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Importance: Adoption of guideline-directed medical therapy for patients with heart failure is variable. Interventions to improve guideline-directed medical therapy have failed to consistently achieve target metrics, and limited data exist to inform efforts to improve heart failure quality of care.Objective: To evaluate the effect of a hospital and postdischarge quality improvement intervention compared with usual care on heart failure outcomes and care.Design, Setting, and Participants: This cluster randomized clinical trial was conducted at 161 US hospitals and included 5647 patients (2675 intervention vs 2972 usual care) followed up after a hospital discharge for acute heart failure with reduced ejection fraction (HFrEF). The trial was performed from 2017 to 2020, and the date of final follow-up was August 31, 2020.Interventions: Hospitals (n = 82) randomized to a hospital and postdischarge quality improvement intervention received regular education of clinicians by a trained group of heart failure and quality improvement experts and audit and feedback on heart failure process measures (eg, use of guideline-directed medical therapy for HFrEF) and outcomes. Hospitals (n = 79) randomized to usual care received access to a generalized heart failure education website.Main Outcomes and Measures: The coprimary outcomes were a composite of first heart failure rehospitalization or all-cause mortality and change in an opportunity-based composite score for heart failure quality (percentage of recommendations followed).Results: Among 5647 patients (mean age, 63 years; 33% women; 38% Black; 87% chronic heart failure; 49% recent heart failure hospitalization), vital status was known for 5636 (99.8%). Heart failure rehospitalization or all-cause mortality occurred in 38.6% in the intervention group vs 39.2% in usual care (adjusted hazard ratio, 0.92 [95% CI, 0.81 to 1.05). The baseline quality-of-care score was 42.1% vs 45.5%, respectively, and the change from baseline to follow-up was 2.3% vs -1.0% (difference, 3.3% [95% CI, -0.8% to 7.3%]), with no significant difference between the 2 groups in the odds of achieving a higher composite quality score at last follow-up (adjusted odds ratio, 1.06 [95% CI, 0.93 to 1.21]).Conclusions and Relevance: Among patients with HFrEF in hospitals randomized to a hospital and postdischarge quality improvement intervention vs usual care, there was no significant difference in time to first heart failure rehospitalization or death, or in change in a composite heart failure quality-of-care score.Trial Registration: ClinicalTrials.gov Identifier: NCT03035474. [ABSTRACT FROM AUTHOR]

Aims: Patients hospitalized for heart failure (HF) are at high risk for 30-day readmission. This study sought to examine the timings and causes of readmission within 30 days of an HF hospitalization.Methods and Results: Timing and cause of readmission in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial were assessed. Early and late readmissions were defined as admissions occurring within 0-7 days and 8-30 days post-discharge, respectively. Patients who died in hospital or remained hospitalized at day 30 post-randomization were excluded. Patients were compared by timing and cause of readmission. Logistic and Cox proportional hazards regression analyses were used to identify independent risk factors for early vs. late readmission and associations with 180-day outcomes. Of the 6584 patients (92%) in the ASCEND-HF population included in this analysis, 751 patients (11%) were readmitted within 30 days for any cause. Overall, 54% of readmissions were for non-HF causes. The median time to rehospitalization was 11 days (interquartile range: 6-18 days) and 33% of rehospitalizations occurred by day 7. Rehospitalization within 30 days was independently associated with increased risk for 180-day all-cause death [hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.93-2.94; P < 0.001]. Risk for 180-day all-cause death did not differ according to early vs. late readmission (HR 0.99, 95% CI 0.67-1.45; P = 0.94).Conclusions: In this hospitalized HF trial population, a significant majority of 30-day readmissions were for non-HF causes and one-third of readmissions occurred in the first 7 days. Early and late readmissions within the 30-day timeframe were associated with similarly increased risk for death. Continued efforts to optimize multidisciplinary transitional care are warranted to improve rates of early readmission. [ABSTRACT FROM AUTHOR]

Patients admitted for acute heart failure (AHF) experience high rates of in-hospital and post-discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin-2, a hormone with vasodilatory and end-organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX-AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all-cause and cardiovascular mortality by 37% through day 180. RELAX-AHF-2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX-AHF-2 is a multicentre, randomized, double-blind, placebo-controlled, event-driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild-to-moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all-cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in-hospital length of stay during index AHF. The results from RELAX-AHF-2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF. [ABSTRACT FROM AUTHOR]

Importance: Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). Glucagon-like peptide 1 (GLP-1) agonists have shown cardioprotective effects in early clinical studies of patients with advanced heart failure, irrespective of type 2 diabetes status.Objective: To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure.Design, Setting, and Participants: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with established heart failure and reduced LVEF who were recently hospitalized. Patients were enrolled between August 2013 and March 2015 at 24 US sites.Interventions: The GLP-1 agonist liraglutide (n = 154) or placebo (n = 146) via a daily subcutaneous injection; study drug was advanced to a dosage of 1.8 mg/d during the first 30 days as tolerated and continued for 180 days.Main Outcomes and Measures: The primary end point was a global rank score in which all patients, regardless of treatment assignment, were ranked across 3 hierarchical tiers: time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide level from baseline to 180 days. Higher values indicate better health (stability). Exploratory secondary outcomes included primary end point components, cardiac structure and function, 6-minute walk distance, quality of life, and combined events.Results: Among the 300 patients who were randomized (median age, 61 years [interquartile range {IQR}, 52-68 years]; 64 [21%] women; 178 [59%] with type 2 diabetes; median LVEF of 25% [IQR, 19%-33%]; median N-terminal pro-B-type natriuretic peptide level of 2049 pg/mL [IQR, 1054-4235 pg/mL]), 271 completed the study. Compared with placebo, liraglutide had no significant effect on the primary end point (mean rank of 146 for the liraglutide group vs 156 for the placebo group, P = .31). There were no significant between-group differences in the number of deaths (19 [12%] in the liraglutide group vs 16 [11%] in the placebo group; hazard ratio, 1.10 [95% CI, 0.57-2.14]; P = .78) or rehospitalizations for heart failure (63 [41%] vs 50 [34%], respectively; hazard ratio, 1.30 [95% CI, 0.89-1.88]; P = .17) or for the exploratory secondary end points. Prespecified subgroup analyses in patients with diabetes did not reveal any significant between-group differences. The number of investigator-reported hyperglycemic events was 16 (10%) in the liraglutide group vs 27 (18%) in the placebo group and hypoglycemic events were infrequent (2 [1%] vs 4 [3%], respectively).Conclusions and Relevance: Among patients recently hospitalized with heart failure and reduced LVEF, the use of liraglutide did not lead to greater posthospitalization clinical stability. These findings do not support the use of liraglutide in this clinical situation.Trial Registration: clinicaltrials.gov Identifier: NCT01800968. [ABSTRACT FROM AUTHOR]

The article discusses the efficacy and safety of loop diuretics in treating acute decompensated heart failure (ADHF) in the U.S. The article states that ADHF has evolved as an essential clinical syndromes in the country due to its high incidence of morbidity and medical costs. It also notes that loop diuretics poses properties that maintains the safety and effectiveness of the treatment supported by different clinical studies.

