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Competing Interests: Disclosures The authors have no conflicts of interest to disclose.

Background: Mechanisms of disease pathobiology, prognosis, and potentially treatment responses might vary by race in patients with heart failure (HF)., Objectives: The authors aimed to examine the safety and efficacy of sacubitril/valsartan among patients with HF by self-reported race., Methods: PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) were global, randomized clinical trials testing sacubitril/valsartan against a renin-angiotensin system inhibitor ([RASi], enalapril or valsartan, respectively) in patients with HF and left ventricular ejection fraction ≤40% (PARADIGM-HF) or left ventricular ejection fraction ≥45% (PARAGON-HF). Patients with self-reported race were categorized as White, Asian, or Black. We assessed the composite of first HF hospitalization or cardiovascular death, its components, and angioedema across races., Results: Among 12,097 participants, 9,451 (78.1%) were White, 2,116 (17.5%) were Asian, and 530 (4.4%) were Black. Over a median follow-up of 2.5 years, Black (adjusted HR: 1.68; 95% CI: 1.42-1.98) and Asian patients (adjusted HR: 1.32; 95% CI: 1.18-1.47) experienced higher risks of the primary outcome compared with White patients. Treatment effects of sacubitril/valsartan vs RASi on the primary endpoint were consistent among White (HR: 0.84; 95% CI: 0.77-0.91), Asian (HR: 0.92; 95% CI: 0.78-1.10), and Black patients (HR: 0.79; 95% CI: 0.58-1.07; P interaction  = 0.58). Rates of severe angioedema were higher with sacubitril/valsartan vs RASi (White: 0.2% vs 0.1%; Black: 1.5% vs 0.0%; Asian: 0.1% vs 0.1%)., Conclusions: In a pooled experience of 2 global trials, Black and Asian patients exhibited a higher risk of cardiovascular events than White patients. The benefits of sacubitril/valsartan were consistent across races. Risks of severe angioedema were low but numerically higher with sacubitril/valsartan. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255; Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)., Competing Interests: Funding Support and Author Disclosures The PARADIGM-HF and PARAGON-HF trials were sponsored by Novartis. Dr Lu has received research funding from the Gottfried und Julia Bangerter-Rhyner Foundation, the SICPA Foundation, and the Société Académique Vaudoise. Dr Claggett has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia, Cardurion, and Novartis. Dr Packer has received consulting fees from 89bio, AbbVie, Actavis, Alderlyx, Amarin, Amgen, AstraZeneca, Attralus, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Pharmacosmos, Reata, Regeneron, Relypsa, and Salamandra. Dr Pfeffer has received the following research grant support Lexicon and Novartis, paid to his institution; has served as a consultant to Alexion, Alnylam, Apnimed, AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, DalCor, Intellia, National Heart, Lung, and Blood Institute—Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (Master Protocol Committee), Novartis, and Novo Nordisk; and has equity in DalCor. Dr Lewis has received personal fees from Amgen and Dal-Cor. Dr Lam has received grants from Novo Nordisk and Roche Diagnostics; has served as a consultant for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb (BMS), CardioRenal, Cytokinetics, Darma, Echonous, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceuticals, Janssen, Medscape/WebMD, Merck, Novartis, Novo Nordisk, Prosciento, Quidel Corporation, Radcliffe Group, Recardio, Recor Medical, Roche Diagnostics, Sanofi, and Siemens Healthcare; has served as cofounder and nonexecutive director of Us2.ai outside the submitted work; and has patents pending (PCT/SG2016/050217; method for diagnosis and prognosis of chronic heart failure) and issued (U.S. Patent No. 10 702 247; automated clinical workflow that recognizes and analyses 2-dimensional and Doppler echo images for cardiac measurements and the diagnosis, prediction and prognosis of heart disease). Dr Rouleau has served as a Data Monitoring Committee member; and has received consulting fees from Alexion, Intellia, BMS, AstraZeneca, Bayer, and Novartis. Dr Zile has received research funding from Novartis; and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. Dr Lefkowitz is an employee of Novartis Pharmaceuticals Corporation. Dr Desai has received research grant support from Abbott, AstraZeneca, Alnylam, Bayer, and Novartis; and has received consulting fees and/or honoraria from Abbott, AstraZeneca, Alnylam, Axon Therapeutics, Avidity Biopharma, Bayer, Biofourmis, GlaxoSmithKline, Merck, Novartis, Parexel, Regeneron, River2Renal, Roche, Verily, Veristat, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, and Sun Pharmaceuticals; advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; has served as the director of Global Clinical Trial Partners; and his employer the University of Glasgow has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis and Novo Nordisk. Dr McMurray has received grants, paid to his employer, from AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study; grants paid to his employer from Novartis, Amgen, BMS, Bayer, Abb-vie, Dal-Cor, Kidney Research UK, and Cardurion; and grants from British Heart Foundation. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and Us2.ai; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and PureTech Health. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Pabon has reported that she has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Predischarge risk stratification of patients with acute heart failure (AHF) could facilitate tailored treatment and follow-up, however, simple scores to predict short-term risk for HF readmission or death are lacking., Methods: We sought to develop a congestion-focused risk score using data from a prospective, two-center observational study in adults hospitalized for AHF. Laboratory data were collected on admission. Patients underwent physical examination, 4-zone, and in a subset 8-zone, lung ultrasound (LUS), and echocardiography at baseline. A second LUS was performed before discharge in a subset of patients. The primary endpoint was the composite of HF hospitalization or all-cause death., Results: Among 350 patients (median age 75 years, 43% women), 88 participants (25%) were hospitalized or died within 90 days after discharge. A stepwise Cox regression model selected four significant independent predictors of the composite outcome, and each was assigned points