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Aims: Although much is known about the usefulness of heart failure (HF)-specific instruments for assessing patient well-being, less is known about the value of generic instruments for the measurement of health-related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores., Methods and Results: We performed a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ-5D-5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator-reported (New York Heart Association class) and patient-self-reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N-terminal pro-B-type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ-5D-5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72-0.91) in Q2, 0.74 (0.65-0.84) in Q3, and 0.62 (0.54-0.72) in Q4. The risk of each component of the composite outcome, and all-cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ-5D-5L VAS and index scores across the range of ejection fraction., Conclusions: Both higher (better) EQ-5D-5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ-5D-5L VAS and index scores, irrespective of ejection fraction., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Type 2 diabetes (T2D) and heart failure (HF) frequently coexist, but whether clinical outcomes and treatment effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vary in relation to background glucose-lowering therapy (GLT) in this population is uncertain., Methods and Results: DELIVER randomized patients with HF and left ventricular ejection fraction (LVEF) >40% to dapagliflozin or placebo. The primary outcome was a composite of worsening HF (HF hospitalization or urgent HF visit) or cardiovascular death. In this pre-specified analysis of participants with T2D, treatment effects were assessed by number and class of background GLT(s). Of 3150 participants with T2D at baseline, 22.9% were on no GLT, 36.5% were treated with 1 GLT, and 40.6% with ≥2 GLTs. During follow-up (median: 2.3 years), treatment benefits of dapagliflozin (vs. placebo) on the primary outcome were consistent irrespective of the number of background GLTs (0 GLTs: hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50-1.00; 1 GLT: HR 1.04, 95% CI 0.80-1.34; ≥2 GLTs: HR 0.71, 95% CI 0.56-0.90; p interaction  = 0.59). Similar findings were observed among participants with (HR 0.73, 95% CI 0.59-0.92) and without background metformin use (HR 0.89, 95% CI 0.72-1.11; p interaction  = 0.22) and in participants with (HR 0.89, 95% CI 0.69-1.16) and without background insulin use (HR 0.78, 95% CI 0.65-0.95; p interaction  = 0.45). Dapagliflozin was well-tolerated irrespective of the number of background GLTs., Conclusions: Dapagliflozin safely and consistently improved clinical outcomes among individuals with T2D and HF with LVEF >40% irrespective of the number and class of background GLTs, and the benefits were not influenced by concomitant metformin or insulin use. These data bolster contemporary guidelines supporting first-line SGLT2i among individuals with T2D and HF, irrespective of background GLT., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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

Aims: Patients with heart failure (HF) and history of myocardial infarction (MI) face a higher risk of disease progression and clinical events. Whether sodium-glucose cotransporter 2 inhibitors may modify clinical trajectory in such individuals remains incompletely understood., Methods and Results: The DAPA-HF and DELIVER trials compared dapagliflozin with placebo in patients with symptomatic HF with left ventricular ejection fraction (LVEF) ≤40% and > 40%, respectively. In this pooled participant-level analysis, we assessed efficacy and safety outcomes by history of MI. The primary outcome in both trials was the composite of cardiovascular death or worsening HF. Of the total of 11 007 patients, 3731 (34%) had a previous MI and were at higher risk of the primary outcome across the spectrum of LVEF in covariate-adjusted models (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.02-1.24). Dapagliflozin reduced the risk of the primary outcome to a similar extent in patients with (HR 0.83, 95% CI 0.72-0.96) and without previous MI (HR 0.76, 95% CI 0.68-0.85; p interaction  = 0.36), with consistent benefits on key secondary outcomes as well. Serious adverse events did not occur more frequently with dapagliflozin, irrespective of previous MI., Conclusion: History of MI confers increased risks of adverse cardiovascular outcomes in patients with HF across the LVEF spectrum, even among those with preserved ejection fraction. Dapagliflozin consistently and safely reduces the risk of cardiovascular death or worsening HF, regardless of previous MI., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain., Methods: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis., Results: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups., Conclusions: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: Diuretics are a mainstay therapy for the symptomatic treatment of heart failure. However, in contemporary US outpatient practice, the degree to which diuretic dosing changes over time and the associations with clinical outcomes and health care resource utilization are unknown., Methods: Among 3426 US outpatients with chronic heart failure with reduced ejection fraction in the Change the Management of Patients with Heart Failure registry with complete medication data and who were prescribed a loop diuretic, diuretic dose increase was defined as: (1) change to a total daily dose higher than their previous total daily dose, (2) addition of metolazone to the regimen, (3) change from furosemide to either bumetanide or torsemide, and the change persists for at least 7 days. Adjusted hazard ratios or rate ratios along with 95% CIs were reported for clinical outcomes among patients with an increase in oral diuretic dose versus no increase in diuretic dose., Results: Overall, 796 (23%) had a diuretic dose increase (18 episodes per 100 patient-years). The proportion of patients with dyspnea at rest (38% versus 26%), dyspnea at exertion (79% versus 67%), orthopnea (32% versus 21%), edema (60% versus 43%), and weight gain (40% versus 23%) were significantly (all P <0.001) higher in the diuretic increase group. Baseline angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (hazard ratio, 0.75 [95% CI, 0.65-0.87]) use were associated with lower likelihood of diuretic increase over time. Patients with a diuretic dose increase had a significantly higher number of heart failure hospitalizations (rate ratio, 2.53 [95% CI, 2.10-3.05]), emergency department visits (rate ratio, 1.84 [95% CI, 1.56-2.17]), and home health visits (rate ratio, 1.88 [95% CI, 1.39-2.54]), but not all-cause mortality (hazard ratio, 1.10 [95% CI, 0.89-1.36]). Similarly, greater furosemide dose equivalent increases were associated with greater resource utilization but not with mortality, compared with smaller increases., Conclusions: In this contemporary US registry, 1 in 4 patients with heart failure with reduced ejection fraction had outpatient escalation of diuretic therapy over longitudinal follow-up, and these patients were more likely to have sign/symptoms of congestion. Outpatient diuretic dose escalation of any magnitude was associated with heart failure hospitalizations and resource utilization, but not all-cause mortality.

Background Sacubitril/Valsartan has been highly efficacious in randomized trials of heart failure with reduced ejection fraction (HFrEF). However, the effectiveness of sacubitril/valsartan in older patients hospitalized for HFrEF in real-world US practice is unclear. Methods and Results This study included Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF ≤40% in the Get With The Guidelines-Heart Failure registry between October 2015 and December 2018, and eligible for sacubitril/valsartan. Associations between discharge prescription of sacubitril/valsartan and clinical outcomes were assessed after inverse probability of treatment weighting and adjustment for other HFrEF medications. Overall, 1551 (10.9%) patients were discharged on sacubitril/valsartan. Of those not prescribed sacubitril/valsartan, 7857 (62.0%) were prescribed an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker. Over 12-month follow-up, compared with a discharge prescription of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, sacubitril/valsartan was independently associated with lower all-cause mortality (adjusted hazard ratio [HR], 0.82; 95% CI, 0.72-0.94; P =0.004) but not all-cause hospitalization (adjusted HR, 0.97; 95% CI, 0.89-1.07; P =0.55) or heart failure hospitalization (adjusted HR, 1.04; 95% CI, 0.91-1.18; P =0.59). Patients prescribed sacubitril/valsartan versus those without a prescription had lower risk of all-cause mortality (adjusted HR, 0.69; 95% CI, 0.60-0.79; P <0.001), all-cause hospitalization (adjusted HR, 0.90; 95% CI, 0.82-0.98; P =0.02), but not heart failure hospitalization (adjusted HR, 0.94; 95% CI, 0.82-1.08; P =0.40). Conclusions Among patients hospitalized for HFrEF, prescription of sacubitril/valsartan at discharge was independently associated with reduced postdischarge mortality compared with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, and reduced mortality and all-cause hospitalization compared with no sacubitril/valsartan. These findings support the use of sacubitril/valsartan to improve postdischarge outcomes among older patients hospitalized for HFrEF in routine US clinical practice.