BACKGROUND: The effectiveness of inhaled glucocorticoids in shortening the time to symptom resolution or preventing hospitalization or death among outpatients with mild-to-moderate coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a decentralized, double-blind, randomized, placebo-controlled platform trial in the United States to assess the use of repurposed medications in outpatients with confirmed coronavirus disease 2019 (Covid-19). Nonhospitalized adults 30 years of age or older who had at least two symptoms of acute infection that had been present for no more than 7 days before enrollment were randomly assigned to receive inhaled fluticasone furoate at a dose of 200/ig once daily for 14 days or placebo. The primary outcome was the time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Key secondary outcomes included hospitalization or death by day 28 and a composite outcome of the need for an urgent-care or emergency department visit or hospitalization or death through day 28. RESULTS: Of the 1277 enrolled participants who were eligible to receive fluticasone furoate, 656 were assigned to receive inhaled fluticasone furoate and 621 to receive placebo. There was no evidence that the use of fluticasone furoate resulted in a shorter time to recovery than placebo (hazard ratio, 1.01; 95%> credible interval, 0.91 to 1.12; posterior probability of benefit [defined as a hazard ratio >1], 0.56). A total of 24 participants (3.7%) in the fluticasone furoate group had urgent-care or emergency department visits or were hospitalized, as compared with 13 participants (2.1%) in the placebo group (hazard ratio, 1.9; 95% credible interval, 0.9 to 3.5). Three participants in each group were hospitalized, and no deaths occurred. Adverse events were uncommon in both groups. CONCLUSIONS: Treatment with inhaled fluticasone furoate for 14 days did not result in a shorter time to recovery than placebo among outpatients with Covid-19 in the United States. [ABSTRACT FROM AUTHOR]

Question: What are the relative efficacy and safety of warfarin and aspirin in patients with heart failure who are in sinus rhythm? Methods Design: Randomized controlled trial (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction [WARCEF] trial). ClinicalTrials.gov NCT00041938. Allocation: {Concealed}*.† Blinding: Blinded† (patients, clinicians, {data collectors, safety committee}*, and outcome assessors). Follow-up period:  6 years (mean 3.5 y). Setting: 168 centers in the USA, Canada, Argentina, and Europe. Patients: 2305 adults =" src="ge9.gif"/> 18 years of age (mean age 61 y, 80% men) who had a left ventricular ejection fraction (LVEF)  35% and normal sinus rhythm, and planned treatment with a β-blocker, angiotensin-converting enzyme inhibitor, or hydralazine and nitrates. Exclusion criteria included modified Rankin score > 4, medical conditions with high risk for cardiac embolism, clear indication for warfarin or aspirin, or contraindication to warfarin. Patients in New York Heart Association class I were eligible but could not comprise > 20% of randomized patients. Intervention: Active warfarin (with target international normalized ratio 2.0 to 3.5) plus aspirin placebo (n = 1142), or aspirin, 325 mg/d, plus warfarin placebo (n = 1163). Outcomes: Primary composite endpoint of ischemic stroke, intracerebral hemorrhage (ICH), or death. Secondary outcome was a composite of ischemic stroke, ICH, death, myocardial infarction, or hospitalization for heart failure. The safety outcome was a composite of ischemic stroke, ICH, death, or intracranial hemorrhage. The trial had 69% power to detect a relative hazard reduction of 17.8% in the primary outcome and 83% power for the secondary outcome. Patient follow-up: {93%}* (96% for vital status; intention-to-treat analysis). Main results: Enrolment was stopped early because of slow recruitment. Groups did not differ for the primary composite outcome or any of its components except for ischemic stroke (Table). Groups also did not differ for the secondary or safety composite endpoints (Table). Conclusion: In patients with heart failure who are in sinus rhythm, warfarin and aspirin did not differ for a composite of death or ischemic or hemorrhage outcomes. [ABSTRACT FROM AUTHOR]

Patient access to a drug after US regulatory approval is controlled by complex interactions between governmental and third-party payers, pharmacy benefit managers, distributers, manufacturers, health systems, and pharmacies that together mediate the receipt of goods by patients after prescription by clinicians. Recent medication approvals highlight why and how the distribution of clinically beneficial novel therapies is controlled. Although imposed limitations on availability may be rational considering the fiduciary responsibilities of payers and escalating spending on health care and pharmaceuticals, transparency and communication are lacking, and some utilization management may disproportionately affect vulnerable populations. Analysis of the current health insurance landscape suggests mechanisms by which patient access to appropriate medications can be improved and patient and clinician frustration reduced while acknowledging the financial realities of the pharmaceutical marketplace. We propose creation of a shared, standardized, and transparent process for coverage decisions that minimizes administrative barriers and is defensible on the basis of clinical and cost-effectiveness evidence. These reforms would benefit patients and improve the efficiency of the pharmaceutical system. [ABSTRACT FROM AUTHOR]

Background: Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N-acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation-Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis.Methods: Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C.Results: Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300-815 mg), which induced a urine output of 8425 mL (interquartile range, 6341-10 528 mL) over the 72-hour intervention period. Levels of N-acetyl-β-d-glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P>0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (-8.7 ng/mg; interquartile range, -169 to 35 ng/mg; P<0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin (P=0.21), N-acetyl-β-d-glucosaminidase (P=0.46), or kidney injury molecule 1 (P=0.22). Increases in neutrophil gelatinase-associated lipocalin, N-acetyl-β-d-glucosaminidase, and kidney injury molecule 1 were paradoxically associated with improved survival (adjusted hazard ratio, 0.80 per 10 percentile increase; 95% confidence interval, 0.69-0.91; P=0.001).Conclusions: Kidney tubular injury does not appear to have an association with WRF in the context of aggressive diuresis of patients with acute heart failure. These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury. [ABSTRACT FROM AUTHOR]

We sought to examine the relation between the United States economic decrease in 2008 and cardiovascular events as measured by local acute myocardial infarction (AMI) rates. Mental stress and traumatic events have been shown to be associated with increased risk of MI in patients with ischemic heart disease. This was an observational study of data from the Duke Databank for Cardiovascular Disease and includes patients undergoing angiography for evaluation of ischemic heart disease from January 2006 to July 2009. Patients with AMI occurring within 3 days before catheterization were used to calculate AMI rates. Stock market values were examined to determine the period of severe economic decrease, and time trends in AMI rates were examined over the same period. Time series models were used to assess the relation between United States stock market National Association of Securities Dealers Automated Quotation (NASDAQ) and rates of AMI. Of 11,590 patients included in the study cohort, 2,465 patients had an AMI during this period. Time series analysis showed a significant increase in AMI rates during a period of stock market decrease from October 2008 to April 2009 (p = 0.003), which remained statistically significant when adjusted for seasons (p = 0.02). In conclusion, unadjusted and adjusted analyses of patients in the Duke Databank for Cardiovascular Disease indicated a significant correlation between a period of stock market decrease and increased AMI rates in our local cohort. [ABSTRACT FROM AUTHOR]

