial, including patients with a QRS interval of >=120 to <150 ms and severe LV systolic dysfunction who have persistent mild to severe HF despite optimal medical therapy (strength of evidence B), some patients with atrial fibrillation, and some with ambulatory class IV HF. Several evidence gaps remain that need to be addressed, including the ideal threshold for QRS duration, QRS morphology, lead placement, degree of myocardial scarring, and the modality for evaluating dyssynchrony. Recommendations will evolve over time as additional data emerge from completed and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Objective To examine whether warfarin use and outcomes differ across CHADS(2) and CHA(2)DS(2)-VASc risk strata for non-valvular atrial fibrillation (NVAF). Design Population-based cohort study using linked administrative databases in Alberta, Canada. Setting Inpatient and outpatient. Patients 42834 consecutive patients >=20 years of age with newly diagnosed NVAF. Main outcome measures Cerebrovascular events and/or mortality in the first year after diagnosis. Results Of 42834 NVAF patients, 22.7% were low risk on the CHADS(2) risk score (0), 27.5% were intermediate risk (1), and 49.8% were high risk (>=2). The CHA(2)DS(2)-VASc risk score reclassified 16722 patients such that 7.8% were defined low risk, 13.8% intermediate risk and 78.4% high risk. Of the elderly cohort (>=65 years) with definite NVAF visits (at least two encounters 30 days apart, n=8780), 49% were taking warfarin within 90 days of diagnosis. Warfarin use did not differ across risk strata using either the CHADS(2) (p for trend=0.85) or CHA(2)DS(2)-VASC (p=0.35). In multivariable adjusted analyses, warfarin use was associated with substantially lower rates of death or cerebrovascular events for patients with CHADS(2) scores of 1 (OR 0.52, 95% CI 0.41 to 0.67) or >=2 (OR 0.61, 95% CI 0.53 to 0.71), or CHA(2)DS(2)-VASc scores of >=2 (OR 0.60, 95% CI 0.53 to 0.68). Conclusions In elderly patients with NVAF and elevated CHADS(2) or CHA(2)DS(2)-VASC scores, warfarin users exhibited lower rates of cerebrovascular events and mortality. However, warfarin use did not differ across risk strata, another example of the risk-treatment paradox in cardiovascular disease. [ABSTRACT FROM AUTHOR]

CONTEXT: Heart failure (HF) is a leading cause of death and disability, and despite optimal care, patients may eventually require palliative care. Little is known about how palliative care questionnaires (the Edmonton Symptom Assessment Scale [ESAS] and the Palliative Performance Scale [PPS]) perform compared with HF assessment using the New York Heart Association (NYHA) functional class and the Kansas City Cardiomyopathy Questionnaire (KCCQ). OBJECTIVES: To assess the utility of a palliative care questionnaire in patients with HF. METHODS: One hundred and five patients (mean age=65 years, 76% male, mean ejection fraction=28%) followed in an HF clinic were surveyed with the NYHA, PPS, ESAS, and KCCQ. RESULTS: The PPS and ESAS were each correlated to the NYHA class (P<0.0001 for both) and the KCCQ score (PPS: R(2)=0.57; ESAS: R(2)=-0.72; both P<0.0001). There were 33 patients who either died (10 deaths) or were hospitalized (26 patients) for more than one year. In addition to age and gender, a higher (worse) ESAS score trended toward significance (P=0.07) and a lower (worse) PPS was a significant (P=0.04) predictor of all-cause hospitalization or death. CONCLUSION: In a cohort of HF patients, we found a modest correlation with NYHA class and KCCQ assessment with the PPS and ESAS, two standard palliative care questionnaires. Given the difficulty in identifying patients with HF eligible for palliative or hospice care, these tools may be of use in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend that patients with heart failure receive beta-blockers in doses used in the trials that have proven their efficacy. Although the adverse effects of beta-blockade are dose-related, it is unclear whether the benefits are.Purpose: To determine whether the survival benefits of beta-blockade in heart failure are associated with the magnitude of heart rate reduction or the beta-blocker dose.Data Sources: MEDLINE, EMBASE, CINAHL, SIGLE, Web of Science, and the Cochrane Central Register of Controlled Trials, supplemented by hand-searches of bibliographies.Study Selection: Randomized, placebo-controlled heart failure trials that reported all-cause mortality.Data Extraction: Two reviewers independently extracted data on study characteristics, beta-blocker dosing and heart rate reduction, and death.Data Synthesis: The mean left ventricular ejection fraction in the 23 beta-blocker trials ranged from 0.17 to 0.36, and more than 95% of the 19 209 patients had systolic dysfunction. The overall risk ratio for death was 0.76 (95% CI, 0.68 to 0.84); however, heterogeneity testing revealed moderate heterogeneity among trials (I (2) = 30%), which was associated with the magnitude of heart rate reduction achieved within each trial (P for meta-regression = 0.006). For every heart rate reduction of 5 beats/min with beta-blocker treatment, a commensurate 18% reduction (CI, 6% to 29%) in the risk for death occurred. No significant relationship between all-cause mortality and beta-blocker dosing was observed (risk ratio for death, 0.74 [CI, 0.64 to 0.86]) in high-dose beta-blocker trials vs. 0.78 [CI, 0.63 to 0.96] in low-dose beta-blocker trials; P for meta-regression = 0.69).Limitations: The analysis is based on aggregate data and resting heart rates. Few patients in these trials had bradycardia or diastolic dysfunction at baseline.Conclusion: The magnitude of heart rate reduction is statistically significantly associated with the survival benefit of beta-blockers in heart failure, whereas the dose of beta-blocker is not. [ABSTRACT FROM AUTHOR]

Heart failure (HF) with preserved systolic function (ejection fraction [EF] >50%) is common, yet no proven therapies exist. Large registries could shed light on what medications may or may not be useful to reduce hospitalization and mortality. The EFFECT Registry, which prospectively enrolled 9,943 patients admitted to the hospital for HF from 1999 to 2001 in 103 hospitals in Ontario, Canada, was used. Patients discharged alive were divided into those with EF >50% and EF <50%. Discharge medications (angiotensin-converting enzyme [ACE] inhibitors, beta blockers [BBs], spironolactone, and digoxin) were examined for their association with HF rehospitalization or death during 1 year. In the HF group with EF >50% (n = 1,026), 199 patients died within 1 year and 349 patients died or were hospitalized for HF within 1 year. In the HF group with EF <50% (n = 1,898), 427 patients died and 720 patients died or were hospitalized for HF. In the HF group with EF >50%, 67% were administered an ACE inhibitor; 32%, a BB; 37%, digoxin; and 12%, spironolactone. No differences were seen in adjusted survival for any medications (ACE inhibitors, BBs, digoxin, or spironolactone) examined in the HF group with EF >50% despite an adjusted survival benefit with ACE inhibitors (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.77 to 0.94), BBs (HR 0.80, 95% CI 0.72 to 0.89), and spironolactone (HR 0.80, 95% CI 0.66 to 0.98) in patients with low EF. In conclusion, none of the medications proved to improve outcomes in patients with HF with low EF showed an association with outcomes in patients with HF and EF >50%, highlighting the need for randomized trial evidence to define therapies that will be beneficial in patients with HF and preserved systolic function. [ABSTRACT FROM AUTHOR]

Stroke is a leading cause of morbidity and mortality in North America. Primary prevention of stroke includes lifestyle modifications and measures to control blood pressure, cholesterol levels, diabetes mellitus, and atrial fibrillation. Lowering blood pressure in patients with hypertension prevents both hemorrhagic and ischemic stroke (relative risk reduction, 35 to 45 percent). Observational studies suggest that higher cholesterol levels are associated with an increased risk of ischemic stroke, and treatment with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) may reduce the risk of fatal and nonfatal stroke by 25 percent. Although high-quality evidence linking tighter glucose control with stroke reduction is lacking, good glucose control and aggressive treatment of hypertension and hyperlipidemia in patients with diabetes mellitus are recommended. The risk of stroke in patients with atrial fibrillation and the role of anticoagulation depend on factors such as age and the presence of comorbid conditions. Controversy exists about the roles of angiotensin-converting enzyme inhibitors and aspirin in the primary prevention of stroke. [ABSTRACT FROM AUTHOR]

Aims: In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy., Methods: The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death. As an event-driven trial, at least 1080 primary events are expected, but follow-up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo., Conclusion: VICTOR is the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF., (© 2024 Bayer AG, Merck Sharp & Dohme LLC and The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Patients visiting the emergency department (ED) or hospitalized for heart failure (HF) are at increased risk for subsequent adverse outcomes, however effective risk stratification remains challenging. We utilized a machine-learning (ML)-based approach to identify HF patients at risk of adverse outcomes after an ED visit or hospitalization using a large regional administrative healthcare data system., Methods and Results: Patients visiting the ED or hospitalized with HF between 2002-2016 in Alberta, Canada were included. Outcomes of interest were 30-day and 1-year HF-related ED visits, HF hospital readmission or all-cause mortality. We applied a feature extraction method using deep feature synthesis from multiple sources of health data and compared performance of a gradient boosting algorithm (CatBoost) with logistic regression modelling. The area under receiver operating characteristic curve (AUC-ROC) was used to assess model performance. We included 50,630 patients with 93,552 HF ED visits/hospitalizations. At 30-day follow-up in the holdout validation cohort, the AUC-ROC for the combined endpoint of HF ED visit, HF hospital readmission or death for the Catboost and logistic regression models was 74.16 (73.18-75.11) versus 62.25 (61.25-63.18), respectively. At 1-year follow-up corresponding values were 76.80 (76.1-77.47) versus 69.52 (68.77-70.26), respectively. AUC-ROC values for the endpoint of all-cause death alone at 30-days and 1-year follow-up were 83.21 (81.83-84.41) versus 69.53 (67.98-71.18), and 85.73 (85.14-86.29) versus 69.40 (68.57-70.26), for the CatBoost and logistic regression models, respectively., Conclusions: ML-based modelling with deep feature synthesis provided superior risk stratification for HF patients at 30-days and 1-year follow-up after an ED visit or hospitalization using data from a large administrative regional healthcare system., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Fine et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: The VICTORIA trial demonstrated a significant reduction in the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death with vericiguat relative to placebo in high-risk HF. This study aimed to contextualize treatment effects of vericiguat in populations with varying risk profiles simulated from the PARADIGM-HF and DAPA-HF trials., Methods: Subgroups of VICTORIA participants (n = 5050) were generated to simulate PARADIGM-HF and DAPA-HF trial populations. The PARADIGM-HF-eligible population excluded participants not meeting left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR), and minimal dose criteria and those with high predicted probability of run-in failure. The DAPA-HF-eligible population excluded those not meeting LVEF and eGFR criteria or with recent (<30 days) HF hospitalization. The time-to-first-event analysis was performed using an unadjusted Cox proportional hazards model., Results: A total of 1982 (39.2%) and 2543 (50.4%) VICTORIA participants were respectively deemed eligible for PARADIGM-HF and DAPA-HF. Vericiguat was associated with numerically larger reductions in the primary outcome of HF hospitalization or cardiovascular death in populations simulated from PARADIGM-HF [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.72-0.99] and DAPA-HF (HR 0.82, 95% CI 0.71-0.94) compared with the overall VICTORIA trial (HR 0.90). Significant reduction in HF hospitalization with vericiguat was also observed in the DAPA-HF-eligible population (HR 0.83, 95%CI 0.73-0.95) and with a nominal reduction in the PARADIGM-HF-eligible population (HR 0.86, 95% CI 0.74-1.01)., Conclusions: A trend towards enhanced efficacy of vericiguat in populations simulated from PARADIGM-HF and DAPA-HF was observed. These findings support further exploration of vericiguat in lower-risk HF populations as is being investigated in the ongoing VICTOR (a study of vericiguat in participants with chronic heart failure with reduced ejection fraction) trial., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Hyperkalemia (HK) is associated with suboptimal renin-angiotensin system (RAS) inhibitor and mineralocorticoid receptor antagonist (MRA) use in heart failure with reduced ejection fraction (HFrEF)., Objectives: This study sought to assess characteristics and RAS inhibitor/MRA use in patients receiving patiromer during the DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) run-in phase., Methods: Patients with HFrEF and HK or past HK entered a run-in phase of ≤12 weeks with patiromer-facilitated RAS inhibitor/MRA optimization to achieve ≥50% recommended RAS inhibitor dose, 50 mg/d MRA, and normokalemia. Patients achieving these criteria (randomized group) were compared with the run-in failure group (patients not meeting the randomization criteria)., Results: Of 1,038 patients completing the run-in, 878 (84.6%) were randomized and 160 (15.4%) were run-in failures. Overall, 422 (40.7%) had HK entering run-in with a similar frequency in the randomized and run-in failure groups (40.3% vs 42.5%; P = 0.605). From start to the end of run-in, in the randomized group, an increase was observed in target RAS inhibitor and MRA use in patients with HK (RAS inhibitor: 76.8% to 98.6%; MRA: 35.9% to 98.6%) and past HK (RAS inhibitor: 60.5% to 98.1%; MRA: 15.6% to 98.7%). Despite not meeting the randomization criteria, an increase after run-in was observed in the run-in failure group in target RAS inhibitor (52.5% to 70.6%) and MRA use (15.0% to 48.1%). This increase was observed in patients with HK (RAS inhibitor: 51.5% to 64.7%; MRA: 19.1% to 39.7%) and past HK (RAS inhibitor: 53.3% to 75.0%; MRA: 12.0% to 54.3%)., Conclusions: In patients with HFrEF and HK or past HK receiving suboptimal RAS inhibitor/MRA therapy, RAS inhibitor/MRA optimization increased during patiromer-facilitated run-in., Competing Interests: Funding Support and Author Disclosures Study funding was provided by Vifor (International) AG. Dr Pitt has received consulting fees, payment or honoraria, support for attending meetings and/or travel, and stock or stock option from Vifor. Dr Anker has recevied grants from Abbott Vascular and Vifor; has received ad hoc consultancy/advisory board participation from Amgen, AstraZeneca, Bioventrix, Brahms, Cordio, CVRx, Edwards, Novartis, Novo Nordisk, Reparion, Sanofi, and Vectorious; has performed trial/registry steering committee work or consulting for Bayer AG, Boehringer Ingelheim, Cardiac Dimensions, Cardior, Impulse Dynamics, Occlutech, Servier, V-Wave, and Vifor Int; and has received fees for advisory board work from Abbott Vascular. Dr Lund has received grants or contracts from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Novartis, and Vifor Pharma; has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Lexicon, MedScope, Merck, Pharmacosmos, Myokardia, Sanofi, Servier, and Vifor Pharma; has received payment or honoraria from Abbott, AstraZeneca, Medscope, Novartis, and Radcliffe; and has been a board member/fellow of ESC Heart Failure Association (HFA), ESC, and Swedish Society of Cardiology, HF Working Group; and has stock or stock options in AnaCardio. Dr Coats has received consulting fees from Actimed, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, Impulse Dynamics, and Respicardia; has received payment or honoraria from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards, Eli Lilly, Menarini, Novartis, Servier, Vifor, and Viatris; and has participated on a data safety monitoring board or advisory board from Impulse Dynamics. Dr Filippatos has been a committee member in trials for the European Commission; has received payment or honoraria from Bayer and Boehringer Ingelheim; has participated on a data safety monitoring board or advisory board from Bayer; has a leadership or fiduciary role from European Academy, Heart Failure Association, and JACC Heart Failure; and has received lecture fees, advisory or committee membership in trials from Amgen, Bayer, Boehringer Ingelheim, Cardior, Impulse Dynamics, Medtronic, Novartis, Servier, and Vifor. Dr Rossignol has been a DIAMOND Steering Committee member and has received honoraria from Vifor; has received personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, CinCor, Idorsia, KBP, Novo Nordisk, Sanofi, Servier, and Vifor; has received support for attending meetings and/or travel from AstraZeneca, Bayer, Boehringer Ingelheim, and Vifor; is cofounder of CardioRenal; has participated on a data safety monitoring board or advisory board from Bayer, Idorsia, and Sequana medical; and has stock in Cardiorenal and stock options in G3P. Dr Weir has served on the DIAMOND Steering Committee and has received personal fees from CSL Vifor, AstraZeneca, Novo Nordisk, Johnson & Johnson, and Care DX. Dr Kosiborod has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant/advisory board member for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research support from AstraZeneca; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; has received support for attending meetings and/or travel from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, and Vifor Pharma; and has stock options in Artera Health and Saghmos Therapeutics. Dr Metra has received honoraria for participation on a DIAMOND trial meeting. Dr Böhm has received research support from Deutsche Forschungsgemeinschaft (DFG, SFB-TTR 219, S-01); has received honoraria for speaking from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Novartis, Servier, and Vifor; and has particiapted in advisory boards for Amgen, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Pfizer, ReCor, Servier, and Vifor. Dr Ezekowitz has received research support for trial leadership or grants from American Regent, Applied Therapeutics, AstraZeneca, Bayer, Cytokinetics, Merck & Co, Novo Nordisk, and Otsuka; and has received honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka. Dr Bayes-Genis has lectured and/or participated in boards for Abbott, AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, Roche Diagnostics, and Vifor. Dr Mentz has received honoraria from Vifor; and has received research support and honoraria from AstraZeneca. Dr Ponikowski has received grants or contracts, consulting fees, and payment or honoraria from Abbott Vascular, Amgen, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Cibiem, BMS, Impulse Dynamics, Merck, Renal Guard Solution, Novartis, Servier, and Vifor. Dr Senni has been a consultant for Novartis, Merck, Bayer, Vifor Pharma, Abbott, Boehringer Ingelheim, AstraZeneca, Bioventrix, Servier, Novo Nordisk, Cardurion, and AnaCardio. Dr Brugts has received an independent research grant from Abbott to the Institute; and has received honoraria for advisory boards or speaker fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Vifor (5-year period). Drs Perrin, Waechter, and Budden have been paid employees and have stock/stock options in CSL Vifor. Dr Butler has received personal consulting fees from Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, 3live, and Vifor; and has received payment from AstraZeneca, Boehringer Ingelheim-Lilly, Janssen, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: For heart failure with reduced ejection fraction (HFrEF), suboptimal use of renin-angiotensin-aldosterone system inhibitors (RAASis), including mineralocorticoid receptor antagonists (MRAs), due to hyperkalemia, may be improved by potassium binders., Objectives: This prespecified analysis of the phase 3 DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) trial assessed the effect of patiromer in patients with HFrEF and either current or past hyperkalemia., Methods: Patients with HFrEF and current or past (within 1 year before enrollment) hyperkalemia (serum potassium [sK + ] >5.0 mmol/L) entered a single-blind, run-in phase to optimize RAASis while receiving patiromer. They were subsequently randomized, double-blind, to continue patiromer or change to placebo., Results: Of the 1,038 patients who completed run-in, 354 (83.9%) of 422 with current hyperkalemia and 524 (85.1%) of 616 with past hyperkalemia achieved RAASi optimization and were randomized to treatment. During the double-blind phase, patiromer lowered sK + levels compared with placebo in both the current and past hyperkalemia subgroups: difference in adjusted mean change from baseline: -0.12 (95% CI: -0.17 to -0.07) and -0.08 (95% CI: -0.12 to -0.05), respectively; P interaction  = 0.166. Patiromer was more effective than placebo in maintaining MRA at target dose in patients with current vs past hyperkalemia (HR: 0.45 [95% CI: 0.26-0.76] vs HR: 0.85 [95% CI: 0.54-1.32]; P interaction  = 0.031). Adverse events were similar between subgroups., Conclusions: The use of patiromer facilitates achieving target doses of RAASis in patients with HFrEF with either current or past hyperkalemia. For those with current hyperkalemia before RAASi optimization, use of patiromer may be more beneficial in helping to maintain sK + control and achieve MRA target dose. (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure [DIAMOND]; NCT03888066)., Competing Interests: Funding Support and Author Disclosures This trial was funded by Vifor Pharma Management Ltd. Dr Coats has received consulting fees from Actimed, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, Impulse Dynamics, and Respicardia; has received payment or honoraria from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards, Eli Lilly, Menarini, Novartis, Servier, Vifor, and Viatris; and has participated on a data safety monitoring board or advisory board from Impulse Dynamics. Dr Anker has received grants and personal fees from Vifor and Abbott Vascular; has received personal fees for consultancies, trial committee work, and/or lectures from Actimed, AstraZeneca, Bayer, Bioventrix, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Cytokinetics, Edwards, Farraday Pharmaceuticals, GlaxoSmithKline, HeartKinetics, Impulse Dynamics, Medtronic, Novartis, Novo Nordisk, Occlutech, Pfizer, Regeneron, Relaxera, Repairon, Scirent, Sensible Medical, Servier, Vectorious, and V-Wave; and is named coinventor of 2 patent applications regarding Midregional pro-atrial natriuretic peptide (DE 102007010834 and DE 102007022367) but does not benefit personally from the related issued patents. Dr Lund has received grants or contracts from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Novartis, and Vifor Pharma; has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Lexicon, Medscope, Merck, Pharmacosmos, MyoKardia, Sanofi, Servier, and Vifor Pharma; has received payment or honoraria from Abbott, AstraZeneca, Medscope, Novartis, and Radcliffe; is a board member/fellow of the European Society of Cardiology Heart Failure Association, the European Society of Cardiology, and the Swedish Society of Cardiology HF Working Group; and has stock or stock options in AnaCardio. Dr Filippatos reports being a committee member in trials for the European Commission; has received payment or honoraria from Bayer and Boehringer Ingelheim; reports participation on a data safety monitoring board or advisory board from Bayer; reports leadership or fiduciary role from European Academy, Heart Failure Association, and JACC: Heart Failure; and reports lecture fees and advisory or committee membership in trials from Amgen, Bayer, Boehringer Ingelheim, Cardior, Impulse Dynamics, Medtronic, Novartis, Servier, and Vifor. Dr Rossignol reports being a DIAMOND Steering Committee member; has received honoraria from Vifor; has received personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, CinCor, Idorsia, KBP Biosciences, Novo Nordisk, Sanofi, Servier, and Vifor; has received support for attending meetings and/or travel from AstraZeneca, Bayer, Boehringer Ingelheim, and Vifor; is a cofounder of CardioRenal; has participated on a data safety monitoring board or advisory board from Bayer, Idorsia, and Sequana Medical; and has stock from Cardiorenal and stock options from G3P. Dr Pitt has received consulting fees, payment or honoraria, support for attending meetings and/or travel, and stock or stock option from Vifor. Dr Weir reports serving on the DIAMOND Steering Committee; and has received personal fees from CSL Vifor, AstraZeneca, Novo Nordisk, Johnson & Johnson, and Care DX. Dr Kosiborod has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; reports consultancy/advisory board activities for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; has received support for attending meetings and/or travel from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, and Vifor Pharma; and reports stock options from Artera Health, and Saghmos Therapeutics. Dr Metra has received honoraria for participation on a DIAMOND trial meeting. Dr Böhm has received research support from Deutsche Forschungsgemeinschaft (DFG, SFB-TTR 219, S-01); has received honoraria for speaking from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Novartis, Servier, and Vifor; and has participated in advisory boards for Amgen, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Pfizer, ReCor, Servier, and Vifor. Dr Ezekowitz has received research support for trial leadership or grants from American Regent, Applied Therapeutics, AstraZeneca, Bayer, Cytokinetics, Merck and Co, Novo Nordisk, and Otsuka; and honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka. Dr Bayes-Genis has received consulting and/or lecturing fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Roche Diagnostics, and Vifor. Dr Mentz has received honoraria from Vifor and research support and honoraria from AstraZeneca. Dr Ponikowski has received grants or contracts, consulting fees, and payment or honoraria from Abbott Vascular, Amgen, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Cibiem, Bristol Myers Squibb, Impulse Dynamics, Merck, Renal Guard Solution, Novartis, Servier, and Vifor. Dr Senni reports consultancy with Novartis, Merck, Bayer, Vifor Pharma, Abbott, Boehringer Ingelheim, AstraZeneca, BioVentrix, Servier, Novo Nordisk, Cardurion Pharmaceuticals, and AnaCardio. Dr Cleland has received personal fees from Abbott, Amgen, AstraZeneca, Idorsia, Innolife, Medtronic, Novartis, Respicardia, Servier and Torrent, and grants and personal fees from Bayer, Bristol Myers Squibb, Cytokinetics, Johnson & Johnson, MyoKardia, Pharmacosmos, Stealth Biopharmaceuticals, Vifor, and VisCardia; and personal fees and nonfinancial support from Boehringer Ingelheim outside the submitted work. Dr Merkely has received personal fees from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi Sankyo, DUKE Clinical Institute, Medtronic, Novartis, and institutional grants from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo, DUKE Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo, and Vifor Pharma. Dr Wächter, Mr Budden, and Dr Perrin report being paid employees and having stock/stock options in CSL Vifor. Dr Butler has received personal consulting fees from Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva Pharma, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, PharmaIN, Roche, Sequana, SQ Innovation, 3live, and Vifor; and payment from AstraZeneca, Boehringer Ingelheim-Lilly, Janssen, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction), participants with heart failure (HF) and reduced ejection fraction, vericiguat decreased the primary composite outcome (time to first HF hospitalization [HFH] or cardiovascular death [CVD]) (897 events) compared with placebo (972 events) (hazard ratio, 0.90; 95% confidence interval [CI], 0.82-0.98; P = .02). In this prespecified secondary analysis, we applied the weighted composite end point (WCE) and the win ratio (WR) methods to provide complementary assessments of treatment effect., Methods and Results: The WCE method estimated the mean HFH-adjusted survival based on prespecified weights from a Delphi panel of the VICTORIA executive committee and national leaders: mild (weight per event, 0.39), moderate (0.5), or severe (0.67) HFH, and CVD (1.0). The unmatched WR was estimated for the descending hierarchy of CVD, then recurrent HFH. The WCE used all 3412 primary clinical events: 875 severe HFH (vericiguat, 416/ placebo, 459), 1614 moderate HFH (767/847), 68 mild HFH (38/30), and 855 CVD (414/441). Improved HFH-adjusted survival occurred with vericiguat (mean 78.2% vs 75.6%, difference 2.4%, 95% CI, 1.7%-3.2%, P < .0001). Based on a comparison of 6,375,624 pairs, the WR of 1.13 (95% CI 1.03-1.24, P = .01) also indicated improved clinical outcomes with vericiguat., Conclusions: The results of the WCE and WR methods were consistent with the primary analysis of the time to first HFH or CVD. Although both WCE and WR assessed recurrent events, the WCE allowed inclusion of all recurrent events, insights on the severity of HFH events, and an absolute measure of the participant-treatment experience. This approach complements conventional assessment, better informing consumers of new therapeutics and future trial designs., Competing Interests: Disclosures of Interest Dr. Westerhout has received consulting fees from Bayer Canada. Dr. Anstrom reports research support from the National Institutes of Health and Patient-Centered Outcomes Research Institute and research support from Bayer and Merck outside the submitted work. Dr. Hernandez reports research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squib, Merck, Novartis, and Verily, as well as consulting from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Myokardia, and Novartis. Dr. Ponikowski reports personal fees from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers Squibb, Amgen, Novartis, Merck, Pfizer, and Berlin Chemie, as well as grants and personal fees from Vifor Pharma. Dr. Ezekowitz has received research grants from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics; and consulting fees from Bayer, Merck, Servier, Amgen, Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr. Voors received research grants from Boehringer Ingelheim and Roche Diagnostics; and consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Myokardia, Novartis, Servier, and Roche Diagnostics. Dr. Felker has received research grants from NHLBI, American Heart Association, Amgen, Bayer, BMS, Merck, Cytokinetics, and CSL-Behring; he has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, Astra-Zeneca, Reprieve, Myovant, Sequana, Windtree Therapuetics, and Whiteswell; and has served on clinical end point committees and data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr. Blaustein is an employee of Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co Inc., Rahway, NJ. Dr. Nkulikiyinka is an employee of Bayer AG, Wuppertal, Germany. Dr. O'Connor has received research funding from Merck; and consulting fees from Bayer, Dey LP, and Bristol Myers Squibb Foundation. Dr. Armstrong reports institutional and personal grants from Merck, Bayer, CLS Limited, Eli Lilly, and Boehringer Ingelheim and personal fees from Merck, Boehringer Ingelheim, Bayer, and Novo Nordisk. All other authors report no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: This post hoc analysis of