Importance: It is unclear how New York Heart Association (NYHA) functional class compares with patient-reported outcomes among patients with heart failure (HF) in contemporary US clinical practice., Objective: To characterize longitudinal changes and concordance between NYHA class and the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS), and their associations with clinical outcomes., Design, Setting, and Participants: This cohort study included 2872 US outpatients with chronic HF with reduced ejection fraction across 145 practices enrolled in the CHAMP-HF registry between December 2015 and October 2017. All patients had complete NYHA class and KCCQ-OS data at baseline and 12 months. Longitudinal changes and correlations between the 2 measure were examined. Multivariable models landmarked at 12 months evaluated associations between improvement in NYHA and KCCQ-OS from baseline to 12 months with clinical outcomes occurring from months 12 through 24. Statistical analyses were performed from March to August 2020., Exposure: Change in health status, as defined by 12-month change in NYHA class or KCCQ-OS., Main Outcomes and Measures: All-cause mortality, HF hospitalization, and mortality or HF hospitalization., Results: In total, 2872 patients were included in this analysis (median [interquartile range] age, 68 [59-75] years; 872 [30.4%] were women; and 2156 [75.1%] were of White race). At baseline, 312 patients (10.9%) were NYHA class I, 1710 patients (59.5%) were class II, 804 patients (28.0%) were class III, and 46 patients (1.6%) were class IV. For KCCQ-OS, 1131 patients (39.4%) scored 75 to 100 (best health status), 967 patients (33.7%) scored 50 to 74, 612 patients (21.3%) scored 25 to 49, and 162 patients (5.6%) scored 0 to 24 (worst health status). At 12 months, 1002 patients (34.9%) had a change in NYHA class (599 [20.9%] with improvement; 403 [14.0%] with worsening) and 2158 patients (75.1%) had a change of 5 or more points in KCCQ-OS (1388 [48.3%] with improvement; 770 [26.8%] with worsening). The most common trajectory for NYHA class was no change (1870 [65.1%]), and the most common trajectory for KCCQ-OS was an improvement of at least 10 points (1047 [36.5%]). After adjustment, improvement in NYHA class was not associated with subsequent clinical outcomes, whereas an improvement of 5 or more points in KCCQ-OS was independently associated with decreased mortality (hazard ratio, 0.59; 95% CI, 0.44-0.80; P < .001) and mortality or HF hospitalization (hazard ratio, 0.73; 95% CI, 0.59-0.89; P = .002)., Conclusions and Relevance: Findings of this cohort study suggest that, in contemporary US clinical practice, compared with NYHA class, KCCQ-OS is more sensitive to clinically meaningful changes in health status over time. Changes in KCCQ-OS may have more prognostic value than changes in NYHA class.

Background: In patients with heart failure and reduced ejection fraction (HFrEF), angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB), or angiotensin receptor neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonists (MRA), and beta-blockers (βB) are underutilized. It is unknown if patients with and without comorbidities have similar ACEi/ARB/ARNI, MRA, and βB prescription patterns., Methods: Baseline data from the CHAMP-HF (Change the Management of Patients with Heart Failure) registry were categorized by history of atrial fibrillation, asthma/chronic lung disease, obstructive sleep apnea, and depression. Using multivariate hierarchical logistic models, associations of ACEi/ARB/ARNI, MRA and βB medication use and dose by comorbidities were assessed after adjusting for patient characteristics., Results: Of 4,815 HFrEF patients from 152 CHAMP-HF sites, ACEi/ARB/ARNI use was lower in patients with more comorbidities, and generally, MRA use was low and βB use was high. In adjusted analyses, patients with HFrEF and comorbid obstructive sleep apnea, vs. without, were more likely to be prescribed ARNI (OR [95% CI]: 1.25 [1.00, 1.55]); P = .047 and MRA (1.31 [1.11, 1.55]); P = .002 and less likely to be prescribed ACEi (0.74 [0.63, 0.88]); P < .001. Patients with atrial fibrillation, vs. without, were less likely to receive ACEi/ARB (0.82 [0.71, 0.95]); P = .006 and any study medication (0.81 [0.67, 0.97]); P = .020. Comorbid lung disease and history of depression were not associated with HFrEF prescriptions., Conclusions: Renin-angiotensin-aldosterone blockade therapy prescription and dose varied by comorbidity status, but βB therapy did not. In quality efforts, leaders need to consider use and dosing of prescriptions in light of prevalent comorbidities., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Hospitalization for heart failure (HF) is associated with increased risk of death among patients with chronic HF. The degree to which hospitalization for HF is a distinct biologic entity with independent prognostic value versus a marker of higher risk chronic HF patients is unclear., Methods: After excluding patients with new-onset HF, the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) included 4205 patients hospitalized for worsening chronic HF with reduced or preserved ejection fraction. The present analysis compared patients by presence or absence of prior HF hospitalization within 12 months and by timing of prior HF hospitalization relative to index hospitalization. Associations with 180-day all-cause mortality were assessed, including adjustment for 27 prespecified clinical factors., Results: Overall, 2241 (53.3%) patients had a HF hospitalization within the prior 12 months and 1964 (46.7%) did not. Mortality rates at 180 days were 15.5% and 11.9%, respectively. In unadjusted analyses, prior HF hospitalization was associated with increased risk of 180-day mortality (HR, 1.35 [95% CI, 1.14-1.59]; P <0.01). After adjustment, the point estimate was attenuated and the association not statistically significant (HR, 1.18 [95% CI, 0.99-1.40]; P =0.064). Similarly, after adjustment, compared with patients without prior hospitalization, prior HF hospitalization was not associated with mortality, irrespective of timing (0-4 months: HR, 1.10 [95% CI, 0.87-1.39], P =0.41; 4-8 months: HR, 0.95 [95% CI, 0.70-1.27]; P =0.72; 8-12 months: HR, 1.06 [95% CI, 0.74-1.51], P =0.77; >12 months: HR, 0.81 [95% CI, 0.63-1.06], P =0.12)., Conclusions: In this cohort of patients hospitalized for worsening HF, prior HF hospitalization was not associated with 180-day mortality after comprehensively accounting for patient characteristics measured during the index patient visit. Clinical confounders measured at the point-of-care may explain previously observed associations between prior HF hospitalization and mortality, and these clinical factors may be a more direct means of predicting patient survival. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00475852.

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.)

Background: Among patients with heart failure (HF) with reduced ejection fraction (EF), improvements in left ventricular EF (LVEF) are associated with better outcomes and remain an important treatment goal. Patient factors associated with LVEF improvement in routine clinical practice have not been clearly defined., Methods: CHAMP-HF (Change the Management of Patients with Heart Failure) is a prospective registry of outpatients with HF with reduced EF. Assessments of LVEF are recorded when performed for routine care. We analyzed patients with both baseline and ≥1 follow-up LVEF assessments to describe factors associated with LVEF improvement., Results: In CHAMP-HF, 2623 patients had a baseline and follow-up LVEF assessment. The median age was 67 (interquartile range, 58-75) years, 40% had an ischemic cardiomyopathy, and median HF duration was 2.8 years (0.7-6.8). Median LVEF was 30% (23-35), and median change on follow-up was 4% (-2 to -13); 19% of patients had a decrease in LVEF, 31% had no change, 49% had a ≥5% increase, and 34% had a ≥10% increase. In a multivariable model, the following factors were associated with ≥5% LVEF increase: shorter HF duration (odds ratio [OR], 1.21 [95% CI, 1.17-1.25]), no implantable cardioverter defibrillator (OR, 1.46 [95% CI, 1.34-1.55]), lower LVEF (OR, 1.15 [95% CI, 1.10-1.19]), nonischemic cardiomyopathy (OR, 1.24 [95% CI, 1.09-1.36]), and no coronary disease (OR, 1.20 [95% CI, 1.03-1.35])., Conclusions: In a large cohort of outpatients with chronic HF with reduced EF, improvements in LVEF were common. Common baseline cardiac characteristics identified a population that was more likely to respond over time. These data may inform clinical decision making and should be the basis for future research on myocardial recovery.