Background Many patients with heart failure (HF) have severely reduced ejection fraction but do not meet threshold for consideration of advanced therapies (ie, stage D HF). The clinical profile and health care costs associated with these patients in US practice is not well described. Methods and Results We examined patients hospitalized for worsening chronic heart failure with reduced ejection fraction ≤40% from 2014 to 2019 in the GWTG-HF (Get With The Guidelines-Heart Failure) registry, who did not receive advanced HF therapies or have end-stage kidney disease. Patients with severely reduced EF defined as EF ≤30% were compared with those with EF 31% to 40% in terms of clinical profile and guideline-directed medical therapy. Among Medicare beneficiaries, postdischarge outcomes and health care expenditure were compared. Among 113 348 patients with EF ≤40%, 69% (78 589) had an EF ≤30%. Patients with severely reduced EF ≤30% tended to be younger and were more likely to be Black. Patients with EF ≤30% also tended to have fewer comorbidities and were more likely to be prescribed guideline-directed medical therapy ("triple therapy" 28.3% versus 18.2%, P <0.001). At 12-months postdischarge, patients with EF ≤30% had significantly higher risk of death (HR, 1.13 [95% CI, 1.08-1.18]) and HF hospitalization (HR, 1.14 [95% CI, 1.09-1.19]), with similar risk of all-cause hospitalizations. Health care expenditures were numerically higher for patients with EF ≤30% (median US$22 648 versus $21 392, P =0.11). Conclusions Among patients hospitalized for worsening chronic heart failure with reduced ejection fraction in US clinical practice, most patients have severely reduced EF ≤30%. Despite younger age and modestly higher use of guideline-directed medical therapy at discharge, patients with severely reduced EF face heightened postdischarge risk of death and HF hospitalization.

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

Heart failure remains among the most common and morbid health conditions. The Heart Failure Strategically Focused Research Network (HF SFRN) was funded by the American Heart Association to facilitate collaborative, high-impact research in the field of heart failure across the domains of basic, clinical, and population research. The Network was also charged with developing training opportunities for young investigators. Four centers were funded in 2016: Duke University, University of Colorado, University of Utah, and Massachusetts General Hospital-University of Massachusetts. This report summarizes the aims of each center and major research accomplishments, as well as training outcomes from the HF SFRN.

Objectives: The authors sought to characterize associations between initiation of metformin and sulfonylurea therapy and clinical outcomes among patients with comorbid heart failure (HF) and diabetes (overall and by ejection fraction [EF] phenotype)., Background: Metformin and sulfonylureas are frequently prescribed to patients with diabetes for glycemic control. The impact of these therapies on clinical outcomes among patients with comorbid HF and diabetes is unclear., Methods: The authors evaluated Medicare beneficiaries hospitalized for HF in the Get With The Guidelines-Heart Failure Registry between 2006 and 2014 with diabetes and not prescribed metformin or sulfonylurea before admission. In parallel separate analyses for metformin and sulfonylurea, patients with newly prescribed therapy within 90 days of discharge were compared with patients not prescribed therapy. Multivariable models landmarked at 90 days evaluated associations between prescription of therapy, and mortality and hospitalization for HF (HHF) at 12 months. Negative control (falsification) endpoints included hospitalization for urinary tract infection, hospitalization for gastrointestinal bleed, and influenza vaccination. Prespecified subgroup analyses were stratified by EF ≤40% versus >40%., Results: Of 5,852 patients, 454 (7.8%) were newly prescribed metformin and 504 (8.6%) were newly prescribed sulfonylurea. After adjustment, metformin prescription was independently associated with reduced risk of composite mortality/HHF (HR: 0.81; 95% CI: 0.67-0.98; P = 0.03), but individual components were not statistically significant. Findings among patients with EF >40% accounted for associations with mortality/HHF (HR: 0.68; 95% CI: 0.52-0.90) and HHF (HR: 0.58; 95% CI: 0.40-0.85) endpoints (all P for interaction ≤0.04). After adjustment, sulfonylurea initiation was associated with increased risk of mortality (HR: 1.24; 95% CI: 1.00-1.52; P = 0.045) and HHF (HR: 1.22; 95% CI: 1.00-1.48; P = 0.050) with nominal statistical significance. Associations between sulfonylurea initiation and endpoints were consistent regardless of EF (all P for interaction >0.11). Neither metformin initiation nor sulfonylurea initiation were associated with negative control endpoints., Conclusions: In this population of older U.S. adults hospitalized for HF with comorbid diabetes, metformin initiation was independently associated with substantial improvements in 12-month clinical outcomes, driven by findings among patients with EF >40%. By contrast, sulfonylurea initiation was associated with excess risk of death and HF hospitalization, regardless of EF., Competing Interests: Funding Support and Author Disclosures This work was supported in part by an American Heart Association (AHA) grant award #16SFRN30180010 (to Dr DeVore). The GWTG-HF program is provided by the AHA and sponsored, in part, by Novartis, Boehringer Ingelheim and Eli Lilly Diabetes Alliance, Novo Nordisk, Sanofi, AstraZeneca, and Bayer. Dr Sharma has received support from the Fonds de Recherche Santé Quebec (FRSQ) Junior 1 Clinical Research Scholar, Canada Institute for Health Research grant #175095, European Society of Cardiology young investigator grant, Roche Diagnostics, Boehringer Ingelheim, Novartis, AstraZeneca, and Takeda. Dr DeVore has received research funding through the Duke Clinical Research Institute from the AHA, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent, Inc, the National Heart, Lung, and Blood Institute (NHLBI), Novartis, and the Patient-Centered Outcomes Research Institute; and consulting for AstraZeneca. Dr Felker has received research grants from National Heart, Lung, and Blood Institute (NHLBI), AHA, Amgen, Bayer Merck, Cytokinetics, and Myokardia; has been a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Innolife, Boehringer Ingelheim, American Reagent, Abbott, Eidos Therapeutics, Reprieve, and Sequana; and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Hernandez has received consulting fees from AstraZeneca, Bayer, Boston Scientific, Merck, Novartis, and Sanofi; and research support from AstraZeneca, GlaxoSmithKline, Luitpold, Merck, and Novartis. Dr Butler has been a consultant to Abbott, Adrenomed, Arena Pharma, Array, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, CVRx, Eli Lilly, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Sequana Medical, V-Wave Limited, and Vifor. Dr Peterson has received research funding from the NHLBI; and personal fees from American Heart Association outside the submitted work. Dr Fonarow has received research funding from the National Institutes of Health; and has been a consultant for Amgen, Bayer, Medtronic, and Novartis. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, the AHA, NHLBI, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, and Cytokinetics; and has served as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck, and Vifor. 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.)