SODIUM-HF (Study of Dietary Intervention under 100 mmol in Heart Failure) assessed the association between baseline dietary sodium intake and change at 6 months with a composite of cardiovascular (CV) hospitalizations, emergency department visits and all-cause death at 12 and 24 months., Background: Dietary sodium restriction is common advice for patients with heart failure (HF). Randomized clinical trials have not shown a beneficial effect of dietary sodium restriction on clinical outcomes., Methods: A multivariable Cox proportional hazard regression model was used to assess the association of dietary sodium intake measured at randomization with primary and secondary endpoints., Results: The study included 792 participants. Baseline sodium intake was ≤ 1500 mg/day in 19.9% (n = 158), 1501-3000 mg/day in 56.5% (n = 448) and > 3000 mg/day in 23.4% (n = 186) of participants. The factors associated with higher baseline sodium intake were higher calorie consumption, higher body mass index and recruitment from Canada. Multivariable analyses showed no association between baseline sodium intake nor magnitude of 6-month change or 12- or 24-month outcomes. In a responder analysis, participants achieving a sodium intake < 1500 mg at 6 months showed an association with a decreased risk for the composite outcome (adjusted HR 0.52 [95% CI 0.25, 1.07] P = 0.08) and CV hospitalization (adjusted HR 0.51 [95% CI 0.24, 1.09] P = 0.08) at 12 months., Conclusion: There was no association between dietary sodium intake and clinical outcomes over 24 months in patients with HF. Responder analyses suggest the need for further investigation of the effects of sodium reduction in those who achieve the targeted dietary sodium-reduction level., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: More women than men have heart failure with preserved ejection fraction (HFpEF)., Objectives: The purpose of this study was to assess baseline characteristics and treatment effect of semaglutide by sex across the STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) program., Methods: In a prespecified secondary analysis of pooled data from STEP-HFpEF and STEP-HFpEF DM (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes), patients with heart failure (HF), left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m 2 , and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to once-weekly semaglutide 2.4 mg or matched placebo for 52 weeks. Dual primary endpoints (KCCQ-CSS change and percentage change in body weight) and confirmatory secondary endpoints (6-minute walking distance [6MWD] change; hierarchical composite endpoint comprising all-cause death, HF events, changes in KCCQ-CSS, and 6MWD; and C-reactive protein) were compared between sexes., Results: Of 1,145 patients, 570 (49.7%) were women. Women had higher body mass index, left ventricular ejection fraction, C-reactive protein, and worse HF symptoms, and were less likely to have atrial fibrillation or coronary artery disease vs men. Semaglutide improved KCCQ-CSS regardless of sex (mean difference in women +7.6 points [95% CI: 4.5-10.7 points]; men +7.5 points [95% CI: 4.3-10.6 points]; P interaction = 0.94) but reduced body weight more in women (mean difference in women -9.6% [95% CI: -10.9% to -8.4%]; men -7.2% [95% CI: -8.4% to -6.0%]; P interaction = 0.006). Semaglutide improved 6MWD (P interaction = 0.21) and the hierarchical composite endpoint (P interaction = 0.66) in both sexes. Fewer serious adverse events were reported with semaglutide vs placebo., Conclusions: In patients with obesity-related HFpEF, semaglutide 2.4 mg reduced body weight to a greater extent in women, and produced similar improvements in HF-related symptoms, physical limitations, and exercise function, regardless of sex. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; and Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM]; NCT04916470)., Competing Interests: Funding Support and Author Disclosures This trial was funded by Novo Nordisk A/S. Administrative support for manuscript development was funded by Novo Nordisk A/S. Dr Verma is supported by the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada; holds the Tier 1 Canada Research Chair in Cardiovascular Surgery; and has received speaking honoraria and/or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. Dr Butler has served as a consultant for Abbott, American Regent, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Daxor Edwards, Element Science, Imbria, Impulse Dynamics, Innolife, Inventiva, Janssen, Lexicon, Lilly, LivaNova, Medtronics, Merck, Novartis, Novo Nordisk, Occlutech, Owkin, Pfizer, Pharmacosmos, Pharmain, Prolaio, Roche, Secretome, Sequana, SQ Innovation, Tenex, and Vifor. Dr Borlaug is supported in part by the National Institutes of Health grants R01HL128526, R01HL162828, and U01HL160226, and by the U.S. Department of Defense grant W81XWH2210245; has received research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, Becton, Dickinson and Company, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, NGM, Novo Nordisk, NXT, and VADovations; and is named inventor (U.S. patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Davies is supported by the Leicester National Institute for Health Research Biomedical Research Centre, Leicester General Hospital; has acted as a consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; has served as an advisory board member and speaker for AstraZeneca; has served as an advisory board member for Medtronic, Pfizer, and ShouTi Pharma; has served as a speaker for Amgen, Novartis, and Sanofi; and has received grants as an investigator in support of investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. Dr Kitzman was supported in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and National Institutes of Health grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, U24AG059624, and U01HL160272; has received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences. Dr Shah was supported by National Institutes of Health grants U54HL160273, R01HL107577, R01HL127028, R01HL140731, and R01HL149423; has received research grants from AstraZeneca, Corvia, and Pfizer; and has received consulting fees from Abbott, Alleviant, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Petrie is supported by the British Heart Foundation Centre of Research Excellence Award (RE/13/5/30177 and RE/18/6/34217+); has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and has served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor. Drs Barros, Rönnbäck, and Vestergaard are employees and shareholders of Novo Nordisk A/S. Dr Schou has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. Dr Ezekowitz has received research support for trial leadership from American Regent, Applied Therapeutics, Bayer, Cytokinetics, Merck, and Novo Nordisk; has received honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka; and has served as an adviser to US2.ai. Dr Sharma is an advisory board member and consultant for Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Janssen, Novartis, Novo Nordisk, and Rivus; and received honoraria from these companies. Dr Kosiborod has served as a consultant or as an advisory board member for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca and Boehringer Ingelheim; holds stocks in Artera Health and Saghmos Therapeutics; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Renin-angiotensin-aldosterone system inhibitor (RAASi; including mineralocorticoid receptor antagonists [MRAs]) benefits are greatest in patients with heart failure with reduced ejection fraction (HFrEF) and chronic kidney disease (CKD); however, the risk of hyperkalemia (HK) is high., Methods: The DIAMOND trial (NCT03888066) assessed the ability of patiromer to control serum potassium (sK+) in patients with HFrEF with/without CKD. Prior to randomization (double-blind withdrawal, 1:1), patients on patiromer had to achieve ≥50% recommended doses of RAASi and 50 mg/day of MRA with normokalemia during a run-in period. The present analysis assessed the effect of baseline estimated glomerular filtration rate (eGFR) in subgroups of ≥/&lt;60, ≥/&lt;45 (prespecified), and ≥/&lt;30 mL/min/1.73 m2 (added post hoc)., Results: In total, 81.3, 78.9, and 81.1% of patients with eGFR &lt;60, &lt;45, and &lt;30 mL/min/1.73 m2 at screening achieved RAASi/MRA targets. A greater efficacy of patiromer versus placebo to control sK+ in patients with more advanced CKD was reported (p-interaction ≤ 0.027 for all eGFR subgroups). Greater effects on secondary endpoints were observed with patiromer versus placebo in patients with eGFR &lt;60 and &lt;45 mL/min/1.73 m2. Adverse effects were similar between patiromer and placebo across subgroups., Conclusion: Patiromer enabled use of RAASi, controlled sK+, and minimized HK risk in patients with HFrEF, with greater effect sizes for most endpoints noted in patient subgroups with lower eGFR. Patiromer was well tolerated by patients in all eGFR subgroups., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Heart failure is a complex clinical syndrome with many etiological factors and complex pathophysiology affecting millions worldwide. Males and females can have distinct clinical presentation and prognosis, and there is an emerging understanding of the factors that highlight the similarities and differences to synthesize and present available data for sex-specific differences in heart failure with preserved ejection fraction (HFpEF). While the majority of data demonstrate more similarities than differences between females and males in terms of heart failure, there are key differences. Data showed that females have a higher risk of developing HFpEF, but a lower risk of mortality and hospitalization. This can be conditioned by different profiles of comorbidities, postmenopausal changes in sex hormone levels, higher levels of inflammation and chronic microvascular dysfunction in females. These factors, combined with different left ventricular dimensions and function, which are more pronounced with age, lead to a higher prevalence of LV diastolic dysfunction at rest and exercise. As a result, females have lower exercise capacity and quality of life when compared to males. Females also have different activities of systems responsible for drug transformation, leading to different efficacy of drugs as well as higher risk of adverse drug reactions. These data prove the necessity for creating sex-specific risk stratification scales and treatment plans., Competing Interests: J.A. Ezekowitz reports research support for trial leadership or grants from American Regent, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck & Co, Novo Nordisk, Novartis, Otsuka. Y. Smereka declares there are no competing interests.

