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Background: Increased hsCRP (high-sensitivity C-reactive protein), a marker of inflammation, is associated with incident cardiovascular events. We aim to determine whether the baseline or trajectory of hsCRP levels over time predicts incident heart failure (HF) hospitalization., Methods: JHS (Jackson Heart Study) participants' (n=3920 Black adults) hsCRP levels were measured over 3 visits (from 2000 to 2013). We assessed the association of hsCRP at baseline (visit 1) with incident HF hospitalization using Cox proportional hazards models. Furthermore, we assessed the association of the trajectory of hsCRP over repeated measurements (visits 1-3) with incident HF using joint models. Hazard ratios are reflective of an increase in hsCRP by 1 SD on a log2 scale. We also assessed the association of change in hsCRP between visit 1 and visit 3 with Cox proportional hazards models by grouping patients by low (<2 mg/L) and high (≥2 mg/L) hsCRP levels. The 4 groups were low-to-low (referent), low-to-high, high-to-low, and high-to-high., Results: Mean baseline age of participants was 54±13 years, and 63.8% were women. Over a median follow-up of 12 years, 308 (7.9%) participants were hospitalized with incident HF. Baseline hsCRP was not associated with incident HF (adjusted hazard ratio, 1.08 [95% CI, 0.96-1.22]). However, increasing hsCRP levels over repeated measures were associated with a higher risk of incident HF overall (adjusted hazard ratio, 1.22 [95% CI, 1.03-1.44]) and HF with preserved ejection fraction (adjusted hazard ratio, 1.30 [95% CI, 1.02-1.65]) but not HF with reduced ejection fraction ( P >0.05). Furthermore, changes in hsCRP from low-to-high and high-to-low levels were associated with incident HF ( P <0.05)., Conclusions: While baseline hsCRP was not associated with incident HF, an increasing trajectory of hsCRP over time was associated with increased risk for incident HF (particularly HF with preserved ejection fraction). Temporal change in hsCRP may be an important marker of risk for incident HF with preserved ejection fraction in Black adults., Competing Interests: 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 Shah reports research support not related to this study from Novartis and Philips Ultrasound and consulting fees from Philips Ultrasound. Dr Virani receives research support from the Department of Veterans Affairs, the National Institutes of Health, and Tahir and Jooma Family. Dr Virani also received an honorarium from the American College of Cardiology in his role as an Associate Editor for Innovations, acc.org. Dr Butler reported personal 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, Relypsa, Roche, V-Wave Ltd, and Vifor outside the submitted work. The other authors report no conflicts. The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, the US Department of Health and Human Services, or the Department of Veterans Affairs.

Purpose of Review: End stage kidney disease can be a slow process and it may be challenging to achieve required follow-up for sufficient events. Therefore, a surrogate kidney endpoint, such as estimated glomerular filtration rate (eGFR) slope maybe attractive to assess the kidney in cardiovascular trials, especially heart failure (HF)., Recent Findings: eGFR slope can generate informative results in a shorter follow-up period, has decreased risk of type-2 error, and is less sensitive to eGFR shifts compared with other surrogate kidney endpoints (eGFR decline≥40% or doubling creatinine). However, eGFR slope has its limitations with acute effects, heterogeneity in slope calculation/reporting, and deviations from linearity. eGFR slope is a kidney endpoint which may be well-suited for HF trials. Cross-collaborated guideline recommendations are needed to optimize the use of eGFR slope as a kidney endpoint in patients with HF., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: U.S. nationwide estimates of the proportion of patients newly diagnosed with heart failure with reduced ejection fraction (HFrEF) eligible for quadruple medical therapy, and the associated benefits of rapid implementation, are not well characterized., Objectives: This study sought to characterize the degree to which patients newly diagnosed with HFrEF are eligible for quadruple medical therapy, and the projected benefits of in-hospital initiation., Methods: Among patients hospitalized for newly diagnosed HFrEF in the Get With The Guidelines-Heart Failure registry from 2016 to 2023, eligibility criteria based on regulatory labeling, guidelines, and expert consensus documents were applied for angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitor therapies. Of those eligible, the projected effect of quadruple therapy on 12-month mortality was modeled using treatment effects from pivotal clinical trials utilized by the AHA/ACC/HFSA Guideline for the Management of Heart Failure, and compared with observed outcomes among patients treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blockers., Results: Of 33,036 patients newly diagnosed with HFrEF, 27,158 (82%) were eligible for quadruple therapy, and 30,613 (93%) were eligible for ≥3 components. From 2021 to 2023, of patients eligible for quadruple therapy, 15.3% were prescribed quadruple therapy and 41.5% were prescribed triple therapy. Among Medicare beneficiaries eligible for quadruple therapy, 12-month incidence of mortality was 24.7% and HF hospitalization was 22.2%. Applying the relative risk reductions in clinical trials, complete implementation of quadruple therapy by time of discharge was projected to yield absolute risk reductions in 12-month mortality of 10.4% (number needed to treat = 10) compared with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blocker, and 24.8% (number needed to treat = 4) compared with no GDMT., Conclusions: In this nationwide U.S. cohort of patients hospitalized for newly diagnosed HFrEF, >4 of 5 patients were projected as eligible for quadruple therapy at discharge; yet, <1 in 6 were prescribed it. If clinical trial benefits can be fully realized, in-hospital initiation of quadruple medical therapy for newly diagnosed HFrEF would yield large absolute reductions in mortality., Competing Interests: Funding Support and Author Disclosures The Get With The Guidelines–Heart Failure (GWTG-HF) program is provided by the American Heart Association and sponsored, in part, by Novartis, Boehringer Ingelheim, and Eli Lilly Diabetes Alliance, Novo Nordisk, Sanofi, AstraZeneca, and Bayer. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards or as consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Corteria Pharmaceuticals, CSL Vifor, Cytokinetics, Eli Lilly, Lexicon, Merck, Roche Diagnostics, Sanofi, scPharmaceuticals, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Bayer, Boehringer Ingelheim, Cytokinetics, Lexicon, and Roche Diagnostics. Dr Fonarow has consulted for Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson and Johnson, Medtronic, Merck, Novartis, and Pfizer. 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.)

Aim: The RESHAPE-HF2 trial is designed to assess the efficacy and safety of the MitraClip device system for the treatment of clinically important functional mitral regurgitation (FMR) in patients with heart failure (HF). This report describes the baseline characteristics of patients enrolled in the RESHAPE-HF2 trial compared to those enrolled in the COAPT and MITRA-FR trials., Methods and Results: The RESHAPE-HF2 study is an investigator-initiated, prospective, randomized, multicentre trial including patients with symptomatic HF, a left ventricular ejection fraction (LVEF) between 20% and 50% with moderate-to-severe or severe FMR, for whom isolated mitral valve surgery was not recommended. Patients were randomized 1:1 to a strategy of delivering or withholding MitraClip. Of 506 patients randomized, the mean age of the patients was 70 ± 10 years, and 99 of them (20%) were women. The median EuroSCORE II was 5.3 (2.8-9.0) and median plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 2745 (1407-5385) pg/ml. Most patients were prescribed beta-blockers (96%), diuretics (96%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (82%) and mineralocorticoid receptor antagonists (82%). The use of sodium-glucose cotransporter 2 inhibitors was rare (7%). Cardiac resynchronization therapy (CRT) devices had been previously implanted in 29% of patients. Mean LVEF, left ventricular end-diastolic volume and effective regurgitant orifice area (EROA) were 31 ± 8%, 211 ± 76 ml and 0.25 ± 0.08 cm 2 , respectively, whereas 44% of patients had mitral regurgitation severity of grade 4+. Compared to patients enrolled in COAPT and MITRA-FR, those enrolled in RESHAPE-HF2 were less likely to have mitral regurgitation grade 4+ and, on average, HAD lower EROA, and plasma NT-proBNP and higher estimated glomerular filtration rate, but otherwise had similar age, comorbidities, CRT therapy and LVEF., Conclusion: Patients enrolled in RESHAPE-HF2 represent a third distinct population where MitraClip was tested in, that is one mainly comprising of patients with moderate-to-severe FMR instead of only severe FMR, as enrolled in the COAPT and MITRA-FR trials. The results of RESHAPE-HF2 will provide crucial insights regarding broader application of the transcatheter edge-to-edge repair procedure in clinical practice., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been studied in patients with heart failure, type 2 diabetes, chronic kidney disease, atherosclerotic cardiovascular disease, and acute myocardial infarction. Individual trials were powered to study composite outcomes in one disease state. We aimed to evaluate the treatment effect of SGLT2 inhibitors on specific clinical endpoints across multiple demographic and disease subgroups., Methods: In this systematic review and meta-analysis, we queried online databases (PubMed, Cochrane CENTRAL, and SCOPUS) up to Feb 10, 2024, for primary and secondary analyses of large trials (n>1000) of SGLT2 inhibitors in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease (including acute myocardial infarction). Outcomes studied included composite of first hospitalisation for heart failure or cardiovascular death, first hospitalisation for heart failure, cardiovascular death, total (first and recurrent) hospitalisation for heart failure, and all-cause mortality. Effect sizes were pooled using random-effects models. This study is registered with PROSPERO, CRD42024513836., Findings: We included 15 trials (N=100 952). Compared with placebo, SGLT2 inhibitors reduced the risk of first hospitalisation for heart failure by 29% in patients with heart failure (hazard ratio [HR] 0·71 [95% CI 0·67-0·77]), 28% in patients with type 2 diabetes (0·72 [0·67-0·77]), 32% in patients with chronic kidney disease (0·68 [0·61-0·77]), and 28% in patients with atherosclerotic cardiovascular disease (0·72 [0·66-0·79]). SGLT2 inhibitors reduced cardiovascular death by 14% in patients with heart failure (HR 0·86 [95% CI 0·79-0·93]), 15% in patients with type 2 diabetes (0·85 [0·79-0·91]), 11% in patients with chronic kidney disease (0·89 [0·82-0·96]), and 13% in patients with atherosclerotic cardiovascular disease (0·87 [0·78-0·97]). The benefit of SGLT2 inhibitors on both first hospitalisation for heart failure and cardiovascular death was consistent across the majority of the 51 subgroups studied. Notable exceptions included acute myocardial infarction (22% reduction in first hospitalisation for heart failure; no effect on cardiovascular death) and heart failure with preserved ejection fraction (26% reduction in first hospitalisation for heart failure; no effect on cardiovascular death)., Interpretation: SGLT2 inhibitors reduced heart failure events and cardiovascular death in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease. These effects were consistent across a wide range of subgroups within these populations. This supports the eligibility of a large population with cardiorenal-metabolic diseases for treatment with SGLT2 inhibitors., Funding: None., Competing Interests: Declaration of interests DLB discloses advisory board membership for Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; board of directors membership for American Heart Association New York City, Angiowave (stock options), BristolMyersSquibb (stock), DRS.LINQ (stock options), and High Enroll (stock); consultancy fees for Broadview Ventures, GSK, Hims, SFJ, and Youngene; data monitoring committee membership for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health-funded MINT Trial); honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/BristolMyersSquibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); other fees from Clinical Cardiology (Deputy Editor); a patent from Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, BristolMyersSquibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); is a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; is a trustee for American College of Cardiology; and unfunded research from FlowCo. SDA declares grants and personal fees from Vifor and Abbott Vascular, and personal fees for consultancies, trial committee work and/or lectures from Actimed, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Cytokinetics, Edwards, Farraday Pharmaceuticals, GSK, HeartKinetics, Impulse Dynamics, Occlutech, Pfizer, Regeneron, Repairon, Scirent, Sensible Medical, Servier, Vectorious, and V-Wave. He is a named co-inventor of two patent applications regarding MR-proANP (DE 102007010834 & DE 102007022367), but he does not benefit personally from the related issued patents. AYYC declares Advisory board membership for, and consulting fees, and speaking fees from, Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, GSK, HLS, Therapeutics, Insulet, Janssen, Medtronic, Novo Nordisk, Pfizer, and Sanofi. AFH reports being a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, BristolMyersSquibb, Cytokinetics, Eidos, GSK, Intellia, Intercept, Myokardia, Novartis, Novo Nordisk, Prolaio, and TikkunLev, and research funding from American