proportional to its regression coefficient: NT-proBNP ≥2000 pg/mL (admission) (3 points), systolic blood pressure < 120 mmHg (baseline) (2 points), left atrial volume index ≥60 mL/m 2 (baseline) (1 point) and ≥ 9 B-lines on predischarge 4-zone LUS (3 points). This risk score provided adequate risk discrimination for the composite outcome (HR 1.48 per 1 point increase, 95% confidence interval: 1.32-1.67, p < 0.001, C-statistic: 0.70). In a subset of patients with 8-zone LUS data (n = 176), results were similar (C-statistic: 0.72)., Conclusions: A four-variable risk score integrating clinical, laboratory and ultrasound data may provide a simple approach for risk discrimination for 90-day adverse outcomes in patients with AHF if validated in future investigations., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: There are sociodemographic disparities in outcomes of heart failure with reduced ejection fraction (HFrEF), but disparities in guideline-directed medical therapy (GDMT) remain poorly characterized., Objectives: This study aimed to analyze GDMT treatment rates in eligible patients with recently diagnosed HFrEF, and to determine how rates vary by sociodemographic characteristics., Methods: This retrospective cohort study included patients diagnosed with HFrEF at Veterans Affairs (VA) hospitals from 2013 to 2019. The authors analyzed GDMT treatment rates and doses, excluding patients with contraindications. Therapies of interest were evidence-based beta-blockers (BBs), renin-angiotensin system inhibitors (RASIs), angiotensin receptor-neprilysin inhibitors (ARNIs), and mineralocorticoid antagonists (MRAs). The authors compared adjusted treatment rates by race and ethnicity, neighborhood social vulnerability, rurality, distance to medical care, and sex., Results: The cohort comprised 126,670 VA patients with recently diagnosed HFrEF. The study found that racial and ethnic minorities had similar or higher treatment rates than White patients. Patients residing in socially vulnerable neighborhoods had 3.4% lower ARNI (95% CI: 1.9%-5.0%) treatment rates. Patients residing farther from specialty care had similar rates of GDMT therapy overall, but were less likely to be taking at least 50% of the target doses of either BBs (4.0% less likely; 95% CI: 3.1%-5.0%) or RASIs (5.0% less likely; 95% CI: 4.1%-6.0%) compared with those closer to care., Conclusions: Among VA patients with recently diagnosed HFrEF, the authors did not find that racial and ethnic minority patients were less likely to receive GDMT. However, appropriate dose up-titration may occur less frequently in more remote patients., Competing Interests: Funding Support and Author Disclosures Support for VA/CMS 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 Tisdale is supported by a Veterans Administration Office of Academic Affairs Advanced Fellowship in Health Services Research. Dr Sandhu has received research support from the National Heart, Lung, and Blood Institute (1K23HL151672-01). Dr Sandhu consults for Acumen. Dr Kohsaka has received unrestricted grants from Daiichi Sankyo; and lecture fees from Bristol-Myers Squibb outside of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and the Academic Research Consortium (ARC) composed of patients, academic investigators from the United States and Europe, the U.S. Food and Drug Administration, the National Institutes of Health, payers, and industry. Members discussed the measure, remote capture, and clinical utility of functional and quality-of-life endpoints for use in clinical trials of heart failure and cardiovascular therapeutics, with the goal of improving the efficiency of heart failure and cardiovascular clinical research, evidence generation, and thereby patient quality of life, functional status, and survival. Assessments of patient-reported outcomes and maximal and submaximal exercise tolerance are standardized and validated, but actigraphy remains inconsistent as a potential endpoint. This paper details those discussions and consensus recommendations., Competing Interests: Funding Support and Author Disclosures The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the FDA or the U.S. Department of Health and Human Services. Dr Abraham has received consulting fees from Boehringer Ingelheim and Zoll Respicardia, speaker honoraria from Impulse Dynamics, salary support from V-Wave Medical, and research support from the U.S. National Institutes of Health/National Heart, Lung, and Blood Institute. Dr Filippatos has received consulting income from Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor; and has received lecture fees from Merck. Dr Lindenfeld has received consulting fees from Novartis, Abbott, ResMed, V-Wave, CVRx, and Cytokinetics. Dr Ahmad has received consulting fees from Amgen, Cytokinetics, Relypsa, and Novartis. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, the American Heart Association, Amgen, Merck, Cytokinetics, and Roche Diagnostics; and has received consulting fees from Novartis, Amgen, Bristol Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Relypsa, V-Wave, Myokardia, Innolife, EBR Systems, Arena, Abbott, Sphingotec, Roche Diagnostics, Alnylam, LivaNova, Windtree Therapeutics, Rocket Pharma, and SC Pharma. Dr Kitzman has received consulting fees from AstraZeneca, Bayer, Novartis, Merck, Pfizer, Boehringer Ingelheim, AbbVie, DCRI, and Corvia; has received grant support from AstraZeneca, Bayer, and Novartis; and has stock in Gilead. Dr Lewis has received consulting fees from Novartis; and has received institutional research grant support from Amgen, Novartis, and Sanofi. Dr Mentz has received consulting fees from Abbott, Amgen, AstraZeneca, Bayer, Boston Scientific, Janssen, Luitpold, Medtronic, Merck, Novartis, and Sanofi; and has received research grants from Akros, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Gilead, InnoLife, Luitpold/American Reagent, Novartis, Otsuka, ResMed, and the National Institutes of Health (grants U01HL125511-01A1 and R01AG045551-01A1). Dr Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, the National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and has received consulting fees from Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck Sharpe & Dohme, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, and Cardiac Dimensions. Dr Teerlink has received consulting fees from Amgen, Bayer, Cytokinetics, Novartis, and Stealth Health; and has received research funding from Abbott, Amgen, Bayer, Bristol Myers Squibb, Novartis, and scPharma. Dr Unger’s employer, Hyman, Phelps & McNamara, has contracts with many companies, some of which are developing treatments for HF. Dr Whellan has received grant support from the National Institutes of Health (grant R01AG045551). Dr Wittes’s employer, Wittes LLC, has contracts with many companies, some of which are developing treatments for HF. Dr Anker has received fees from Abbott, Bayer, Boehringer Ingelheim, Cardiac Dimension, Cordio, Impulse Dynamics, Novartis, Occlutech, Servier, and Vifor Pharma; and has received grant support from Abbott and Vifor Pharma. Dr O’Connor has received grant or research support from Roche Diagnostics and Merck; and has received consulting fees from Merck, Bayer, Bristol Myers Squibb, Abiomed, and Windtree. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with heart failure with preserved ejection fraction (HFpEF) have poor health-related quality of life (HR-QoL). However, the relationship between HR-QoL measures and the alterations of cardiac structure and function that are present in patients with HFpEF remains unknown., Aims: To study the associations between HR-QoL and echocardiographic parameters in HFpEF., Methods: Regression modelling in patients from TOPCAT-Americas who had both HR-QoL questionnaires and a baseline echocardiogram., Results: A total of 631 patients (36% of the TOPCAT-Americas population) had both echocardiographic and HR-QoL at baseline. KCCQ-23 Overall Summary Score (OSS; 0-100 points) was negatively (higher echocardiographic values-poorer/lower HR-QoL scores) associated with left ventricular end-diastolic diameter (LVEDD: β = -3.56 [-7.00 to -0.13] points-per-1 cm, P = 0.042), interventricular septum thickness (β = -1.31 [-2.19 to -0.42] points-per-1 mm, P = 0.004), posterior wall thickness (β = -1.57 [-2.52 to -0.63] points-per-1 mm, P = 0.001 and left atrial width (β = -3.27 [-6.39 to -0.15], P = 0.040) points-per-1 cm, and positively (higher echocardiographic values-better/higher HR-QoL scores) associated with left ventricular end-diastolic volume index (LVEDVi: β = 0.23 [0.09 to 0.37] points-per-1 ml/m2, P = 0.002) and left ventricular end-systolic volume index (LVESVi: β = 0.41 [0.18 to 0.63] points-per-1 ml/m2, P < 0.001). Body mass index (BMI: β = -0.74 [-1.02 to -0.47] points-per-1Kg/m2, P < 0.001), diabetes (β = -6.01 [-10.05 to -1.97], P = 0.004), and asthma (β = -6.78 [-13.52 to -0.04], P = 0.049) were negatively associated with OSS. A similar pattern of associations was observed for KCCQ-23 Clinical Summary Score, EQ5D-VAS and NYHA class., Conclusion: In patients with HFpEF, HR-QoL measures were associated with cardiac structure and function alterations. Extra-cardiac factors were also associated with HR-QoL, which may influence HR-QoL results when testing cardiovascular drugs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: This study analyzed changes in depressive symptoms in patients with heart failure and preserved ejection fraction (HFpEF) who were enrolled in the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial., Background: There are limited longitudinal data for depressive symptoms in patients with HFpEF., Methods: In patients enrolled in the United States and Canada (n = 1,431), depressive symptoms were measured using Patient Health Questionnaire-9 (PHQ-9). Clinically meaningful changes in PHQ-9 scores were defined as worse (≥3-point increase) or better (≥3-point decrease). Multivariate models were used to identify predictors of change in depressive symptoms. Cox proportional hazard models were used to determine the impact of symptom changes from baseline on subsequent incident cardiovascular events., Results: At 12 months, 19% of patients experienced clinically worsening depressive symptoms, 31% better, and 49% unchanged. Independent predictors of clinically meaningful improvement in depressive symptoms included higher baseline PHQ-9 scores, male sex, lack of chronic obstructive pulmonary disease, and randomization to spironolactone. After data were adjusted for cardiovascular comorbidities, higher baseline PHQ-9 was associated with all-cause mortality (hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 1.02 to 1.16; p = 0.011), whereas worsening depressive symptoms at 12 months were associated with cardiovascular death (HR: 2.47; 95% CI: 1.32 to 4.63; p = 0.005) and all-cause mortality (HR: 1.82; 95% CI: 1.13 to 2.93; p = 0.014). Randomization to spironolactone was associated with modest but statistically significant reduction in depressive symptoms over the course of the trial (p = 0.014)., Conclusions: Higher baseline depressive symptoms and worsening depressive symptoms were associated with all-cause mortality. Randomization to spironolactone was associated with modest reduction in depressive symptoms. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302)., Competing Interests: Author Disclosures The TOPCAT trial was funded by the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD (N01 HC45207). No additional funding was received to conduct this study. Dr. Chandra was supported by the National Heart, Lung, and Blood Institute (NHLBI) T32 postdoctoral training grant (5T32HL094301-09). Dr. Desai received research grants from Novartis, Alnylam, AstraZeneca; has received consulting fees from Novartis, Alnylam, AstraZeneca, Abbott, Amgen, Relypsa, Biofourmis, Boston Scientific, Boehringer-Ingelheim, Corvidia, Merck, Novartis, Relypsa, Regeneron, and DalCor Pharma; and research grants from Novartis. Dr. Fang has served on steering committees for Novartis, Amgen, AstraZeneca, and J & J. Dr. Pitt has received consulting fees from Amorcyte, AstraZeneca, Aurasense, Bayer, BG Medicine, Gambro, Johnson & Johnson, Mesoblast, Novartis, Pfizer, Relypsa, and Takeda; research grant support from Forest Laboratories; holds stock in Aurasense, Relypsa, BG Medicine, and Aurasense; and has a pending patent related to site-specific delivery of eplerenone to the myocardium. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Novartis, Sanofi Pasteur, Theracos, and has consulted for Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Dinaqor, Tremeau. Dr. Pfeffer has received research support from Novartis; serves as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, DalCor, Genzyme, Gilead, GlaxoSmithKline, Janssen, Lilly, Novartis, Novo Nordisk, Sanofi, Teva, and Thrasos; and has stock options in DalCor. Dr. Lewis has received funding from Novartis (research support), Merck, and Dal-Cor (consulting agreement). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020. Published by Elsevier Inc.)