Background: Decongestion is a primary goal during hospitalizations for decompensated heart failure (HF). However, data surrounding the preferred route and strategy of diuretic administration are limited with varying results in prior studies., Methods: This is a retrospective analysis using patients from ASCEND-HF with a stable diuretic strategy in the first 24 hours following randomization. Patients were divided into three groups: intravenous (IV) continuous, IV bolus and oral strategy. Baseline characteristics, in-hospital outcomes, 30-day composite cardiovascular mortality or HF rehospitalization and 180-day all-cause mortality were compared across groups. Inverse propensity weighted modeling was used for adjustment., Results: Among 5,738 patients with a stable diuretic regimen in the first 24 hours (80% of overall ASCEND trial), 3,944 (68.7%) patients received IV intermittent bolus administration of diuretics, 799 (13.9%) patients received IV continuous therapy and 995 (17.3%) patients with oral administration. Patients in the IV continuous group had a higher baseline creatinine (IV continuous 1.4 [1.1-1.7]; intermittent bolus 1.2 [1.0-1.6]; oral 1.2 [1.0-1.4] mg/dL; P <0.001) and high NTproBNP (IV continuous 5,216 [2,599-11,603]; intermittent bolus 4,944 [2,339-9,970]; oral 3,344 [1,570-7,077] pg/mL; P <0.001). There was no difference between IV continuous and intermittent bolus group in weight change, total urine output and change in renal function till 10 days/discharge (adjusted P >0.05 for all). There was no difference in 30 day mortality and HF readmission (adjusted OR 1.08 [95%CI: 0.74, 1.57]; P = 0.701) and 180 days mortality (adjusted OR 1.04 [95%CI: 0.75, 1.43]; P = 0.832)., Conclusion: In a large cohort of patients with decompensated HF, there were no significant differences in diuretic-related in-hospital, or post-discharge outcomes between IV continuous and intermittent bolus administration. Tailoring appropriate diuretic strategy to different states of acute HF and congestion phenotypes needs to be further investigated., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: The aim of this study was to examine patterns of care and clinical outcomes among patients with heart failure with reduced ejection fraction (HFrEF) in the United States and Canada., Background: In the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial, the use of N-terminal pro-B-type natriuretic peptide-guided titration of guideline-directed medical therapy (GDMT) was compared with usual care alone for patients with HFrEF in the United States and Canada. It remains unknown whether the country of enrollment had an impact on outcomes or GDMT use., Methods: A total of 894 patients at 45 sites across the United States and Canada with HFrEF (ejection fraction ≤40%) were enrolled in the trial. Kaplan-Meier survival estimates stratified by country of enrollment were developed for the trial outcomes, and log-rank testing was compared between the groups. GDMT use and titration were also compared., Results: U.S. patients were more likely to be younger, to be Black, to have higher body mass index, and to have histories of defibrillator placement or sleep apnea. Use of β-blockers was significantly higher in Canada at baseline (99.3% vs. 94.0%; p = 0.01) and 6 months (99.0% vs. 94.1%; p = 0.04), and use of mineralocorticoid receptor antagonists was higher in Canada at 6 months (68.3% vs. 55.1%; p = 0.01). Canadian patients were less likely to experience the primary study endpoint (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.45 to 0.93; p = 0.01) due to decreased rates of HF hospitalization (HR: 0.57; 95% CI: 0.38 to 0.86; p = 0.003). The differences in outcomes were driven by increased heart failure hospitalization among U.S. Black patients., Conclusions: In GUIDE-IT, patients with HFrEF in Canada were significantly less likely to be hospitalized for heart failure. Differences in GDMT use, along with differences in sociodemographics and care delivery structures, may contribute to these differences, highlighting the importance of increasing diversity in clinical trials. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840)., Competing Interests: Funding Support and Author Disclosures The GUIDE-IT trial was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Additional substudies were supported by Roche Diagnostics. The sponsors had no role in the design and conduct of the present study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Dr. Januzzi is a trustee of the American College of Cardiology; has received grant support from Roche Diagnostics, Novartis Pharmaceuticals, and Applied Therapeutics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees and data and safety monitoring boards for Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda. Dr. Desai works under contract with the Centers for Medicare and Medicaid Services to develop and maintain performance measures used for public reporting and pay-for-performance programs; and has received research grants and consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, The Medicines Company, Relypsa, Novartis, and SCPharmaceuticals. Dr. Felker has received research grants from the National Heart, Lung, and Blood Institute, the American Heart Association, Amgen, Bayer Merck, Cytokinetics, and Myokardia; has acted as a consultant to Novartis, Amgen, Bristol Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Innolife, Boehringer Ingelheim, Abbott, Eidos Therapeutics, Reprieve, and Sequana; and has served on clinical endpoint committees and data and safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, and Rocket Pharma. Dr. Fiuzat has received grant support from the National Institutes of Health and Roche Diagnostics. Dr. O’Connor has received grant support from Roche Diagnostics and the National Institutes of Health. Dr. Ahmad is a consultant for Amgen, Cytokinetics, Relypsa, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a prognostic biomarker in heart failure (HF) with reduced ejection fraction. However, it is unclear whether there is a sex difference in NT-proBNP response and whether the therapeutic goal of NT-proBNP ≤1000 pg/mL has equivalent prognostic value in men and women with HF with reduced ejection fraction. Methods and Results In a secondary analysis of the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial we analyzed trends in NT-proBNP and goal attainment by sex. Differences in clinical characteristics, HF treatment, and time to all-cause death or HF hospitalization were compared. Landmark analysis at 3 months determined the prognostic value of early NT-proBNP goal achievement in men and women. Of the 286 (32%) women and 608 (68%) men in the GUIDE-IT trial, women were more likely to have a nonischemic cause and shorter duration of HF. Guideline-directed medical therapy was less intense over time in women. The absolute NT-proBNP values were consistently lower in women; however, the change in NT-proBNP and clinical outcomes were similar. After adjustment, women achieving the NT-proBNP goal had an 82% reduction in death or HF hospitalization compared with a 59% reduction in men. Conclusions Men and women with HF with reduced ejection fraction had a similar NT-proBNP response despite less intensive HF treatment among women. However, compared with men, the early NT-proBNP goal of ≤1000 pg/mL had greater prognostic value in women. Future efforts should be aimed at intensifying guideline-directed medical therapy in women, which may result in greater NT-proBNP reductions and improved outcomes in women with HF with reduced ejection fraction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01685840.