Introduction: Short-term clinical outcomes from SARS-CoV-2 infection are generally favorable. However, 15-20% of patients report persistent symptoms of at least 12 weeks duration, often referred to as long COVID. Population studies have also demonstrated an increased risk of incident diabetes and cardiovascular disease at 12 months following infection. While imaging studies have identified multi-organ injury patterns in patients with recovered COVID-19, their respective contributions to the disability and morbidity of long COVID is unclear., Methods: A multicenter, observational study of 215 vaccine-naïve patients with clinically recovered COVID-19, studied at 3-6 months following infection, and 133 healthy volunteers without prior SARS-CoV-2 infection. Patients with recovered COVID-19 were screened for long COVID related symptoms and their impact on daily living. Multi-organ, multi-parametric magnetic resonance imaging (MRI) and circulating biomarkers were acquired to document sub-clinical organ pathology. All participants underwent pulmonary function, aerobic endurance (6 min walk test), cognition testing and olfaction assessment. Clinical outcomes were collected up to 1 year from infection. The primary objective of this study is to identify associations between organ injury and disability in patients with long-COVID symptoms in comparison to controls. As a secondary objective, imaging and circulating biomarkers with the potential to exacerbate cardiovascular health were characterized., Discussion: Long-term sequelae of COVID-19 are common and can result in significant disability and cardiometabolic disease. The overall goal of this project is to identify novel targets for the treatment of long COVID including mitigating the risk of incident cardiovascular disease., Study Registration: clinicaltrials.gov (MOIST late cross-sectional study; NCT04525404)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Paterson, White, Beaulieu, Sherrington, Prado, Tandon, Halloran, Smith, McCombe, Ritchie, Pituskin, Haykowsky, Coulden, Emery, Tsui, Wu, Oudit, Ezekowitz and Thompson.)

Background: Diabetic cardiomyopathy (DbCM) increases risk of overt heart failure in individuals with diabetes mellitus. Racial and ethnic differences in DbCM remain unexplored., Objectives: The authors sought to identify racial and ethnic differences among individuals with type 2 diabetes mellitus, structural heart disease, and impaired exercise capacity., Methods: The ARISE-HF (Aldolase Reductase Inhibitor for Stabilization of Exercise Capacity in Heart Failure) trial is assessing the efficacy of an aldose reductase inhibitor for exercise capacity preservation in 691 persons with DbCM. Baseline characteristics, echocardiographic parameters, and functional capacity were analyzed and stratified by race and ethnicity., Results: The mean age of the study participants was 67.4 years; 50% were women. Black and Hispanic patients had lower use of diabetes mellitus treatments. Black patients had poorer baseline ventricular function and more impaired global longitudinal strain. Overall, health status was preserved, based on Kansas City Cardiomyopathy Questionnaire scores, but reduced exercise capacity was present as evidenced by reduced Physical Activity Scale for the Elderly (PASE) scores. When stratified by race and ethnicity and compared with the entire cohort, Black patients had poorer health status, more reduced physical activity, and a greater impairment in exercise capacity during cardiopulmonary exercise testing, whereas Hispanic patients also displayed compromised cardiopulmonary exercise testing functional capacity. White patients demonstrated higher physical activity and functional capacity., Conclusions: Racial and ethnic differences exist in baseline characteristics of persons affected by DbCM, with Black and Hispanic study participants demonstrating higher risk features. These insights inform the need to address differences in the population with DbCM. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339)., Competing Interests: Funding Support and Author Disclosures The ARISE-HF trial is sponsored by Applied Therapeutics, Inc. Dr Januzzi is funded in part by the Hutter Family Professorship. This work did not receive financial support from external sources. Dr Del Prato has received research support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on the advisory board/steering committee/executive committee for Abbott, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Co, Merck & Co, Hengrui Europe Therapeutics, Novartis Pharmaceuticals, Novo Nordisk, and Sanofi; and has received speaker honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Co, Merck & Co, Novartis Pharmaceuticals, Novo Nordisk, and Sanofi. Dr Ezekowitz has received research support or honoraria from Applied Therapeutics, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Merck, Bayer, Novartis, Pfizer, Amgen, and Cytokinetics. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as a consultant or on the advisory board/steering committee/executive committee for Abbott, Actelion, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder & nonexecutive director of Us2.ai. Dr Marwick has received research support from General Electric Medical Systems, Philips, Tomtec, Siemens, and AstraZeneca; has received unrestricted educational support from AstraZeneca, Bayer, and Edwards Lifesciences; and serves on the ARISE-HF Steering Committee for Applied Therapeutics. Dr Rosenstock has served on advisory panels for Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Intarcia, Janssen, Novo Nordisk, Oramed, Sanofi, Hanmi, and Zealand; and has received research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, Intarcia, Janssen, Lexicon, Merck, Novartis, Novo Nordisk, Oramed, Pfizer, and Sanofi. Dr Tang has served as a consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Boston Scientific, WhiteSwell, Kiniksa Pharmaceuticals, CardiaTec Biosciences, Intellia Therapeutics, Bristol Myers Squibb, Alleviant Medial, and Alexion; and has received honoraria from Springer Nature, Belvoir Media Group, and American Board of Internal Medicine. Dr Perfetti is the CMO and a stock owner of Applied Therapeutics. Dr Urbinati is an employee and a stock owner of Applied Therapeutics. Dr Januzzi is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received research support from Abbott, Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Roche Diagnostics; has received consulting income from Abbott, Beckman, Bristol Myers, Boehringer Ingelheim, Janssen, Novartis, Pfizer, Merck, Roche Diagnostics, and Siemens; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx, Intercept, Janssen, and Takeda. Dr. Ibrahim has received speaker honoraria from Cytokinetics and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Progression to symptomatic heart failure is a complication of type 2 diabetes; heart failure onset in this setting is commonly preceded by deterioration in exercise capacity., Objectives: This study sought to determine whether AT-001, a highly selective aldose reductase inhibitor, can stabilize exercise capacity among individuals with diabetic cardiomyopathy (DbCM) and reduced peak oxygen uptake (Vo 2 )., Methods: A total of 691 individuals with DbCM meeting inclusion and exclusion criteria were randomized to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. The primary endpoint was proportional change in peak Vo 2 from baseline to 15 months. Subgroup analyses included measures of disease severity and stratification variables., Results: The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak Vo 2 fell in the placebo-treated patients by -0.31 mL/kg/min (P = 0.005 compared to baseline), whereas in those receiving high-dose AT-001, peak Vo 2 fell by -0.01 mL/kg/min (P = 0.21); the difference in peak Vo 2 between placebo and high-dose AT-001 was 0.30 (P = 0.19). In prespecified subgroup analyses among those not receiving sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists at baseline, the difference between peak Vo 2 in placebo vs high-dose AT-001 at 15 months was 0.62 mL/kg/min (P = 0.04; interaction P = 0.10)., Conclusions: Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339)., Competing Interests: Funding Support and Author Disclosures This study was funded by Applied Therapeutics, Inc. Dr Januzzi is supported in part by the Adolph Hutter Professorship at Harvard Medical School; is a trustee of the American College of Cardiology; is a Board member of Imbria Pharmaceuticals; is a director at Jana Care; has received research support from Abbott, Applied Therapeutics, Bayer, Bristol Myers Squibb, HeartFlow Inc, Innolife, Medtronic, and Roche Diagnostics; has received consulting income from Abbott, AstraZeneca, Bayer, Beckman, Boehringer Ingelheim, Cytokinetics, Janssen, Merck, Novartis, Prevencio, Quidel/Ortho, and Roche Diagnostics; and participates in Clinical Endpoint Committees/Data Safety Monitoring Boards for Abbott, AbbVie, Axon, Bayer, CVRx, Medtronic, Pfizer, Roche Diagnostics, and Takeda. Dr Butler is a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr Del Prato has served as president of the European Society for the Study of Diabetes/European Foundation for the Study of Diabetes (2020-2022); has received research grants to the institution from AstraZeneca and Boehringer Ingelheim; has served as an advisor for Abbott, Amarin Corporation, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co, EvaPharma, Jiangsu Hengrui Pharmaceuticals Co, Menarini International, Merck Sharp & Dohme, Novartis Pharmaceutical Co, Novo Nordisk, Sanofi, and Sun Pharmaceuticals; and has received fees for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co, Laboratori Guidotti, Menarini International, Merck Sharp & Dohme, and Novo Nordisk. Dr Ezekowitz has received research support for trial leadership, honoraria, or grants from American Regent, Applied Therapeutics, AstraZeneca, Bayer, Cytokinetics, Merck & Co, Novo Nordisk, and Otsuka. Dr Ibrahim has served as a consultant for Cytokinetics; and has served on the Steering Committee for Applied Therapeutics. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and nonexecutive director of Us2.ai. Dr Lewis has received research funding from the National Institutes of Health (U01 HL160278, R01-HL 151841, R01-HL131029, R01-HL159514), Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, Imbria, Pfizer, Rivus, and SoniVie; has received honoraria for consulting and Advisory Boards outside of the current study from American Regent, Amgen, Cytokinetics, Edwards, Pfizer, Merck, Boehringer Ingelheim, NXT, and Amgen; and receives royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Perfetti is an employee of Applied Therapeutics. Dr Rosenstock has served on Scientific Advisory Boards and received honoraria or consulting fees from Applied Therapeutics, Biomea Fusion, Boehringer Ingelheim, Eli Lilly, Endogenex, Hanmi, Novo Nordisk, Oramed, Regor, Sanofi, Scholar Rock, Structure Therapeutics, Terns Pharma, and Zealand; and has received grants/research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, Merck, Oramed, Novartis, Novo Nordisk, Pfizer, and Sanofi. Dr Solomon has received a research grant to his institution from Applied Therapeutics for the conduct of the trial; has received research grants to his institution from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cytokinetics, Edgewise, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, the National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI outside the submitted work; and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo outside the submitted work. Dr Tang has served as consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Boston Scientific, WhiteSwell, Kiniksa Pharmaceuticals, Intellia Therapeutics, CardiaTec Biosciences, Bristol Myers Squibb, and Alleviant Medical; and has received honoraria from Springer Nature, Belvoir Media Group, and the American Board of Internal Medicine. Dr Zannad has received personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, Bristol Myers Squibb, CVRx, Cambrian, Cardior, Cereno Pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, Novo Nordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, and USa2; holds stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, and Eshmoun Clinical Research; and is the founder of Cardiovascular Clinical Trialists. Dr Marwick has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The glucagon-like peptide-1 receptor agonist, semaglutide, improved health status and reduced body weight in patients with obesity-related heart failure (HF) with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with Obesity and HFpEF) program. Whether benefits were due to mechanical unloading or effects on HF pathobiology is uncertain., Objectives: This study sought to determine if semaglutide 2.4 mg reduced N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with obesity-related HFpEF and compare treatment responses by baseline NT-proBNP., Methods: This was a prespecified secondary analysis of pooled data from 2 double-blind, placebo-controlled, randomized trials (STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes]) testing effects of semaglutide in patients with obesity-related HFpEF. The main outcomes were change in NT-proBNP at 52 weeks and change in the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and body weight by baseline NT-proBNP., Results: In total, 1,145 patients were randomized. Semaglutide compared with placebo reduced NT-proBNP at 52 weeks (estimated treatment ratio: 0.82; 95% CI: 0.74-0.91; P = 0.0002). Improvements in health status were more pronounced in those with higher vs lower baseline NT-proBNP (estimated difference: tertile 1: 4.5 points, 95% CI: 0.8-8.2; tertile 2: 6.2 points, 95% CI: 2.4-10.0; tertile 3: 11.9 points, 95% CI: 8.1-15.7; P interaction = 0.02; baseline NT-proBNP as a continuous variable: P interaction = 0.004). Reductions in body weight were consistent across baseline NT-proBNP levels (P interaction = 0.21)., Conclusions: In patients with obesity-related HFpEF, semaglutide reduced NT-proBNP. Participants with higher baseline NT-proBNP had a similar degree of weight loss but experienced larger reductions in HF-related symptoms and physical limitations with semaglutide than those with lower NT-proBNP., Competing Interests: Funding Support and Author Disclosures The STEP-HFpEF program was funded by Novo Nordisk. Dr Petrie has received grants from the British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217; has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novo Nordisk, Novartis, Pharmacosmos, Roche, and SQ Innovations; and has served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor. Dr Borlaug has received grants from the National Institutes of Health (NIH), the United States Department of Defense, AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; has received consulting fees from Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, NGM, Novo Nordisk, NXT, and VADovations; and has been named inventor (U.S. patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Butler has received consulting fees from Abbott, American Regent, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Daxor, Edwards Lifesciences, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, PharmaIN, Prolaio, Roche, Secretome, Sequana, SQ Innovation, Tenex, and Vifor. Dr Davies has received consulting fees from, been an advisory board member for, and has been speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; has been an advisory board member and speaker for AstraZeneca; has been an advisory board member for Medtronic, Pfizer, and ShouTi Pharma; has been a speaker for Amgen, Novartis, and Sanofi; and has received grants as an investigator in support of investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. Dr Kitzman has received grants from the Kermit Glenn Phillips II Chair in Cardiovascular Medicine, NIH grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, U24AG059624, and U01HL160272; has received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences. Dr Shah has received grants from AstraZeneca, Corvia, Pfizer, the National Heart, Lung, and Blood Institute (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423); and has received consulting fees from Abbott, Alleviant, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. Dr Verma has received speaking honoraria and/or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. Drs Jensen and Einfeldt and Ms Liisberg are employees of Novo Nordisk A/S and shareholders. Dr Perna has received honoraria from Novo Nordisk. Dr Sharma has been an advisory board member for and has received consulting fees from Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Janssen, Novartis, Novo Nordisk, and Rivus. Dr Ezekowitz has received research support for trial leadership from American Regent, Applied Therapeutics, Bayer, Cytokinetics, Merck, and Novo Nordisk; has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka; and has served as an advisor to US2.ai. Dr Melenovský has received consulting fees from Bayer, Merck Sharp & Dohme, and Novo Nordisk; has received research grants from Regeneron; and has received research support from the National Institute for Research on Metabolic and Cardiovascular Diseases (Programme EXCELES, ID Project No. LX22NPO5104), funded by the European Union – Next Generation EU. Dr Ito has received honoraria and/or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Mochida, Novartis, and Novo Nordisk. Dr Lelonek has received honoraria and/or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Ewopharma, Gedeon Richter, Novartis, Novo Nordisk, Roche, and Servier. Dr Kosiborod has received consulting or advisory board fees from 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received other research support from AstraZeneca. Dr Fu has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Ferric carboxymaltose (FCM) is guideline-recommended for iron deficiency (ID) in heart failure with reduced ejection fraction (HFrEF). Despite a well-established safety profile, the magnitude and clinical significance of FCM-induced hypophosphataemia in HFrEF remains unclear. This pre-specified substudy of HEART-FID evaluated serum phosphate, 1,25-dihydroxyvitamin D, and plasma parathyroid hormone (PTH) subsequent to FCM., Methods and Results: HEART-FID was a randomized, double-blind, placebo-controlled trial of ambulatory patients with HFrEF and ID randomized to FCM versus placebo. This substudy assessed mean change from baseline across eight visits over 6 months for the following endpoints: serum phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTH, in addition to the clinical severity of potential hypophosphataemia. Overall, 133 patients (n = 62 FCM, n = 71 placebo) were prospectively enrolled. Mean age was 68 ± 11 years, 55 (41.4%) were women, and 29 (21.8%) had chronic kidney disease. Phosphate levels decreased in 34 (57.6%) patients in the FCM group compared with 7 (10.3%) in the placebo group. Mean change in phosphate levels reached a nadir at day 21 (-0.36 ± 0.27 mmol/L) subsequent to FCM infusion with 28 (51%) having moderate-to-severe hypophosphataemia. Reductions in 1,25-dihydroxyvitamin D were also observed, whilst PTH increased. These biochemical changes returned to baseline levels by day 91. Serum levels of 25-hydroxyvitamin D remained stable throughout the study. No serious adverse events associated with hypophosphataemia were reported., Conclusions: Transient moderate-to-severe hypophosphataemia was frequent subsequent to FCM infusion, accompanied by 1,25-dihydroxyvitamin D decrease and PTH increase. Serum levels of 25-hydroxyvitamin D remained stable. No evidence of symptomatic hypophosphataemia was reported, collectively indicating FCM-related hypophosphataemia to be clinically benign and transient in HFrEF., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: In VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), vericiguat compared with placebo reduced cardiovascular death or heart failure (HF) hospitalization in patients with HF with reduced ejection fraction., Objectives: This study explored the association between vericiguat and recurrent hospitalizations and subsequent mortality after HF hospitalization., Methods: The treatment effect of vericiguat on the burden of HF hospitalizations was evaluated by assessing total HF hospitalization and cardiovascular death in the overall trial and based on baseline N-terminal pro-B-type natriuretic peptide levels with and without adjustment for VICTORIA model covariates (ie, baseline variables associated with the primary endpoint) assessed via the Andersen-Gill method. Associations between vericiguat and recurrent hospitalization and mortality adjusted for VICTORIA model covariates are reported., Results: There were 1,222 total HF hospitalizations and cardiovascular deaths among 2,526 patients in the vericiguat group and 1,336 total events among 2,524 patients in the placebo group (unadjusted HR: 0.89 [95% CI: 0.81-0.97] and adjusted HR: 0.92 [95% CI: 0.84-1.01]). In the subgroup with N-terminal pro-B-type natriuretic peptide levels ≤2,816 pg/mL (ie, Q1 and Q2; median or below), there was a suggestion of a benefit with vericiguat (adjusted HRs of 0.80 [95% CI: 0.64-1.01] and 0.77 [95% CI: 0.62-0.94], respectively) compared with those above this value (adjusted HRs of 1.12 [95% CI: 0.93-1.34] and 0.87 [95% CI: 0.74-1.04] for Q3 and Q4). There was no significant difference in treatment effect between patients with vs without an HF hospitalization. After HF hospitalization, the all-cause mortality rate (events per 100 patient-years) was 48.6 for vericiguat and 44.1 for placebo., Conclusions: Additional investigation of the association between vericiguat and cardiovascular death and total HF hospitalizations by recurrent event analysis did not show a statistically significant reduction in events. Mortality was high after HF hospitalization, emphasizing the need for further therapies to reduce morbidity and mortality. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534)., Competing Interests: Funding Support and Author Disclosures The VICTORIA trial was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Company, Inc, and Bayer AG. Dr Mentz has received research support and honoraria from Bayer and Merck Sharp & Dohme Corporation, a subsidiary of Merck & Company, Inc. Dr Butler has received consulting fees from Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Roche, and Vifor. Dr Chiang has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, and Sanofi. Dr Ezekowitz has received research grants and consulting fees from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr Hernandez has received research grants from Merck, AstraZeneca, Novartis, and Verily; and received honoraria from Merck, Bayer, Amgen, AstraZeneca, and Novartis. Dr Hilkert is an employee of Merck & Company, Inc. Dr Lam has received research grants from Bayer, the National Medical Research Council of Singapore, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma, and AstraZeneca; has received consulting fees from Merck, Bayer, Boston Scientific, Roche Diagnostic, Vifor Pharma, AstraZeneca, Novartis, Amgen, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, and Radcliffe Group Ltd, Corpus; has a patent pending (PCT/SG2016/050217 & 16/216929); and is a co-founder and nonexecutive director of eKo.ai. Dr O’Connor has received research funding from Merck and consulting fees from Bayer, Dey LP, and the Bristol Myers Squibb Foundation. Dr Pieske has received research support from Boston Scientific and honoraria from Bayer, MSD, Novartis, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, BMS, Edwards Lifesciences, and Boston Scientific. Dr Ponikowski has received research grants, consulting fees, and Speakers Bureau for Bayer, MSD, Servier, Novartis, Vifor Pharma Ltd, BMS, Boehringer Ingelheim, Respicardia, AstraZeneca, Cibiem, RenalGuard Solutions, and Berlin-Chemie. Dr Roessig is an employee of Bayer AG. Dr Voors has received research support and honoraria from AstraZeneca, BMS, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. Dr Anstrom has received research grants from Merck and the National Institutes of Health. Dr Armstrong has received research grants from Merck, Bayer, Sanofi-Aventis Recherche & Développement, Boehringer Ingelheim, and CSL Limited; and has received consulting fees from Merck, Bayer, AstraZeneca, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In heart failure (HF) trials, there has been an emphasis on utilizing more patient-centered outcomes, including quality of life (QoL) and days alive and out of hospital. We aimed to explore the impact of QoL adjusted days alive and out of hospital as an outcome in 2 HF clinical trials., Methods: Using data from 2 trials in HF (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT] and Study of Dietary Intervention under 100 mmol in Heart Failure [SODIUM-HF]), we determined treatment differences using percentage days alive and out of hospital (%DAOH) adjusted for QoL at 18 months as the primary outcome. For each participant, %DAOH was calculated as a ratio between days alive and out of hospital/total follow-up. Using a regression model, %DAOH was subsequently adjusted for QoL measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score., Results: In the GUIDE-IT trial, 847 participants had a median baseline Kansas City Cardiomyopathy Questionnaire Overall Summary Score of 59.0 (interquartile range, 40.8-74.3), which did not change over 18 months. %DAOH was 90.76%±22.09% in the biomarker-guided arm and 88.56%±25.27% in the usual care arm. No significant difference in QoL adjusted %DAOH was observed (1.09% [95% CI, -1.57% to 3.97%]). In the SODIUM-HF trial, 796 participants had a median baseline Kansas City Cardiomyopathy Questionnaire Overall Summary Score of 69.8 (interquartile range, 49.3-84.3), which did not change over 18 months. %DAOH was 95.69%±16.31% in the low-sodium arm and 95.95%±14.76% in the usual care arm. No significant difference was observed (1.91% [95% CI, -0.85% to 4.77%])., Conclusions: In 2 large HF clinical trials, adjusting %DAOH for QoL was feasible and may provide complementary information on treatment effects in clinical trials., Competing Interests: Disclosures Dr Felker reported receiving grant support from Merck and personal fees from Medtronic, Bristol Myers Squibb, Trevena, GlaxoSmithKline, Myokardia, and Stealth BioTherapeutics. Dr Macdonald reports research grants from the National Health and Medical Research Committee, the New South Wales Department of Health, and the St Vincent’s Clinic Foundation; consulting fees from AstraZeneca, Boehringer Ingelheim, and Novartis; honoraria payments from the Japanese Circulation Society; support for attending meetings or travel from Astellas; and stock or stock options in Infensa Biologics. R.W. Troughton reports research grants from the Health Research Council of New Zealand, consulting fees from Merck and Roche Diagnostics, and honoraria payments from Roche Diagnostics. Dr O’Connor reported receiving grant support from Roche Diagnostics and the National Institutes of Health. J.A. Ezekowitz reports research support for trial leadership or grants from American Regent, Applied Therapeutics, AstraZeneca, Bayer, Cytokinetics, Merck & Co, Novo Nordisk, and Otsuka; honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka; and serves as an advisor to US2.ai. The other authors report no conflicts.

Background: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups., Methods: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m 2 , New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A 1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA 1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug., Findings: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group., Interpretation: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated., Funding: Novo Nordisk., Competing Interests: Declaration of interests JB is a paid consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Daxor Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Roche, Secretome, Sequana, SQ Innovation, Tenex, and Vifor. SJS has received research grants from AstraZeneca, Corvia, and Pfizer, and consulting fees from Abbott, Alleviant, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. MCP has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novo Nordisk, Novartis, Pharmacosmos, Roche, and SQ Innovations, and has served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor. BAB has received research funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics, has served as a paid consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, NGM, Novo Nordisk, NXT, and VADovations, and is named inventor (US patent number 10 307 179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. SZA, GKH, DVM, MNE, MLL, and SR are employees of, and shareholders in, Novo Nordisk. MJD has acted as paid consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi, a paid advisory board member and speaker for AstraZeneca, a paid advisory board member for Medtronic, Pfizer, and ShouTi Pharma, and a paid speaker for Amgen, Novartis, and Sanofi, and has received grants as an investigator in support of investigator-initiated trials from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi-Aventis. DWK reports receiving honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus, has received grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus, and owns stock in Gilead. SV reports speaking honoraria or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. WA reports honoraria or consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk. FZA reports honoraria or consulting fees from Abbott, AstraZeneca, Medtronic, Novo Nordisk, Occlutech, Pharmacosmos, and Vifor. VC reports speaker fees from AstraZeneca, Boehringer Ingelheim, Cipla, Dr Reddy's, Lupin, Novartis, Novo Nordisk, Mankind, Pfizer, Sanofi, Sun Pharma, and Torrent. JAE reports research support for trial leadership from American Regent, Applied Therapeutics, Bayer, Cytokinetics, Merck, and Novo Nordisk, reports honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, and Otsuka, and serves as an advisor to US2.ai. HI reports honoraria or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Mochida, Novartis, and Novo Nordisk. ML reports honoraria or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Ewopharma, Gedeon Richter, Novartis, Novo Nordisk, Roche, and Servier. VM reports consulting fees from Bayer, Merck Sharp & Dohme, and Novo Nordisk and research grants from Regeneron. BM reports speaker fees or research payments from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, DUKE Clinical Institute, Medtronic, and Novartis, and institutional grants from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, DUKE Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo, and Vifor. JN reports honoraria or consulting fees from Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Pfizer, Novartis, Novo Nordisk, Rovi, and Vifor. EP reports honoraria from Novo Nordisk. MSc reports speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk. MSe reports honoraria or consulting fees from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Vifor. KS received honoraria for serving as an advisory board member and consultant for Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Janssen, Novartis, Novo Nordisk, and Rivus. PvdM reports institutional payments for consultancy fees or grants from AstraZeneca, Boehringer Ingelheim, BridgeBio, Ionis, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharma Nord, and Vifor. DVL reports honoraria or consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Novo Nordisk, Recardio, Sanofi, Sanova, and Vaxxinity. DW reports consultancy fees from Novo Nordisk. MNK served as a paid consultant or advisory board member for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor, and Youngene Therapeutics, has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer, holds stocks in Artera Health and Saghmos Therapeutics, has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk, and has received other research support from AstraZeneca. TB-G and MF report no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes., Methods: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level., Results: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group., Conclusions: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Studies have shown an association between iron deficiency (ID) and clinical outcomes in patients with heart failure (HF), irrespective of the presence of ID anemia (IDA). The current study used population-level data from a large, single-payer health care system in Canada to investigate the epidemiology of ID and IDA in patients with acute HF and those with chronic HF, and the iron supplementation practices in these settings., Methods: All adult patients with HF in Alberta between 2012 and 2019 were identified and categorized as acute or chronic HF. HF subtypes were determined through echocardiography data, and ID (serum ferritin concentration <100 μg/L, or ferritin concentration between 100 and 300 μg/L along with transferrin saturation <20%), and IDA through laboratory data. Broad eligibility for 3 clinical trials (AFFIRM-AHF [Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute HF and ID], IRONMAN [Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency], and HEART-FID [Randomized Placebocontrolled Trial of Ferric Carboxymaltose as Treatment for HF With ID]) was determined., Results: Among the 17 463 patients with acute HF, 38.5% had iron studies tested within 30 days post-index-HF episode (and 34.2% of the 11 320 patients with chronic HF). Among tested patients, 72.6% of the acute HF and 73.9% of the chronic HF were iron-deficient, and 51.4% and 49.0% had IDA, respectively. Iron therapy was provided to 41.8% and 40.5% of patients with IDA and acute or chronic HF, respectively. Of ID patients without anemia, 19.9% and 21.7% were prescribed iron therapy. The most common type of iron therapy was oral (28.1% of patients). Approximately half of the cohort was eligible for each of the AFFIRM-AHF, intravenous iron treatment in patients with HF and ID, and HEART-FID trials., Conclusions: Current practices for investigating and treating ID in patients with HF do not align with existing guideline recommendations. Considering the gap in care, innovative strategies to optimize iron therapy in patients with HF are required., Competing Interests: Disclosures Dr McAlister is supported by the Alberta Health Services Chair in Cardiovascular Outcomes Research. Dr Ezekowitz is supported by the Alberta Health Services Chair in Cardiac Sciences; reports research support for trial leadership from Bayer, Merck and Co, Novo Nordisk, Cytokinetics, Applied Therapeutics, American Regent; honoraria for consultancy from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Otsuka, Bayer, Novartis; and serves as an advisor to US2.ai. The other authors report no conflicts.