Objectives: The purpose of this study was to characterize the clinical profile, treatment patterns, and clinical outcomes of patients with comorbid diabetes mellitus (DM) and heart failure with reduced ejection fraction (HFrEF) in a contemporary, real-world U.S. outpatient registry in the context of evolving treatment strategies., Background: Specific antihyperglycemic classes have differential risks and benefits with respect to HF. Limited data are available evaluating contemporary treatment patterns and outcomes of patients with comorbid DM and HFrEF., Methods: Among 4,970 patients with chronic HFrEF (≤40%) across 152 U.S. sites in the CHAMP-HF prospective, observational registry (2015 to 2017), we examined therapies and clinical outcomes by DM status., Results: Median age was 68 (58 to 75) years of age; 29% were women; 73.5% were white; and 64% had coronary artery disease. Overall, 42% (n = 2,085) had comorbid DM with a median hemoglobin A1c (HbA1c) level of 7.2% (interquartile range [IQR]: 6.4% to 8.3%). One-fourth of DM patients (24%) were not treated with an antihyperglycemic therapy. Most patients with DM were taking 1 (46%) or 2 (23%) antihyperglycemic therapies: metformin (40%); insulin (33%); sulfonylureas (24%); dipeptidyl peptidase-4 inhibitors (10%); glucagon-like peptide (GLP)-1 receptor agonists (4%); sodium-glucose cotransporter (SGLT)-2 inhibitors (2%); and thiazolidinediones (2%). Among patients with DM, 62%, 16%, 80%, and 33.5% were receiving any angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitor (ARNI), β-blockers, or mineralocorticoid receptor antagonists (MRAs) at baseline, respectively. Among patients without DM, corresponding baseline rates were 65%, 15%, 80%, and 37%, respectively. Patients with or without DM were infrequently treated with guideline-directed HFrEF therapies at target doses (≤27% across classes). During median 15-month follow-up, patients with DM experienced higher rates of all-cause mortality or HF hospitalization (30% vs. 23%, respectively), independent of 11 pre-specified covariates (adjusted hazard ratio: 1.35 (95% confidence interval: 1.21 to 1.52); p < 0.001)., Conclusions: Despite higher risk-adjusted clinical event rates in patients with comorbid HFrEF and DM, guideline-directed medical therapies for both disease states are incomplete and represent an important target for quality improvement through multidisciplinary care pathways., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Little is known about the utilization rates and outcomes of implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy defibrillator (CRT-D) placement among patients with advanced heart failure (HF)., Objective: To examine utilization rates, patient characteristics, and outcomes of ICD and CRT-D placements among patients with advanced HF., Design, Setting, and Participants: This cohort study was a post hoc analysis of 81 492 Medicare fee-for-service beneficiaries enrolled in the National Cardiovascular Data Registry ICD Registry between January 2010 and December 2014. Inclusion criteria were patients who had received an HF diagnosis, had a left ventricular ejection fraction of 35% or lower, and showed evidence of advanced HF, which was defined as New York Heart Association (NYHA) class IV symptoms, inotrope use within the last 60 days, left ventricular assist device in situ, or orthotopic heart transplant listing. The comparator group included patients with NYHA class II and no HF hospitalization within the last 12 months, no left ventricular assist device, no orthotopic heart transplant listing, and no current or recent inotrope use. All eligible patients underwent first-time ICD or CRT-D placement for primary prevention of sudden cardiac death. Data were analyzed from January 2010 to December 2014., Main Outcomes and Measures: All-cause mortality and periprocedural complications., Results: Of 81 492 Medicare patients, 3343 had advanced HF (4.1%) and 19 424 were in the comparator group (23.8%). Among the advanced HF population, the mean (SD) age of patients was 74 (9) years, and patients were predominantly white individuals (81.5%) and men (71.1%). The all-cause mortality rate at 30 days was 3.1% (95% CI, 2.6%-3.8%) in the advanced HF group vs 0.5% (0.4%-0.6%) in the comparator group (P < .001). In the advanced HF population, the aggregate in-hospital periprocedural complication rate was 3.74% (95% CI, 3.12%-4.44%) vs 1.10% (95% CI, 0.95%-1.25%) in the comparator group (P < .001). Most adverse events in this group were in-hospital fatality (1.82%; 95% CI, 1.40%-2.34%) and resuscitated cardiac arrest (1.05%; 95% CI, 0.73%-1.45%). Patients with NYHA class IV (hazard ratio, 1.40; 95% CI, 1.02-1.93; P = .04), ischemic heart disease (hazard ratio, 1.24; 95% CI, 1.04-1.48; P = .02), or diabetes (hazard ratio, 1.17; 95% CI, 1.04-1.33; P = .01) had a higher risk of death., Conclusions and Relevance: Among patients undergoing ICD or CRT-D placement for primary prevention of sudden cardiac death, only a small proportion had advanced HF. These patients experienced clinically important periprocedural complication rates associated with in-hospital death and cardiac arrest relative to patients with nonadvanced HF.

The TOPCAT trial investigated spironolactone vs placebo in patients with heart failure with preserved ejection fraction (HFpEF). Although the primary endpoint was not statistically significant, treatment with spironolactone did reduce heart failure hospitalizations compared with placebo. TOPCAT's impact on prescribing patterns in the United States is not well-characterized. We performed a retrospective analysis of discharge prescribing data in the Get With The Guidelines-Heart Failure Registry among patients with left ventricular ejection fraction ≥50% discharged between January 2009 and December 2016 to assess prescribing trends upon dissemination of TOPCAT results. Of 142,201 patients included in the study, 18,581 (13.1%) were prescribed mineralocorticoid receptor antagonists (MRAs) at discharge. Compared with those not prescribed MRAs, patients discharged on MRAs were generally younger (75 vs 78 years), and report white race (76.7% vs 72.0%), more likely to have had prior heart failure hospitalizations (75.5% vs 65.7%), lower brain natriuretic peptide levels (492 vs 545 pg/mL), but similar serum creatinine levels (1.2 vs 1.2 mg/dL) upon admission. MRA prescribing modestly increased over time (p <0.0001), without significant change in the overall trend of prescribing rate for MRAs after TOPCAT results were presented (p =0.17). In conclusion, our findings suggest that for patients with HFpEF, the use of MRAs at hospital discharge is low, with only modest increases over time and no discernible change in the rate of MRA use after the TOPCAT results were released. There remains an important need for more clinical trials to better establish the efficacy and safety of MRAs for the treatment of HFpEF., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The FIGHT (Functional Impact of GLP-1 [glucagon-like peptide-1] for Heart Failure Treatment) trial randomized 300 patients with heart failure with reduced ejection fraction (HFrEF) and a recent hospitalization for heart failure to liraglutide versus placebo. While there was no difference in the primary outcome (rank score of time to death, time to rehospitalization for heart failure, and change in NT-proBNP [N-terminal pro-B-type natriuretic peptide]), there was a significant increase in cystatin C among patients randomized to liraglutide raising concern of adverse renal outcomes. We performed a post hoc analysis of FIGHT to investigate whether liraglutide was associated with worsening renal function (WRF)., Methods: The relationship between randomization to liraglutide and WRF was evaluated using logistic regression models. Two hundred seventy-four patients (91%) had complete data to assess for WRF defined as: increase in SCr ≥0.3 mg/dL, or ≥25% decrease in estimated glomerular filtration rate, or an increase in cystatin C ≥0.3 mg/L from baseline to 180-days., Results: Patients with WRF (n=113, 41%), compared with those without, were older, had more comorbidities, and lower utilization of guideline-directed medical treatment. Logistic regression models showed that age and baseline cystatin C levels were associated with WRF. In adjusted models, liraglutide was not associated with excess risk of WRF compared with placebo (odds ratio, 1.02 [95% CI, 0.62-1.67]). There was also no difference in the rank score when WRF was added as a fourth-tier outcome., Conclusions: Liraglutide was not associated with WRF among patients with HFrEF and a recent hospitalization for heart failure. These data support the relative renal safety profile of liraglutide among patients with HFrEF. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01800968.