Objectives: This study sought to characterize in-hospital treatment patterns and associated patient outcomes among patients hospitalized for heart failure (HF) in U.S. clinical practice., Background: Hospitalizations for HF are common and associated with poor patient outcomes. Real-world patterns of in-hospital treatment, including diuretic therapy, in contemporary U.S. practice are unknown., Methods: Using Optum de-identified Electronic Health Record data from 2007 through 2018, patients hospitalized for a primary diagnosis of HF (ejection fraction ≤40%) and who were hemodynamically stable at admission, without concurrent acute coronary syndrome or end-stage renal disease, and treated with intravenous (IV) diuretic agents within 48 h of admission were identified. Patients were categorized into 1 of 4 mutually exclusive hierarchical treatment groups defined by complexity of treatment during hospitalization (intensified treatment with mechanical support or IV vasoactive therapy, IV diuretic therapy reinitiated after discontinuation for ≥1 day without intensified treatment, IV diuretic dose increase/combination diuretic treatment without intensified treatment or IV diuretic reinitiation, or uncomplicated)., Results: Of 22,677 patients hospitalized for HF with reduced ejection fraction (HFrEF), 66% had uncomplicated hospitalizations without escalation of treatment beyond initial IV diuretic therapy. Among 7,809 remaining patients, the highest level of therapy received was IV diuretic dose increase/combination diuretic treatment in 25%, IV diuretic reinitiation in 36%, and intensified therapy in 39%. Overall, 19% of all patients had reinitiation of IV diuretic agents (26% of such patients had multiple instances), 12% were simultaneously treated with multiple diuretics, and 61% were transitioned to oral diuretic agents before discharge. Compared with uncomplicated treatment, IV diuretic reinitiation and intensified treatment were associated with significantly longer median length of stay (uncomplicated: 4 days; IV diuretic reinitiation: 8 days; intensified: 10 days) and higher rates of in-hospital (uncomplicated: 1.6%; IV diuretic reinitiation: 4.2%; intensified: 13.2%) and 30-day post-discharge mortality (uncomplicated: 5.2%; IV diuretic reinitiation: 9.7%; intensified: 12.7%)., Conclusions: In this contemporary real-world population of U.S. patients hospitalized for HFrEF, one-third of patients had in-hospital treatment escalated beyond initial IV diuretic therapy. These more complex treatment patterns were associated with highly variable patterns of diuretic use, longer hospital lengths of stay, and higher mortality. Standardized and evidence-based approaches are needed to improve the efficiency and effectiveness of in-hospital HFrEF care., Competing Interests: Author Relationship With Industry Dr. Greene has received a Heart Failure Society of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis; has received research support from Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, and Novartis; serves on Advisory Boards for Amgen and Cytokinetics; and serves as a consultant for Amgen and Merck. Drs. Ionescu-Ittu and Burne and Ms. Guérin are employees of Analysis Group Inc., which has received consultancy fees from Bristol-Myers Squibb for this study. Drs. Borentain, Kessler, Tugcu, and DeSouza are employees of Bristol-Myers Squibb. Dr. Felker has received research funding from Otsuka, Novartis, Roche Diagnostics, Amgen, Merck, the American Heart Association, and the National Heart, Lung, and Blood Institute; and has served as a consultant for Novartis, Roche Diagnostics, Amgen, Trevena, Cytokinetics, Madeleine, MyoKardia, Bristol-Myers Squibb, Stealth Biotherapeutics, and GlaxoSmithKline. Dr. Chen was an employee of Bristol-Myers Squibb at the time the research was conducted. Dr. Triana has reported that she has no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Among patients with heart failure and reduced ejection fraction (left ventricular (LV) ejection fraction ≤40%), sacubitril/valsartan (S/V) treatment is associated with improved health status and reverse cardiac remodeling. Data regarding racial and ethnic differences in response to S/V are lacking., Methods: This was an analysis from the PROVE-HF study (Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure). Longitudinal changes in NT-proBNP (N-terminal pro-B-type natriuretic peptide), cardiac reverse remodeling, and health status scores were compared between groups using multivariate latent growth curve modeling., Results: Among the 782 patients included in this study, 22.7% were non-Hispanic Black (from here referred to as Black), 14.9% were Hispanic, and 62.4% were non-Hispanic White (from here referred to as White). At baseline, compared with White patients, Black and Hispanic patients had lower NT-proBNP ( g =0.34) and differences between groups in baseline values for LV end-diastolic volume index and LV end-systolic volume index were negligible ( g <0.10). Following S/V initiation, NT-proBNP decreased in all 3 groups ( P <0.0001) associated with improvements in LV ejection fraction, LV end-diastolic volume index, and LV end-systolic volume index. Although total improvement in LV measures was similar between groups, Black patients averaged larger gains in the first half of the trial while White patients averaged larger gains in the second half. Improvements in Kansas City Cardiomyopathy Questionnaire-23 Total Symptom scores were seen in all 3 groups. Treatment with S/V was well-tolerated., Conclusions: Among Black, Hispanic, and White patients with heart failure and reduced ejection fraction, treatment with S/V was associated with similar reduction in NT-proBNP, improvement in health status, and reverse remodeling. More data regarding racial and ethnic responses to heart failure and reduced ejection fraction treatment are needed. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02887183.

Background There are conflicting data regarding the benefit of primary prevention implantable cardioverter-defibrillators (ICDs) in patients with diabetes mellitus and heart failure (HF) with reduced ejection fraction. We aimed to assess the comparative effectiveness of ICD placement in patients with diabetes mellitus and HF with reduced ejection fraction. Methods and Results Data were obtained from the Get With the Guidelines-Health Failure registry, linked with claims from the Centers for Medicare & Medicaid Services. We used a Cox proportional hazards model censored at 5 years with propensity score matching. Of the 17 186 patients with HF with reduced ejection fraction from the Centers for Medicare & Medicaid Services claims database (6540 with diabetes mellitus; 38%), 1677 (646 with diabetes mellitus; 39%) received an ICD during their index HF hospitalization or were prescribed an ICD at discharge. Patients with diabetes mellitus and an ICD (n=646), as compared with those without an ICD (n=1031), were more likely to be younger (74 versus 78 years of age) and have coronary artery disease (68% versus 60%). After propensity matching, ICD use among patients with diabetes mellitus, as compared with those without an ICD, was associated with a reduced risk of all-cause mortality at 5 years after HF discharge (54% versus 59%; multivariable hazard ratio, 0.73; 95% CI, 0.64-0.82; P <0.0001). Ischemic heart disease did not modify the association between ICD use and all-cause mortality ( P =0.95 for interaction). Similar results were seen in patients without diabetes mellitus. Conclusions Primary prevention ICD use among older patients with HF with reduced ejection fraction and diabetes mellitus was associated with a reduced risk of all-cause mortality. Our analysis supports current guideline recommendations for implantation of primary prevention ICDs among older patients with diabetes mellitus and HF with reduced ejection fraction.

