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ObjectivesThe aim of this study was to use a multicenter, observational outpatient registry of patients with heart failure with reduced ejection fraction (HFrEF) to describe the association between changes in patients' medications with changes in health status.BackgroundAlleviating symptoms and improving function and quality of life for patients with HFrEF are primary treatment goals and potential indicators of quality. Whether titrating medications in routine clinical care improves patients' health status is unknown.MethodsThe association of any change in HFrEF medications with 3-month change in health status, as measured using the 12-item Kansas City Cardiomyopathy Questionnaire Overall Summary Scale, was determined in unadjusted and multivariate-adjusted (25 clinical characteristics, baseline health status) models using hierarchical linear regression.ResultsAmong 3,313 outpatients with HFrEF from 140 centers, 21.9% had medication changes. Three months later, 23.7% and 46.4% had clinically meaningfully worse (≥5-point decrease) and improved (≥5-point increase) Kansas City Cardiomyopathy Questionnaire Overall Summary Scale scores. The 3-month median change in Kansas City Cardiomyopathy Questionnaire Overall Summary Scale score for patients whose HFrEF medications were changed was significantly larger (7.3 points; interquartile range: -3.1 to 20.8 points) than in patients whose medications were not changed (3.1 points; interquartile range: -4.7 to 12.5 points) (adjusted difference 3.0 points; 95% confidence interval: 1.4 to 4.6 points; p

Guideline-directed medical therapy utilization in patients with heart failure with reduced ejection fraction (HFrEF) remains low despite benefits in morbidity and mortality. The authors describe a unique quality improvement initiative designed to increase angiotensin receptor-neprilysin inhibitor (ARNI) and mineralocorticoid receptor antagonist (MRA) utilization in outpatients with HFrEF in a large cardiology practice, whereby eligible patients were identified in a standardized review process and medication utilization rates were linked to group quality metrics. Eligible HFrEF patients were defined as having a left ventricular ejection fraction (LVEF) ≤40% and NYHA functional class II to IV level of symptoms. Those with an LVEF >40%, no documented LVEF, or with NYHA functional class I symptoms were excluded. ARNI utilization was defined as any dose of sacubitril/valsartan prescribed, and MRA utilization was defined as any dose of either spironolactone or eplerenone prescribed. Group quality metric targets were set at >25% ARNI prescription and >60% MRA prescription in eligible patients. Following project implementation, ARNI utilization rose from 31% to 67% and MRA increased from 28% to 66%. Establishing clear quality metrics and formulating a proactive evaluation process was associated with a significant increase in prescription rates., Competing Interests: Funding Support and Author Disclosures The statistical analysis for this manuscript was supported by grant funding from iTHRIV: National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR003015/KL2TR003016. Dr O’Connor served as a consultant for Abiomed and ZealCare; and has received research funding from Merck. 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.)

Pulmonary hypertension associated with left heart disease (PH-LHD) remains the most common cause of pulmonary hypertension globally. Etiologies include heart failure with reduced and preserved ejection fraction and left-sided valvular heart diseases. Despite the increasing prevalence of PH-LHD, there remains a paucity of knowledge about the hemodynamic definition, diagnosis, treatment modalities, and prognosis among clinicians. Moreover, clinical trials have produced mixed results on the usefulness of pulmonary vasodilator therapies for PH-LHD. In this expert review, we have outlined the critical role of meticulous hemodynamic evaluation and provocative testing for cases of diagnostic uncertainty. Therapeutic strategies-pharmacologic, device-based, and surgical therapies used for managing PH-LHD-are also outlined. PH-LHD in advanced heart failure, and the role of mechanical circulatory support in PH-LHD is briefly explored. An in-depth understanding of PH-LHD by all clinicians is needed for improved recognition and outcomes among patients with PH-LHD., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Optimal medical therapy (OMT) scoring may stratify clinical risk in real-world chronic heart failure with reduced ejection fraction (HFrEF) by integrating use and dosing of guideline-directed medical therapy (GDMT) for HFrEF., Objectives: The purpose of this study was to characterize patients and associated long-term clinical outcomes by OMT score-derived treatment groups., Methods: CHAMP-HF (Change the Management of Patients with Heart Failure) included U.S. outpatients with chronic HFrEF receiving ≥1 GDMT. OMT subgroups were defined as suboptimal (score <3), acceptable (score = 3), and optimal (score ≥4) by baseline use and dose of GDMT, as proposed by the HF Collaboratory consortium. Cox proportional hazard analyses were used to assess for all-cause and cardiovascular death across subgroups, after adjusting for demographic and clinical covariates., Results: The authors studied 4,582 participants enrolled in CHAMP-HF with available 2-year follow-up. Median age was 68 years, 1,327 (29%) were women, and 2,842 (62%) were White, non-Hispanic. Median OMT score across the population was 4 (Q1-Q3: 2-5), and 1,628 (35%) had suboptimal, 665 (14%) had acceptable, and 2,289 (50%) had optimal therapy. Participants with optimal treatment were younger, had higher annual household income, and were enrolled from practices with dedicated HF clinics (all P < 0.001) than participants with acceptable or suboptimal treatment. Participants with optimal treatment had lower all-cause death (adjusted HR: 0.77; 95% CI: 0.64-0.92) and cardiovascular death (adjusted HR: 0.79; 95% CI: 0.65-0.96) than those with suboptimal treatment., Conclusions: Across a large cohort of chronic ambulatory HFrEF, OMT scores stratified risk of all-cause and cardiovascular death., Competing Interests: Funding Support and Author Disclosures CHAMP-HF was supported by Novartis Pharmaceuticals. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr Rao has received salary support by a National Institutes of Health training grant (5T32HL069749-18). Dr Spertus has provided consultative services on patient-reported outcomes and evidence evaluation to Abbott, Alnylam, AstraZeneca, Bayer, Janssen, Bristol Meyers Squibb, Edwards, Terumo, Cytokinetics, and Imbria. He holds research grants from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, the American College of Cardiology Foundation, Bristol Meyers Squibb, Cytokinetics, Imbria, and Janssen. He owns the copyright to the Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire, and Peripheral Artery Questionnaire and serves on the Board of Directors for Blue Cross Blue Shield of Kansas City. Dr Butler is a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Levator, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Pulnovo, Regeneron, Renibus, Roche, Salamandra, Salubris, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr DeVore has received research funding through his institution from the American Heart Association, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent, Inc, the National Heart, Lung, and Blood Institute, Novartis, and PCORI; he provides consulting services for Amgen, AstraZeneca, Bayer, CareDx, InnaMed, LivaNova, Mardil Medical, Novartis, Procyrion, scPharmaceuticals, Story Health, and Zoll; and has received nonfinancial support from Abbott for educational activities. 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.)

ObjectivesThis study sought to evaluate the effectiveness of hydralazine-isosorbide dinitrate (H-ISDN) in African Americans with heart failure (HF) with reduced ejection fraction (HFrEF).BackgroundAmong African-American patients with HFrEF, H-ISDN was found to improve quality of life and lower HF-related hospitalization and mortality rates in the A-HEFT (African-American Heart Failure Trial). Few studies have evaluated the effectiveness of this therapy in clinical practice.MethodsVeterans Affairs patients with a hospital admission for HF between 2007 and 2013 were screened. Inclusion criteria included African-American race, left ventricular ejection fraction 2.0 mg/dl, or intolerance to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Adjusted hazard ratios were calculated for patients who received H-ISDN 6-months before admission compared with patients who did not receive H-ISDN, by using inverse probability weighting of propensity scores and a time to death analysis for 18 months of follow-up. Propensity scores were generated using patients' characteristics, left ventricular ejection fraction, laboratory values, and hospital characteristics.ResultsThe final cohort included 5,168 African-American patients with HF (mean age 65.2 years), with 15.2% treated with H-ISDN before index admission. After 18 months, there were 1,275 reported deaths (24.7%). The adjusted mortality rate at 18 months was 22.1% for patients receiving H-ISDN treatment and 25.2% for untreated patients (p = 0.009); adjusted hazard ratio: 0.85 (95% confidence interval: 0.73 to 1.00; p = 0.057).ConclusionsH-ISDN remains underused in African-American patients with HFrEF. In this cohort, the study found that H-ISDN use was associated with lower mortality rates in African-American patients with HFrEF when controlling for patient selection by using an inverse probability weighting of propensity scores.