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation., Competing Interests: Author Disclosures W.T.A. has received consulting fees from Abbott, Boehringer Ingelheim, CVRx, Edwards Lifesciences, Respicardia, and research support from the U.S. National Institutes of Health/National Heart, Lung, and Blood Institute. M.A.P. has received consulting fees from Amgen, Cytokinetics, and Windtree, and grant support from the United States Food and Drug Administration. G.F. has received consulting income from Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor, and lecture fees from Merck. J.L. has received consulting fees from Novartis, Abbott, ResMed, VWave, CVRx, and Cytokinetics. R.M. has received institutional research grant support from Abbott Laboratories, AstraZeneca, Bayer, Beth Israel Deaconess Medical Center, Bristol-Myers Squibb, CSL Behring, Eli Lilly/Daiichi-Sankyo, Medtronic, Novartis Pharmaceuticals, and OrbusNeich; has served on scientific advisory boards of PLx Opco/PLx Pharma, Medtelligence (Janssen Scientific Affairs), and Bristol-Myers Squibb; has served on the executive committees of Janssen Pharmaceuticals and Osprey Medical; has served on the data safety monitoring board of Watermark Research Partners; has served as a consultant for Abbott Laboratories, Abiomed (spouse), Boston Scientific, Cardiovascular Systems, Medscape/Web MD, Siemens Medical Solutions, The Medicines Company (spouse), Regeneron Pharmaceuticals, Roivant Sciences, Spectranetics/Philips/Volcano Corporation, and Sanofi; and has equity in Claret Medical and Elixir Medical Corporation. J.L.J. is a trustee of the American College of Cardiology, is a board member of Imbria Pharmaceuticals, has received grant support from Novartis Pharmaceuticals, Roche Diagnostics, Abbott, Singulex and Prevencio, consulting income from Abbott, Janssen, Novartis, Pfizer, Merck, and Roche Diagnostics, and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Boehringer Ingelheim, Janssen, and Takeda. M.A.K. has received consulting fees from Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, and Novartis; and grants and research support from Ironwood and Livanova. M.W.K. has received consulting fees from Abbott Vascular, Angel Medical Systems, Biosensors, CSI, Boston Scientific, Medtronic, OrbusNeich, and St Jude Medical, and has received grant funding from Abbott Vascular, Angel Medical Systems, Boston Scientific, Medtronic, OrbusNeich, Biosensors, CSI, and St Jude Medical. E.F.L. has received consulting fees from Novartis, and institutional research grant support from Amgen, Novartis, and Sanofi. J.P.P. has received grant support from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, the National Heart, Lung, and Blood Institute, and Philips, and has received consulting fees from Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, Sanofi, Philips, and Up-to-Date. S.D.S. has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, U.S. National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos; and consulting fees from Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck Sharpe & Dohme, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, and Cardiac Dimensions. J.R.T. has received consulting fees from Amgen, Bayer, Cytokinetics, Novartis, and Stealth Health, and research funding from Abbott, Amgen, Bayer, Bristol-Myers Squibb, Novartis, scPharma. S.D.A. has received clinical trial-related fees from Abbott Vascular, Servier, Vifor, Bayer, Boehringer Ingelheim, Thermo Fisher, Respicardia, and Novartis. C.M.O’C. has received research support from Roche Diagnostics; has received research support and is a consultant for Merck, Bristol-Myers Squibb, Windtree, and Neurotronik, and is a co-owner of Biscardia. All other authors have nothing to disclose. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the United States Food and Drug Administration or the United States Department of Health and Human Services., (Copyright © 2020. Published by Elsevier Inc.)

Background: The Trial to Assess Chelation Therapy (TACT) found that chelation therapy significantly reduced clinical events in patients with a history of myocardial infarction (MI). The initial report of TACT included the observation of an interaction between edetate disodium infusions and MI location, as well as diabetes. Thus, we examined in greater detail the effect of edetate disodium chelation therapy as a function of MI location and diabetes., Methods: Patients (n = 1708) at least 6 weeks post-MI and age ≥ 50 were randomized to receive 40 infusions of a 500 mL chelation solution or placebo (median follow-up 55 months). The effect of edetate disodium on the primary outcome (all-cause mortality, MI, stroke, hospitalization for angina, or coronary revascularization) was assessed as a function of MI location using log-rank test and Cox regression model, adjusting for other prognostic variables., Results: Among patients with post anterior MI (n = 674), chelation was associated with a lower risk of the primary endpoint (HR 0.63, 95% CI 0.47-0.86, p = 0.003) among anterior MI patients, but not in post non-anterior MI (n = 1034) patients (HR 0.96, 95% CI 0.77-1.20, p = 0.702) (p-for-interaction = 0.032). The point estimates for each component of the primary endpoint favored chelation therapy. The differing treatment effect in patients with post anterior vs. non-anterior MI was consistent among patients with or without diabetes and remained significant after adjusting for other prognostic variables (p < 0.01)., Conclusions: Edetate disodium infusions reduced the risk of cardiovascular events among patients with a prior anterior MI. Future studies should focus on replicating these results and understanding the mechanisms of benefit., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: The authors investigated the relationship between past or incident myocardial infarction (MI) and cardiovascular (CV) events in heart failure with preserved ejection fraction (HFpEF)., Background: MI and HFpEF share some common risk factors. The prognostic significance of MI in patients with HFpEF is uncertain., Methods: The authors pooled data from 3 trials-CHARM Preserved (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity), I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function), and the Americas region of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) (N = 8,916)-and examined whether MI before or following enrollment independently predicted CV death and heart failure (HF) hospitalization., Results: At baseline, 2,668 patients (30%) had history of MI. Prior MI was independently associated with greater risk of CV death (4.7 vs. 3.5 events/100 patient-years [py], adjusted hazard ratio [HR]: 1.42 [95% confidence interval (CI): 1.23 to 1.64]; p < 0.001). Excess sudden death drove this difference (1.9 vs. 1.2 events/100 py, adjusted HR: 1.55 [95% CI: 1.23 to 1.97]; p < 0.001). There was no difference in HF hospitalization (5.9 vs. 5.5 events/100 py, adjusted HR: 1.05, 95% CI: 0.92 to 1.19) or HF death by prior MI. During follow-up, MI occurred in 336 patients (3.8%). Risk of CV death increased 31-fold in the first 30 days after first post-enrollment MI, and remained 58% higher beyond 1 year after MI. Risk of first or recurrent HF hospitalization increased 2.4-fold after MI., Conclusions: Prior MI in HFpEF is associated with greater CV and sudden death but similar risk of HF outcomes. Patients with HFpEF who experience MI are at high risk of subsequent CV death and HF hospitalization. These data highlight the importance of primary and secondary prevention of MI in patients with HFpEF. (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM Preserved]; NCT00634712; Irbesartan in Heart Failure With Preserved Systolic Function [I-Preserve]; NCT00095238; and Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) patients experience a high burden of symptoms and functional limitations, and morbidity and mortality remain high despite successful therapies. The majority of HF drugs in the United States are approved for reducing hospitalization and mortality, while only a few have indications for improving quality of life, physical function, or symptoms. Patient-reported outcomes that directly measure patient's perception of health status (symptoms, physical function, or quality of life) are potentially approvable endpoints in drug development. This paper summarizes the history of endpoints used for HF drug approvals in the United States and reviews endpoints that measure symptoms, physical function, or quality of life in HF patients., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: The authors examined efficacy and safety of spironolactone by age in the Americas region (N = 1,767) of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial., Background: Heart failure with preserved ejection fraction disproportionately affects older adults who may exhibit changes in physiology and variable pharmacokinetics., Methods: TOPCAT enrolled patients with heart failure and a left ventricular ejection fraction ≥45% who were age 50 or older with an estimated glomerular filtration rate ≥30 mL/min/1.73 m 2 and prior heart failure hospitalization or elevated natriuretic peptide levels. Participants were randomized to spironolactone or placebo with a mean follow-up duration of 3.3 years. We assessed treatment effect and safety by protocol-defined age categories (<65, 65 to 74, and ≥75 years)., Results: The mean age was 72 ± 10 years (range 50 to 97 years) with 41% over the age of 75 years. Participants ≥75 years were more commonly women and white and had a lower body mass index and estimated glomerular filtration rate compared with the younger age categories. Spironolactone reduced the primary composite outcome compared with placebo across all age categories (p interaction = 0.42). However, spironolactone was associated with an increased risk of the safety endpoint (hazard ratio: 2.54; 95% confidence interval: 1.91 to 3.37; p < 0.001), particularly in older age groups (p interaction = 0.02). Findings in the whole TOPCAT cohort were consistent with results from the Americas region., Conclusions: In this post hoc, exploratory analysis of the TOPCAT trial data from the Americas region, although there was no effect of age on efficacy, there were considerable effects of age on increased rates of adverse safety outcomes. These results should be weighed when considering spironolactone for older heart failure with preserved ejection fraction patients. (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist [TOPCAT]; NCT00094302)., (Published by Elsevier Inc.)