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

Many therapies have been shown to improve outcomes for patients with heart failure (HF) in controlled settings, but there are limited data available to inform best practices for hospital and post-discharge quality improvement initiatives. The CONNECT-HF study is a prospective, cluster-randomized trial of 161 hospitals in the United States with a 2×2 factorial design. The study is designed to assess the effect of a hospital and post-discharge quality improvement intervention compared with usual care (primary objective) on HF outcomes and quality-of-care, as well as to evaluate the effect of hospitals implementing a patient-level digital intervention compared with usual care (secondary objective). The hospital and post-discharge intervention includes audit and feedback on HF clinical process measures and outcomes for patients with HF with reduced ejection fraction (HFrEF) paired with education to sites and clinicians by a trained, nationally representative group of HF and quality improvement experts. The patient-level digital intervention is an optional ancillary study and includes a mobile application and behavioral tools that are intended to facilitate improved use of guideline-directed recommendations for self-monitoring and self-management of activity and medications for HFrEF. The effects of the interventions will be measured through an opportunity-based composite score on quality and time-to-first HF readmission or death among patients with HFrEF who present to study hospitals with acute HF and who consent to participate. The CONNECT-HF study is evaluating approaches for implementing HF guideline recommendations into practice and is one of the largest HF implementation science trials performed to date., (Copyright © 2019. Published by Elsevier Inc.)

Background Patient-reported outcomes (PROs) objectively measure health-related quality of life and provide prognostic information. Advances in technology now allow for rapid, patient-friendly PRO assessment and scoring, yet the adoption of PROs in clinic has been slow. We conducted a multicenter qualitative study of diverse providers to describe the barriers and facilitators of routine PRO use in heart failure clinics. Methods and Results Sixty heart failure providers from 5 institutions participated in 8 focus groups to explore provider perspectives on the use of heart failure-specific and generic PROs in clinical practice. A qualitative editing approach was used to analyze the data, whereby a coding dictionary was iteratively developed and applied using the qualitative software program Altas.ti. Three main themes, supporting and impeding PRO use, emerged: (1) data collection; (2) presentation and interpretation; and (3) utility and value. For each construct, we identified perspectives that highlighted both barriers and facilitators. Providers identified burden, survey fatigue, and language/health literacy barriers as potentially impeding data collection. Optimal workflow, PRO frequency and length, use of PRO translations, and assistance of a patient's proxy were suggested as facilitators. Focus group discussions provided insight on how to display PROs to support its interpretability and sharing. Furthermore, the need to educate providers on the utility and value PROs over and above current clinical approaches emerged. Conclusions Overcoming the barriers and supporting facilitators of PRO adoption could potentially lead to more successful adoption of PROs in heart failure clinics.

Aims: Neurohormonal activation characterizes chronic heart failure (HF) and is a well-established therapeutic target. Neurohormonal activation may also play a key role in acute HF (AHF). We aim to describe the association between plasma renin activity (PRA) and three AHF outcomes: (i) worsening HF or death through day 5 of hospitalization; (ii) HF rehospitalization or death through day 30; and (iii) all-cause death through day 30., Methods and Results: A secondary analysis of the BLAST-AHF trial was performed. Eligible patients had a history of HF, elevated natriuretic peptides, signs and symptoms of HF, systolic blood pressure >120 mmHg, and an estimated glomerular filtration rate between 20-75 mL/min/1.73 m 2 . The primary trial was neutral, with no differential effect of study drug by PRA levels. Baseline PRA levels were grouped into tertiles. Adjusted Cox proportional hazard model determined the association of PRA levels with outcomes (α set at P < 0.05). Of 618 randomized patients, 578 (93.5%) had a baseline PRA. PRA was modestly, but significantly, associated with each outcome without adjustment [worsening HF or death through day 5: hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.01-1.23, P = 0.04; HF rehospitalization or death through day 30: HR 1.13, 95% CI 1.02-1.26, P = 0.02; all-cause death through day 30: HR 1.18, 95% CI 1.02-1.37, P = 0.03]. After multivariable adjustment, PRA was only significantly associated with HF rehospitalization or death through day 30 (HR 1.15, 95% CI 1.01-1.32, P = 0.04)., Conclusion: Baseline PRA levels are associated with increased risk for the composite of 30-day HF rehospitalization or death in patients with AHF., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Background: Most heart failure (HF) risk scores have been derived from cohorts of stable HF patients and may not incorporate up to date treatment regimens or deep phenotype characterization that change baseline risk over the short- and long-term follow-up period. We undertook the current analysis of participants in the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment) trial to address these limitations., Methods and Results: The GUIDE-IT study randomized 894 high-risk patients with HF and reduced ejection fraction (≤ 40%) to biomarker-guided treatment strategy vs. usual care. We performed risk modelling using Cox proportional hazards models and analysed the relationship between 35 baseline clinical factors and the primary composite endpoint of cardiovascular (CV) death or HF hospitalization, the secondary endpoint of all-cause mortality, and the exploratory endpoint of 90-day HF hospitalization or death. Prognostic relationships for continuous variables were examined and key predictors were identified using a backward variable selection process. Predictive models and risk scores were developed. Over a median follow-up of 15 months, the cumulative number of HF hospitalizations and CV deaths was 328 out of 894 patients (Kaplan-Meier event rate 34.5% at 12 months). Frequency of all-cause deaths was 143 out of 894 patients (Kaplan-Meier event rate 12.2% at 12 months). Outcomes for the primary and secondary endpoints between strategy arms of the study were similar. The most important predictor that was present in all three models was the baseline natriuretic peptide level. Hispanic ethnicity, low sodium and high heart rate were present in two of the three models. Other important predictors included the presence or absence of a device, New York Heart Association class, HF duration, black race, co-morbidities (sleep apnoea, elevated creatinine, ischaemic heart disease), low blood pressure, and a high congestion score., Conclusion: Risk models using readily available clinical information are able to accurately predict short- and long-term CV events and may be useful in optimizing care and enriching patients for clinical trials., Clinical Trial Registration: ClinicalTrials.gov ID number NCT01685840., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Aim: There is limited information on the outcomes after primary prevention implantable cardioverter-defibrillator (ICD) implantation in patients with heart failure (HF) and diabetes. This analysis evaluates the effectiveness of a strategy of ICD plus medical therapy vs. medical therapy alone among patients with HF and diabetes., Methods and Results: A patient-level combined-analysis was conducted from a combined dataset that included four primary prevention ICD trials of patients with HF or severely reduced ejection fractions: Multicenter Automatic Defibrillator Implantation Trial I (MADIT I), MADIT II, Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE), and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). In total, 3359 patients were included in the analysis. The primary outcome of interest was all-cause death. Compared with patients without diabetes (n = 2363), patients with diabetes (n = 996) were older and had a higher burden of cardiovascular risk factors. During a median follow-up of 2.6 years, 437 patients without diabetes died (178 with ICD vs. 259 without) and 280 patients with diabetes died (128 with ICD vs. 152 without). ICDs were associated with a reduced risk of all-cause mortality among patients without diabetes [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46-0.67] but not among patients with diabetes (HR 0.88, 95% CI 0.7-1.12; interaction P = 0.015)., Conclusion: Among patients with HF and diabetes, primary prevention ICD in combination with medical therapy vs. medical therapy alone was not significantly associated with a reduced risk of all-cause death. Further studies are needed to evaluate the effectiveness of ICDs among patients with diabetes., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Introduction: TRV027, a 'biased' ligand of the angiotensin II type 1 receptor (AT1R), did not affect a composite clinical outcome at 30 days in a phase 2b acute heart failure (AHF) trial (BLAST-AHF)., Methods: Post-hoc analyses from BLAST-AHF (n = 618) examined the effects of TRV027 by baseline systolic blood pressure (SBP) on changes in renal function and 180-day outcomes. Interactions between baseline SBP and select endpoints were identified utilizing a subpopulation treatment effect pattern plots (STEPP) analysis, then grouping of patients by SBP tertile: < 127, ≥ 127 to < 140, and ≥ 140 mmHg., Results: A trend towards increased creatinine in the first 3 days was noted in the lower SBP tertile, while in those in the higher two tertiles, TRV027, especially the 1 mg/h dose, reduced creatinine at days 5 and 30. Beneficial effects on 180-day all-cause mortality and cardiovascular (CV) death or readmission were observed in the two higher SBP tertiles (SBP ≥ 127 mmHg) in the TRV027 1 mg/h dose group (all-cause mortality HR 0.39, 95% CI 0.14-1.06, p = 0.056; CV death or HF/RF rehospitalization HR 0.53, 95% CI 0.28-1.01, p = 0.049), while more adverse outcomes were observed in patients in the lower SBP tertile., Conclusions: This post-hoc analysis of the BLAST-AHF study suggests contrasting effects of TRV027 by baseline SBP, with trends towards lower 180-day event rates in patients enrolled with higher baseline SBP, especially when given lower doses of TRV027.