Background: In PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-pro BNP in Patients Stabilized From an Acute Heart Failure Episode), the in-hospital initiation of sacubitril/valsartan in patients hospitalized for acute decompensated heart failure (ADHF) was well-tolerated and led to improved outcomes. We aim to determine the representativeness of the PIONEER-HF trial among patients hospitalized for ADHF using real-world data., Methods: The study population was derived from all patients discharged alive for ADHF in the Get With The Guidelines-HF registry from 2006 to 2018 with HF with reduced ejection fraction (HFrEF; all HFrEF with ADHF). We then determined the proportion of patients meeting PIONEER-HF eligibility criteria (PIONEER-HF eligible) and those meeting a set of limited eligibility criteria (actionable cohort). Rates of HF readmissions and all-cause mortality were then compared between the all HFrEF with ADHF, PIONEER-HF eligible, and actionable cohorts using linked Medicare claims data., Results: A total of 99 767 patients with HFrEF in Get With The Guidelines-HF were hospitalized for ADHF. PIONEER-HF inclusion criteria were met by 71 633 (71.8%) patients, and both inclusion and exclusion criteria were met by 20 704 (20.8%) patients. Further, 68 739 (68.9%) patients met the criteria for the actionable cohort. Among the Centers for Medicare and Medicaid-linked patients, the HF rehospitalization rate at 1 year was 35.1% (95% CI, 34.5-35.8) for all HFrEF with ADHF patients, 32.6% (95% CI, 31.3-33.9) for the PIONEER-HF eligible cohort, and 33.1% (95% CI, 32.3-33.9) for the actionable cohort. The 1-year all-cause mortality was 36.7% (95% CI, 36.1-7.4) for all HFrEF with ADHF patients, 31.6% (95% CI, 30.3-32.9) for the PIONEER-HF eligible cohort, and 32.2% (95% CI, 31.4-33.0) for the actionable cohort., Conclusions: Patient characteristics and clinical outcomes for patients eligible for PIONEER-HF only modestly differ when compared with those encountered in routine practice, suggesting that the in-hospital initiation of sacubitril/valsartan should be routinely considered for patients with HFrEF hospitalized for ADHF.

Background: In heart failure with reduced ejection fraction (HFrEF), elevated soluble neprilysin (sNEP) levels are associated with an increased risk of cardiovascular death, and its inhibition with sacubitril/valsartan has improved survival., Objectives: This study sought to determine the relevance of sNEP as a biomarker in heart failure with preserved ejection fraction (HFpEF) and to compare circulating sNEP levels in patients with HFpEF with normal controls., Methods: A case-control study was performed in 242 symptomatic patients with HFpEF previously enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) and Nitrates's Effect on Activity Tolerance in Heart Failure With Preserved Ejection (NEAT-HFpEF) clinical trials and 891 asymptomatic subjects without HF or diastolic dysfunction (confirmed by NT-proBNP levels <200 pg/ml and echocardiography) who were enrolled in the Prevalence of Asymptomatic Left Ventricular Dysfunction study. sNEP was measured using a sandwich enzyme-linked immunosorbent assay (ELISA) in all subjects., Results: Overall, sNEP levels were lower in HFpEF compared with controls (3.5 ng/ml; confidence interval [CI]: 2.5 to 4.8 vs. 8.5 ng/ml; CI: 7.2 to 10.0; p < 0.001). After adjusting for age, gender, body mass index (BMI), and smoking history, mean sNEP levels were also lower in HFpEF compared with controls (4.0 ng/ml [CI: 2.7 to 5.4] vs. 8.2 ng/ml [CI: 6.8 to 9.7]; p = 0.002). The cohorts were propensity matched based on age, BMI, diabetes, hypertension, smoking history, and renal function, and sNEP levels remained lower in HFpEF compared with controls (median 2.4 ng/ml [interquartile range: 0.6 to 27.7] vs. 4.9 ng/ml [interquartile range: 1.2 to 42.2]; p = 0.02)., Conclusions: Patients with HFpEF on average have significantly lower circulating sNEP levels compared with controls. These findings challenge our current understanding of the complex biology of circulating sNEP in HFpEF., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background Limited data exist to guide treatment for patients with heart failure with preserved ejection fraction and atrial fibrillation, including the important decision regarding rate versus rhythm control. Methods and Results We analyzed the Get With The Guidelines-Heart Failure (GWTG-HF) registry linked to Medicare claims data from 2008 to 2014 to describe current treatments for rate versus rhythm control and subsequent outcomes in patients with heart failure with preserved ejection fraction and atrial fibrillation using inverse probability weighted analysis. Rhythm control was defined as use of an antiarrhythmic medication, cardioversion, or AF ablation or surgery. Rate control was defined as use of any combination of β-blocker, calcium channel blocker, and digoxin without evidence of rhythm control. Among 15 682 fee-for-service Medicare patients, at the time of discharge, 1857 were treated with rhythm control and 13 825 with rate control, with minimal differences in baseline characteristics between groups. There was higher all-cause death at 1 year in the rate control compared with the rhythm control group (37.5% and 30.8%, respectively, P <0.01). The lower 1-year all-cause death in the rhythm control group remained after risk adjustment (adjusted hazard ratio, 0.86; 95% CI, 0.75-0.98; P =0.02). Conclusions Rhythm control in patients aged 65 and older with heart failure with preserved ejection fraction and AF was associated with a lower risk of 1 year all-cause mortality. Future prospective randomized studies are needed to explore this potential benefit.