Background: Type 2 diabetes mellitus (T2DM) significantly worsens heart failure (HF) prognosis., Objectives: This study sought to investigate the impact of T2DM on outcomes in patients enrolled in VICTORIA and assess the efficacy of vericiguat in patients with and without T2DM., Methods: Patients with HF with reduced ejection fraction were randomized to receive vericiguat or placebo in addition to standard therapy. The primary outcome was a composite of cardiovascular death or first heart failure hospitalization (HFH). A Cox proportional hazards model was used to calculate HRs and 95% CIs to assess if the effect of vericiguat differed by history of T2DM., Results: Of 5,050 patients enrolled, 3,683 (72.9%) had glycosylated hemoglobin (HbA 1c ) measured at baseline. Of these, 2,270 (61.6%) had T2DM, 741 (20.1%) had pre-T2DM, 449 (12.2%) did not have T2DM, and 178 (4.8%) had undiagnosed T2DM. The risks of the primary outcome, HFH, and all-cause and cardiovascular mortality were high across all categories. The efficacy of vericiguat on the primary outcome did not differ in patients stratified by T2DM by history (HR: 0.92; 95% CI: 0.81-1.04), T2DM measured by HbA 1c (HR: 0.77; 95% CI: 0.49-1.20), and pre-T2DM measured by HbA 1c (HR: 0.88; 95% CI: 0.68-1.13) and in those with normoglycemia (HR: 1.02: 95% CI: 0.75-1.39; P for interaction = 0.752). No significant differences were observed in subgroups with respect to the efficacy of vericiguat on HFH and all-cause or cardiovascular death., Conclusions: In this post hoc analysis of VICTORIA, vericiguat compared with placebo significantly reduced the risk of cardiovascular death or HFH in patients with worsening HF with reduced ejection fraction regardless of T2DM status. (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction [HFrEF] [Mk-1242-001] [VICTORIA]; NCT02861534)., Competing Interests: Funding Support and Author Disclosures VICTORIA was funded by Bayer and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, USA. Dr Khan has served as an Advisory Board Member for Bayer. 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 Roessig has been an employee of Bayer AG. Dr Blaustein has been an employee of Merck & Co, Inc. Dr Lam has received research grants from Bayer, National Medical Research Council of Singapore, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma, and AstraZeneca; has received consulting fees from Merck, Bayer, Boston Scientific, Roche Diagnostic, Vifor Pharma, AstraZeneca, Novartis, Amgen, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, Radcliffe Group Ltd, and Corpus; has patent PCT/SG2016/050217 pending and patent 16/216929 pending; and is cofounder and nonexecutive director of eKo.ai. Dr Voors has received research grants from Boehringer Ingelheim and Roche Diagnostics and consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, MyoKardia, Novartis, Servier, and Roche Diagnostics. Dr Ponikowski has received research grants, has received consulting fees, and has served on the Speakers Bureau for Bayer, MSD, Servier, Novartis, Vifor Pharma Ltd, BMS, Boehringer Ingelheim, Respicardia, AstraZeneca, Cibiem, RenalGuardSolution, and Berlin Chemie. Dr Anstrom has received research grants from Merck and the National Institutes of Health. Dr Armstrong has received consulting fees from Merck, Bayer, Boehringer Ingelheim, and Novo Nordisk and research grants from Merck, Bayer, Boehringer Ingelheim/Eli Lilly, and CSL Limited. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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

Background: Despite robust evidence and strong guideline recommendations supporting use of mineralocorticoid receptor antagonists (MRAs) to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF), these medications remain underused in clinical practice., Objectives: The goal is to determine if providing a tailored best practice alert (BPA) to outpatient providers suggesting guideline-recommended MRAs or information about available hyperkalemia treatment, if present, for patients with HFrEF will increase short-term MRA prescriptions., Methods: PROMPT-MRA (Pragmatic Trial of Messaging to Providers About Treatment With Mineralocorticoid Receptor Antagonists) is a pragmatic, cluster-randomized, controlled study. A total of 119 providers were randomized to receive a BPA or usual care. During an outpatient visit with participating providers, the BPA displayed recent laboratory test values and ejection fraction. The alert suggested guideline-recommended MRAs for eligible patients with a serum potassium of <5.0 mEq/L or novel potassium binders for those with a serum potassium of ≥5.0 mEq/L, each linked to an order set containing the corresponding medication and laboratory monitoring., Results: PROMPT-MRA completed enrollment with 1,210 patients. The primary outcome of PROMPT-MRA is to determine if a tailored BPA for outpatients with HFrEF will lead to higher MRA prescriptions 6 months following randomization compared with usual care. Secondary outcomes included incidence of hyperkalemia, use of novel potassium binders, heart failure hospitalizations, and mortality., Conclusions: If effective, the BPA can be scaled to improve population health outcomes with increased MRA prescribing among eligible patients with HFrEF, with or without a history of hyperkalemia. (Pragmatic Trial of Alerts for Use of Mineralocorticoid Receptor Antagonists [PROMPT-MRA]; NCT04903717)., Competing Interests: Funding Support and Author Disclosures PROMPT-MRA (Pragmatic Trial of Alerts for Use of Mineralocorticoid Receptor Antagonists; NCT04903717) was supported by CSL Vifor. Dr Riello has participated on Advisory Boards for Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Johnson and Johnson, Medicure, PhaseBio, Portola, and Salix; honoraria and consulting fees from Alexion, Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Johnson and Johnson, Pfizer, Portola, and Salix; and stock ownership in Akebia Therapeutics, Cytokinetics, Emergent BioSolutions, Iterum, Olema Pharmaceuticals, PhaseBio, and Verve Therapeutics. Dr Ahmad has received consulting fees from Sanofi, Amgen, and Cytokinetics; and has received research funding from Boehringer Ingelheim, AstraZeneca, Cytokinetics, and Relypsa. Dr Wilson has received grants R01DK11391, R01HS027626, and P30DK079310 and research support from AstraZeneca, CSL Vifor, and WHOOP. Dr Desai has worked 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; and has received research grants from and consulted for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Novartis, SCPharmaceuticals, and CSL Vifor. Drs Wilson and Desai are primary investigators of the ongoing PROMPT-MRA funded by CSL Vifor. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: Assessment of functional capacity in patients with heart failure with reduced ejection fraction (HFrEF) is essential for risk stratification, and it traditionally relied on cardiopulmonary exercise testing (CPET)-derived peak oxygen consumption (peak Vo 2 )., Objectives: This study sought to investigate the prognostic value of alternative nonmetabolic exercise testing parameters in a contemporary cohort with HFrEF., Methods: Medical records of 1,067 consecutive patients with chronic HFrEF who underwent CPET from December 2012 to September 2020 were reviewed for a primary outcome that was a composite of all-cause mortality, left ventricular assist device implantation, and/or heart transplantation. Multivariable Cox regression and log-rank testing were used to determine prognostic values of various exercise testing variables., Results: The primary outcome was identified in 331 of 954 patients (34.7%) of the HFrEF cohort (median follow-up time, 946 days). After adjustment for demographics, cardiac parameters, and comorbidities, higher hemodynamic gain index (HGI) and peak rate-pressure product (RPP) were associated with greater event-free survival (adjusted HR per doubling: 0.76 and 0.36; 95% CI: 0.67-0.87 and 0.28-0.47; all P < 0.001, respectively). Moreover, HGI (area under the curve [AUC]: 0.69; 95% CI: 0.65-0.72) and peak RPP (AUC: 0.71; 95% CI: 0.68-0.74) were comparable to the standard peak Vo 2 (AUC: 0.70; 95% CI: 0.66-0.73; P for comparison = 0.607 and 0.393, respectively) for primary outcome discrimination., Conclusions: HGI and peak RPP show good correlation with peak Vo 2 in terms of prognostication and outcome discrimination in patients with HFrEF and may serve as suitable alternatives to CPET-derived prognostic variables., Competing Interests: Funding Support and Author Disclosures Dr Finet has served a consultant for Wolters Kluwer Health and Lexicomp. Dr Martens has received support from a grant from the Belgian American Educational Foundation and the Frans Van de Werf Fund; and has received consultancy fees from AstraZeneca, Abbott, Bayer, Boehringer-Ingelheim, Daiichi Sankyo, Novartis, Novo Nordisk, and Vifor Pharma. Dr Grodin has received research funding from the Texas Health Resources Clinical Scholarship, Eidos/BridgeBio, Pfizer and the National Institutes of Health (NIH) National Heart, Lung and Blood Institute (NHLBI) (R01HL160892); and has received consulting fees from Pfizer, Eidos/BridgeBio, Alnylam, AstraZeneca, and Sarepta. Dr Tang has received partial support from grants from the NIH NHLBI (R01HL146754); has served as a consultant for Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Renovacor, WhiteSwell, Kiniksa Pharmaceuticals, Boston Scientific, and CardiaTec Biosciences; and has received honoraria from Springer Nature and the American Board of Internal Medicine. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial established the efficacy of empagliflozin in reducing heart failure (HF) outcomes among patients with heart failure with reduced ejection fraction (HFrEF)., Objectives: The authors examined the outcomes of EMPEROR-Reduced as a function of background diuretic therapy., Methods: The EMPEROR-Reduced trial was a double-blind, randomized controlled trial of placebo vs empagliflozin 10 mg among 3,730 HFrEF patients. Herein, the population was stratified into 4 groups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline., Results: A total of 3,656 patients from the EMPEROR-Reduced trial were available for analysis. Of those patients, 482 (13.2%) were receiving no diuretic therapy, and 731 (20.0%), 1,411 (38.6%), and 1,032 (28.2%) were receiving <40 mg, 40 mg, and >40 mg, respectively. The efficacy of empagliflozin on the primary outcome (time to first event of hospitalization for HF or cardiovascular [CV] death) was consistent regardless of background diuretic therapy (>40 mg: HR: 0.88 [95% CI: 0.71-1.10]; 40 mg: HR: 0.65 [95% CI: 0.51-0.82]; <40 mg: HR: 0.65 [95% CI: 0.46-0.92]); no diuretic agents: HR: 0.78 [95% CI: 0.47-1.29]; P trend test  = 0.192). Baseline diuretic doses did not influence the effect of empagliflozin on body weight, systolic blood pressure, NT-proBNP, or hematocrit at 52 weeks. The safety profile of empagliflozin vs placebo was unaffected by baseline diuretic dose; however, independently of treatment allocation, total rates of adverse events were higher among patients with higher baseline doses of diuretic agents., Conclusions: Empagliflozin exhibits a consistent effect on time to CV death or HF hospitalization and an unaltered safety profile regardless of baseline diuretic therapy. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977)., Competing Interests: Funding Support and Author Disclosures Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; has received research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Sun Pharmaceuticals, PhaseBio, and the Toronto Knowledge Translation Working Group; is a member of the scientific excellence committee of the EMPEROR-Reduced trial; 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 research support from the National Institutes of Health, Patient Centered Outcomes Research, and the European Union; has served on the Speakers Bureau for Novartis, Janssen, and Novo Nordisk; and has served as a consultant and has served on steering committee, clinical events committee, or data safety monitoring boards for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Berlin-Cures, Boehringer Ingelheim, Bristol Myers Squib, Cardiocell, CVRx, G3 Pharmaceutical, Innolife, Janssen, Lantheus, LinaNova, Luitpold, Medscape, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Stealth-Peptide, SC Pharma, V-Wave Limited, Vifor, and ZS Pharma. Dr Anker has received grants and personal fees from Vifor International and Abbott Vascular; and has received personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor International. Dr Ferreira is a consultant for Boehringer Ingelheim. Dr Filippatos has received lecture fees and/or committee member contributions in trials sponsored by Bayer, Medtronic, Vifor, Servier, Novartis, Amgen, and Boehringer Ingelheim; and has received research support from the European Union. Dr Januzzi is a Trustee of the American College of Cardiology, a Board member of Imbria Pharmaceuticals, Applied Therapeutics, Innolife, Novartis Pharmaceuticals and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and has participated in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. Dr Lam has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has received fees as consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research and Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and holds a position as co-founder and nonexecutive director of Us2.ai. Dr Sattar has received personal fees from Abbott Laboratories, Afimmune, Amgen, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp and Dohme, Novo Nordisk, Pfizer, and Sanofi; and has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside of the submitted work. Dr Zaremba-Pechmann is a contractor to Boehringer Ingelheim via Elderbrook Solutions Gmbh. Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. Drs Nordaby and Brueckmann are employees of Boehringer Ingelheim International GmbH. Dr Pocock is a consultant for Boehringer Ingelheim. Dr Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius. Dr Packer has received personal fees from Abbvie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, and Salamandra. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Data Sharing Statement: To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript and secondary analyses in a peer-reviewed journals and regulatory and reimbursement activities are completed, normally within 1 year after the marketing application has been granted by major Regulatory Authorities. Researchers should use https://vivli.org/ to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with heart failure with reduced ejection fraction (HFrEF) have persistent impairments in functional capacity after continuous-flow left ventricular assist device (CF-LVAD) implantation., Objectives: This study aims to characterize longitudinal changes in exercise hemodynamics and functional capacity among patients with HFrEF before and after CF-LVAD implantation., Methods: Ten patients underwent 3 invasive cardiopulmonary exercise tests on upright cycle ergometry with pulmonary artery catheterization: 1) Visit 1 before CF-LVAD implantation; 2) Visit 2 after device implantation with CF-LVAD pump speed held constant at baseline speed; and 3) Visit 3 with increases in pump speed during exercise (median: 1,050 rpm [IQR: 750-1,150 rpm] and 220 rpm [IQR: 120-220 rpm] for HeartMate 3 and HeartWare VAD, respectively). Hemodynamics and direct Fick cardiac output were monitored using pulmonary artery catheterization. Gas exchange metrics were determined using indirect calorimetry., Results: Maximal oxygen uptake (Visits 1, 2, and 3: 10.8 ± 2.5 mL/kg/min, 10.7 ± 2.2 mL/kg/min, and 11.5 ± 1.7 mL/kg/min; P = 0.92) did not improve after device implantation. Mean pulmonary arterial and pulmonary capillary wedge pressures increased significantly during submaximal and peak exercise on preimplantation testing (P < 0.01 for rest vs peak exercise) and remained elevated, with minimal change on Visits 2 and 3 regardless of whether pump speed was fixed or increased., Conclusions: Among patients with HFrEF, cardiovascular hemodynamics and exercise capacity were similar after CF-LVAD implantation, regardless of whether patients exercised at fixed or adjusted pump speeds during exercise. Further research is needed to determine methods by which LVADs may alleviate the HFrEF syndrome after device implantation. (Effect of mechanIcal circulatoRy support ON exercise capacity aMong pAtieNts with heart failure [IRONMAN]; NCT03078972)., Competing Interests: Funding Support and Author Disclosures Dr Cornwell has received funding by an National Institutes of Health/National Heart, Lung and Blood Institute Mentored Patient-Oriented Research Career Development Award (#1K23HLI32048-01), as well as the National Institutes of Health/National Center for Advancing Translational Sciences (#UL1TR002535), the Clinical Translational Science Institute at the University of Colorado Anschutz Medical Campus, and Medtronic Inc. Dr Allen has received consulting fees from Boston Scientific, Medtronic, Abbott, ACI Clinical, Amgen, Cytokinetics, and Novartis. Dr Cornwell has received research funding from Merck Corp and Medtronic Inc; and is a consultant for Merck Corp, Medtronic Inc, and Bioventrix Inc. All other author have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Some studies have indicated that sodium-glucose cotransporter-2 (SGLT2) inhibitors promote an increase in cell iron use., Objectives: The aim of this study was to examine, in patients with stable heart failure with reduced left ventricular ejection fraction (HFrEF), the effect of dapagliflozin on ferrokinetic parameters and whether short-term changes in peak oxygen consumption (Vo 2 ) after dapagliflozin treatment are influenced by baseline and serial ferrokinetic status., Methods: This was an exploratory analysis of a randomized, double-blind clinical trial that evaluated the effect of dapagliflozin vs placebo on peak Vo 2 in patients with HFrEF (NCT04197635) and included 76 of the 90 patients initially enrolled in the trial. Changes in peak Vo 2 at 1 and 3 months were explored according to baseline and longitudinal ferrokinetic parameters (natural logarithm [ln] ferritin, transferrin saturation index [TSAT], soluble transferrin receptor, and hepcidin). Linear mixed-effect regression was used for the analyses., Results: Compared with placebo, dapagliflozin led to a significant decrease in 3-month ln ferritin (P = 0.040) and an increase in 1-month ln soluble transferrin receptor (P = 0.023). Between-treatment comparisons revealed a stepwise increase in peak Vo 2 in the dapagliflozin group at 1 and 3 months, which was especially apparent at lower baseline values of TSAT and ferritin (P < 0.05). Lower time-varying values of TSAT (1 and 3 months) also identified patients with greater improvements in peak Vo 2 ., Conclusions: In patients with stable HFrEF, treatment with dapagliflozin resulted in short-term increases in peak Vo 2 , which were most marked in patients with surrogates of greater iron deficiency at baseline and during treatment. (Short-Term Effects of Dapagliflozin on Peak Vo 2 in HFrEF [DAPA-VO 2 ]; NCT04197635)., Competing Interests: Funding Support and Author Disclosures This work was supported in part by an unrestricted grant from AstraZeneca España, Unidad de Investigación Clínica y Ensayos Clínicos INCLIVA Health Research Institute, the Spanish Clinical Research Network (PT17/0017/0003 and PT20/00100), and CIBER Cardiovascular (grants 16/11/00420, 16/11/00403, and 16/11/00486). Dr Packer has received consulting fees from AbbVie, Altimmune, Amgen, Ardelyx, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Eli Lilly, Moderna, Novartis, Reata, Regeneron, Relypsa, and Salamandra (outside the scope of this work). Dr Espriella has received personal fees from AstraZeneca, Novartis, Boehringer Ingelheim, and Novo Nordisk (outside the submitted work). Dr Bayés-Genis has received personal fees from and/or is an advisory board member for AstraZeneca, Novartis, Boehringer Ingelheim, Abbott, Roche Diagnostics, and Vifor Pharma. Dr Soler has received personal fees from and/or is an advisory board member for AstraZeneca, Novartis, Boehringer Ingelheim, Abbott, Roche Diagnostics, and Vifor Pharma. Dr Núñez has received personal fees from or is an advisory board member for Alleviant, AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, Novo Nordisk, Rovi, and Vifor Pharma (outside the submitted work). 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.)