Each year over one million patients with acute heart failure (AHF) present to a United States emergency department (ED). The vast majority are hospitalized for further management. The length of stay and high postdischarge event rate in this cohort have changed little over the past decade. Therapeutic trials have failed to yield substantive improvement in postdischarge outcomes; subsequently, AHF care has changed little in the past 40 years. Prior research studies have been fragmented as either "inpatient" or "ED-based." Recognizing the challenges in identification and enrollment of ED patients with AHF, and the lack of robust evidence to guide management, an AHF clinical trials network was developed. This network has demonstrated, through organized collaboration between cardiology and emergency medicine, that many of the hurdles in AHF research can be overcome. The development of a network that supports the collaboration of acute care and HF researchers, combined with the availability of federally funded infrastructure, will facilitate more efficient conduct of both explanatory and pragmatic trials in AHF. Yet many important questions remain, and in this document our group of emergency medicine and cardiology investigators have identified four high-priority research areas., (© 2017 by the Society for Academic Emergency Medicine.)

Aims: We evaluated the added prognostic value of a multi-time point-based multimarker panel of biomarkers in patients with acute heart failure (AHF)., Methods and Results: Seven circulating biomarkers [NT-proBNP, high sensitivity cardiac troponin T (hs-cTnT), soluble ST2 (sST2), growth differentiation factor 15 (GDF-15), cystatin-C, galectin-3, and high sensitivity C-reactive protein (hs-CRP)] were measured at baseline and on days 2, 5, 14, and 60 in 1161 patients enrolled in the RELAX-AHF trial. Patients with BNP ≥350 ng/L or NT-proBNP ≥1400 ng/L, mild to moderate renal impairment, and systolic blood pressure >125 mmHg were included in the trial. Time-dependent Cox regression analysis was utilized to evaluate the incremental value of serial measurement of biomarkers. Added value of individual biomarkers and their combination, on top of a pre-specified baseline model, was quantified with the gain in the C-index. Serial biomarker evaluation showed incremental predictive value over baseline measurements alone for the prediction of 180-day cardiovascular mortality except for galectin-3. While a repeat measurement as early as day 2 was adequate for NT-proBNP and cystatin-C in terms of maximizing discriminatory accuracy, further measurements on days 14 and 60 provided added value for hs-cTnT, GDF-15, sST2, and hs-CRP. Individual biomarker additions on top of the baseline model showed additional prognostic value. The greatest prognostic gain was, however, attained with the combination of NT-proBNP, hs-cTnT, GDF-15, and sST2, which yielded 0.08 unit absolute increment in the C-index to 0.87 (95% confidence interval 0.83-0.91]., Conclusion: In patients with AHF and mild to moderate renal impairment, a multimarker approach based on a panel of serially evaluated biomarkers provides the greatest prognostic improvement unmatched by a single time point-based single marker strategy., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