Regent, Amgen, Bayer, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Novo Nordisk, and Verily. WSJ reports research grants from Bayer, Boehringer Ingelheim, Merck, Novartis, PCORI, and National Institutes of Health. MSK discloses fees from Bayer. MCP discloses research funding from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; and consultancy and trial committee memberships for Akero, Applied Therapeutics, Amgen, AnaCardio, Biosensors, Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, Abbvie, Bayer, Horizon Therapeutics, Takeda, Cardiorentis, Pharmacosmos, Siemens, Eli Lilly, Vifor, New Amsterdam, Moderna, Teikoku, LIB Therapeutics, and 3R Lifesciences. JAU discloses advisory board membership for Boehringer Ingelheim, Novavax, Novo Nordisk, and Sanofi; speaker honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, and Eli Lilly; and research funding to his institution from Amgen, Bayer, Boehringer Ingelheim, and Novartis. TF declares personal fees for statistical consultancies (including data monitoring committees) from Actimed, Aslan, Bayer, BiosenseWebster, BMS, CSL Behring, Daiichi Sankyo, Enanta, Fresenius Kabi, Galapagos, IQVIA, Immunic, KyowaKirin, LivaNova, Minoryx, Novartis, PINK! gegen Brustkrebs, PPD, RECARDIO, Recordati, Relaxera, Roche, Servier, Viatris, Vifor, and VICO Therapeutics, all outside of the submitted work. JB serves as a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, BristolMyersSquibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Eli 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. MSU and IH declare no competing interests., (Copyright © 2024 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Frailty affects half of all patients with heart failure with reduced ejection fraction (HFrEF) and carries a ∼2-fold increased risk of mortality. The relationship between frailty and HFrEF is bidirectional, with one condition exacerbating the other. Paradoxical to their higher clinical risk, frail patients with HFrEF are more often under-treated due to concerns over medication-related adverse clinical events. However, current evidence suggests consistent safety of HF medical therapies among older frail patients with HFrEF. A multidisciplinary effort is necessary for the appropriate management of these high-risk patients which focuses on the optimization of known beneficial therapies with a goal-directed effort toward improving quality of life., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Patterns and disparities in guideline-directed medical therapy (GDMT) uptake for heart failure with reduced ejection fraction (HFrEF) across rural vs urban regions are not well described., Objectives: This study aims to evaluate patterns, prognostic implications, and rural-urban differences in GDMT use among Medicare beneficiaries following new-onset HFrEF., Methods: Patients with a diagnosis of new-onset HFrEF in a 5% Medicare sample with available data for Part D medication use were identified from January 2015 through December 2020. The primary exposure was residence in rural vs urban zip codes. Optimal triple GDMT was defined as ≥50% of the target daily dose of beta-blockers, ≥50% of the target daily dose of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker or any dose of sacubitril/valsartan, and any dose of mineralocorticoid receptor antagonist. The association between the achievement of optimal GDMT over time following new-onset HFrEF diagnosis and risk of all-cause mortality and subsequent HF hospitalization was also evaluated using adjusted Cox models. The association between living in rural vs urban location and time to optimal GDMT achievement over a 12-month follow-up was assessed using cumulative incidence curves and adjusted Fine-Gray subdistribution hazard models., Results: A total of 41,296 patients (age: 76.7 years; 15.0% Black; 27.6% rural) were included. Optimal GDMT use over the 12-month follow-up was low, with 22.5% initiated on any dose of triple GDMT and 9.1% on optimal GDMT doses. Optimal GDMT on follow-up was significantly associated with a lower risk of death (HR: 0.89 [95% CI: 0.85-0.94]; P < 0.001) and subsequent HF hospitalization (HR: 0.93 [95% CI: 0.87-0.98]; P = 0.02). Optimal GDMT use at 12 months was significantly lower among patients living in rural (vs urban) areas (8.4% vs 9.3%; P = 0.02). In adjusted analysis, living in rural (vs urban) locations was associated with a significantly lower probability of achieving optimal GDMT (HR: 0.92 [95% CI: 0.86-0.98]; P = 0.01 Differences in optimal GDMT use following HFrEF diagnosis accounted for 16% of excess mortality risk among patients living in rural (vs urban) areas., Conclusions: Use of optimal GDMT following new-onset HFrEF diagnosis is low, with substantially lower use noted among patients living in rural vs urban locations. Suboptimal GDMT use following new-onset HFrEF was associated with an increased risk of mortality and subsequent HF hospitalization., Competing Interests: Funding Support and Author Disclosures This study is supported by a National Institute of Minority Health and Disparities R01 grant (R01MD017529) and an American Heart Association grant (23DSG1154425) to Dr Pandey. Dr Keshvani has received grants from the National Heart, Lung, and Blood Institute (5T32HL125247-08) and consulting fees from Heart Test Laboratories and Tricog Health. Dr Khan has received consulting fees from Bayer. Dr Hsich is supported by grants from the National Heart, Lung, and Blood Institute (R01HL164405). Dr Fonarow has done consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Janssen, Medtronic, Merck, Novartis, and Pfizer. Dr Pandey has received research funding from the Texas Health Resources Clinical Scholarship, Gilead Sciences Research Scholar Program, Applied Therapeutics (investigator-initiated grant), and National Institute of Aging (GEMSSTAR grant 1R03AG067960-01); serves on the Advisory Board of Roche Diagnostics; has received grants from the National Institute on Aging (1R03AG067960-01), the National Institute on Minority Health and Disparities (R01MD017529), Applied Therapeutics, Gilead Sciences Research, and Myovista Research; has received consultant fees from Roche Diagnostics, Tricog Health, Pieces Technologies, Rivus, Palomarin Inc, Emmi Solutions; has received nonfinancial support from Pfizer and Merck; and has received Advisory Board fees from Lilly Inc, Cytokinetics, Alleviant Medical, Axon Therapies, and Bayer. 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.)

Heart failure (HF) affects more than 60 million individuals globally. Empagliflozin is currently approved for type 2 diabetes and chronic HF. Clinical trials have demonstrated that empagliflozin reduces the composite end point of hospitalizations for HF and mortality and improves the quality of life irrespective of left ventricular ejection fraction. Empagliflozin is a once-daily medication with minimal drug-drug interactions and does not require titration. Empagliflozin causes mild weight loss and does not significantly reduce blood pressure. Empagliflozin acts as an enabler for other HF drugs by reducing the risk of hyperkalemia. Empagliflozin is also beneficial for chronic kidney disease which exists commonly with HF. This review outlines the pharmacokinetics, pharmacodynamics, safety, and efficacy of empagliflozin in HF across various sub-groups and settings.

Background: Recent evidence suggests that acetazolamide may be beneficial as an adjunctive diuretic therapy in patients with acute decompensated heart failure (HF). We aim to pool all the studies conducted until now and provide updated evidence regarding the role of acetazolamide as adjunctive diuretic in patients with acute decompensated HF., Methods: PubMed/Medline, Cochrane Library, and Scopus were searched from inception until July 2023, for randomized and nonrandomized studies evaluating acetazolamide as add-on diuretic in patients with acute decompensated HF. Data about natriuresis, urine output, decongestion, and the clinical signs of congestion were extracted, pooled, and analyzed. Data were pooled using a random effects model. Results were presented as risk ratios (RRs), odds ratios (ORs), or weighted mean differences (WMD) with 95% confidence intervals (95% CIs). Certainty of evidence was assessed using the grading of recommendation, assessment, development, and evaluation (GRADE) approach. A P value of < 0.05 was considered significant in all cases., Results: A total of 5 studies (n = 684 patients) were included with a median follow-up time of 3 months. Pooled analysis demonstrated significantly increased natriuresis (MD 55.07, 95% CI 35.1-77.04, P < 0.00001; I 2 = 54%; moderate certainty), urine output (MD 1.04, 95% CI 0.10-1.97, P = 0.03; I 2 = 79%; moderate certainty) and decongestion [odds ratio (OR) 1.62, 95% CI 1.14-2.31, P = 0.007; I 2 = 0%; high certainty] in the acetazolamide group, as compared with controls. There was no significant difference in ascites (RR 0.56, 95% CI 0.23-1.36, P = 0.20; I 2 = 0%; low certainty), edema (RR 1.02, 95% CI 0.52-2.0, P = 0.95; I 2 = 45%; very low certainty), raised jugular venous pressure (JVP) (RR 0.86, 95% CI 0.63-1.17, P = 0.35; I 2 = 0%; low certainty), and pulmonary rales (RR 0.82, 95% CI 0.44-1.51, P = 0.52; I 2 = 25%; low certainty) between the two groups., Conclusions: Acetazolamide as an adjunctive diuretic significantly improves global surrogate endpoints for decongestion therapy but not all individual signs and symptoms of volume overload., Systematic Review Registration: This systematic review was prospectively registered on the PROSPERO ( https://www.crd.york.ac.uk/PROSPERO/ ), registration number CRD498330., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Individuals with acute decompensated heart failure (ADHF) have a varying response to diuretic therapy. Strategies for the early identification of low diuretic efficiency to inform decongestion therapies are lacking., Objectives: The authors sought to develop and externally validate a machine learning-based phenomapping approach and integer-based diuresis score to identify patients with low diuretic efficiency., Methods: Participants with ADHF from ROSE-AHF, CARRESS-HF, and ATHENA-HF were pooled in the derivation cohort (n = 794). Multivariable finite-mixture model-based phenomapping was performed to identify phenogroups based on diuretic efficiency (urine output over the first 72 hours per total intravenous furosemide equivalent loop diuretic dose). Phenogroups were externally validated in other pooled ADHF trials (DOSE/ESCAPE). An integer-based diuresis score (BAN-ADHF score: blood urea nitrogen, creatinine, natriuretic peptide levels, atrial fibrillation, diastolic blood pressure, hypertension and home diuretic, and heart failure hospitalization) was developed and validated based on predictors of the diuretic efficiency phenogroups to estimate the probability of low diuretic efficiency using the pooled ADHF trials described earlier. The associations of the BAN-ADHF score with markers and symptoms of congestion, length of stay, in-hospital mortality, and global well-being were assessed using adjusted regression models., Results: Clustering identified 3 phenogroups based on diuretic efficiency: phenogroup 1 (n = 370; 47%) had lower diuretic efficiency (median: 13.1 mL/mg; Q1-Q3: 7.7-19.4 mL/mg) than phenogroups 2 (n = 290; 37%) and 3 (n = 134; 17%) (median: 17.8 mL/mg; Q1-Q3: 10.8-26.1 mL/mg and median: 35.3 mL/mg; Q1-Q3: 17.5-49.0 mL/mg, respectively) (P < 0.001). The median urine output difference in response to 80 mg intravenous twice-daily furosemide between the lowest and highest diuretic efficiency group (phenogroup 1 vs 3) was 3,520 mL/d. The BAN-ADHF score demonstrated good model performance for predicting the lowest diuretic efficiency phenogroup membership (C-index: 0.92 in DOSE/ESCAPE validation cohort) that was superior to measures of kidney function (creatinine or blood urea nitrogen), natriuretic peptide levels, or home diuretic dose (DeLong P < 0.001 for all). Net urine output in response to 80 mg intravenous twice-daily furosemide among patients with a low vs high (5 vs 20) BAN-ADHF score was 2,650 vs 660 mL per 24 hours, respectively. Participants with higher BAN-ADHF scores had significantly lower global well-being, higher natriuretic peptide levels on discharge, a longer in-hospital stay, and a higher risk of in-hospital mortality in both derivation and validation cohorts., Conclusions: The authors developed and validated a phenomapping strategy and diuresis score for individuals with ADHF and differential response to diuretic therapy, which was associated with length of stay and mortality., Competing Interests: Funding Support and Author Disclosures Dr Pandey has received research support from the National Institute of Health (5R01MD017529, R21HL169708) and grant funding from Applied Therapeutics and Gilead Sciences; has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Axon Therapies, Medtronic, Edward Lifesciences, Science37, Novo Nordisk, Bayer, Merck, Sarfez Pharmaceuticals, and Emmi Solutions; has received nonfinancial support from Pfizer and Merck; and is also a consultant for Palomarin Inc with stock compensation. Dr Segar has received honoraria from Merck. Dr Patel has served as a consultant to Novo Nordisk. Dr Fonarow has done consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Medtronic, Merck, and Novartis. Dr Mentz has 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 Allen reports grant funding from American Heart Association, National Institutes of Health, and PCORI; and consulting fees from Amgen, Boston Scientific, Cytokinetics, Novartis, and WCG ACI Clinical. Dr Pandey has received grant funding from Applied Therapeutics and Gilead Sciences; has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Bayer, Edwards Lifesciences, Medtronic, Sarfez Pharmacuticals, Novo Nordisk, and Roche Diagnostics; has received support from Pfizer and Merck; and is a consultant for Palomarin Inc with stock compensation. Dr Khan serves as an advisory board member for Bayer. 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.)