Aim: Describe the distinguishing features of heart failure (HF) patients with reduced ejection fraction (HFrEF) in the VICTORIA (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction) trial., Methods and Results: Key background characteristics were evaluated in 5050 patients randomized in VICTORIA and categorized into three cohorts reflecting their index worsening HF event. Differences within the VICTORIA population were assessed and compared with PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and 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). VICTORIA patients had increased risk of mortality and rehospitalization: New York Heart Association class (40% class III), atrial fibrillation (45%), diabetes (47%), hypertension (79%) and mean estimated glomerular filtration rate of 61.5 mL/min/1.73 m 2 . Baseline standard of HF care was very good: 60% received triple therapy. Their N-terminal pro-B-type natriuretic peptide was 3377 pg/mL [interquartile range (IQR) 1992-6380]. Natriuretic peptides were 30% higher level in the 67% patients with HF hospitalization <3 months, compared to those within 3-6 months of HF hospitalization and those randomized after recent outpatient intravenous diuretic therapy. Overall the median MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) risk score in VICTORIA was 23 (IQR 18-27) as compared to the MAGGIC risk score in PARADIGM-HF of 20 (IQR 16-24)., Conclusions: VICTORIA comprises a broadly generalizable high-risk population of three unique clinical strata of worsening chronic HFrEF despite very good HF therapy. VICTORIA will establish the role of vericiguat, a soluble guanylate cyclase stimulator, in HFrEF., (© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Neladenoson bialanate is a partial adenosine A1 receptor agonist with demonstrated beneficial effects on cardiac function in animal models. We aimed to assess the dose-response effect of neladenoson bialanate on cardiac structure and function, clinical outcome, and safety in patients with heart failure (HF) with reduced ejection fraction (HFrEF)., Methods and Results: PANTHEON was a dose-finding, phase IIb, randomized, double-blind, placebo-controlled trial conducted in 92 centres in 11 countries including 462 patients with chronic HFrEF, randomized to once daily oral dose of neladenoson bialanate (5, 10, 20, 30, and 40 mg) or placebo. The primary endpoints were change from baseline to 20 weeks in left ventricular ejection fraction (LVEF) (echocardiography) and in N-terminal pro-B-type natriuretic peptide (NT-proBNP). Mean age of the patients was 67 years, 17% were female, mean LVEF was 28%, mean NT-proBNP was 2085 ng/L. After 20 weeks of treatment, there was no dose-effect of neladenoson bialanate on changes in NT-proBNP or LVEF (primary endpoints). No effect of neladenoson bialanate was found on left ventricular volumes, high-sensitivity troponin T, or cardiovascular mortality, HF hospitalization, and urgent visits for HF (secondary endpoints). There was a dose-dependent increase in creatinine and cystatin C, and a dose-dependent decrease in estimated glomerular filtration rate and heart rate., Conclusions: In patients with chronic HFrEF, treatment with neladenoson bialanate was not associated with dose-dependent favourable effects on cardiac structure and function, cardiac risk markers, or clinical outcome but was associated with a dose-dependent decrease in renal function., Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02992288., (© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: This study sought to determine the rate of use of target doses of foundational guideline-directed medical therapy (GDMT) in a contemporary cohort of patients with heart failure with reduced ejection fraction (HFrEF) across systolic blood pressure (SBP) categories., Background: Patients with HFrEF are infrequently titrated to recommended doses of GDMT. The relationship between SBP and achieving GDMT target doses is not well studied., Methods: Patients enrolled in the CHAMP-HF (Change the Management of Patients With Heart Failure) registry without documented intolerance to angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), and beta blockers (BBs) were assessed at enrollment. We estimated the proportion receiving target doses (% of target dose [95% confidence interval (CI)]) based on the most recent American College of Cardiology/American Heart Association/Heart Failure Society of America heart failure guidelines at baseline in all patients, and by SBP category (≥110 vs. <110 mm Hg)., Results: Of the 3,095 patients eligible for analysis, 2,421 (78.2%) had SBP ≥110 mm Hg. The proportion of patients receiving target doses were 18.7% (95% CI: 17.3% to 20.0%; BB), 10.8% (95% CI: 9.7% to 11.9%; ACEI/ARB), and 2.0% (95% CI: 1.5% to 2.5%; ARNI). Among those with SBP <110 mm Hg (n = 674), 17.5% (95% CI: 14.6% to 20.4%; BB), 6.2% (95% CI: 4.4% to 8.1%; ACEI/ARB), and 1.8% (95% CI: 0.8% to 2.8%; ARNI) were receiving target doses. Among those with SBP ≥110 mm Hg (n = 2,421), 19.0% (95% CI: 17.4% to 20.6%; BB), 12.1% (95% CI: 10.8% to 13.4%; ACEI/ARB), and 2.0% (95% CI: 1.5% to 2.6%; ARNI) were receiving target doses., Conclusions: In a large, contemporary registry of outpatients with chronic HFrEF eligible for treatment with BBs and ACEI/ARB/ARNI, <20% of patients were receiving target doses, even among those with SBP ≥110 mm Hg., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background The angiotensin-receptor/neprilysin inhibitor ( ARNI ) sacubitril/valsartan reduces hospitalization and mortality for patients with heart failure with reduced ejection fraction. However, adoption of ARNI into clinical practice has been slow. Factors influencing use of ARNI have not been fully elucidated. Using data from the Get With The Guidelines-Heart Failure registry, Hospital Compare, Dartmouth Atlas, and the American Hospital Association Survey, we sought to identify hospital characteristics associated with patient-level receipt of an ARNI prescription. Methods and Results We analyzed patients with heart failure with reduced ejection fraction who were eligible for ARNI prescription (ejection fraction≤40%, no contraindications) and hospitalized from October 1, 2015 through December 31, 2016. We used logistic regression to estimate the associations between hospital characteristics and patient ARNI prescription at hospital discharge, accounting for clustering of patients within hospitals using generalized estimating equation methods and adjusting for patient-level covariates. Of 16 674 eligible hospitalizations from 210 hospitals, 1020 patients (6.1%) were prescribed ARNI at discharge. The median hospital-level proportion of patients prescribed ARNI was 3.3% (Q1, Q3: 0%, 12.6%). After adjustment for patient-level covariates, for-profit hospitals had significantly higher odds of ARNI prescription compared with not-for-profit hospitals (odds ratio, 2.53; 95% CI , 1.05-6.10; P=0.04), and hospitals located in the Western United States had lower odds of ARNI prescription compared with those in the Northeast (odds ratio, 0.33; 95% CI , 0.13-0.84; P=0.02). Conclusions Relatively few hospital characteristics were associated with ARNI prescription at hospital discharge, in contrast to what has been observed in early adoption in other disease areas. Additional evaluation of barriers to implementing new evidence into heart failure practice is needed.

Background We sought to study the prevalence of high-sensitivity troponin and its association with cardiac structure and outcomes in ambulatory and hospitalized patients with heart failure with a preserved ejection fraction ( HF p EF ). Methods and Results A post hoc analysis utilized data from HF p EF patients: DOSE (Diuretic Optimization Strategies Evaluation) and CARRESS - HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) enrolled patients hospitalized with acute HF p EF , and RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) enrolled ambulatory patients with HF p EF . High-sensitivity troponin I (hs-TnI) was measured in hospitalized patients at baseline, at 72 to 96 hours, on day 7, and on day 60. In ambulatory patients hs-TnI was measured at baseline and at week 24. In the ambulatory cohort, correlations between hs-TnI and cardiac structure and function were assessed. The association between hs-TnI and a 60-day composite of emergency room visits, readmissions, and death was assessed for hospitalized patients using multivariable Cox proportional hazard models. The study population included 139 hospitalized and 212 ambulatory patients with HF p EF and hs-TnI measured at baseline. The median (25th, 75th percentiles) baseline troponin was 17.6 (11.1, 41.0) ng/L in hospitalized patients and 9.5 (5.3, 19.7) ng/L in ambulatory patients ( P<0.001). The prevalence of elevated hs-TnI (>99% percentile upper reference limit was 86% in hospitalized patients and 53% among ambulatory patients, with stable elevation in ambulatory patients during follow-up. HF p EF patients with a hs-TnI above the median were older with worse left ventricular hypertrophy and diastolic dysfunction. Continuously valued hs-TnI (per doubling) was associated with increased risk of composite end point (adjusted hazard ratio 1.20, 95% confidence interval 1.00-1.43; P=0.042). Conclusions Hs-TnI is commonly elevated among both hospitalized and ambulatory patients with HF p EF . Increased hs-TnI levels are associated with worse cardiac structure and increased risk of adverse events.