Background: The contribution of clinical inertia to suboptimal guideline-directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF) remains unclear., Objectives: This study examined reasons for GDMT nonintensification and characterized clinical inertia., Methods: In this secondary analysis of EPIC-HF (Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction), a randomized clinical trial evaluating a patient-activation tool on GDMT utilization, we performed a sequential, explanatory mixed-methods study. Reasons for nonintensification among 4 medication classes were assigned according to an expanded published taxonomy using structured chart reviews. Audio transcripts of clinic encounters were analyzed to further characterize nonintensification reasons. Integration occurred during the interpretation phase., Results: Among 292 HFrEF patients who completed a cardiology visit, 185 (63.4%) experienced no treatment intensification, of whom 90 (48.6%) had at least 1 opportunity for intensification of a medication class with no documented contraindication or barriers (ie, clinical inertia). Nonintensification reasons varied by medication class, and included heightened risk of adverse effects (range 18.2%-31.6%), patient nonadherence (range 0.8%-1.1%), patient preferences and beliefs (range 0.6%-0.9%), comanagement with other providers (range 4.6%-5.6%), prioritization of other issues (range 15.6%-31.8%), multiple categories (range 16.5%-22.7%), and clinical inertia (range 22.7%-31.6%). A qualitative analysis of 32 clinic audio recordings demonstrated common characteristics of clinical inertia: 1) clinician review of medication regimens without education or intensification discussions; 2) patient stability as justification for nonintensification; and 3) shorter encounters for nonintensification vs intensification., Conclusions: In this comprehensive study exploring HFrEF prescribing, clinical inertia is a main contributor to nonintensification within an updated taxonomy classification for suboptimal GDMT prescribing. This approach should help target strategies overcoming GDMT underuse., Competing Interests: Funding Support and Author Disclosures This project/publication is supported in part by National Institutes of Health/NCATS Colorado CTSA Grant Number UL1 TR002535. Contents are the authors’ sole responsibility and do not necessarily represent official National Institutes of Health views. Dr Swat has received funding from the National Institutes of Health T32 Training Grant 5T32-HL-007822-22. Dr Allen has received grant funding from the American Heart Association, National Institutes of Health, and Patient-Centered Outcomes Research Institute; and has received consulting fees from Abbott, ACI Clinical, Amgen, Boston Scientific, Cytokinetics, Novartis, Quidel, and UpToDate. 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.)

Background: Age and sex influence treatment and outcomes in patients with heart failure (HF)., Objectives: The authors examined the associations of age and sex with clinical characteristics, background therapies, outcomes, and response to vericiguat in this post hoc analysis of 5,050 VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) patients with HF and reduced ejection fraction; 1,568 (31%) were ≥75 years of age, of whom 445 (24%) were women., Methods: Clinical characteristics were compared across age (<65, 65 to <75, and ≥75 years) and sex. The treatment effect of vericiguat was estimated by age and sex on the primary composite outcome (time to first HF hospitalization or cardiovascular death) using Cox proportional hazards regression., Results: Compared with younger patients, those ≥75 years of age had more class III and IV symptoms, higher N-terminal pro-B-type natriuretic peptide levels, and worse kidney function but had the lowest use of triple therapy. No sex differences in triple therapy existed by age, but achieving target doses of triple therapy was less likely in older patients. Men ≥75 years of age were more than twice as likely to receive defibrillators and 65% more likely to undergo cardiac resynchronization than women. The primary composite outcome was nominally lower in women than men across all age groups. Vericiguat dosing did not differ between sexes in each age group, and its beneficial effect on the primary endpoint was not modified by age (continuous age, P interaction  = 0.169; categorical age, P interaction  = 0.189); and sex (3-way interaction; P = 0.847)., Conclusions: Although elderly women received less intense background HF therapy than men, their prognosis was nominally better. The benefit of vericiguat was independent of age and sex. (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction [HFrEF] [MK-1242-001] [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 (Rahway, New Jersey, USA), and Bayer AG (Wuppertal, Germany). Dr Lam has received research grants from Bayer, the National Medical Research Council of Singapore, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma, and AstraZeneca; has received consulting fees from Merck, Bayer, Boston Scientific, Roche Diagnostic, Vifor Pharma, AstraZeneca, Novartis, Amgen, Janssen Research and Development, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global, Radcliffe Group, and Corpus; has patent PCT/SG2016/050217 pending and patent 16/216929 pending; and is a cofounder and nonexecutive director of eKo.ai. Dr Pieske has received research grants from Merck Sharpe and Dohme, Bayer, and Servier; has received consulting fees from Merck Sharpe and Dohme, Bayer, Servier, Bristol Myers Squibb, MedScape, Daiichi Sankyo, and Novartis; and has received nonfinancial support from Merck Sharpe and Dohme, Bayer, and Novartis. Dr Blaustein is an employee of Merck. Dr Nkulikiyinka is an employee of Bayer. Dr Westerhout has received consulting fees from Bayer. Dr Armstrong has received consulting fees from Merck, Bayer, Boehringer Ingelheim, and Novo Nordisk; and has received research grants from Merck, Bayer, Boehringer Ingelheim/Eli Lilly, and CSL Limited. 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.)

Background: Initiation of evidence-based medications for patients with heart failure with reduced ejection fraction (HFrEF) during hospitalization in contemporary practice is unknown., Objectives: This study characterized opportunities for and achievement of heart failure (HF) medication initiation., Methods: Using the GWTG-HF (Get With The Guidelines-Heart Failure) Registry 2017-2020, which collected data on contraindications and prescribing for 7 evidence-based HF-related medications, we assessed the number of medications for which each patient with HFrEF was eligible, use before admission, and prescribed at discharge. Multivariable logistic regression identified factors associated with medication initiation., Results: Among 50,170 patients from 160 sites, patients were eligible for mean number of 3.9 ± 1.1 evidence-based medications with 2.1 ± 1.3 used before admission and 3.0 ± 1.0 prescribed on discharge. The number of patients receiving all indicated medications increased from admission (14.9%) to discharge (32.8%), a mean net gain of 0.9 ± 1.3 medications over a mean of 5.6 ± 5.3 days. In multivariable analysis, factors associated with lower odds of HF medication initiation included older age, female sex, medical pre-existing conditions (stroke, peripheral arterial disease, pulmonary disease, and renal insufficiency), and rural location. Odds of medication initiation increased during the study period (adjusted OR: 1.08; 95% CI: 1.06-1.10)., Conclusions: Nearly 1 in 6 patients received all indicated HF-related medications on admission, increasing to 1 in 3 on discharge with an average of 1 new medication initiation. Opportunities to initiate evidence-based medications persist, particularly among women, those with comorbidities, and those receiving care at rural hospitals., Competing Interests: Funding Support and Author Disclosures Dr Swat has received funding from the National Institutes of Health (NIH) T32 Training Grant 5T32-HL-007822-22. The GWTG-HF (Get With The Guidelines–Heart Failure) program is provided by the American Heart Association. GWTG-HF is sponsored, in part, by Novartis, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Bayer, Tylenol, and Alnylam Pharmaceuticals. Dr Allen has received grant funding from American Heart Association (AHA), NIH, and Patient-Centered Outcomes Research Institute (PCORI); and has received consulting fees from Abbott, ACI Clinical, Amgen, Boston Scientific, Cytokinetics, and Novartis. Dr Greene 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, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, and Sanofi; has received speaker fees from Boehringer Ingelheim; and has served as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck, PharmaIN, Roche Diagnostics, Sanofi, Urovant Pharmaceuticals, and Vifor. Dr DeVore has received research funding through his institution from the American Heart Association, Amgen, Biofourmis, Bodyport, Cytokinetics, American Regent Inc, the National Heart, Lung, and Blood Institute (NHLBI), and Novartis; he has also provided consulting services for and/or received honoraria from Abiomed, Amgen, AstraZeneca, Cardionomic, InnaMed, LivaNova, Natera, Novartis, Procyrion, Story Health, Vifor, and Zoll; he has also received nonfinancial support from Abbott for educational and research activities. Dr Peterson is supported by the NHLBI of the NIH under Award Number R33HL143324. Dr Fonarow has consulted for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Janssen, Medtronic, Merck, and Novartis. Dr Hess is supported by VA Career Development Award HX002621 and American Heart Association Career Development Award 19CDA34760126. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

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.)