Various pharmacotherapies exist for heart failure with preserved ejection fraction (HFpEF), but with unclear comparative efficacy. We searched EMBASE, Medline, and Cochrane Library from inception through August 2021 for all randomized clinical trials in HFpEF (EF >40%) that evaluated beta-blockers, mineralocorticoid receptor antagonist (MRA), angiotensin-converting enzyme inhibitors (ACE), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitor (ARNI), and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Outcomes assessed were cardiovascular mortality, all-cause mortality, and HF hospitalization. A frequentist network meta-analysis was performed with a random-effects model. We included 22 randomized clinical trials (30,673 participants; mean age = 71.7 ± 4.2 years; females = 49.3 ± 7.7%; median follow-up = 24.4 ± 11.1 months). Compared with placebo, there was no statistically significant difference in cardiovascular mortality [beta-blockers; odds ratio (OR) 0.79 (0.46-1.34), MRA; OR 0.90 (0.70-1.14), ACE OR 0.95 (0.59-1.53), ARB; OR 1.02 (0.87-1.19), ARNI; OR 0.97 (0.74-1.26) and SGLT2i; OR 1.00 (0.84-1.18)] or all-cause mortality [beta blockers; OR 0.75 (0.54-1.04), MRA; OR 0.90 (0.75-1.08) ACE; OR 1.05 (0.71-1.54), ARB; OR 1.03 (0.91-1.15), ARNI; OR 0.99 (0.82-1.20) and SGLT2i; OR 1.00 (0.89-1.13)]. The certainty in these estimates was low or very low. There was a significantly reduction in HF hospitalization with the use of SGLT2i [OR 0.71 (0.62-0.82), moderate certainty], ARNI [OR 0.77 (0.63-0.94), low certainty], and MRA [OR 0.81 (0.66-0.98), moderate certainty]; with corresponding P scores of 0.84, 0.68, and 0.58, respectively. In HFpEF, the use of beta-blockers, MRA, ACE/ARB/ARNI, or SGLT2i was not associated with improved cardiovascular or all-cause mortality. SGLT2i, ARNI, and MRA reduced the risk of HF hospitalizations., Competing Interests: Disclosure: Dr S.J.G. has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, and Pfizer; has served on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, and Cytokinetics; and serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck, and Vifor. N.R.D. works under contract with the Centers for Medicare and Medicaid Services to develop and maintain performance measures used for public reporting and pay for performance programs. He reports research grants and consulting for Amgen, Astra Zeneca, Boehringer Ingelheim, Cytokinetics, MyoKardia, Novartis, SCPharmaceuticals, and Vifor Pharma. Dr E.D.M. reports Advisory Boards for AstraZeneca, Amarin, Bayer, Esperion, Novartis, and Novo Nordisk. Dr R.J.M. 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. All other authors have no conflicts of interests to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: The therapeutic mechanism of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on left cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF) is not well-established. This study meta-analysed the impact of SGLT2i on left cardiac structure and function in patients with HFrEF., Methods and Results: Online databases were queried up to April 2023 for trials reporting indicators of left cardiac structure and function in patients with HFrEF treated with SGLT2i. Data from studies were pooled using a random-effects model to derive weighted mean differences (WMDs) and 95% confidence intervals (CIs). Six trials were included (n = 555). Compared with control, SGLT2i significantly improved left ventricular end-diastolic volume (LVEDV; WMD: -17.07 ml [-23.84, -10.31]; p < 0.001), LVEDV index (WMD: -5.62 ml/m 2 [-10.28, -0.97]; p = 0.02), left ventricular end-systolic volume (LVESV; WMD: -15.63 ml [-26.15, -5.12]; p = 0.004), LVESV index (WMD: -6.90 ml/m 2 [-10.68, -3.11]; p = 0.001), left ventricular ejection fraction (WMD: 2.71% [0.70, 4.72]; p = 0.008), and left atrial volume index (WMD: -2.19 ml/m 2 [-4.26, -0.11]; p = 0.04) in patients with HFrEF. SGLT2i use was associated with a non-significant trend towards a reduction in left ventricular mass index (WMD: -6.25 g/m 2 [-12.79, 0.28]; p = 0.06). No significant impact on left ventricular global longitudinal strain was noted (WMD: 0.21% [-0.25, 0.67]; p = 0.38)., Conclusions: Sodium-glucose cotransporter 2 inhibitors improve cardiac structure and function in patients with HFrEF., (© 2024 European Society of Cardiology.)

Aims: The relationship between accelerometry data and changes in Kansas City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS) or 6 min walk test (6MWT) is not well understood., Methods and Results: VITALITY-HFpEF accelerometry substudy (n = 69) data were assessed at baseline and 24 weeks. Ordinal logistic regression models were used to assess the association between accelerometry activity and deterioration, improved, or unchanged KCCQ-PLS (≥8.33 and ≤ -4.17 points) and 6MWT (≥32 vs. ≤ -32 m). KCCQ-PLS score deteriorated in 16 patients, improved in 34, and was unchanged in 19. 6MWT deteriorated in 8 patients, improved in 21, and was unchanged in 19. Mean accelerometer wear was 21.4 (±2.1) h/day. Changes in hours active from baseline to 24 weeks were not significantly different among patients who exhibited deterioration, improvement, or no change in KCCQ-PLS [odds ratio (OR) 0.91, 95% confidence interval (CI) 0.71-1.18; P = 0.48] or 6MWT (OR 1.21, 95% CI 0.91-1.60; P = 0.18). Similar lack of association was observed for other accelerometry metrics and change in KCCQ and 6MWT. These findings were unaffected when KCCQ and 6MWT were examined as continuous variables., Conclusions: Accelerometer-based activity measures did not correlate with subjective or objective standard measures of health status and functional capacity in heart failure with preserved ejection fraction. Further investigation of their relationships to clinical outcomes is required., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The optimal approach to identify individuals with diabetes who are at a high risk for developing heart failure (HF) to inform implementation of preventive therapies is unknown, especially in those without atherosclerotic cardiovascular disease (ASCVD)., Methods: Adults with diabetes and no HF at baseline from 7 community-based cohorts were included. Participants without ASCVD who were at high risk for developing HF were identified using 1-step screening strategies: risk score (WATCH-DM [Weight, Age, Hypertension, Creatinine, HDL-C, Diabetes Control, QRS Duration, MI, and CABG] ≥12), NT-proBNP (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL), hs-cTn (high-sensitivity cardiac troponin T ≥14 ng/L; hs-cTnI ≥31 ng/L), and echocardiography-based diabetic cardiomyopathy (echo-DbCM; left atrial enlargement, left ventricular hypertrophy, or diastolic dysfunction). High-risk participants were also identified using 2-step screening strategies with a second test to identify residual risk among those deemed low risk by the first test: WATCH-DM/NT-proBNP, NT-proBNP/hs-cTn, NT-proBNP/echo-DbCM. Across screening strategies, the proportion of HF events identified, 5-year number needed to treat and number needed to screen to prevent 1 HF event with an SGLT2i (sodium-glucose cotransporter 2 inhibitor) among high-risk participants, and cost of screening were estimated., Results: The initial study cohort included 6293 participants (48.2% women), of whom 77.7% without prevalent ASCVD were evaluated with different HF screening strategies. At 5-year follow-up, 6.2% of participants without ASCVD developed incident HF. The 5-year number needed to treat to prevent 1 HF event with an SGLT2i among participants without ASCVD was 43 (95% CI, 29-72). In the cohort without ASCVD, high-risk participants identified using 1-step screening strategies had a low 5-year number needed to treat (22 for NT-proBNP to 37 for echo-DbCM). However, a substantial proportion of HF events occurred among participants identified as low risk using 1-step screening approaches (29% for echo-DbCM to 47% for hs-cTn). Two-step screening strategies captured most HF events (75-89%) in the high-risk subgroup with a comparable 5-year number needed to treat as the 1-step screening approaches (30-32). The 5-year number needed to screen to prevent 1 HF event was similar across 2-step screening strategies (45-61). However, the number of tests and associated costs were lowest for WATCH-DM/NT-proBNP ($1061) compared with other 2-step screening strategies (NT-proBNP/hs-cTn: $2894; NT-proBNP/echo-DbCM: $16 358)., Conclusions: Selective NT-proBNP testing based on the WATCH-DM score efficiently identified a high-risk primary prevention population with diabetes expected to derive marked absolute benefits from SGLT2i to prevent HF., Competing Interests: Disclosures Dr Patel has served as a consultant to Novo Nordisk. Dr Segar has received honoraria from Merck. Dr Klonoff has served as a consultant for Afon, Atropos Health, Better Therapeutics, Glucotrack, Lifecare, Novo, Samsung, and Thirdwayv. Dr Khan has received personal fees from Merck. Dr Lam has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on advisory boards/steering committees/executive committees for Actelion, Alleviant Medical, Allysta, Amgen, ANaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, EchoNous, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Us2.ai, and WebMD Global; and has served as cofounder and nonexecutive director of Us2.ai. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; has received research grants and honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, PhaseBio, and Pfizer; has received honoraria from Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; is a member of the scientific excellence committee of the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure With Reduced Ejection Fraction); has served as a national lead investigator of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and EMPEROR-Reduced trials; and is the president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Nasir is on the advisory board of Amgen, Novartis, and Novo Nordisk, and his research is partly supported by the Jerold B. Katz Academy of Translational Research. Dr Butler has served as a consultant for 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. Dr Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health/National Center for Advancing Translational Sciences Award UL 1TR002541) and has served on advisory boards or has received research grant support from American Regent, Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr Pandey has received research support from the National Institute on Aging GEMSSTAR Grant (1R03AG067960-01) and the National Institute on Minority Health and Disparities (R01MD017529). Dr Pandey has received grant funding (to the institution) from Applied Therapeutics, Gilead Sciences, Ultromics, Myovista, and Roche; has served as a consultant for and/or has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, Roche Diagnostics, Sarfez Therapeutics, Edwards Lifesciences, Merck, Bayer, Novo Nordisk, Alleviant, Axon Therapies; and has received nonfinancial support from Pfizer and Merck. Dr Pandey is also a consultant for Palomarin Inc with stocks compensation. The other authors report no conflicts.