Background: Clinical trials in heart failure (HF) traditionally use time-to-event analyses focusing on death and hospitalization for HF. These time-to-first event analyses may have more limited abilities to assess the probability of benefiting from a therapy, especially if that benefit manifests as improved functional status rather than reduced risk of death or HF hospitalization. Hierarchical end points including clinical outcomes and patient status measures allow for ranked evaluation of outcomes in 1 metric assessing whether patients randomized to intervention or control are more likely to derive an overall benefit while also allowing more patients to contribute to the primary outcome., Methods: We review the rationale for using hierarchical end points in HF trials, provide examples of HF trials that used this type of end point, and discuss its use in the HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency), the largest HF trial to date implementing a hierarchical end point analysis for the primary outcome., Results: Using a hierarchical end point as the primary outcome allows for the inclusion of different types of outcomes in 1 ranked end point, making it possible to more holistically assess the potential utility of a new therapy on patient well-being and outcomes., Conclusions: Hierarchical end points assess the potential utility of a new therapy on patient well-being and outcome more holistically than time-to-first event analysis. Trials that would not have been feasible due to decreasing rates of death and hospitalization in the HF population can use hierarchical end points to successfully power studies to identify promising HF therapies. The HEART-FID trial used hierarchical end points to better determine the role of intravenous ferric carboxymaltose in patients with HF., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931., Competing Interests: Disclosures Dr Harrington receives salary support from T32 training grant T32HL069749. Dr Mentz received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. Dr Rockhold receives research support from the National Institutes of Health (NIH), PCORI, Bristol Myers Squibb, AstraZeneca, American Regent, Gates Foundation, and Eidos; consulting for Janssen, Clover, Doctor Evidence, and Intercept; data safety monitoring board for Lilly, AstraZeneca, Merck, Gilead, Novartis, Icosavax, Sanofi, UCB, Amgen, Biogen, Bristol Myers Squibb, Pulmocide, Alkermes, and Diurnal; nonprofit chairman of the board (unpaid) for the Frontier Science Foundation; and stock/stock options from GlaxoSmithKline, Clover, Athira, Doctor Evidence, Datavant, Spencer Health Solutions, and Adaptic Health. Dr Wong received research support and honoraria from American Regent, AstraZeneca, Novartis, Pfizer, and Vifor. Dr Troughton received research support and honoraria from American Regent, Bayer, Merck, and Roche Diagnostics. Dr De Pasquale received consultant fees or honoraria from American Regent, AstraZeneca, Bayer, Biotronic, Boehringer Ingelheim, Lilly, Novartis, Otsuka, Roche Servier, St Jude, and Vifor and research support from AstraZeneca and Novartis. Dr O’Meara received research support from the Canadian Heart Function Alliance, the TIMI Group, American Regent, Cardurion, and AstraZeneca for work as a steering committee member; Cardurion (paid to her institution); and consulting and speaking fees from AstraZeneca, Boehringer Ingelheim, Bayer, Eli Lilly, and Janssen. J.A. Ezekowitz reports research grants or consulting fees from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr Lewis reports research funding from the NIH, the American Heart Association, Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, SoniVie, and NXT. Dr Lewis received honoraria as an advisory board member for American Regent and as an advisory board member for Pfizer, Merck, Boehringer Ingelheim, NXT, American Regent, Cyclerion, Cytokinetics, and Amgen outside of the subject content of the current study. Dr Lewis receives royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Hernandez reports research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Merck, Novartis, and Verily and consulting from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squib, Myokardia, and Novo Nordisk. Dr Butler reports serving as a consultant to Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Berlin Cures, Boehringer Ingelheim, Bristol Myers Squib, CVRx, G3 Pharmaceutical, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Occlutech, Relypsa, Roche, Sanofi, SC Pharma, V-Wave Ltd, and Vifor. R. Adamczyk and Drs Storie and Blackman are employees of American Regent. The other authors report no conflicts.

The field of heart failure has evolved in terms of the therapies that are available including pharmaceutical and device therapies. There is now substantial randomized trial data to indicate that dietary sodium restriction does not provide the reduction in clinical events with accepted heterogeneity in the clinical trial results. Dietary sodium restriction should be considered for some but not all patients and with different objectives than clinical outcomes but instead for potential quality of life benefit. In addition, fluid restriction, once the mainstay of clinical practice, has not shown to be of any additional benefit for patients in hospital or in the ambulatory care setting and therefore should be considered to be used cautiously (if at all) in clinical practice. Further developments and clinical trials are needed in this area to better identify patients who may benefit or have harm from these lower cost interventions and future research should focus on large scale, high quality, clinical trials rather than observational data to drive clinical practice., Competing Interests: Declaration of competing interest The authors confirm that they have no conflicts of interest. Dr. Ezekowitz reports research support for trial leadership or grants from American Regent, Applied Therapeutics, AstraZeneca, Bayer, Cytokinetics, Merck & Co, Novo Nordisk, Otsuka; honoraria for consultancy from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, Otsuka; serves as an advisor to US2.ai., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) and chronic kidney disease (CKD) frequently co-exist. The frequency of kidney monitoring and range of kidney function in patients with AF in clinical practice are uncertain., Methods: All adult Albertans with AF between 2008 and 2017 were identified using ICD-9 and -10 codes 427.3 and I48. Kidney Disease Improving Global Outcomes (KDIGO) risk categories were defined using eGFR by the Chronic Kidney Disease Epidemiology Collaborative equation and albuminuria results within 6 months of eGFR measurement. eGFR trajectories were compared from baseline to maximum value within the following year., Results: Among 105,946 patients with AF, 16.0% were KDIGO category G1 (eGFR ≥ 90), 49.0% G2 (60-89.9), 19.8% G3a (45-59.9), 11.4% G3b (30-44.9), and G4 3.8% (15-29.9). Albuminuria was normal/mild 83.4%, moderate 11.7%, and severe 4.9%. Kidney monitoring was more common among people with lower eGFR and worse albuminuria, from approximately twice annually for G1-2/A1-2 to 8 times annually in stage G4A3. Approximately 60-80% of patients received guideline-recommended monitoring, consistent across KDIGO stages. With lower baseline eGFR, annual change in eGFR decreased while the relative proportion of patients who worsened compared to improved increased: for baseline eGFR 60-89.9, 16.7% worsened vs 6.7% improved, but for eGFR 30-44.9, 8.8% worsened but only 1.0% improved., Conclusion: The frequency of kidney function monitoring in patients with AF increased with worsening KDIGO risk category and adhered to KDIGO guidelines in approximately three quarters of patients. A minority of patients had moderate to severe eGFR impairment, of whom most remained stable over 1 year., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

Background: Prior clinical trials have investigated intravenous iron in patients with heart failure (HF) and iron deficiency, but the safety and efficacy of this therapy remains unclear., Methods: We report the baseline demographics and clinical characteristics of patients enrolled in the HEART-FID study and compare HEART-FID participants with patients within other contemporary clinical trials of patients with HF with reduced ejection fraction (HFrEF), including other intravenous iron trials., Results: In the 3,065 participants randomized in HEART-FID, median (IQR) age was 69.7 (62.0-76.5) years, 1,037 (33.8%) were female, 322 (10.5%) were Black, median ejection fraction was 32% (25%-37%), 1,837 (60.0%) had ischemic etiology, and baseline median NT-proBNP was 1,462 (721-2,966) pg/mL. Median baseline hemoglobin was 12.6 (11.6-13.6) g/dL, and median 6-minute walk test distance was 272 (196-350) m, similar to prior intravenous iron HFrEF trials. Common comorbidities included atrial fibrillation/flutter (43.7%), and type 2 diabetes (45.2%). Compared with several recent HFrEF trials, patients enrolled in HEART-FID had similar baseline demographics and clinical characteristics, though a greater proportion of women and Black participants were recruited in HEART-FID. In HEART-FID, HFrEF therapy included a beta-blocker in 92.5%, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitors (ARNI) in 86.1% (with 29.7% ARNI), and a mineralocorticoid antagonist (MRA) in 55.6%., Conclusions: Patients enrolled in HEART-FID were similar to those enrolled in other contemporary HFrEF trials and registries, including trials of intravenous iron in HFrEF. However, the HEART-FID cohort is substantially larger and more racially diverse than prior trials of intravenous iron in HFrEF., Trial Registration: ClinicalTrials.gov (NCT03037931)., (Copyright © 2023 Elsevier Inc. All rights reserved.)