Background: Heart failure with reduced ejection fraction (HFrEF) is one of the most costly and deadly chronic disease states. The cost effectiveness of a comprehensive quadruple therapy regimen for HFrEF has not been studied., Objectives: The authors sought to determine the cost-effectiveness of quadruple therapy comprised of beta-blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium glucose cotransporter-2 inhibitors vs regimens composed of only beta-blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists (triple therapy), and angiotensin-converting enzyme inhibitors and beta-blockers (double therapy)., Methods: Using a 2-state Markov model, the authors performed a cost-effectiveness study using simulated populations of 1,000 patients with HFrEF based on the participants in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial and compared them by treatment strategy (quadruple therapy vs triple and double therapy) from a United States health care system perspective. The authors also performed 10,000 probabilistic simulations., Results: Treatment with quadruple therapy resulted in an increase of 1.73 and 2.87 life-years compared with triple therapy and double therapy, respectively, and an increase in quality-adjusted life-years of 1.12 and 1.85 years, respectively. The incremental cost-effectiveness ratios of quadruple therapy vs triple therapy and double therapy were $81,000 and $51,081, respectively. In 91.7% and 99.9% of probabilistic simulations quadruple therapy had an incremental cost-effectiveness ratio of <$150,000 compared with triple therapy and double therapy, respectively., Conclusions: At current pricing, the use of quadruple therapy in patients with HFrEF was cost effective compared with triple therapy and double therapy. These findings highlight the need for improved access and optimal implementation of comprehensive quadruple therapy in eligible patients with HFrEF., Competing Interests: Funding Support and Author Disclosures Dr Fonarow has consulted for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Janssen, 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 American College of Cardiology Foundation. All rights reserved.)

Objectives: In this study, we sought to evaluate the association of frailty with the use of optimal guideline-directed medical therapy (GDMT) and outcomes in heart failure with reduced ejection fraction (HFrEF)., Background: The burden of frailty in HFrEF is high, and the patterns of GDMT use according to frailty status have not been studied previously., Methods: A post hoc analysis of patients with HFrEF enrolled in the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial was conducted. Frailty was assessed with the use of a frailty index (FI) using a 38-variable deficit model, and participants were categorized into 3 groups: class 1: nonfrail, FI <0.21); class 2: intermediate frailty, FI 0.21-0.31), and class 3: high frailty, FI >0.31). Multivariate-adjusted Cox models were used to study the association of frailty status with clinical outcomes. Use of optimal GDMT over time (beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and mineralocorticoid receptor antagonists) across frailty strata was assessed with the use of adjusted linear and logistic mixed-effect models., Results: The study included 879 participants, of which 56.3% had high frailty burden (class 3 FI). A higher frailty burden was associated with a significantly higher risk of HF hospitalization or death in adjusted Cox models: high frailty vs nonfrail HR: 1.76, 95% CI: 1.20-2.58. On follow-up, participants with high frailty burden also had a significantly lower likelihood of achieving optimal GDMT: high frailty vs non-frail GDMT triple therapy use at study end: 17.7% vs 28.4%; P interaction, frailty class × time <0.001., Conclusions: Patients with HFrEF with a high burden of frailty have a significantly higher risk for adverse clinical outcomes and are less likely to be initiated and up-titrated on an optimal GDMT regimen., Competing Interests: Funding Support and Author Disclosures The GUIDE-IT study was funded by grants HL105448, HL105451, and HL105457 from the National Institutes of Health, and Roche Diagnostics provided support for NT-proBNP testing. Dr Greene 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, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, and Sanofi; and serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck, and Vifor. Dr Fonarow is a consultant for Abbott, Amgen, AstraZeneca, Bayer, Janssen, Medtronic, Merck, and Novartis, and Associate Section Editor for the JAMA Cardiology. Dr Anker has received research support from Vifor International and Abbott Vascular; and fees for consultancy and/or speaking from AstraZeneca, Bayer, Boehringer Ingelheim, Respicardia, Impulse Dynamics, Janssen, Novartis, Servier, and Vifor International. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, American Heart Association, Amgen, Bayer Merck, Cytokinetics, Myokardia; has acted as a consultant to Novartis, Amgen, Bristol Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, and Sequana; and has served on clinical end point committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Januzzi has received grant support from Roche Diagnostics, Abbott Diagnostics, Singulex, Prevencio, Novartis, and Cleveland Heart Labs; has received consulting income from Roche Diagnostics, Abbott, Prevencio, and Critical Diagnostics; and participates in clinical end point committees/data safety monitoring boards for Siemens Diagnostics, Novartis, Bayer, AbbVie, and Amgen. Dr Butler has acted as a consultant to 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, V-Wave Limited, and Vifor; and has served on speaker bureaus for Novartis, Boehringer Ingelheim–Lilly, AstraZeneca, and Janssen. Dr Pandey is supported by the Texas Health Resources Clinical Scholars Program; and has served on the advisory board of Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to determine whether patients with heart failure with reduced ejection fraction (HFrEF) due to nonischemic etiology eligible for cardiac resynchronization therapy (CRT) benefit from an implantable cardioverter-defibrillator (ICD)., Background: It is uncertain whether CRT with an ICD (CRT-D) compared to without an ICD (CRT-P) is associated with a survival benefit in patients with nonischemic etiologies of HFrEF., Methods: Analyses of the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial were performed, using Cox proportional hazards modeling stratified by HFrEF etiology of nonischemic cardiomyopathy (NICM) or ischemic cardiomyopathy (ICM). The primary outcome was all-cause mortality (ACM), and secondary outcomes were the combination of cardiovascular mortality or heart failure hospitalization and sudden cardiac death., Results: Among patients randomized to CRT (n = 1,212), 236 (19.5%) died, 131 and 105 in the CRT-P and CRT-D arms, respectively. The unadjusted and adjusted hazard ratios (HRs) for CRT-D versus CRT-P were both 0.84 (95% confidence interval [CI]: 0.65 to 1.09) for ACM, with a significant device-etiology interaction (p interaction  = 0.015 adjusted; p interaction  = 0.040 unadjusted). In patients with NICM (n = 555), CRT-D versus CRT-P was associated with reduced ACM (adjusted HR: 0.54; 95% CI: 0.34 to 0.86), while patients with ICM (n = 657) did not exhibit a between-device reduction in ACM (adjusted HR: 1.05; 95% CI: 0.77 to 1.44). The effects of CRT-D versus CRT-P on sudden cardiac death (advantage CRT-D) and cardiovascular mortality or heart failure hospitalization (no difference between CRT-P and CRT-D) were similar between the 2 HFrEF etiologies., Conclusions: COMPANION patients with NICM exhibited a decrease in ACM associated with CRT-D but not CRT-P treatment, whereas patients with ICM did not., Competing Interests: Funding Support and Author Disclosures This analysis was supported by the Statistical Data Analysis Center at the University of Wisconsin, by the University of Colorado Division of Cardiology, and by an American Heart Association Strategically Focused Network Grant in Heart Failure awarded to Drs. Bristow and Buttrick. The corporate sponsor of the COMPANION trial, Boston Scientific, provided no funding to the study. Drs. Feldman, Saxon, and Bristow were consultants for Guidant Corporation during the planning and execution of the COMPANION trial. Drs. Doran and Bristow are supported by an American Heart Association Strategically Focused Network Grant in Heart Failure. Dr. DeMets is a founder of the Statistical Data Analysis Center at the University of Wisconsin, where he is an emeritus professor. The Statistical and Data Analysis Center provided biostatistical support for the analyses performed by Mr. Mei in the current study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to examine the treatment effect of vericiguat in relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at randomization., Background: Vericiguat compared with placebo reduced the primary outcome of cardiovascular death (CVD) or heart failure hospitalization (HFH) in patients with HF with reduced ejection fraction (HFrEF) in the VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial. Because an interaction existed between treatment and the primary outcome according to pre-specified quartiles of NT-proBNP at randomization, we examined this further., Methods: This study evaluated the NT-proBNP relationship with the primary outcome in 4,805 of 5,050 patients as a risk-adjusted, log-transformed continuous variable. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented., Results: Median NT-proBNP was 2,816 pg/ml (25th to 75th percentile: 1,556 to 5,314 pg/ml). The study treatment effect varied across the spectrum of NT-proBNP at randomization (with log 2 transformation, p for interaction = 0.002). A significant association between treatment effects existed in patients with levels <4,000 pg/ml and remained evident up to 8,000 pg/ml. A 23% relative risk reduction occurred in the primary endpoint with NT-proBNP ≤4,000 pg/ml (HR: 0.77; 95% CI: 0.68 to 0.88). For NT-proBNP values ≤4,000 pg/ml (n = 3,100), the HR was 0.78 (95% CI: 0.67 to 0.90) for HFH and 0.75 (95% CI: 0.60 to 0.94) for CVD. For NT-proBNP ≤8,000 pg/ml (n = 4,133), the HR was 0.85 (95% CI: 0.76 to 0.95) for the primary outcome, 0.84 (95% CI: 0.75 to 0.95) for HFH, and 0.84 (95% CI: 0.71 to 0.99) for CVD. For NT-proBNP >8,000 pg/ml (n = 672), the HR was 1.16 (95% CI: 0.94 to 1.41) for the primary outcome., Conclusions: A reduction in the primary composite endpoint and its CVD and HFH components was observed in patients on vericiguat compared with subjects on placebo with NT-proBNP levels up to 8,000 pg/ml. This provided new insight into the benefit observed in high-risk patients with worsening HFrEF. (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534)., Competing Interests: Author Relationship With Industry This study was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and Bayer AG. Mr. Ezekowitz has received research grants from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics; has received consulting fees from Bayer, Merck, Servier, Amgen, Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr. O’Connor has received research funding from Merck; and has received consulting fees from Bayer, Dey LP, and Bristol-Myers Squibb Foundation. Dr. Troughton has received research grants from and personal fees from Merck and Roche Diagnostics. 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. Butler has received consulting fees from Bayer, Merck, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, G3 Pharmaceutical, Janssen, Luitpold, Medtronic, Novartis, Vifor, and Novo Nordisk. Dr. Lam has received research grants from Bayer, National Medical Research Council of Singapore, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma, and AstraZeneca; has received consulting fees from Merck, Bayer, Boston Scientific, Roche Diagnostic, Vifor Pharma, AstraZeneca, Novartis, Amgen, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, Radcliffe Group Ltd, and Corpus; has a patents pending for PCT/SG2016/050217 and 16/216,929; and is the Cofounder and non-executive director of eKo.ai. Dr. Ponikowski has received research grants from Vifor Pharma Ltd, and Servier; has received consulting fees from MSD, Novartis, Vifor Pharma Ltd, Servier, Bristol-Myers Squibb, Boehringer Ingelheim, Respicardia, AstraZeneca, Cibiem, RenalGuardSolution, and Berlin Chemie. Dr. Pieske has received research grants from MSD, Bayer, and Servier; has received consulting fees from MSD, Bayer, Servier, Bristol-Myers Squibb, MedScape, Daiichi-Sankyo, and Novartis; and has received non-financial support from MSD, Bayer, and Novartis. Dr. Hernandez has received research grants from Merck, AstraZeneca, Novartis, and Verily; and has received consulting fees from Merck, Bayer, Amgen, AstraZeneca, and Novartis. Dr. Armstrong has received research grants from Merck, Bayer, Sanofi-Aventis Recherche & Développement, Boehringer Ingelheim, and CSL Limited; and has received consulting fees from Merck, Bayer, AstraZeneca, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study examined the effects of sacubitril/valsartan on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and determined patient characteristics associated with favorable NT-proBNP reduction response., Background: NT-proBNP levels reflect cardiac wall stress and predict event risk in patients with acute decompensated heart failure (ADHF)., Methods: Post-hoc analysis of the TRANSITION (Comparison of Pre- and Post-discharge Initiation of Sacubitril/Valsartan Therapy in HFrEF Patients After an Acute Decompensation Event) study, including stabilized ADHF patients with reduced ejection fraction, randomized to open-label sacubitril/valsartan initiation in-hospital (pre-discharge) versus post-discharge. NT-proBNP was measured at randomization (baseline), discharge, and 4 and 10 weeks post-randomization. A favorable NT-proBNP response was defined as reduction to ≤1,000 pg/ml or >30% from baseline., Results: In patients receiving sacubitril/valsartan in-hospital, NT-proBNP was reduced by 28% at discharge, with 46% of patients obtaining favorable NT-proBNP reduction response compared with a 4% reduction and 18% favorable response rate in patients initiated post-discharge (p < 0.001). NT-proBNP was reduced similarly in patients initiating sacubitril/valsartan pre- and post-discharge (reduction at 4 weeks: 25%/22%; 10 weeks: 38%/34%) with comparable favorable response rates (46%/42% and 51%/48% at 4 and 10 weeks, respectively). NT-proBNP favorable response at 4 weeks was associated with lower risk of first heart failure (HF) rehospitalization or cardiovascular death through 26 weeks (hazard ratio: 0.57; 95% confidence interval [CI]: 0.38 to 0.86; p = 0.007). Predictors of a favorable response at 4 weeks were starting dose ≥49/51 mg twice daily, higher baseline NT-proBNP, lower baseline serum creatinine, de novo HF, no atrial fibrillation, angiotensin-converting enzyme inhibitor-naive or angiotensin receptor blocker-naive, and no prior myocardial infarction., Conclusions: In-hospital initiation of sacubitril/valsartan produced rapid reductions in NT-proBNP, statistically significant at discharge. A favorable NT-proBNP response over time was associated with a better prognosis and predicted by higher starting dose and predisposing clinical profile. (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event [TRANSITION]; NCT02661217)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study investigated the effects of a mid-trial protocol amendment requiring elevated natriuretic peptides for inclusion in the COMMANDER-HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) trial., Background: Heart failure (HF) trials that select patients based on history of HF hospitalization alone are susceptible to regional variations in event rates. Elevated plasma concentrations of natriuretic peptides (NPs) as selection criteria may help HF ascertainment and risk enrichment. In the COMMANDER-HF trial, B-type natriuretic peptide ≥200 ng/l or N-terminal pro-B-type natriuretic peptide ≥800 ng/l were added to inclusion criteria as a mid-trial protocol amendment, providing a unique case-study of NP-based inclusion criteria., Methods: We compared the baseline characteristics, event rates, and treatment effects for patients enrolled before and after the NP protocol amendment. The primary endpoint was all-cause death, myocardial infarction, or stroke. Secondary endpoints included HF rehospitalization and cardiovascular death., Results: A total of 5,022 patients with left ventricular ejection fraction ≤40% and coronary artery disease were included. Compared to patients enrolled before the NP protocol amendment, those enrolled post-amendment (n = 3,867, 77%) were older, more often had diabetes, and had lower values for body mass index, left ventricular ejection fraction, and estimated glomerular filtration rate, higher heart rate, and higher event rates: primary endpoint (hazard ratio [HR]: 1.32; 95% confidence interval [CI]: 1.16 to 1.50), cardiovascular death (HR: 1.29; 95% CI: 1.11 to 1.50), HF rehospitalization (HR: 1.31; 95% CI: 1.15 to 1.49), and major bleeding (HR: 1.71; 95% CI: 1.11 to 2.65). Differences between pre- and post-amendment rates were confined to and driven by Eastern Europe. This protocol amendment did not modify the neutral effect of rivaroxaban on the primary endpoint (p interaction = 0.36) or secondary endpoints., Conclusions: In a global event-driven trial of rivaroxaban in HF, requiring elevated NPs for inclusion increased event rates allowing earlier completion of the trial but did not modify treatment effect. These data inform future HF trials regarding the expected impact of NP-based inclusion criteria on patient characteristics and event rates. (COMMANDER HF [A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure] NCT01877915)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine whether age modifies the impact of key comorbidities on clinical outcomes for patients with heart failure with reduced ejection fraction (HFrEF)., Background: Comorbidities impact outcomes in HFrEF. However, the effect of age on the impact of comorbidities on prognosis is not clearly understood., Methods: Cox proportional hazards models were used assessed interactions between age and comorbidities on the primary composite endpoint (all-cause mortality or hospitalization) and secondary endpoints in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) multicenter trial of 2,331 patients with HFrEF., Results: Age did not significantly modify the effect of any comorbidity on the primary endpoint. However, age significantly modified the effect of body mass index (BMI) on all-cause mortality (interaction p = 0.02). Among patients ≥70 years of age, there was a U-shaped relationship between BMI and 1-year mortality, where BMI of 20 kg/m 2 corresponded to 17.6%; a BMI of 30 kg/m 2 corresponded to 7.0%; and a BMI of 40 kg/m 2 corresponded to 11%. For patients <60 years of age, mortality increased nonsignificantly from 3.2% to 3.7% with increasing BMI. Age also modified the effect of depressive symptoms on all-cause mortality (interaction p = 0.03). Among patients ≥70 years of age, a 1-year mortality rate significantly increased from 7.8% for a Beck Depression Inventory (BDI) score of 5% to 15.6% for BDI of 20. For patients <60 years of age, mortality was nonsignificantly related to BDI. Cumulative comorbidity scores were stronger predictors than age for mortality/hospitalization., Conclusions: In chronic HFrEF, age markedly altered the impact of BMI and depressive symptoms on all-cause mortality, with much higher risk in older patients, but was not as strong a predictor of mortality/hospitalizations as cumulative comorbidity score. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)., (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 assessed sex-related differences in a large cohort of unselected patients with heart failure (HF) across the ejection fraction (EF) spectrum., Background: Females are under-represented in randomized clinical trials. Potential sex-related differences in HF may question the generalizability of trials., Methods: In the Swedish Heart Failure Registry population multivariate Cox and logistic regression models were fitted to investigate differences in prognosis, prognostic predictors, and treatments across males and females., Results: Of 42,987 patients, 37% were females (55% with HF with preserved EF [HFpEF], 39% with HF with mid-range EF [HFmrEF], and 29% with HF with reduced EF [HFrEF]). Females were older and more symptomatic and more likely to have hypertension and kidney disease but less likely to have diabetes and ischemic heart disease. After adjustments, females were more likely to use beta-blockers and digoxin but less likely to receive HF device therapy. Crude mortality/HF hospitalization rates for HFpEF (hazard ratio [HR]: 1.16) and HFmrEF (HR: 1.14) were significantly higher in females but lower in females with HFrEF (HR: 0.95). After adjustments, the risk was significantly lower in females regardless of EF (HR: 0.80 in HFrEF, HR: 0.91 in HFmrEF, and HR: 0.93 in HFpEF). The main sex-related differences in prognostic predictors concerned diabetes in HFrEF and anemia in HFmrEF., Conclusions: Males and females with HF showed different characteristics across the EF spectrum. Males reported a lower crude risk of mortality/morbidity in HFpEF and HFmrEF but higher risk of HFrEF, although after adjustments, prognosis was better in females regardless of EF. The observed sex-related differences highlight the need for an adequate representation of females in HF randomized controlled trials to improve generalizability., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Large randomized clinical trials (RCT) supporting guidelines for the management of heart failure with reduced ejection fraction (HFrEF) have typically excluded patients with advanced chronic kidney disease (CKD). Patients with concomitant advanced CKD and HFrEF experience poor cardiovascular outcomes and mortality relative to either disease in isolation and have been shown to consistently receive lower rates of HFrEF guideline-directed medical therapy (GDMT). This review evaluated recent evidence for the use of GDMT in patients with HFrEF and advanced CKD approaching dialysis from RCTs and observational cohorts. The authors also discuss the limitations and challenges inherent in the evidence for GDMT in this population, and offer guidance to clinicians for proper clinical use and future research directions., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling., Background: In patients with heart failure with reduced ejection fraction (HFrEF), it is unclear if lowering natriuretic peptides reflects structural and functional changes in the heart. This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling., Methods: The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) Echo Substudy was a multicenter study that randomized 268 patients with HFrEF (EF ≤40%) to either pro-B-type natriuretic peptide (NT-proBNP)-guided treatment or usual care. Echocardiograms were performed at baseline and 12 months in 124 patients. Remodeling indices and clinical outcomes were compared between treatment arms and by achievement of the NT-proBNP goal of <1,000 pg/ml at 12 months., Results: At 12 months, the changes in EF and LV volumes were similar between the biomarker-guided and usual care arms with no difference in clinical outcomes; however, lowering NT-proBNP to <1,000 pg/ml, regardless of treatment strategy, was associated with a significantly greater increase in EF compared with those not reaching goal (9.9 ± 8.8% vs. 2.9 ± 7.9%; p < 0.001) and lower LV volumes. The extent of reverse remodeling correlated with the change in NT-proBNP: a decrease of 1,000 pg/ml was associated with an increase in EF of 6.7% and a reduction in systolic and diastolic volumes of 17.3 ml/m 2 and 15.7 ml/m 2 , respectively. Adverse events were significantly lower among patients achieving the NT-proBNP goal (p < 0.001)., Conclusions: Among patients with HFrEF, lowering NT-proBNP to <1,000 pg/ml by 12 months was associated with significant reverse remodeling and improved outcomes. A greater reduction in NT-proBNP was associated with more extensive reverse remodeling. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840)., (Copyright © 2019 American College of Cardiology Foundation. All rights reserved.)

Objectives: This study sought to evaluate INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profiles for prognostic use among ambulatory non-inotrope-dependent patients with heart failure with reduced ejection fraction (HFrEF)., Background: Data for INTERMACS profiles and prognoses in ambulatory patients with HFrEF are limited., Methods: We evaluated 3-year outcomes in 969 non-inotrope-dependent outpatients with HFrEF (EF: ≤40%) not previously receiving advanced HF therapies. Patients meeting an INTERMACS profile at baseline were classified as profile 7 (n = 348 [34.7%]); 146 patients (14.5%) were classified profile 6; and 52 patients (5.2%) were classified profile 4 to 5. Remaining patients were classified "stable Stage C" (n = 423 [42.1%])., Results: Three-year mortality rate was 10.0% among stable Stage C patients compared with 21.8% among INTERMACS profile 7 (hazard ratio [HR] vs. Stage C: 2.45; 95% confidence interval [CI]: 1.64 to 3.66), 26.0% among profile 6 (HR: 3.93; 95% CI: 1.64 to 3.66), and 43.8% among profile 4 to 5 (HR: 6.35; 95% CI: 3.51 to 11.5) patients. Hospitalization rates for HF were 4-fold higher among INTERMACS profile 7 (38 per 100 patient-years; rate ratio [RR] vs. Stage C: 3.88; 95% CI: 2.70 to 5.35), 6-fold higher among profile 6 patients (54 per 100 patient-years; RR: 5.69; 95% CI: 3.72 to 8.71), and 10-fold higher among profile 4 to 5 patients (69 per 100 patient-years; RR: 9.96; 95% CI: 5.15 to 19.3) than stable Stage C patients (11 per 100 patient-years). All-cause hospitalization rates had similar trends. INTERMACS profiles offered better prognostic separation than NYHA functional classifications., Conclusions: INTERMACS profiles strongly predict subsequent mortality and hospitalization burden in non-inotrope-dependent outpatients with HFrEF. These simple profiles could therefore facilitate and promote advanced HF awareness among clinicians and planning for advanced HF therapies., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This trial sought to evaluate whether vericiguat, a novel oral soluble guanylate cyclase (sGC) stimulator, was superior to placebo, on a background of standard of care, in increasing the time to the first occurrence of the composite endpoints of cardiovascular (CV) death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Deficiency in sGC-derived cyclic guanosine monophosphate (cGMP) causes both myocardial dysfunction and impaired endothelium-dependent vasomotor regulation that includes the myocardial microcirculation. Experimental studies have suggested multiple potential benefits of sGC stimulators including prevention, or even reversal, of left ventricular hypertrophy and fibrosis, as well as reduction of ventricular afterload through both systemic and pulmonary vasodilation. Hence, restoration of sufficient nitric oxide (NO)-sGC-cGMP signaling has been proposed as an important treatment target in HF. Vericiguat has been shown to directly stimulate sGC and enhance sGC sensitivity to endogenous NO. Available phase IIb data in HFrEF patients indicate vericiguat is safe and well-tolerated, and exploratory analyses indicate that it results in a dose-dependent, clinically significant reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at the highest tested dose. VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) is a randomized, placebo-controlled, parallel group, multicenter, double-blind, event-driven phase 3 trial of vericiguat in subjects with HFrEF. Approximately 4,872 subjects will be randomized to evaluate the efficacy and safety of vericiguat compared with placebo on a background of standard of care. After a screening phase of up to 30 days, eligible subjects will be treated until the required number of cardiovascular deaths is observed. The estimated median follow-up duration is approximately 18 months. All subjects will be followed until study completion to assess for the occurrence of endpoint events. VICTORIA will establish the efficacy and safety of vericiguat on cardiovascular death and HF hospitalization in patients with HFrEF. (A Randomized Parallel-Group, Placebo-Controlled, Double-Blind, Event-Driven, Multi-Center Pivotal Phase III Clinical Outcome Trial of Efficacy and Safety of the Oral sGC Stimulator Vericiguat in Subjects With Heart Failure With Reduced Ejection Fraction [HFrEF]-VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to assess the relationship between on-treatment blood pressure (BP) and clinical outcomes of patients with heart failure (HF)., Background: Lower BP has been reported to be related to increased mortality in various cardiovascular diseases. The optimal BP level for patients already experiencing HF is contentious., Methods: The Korean Acute Heart Failure registry prospectively enrolled a total of 5,625 consecutive patients hospitalized for acute HF in 10 tertiary university hospitals in Korea between March 2011 and February 2014. Clinical profiles including BP were collected at admission, discharge, and during outpatient follow-up. Mean on-treatment BP was calculated from BP at discharge and at each follow-up visit. We evaluated the effects of mean on-treatment BP on the clinical outcomes of patients., Results: Patients were followed up for a median 2.2 years. One-year mortality after discharge was 18.2%. The relationship between on-treatment BP and all-cause mortality followed a reversed J-curve relationship. A nonlinear, multivariable Cox proportional hazard model identified a nadir of systolic and diastolic BPs of 132.4/74.2 mm Hg in patients, for whom the mortality rate was lowest (p < 0.0001). The relationship with increased mortality above and below the reference BP was more definitive for diastolic BP and for HF with a preserved ejection fraction., Conclusions: Systolic and diastolic BPs <130/70 mm Hg at discharge and during follow-up was associated with worse survival in HF patients. These