Objectives: This study sought to assess the prevalence, changes in, and prognostic importance of B-lines, a pulmonary congestion measure by using a simplified lung ultrasonography (LUS) method in acute heart failure (AHF)., Background: Pulmonary congestion is an important finding in AHF, but conventional methods for its detection are insensitive., Methods: In a 2-site, prospective, observational study, 4-zone LUS was performed early during hospitalization for AHF (LUS1) and at discharge (LUS2). B-lines were quantified off-line, blinded to clinical findings and outcomes, by a core laboratory., Results: Among 349 patients (median, 75 years of age; 59% men; mean ejection fraction 39%), the sum of B-lines in 4 zones ranged from 0 to 18 (LUS1). The risk of an adverse in-hospital event increased with rising number of B-lines on LUS1: the odds ratio for each B-line tertile was 1.82 (95% confidence interval [CI]: 1.14 to 2.88; p = 0.011). B-line count decreased from a median of 6 (LUS1) to 4 (LUS2; p < 0.001) over 6 days (median). In 132 patients with LUS2 images, the risk of HF hospitalization or all-cause death was greater in patients with a higher number of B-lines at discharge. This relationship was stronger closer to discharge: unadjusted hazard ratio (HR) at 60 days was 3.30 (95% CI: 1.52 to 7.17; p = 0.002); 2.94 at 90 days (95% CI: 1.46 to 5.93; p = 0.003); and 2.01 at 180 days (95% CI: 1.11 to 3.64; p = 0.021). The association between number of B-lines and short- and long-term outcomes persisted after adjusting for important clinical variables, including N-terminal pro-B-type natriuretic peptide., Conclusions: Pulmonary congestion using a simplified 4-zone LUS method was common in patients with AHF and improved with therapy. A higher number of B-lines at baseline and discharge identified patients at increased risk for adverse events., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to describe baseline health-related quality of life (HRQL) in the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) trial, the largest heart failure with preserved ejection fraction (HFpEF) trial to date., Background: There are limited data characterizing HRQL in patients with HFpEF using validated metrics., Methods: The PARAGON-HF trial randomized symptomatic patients with HFpEF (≥45%) ≥50 years of age to either sacubitril/valsartan or valsartan. The study reports comprehensive baseline HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) administered at randomization after active run-in period. The study then compares baseline HRQL with patients with heart failure with reduced ejection fraction (HFrEF) (≤40%) enrolled in the PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Forward multivariable stepwise regression modeling was performed separately in both trials to identify independent clinical correlates of KCCQ-Overall Summary (KCCQ-OS) score. PARADIGM-HF trial patients <50 years of age were excluded to enable comparison., Results: In the PARAGON-HF trial, 4,735 of 4,822 patients (mean age 73 ± 8 years; 48% men) completed baseline KCCQ at randomization. Mean KCCQ-OS score was 71. Women had worse mean KCCQ-OS score than men did. Patients in the PARAGON-HF trial reported lower KCCQ scores in nearly all domains when compared with the PARADIGM-HF trial (KCCQ-OS score 71 ± 19 vs. 73 ± 19; p < 0.001). The strongest independent clinical correlates of adverse HRQL in both the PARAGON-HF and PARADIGM-HF trials were New York Heart Association functional class, female gender, lower extremity edema, body mass index, angina, dyspnea, and paroxysmal nocturnal dyspnea. After accounting for these clinical correlates of adverse HRQL that were common to both HFpEF and HFrEF patients, KCCQ-OS score did not differ significantly., Conclusions: HRQL was largely worse in women and was similar in HFpEF and HFrEF after accounting for variation in demographics, functional status, and symptom burden. (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF [PARAGON-HF] NCT01920711; Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)., (Copyright © 2019. Published by Elsevier Inc.)

Objectives: This study sought to investigate the relationship between malnutrition and adverse cardiovascular (CV) events in heart failure with preserved ejection fraction (HFpEF)., Background: Malnutrition is associated with poor prognosis in a wide range of illnesses, however, the prognostic impact of malnutrition in HFpEF patients is not well known., Methods: Baseline malnutrition risk was determined in 1,677 patients with HFpEF enrolled in the Americas regions of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial, according to 3 categories of the geriatric nutritional risk index (GNRI) as previously validated: moderate to severe, GNRI of <92; low, GNRI of 92 to <98; and absence of risk, GNRI of ≥98. The relationships between malnutrition risk and the primary composite outcome of CV events (CV death, heart failure hospitalization, or resuscitated sudden death) and all-cause death were examined., Results: Approximately one-third of patients were at risk for malnutrition (moderate to severe: 11%; low: 25%; and absence of risk: 64%). Over a median of 2.9-years' follow-up, compared to those with absent risk for malnutrition, moderate to severe risk was associated with significantly increased risk for the primary outcome, CV death and all-cause death (hazard ratio [HR]: 1.34; 95% confidence interval [CI]: 1.02 to 1.76; HR: 2.06; 95% CI: 1.40 to 3.03; and HR: 1.79; 95% CI: 1.33 to 2.42, respectively) after multivariate adjustment for age, sex, history of CV diseases, and laboratory biomarkers., Conclusions: Patients with HFpEF are at an elevated risk for malnutrition, which was associated with an increased risk for CV events in this population., (Copyright © 2019 American College of Cardiology Foundation. All rights reserved.)