Aims: Obesity is present in up to 45% of patients with heart failure (HF). Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor antagonist, facilitates weight loss in obese patients. The efficacy of liraglutide as a weight loss agent among patients with HF and reduced ejection fraction (HFrEF) and a recent acute HF hospitalization remains unknown., Methods and Results: The Functional Impact of GLP-1 for Heart Failure Treatment study randomized 300 patients with HFrEF (ejection fraction ≤ 40%), both with and without diabetes and a recent HF hospitalization to liraglutide or placebo. The primary outcome for this post hoc analysis was the change in weight from baseline to last study visit. We conducted an 'on-treatment' analysis of patients with at least one follow-up visit on study drug (123 on liraglutide and 124 on placebo). The median age was 61 years, 21% were female, and 69% of patients had New York Heart Association functional Class III or IV symptoms. The median ejection fraction was 25% (25th, 75th percentile 19-32%). Liraglutide use was associated with a significant weight reduction [liraglutide -1.00 lbs vs. placebo 2.00 lbs; treatment difference -4.10 lbs; 95% confidence interval (CI) -7.94, -0.25; P = 0.0367; percentage treatment difference -2.07%, 95% CI -3.86, -0.28; P = 0.0237]. Similar results were seen after multivariable adjustments. Liraglutide also significantly reduced triglyceride levels (liraglutide 7.5 mg/dL vs. placebo 12.0 mg/dL; treatment difference -33.1 mg/dL; 95% CI -60.7, -5.6; P = 0.019)., Conclusions: Liraglutide is an efficacious weight loss agent in patients with HFrEF. These findings will require further exploration in a well-powered cardiovascular outcomes trial., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

We aimed to study whether jugular venous distension (JVD) and peripheral edema were associated with worse outcomes in patients with acute heart failure in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure trial. Of 7,141 patients in Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure, 7,135 had complete data on baseline JVD and peripheral edema status. Patients were grouped according to baseline examination findings: (1) no JVD or peripheral edema; (2) JVD only; (3) peripheral edema only; (4) JVD and peripheral edema. We used unadjusted and adjusted logistic or Cox regression analyses to assess associations between groups and the outcomes of index length of stay (LOS), in-hospital mortality, 30- and 180-day all-cause mortality. Patients with peripheral edema (Groups 3 and 4) had higher body mass index, NT-proBNP and BNP values, and more co-morbid disease, and reduced left ventricular ejection fraction compared with patients in Groups 1-2. The median (25th-75th) LOS for Groups 1-4 was 6 (4-9), 5 (4-8), 7 (4-11), and 6 days (4-10), respectively. For the 30-day and 180-day outcomes, adjusted analyses found no significant difference in risk for patients presenting with JVD only or peripheral edema only as compared with patients without evidence of JVD or peripheral edema (p >0.05 for all). The presence of both JVD and peripheral edema was associated with an adjusted 24% increase in risk for all-cause mortality at 30 days, but no risk difference at 180 days. In conclusion, in patients with heart failure presenting to the hospital with dyspnea, the presence of peripheral edema is associated with a longer hospital LOS, but no difference in short- and long-term clinical outcomes when compared with patients wihout peripheral edema. The combination of peripheral edema and JVD identifies the highest risk cohort for poor clinical outcomes., (Copyright © 2018. Published by Elsevier Inc.)

Despite major advances in the treatment of chronic heart failure (HF) with reduced ejection fraction (HFrEF), morbidity and mortality associated with the condition remain high, suggesting the need for additional treatment options, particularly haemodynamically neutral treatments that do not alter blood pressure, heart rate, or renal function. HF with preserved ejection fraction (HFpEF) is also associated with high morbidity and mortality and adequate treatment options are limited; thus there is a critical unmet need for the development of novel therapies for HFpEF. Chronic HFrEF and HFpEF are both systemic disorders that affect not only the heart but several other tissues and organs including skeletal muscle, leading to exercise intolerance and dyspnoea. Partial adenosine A1-receptor agonists represent a novel potential therapy for HF regardless of underlying ejection fraction given their minimal effect on heart rate and blood pressure, and preclinical data demonstrate several possible beneficial mechanisms, including improved mitochondrial function and sarcoplasmic reticulum Ca 2+ -ATPase (SERCA2a) activity, enhanced energy substrate utilization, reverse ventricular remodelling, and anti-ischemic, cardioprotective properties. However, data on this class of drugs in humans are scarce, and the optimal dose of the partial adenosine A1 receptor, neladenoson bialanate, has not been defined. Here we describe the design and rationale of two randomized, double-blind, placebo-controlled, parallel-group, dose-finding phase 2b trials, PANTHEON (HFrEF) and PANACHE (HFpEF), that will advance our understanding of the potential benefit and optimal dose of neladenoson bialanate and provide critical information for the planning of future phase 3 trials., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Background: Circulating cardiac troponin levels (cTn), representative of myocardial injury, are commonly elevated in heart failure (HF) and related to adverse clinical events. However, whether cTn represents a spectrum of risk in HF is unclear., Methods: Baseline, 48-72-hour, and 30-day plasma cTnI was measured with the use of a new highly sensitive assay in 900 subjects with acute decompensated HF (ADHF) in ASCEND-HF. Multivariable models determined the relationship between cTnI and outcomes., Results: The median (interquartile range) cTnI was 16.4 (9.3-31.6) ng/L at baseline, 14.1 (7.8-29.7) ng/L at 48-72 hours, and 11.6 (6.8-22.5) ng/L at 30 days. After additional adjustment for N-terminal pro-B-type natriuretic peptide (NT-proBNP) to established risk predictors, both baseline (odds ratio [OR] 1.25; P = .03) and 48-72-hour (OR 1.43; P = .001) cTnI were associated with higher risk for death or worsening HF before discharge. However, only cTnI at 30 days was associated with 180-day death (hazard ratio 1.25; P = .007). There were no curvilinear associations between changing cTnI and clinical outcomes., Conclusions: Circulating cTnI level was associated with clinical outcomes in ADHF, but these observations diminished with additional adjustment for NT-proBNP. Although they likely represent a spectrum of risk in ADHF, these findings question the implications of changing cTnI levels during treatment., (Copyright © 2018. Published by Elsevier Inc.)