data suggest that the lowest BP possible might not be an optimal target for HF patients. Further studies should establish a proper BP goal in HF patients. (Registry [Prospective Cohort] for Heart Failure in Korea [KorAHF]; NCT01389843)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to estimate the rate of progression to Stage D heart failure (HF) among outpatients with Stage C HF and to identify risk factors for progression., Background: The pool of patients who may be candidates for advanced HF therapies is growing., Methods: We estimated 3-year progression to clinically determined Stage D HF and competing mortality among 964 outpatients with Stage C heart failure with reduced ejection fraction (HFrEF), where ejection fraction is ≤40%., Results: The mean age of patients was 62 ± 15 years; 35% were women; 47% were white; 46% were black, and 7% were of other races; median baseline ejection fraction was 28% (25th to 75th percentile: 20% to 35%); and 47% had ischemic heart disease. After 3.0 years (25th to 75th percentile: 1.7 to 3.2 years), 112 patients progressed to Stage D (3-year incidence: 12.2%; 95% confidence interval [CI]: 10.2% to 14.6%; annualized: 4.5%; 95% CI: 3.8% to 5.5%), and 116 patients died before progression (3-year competing mortality: 12.9%; annualized: 4.7%; 95% CI: 3.9% to 5.6%). By 3 years, 25.1% of patients (95% CI: 22.2% to 28.1%) had either progressed to Stage D or died (annualized: 9.2%; 95% CI: 8.1% to 10.5%). Annualized progression rates were higher in black versus white patients (6.3% vs. 2.7%, respectively; p < 0.001), nonischemic versus ischemic patients (6.1% vs. 2.9%, respectively; p < 0.001), and in New York Heart Association functional class III to IV versus I to II patients (7.5% vs. 1.9%, respectively; p < 0.001) but were similar for men and women (4.7% vs. 4.2%, respectively; p = 0.53). Lower ejection fraction and blood pressure, renal and hepatic dysfunction, and chronic lung disease rates were additional predictors of progression. Predictors of competing mortality were different from those of disease progression., Conclusions: Among patients with Stage C HFrEF receiving care in a referral center, 4.5% progressed to Stage D HF each year, with earlier progression among black and nonischemic patients. These findings have implications for healthcare planning and resource allocation for these patients., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The study sought to compare the prevalence, clinical correlates and prognostic impact of diabetes in Southeast Asian versus white patients with heart failure (HF) with preserved or reduced ejection fraction., Background: Diabetes mellitus is common in HF and is associated with impaired prognosis. Asia is home to the majority of the world's diabetic population, yet data on the prevalence and clinical significance of diabetes in Asian patients with HF are sparse, and no studies have directly compared Asian and white patients., Methods: Two contemporary population-based HF cohorts were combined: from Singapore (n = 1,002, median [25th to 75th percentile] age 62 [54 to 70] years, 76% men, 19.5% obesity) and Sweden (n = 19,537, 77 [68 to 84] years, 60% men, 24.8% obesity). The modifying effect of ethnicity on the relationship between diabetes and clinical correlates or prognosis (HF hospitalization and all-cause mortality) was examined using interaction terms., Results: Diabetes was present in 569 (57%) Asian patients versus 4,680 (24%) white patients (p < 0.001). Adjusting for clinical covariates, obesity was more strongly associated with diabetes in white patients (odds ratio [OR]: 3.45; 95% confidence interval [CI]: 2.86 to 4.17) than in Asian patients (OR: 1.82; 95% CI: 1.13 to 2.96; p interaction  = 0.026). Diabetes was more strongly associated with increased HF hospitalization and all-cause mortality in Asian patients (hazard ratio: 1.50; 95% CI: 1.21 to 1.87) than in white patients (hazard ratio: 1.29; 95% CI: 1.22 to 1.36; p interaction  = 0.045)., Conclusions: Diabetes was 3-fold more common in Southeast Asian compared to white patients with HF, despite younger age and less obesity, and more strongly associated with poor outcomes in Asian patients than white patients. These results underscore the importance of ethnicity-tailored aggressive strategies to prevent diabetes and its complications., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to determine the temporal trends in the adherence to heart failure (HF)-related process of care measures and clinical outcomes among patients with acute decompensated HF with reduced ejection fraction (HFrEF) and end-stage renal disease (ESRD)., Background: Previous studies have demonstrated significant underuse of evidence-based HF therapies among patients with coexisting ESRD and HFrEF. However, it is unclear if the proportional use of evidence-based medical therapies and associated clinical outcomes among these patients has changed over time., Methods: Get With The Guidelines-HF study participants who were admitted for acute HFrEF between January 2005 and June 2014 were stratified into 3 groups on the basis of their admission renal function: normal renal function, renal insufficiency without dialysis, and dialysis. Temporal change in proportional adherence to the HF-related process of care measures and incidence of clinical outcomes (1-year mortality, HF hospitalization, and all-cause hospitalization) during the study period was evaluated across the 3 renal function groups., Results: The study included 111,846 patients with HFrEF from 390 participating centers, of whom 19% had renal insufficiency but who did not require dialysis, and 3% were on dialysis. There was a significant temporal increase in adherence to evidence-based medical therapies (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker: p trend <0.0001, β-blockers: p trend = 0.0089; post-discharge follow-up referral: p trend <0.0001) and defect-free composite care (p trend <0.0001) among dialysis patients. An improvement in adherence to these measures was also observed among patients with normal renal function and patients with renal insufficiency without a need for dialysis. There was no significant change in cumulative incidence of clinical outcomes over time among the HF patients on dialysis., Conclusions: In a large contemporary cohort of HFrEF patients with ESRD, adherence to the HF process of care measures has improved significantly over the past 10 years. Unlike patients with normal renal function, there was no significant change in 1-year clinical outcomes over time among HF patients on dialysis., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess for a treatment interaction between statin use and exercise training (ET) response., Background: Recent data suggest that statins may attenuate ET response, but limited data exist in patients with heart failure (HF)., Methods: HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) was a randomized trial of 2,331 patients with chronic HF with ejection fraction ≤35% who were randomized to usual care with or without ET. We evaluated whether there was a treatment interaction between statins and ET response for the change in quality of life and aerobic capacity (peak oxygen consumption and 6-min walk distance) from baseline to 3 months. We also assessed for a treatment interaction among atorvastatin, simvastatin, and pravastatin and change in these endpoints with ET. Multiple linear regression analyses were performed for each endpoint, adjusting for baseline covariates., Results: Of 2,331 patients in the HF-ACTION trial, 1,353 (58%) were prescribed statins at baseline. Patients treated with statins were more likely to be older men with ischemic HF etiology but had similar use of renin angiotensin system blockers and beta-blockers. There was no evidence of a treatment interaction between statin use and ET on changes in quality of life or exercise capacity, nor was there evidence of differential association between statin type and ET response for these endpoints (all p values >0.05)., Conclusions: In a large chronic HF cohort, there was no evidence of a treatment interaction between statin use and short-term change in aerobic capacity and quality of life with ET. These findings contrast with recent reports of an attenuation in ET response with statins in a different population, highlighting the need for future prospective studies. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study examined the trends in the relative contributions of cardiovascular and noncardiovascular mortality to total mortality according to use of beta-blockers in clinical trials of patients with heart failure with reduced ejection fraction (HF-REF)., Background: With the increasingly widespread use of disease-modifying therapies, particularly beta-blockers, in HF-REF, the proportion of patients dying from cardiovascular causes is likely to be decreasing., Methods: In a systematic review, 2 investigators independently searched online databases to identify clinical trials including >400 patients with chronic heart failure published between 1986 and 2014 and that adjudicated cause of death. Trials were divided into 3 groups on the basis of the proportion of patients treated with a beta-blocker (<33% [low], 33% to 66% [medium], and >66% [high]). Percentages of total deaths adjudicated as cardiovascular or noncardiovascular were calculated by weighted means and weighted standard deviations. Weighted Student t tests were used to compare results between groups., Results: Sixty-six trials met the inclusion criteria with a total of 136,182 patients and 32,140 deaths. There was a sequential increase in the percentage of noncardiovascular deaths with increasing beta-blocker use from 11.4% of all deaths in trials with low beta-blocker use to 19.1% in those with high beta-blocker use (p < 0.001)., Conclusions: In trials of patients with HF-REF, the proportion of deaths adjudicated as cardiovascular has decreased. Cardiovascular mortality, and not all-cause mortality, should be used as an endpoint for trials of new treatments for HF-REF., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)