Objectives: This study investigated the association between baseline renal function and the net benefit of spironolactone in patients with heart failure (HF) with a preserved ejection fraction (HFpEF)., Background: Guidelines recommend consideration of spironolactone to reduce HF hospitalization in HFpEF. However, spironolactone may increase risk for hyperkalemia and worsening renal function, particularly in patients with chronic kidney disease., Methods: This investigation analyzed data from patients enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) Americas study (N = 1,767) to examine the association between the baseline estimated glomerular filtration rate (eGFR) and the primary composite outcome of cardiovascular death, HF hospitalization, or aborted cardiac arrest, as well as safety outcomes, including hyperkalemia, worsening renal function, and permanent drug discontinuation for adverse events (AEs). Variations in the efficacy and safety of spironolactone according to eGFR were examined in Cox models using interaction terms., Results: The incidence of both the primary outcome and drug-related AEs increased with declining eGFR. Compared with placebo, across all eGFR categories, spironolactone was associated with lower relative risk for the primary efficacy outcome and for hypokalemia, but higher relative risk for hyperkalemia, worsening renal function, and drug discontinuation. During 4-year follow-up, the absolute risk for AEs that prompted drug discontinuation was amplified in the lower eGFR categories, which suggested heightened risk for drug intolerance with declining renal function., Conclusions: Although consistent efficacy of spironolactone was observed across the range of eGFR, the risk of AEs was amplified in the lower eGFR categories. These data supported use of spironolactone to treat HFpEF patients with advanced chronic kidney disease only when close laboratory surveillance is possible., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aims to characterize caregivers of patients considering destination therapy left ventricular assist device (DT-LVAD) and evaluate the effectiveness of a shared decision-making (SDM) intervention., Background: Caregivers play an integral role in the care of patients with chronic illness. At the extreme, pursuing a DT-LVAD is a major preference-sensitive decision that requires high-level caregiver engagement. Yet, little is known about caregivers of patients considering DT-LVAD, and there is a paucity of research on the involvement of caregivers in medical decision-making., Methods: A 6-center, stepped-wedge trial was conducted. After varying time in usual care (control), sites were transitioned to an SDM intervention consisting of staff education and pamphlet and video decision aids (DAs). The primary outcome was decision quality, measured by knowledge and values-choice concordance., Results: From 2015 to 2017, 182 caregivers of patients considering DT-LVAD were enrolled (control group, n = 111; intervention group, n = 71). The median age was 61 years, 86.5% were female, and 75.8% were spouses. Caregiver knowledge (0% to 100%) improved from baseline to post-education in both groups: in the control group it improved from 64.2% to 73.3%; in the intervention group it improved from 62.6% to 76.4% (adjusted difference of difference: 4.8%; p = 0.08). At 1 month, correlation between stated values and caregiver-reported treatment choice was stronger in the intervention group (difference in Kendall's tau: 0.36, 95% confidence interval: 0.04 to 0.71; p = 0.03). Caregivers reported decisional conflict (0 to 100) at baseline (control group: 19.0 ± 2.1; intervention group: 21.4 ± 2.6), which decreased post-education more in the control group (control group: 9.0 ± 1.9, intervention group: 18.8 ± 2.4; p = 0.009). Caregivers in the control group were more likely to "definitely recommend" the educational materials than those in the intervention group (93.5% vs. 74.5%, respectively; p = 0.004)., Conclusions: An SDM intervention improved concordance between caregiver values and treatment choice for their loved ones but did not significantly impact knowledge. Caregivers found the DAs less acceptable than more biased educational materials and exposure to DAs led to higher conflict initially. These findings highlight the complexity of SDM involving caregivers of patients with chronic illness. (PCORI-1310-06998 Trial of a Decision Support Intervention for Patients and Caregivers Offered Destination Therapy Heart Assist Device [DECIDE-LVAD]; NCT02344576)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study assessed the relationship between atrial fibrillation (AF) and outcomes in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, to evaluate whether AF modified the treatment response to spironolactone and whether spironolactone influenced post-randomization AF., Background: AF is common in heart failure with preserved ejection fraction (HFpEF) and likely contributes to increased risk of adverse outcomes., Methods: A total 1,765 patients enrolled in TOPCAT trial in North and South America were divided into 3 groups: no known AF, history of AF without AF at enrollment, and AF found on the electrocardiogram (ECG) at enrollment. We assessed outcomes and treatment response to spironolactone in all groups, and the association between post-randomization AF and outcomes in patients free of AF at baseline. The primary outcome of the TOPCAT trial was a composite of cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization., Results: A total of 760 patients (43%) had a history of AF (18%) or AF on ECG at enrollment (25%). The highest adjusted risk was associated with AF at enrollment (primary outcome, hazard ratio: 1.34; 95% confidence interval: 1.09 to 1.65; p = 0.006; and an increased early risk of secondary outcomes). Neither history of AF nor AF at enrollment modified the beneficial treatment effect of spironolactone. Post-randomization AF, which occurred in 6.3% of patients, was not influenced by spironolactone treatment, but was associated with an increased early risk of the primary outcome (hazard ratio: 2.32; 95% confidence interval: 1.59 to 3.40; p < 0.0001) and secondary outcomes., Conclusions: AF at enrollment was associated with increased cardiovascular risk in HFpEF patients in the TOPCAT study. Post-randomization AF, which was associated with an increased risk of morbidity and mortality, was not influenced by spironolactone. (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study investigated the rates and predictors of SD or aborted cardiac arrest (ACA) in HFpEF., Background: Sudden death (SD) may be an important mode of death in heart failure with preserved ejection fraction (HFpEF)., Methods: We studied 1,767 patients with HFpEF (EF ≥45%) enrolled in the Americas region of the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial. We identified independent predictors of composite SD/ACA with stepwise backward selection using competing risks regression analysis that accounted for nonsudden causes of death., Results: During a median 3.0-year (25th to 75th percentile: 1.9 to 4.4 years) follow-up, 77 patients experienced SD/ACA, and 312 experienced non-SD/ACA. Corresponding incidence rates were 1.4 events/100 patient-years (25th to 75th percentile: 1.1 to 1.8 events/100 patient-years) and 5.8 events/100 patient-years (25th to 75th percentile: 5.1 to 6.4 events/100 patient-years). SD/ACA was numerically lower but not statistically reduced in those randomized to spironolactone: 1.2 events/100 patient-years (25th to 75th percentile: 0.9 to 1.7 events/100 patient-years) versus 1.6 events/100 patient-years (25th to 75th percentile: 1.2 to 2.2 events/100 patient-years); the subdistributional hazard ratio was 0.74 (95% confidence interval: 0.47 to 1.16; p = 0.19). After accounting for competing risks of non-SD/ACA, male sex and insulin-treated diabetes mellitus were independently predictive of composite SD/ACA (C-statistic = 0.65). Covariates, including eligibility criteria, age, ejection fraction, coronary artery disease, left bundle branch block, and baseline therapies, were not independently associated with SD/ACA. Sex and diabetes mellitus status remained independent predictors in sensitivity analyses, excluding patients with implantable cardioverter-defibrillators and when predicting SD alone., Conclusions: SD accounted for ∼20% of deaths in HFpEF. Male sex and insulin-treated diabetes mellitus identified patients at higher risk for SD/ACA with modest discrimination. These data might guide future SD preventative efforts in HFpEF. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]); NCT00094302., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine whether the likelihood of receiving primary intensive care unit (ICU) care by a cardiologist versus a noncardiologist was greater for Caucasians than for African Americans admitted to an ICU for heart failure (HF). The authors further evaluated whether primary ICU care by a cardiologist is associated with higher in-hospital survival, irrespective of race., Background: Increasing data demonstrate an association between better HF outcomes and care by a cardiologist. It is unclear if previously noted racial differences in cardiology care persist in an ICU setting., Methods: Using the Premier database, adult patients admitted to an ICU with a primary discharge diagnosis of HF from 2010 to 2014 were included. Hierarchical logistic regression models were used to determine the association between race and primary ICU care by a cardiologist, adjusting for patient and hospital variables. Cox regression with inverse probability weighting was used to assess the association between cardiology care and in-hospital mortality., Results: Among 104,835 patients (80.3% Caucasians, 19.7% African Americans), Caucasians had higher odds of care by a cardiologist than African Americans (adjusted odds ratio: 1.42; 95% confidence interval: 1.34 to 1.51). Compared with a noncardiologist, primary ICU care by a cardiologist was associated with higher in-hospital survival (adjusted hazard ratio: 1.20, 95% confidence interval: 1.11 to 1.28). The higher likelihood of survival did not differ by patient race (interaction p = 0.32)., Conclusions: Among patients admitted to an ICU for HF, African Americans were less likely than Caucasians to receive primary care by a cardiologist. Primary care by a cardiologist was associated with higher survival for both Caucasians and African Americans., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study examined the relationship between baseline QRS duration and clinical outcomes in subjects enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial., Background: Heart failure with preserved ejection fraction (HFPEF) is a heterogeneous clinical syndrome. Whether QRS duration identifies HFPEF subjects at an increased risk of adverse outcomes has not been well studied., Methods: QRS duration was analyzed as a dichotomous variable (≥120 ms or <120 ms) and as a continuous variable to determine its relation to the primary outcome (composite of cardiovascular death, aborted cardiac arrest, or HF hospitalization [HFH]) and to each component of the primary outcome. Multivariate analyses were conducted in the entire study cohort as well as in separate analyses for subjects enrolled only from North and South America, or from Russia and Georgia., Results: The QRS duration of ≥120 ms was independently associated with an increased risk of the primary outcome (p = 0.009) and HFH (p = 0.003) in the entire study cohort and in the subset enrolled in the Americas. There was a linear relation of QRS duration with risk of the primary outcome and HFH. No interaction was observed between treatment with spironolactone and QRS duration. The risk of adverse outcomes was increased independently of the type of conduction abnormality underlying prolonged QRS duration., Conclusions: This post hoc analysis demonstrated that prolonged QRS duration identifies HFPEF subjects at a higher risk of adverse clinical outcomes and that spironolactone had a similar effect on outcomes independent of QRS duration. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study was developed to determine contemporary management of digoxin toxicity and clinical outcomes., Background: Although the use of digoxin in heart failure management has declined, toxicity remains a prevalent complication., Methods: The Premier Perspective Comparative Hospital Database (Premier Inc., Charlotte, North Carolina) was used to retrospectively identify patients diagnosed with digoxin toxicity and/or who received digoxin immune fab (DIF) over a 5-year period (2007 to 2011). DIF was evaluated using treatment date, number of vials administered, and total cost. Clinical outcomes included length of stay (total hospitalization; days after DIF), cost of hospitalization, and in-hospital mortality. Exploratory multivariate analyses were conducted to determine predictors of DIF and effect on length of stay, adjusting for patient characteristics and selection bias., Results: Digoxin toxicity diagnosis without DIF treatment accounted for 19,543 cases; 5,004 patients received DIF of whom 3086 had a diagnosis of toxicity. Most patients were >65 years old (88%). The predictors of DIF use were urgent/emergent admission, hyperkalemia, arrhythmia associated with digoxin toxicity, acute renal failure, or suicidal intent (odds ratios 1.7, 2.4, 3.6, 2.1, and 3.7, respectively; p < 0.0001 for all). The majority (78%) of DIF was administered on days 1 and 2 of the hospitalization; 10% received treatment after day 7. Digoxin was used after DIF administration in 14% of cases. Among patients who received DIF within 2 days of admission, there was no difference for in-hospital mortality or length of stay compared with patients not receiving DIF., Conclusions: Digoxin toxicity diagnoses are clustered in the elderly. One-fifth of cases receive treatment with DIF, most within 2 days of admission. Opportunities exist for improved diagnosis and post-DIF management. Prospective data may be required to assess the impact of DIF on length of stay., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The relative contribution of heart failure (HF) compared with other medical and nonmedical factors on diminished quality of life (QOL) across subtypes with reduced, better, and preserved left ventricular ejection fraction (LVEF) in a large ambulatory HF population was evaluated., Background: Dominant factors influencing limited QOL in patients with HF have not been investigated., Methods: Before routine HF clinic visits, 726 patients with ambulatory HF (mean age 56 ± 15 years, 37% women) completed a 1-page questionnaire that assessed QOL and relative contributions of HF compared with other medical and nonmedical factors to their QOL limitations. Visual analogue scales were used to assess overall QOL, breathing, and energy level. Results were compared across reduced (57%), preserved (16%) and better (improvement in LVEF ≥50%) (19%) subtypes., Results: Just under one-half of patients (48%) rated QOL as limited dominantly by HF, 19% rated HF and medical problems as equally limiting, 18% cited medical problems as dominant, and 15% cited nonmedical factors. Patients with HF with better LVEF had the highest overall QOL score and less dyspnea burden than those with HF with preserved EF. Independent correlates