In-hospital worsening heart failure represents a clinical scenario wherein a patient hospitalized for acute heart failure experiences a worsening of their condition, requiring escalation of therapy. Worsening heart failure is associated with worse in-hospital and postdischarge outcomes. Worsening heart failure is increasingly being used as an endpoint or combined endpoint in clinical trials, as it is unique to episodes of acute heart failure and captures an important event during the inpatient course. While prediction models have been developed to identify worsening heart failure, there are no known FDA-approved medications associated with decreased worsening heart failure. Continued study is warranted., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: This study sought to evaluate if diastolic pulmonary gradient (DPG) can predict survival in patients with pulmonary hypertension due to left heart disease (PH-LHD)., Background: Patients with combined post- and pre-capillary PH-LHD have worse prognosis than those with passive pulmonary hypertension. The transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR) have commonly been used to identify high-risk patients. However, these parameters have significant shortcomings and do not always correlate with pulmonary vasculature remodeling. Recently, it has been suggested that DPG may be better a marker, yet its prognostic ability in patients with cardiomyopathy has not been fully assessed., Methods: A retrospective cohort of 1,236 patients evaluated for unexplained cardiomyopathy at Johns Hopkins Hospital was studied. All patients underwent right heart catheterization and were followed until death, cardiac transplantation, or the end of the study period (mean time 4.4 years). The relationships between DPG, TPG, or PVR and survival in subjects with PH-LHD (n = 469) were evaluated with Cox proportional hazards regression and Kaplan-Meier analyses., Results: DPG was not significantly associated with mortality (hazard ratio [HR]: 1.02, p = 0.10) in PH-LHD whereas elevated TPG and PVR predicted death (HR: 1.02, p = 0.046; and HR: 1.11, p = 0.002, respectively). Similarly, DPG did not differentiate survivors from non-survivors at any selected cut points including a DPG of 7 mm Hg., Conclusions: In this retrospective study of patients with cardiomyopathy and PH-LHD, an elevated DPG was not associated with worse survival., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) afflicts nearly 6 million Americans, resulting in one million emergency department (ED) visits and over one million annual hospital discharges. An aging population and improved survival from cardiovascular diseases is expected to further increase HF prevalence. Emergency providers play a significant role in the management of patients with acute heart failure (AHF). It is crucial that emergency physicians and other providers involved in early management understand the latest developments in diagnostic testing, therapeutics and alternatives to hospitalization. Further, clinical trials must be conducted in the ED in order to improve the evidence base and drive optimal initial therapy for AHF. Should ongoing and future studies suggest early phenotype-driven therapy improves in-hospital and post-discharge outcomes, ED treatment decisions will need to evolve accordingly. The potential impact of future studies which incorporate risk-stratification into ED disposition decisions cannot be underestimated. Predictive instruments that identify a cohort of patients safe for ED discharge, while simultaneously addressing barriers to successful outpatient management, have the potential to significantly impact quality of life and resource expenditures., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Extended criteria cardiac transplant (ECCT) programs expand the transplant pool by matching donors and recipients typically excluded from the transplant process because of age or comorbidity. There is a paucity of data examining long-term outcomes with this strategy., Methods and Results: Between January 2000 and December 2009, adult patients undergoing isolated heart transplant were prospectively classified as ECCT based on prespecified criteria. Baseline characteristics and outcomes were compared between ECCT and standard criteria cardiac transplant recipients. Two Cox proportional hazards models were developed. The first to identify clinical variables contributing to survival between the 2 groups, and the second to determine the additional risk associated with assignment to ECCT. Among the 454 patients who underwent heart transplant, 84 (18.5%) were ECCT. Compared with the patients who underwent standard criteria cardiac transplant, ECCT patients were older (median, 66.6 years versus 53.2 years; P<0.001), with higher frequency of diabetes mellitus (46.4% versus 24.6%; P<0.001) and chronic kidney disease (median estimated glomerular filtration rate, 55 versus 61.6 mL/min; P=0.001). After adjustment for baseline characteristics, standard criteria cardiac transplant survival was higher than ECCT at 1 (89% versus 86%; P=0.18) and 5 (77% versus 66%; P=0.035) years. In a multivariate model that included listing criteria, creatinine (hazard ratio, 1.05 per 0.1 mg/dL; 95% confidence interval, 1.02-1.09; P=0.001) was a significant predictor of post-transplant mortality., Conclusions: ECCT is an acceptable alternative for advanced heart failure therapy in select patients. Age and renal dysfunction are important determinants of long-term survival and post-transplant morbidity.

Background: B-type natriuretic peptide (BNP) has been associated with short- and long-term postdischarge prognosis among hospitalized patients with heart failure. It is unknown if admission, discharge, or change from admission to discharge BNP measure is the most important predictor of long-term outcomes., Methods and Results: We linked patients ≥65 years of age from hospitals in Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) to Medicare claims. Among patients with recorded admission and discharge BNP, we compared Cox models predicting 1-year mortality and/or rehospitalization, including clinical variables and clinical variables plus BNP. We calculated the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) for the best-fit model for each outcome versus the model with clinical variables alone. Among 7039 patients in 220 hospitals, median (25th, 75th) admission and discharge BNP were 832 pg/mL (451, 1660) and 534 pg/mL (281, 1111). Observed 1-year mortality and 1-year mortality or rehospitalization rates were 35.2% and 79.4%. The discharge BNP model had the best performance and was the most important characteristic for predicting 1-year mortality (hazard ratio for log transformation, 1.34; 95% confidence interval, 1.28 to 1.40) and 1-year death or rehospitalization (hazard ratio, 1.15; 95% confidence interval, 1.12 to 1.18). Compared with a clinical variables only model, the discharge BNP model improved risk reclassification and discrimination in predicting each outcome (1-year mortality: NRI, 5.5%, P<0.0001; IDI, 0.023, P<0.0001; 1-year mortality or rehospitalization: NRI, 4.2%, P<0.0001; IDI, 0.010, P<0.0001)., Conclusions: Discharge BNP best predicts 1-year mortality and/or rehospitalization among older patients hospitalized with heart failure. Discharge BNP plus clinical variables modestly improves risk classification and model discrimination for long-term outcomes.

Acute heart failure syndromes (AHFS) remain a major cause of morbidity and mortality, in part because the development of new therapies for these disorders has been marked by frequent failure and little success. The heterogeneity of current approaches to AHFS drug development, particularly with regard to end points, remains a major potential barrier to progress in the field. End points involving hemodynamic status, biomarkers, symptoms, hospital stay, end organ function, and mortality have all been employed either alone or in combination in recent randomized clinical trials in AHFS. In this review, we will discuss the various end point domains from both a clinical and a statistical perspective, summarize the wide variety of end points used in completed and ongoing AHFS studies, and suggest steps for greater standardization of end points across AHFS trials.

Background: Heart transplantation (HT) is an effective therapy for end-stage heart failure, but its impact is limited by the scarcity of donor organs and stringent selection criteria for both donors and recipients. The creation of an alternate list to match recipients with contraindications to traditional HT with sub-optimal donor organs has been implemented at some centers, but outcomes using this approach are uncertain., Methods: We created an alternate list that matched recipients in whom standard HT was contraindicated with donor organs that had been rejected for use in standard transplantation. Data on patient characteristics and outcomes were compared with a control group of patients transplanted on the standard list over the same time period., Results: Fifty patients received HT on the alternate list, compared with 195 on the standard list. The most common reasons for recipient listing on the alternate list were age >65 years (n = 28) and diabetes with end-organ dysfunction (n = 9). Alternate-list patients were older and more likely to have an ischemic etiology and diabetes mellitus. The most common reasons for allocation of donor organs to alternate-list patients were coronary artery disease (n = 12), positive hepatitis serology (n = 12) or left ventricular (LV) dysfunction (n = 8). Two-year survival was 70% for alternate-list patients compared with 88% for standard-list patients (p = 0.02). Post-transplant morbidity did not differ significantly between the 2 groups except that alternate-list patients were hospitalized more frequently., Conclusions: The use of an alternate list can expand the applicability of HT to patients who would otherwise be denied this therapy. Although associated with greater morbidity and mortality than standard-list HT, alternate-list HT resulted in clinical outcomes that were significantly better than the natural history of end-stage heart failure.