Background: The US Food and Drug Administration approved sacubitril/valsartan for patients with chronic heart failure (HF) with reduced ejection fraction in 2015 on the basis of the results of the PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor Neprilysin Inhibitor] With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. There are limited data assessing the generalizability of PARADIGM-HF trial participants to a broader population of patients with HF with reduced ejection fraction routinely encountered in outpatient clinical practice., Methods and Results: We compared the baseline characteristics of patients in the PARADIGM-HF trial with those in the CHAMP-HF (Change the Management of Patients With Heart Failure) study a large US outpatient registry of patients with HF with reduced ejection fraction. Patients in the PARADIGM-HF trial (n=8442) were similar to those in the CHAMP-HF registry (n=3497) in terms of age (mean, 64 versus 66 years), sex (22% versus 29% women), New York Heart Association class III to IV (25% versus 32%), systolic blood pressure (mean, 121 versus 121 mm Hg), left ventricular ejection fraction (mean, 29% versus 29%), and other key baseline characteristics. The median (25th-75 th percentile) Meta-Analysis Global Group in Chronic Heart Failure risk scores were similar for the 2 studies (20 [16-24] versus 22 [8-27]). Despite this, only 13% of patients in the CHAMP-HF registry were prescribed sacubitril/valsartan at baseline., Conclusions: These data suggest participants randomized in the PARADIGM-HF trial have similar baseline characteristics to those encountered in routine outpatient clinical practice, but there is a substantial lag in the adoption of sacubitril/valsartan for patients with chronic HF with reduced ejection fraction., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: The increase in medical complexity among patients hospitalized with heart failure (HF) may be reflected by an increase in concomitant noncardiovascular comorbidities. Among patients hospitalized with HF, the temporal trends in the prevalence of noncardiovascular comorbidities have not been well described., Methods and Results: We used data from 207 984 patients in the Get With The Guidelines-Heart Failure registry (from 2005 to 2014) to evaluate the prevalence and trends of noncardiovascular comorbidities (chronic obstructive pulmonary disorder/asthma, anemia, diabetes mellitus, obesity [body mass index ≥30 kg/m 2 ], and renal impairment) among patients hospitalized with HF. Medicare beneficiaries aged ≥65 years were used to assess 30-day mortality. The prevalence of 0, 1, 2, and ≥3 noncardiovascular comorbidities was 18%, 30%, 27%, 25%, respectively. From 2005 to 2014, there was a decline in patients with 0 noncardiovascular comorbidities (22%-16%; P <0.0001) and an increase in patients with ≥3 noncardiovascular comorbidities (18%-29%; P <0.0001). Among Medicare beneficiaries, there was an increased 30-day adjusted mortality risk among patients with 1 noncardiovascular comorbidity (hazard ratio, 1.16; 95% confidence interval, 1.09-1.24; P <0.0001), 2 noncardiovascular comorbidities (hazard ratio, 1.34; 95% confidence interval, 1.25-1.44; P <0.0001), and ≥3 noncardiovascular comorbidities (hazard ratio, 1.63; 95% confidence interval, 1.51-1.75; P <0.0001). Similar trends were seen for in-hospital mortality., Conclusions: Patients admitted in hospital for HF have an increasing number of noncardiovascular comorbidities over time, which are associated with worse outcomes. Strategies addressing the growing burden of noncardiovascular comorbidities may represent an avenue to improve outcomes and should be included in the delivery of in-hospital HF care., (© 2018 American Heart Association, Inc.)

Background: Heart failure with preserved ejection fraction may be associated with chronotropic incompetence, but little is known about the incidence and prevalence of permanent pacemaker use in this population or factors associated with its use., Methods: We analyzed patients with heart failure with preserved ejection fraction (ie, left ventricular ejection fraction greater than 40%) from the ADHERE registry (2001-2006) linked with Medicare claims. We described the use of both prevalent and incident permanent pacemakers in heart failure with preserved ejection fraction and determined factors associated with pacemaker use with logistic regression models., Results: Among 13,881 patients with heart failure with preserved ejection fraction, 3136 (22.6%) had a permanent pacemaker, and of these patients, 636 had a permanent pacemaker implanted during hospitalization. Permanent pacemaker use was more common among older patients (81 vs 79 years; P < .001), men (38% vs 34%; P < .001), patients with atrial fibrillation (58% vs 36%; P < .001), and patients with wider QRS duration (140 ms vs 94 ms; P < .001). Rates of digoxin, aldosterone antagonist, and loop diuretic use were slightly higher in patients with a permanent pacemaker compared with patients with no permanent pacemaker. Factors associated with both prevalent and incident pacemaker use included age, fast or slow heart rate, atrial fibrillation, and lower body mass index., Conclusions: Use of permanent pacemakers is relatively common among patients with heart failure with preserved ejection fraction., (Copyright © 2018. Published by Elsevier Inc.)

Antiretroviral therapy (ART) has been associated with a shift in the epidemiology of human immunodeficiency virus (HIV)-associated cardiomyopathy from a phenotype of primarily left ventricular (LV) systolic dysfunction to LV diastolic dysfunction (DD). Patients with HIV receiving ART have higher rates of DD compared with age-matched control subjects and develop DD at a younger age. However, little is known about the natural history and pathogenesis of DD in virally suppressed HIV-infected patients. Current evidence suggests that immune processes modulate the risk for cardiac involvement in HIV-infected persons. Ongoing inflammation appears to have myocardial effects, and accelerated myocardial fibrosis appears to be a key mediator of HIV-induced DD. The Characterizing Heart Function on Antiretroviral Therapy (CHART) study aims to systematically investigate determinants, mechanisms, and consequences of DD in HIV-infected patients. We will compare ART-treated virally suppressed HIV-infected individuals with and without DD and HIV- individuals with DD regarding (1) systemic inflammation, myocardial stress, and subclinical myocardial necrosis as indicated by circulating biomarkers; (2) immune system activation as indicated by cell surface receptors; (3) myocardial fibrosis according to cardiac magnetic resonance examination; (4) markers of fibrosis and remodeling, oxidative stress, and hypercoagulability; (5) left atrial function according to echocardiographic examination; (6) myocardial stress and subclinical necrosis as indicated by circulating biomarkers; (7) proteomic and metabolic profiles; and (8) phenotype signatures derived from clinical, biomarker, and imaging data., (Copyright © 2018 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.)