of HF-dominated diminished QOL were prior cardiac surgery, worse New York Heart Association functional class, renin-angiotensin-aldosterone antagonism, use of diuretic agents, lower body mass index, lower LVEF, and lack of arthritis or history of cancer., Conclusions: Fewer than one-half of patients with ambulatory HF rated HF as the greatest limitation to their QOL, suggesting that this important outcome will be difficult to affect by HF-targeted therapies alone, particularly in those with higher LVEFs and comorbidities. Patients with HF with better LVEF represent a distinct subtype with better overall QOL., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The objective of this study was to determine the impact of nonfatal cardiovascular (CV) events on changes in health-related quality of life (HRQL)., Background: There is limited understanding of the impact of nonfatal CV events on long-term changes in HRQL in survivors of myocardial infarction (MI)., Methods: The VALIANT (Valsartan In Acute Myocardial Infarction) trial enrolled 14,703 patients post-MI complicated by Killip class II or higher (scale measuring heart failure severity post-MI ranging from class I to IV) and/or reduced ejection fraction. The HRQL substudy included 2,556 (17.4%) patients who completed the EQ-5D with 5 questions, with responses mapped to utility weight on a scale of 0 to 1 and a visual analog scale (VAS) ranging from 0 (worst) to 100 (best) imaginable health state. EQ-5D was administered at baseline and 6, 12, 20, and 24 months. The trajectory of EQ-5D scores was developed by using linear mixed effects regression models with calculation of deviation from this trajectory after nonfatal CV events. Patients who died before the next EQ-5D assessment were excluded., Results: Over a 2-year period, 597 patients experienced a nonfatal CV event and survived to have another EQ-5D assessment. Their baseline EQ-5D scores were lower than patients without a subsequent nonfatal CV event (VAS 61.0 ± 19 vs 68.2 ± 18 [p < 0.001] and US-based utility score 0.76 ± 0.22 vs 0.83 ± 0.17 [p < 0.001]). These patients with CV events experienced a trajectory-adjusted 6.6 point decrease (p < 0.001) in VAS scores and a 0.07 decrease (p < 0.001) in utility score after the nonfatal CV event., Conclusions: MI survivors suffering a CV event experienced significantly worse HRQL than their previous trajectory, suggesting that generic instruments can be responsive to nonfatal events. Reduction in nonfatal CV events may affect longitudinal changes in HRQL., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The interdependence of cardiac and renal dysfunction has emerged as a focus of intense interest in heart failure management due to the substantial associated morbidity and mortality. Captured in the clinical entity known as cardiorenal syndrome, recent definitions afford discussion of the acute and longitudinal evaluation and management of these patients. This article discusses potential pathophysiologic mechanisms of cardiorenal syndrome, epidemiology, inpatient and long-term care (including investigational therapies and mechanical fluid removal), and end-of-life and palliative care.

Background: Oxidative stress and inflammation are involved in the pathophysiology of atherosclerosis. Our aim was to assess the effects of the antioxidant succinobucol (AGI-1067) on cardiovascular outcomes in patients with recent acute coronary syndromes already managed with conventional treatments., Methods: After an acute coronary syndrome occurring 14-365 days before recruitment, 6144 patients were randomly assigned with a computer-generated randomisation list, stratified by study site, to receive succinobucol (n=3078) or placebo (n=3066) in addition to standard of care. Enrolment began in July, 2003; this event-driven trial was stopped in August, 2006, after the prespecified number of primary outcome events had occurred. The composite primary endpoint was time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, unstable angina, or coronary revascularisation. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00066898., Findings: All randomised patients were included in the efficacy analyses. Succinobucol had no effect on the primary endpoint (530 events in succinobucol group vs 529 in placebo group; hazard ratio 1.00, 95% CI 0.89-1.13, p=0.96). The composite secondary endpoint of cardiovascular death, cardiac arrest, myocardial infarction, or stroke occurred in fewer patients in the succinobucol group than in the placebo group (207 vs 252 events; 0.81, 0.68-0.98, p=0.029). The tertiary endpoint of new-onset diabetes developed in fewer patients without diabetes at baseline in the succinobucol group than in such patients in the placebo group (30 of 1923 vs 82 of 1950 patients; 0.37, 0.24-0.56, p<0.0001). New-onset atrial fibrillation occurred more often in the succinobucol group than in the placebo group (107 of 2818 vs 55 of 2787 patients; 1.87, 1.67-2.09, p=0.0002). Although the number of patients who reported any treatment emergent adverse event was much the same in the two groups, more patients in the succinobucol group than in the placebo group reported bleeding episodes or anaemia (32 vs 18 and 37 vs ten, respectively) as serious adverse events. Relative to treatment with placebo, succinobucol increased LDL cholesterol and systolic blood pressure, and decreased HDL cholesterol and glycated haemoglobin (p<0.0001 for all)., Interpretation: Although succinobucol had no effect on the primary endpoint, changes in the rates of other clinical outcomes-both beneficial and harmful-will need to be further assessed before succinobucol is used in patients with atherosclerosis or as an antidiabetic agent.

Background: This study evaluates the significance of tricuspid regurgitation (TR) on long-term survival as detected by intraoperative transesophageal echocardiography at the time of orthotopic heart transplantation. Although significant (2+ to 4+) TR after orthotopic heart transplantation is rare, its influence on long-term survival is unknown, warranting further investigation., Methods: Between January 1992 and July 2001, 181 consecutive patients underwent orthotopic heart transplantation. Tricuspid regurgitation was graded by intraoperative transesophageal echocardiography after final separation from cardiopulmonary bypass in 130 of 181 patients (72%)., Results: Although 80% (104/130) of patients had either no (0, n = 77) or trace (1+, n = 27) TR, 9% (12/130 patients) had mild (2+), 10% (13/130 patients) had moderate (3+), and 0.8% (1/130 patients) had severe (4+) TR. The severity correlated strongly with the presence of right ventricular dysfunction (p < 0.001). In a multivariate regression model, gender mismatch (p = 0.002) and right ventricular dysfunction (p < 0.001) were independent predictors for equal to or greater than mild (2+ to 4+) TR (p = 0.015). Although the degree of recipient pulmonary vascular resistance did not influence the grade (p = 0.600), higher pulmonary vascular resistance tended to increase the severity of TR in the setting of prolonged donor ischemic times (p = 0.054). Proportional hazards regression analysis demonstrated significantly decreased survival for patients with mild or greater (2+ to 4+) TR detected by transesophageal echocardiography at the time of transplantation (p < 0.001) and RV dysfunction (p = 0.023)., Conclusions: Even mild (> or = 2+) TR identified by transesophageal echocardiography at the time of orthotopic heart transplant predicts poor late survival, suggesting a possible role for concomitant tricuspid valve repair at the time of transplant. Whether or not tricuspid valve repair will improve long-term survival is unknown.