Preload reserve represents an important concept in the normal physiologic responses of the body to meet the changing metabolic demands. The recruitment of preload in healthy patients leads to an increase in effective circulating blood volume with a concomitant increase in cardiac output. However, in the setting of heart failure (HF), preload augmentation may precipitate HF decompensation. In this review, we focus on the role of splanchnic nerve modulation and pharmacological therapeutic interventions to prevent HF decompensation through preload reduction. Furthermore, we explore the emerging device-based approaches for cardiac preload reduction while reviewing the ongoing clinical trials., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Heart failure (HF) is the leading cause of mortality in patients with acute myocardial infarction (AMI), with incidence ranging from 14% to 36% in patients admitted due to AMI. HF post-MI develops due to complex inter-play between macrovascular obstruction, microvascular dysfunction, myocardial stunning and remodeling, inflammation, and neuro-hormonal activation. Cardiogenic shock is an extreme presentation of HF post-MI and is associated with a high mortality. Early revascularization is the only therapy shown to improve survival in patients with cardiogenic shock. Treatment of HF post-MI requires prompt recognition and timely introduction of guideline-directed therapies to improve mortality and morbidity. This article aims to provide an up-to-date review on the incidence and pathogenesis of HF post-MI, current strategies to prevent and treat onset of HF post-MI, promising therapeutic strategies, and knowledge gaps in the field., Competing Interests: Declaration of competing interest Dr. Baron has received research support from Abiomed and Boston Scientific Corp; and has served as a consultant, on an advisory board, or as a paid speaker for Zoll Medical, Medtronic, Biotronik, Boston Scientific Corp, and Shockwave. Dr. Zieroth has received research grant support, served on advisory boards, or been a speaker for Abbott, Akcea Therapeutics, Inc., AstraZeneca, Amgen, Alnylam, Bayer, BMS, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, NovoNordisk, Otsuka, Pfizer, Servier, and Vifor Pharma; and has served on a clinical trial steering committee or as a national lead for studies sponsored by AstraZeneca, Bayer, Boehringer Ingelheim, Merck, and Novartis. Dr. Estep has served as a consultant for Abbott, and as a medical advisor for Medtronic. Dr. Burkhoff has received institutional support from Abiomed, Alleviant, Axon Therapies, Edwards Lifesciences, and Fire1; and has received consulting fees from Aquapass, Axon Therapies, BackBeat Medical, Corvia, BioMind, Impulse Dynamics, and Therox/Zoll. Dr. Butler has served as a consultant for Abbott, Adrenomed AG, Amgen, American Regent, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3Pharmaceutical, ImpulseDynamics, Innolife, Janssen Pharmaceuticals, LivaNova, Medtronic, Merck, Novartis, NovoNordisk, Pfizer, Roche, and Vifor Pharma. Dr. Fudim is a consultant to Zoll. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The prevalence of heart failure (HF) is increasing among young adults in the United States with pervasive racial and ethnic differences in this population., Objective: To evaluate contemporary associations between race and ethnicity, clinical comorbidities, and outcomes among young to middle-aged adults with HF., Methods: A retrospective analysis was performed using the National Health and Nutrition Examination Survey. All participants with a self-report of HF aged 20-64 years from 2005 to 2018 were included and stratified by race and ethnicity [non-Hispanic (NH) Whites, NH Blacks, and Hispanics]. Data on baseline characteristics including age, sex, marital status, citizenship, education level, body mass index, insurance, waist circumference, cigarette smoking, marijuana use, and relevant clinical comorbidities were included. Weighted logistic regression was performed to estimate adjusted odds ratios (aOR) to determine the association of race and ethnicity with HF. Cox proportional-hazards models were used to assess the association of race and ethnicity with all-cause and cardiac mortality., Results: A total of 1,940,447 young to middle-aged adults had self-reported HF between 2005 and 2018, of whom 61% were NH White, 40% were NH Black, and 22% were Hispanic. When compared with NH White adults, NH Black adults had higher odds of HF adjusted for age, sex, insurance status, marital status, education level, citizenship status, and clinical comorbidities (adjusted aOR 2.63, 95% CI: 1.71-4.05, p  < 0.001). There was no significant difference in the odds of HF between Hispanic and NH White adults (aOR 1.18, 95% CI: 0.64-2.18, p  = 0.585). NH Black adults had higher mean systolic and diastolic blood pressure, and a comparable or lower burden of cardiovascular and non-cardiovascular clinical comorbidities compared with NH White and Hispanic adults. No statistical significance was noted by race and ethnicity for all-cause and cardiac mortality during a follow-up of 5 years., Conclusion: NH Black young to middle-aged adults were more likely to have HF which may be related to higher blood pressure given the largely similar burden of clinically relevant comorbidities compared with other racial and ethnic groups.

Despite robust scientific evidence and strong guideline recommendations, there remain significant gaps in initiation and dose titration of guideline-directed medical therapy (GDMT) for heart failure (HF) among eligible patients. Reasons surrounding these gaps are multifactorial, and largely attributed to patient, healthcare professionals, and institutional challenges. Concurrently, HF remains a predominant cause of mortality and hospitalization, emphasizing the critical need for improved delivery of therapy to patients in routine clinical practice. To optimize GDMT, various implementation strategies have emerged in the recent decade such as in-hospital rapid initiation of GDMT, improving patient adherence, addressing clinical inertia, improving affordability, engagement in quality improvement registries, multidisciplinary clinics, and EHR-integrated interventions. This review highlights the current use and barriers to optimal utilization of GDMT, and proposes novel strategies aimed at improving GDMT in HF., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

Background and Aims: Whereas a beneficial effect of intravenous ferric carboxymaltose (FCM) on symptoms and exercise capacity among patients with iron deficiency and heart failure (HF) has been consistently demonstrated, the effects of treatment on clinical events remain the subject of research. This meta-analysis aimed to characterize the effects of FCM therapy on hospitalizations and mortality., Methods: Patient-level data from randomized, placebo-controlled FCM trials including adults with HF and iron deficiency with ≥52 weeks follow-up were analysed. The co-primary efficacy endpoints were (i) composite of total/recurrent cardiovascular hospitalizations and cardiovascular death and (ii) composite of total HF hospitalizations and cardiovascular death, through 52 weeks. Key secondary endpoints included individual composite endpoint components. Event rates were analysed using a negative binomial model. Treatment-emergent adverse events were also examined., Results: Three FCM trials with a total of 4501 patients were included. Ferric carboxymaltose was associated with a significantly reduced risk of co-primary endpoint 1 (rate ratio 0.86; 95% confidence interval 0.75-0.98; P = .029; Cochran Q: 0.008), with a trend towards a reduction of co-primary endpoint 2 (rate ratio 0.87; 95% confidence interval 0.75-1.01; P = .076; Cochran Q: 0.024). Treatment effects appeared to result from reduced hospitalization rates, not improved survival. Treatment appeared to have a good safety profile and was well tolerated., Conclusions: In iron-deficient patients with HF with reduced left ventricular ejection fraction, intravenous FCM was associated with significantly reduced risk of hospital admissions for HF and cardiovascular causes, with no apparent effect on mortality., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Endpoint adjudication (EA) is a common feature of contemporary randomized controlled trials (RCTs) in cardiovascular medicine. Endpoint adjudication refers to a process wherein a group of expert reviewers, known as the clinical endpoint committee (CEC), verify potential endpoints identified by site investigators. Events that are determined by the CEC to meet pre-specified trial definitions are then utilized for analysis. The rationale behind the use of EA is that it may lessen the potential misclassification of clinical events, thereby reducing statistical noise and bias. However, it has been questioned whether this is universally true, especially given that EA significantly increases the time, effort, and resources required to conduct a trial. Herein, we compare the summary estimates obtained using adjudicated vs. non-adjudicated site designated endpoints in major cardiovascular RCTs in which both were reported. Based on these data, we lay out a framework to determine which trials may warrant EA and where it may be redundant. The value of EA is likely greater when cardiovascular trials have nuanced primary endpoints, endpoint definitions that align poorly with practice, sub-optimal data completeness, greater operator variability, and lack of blinding. EA may not be needed if the primary endpoint is all-cause death or all-cause hospitalization. In contrast, EA is likely merited for more nuanced endpoints such as myocardial infarction, bleeding, worsening heart failure as an outpatient, unstable angina, or transient ischaemic attack. A risk-based approach to adjudication can potentially allow compromise between costs and accuracy. This would involve adjudication of a small proportion of events, with further adjudication done if inconsistencies are detected., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Declaration of Competing Interest Dr. Greene has received research support from the Duke University Department of Medicine Chair's Research Award, American Heart Association (number 929502), National Heart Lung and Blood Institute, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim/ Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, Sanofi, and scPharmaceuticals; serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Corteria Pharmaceuticals, CSL Vifor, Merck, PharmaIN, Roche Diagnostics, Sanofi, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Boehringer Ingelheim, cytokinetics, and Roche Diagnostics. The remaining authors have no competing interests to declare.

Background: Polypharmacy is common among patients with heart failure with reduced ejection fraction (HFrEF). However, its impact on the use of optimal guideline-directed medical therapy (GDMT) is not well established., Objectives: This study sought to evaluate the association between polypharmacy and odds of receiving optimal GDMT over time among patients with HFrEF., Methods: The authors conducted a post hoc analysis of the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment) trial. Polypharmacy was defined as receiving ≥5 medications (excluding HFrEF GDMT) at baseline. The outcome of interest was optimal triple therapy GDMT (concurrent administration of a renin-angiotensin-aldosterone blocker and beta-blocker at 50% of the target dose and a mineralocorticoid receptor antagonist at any dose) achieved over the 12-month follow-up. Multivariable adjusted mixed-effect logistic regression models with multiplicative interaction terms (time × polypharmacy) were constructed to evaluate how polypharmacy at baseline modified the odds of achieving optimal GDMT on follow-up., Results: The study included 891 participants with HFrEF. The median number of non-GDMT medications at baseline was 4 (IQR: 3-6), with 414 (46.5%) prescribed ≥5 and identified as being on polypharmacy. The proportion of participants who achieved optimal GDMT at the end of the 12-month follow-up was lower with vs without polypharmacy at baseline (15% vs 19%, respectively). In adjusted mixed models, the odds of achieving optimal GDMT over time were modified by baseline polypharmacy status (P for interaction < 0.001). Patients without polypharmacy at baseline had increased odds of achieving GDMT (OR: 1.16 [95% CI: 1.12-1.21] per 1-month increase; P < 0.001) but not patients with polypharmacy (OR: 1.01 [95% CI: 0.96-1.06)] per 1-month increase)., Conclusions: Patients with HFrEF who are on non-GDMT polypharmacy have lower odds of achieving optimal GDMT on follow-up., Competing Interests: Funding Support and Author Disclosures Dr Pandey has received research support from the National Institute on Aging GEMSSTAR grant (1R03AG067960-01) and the National Institute on Minority Health and Disparities (R01MD017529); grant funding from Applied Therapeutics and Gilead Sciences; honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, and Roche Diagnostics; nonfinancial support from Pfizer and Merck; and is a consultant for Palomarin Inc with stock compensation. Dr Segar has received speaker fees from Merck and Co outside the present study. Dr Butler is a consultant for 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. Dr Fonarow has done consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Frailty affects half of all patients with heart failure with reduced ejection fraction (HFrEF) and carries a ∼2-fold increased risk of mortality. The relationship between frailty and HFrEF is bidirectional, with one condition exacerbating the other. Paradoxical to their higher clinical risk, frail patients with HFrEF are more often under-treated due to concerns over medication-related adverse clinical events. However, current evidence suggests consistent safety of HF medical therapies among older frail patients with HFrEF. A multidisciplinary effort is necessary for the appropriate management of these high-risk patients which focuses on the optimization of known beneficial therapies with a goal-directed effort toward improving quality of life., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Whether the timing of hospital presentation impacts care delivery and clinical outcomes for patients hospitalized for heart failure (HF) remains a matter of debate. In this study, we examined all-cause and HF-specific 30-day readmission rates for patients who were admitted for HF on a weekend vs admitted for HF on a weekday., Methods and Results: We conducted a retrospective analysis using the 2010-2019 Nationwide Readmission Database to compare 30-day readmission rates among patients who were admitted for HF on a weekday (Monday to Friday) vs patients who were admitted for HF on a weekend (Saturday or Sunday). We also compared in-hospital cardiac procedures and temporal trends in 30-day readmission by day of index hospital admission. Among 8,270,717 index HF hospitalizations, 6,302,775 were admitted on a weekday and 1,967,942 admitted on a weekend. For weekday and weekend admissions, the 30-day all-cause readmission rates were 19.8% vs 20.3%, and HF-specific readmission rates were 8.1% vs 8.4%, respectively. Weekend admissions were independently associated with higher risk of all-cause (adjusted odds ratio [aOR] 1.04, 95% confidence interval [CI] 1.03-1.05, P < .001) and HF-specific readmission (aOR 1.04, 95% CI 1.03-1.05, P < .001). Weekend HF admissions were less likely to undergo echocardiography (aOR 0.95, 95% CI 0.94-0.96, P < .001), right heart catheterization (aOR 0.80, 95% CI 0.79-0.81, P < .001), electrical cardioversion (aOR 0.90, 95% CI 0.88-0.93, P < .001), or receive temporary mechanical support devices (aOR 0.84, 95% CI 0.79-0.89, P < .001). The mean length of stay was shorter for weekend HF admissions (5.1 days vs 5.4 days, P < .001). Between 2010 and 2019, 30-day all-cause (18.5% to 18.2%, trend P < .001) and HF-specific (8.4% to 8.3%, trend P < .001) readmission rates decreased among weekday HF admissions. Among weekend HF admissions, the HF-specific 30-day readmission rate decreased (8.8% to 8.7%, trend P < .001), but the all-cause 30-day readmission rate remained stable (trend P = .280)., Conclusions: Among patients hospitalized for HF, weekend admissions were independently associated with excess risk of 30-day all-cause and HF-specific readmission and a lower likelihood of undergoing in-hospital cardiovascular testing and procedures. The 30-day all-cause readmission rate has decreased modestly over time among patients admitted on weekdays, but has remained stable among patients admitted on weekends., Competing Interests: Disclosures Dr Butler serves as a consultant for Abbott, Adrenomed AG, Amgen, American Regent, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen Pharmaceuticals, LivaNova, Medtronic, Merck, Novartis, NovoNordisk, Pfizer, Roche, and Vifor Pharma. Dr. Greene has received research support from the Duke University Department of Medicine Chair's Research Award, American Heart Association (#929502), National Heart Lung and Blood Institute, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, Sanofi, and scPharmaceuticals; serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Corteria Pharmaceuticals, CSL Vifor, Merck, PharmaIN, Roche Diagnostics, Sanofi, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Boehringer Ingelheim, Cytokinetics, and Roche Diagnostics. All other authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hospital at home (HaH) is an innovative care model that may be particularly suited for heart failure (HF). Outpatient visits and inpatient care have been the 2 traditional settings for HF care, yet may not match the social and medical needs of patients at all times. Alternative models such as HaH may represent an effective and patient-centered option for select patients with worsening HF. To date, limited research in HF and other disease states has supported HaH as being safe and lower cost than traditional inpatient admission. Supporting HaH are new payment structures, such as Medicare's Acute Hospital Care at Home waiver program. In combination with outpatient visits, outpatient intravenous diuretic clinics, inpatient care, and cardiac intensive care, HaH could be a core component of a comprehensive care model with the potential to match resource utilization with the needs of patients across the spectrum of HF severity, and improve patient outcomes., Competing Interests: Disclosures Dr Fonarow reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Medtronic, Merck, and Novartis. Dr Butler serves as a consultant for Abbott, Adrenomed, Amgen, American Regent, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Medtronic, Merck, Novartis, NovoNordisk, Pfizer, Roche, and Vifor. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association (No. 929502), National Heart, Lung, and Blood Institute, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, scPharmaceuticals, and Sanofi; serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Corteria Pharmaceuticals, CSL Vifor, Lexicon, Lilly, Merck, PharmaIN, Roche Diagnostics, Sanofi, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Boehringer Ingelheim, Cytokinetics, Lexicon, and Roche Diagnostics. All other authors report no disclosures.

Heart failure (HF) is a heterogeneous syndrome affecting more than 60 million individuals globally. Despite recent advancements in understanding of the pathophysiology of HF, many issues remain including residual risk despite therapy, understanding the pathophysiology and phenotypes of patients with HF and preserved ejection fraction, and the challenges related to integrating a large amount of disparate information available for risk stratification and management of these patients. Risk prediction algorithms based on artificial intelligence (AI) may have superior predictive ability compared to traditional methods in certain instances. AI algorithms can play a pivotal role in the evolution of HF care by facilitating clinical decision making to overcome various challenges such as allocation of treatment to patients who are at highest risk or are more likely to benefit from therapies, prediction of adverse outcomes, and early identification of patients with subclinical disease or worsening HF. With the ability to integrate and synthesize large amounts of data with multidimensional interactions, AI algorithms can supply information with which physicians can improve their ability to make timely and better decisions. In this review, we provide an overview of the AI algorithms that have been developed for establishing early diagnosis of HF, phenotyping HF with preserved ejection fraction, and stratifying HF disease severity. This review also discusses the challenges in clinical deployment of AI algorithms in HF, and the potential path forward for developing future novel learning-based algorithms to improve HF care., (© 2023 European Society of Cardiology.)

Chronic kidney disease (CKD) is a major co-morbidity in patients with heart failure (HF). There are limited contemporary data characterizing the clinical profile, inhospital outcomes, and resource use in patients hospitalized for HF with co-morbid CKD. We utilized a nationally representative population to address the knowledge gap. We examined the National Inpatient Sample 2004 to 2018 database to study the co-morbid profile, in-hospital mortality, clinical resource utilization, healthcare cost, and length of stay (LOS) in primary adult HF hospitalizations stratified by presence versus absence of a diagnosis codes of CKD. There were a total of 16,050,301 adult hospitalizations with a primary HF diagnosis from January 1, 2004, to December 31, 2018. Of these, 428,175 (33.81%) had CKD; 1,110,778 (6.92%) had end-stage kidney disease (ESKD); and 9,511,348 (59.25%) had no diagnosis of CKD. Patients with hospitalizations for HF with ESKD were younger (mean age 65.4 years) compared with those without ESKD. In multivariable analysis, those with CKD had higher odds of inhospital mortality (2.82% vs 3.57%, adjusted odds ratio [aOR] 1.30, confidence interval [CI] 1.28 to 1.26, p <0.001), cardiogenic shock (1.01% vs 1.79% aOR 2.00, CI 1.95 to 2.05, p <0.001), and the need for mechanical circulatory support (0.4% vs 0.5%, aOR 1.51, 1.44 to 1.57, p <0.001) compared with those without CKD. In multivariable analysis, those with ESKD had higher odds of inhospital mortality (2.82% vs 3.84%, aOR 2.07, CI 2.01 to 2.12, p <0.001), need for invasive mechanical ventilation use (2.04% vs 3.94%, aOR 1.79, CI 1.75 to 1.84, p <0.001), cardiac arrest (0.72% vs 1.54%, aOR 2.09, CI 2.00 to 2.17, p <0.001), longer LOS (Adjusted mean difference 1.48, 1.44 to 1.53, p <0.001) and higher inflation-adjusted cost (Adjusted mean difference 3,411.63, CI 3,238.35 to 3,584.91, p <0.001) compared with those without CKD. CKD and ESKD affected about 40.7% of all primary HF hospitalizations from 2004 to 2018. The inhospital mortality, clinical complications, LOS, and inflation-adjusted cost were higher in hospitalized patients with ESKD compared with patients with and without CKD. In addition, compared with those without CKD, hospitalized patients with CKD had higher inhospital mortality, clinical complications, LOS, and inflation-adjusted cost compared with patients with no diagnosis of CKD., Competing Interests: Declaration of Competing Interest Dr. Greene has received research support from the Duke University Department of Medicine Chair's Research Award, American Heart Association, National Heart Lung and Blood Institute, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck & Co., Inc., Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim/ Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, and Sanofi; serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck & Co., Inc., PhamaIN, Roche Diagnostics, Sanofi, Tricog Health, Urovant Pharmaceuticals, and Vifor; and has received speaker fees from Boehringer Ingelheim. Dr. Fudim was supported by the National Heart, Lung, and Blood Institute (NHLBI) (K23HL151744), the American Heart Association (20IPA35310955), Bayer, Bodyport, BTG Specialty Pharmaceuticals, and Verily. He receives consulting fees from Abbott, Alleviant, Audicor, AxonTherapies, Bayer, Bodyguide, Bodyport, Boston Scientific, Coridea, CVRx, Daxor, Deerfield Catalyst, Edwards Lifesciences, Feldschuh Foundation, Fire1, Gradient, Intershunt, Medtronic, NXT Biomedical, Pharmacosmos, PreHealth, Shifamed, Splendo, Vironix, Viscardia, Zoll. Dr. Virani has received research support from the Department of Veterans Affairs, the National Institutes of Health, the World Heart Federation, Tahir, and the Jooma Family; and an honorarium from the American College of Cardiology (Associate Editor for Innovations, acc.org). The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Despite the availability of lifesaving guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF), there remain major gaps in utilization of these therapies among eligible patients. Simultaneous with these gaps in quality of care, HFrEF continues as a leading cause of death and hospitalization with associated clinical risk far exceeding most other cardiovascular and noncardiovascular conditions. In the context of this urgent need to improve provision of appropriate therapy, multiple lines of evidence support various implementation strategies. Such strategies include in-hospital initiation of GDMT, simultaneous or rapid sequence initiation of GDMT, participation in quality improvement registries to assess site performance and provide feedback, multidisciplinary titration clinics, virtual consult teams, reduction of cost-sharing, remote algorithm-based medication optimization, electronic health record-based interventions, and direct-to-patient educational initiatives. This review describes and contextualizes the evidence surrounding each of these potential avenues for improving use of foundational GDMTs for patients with HFrEF., Competing Interests: Funding Support and Author Disclosures Dr Khan has served on an advisory board for Bayer. Dr Fonarow has served as a consultant for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Janssen, Medtronic, Merck, Novartis, and Pfizer. Dr Butler has served as a consultant for Abbott, Adrenomed, Amgen, American Regent, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Medtronic, Merck, Novartis, Novo Nordisk, Pfizer, Roche, and Vifor. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association (#929502), Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, Sanofi, and scPharmaceuticals; has served as a consultant for Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim/Lilly, Corteria Pharmaceuticals, CSL Vifor, Lexicon, Merck, PharmaIN, Roche Diagnostics, Sanofi, scPharmaceuticals, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Boehringer Ingelheim, Cytokinetics, Lexicon, and Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Data are limited regarding the impact of ischemic cardiomyopathy (ICM) or non-ICM (NICM) on the trajectory of in-hospital decongestion among patients with acute decompensated heart failure (ADHF). Therefore, we aimed to assess the course of decongestion among patients admitted for ADHF by history of ICM and NICM. Patients included in the DOSE (Diuretic strategies in patients with acute decompensated heart failure), ROSE (ROSE acute heart failure randomized trial), and Ultrafiltration in decompensated heart failure with cardiorenal syndrome (CARRESS-HF) trials of patients with ADHF were categorized into ICM and NICM based on history. Among 762 patients included in our meta-analysis, 433 (56.8%) had a history of ICM. Patients with ICM were older (70.8 vs 63.9 years; p ≤0.001) and had higher rates of co-morbidities. After covariate adjustment, there was no significant differences between NICM and ICM regarding net fluid loss (4,952 vs 4,384 ml, p = 0.81) or mean change in serum N-terminal pro-brain natriuretic peptide (-2,162 vs -1,809 pg/ml, p = 0.092). Mean change in weight showed modest improvement in favor of patients with NICM, but this did not meet statistical significance (-8.24 vs -7.70 pounds, p = 0.068). After adjustment, there was no significant difference in the risk of 60-day composite all-cause mortality or hospitalization for HF among those with ICM versus NICM. Among patients with left ventricular ejection fraction <40%, NICM was associated with higher scoring on global sense of well-being (global visual analog scale; +25.5 vs +19.1, p = 0.023) and improvement in serum creatinine (-0.031 mg/100 ml vs +0.042 mg/100 ml, p = 0.009) at 72 hours. Among patients with left ventricular ejection fraction >40%, NICM was associated with decreased scoring on global visual analog scale at 72 hours (+15.7 vs +21.2, p = 0.049). In conclusion, more than half of the patients admitted for ADHF had ICM. History of ICM was not independently associated with a difference in course of decongestion, self-assessment of well-being and dyspnea, or short-term clinical outcomes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Recent studies focusing on the prevalence, characteristics, and outcomes of primary heart failure (HF) with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF) in non-alcoholic fatty liver disease (NAFLD) are sparse. We sought to assess these using a nationally-representative population. We used the 2016-2018 National Inpatient Sample database to study the prevalence, characteristics, clinical risk profiles, morbidity, mortality, cost, and resource utilization among primary HFpEF and HFrEF hospitalizations with and without NAFLD. In the period from January 1, 2016, to December 31, 2018, there were 3,522,459 admissions of patients aged ≥18 years with a diagnosis of primary HF. Of these, 82,585 (2.3%) hospitalizations had secondary diagnosis of NAFLD. Admissions with NAFLD and HFrEF were associated with higher rates of in-hospital mortality (aOR 1.84, CI 1.66-2.04, P < 0.001) compared to admissions of HFrEF without NAFLD. Similarly, hospitalizations with HFpEF-NAFLD were associated with higher rates of in hospital mortality (aOR 1.65 CI 1.43-1.9, P < 0.001) compared to HFpEF admissions without NAFLD. Pressors use, cardiogenic shock, AKI with or without dialysis use, cardiac arrest, LOS and hospitalization cost were higher in admissions of HFrEF and HFpEF with NAFLD compared to those without NAFLD. In-hospital mortality, was higher in primary HFrEF and HFpEF admissions with NAFLD compared to without NAFLD. Physicians must be aware of the worse clinical outcomes of HFrEF and HFpEF in patients with NAFLD. Further clinical research is needed to address the knowledge gap and treatment options available for the patients with HF and NAFLD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The burden of heart failure among people with type 2 diabetes is increasing globally. People with comorbid type 2 diabetes and heart failure often have worse outcomes than those with only one of these conditions-eg, higher hospitalisation and mortality rates. Therefore, it is essential to implement optimal heart failure prevention strategies for people with type 2 diabetes. A detailed understanding of the pathophysiology underlying the occurrence of heart failure in type 2 diabetes can aid clinicians in identifying relevant risk factors and lead to early interventions that can help prevent heart failure. In this Review, we discuss the pathophysiology and risk factors of heart failure in type 2 diabetes. We also review the risk assessment tools for predicting heart failure incidence in people with type 2 diabetes as well as the data from clinical trials that have assessed the efficacy of lifestyle and pharmacological interventions. Finally, we discuss the potential challenges in implementing new management approaches and offer pragmatic recommendations to help overcome these challenges., Competing Interests: Declaration of interests AP has received research support from the National Institute on Aging (GEMSSTAR grant: 1R03AG067960-01) and the National Institute on Minority Health and Disparities (R01MD017529); grant funding from Applied Therapeutics and Gilead Sciences; has received honoraria outside of the present study as an advisor or consultant for Tricog Health, Eli Lilly, Rivus, Cytokinetics, and Roche Diagnostics; has received non-financial support from Pfizer and Merck; and is also a consultant for Palomarin with stocks compensation. KVP has served as a consultant to Novo Nordisk. DLB sits on the advisory board of Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; and on the board of directors of Angiowave (with stock options), Boston VA Research Institute, Bristol Myers Squibb (with stock), DRS.LINQ (with stock options), High Enroll (with stock), Society of Cardiovascular Patient Care, and TobeSoft. DLB was the inaugural chair of the American Heart Association Quality Oversight Committee. DLB is a consultant for Broadview Ventures and Hims; and sits on data monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute) for the PORTICO trial funded by St Jude Medical (now Abbott), Boston Scientific (chair for PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (chair for PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine for the ENVISAGE trial funded by Daiichi Sankyo and for the ABILITY-DM trial funded by Concept Medical, Novartis, Population Health Research Institute, and Rutgers University for the National Institutes of Health-funded MINT Trial. DLB reports honoraria from the American College of Cardiology as Senior Associate Editor of Clinical Trials and News and chair of American College of Cardiology Accreditation Oversight Committee; Arnold and Porter law firm for work related to Sanofi–Bristol Myers Squibb clopidogrel litigation; Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute) for the RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim and AEGIS-II executive committee funded by CSL Behring; Belvoir Publications as Editor in Chief of Harvard Heart Letter; Canadian Medical and Surgical Knowledge Translation Research Group for clinical trial steering committees; Cowen and Company; Duke Clinical Research Institute for clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals; HMP Global as Editor in Chief of the Journal of Invasive Cardiology; Journal of the American College of Cardiology as Guest Editor and Associate Editor; K2P as co-chair of interdisciplinary curriculum; Level Ex; Medtelligence–ReachMD for continuing medical education steering committees; MJH Life Sciences; Oakstone CME as Course Director of the Comprehensive Review of Interventional Cardiology; Piper Sandler; Population Health Research Institute for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer; Slack Publications as Chief Medical Editor of Cardiology Intervention Today; Society of Cardiovascular Patient Care as secretary and treasurer; WebMD for continuing medical education steering committees; Wiley for steering committee. DLB reports non-financial relationships as Deputy Editor of Clinical Cardiology; as chair of the National Cardiovascular Data Registry–Acute Coronary Intervention and Outcomes Network Registry steering committee; as chair of the Veterans Affairs Cardiovascular Assessment, Reporting, and Tracking Research and publications committee. DLB reports a patent for sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; however, neither DLB or Brigham and Women's Hospital receive any income from this patent). DLB reports research funding for Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Eli Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio. DLB reports royalties from Elsevier as Editor of Braunwald's Heart Disease; as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; as trustee for the American College of Cardiology; and for unfunded research of FlowCo and Takeda. SV holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical, and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management, and Sanofi. SV is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organisation. MSK declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Multiple clinical trials have demonstrated significant cardiovascular benefit with use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with type 2 diabetes (T2DM) and heart failure (HF) irrespective of ejection fraction. There are limited data evaluating real-world prescription and practice patterns of SGLT2 inhibitors., Objectives: The authors sought to assess utilization rates and facility-level variation in the use among patients with established atherosclerotic cardiovascular disease (ASCVD), HF, and T2DM using data from the nationwide Veterans Affairs health care system., Methods: The authors included patients with established ASCVD, HF, and T2DM seen by a primary care provider between January 1, 2020, and December 31, 2020. They assessed the use of SGLT2 inhibitors and the facility-level variation in their use. Facility-level variation was computed using median rate ratios, a measure of likelihood that 2 random facilities differ in use of SGLT2 inhibitors., Results: Among 105,799 patients with ASCVD, HF, and T2DM across 130 Veterans Affairs facilities, 14.6% received SGLT2 inhibitors. Patients receiving SGLT2 inhibitors were younger men with higher hemoglobin A1c and estimated glomerular filtration rate and were more likely to have HF with reduced ejection fraction and ischemic heart disease. There was significant facility-level variation of SGLT2 inhibitor use, with an adjusted median rate ratio of 1.55 (95% CI: 1.46-1.64), indicating a 55% residual difference in SGLT2 inhibitor use among similar patients with ASCVD, HF, and T2DM receiving care at 2 random facilities., Conclusions: Utilization rates of SGLT2 inhibitors are low in patients with ASCVD, HF, and T2DM, with high residual facility-level variation. These findings suggest opportunities to optimize SGLT2 inhibitor use to prevent future adverse cardiovascular events., Competing Interests: Funding Support and Author Disclosures This work was supported by a Department of Veterans Affairs (VA) Health Services Research and Development Service Investigator Initiated grants (IIR 16-072, IIR 19-069) and the Houston VA Health Services Research and Development Center for Innovations grant (CIN13-413). Support for VA/Centers for Medicare and Medicaid Services data was provided by the Department of Veterans Affairs, VA Health Services Research and Development Service, VA Information Resource Center (Project Numbers SDR 02-237 and 98-004). Dr Nambi was the site primary investigator for the study sponsored by Merck and Amgen. Dr Ballantyne has received grant/research support (to his institution) from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, Novartis, Novo Nordisk, Regeneron, and Roche Diagnostic; and has been a consultant for 89Bio, Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Matinas BioPharma Inc, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostic, and Sanofi-Synthelabo. Dr Slipczuk has received consulting honoraria from Amgen, Regeneron, and Phillips and grant support from Amgen. Dr Bozkurt has received consulting fees from Amgen, scPharmaceuticals, Baxter, Sanofi-Aventis, Relypsa, Vifor, Roche, Boehringer Ingelheim, the Clinical Event Committee for Abbott Vascular, the Data Safety Monitoring Committees of Liva Nova and Cardurion, and the Steering Committee of Renovocor. Dr Virani has received research funding from the Department of Veterans Affairs, National Institutes of Health, World Heart Federation, and Tahir and Jooma Family; and has received an honorarium from American College of Cardiology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

Source Citation: Gaertner J, Fusi-Schmidhauser T, Stock S, et al. Effect of opioids for breathlessness in heart failure: a systematic review and meta-analysis. Heart. 2023;109:1064-1071.36878671., Competing Interests: Disclosures: The commentators have reported no disclosures of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=J23-0051.

Background: In the CANVAS (Canagliflozin Cardiovascular Assessment Study) program, canagliflozin reduced the risk of heart failure (HF) hospitalization among individuals with type 2 diabetes mellitus (T2DM)., Objectives: The purpose of this study was to evaluate heterogeneity in absolute and relative treatment effects of canagliflozin on HF hospitalization according to baseline HF risk as assessed by diabetes-specific HF risk scores (WATCH-DM [Weight (body mass index), Age, hyperTension, Creatinine, HDL-C, Diabetes control (fasting plasma glucose) and QRS Duration, MI and CABG] and TRS-HF DM [TIMI Risk Score for HF in Diabetes])., Methods: Participants in the CANVAS trial were categorized into low, medium, and high risk for HF using the WATCH-DM score (for participants without prevalent HF) and the TRS-HF DM score (for all participants). The outcome of interest was time to first HF hospitalization. The treatment effect of canagliflozin vs placebo for HF hospitalization was compared across risk strata., Results: Among 10,137 participants with available HF data, 1,446 (14.3%) had HF at baseline. Among participants without baseline HF, WATCH-DM risk category did not modify the treatment effect of canagliflozin (vs placebo) on HF hospitalization (P interaction = 0.56). However, the absolute and relative risk reduction with canagliflozin was numerically greater in the high-risk group (cumulative incidence, canagliflozin vs placebo: 8.1% vs 12.7%; HR: 0.62 [95% CI: 0.37-0.93]; P = 0.03; number needed to treat: 22) than in the low- and intermediate-risk groups. When overall study participants were categorized according to the TRS-HF DM score, a statistically significant difference in the treatment effect of canagliflozin across risk strata was observed (P interaction = 0.04). Canagliflozin significantly reduced the risk of HF hospitalization by 39% in the high-risk group (HR: 0.61 [95% CI: 0.48-0.78]; P < 0.001; number needed to treat: 20) but not in the intermediate- or low-risk groups., Conclusions: Among participants with T2DM, the WATCH-DM and TRS-HF DM can reliably identify those at high risk for HF hospitalization and most likely to benefit from canagliflozin., Competing Interests: Funding Support and Author Disclosures This study, carried out under YODA Project # 2020-4213, used data obtained from the Yale University Open Data Access Project, which has an agreement with Janssen Research and Development, LLC. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or Janssen Research and Development, LLC. Dr Khan has received personal fees from Merck. Dr Patel has served as a consultant to Novo Nordisk. Dr DeVore has received research funding through his institution from the American Heart Association, Biofourmis, Bodyport, Cytokinetics, American Regent Inc, the National Heart, Lung, and Blood Institute, Novartis, and Story Health; has provided consulting services for and/or received honoraria from Abiomed, AstraZeneca, Cardionomic, InnaMed, LivaNova, Natera, Novartis, Procyrion, Story Health, Vifor, and Zoll; and has received nonfinancial support from Abbott for educational and research activities. Dr Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health/National Center for Advancing Translational Sciences Award UL 1TR002541); and has served on advisory boards or has received research grant support from American Regent, Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr Lam has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on advisory boards/steering committees/executive committees for Actelion, Alleviant Medical, Allysta, Amgen, ANaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, EchoNous, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Us2.ai and WebMD Global; and has served as cofounder and non-executive director of Us2.ai. Dr Zannad has received personal fees from Boehringer Ingelheim during the conduct of the study; has received personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer, and Cellprothera outside of the submitted work; and has received other support from cardiovascular clinical trialists and Cardiorenal outside of the submitted work. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; has received research grants and honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, PhaseBio, and Pfizer; has received honoraria from Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; is a member of the scientific excellence committee of the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure With Reduced Ejection Fraction); has served as a national lead investigator of the DAPA-HF and EMPEROR-Reduced trials; and is the president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd, and Vifor. Dr Pandey has received grant funding outside the present study from Applied Therapeutics; has received honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly, USA, Rivus, and Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; is supported by the Texas Health Resources Clinical Scholarship, Gilead Sciences Research Scholar Program, and the National Institute of Aging GEMSSTAR Grant (1R03AG067960-01); and has received grant support from Applied Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Iron deficiency is common in patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with a poor prognosis. Whether intravenous iron replacement improves recurrent HF hospitalizations and cardiovascular mortality of these patients is uncertain although several trials were conducted. Moreover, none of the trials were powered to assess the effect of intravenous iron in clinically important subgroups. Therefore, we conducted a Bayesian analysis to derive precise estimates of the effect of intravenous iron replacement on recurrent HF hospitalizations and cardiovascular mortality in iron-deficient HFrEF patients using consistent subgroup definitions across trials., Methods and Results: Individual participant data were used from the FAIR-HF (n = 459), CONFIRM-HF (n = 304) and AFFIRM-AHF (n = 1108) trials. These data were re-analysed following as closely as possible the approach taken in the analyses of IRONMAN (n = 1137), for which study level data were used. Definitions of outcomes and subgroups from the FAIR-HF, CONFIRM-HF and AFFIRM-AHF were matched with those used in IRONMAN. The primary endpoint was recurrent HF hospitalizations and cardiovascular mortality. The analysis of recurrent events was based on rate ratios (RR) derived from the Lin-Wei-Yang-Ying model, and the data were pooled using Bayesian random-effects meta-analysis. Compared with placebo, intravenous iron significantly reduced the rates of recurrent HF hospitalizations and cardiovascular mortality (RR 0.73, 95% credible interval [CI] 0.48-0.99; between-trial heterogeneity tau = 0.16). The pooled treatment effects did not provide evidence for any differential effects for subgroups based on sex (ratio of rate ratios [RRR] 1.49 [95% CI 0.95-2.37], age <69.4 vs. ≥69.4 years) (RRR 0.68 [0.40-1.15]), ischaemic versus non-ischaemic aetiology of HF (RRR 0.73 [0.42-1.33]), transferrin saturation <20% vs. ≥20% (RRR 0.75 [0.40-1.34]), estimated glomerular filtration rate ≤60 versus >60 ml/min/1.73 m 2 (RRR 0.97 [0.56-1.68]), haemoglobin <11.8 versus ≥11.8 (RRR 0.95 [0.53-1.60]), ferritin <35 versus ≥35 μg/L (RRR 1.26 [0.72-2.48]) and New York Heart Association class II versus III/IV (RRR 0.91 [0.54-1.56])., Conclusions: Treatment of iron-deficient HFrEF patients with intravenous iron - namely with ferric carboxymaltose or ferric derisomaltose - results in significant reduction in recurrent HF hospitalizations and cardiovascular mortality. Results were nominally consistent across the subgroups studied, but for several of these subgroups uncertainty remains present., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on heart failure (HF) outcomes and cardiovascular (CV) death in patients with varying combinations of type 2 diabetes mellitus (T2DM), HF, and chronic kidney disease (CKD) are uncertain., Objectives: The authors conducted a meta-analysis assessing the effects of SGLT2 inhibitors on HF outcomes and CV death across different patient populations., Methods: Online databases were queried up to November 2022 for primary and secondary analyses of trials of SGLT2 inhibitors in patients with HF, T2DM, or CKD. Outcomes of interest were composite of first heart failure hospitalization (HFH) or CV death (first HFH/CV death), first HFH, and CV death. Data were pooled by means of a random-effects model to derive HRs and 95% CIs., Results: Thirteen trials (n = 90,413) were included. Compared with placebo, SGLT2 inhibitors reduced the risk of first HFH/CV death by 24% in HF (HR: 0.76; 95% CI: 0.72-0.81), 23% in T2DM (HR: 0.77; 95% CI: 0.73-0.81), and 23% in CKD (HR: 0.77; 95% CI: 0.72-0.82). The benefit was consistent in HF with reduced or preserved ejection fraction, HF with or without T2DM, and HF with or without CKD. The benefit was also consistent in T2DM with or without CKD, T2DM without HF, CKD without HF, and in patients with all 3 comorbidities. SGLT2 inhibitors significantly reduced CV death by 16% in HF, 15% in T2DM, and 12% in CKD., Conclusions: SGLT2 inhibitors reduce HF events and CV death in cohorts of HF, T2DM and CKD, and these effects appear consistent in patients with varying combinations of these diseases., Competing Interests: Funding Support and Author Disclosures Dr Anker has received grants or personal fees from Vifor Int, Bayer, Boehringer Ingelheim, Servier, Abbott Vascular, Cardiac Dimensions, Actimed, AstraZeneca, Amgen, Bioventrix, Janssen, Respicardia, V-Wave, Brahms, Cordio, and Occlutech outside of the submitted work. Dr Bakris has received research funding paid to the University of Chicago Medicine from Bayer, Novo Nordisk, and Vascular Dynamics; and has acted as a consultant for and received personal fees from Alnylam, Merck, and Ionisand Relypsa. Dr Bhatt has served on the Advisory Board for Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has served on the Board of Directors for Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; Inaugural Chair of American Heart Association Quality Oversight Committee; has been a consultant for Broadview Ventures; has served on the Data Monitoring Committee for Acesion Pharma, Assistance Publique–Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; and the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the NIH-funded MINT Trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; and Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), and Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for Clinical Trial Steering Committee for RE-DUAL PCI (funded by Boehringer Ingelheim) and Executive Committee for AEGIS-II (funded by CSL Behring), and from Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (Clinical Trial Steering Committees), Cowen and Company, Duke Clinical Research Institute (Clinical Trial Steering Committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, Interdisciplinary Curriculum), Level Ex, Medtelligence/ReachMD (CME Steering Committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS Operations Committee, Publications Committee, Steering Committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME Steering Committees), and Wiley (Steering Committee); Deputy Editor, Clinical Cardiology, Registry Steering Committee (Chair) for NCDR-ACTION, Research and Publications Committee (Chair) for VA CART; named on patent for sotagliflozin (no income), assigned to Brigham and Women’s Hospital (no income), who assigned to Lexicon; has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); is site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; is a trustee of American College of Cardiology; and has performed unfunded research for FlowCo and Takeda. Dr Fillipatos lectures and/or has committee member contributions in trials sponsored by Medtronic, Vifor, Servier, Novartis, Bayer, Amgen, and Boehringer Ingelheim; and has received research grants from the European Union. Dr Fonarow has received research support from the National Institutes of Health; and has consulted for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Medtronic, Merck, and Novartis. Dr Greene has received research support from the Duke University Department of Medicine Chair's Research Award, American Heart Association, National Heart, Lung, and Blood Institute, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim and Eli Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, scPharmaceuticals, and Sanofi; serves as a consultant for Amgen, Bayer, Boehringer Ingelheim and Eli Lilly, Bristol Myers Squibb, Corteria Pharmaceuticals, CSL Vifor, Merck, PharmaIN, Roche Diagnostics, Sanofi, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Boehringer Ingelheim, Cytokinetics, and Roche Diagnostics. Dr Januzzi is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, and Novartis; has received consulting income from Abbott Diagnostics, Boehringer Ingelheim, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for AbbVie, Siemens, Takeda, and Vifor. Dr Kosiborod has received research grants from AstraZeneca and Boehringer Ingelheim; has consultant/advisory board roles at Amgen, Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, and Vifor Pharma; has received financial support for analysis from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr McGuire has had leadership roles in clinical trials for AstraZeneca, Boehringer Ingelheim, Eisai, Esperion, GlaxoSmithKline, Janssen, Lexicon, Merck & Co, Novo Nordisk, CSL Behring, and Sanofi USA; and has received consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Lilly USA, Merck & Co, Pfizer, Novo Nordisk, Metavant, Afimmune, and Sanofi. Dr Piña is on the advisory board for Vifor and AstraZeneca; and is on the steering committee of the DIAMOND trial (funded by Vifor). Dr Rosenstock has served on advisory boards for Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Hanmi, Intarcia, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Terns Pharmaceuticals, and Zealand; and has received research support from Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Hanmi, Intarcia, Lexicon, Merck, Novo Nordisk, Novartis, Oramed, Pfizer, and Sanofi. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer, Occlutech, and Impulse Dynamics. Dr Verma has received personal fees from AstraZeneca, Sun Pharmaceuticals, and Toronto Knowledge Translation Working Group; has received grants and personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, and Merck; has received grants from Bristol Myers Squibb; and has received personal fees from Eli Lilly, Janssen, Novartis, Novo Nordisk, and Sanofi. Dr Zieroth has received personal fees for Speakers Bureau and/or consulting in advisory board for Abbott, Akcea AstraZeneca, Amgen, Alnylam, Bayer, BMS, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer, Roche, Servier, and Vifor Pharma; and serves on a clinical trial committee or as a national lead for studies sponsored by AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, and Pfizer, outside of the submitted work. Dr Butler is a consultant to Abbott, Adrenomed, American Regent, Arca Biopharma, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior CVRx, Cytokinetics, Edwards, Element Science, Fast Biomedical, G3 Pharmaceutical, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova Janssen, Johnson and Johnson, Medtronics, Merck, Occlutech, Nestle, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sanofi, Sequana, SQ Innovation, 3live, and Vifor. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF), diabetes, and chronic kidney disease (CKD) frequently coexist, with one comorbidity worsening the prognosis of another. β-blockers, angiotensin-receptor-neprilysin inhibitors, renin-angiotensin-aldosterone system inhibitors, mineralocorticoid-receptor antagonists, and sodium-glucose cotransporter-2 inhibitors all have been shown to reduce mortality in patients with HF with reduced ejection fraction. However, their uptake in real-world clinical practice remains low, especially among patients who have multiple other comorbidities such as CKD and diabetes. The management of HF in patients with diabetes and CKD can be especially challenging because these patients typically are older, frail, and have multiple other comorbidities, and guideline-directed medical therapy used in HF potentially can affect renal function acutely and chronically. In this article, we discuss the available evidence for each of the foundational HF therapies in patients with diabetes and CKD, emphasizing the current challenges and outlining future directions to optimize the management of HF among these high-risk patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The 6-minute walk test (6MWT) is widely used to measure exercise capacity; however, the magnitude of change that is clinically meaningful for individuals is not well established in heart failure with reduced ejection fraction (HFrEF)., Objective: To calculate the minimal clinically important difference (MCID) for change in exercise capacity in the 6MWT in iron-deficient populations with HFrEF., Methods: In this pooled secondary analysis of the FAIR-HF and CONFIRM-HF trials, mean changes in the 6MWT from baseline to weeks 12 and 24 were calculated and calibrated against the Patient Global Assessment (PGA) tool (clinical anchor) to derive MCIDs in improvement and deterioration., Results: Of 760 patients included in the 2 trials, 6MWT and PGA data were available for 680 (89%) and 656 (86%) patients at weeks 12 and 24, respectively. The mean 6MWT distance at baseline was 281 ± 103 meters. There was a modest correlation between changes in 6MWT and PGA from baseline to week 12 (r = 0.31; P < 0.0001) and week 24 (r = 0.43; P < 0.0001). Respective estimates (95% confidence intervals) of MCID in 6MWT at weeks 12 and 24 were 14 meters (5;23) and 15 meters (3;27) for a "little improvement" (vs no change), 20 meters (10;30) and 24 meters (12;36) for moderate improvement vs a "little improvement,", -11 meters (-32;9.2) and -31 meters (-53;-8) for a "little deterioration" (vs no change), and -84 meters (-144;-24) and -69 meters (-118;-20) for "moderate deterioration" vs a "little deterioration"., Conclusions: The MCID for improvement in exercise capacity in the 6MWT was 14 meters-15 meters in patients with HFrEF and iron deficiency. These MCIDs can aid clinical interpretation of study data., Competing Interests: Conflicts of Interest SDA has received research grants and personal fees from Vifor Int and Abbott Vascular (IIT/Trial steering committee work), personal fees from Bayer, Boehringer Ingelheim and Impulse Dynamics (Trial steering committee work), Novartis, Cardiac Dimensions and Occlutech (Adivsory committee work), and Servier (Registry Steering Committee). TF reports support for statistical consultancies and personal fees from Vifor for the present manuscript, consulting fees for statistical consultancies and personal fees from Bayer, CSL Behring, Galapagos, Minoryx, Vifor, Novartis, and LivaNova outside of the current work; payment for educational events from Fresenius Kabi outside of the current work; personal fees from Novartis, Eli Lilly, Bayer, BiosenseWebster, Janssen, Roche, and Enanta for participation on a Data Safety Monitoring Board. EAJ has received research grants and personal fees from Vifor Pharma (co-PI of the AFFIRM trial); personal fees from Bayer, Novartis, Abbott, Boehringer Ingelheim, Pfizer, Servier, AstraZeneca, Berlin Chemie, Cardiac Dimensions, Fresenius, Respicardia, Takeda, Swixx Biopharma, and Gedeon Richter; treasurer of the Executive Committee for the Heart Failure Association. MM has received personal fees from Vifor Pharma (Executive Committee member), Amgen (Executive Committee member and National PI), AstraZeneca, Abbott vascular, Bayer (participation in Advisory Boards), Boehringer Ingelheim (advisory board member), Servier (participation in Advisory Boards and speeches at sponsored symposia), Edwards Therapeutics (speeches at sponsored symposia), Actelion (DMC Member), LivaNova (Executive Committee member), and Windtree Therapeutics (Executive Committee member and Advisory Board). ILP reports personal fees from Boehringer Ingelheim outside of the submitted work. AJSC reports personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, Gore, Impulse Dynamics, and Respicardia outside of the submitted work. BR, UMG and FD are full-time employees of Vifor Pharma. JCC reports unrestricted grants from Vifor Pharma and Novartis; consulting fees from Vifor Pharma, AstraZenica and Boehringer Ingelheim; and honoraria for conference activities from Vifor Pharma, AstraZenica and Boehringer Ingelheim. GSF reports grants from the European Commission; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer and Boehringer Ingelheim; participation on a data safety monitoring board or advisory board from Bayer and Boehringer Ingelheim; leadership or fiduciary role in the Heart Failure Association; and other financial or nonfinancial interests as a committee member for Medtronic, Vifor Pharma, Amgen, Servier, and Novartis. PP reports participation in clinical trials for and grants and personal fees from Vifor Pharma during the conduct of the study; participation in clinical trials for and personal fees from Amgen, Bayer, Novartis, AbbottVascular, Boehringer Ingelheim, Pfizer, Servier, Astra Zeneca, Cibiem, BMS, and Impulse Dynamics outside of the submitted work; participation in clinical trials for Cardiac Dimensions outside of the submitted work; and personal fees from Berlin Chemie outside of the submitted work. JB reports personal consulting fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Sequana Medical, and Vifor Pharma, and payment for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from AstraZeneca, Eli-Lilly, Janssen, and Novartis. DJVV, GR and MSK have no conflicts of interest relating to the performance of this research or in the evaluation and publication process of the manuscript., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Vericiguat reduced the risk of cardiovascular death (CVD) or hospitalization for heart failure (HF) in patients with worsening HF and reduced left ventricular ejection fraction (LVEF)., Objectives: The authors assessed the association of LVEF with biomarker levels, risk of outcome, and whether the effect of vericiguat was homogeneous across LVEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction) trial., Methods: Patients were grouped by LVEF tertiles (≤24%, 25%-33%, and >33%). Patient characteristics, clinical outcomes, and efficacy and safety of vericiguat were examined by tertile. Prespecified biomarkers including N-terminal pro-B-type natriuretic peptide, cardiac troponin T, growth differentiation factor 15, interleukin 6, high-sensitivity C-reactive protein, and cystatin C were examined., Results: The mean LVEF was 29% ± 8% (range: 5%-45%). A pattern of higher N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and interleukin 6 was evident in patients in the lowest LVEF tertile vs the other tertiles. Patients with lower LVEF experienced higher rates of the composite outcome (41.7%, 36.3%, and 33.4% for LVEF ≤24, 25-33, and >33; P < 0.001). There was no significant treatment effect heterogeneity of vericiguat across LVEF groups (adjusted HR from lowest to highest tertiles: 0.79 [95% CI: 0.68-0.94]; 0.95 [95% CI: 0.82-1.11]; 0.94 [95% CI: 0.79-1.11]; P for interaction = 0.222), although the HR was numerically lower in the lowest tertile. There was also no heterogeneity of effect for CVD and HF hospitalization individually (P interaction for CVD = 0.964; HF hospitalization = 0.438). Discontinuation of treatment because of adverse events, symptomatic hypotension, or syncope was consistent across the range of LVEF., Conclusions: Patients with lower LVEF had a distinctive biomarker profile and a higher risk for adverse clinical outcomes vs those with a higher LVEF. There was no significant interaction for the benefit of vericiguat across LVEF tertiles, although the largest signal for benefit in both the primary outcome and HF hospitalizations was noted in tertile 1 (LVEF ≤24%). (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 and Dohme Corp, a subsidiary of Merck and Co Inc, and Bayer AG. 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 Lund is a consultant for Bayer/Merck; has received grants unrelated to the present work from AstraZeneca, Vifor, Boston Scientific, Boehringer Ingelheim, and Novartis; has received consulting fees from Merck, Vifor, AstraZeneca, Bayer, Pharmacosmos, MedScape, Sanofi, Lexicon, Myokardia, Boehringer Ingelheim, and Servier; has received speaker honoraria from Abbott, MedScape, Radcliffe, AstraZeneca, Novartis, and patent AnaCardio; and has stock ownership in AnaCardio. Dr deFilippi has received institutional research grants from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics; and has received consulting fees from FujiRebio, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics. Dr Blaustein is an employee of Merck and Co, Inc. Mr Ezekowitz has received research grants and consulting fees from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr Freitas is an employee of Bayer AG. Dr Hernandez has received research grants from Merck, AstraZeneca, Novartis, and Verily; and has received honoraria from Merck, Bayer, Amgen, AstraZeneca, and Novartis. Dr O’Connor has received research grants from Merck; and has received consulting fees from Bayer, Dey LP, and Bristol Myers Squibb Foundation. Dr Voors has received research grants from Boehringer Ingelheim and Roche Diagnostics; and has received consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Myokardia, Novartis, Servier, and Roche Diagnostics. Dr Westerhout has received consulting fees from Bayer. Dr Lam has received research grants from Bayer and Roche Diagnostics; has received consulting fees from Abbott, Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and 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 is a cofounder and nonexecutive director of Us2.ai. Dr Armstrong has received research grants from Merck, Bayer, Sanofi-Aventis Recherche and Développement, Boehringer Ingelheim, and CSL Limited; and has received consulting fees from Merck, Bayer, AstraZeneca, and Novartis., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure with reduced ejection fraction (HFrEF) is a complex and progressive clinical condition characterized by dyspnea and functional impairment. HFrEF has a high burden of mortality and readmission rate making it one of the most significant public health challenges. Basic treatment strategies include diuretics for symptom relief and use of quadruple therapy (Angiotensin receptor blocker/neprilysin inhibitors, evidence-based beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors) for reduction in hospitalizations, all-cause mortality, and cardiovascular mortality. Despite compelling evidence of clinical benefit, guideline directed medical therapy is vastly underutilized in the real-world clinical practice. Other medications such as intravenous iron, ivabradine, hydralazine/nitrates and vericiguat may also have a role in certain subgroup of HFrEF patients. Specific groups of patients with HFrEF may also be candidates for various device therapies such as implanted cardioverter defibrillators, cardiac resynchronization therapy and trans catheter mitral valve repair. This review provides a comprehensive overview of drug and device management approaches for patients with HFrEF, recommendations for initiation and titrations of therapies, and challenges associated with guideline directed medical therapy in the management of patients with HFrEF (Graphical abstract)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Despite significant therapeutic advancements in heart failure with reduced ejection fraction (HFrEF), the residual risk of all-cause mortality and hospitalizations remains high among patients with HFrEF. Vericiguat is a novel oral soluble guanylate cyclase (sGC) stimulator which was approved by the US Food and Drug administration (FDA) in January 2021 for use in patients with symptomatic chronic HF and an ejection fraction less than 45% following a hospitalization for HF or the need for outpatient intravenous diuretics., Areas Covered: We provide a concise review of the pharmacology, clinical efficacy, and tolerability of vericiguat in HFrEF. We also discuss the role of vericiguat in current clinical practice., Expert Opinion: Vericiguat reduces the risk of cardiovascular mortality or HF hospitalizations by an absolute event-rate reduction of 4.2 events per 100 patient-years with a number needed to treat of 24 patients, on a background of guideline-directed medical therapy. Almost 90% of the patients with HFrEF were adherent to the 10 mg dose of vericiguat in the VICTORIA trial with a favorable tolerability and safety profile. Considering the high residual risk that persists in HFrEF, vericiguat has a role to improve outcomes among patients with worsening HFrEF.