Background: Patients with heart failure (HF) have a poor prognosis and are categorized by ejection fraction (EF)., Objectives: This study sought to characterize differences in outcomes in patients hospitalized with heart failure with preserved ejection fraction (HFpEF) (EF ≥50%), heart failure with borderline ejection fraction (HFbEF) (EF 41% to 49%), and heart failure with reduced ejection fraction (HFrEF) (EF ≤40%)., Methods: Data from GWTG-HF (Get With The Guidelines-Heart Failure) were linked to Medicare data for longitudinal follow-up. Multivariable models were constructed to examine 5-year outcomes and to compare survival to median survival of the U.S., Results: A total of 39,982 patients from 254 hospitals who were admitted for HF between 2005 and 2009 were included: 18,299 (46%) had HFpEF, 3,285 (8.2%) had HFbEF, and 18,398 (46%) had HFrEF. Overall, median survival was 2.1 years. In risk-adjusted survival analysis, all 3 groups had similar 5-year mortality (HFrEF 75.3% vs. HFpEF 75.7%; hazard ratio: 0.99 [95% confidence interval: 0.958 to 1.022]; HFbEF 75.7% vs. HFpEF 75.7%; hazard ratio: 0.99 [95% confidence interval: 0.947 to 1.046]). In risk-adjusted analyses, the composite of mortality and rehospitalization was similar for all subgroups. Cardiovascular and HF readmission rates were higher in those with HFrEF and HFbEF compared with those with HFpEF. When compared with the U.S. population, HF patients across all age and EF groups had markedly lower median survival., Conclusions: Among patients hospitalized with HF, patients across the EF spectrum have a similarly poor 5-year survival with an elevated risk for cardiovascular and HF admission. These findings underscore the need to improve treatment of patients with HF., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Differences in the clinical course of congestion by underlying ejection fraction (EF) have not been well-characterized in acute heart failure (AHF). A post hoc analysis was performed using pooled data from the Diuretic Optimization Strategies Evaluation in Acute Heart Failure, Cardiorenal Rescue Study in Acute Decompensated Heart Failure, and Renal Optimization Strategies Evaluation in Acute Heart Failure trials. All patients were admitted for a primary diagnosis of AHF. Patients were grouped as reduced EF ≤40%, borderline 40% < EF < 50%, or preserved EF ≥50%. Multivariable Cox regression analysis was used to assess the association among measures of congestion and the composite of unscheduled outpatient visits, rehospitalization, or death. Mean age was 68 ± 13 years and 74% were male. Patients with a preserved EF were older, more likely to be female, less likely to have an ischemic etiology of HF, and had a higher prevalence of atrial fibrillation/flutter and chronic obstructive pulmonary disease. Compared with patients with a reduced EF, preserved EF patients had lower amino-terminal pro-b-type natriuretic peptide levels at baseline (i.e., reduced: 5,998 pg/ml [3,009 to 11,414] vs borderline: 4,420 pg/ml [1,740 to 8,057] vs preserved: 3,272 pg/ml [1,687 to 6,536]) and experienced smaller changes during hospitalization. In general, there were few differences between EF groups in the clinical course of congestion as measured by signs and symptoms of HF, body weight change, and net fluid loss. After adjusting for potential confounders, a greater improvement in global visual analog scale was associated with lower risk of unscheduled outpatient visits, rehospitalization, or death at day 60 (hazard ratio 0.94 per 10 mm increase, 95% confidence interval 0.89 to 0.995). This relation did not differ by EF (p = 0.54). In conclusion, among patients hospitalized for AHF, there were few differences in the in-hospital trajectory or prognostic value of routine markers of congestion by EF., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: While abnormal left ventricular (LV) global longitudinal strain (GLS) has been described in patients with heart failure with preserved ejection fraction (HFpEF), its prevalence and clinical significance are poorly understood., Methods and Results: Patients enrolled in the RELAX trial of sildenafil in HFpEF (LV ejection fraction ≥50%) in whom two-dimensional, speckle-tracking LV GLS was possible (n = 187) were analysed. The distribution of LV GLS and its associations with clinical characteristics, LV structure and function, biomarkers, exercise capacity and quality of life were assessed. Baseline median LV GLS was -14.6% (25th and 75th percentile, -17.0% and -11.9%, respectively) and abnormal (≥ - 16%) in 122/187 (65%) patients. Patients in the tertile with the best LV GLS had lower N-terminal pro-brain natriuretic peptide (NT-proBNP) [median 505 pg/mL (161, 1065) vs. 875 pg/mL (488, 1802), P = 0.008) and lower collagen III N-terminal propeptide (PIIINP) levels [median 6.7 µg/L (5.1, 8.1) vs. 8.1 µg/L (6.5, 10.5), P = 0.001] compared with the tertile with the worst LV GLS. There was also a modest linear relationship with LV GLS and log-transformed NT-proBNP and PIIINP (r = 0.29, P < 0.001 and r = 0.19, P = 0.009, respectively). We observed no linear association of LV GLS with Minnesota Living with Heart Failure scores, 6-min walk distance, peak oxygen consumption, or expiratory minute ventilation/carbon dioxide excretion slope., Conclusions: Impaired LV GLS is common among HFpEF patients, indicating the presence of covert systolic dysfunction despite normal LV ejection fraction. Impaired LV GLS was associated with biomarkers of wall stress and collagen synthesis and diastolic dysfunction but not with quality of life or exercise capacity, suggesting other processes may be more responsible for these aspects of the HFpEF syndrome., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: Daily physical activity assessed by accelerometers represents a novel method to assess the impact of interventions on heart failure (HF) patients' functional status. We hypothesized that daily activity varies by patient characteristics and correlates with established measures of HF severity in HF with preserved ejection fraction., Methods and Results: In this ancillary study of the NEAT-HFpEF trial (Nitrate's Effects on Activity Tolerance in HF With Preserved Ejection Fraction), average daily accelerometer units (ADAU) and hours active per day were assessed during a 14-day period before starting isosorbide mononitrate or placebo (n=110). Baseline ADAU was negatively associated with age, female sex, height, and body mass index, and these variables accounted for 28% of the variability in ADAU ( P <0.007 for all). Adjusting for these factors, patients with lower ADAU were more likely to have had an HF hospitalization, orthopnea, diabetes mellitus and anemia, be treated with β-blockers, have higher ejection fraction, relative wall thickness and left atrial volume, and worse New York Heart Association class, HF-specific quality of life scores, 6-minute walk distance, and NT-proBNP (N-terminal pro-B-type natriuretic peptide; P <0.05 for all). Associations between hours active per day and clinical characteristics were similar. Relative to baseline, there were no significant associations between changes in ADAU or hours active per day and changes in standard functional assessments (New York Heart Association, quality of life, 6-minute walk distance, and NT-proBNP) with isosorbide mononitrate., Conclusions: Daily activity is a measure of HF-related and global functional status in HF with preserved ejection fraction. As compared with intermittently assessed standard HF assessments, change in daily activity may provide unique information about the impact of HF interventions on functional status., Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02053493., (© 2017 American Heart Association, Inc.)

Importance: Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown., Objective: To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency., Design, Setting, and Participants: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF (<40%) and iron deficiency, defined as a serum ferritin level of 15 to 100 ng/mL or a serum ferritin level of 101 to 299 ng/mL with transferrin saturation of less than 20%. Participants were enrolled between September 2014 and November 2015 at 23 US sites., Interventions: Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks., Main Outcomes and Measures: The primary end point was a change in peak oxygen uptake (V̇o2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life)., Results: Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V̇o2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V̇o2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs -2 mL/min; difference, 21 mL/min [95% CI, -34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (-13 m; 95% CI, -32 to 6 m), NT-proBNP levels (159; 95% CI, -280 to 599 pg/mL), or KCCQ score (1; 95% CI, -2.4 to 4.4), all P > .05., Conclusions and Relevance: Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF., Trial Registration: clinicaltrials.gov Identifier: NCT02188784.

Objectives: This study sought to ascertain the impact of heart failure (HF) guideline change on the number of patients eligible to undergo cardiac resynchronization therapy (CRT)., Background: The 2013 HF guideline of the American College of Cardiology Foundation and American Heart Association (ACCF/AHA) narrowed the recommendations for CRT. The impact of this guideline change on the number of eligible patients for CRT has not been described., Methods: Using data from Get With The Guidelines-Heart Failure between 2012 and 2015, this study evaluated the proportion of hospitalized patients with HF who were eligible for CRT on the basis of historical and current guideline recommendations. The authors identified 25,102 hospitalizations for HF that included patients with a left ventricular ejection fraction (LVEF) ≤35% from 283 hospitals. Patients with a medical, system-related, or patient-related reason for not undergoing CRT were excluded., Results: Overall, 49.1% (n = 12,336) of patients with HF, an LVEF ≤35%, and no documented contraindication were eligible for CRT on the basis of historical guidelines, and 33.1% (n = 8,299) of patients were eligible for CRT on the basis of current guidelines, a 16.1% absolute reduction in eligibility (p < 0.0001). Patients eligible for CRT on the basis of current guidelines were more likely to have CRT with an implantable cardioverter-defibrillator or CRT with pacing only placed or prescribed at discharge (57.8% vs. 54.9%; p < 0.0001) compared with patients eligible for CRT on the basis of historical guidelines., Conclusions: In this population of patients with HF, an LVEF ≤35%, and no documented contraindication for CRT, the current ACCF/AHA HF guidelines reduce the proportion of patients eligible for CRT by approximately 15%., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess the prevalence and variation in angiotensin receptor/neprilysin inhibitor (ARNI) prescription among a real-world population with heart failure with reduced ejection fraction (HFrEF)., Background: The U.S. Food and Drug Administration approved sacubitril/valsartan for patients with HFrEF in July 2015. Little is known about the early patterns of use of this novel therapy., Methods: The study included patients discharged alive from hospitals in Get With the Guidelines-Heart Failure (GWTG-HF), a registry of hospitalized patients with heart failure, between July 2015 and June 2016 who had documentation of whether ARNIs were prescribed at discharge. Patient and hospital characteristics were compared among patients with HFrEF (ejection fraction ≤40%) with and without ARNI prescription at discharge, excluding those with documented contraindications to ARNIs. To evaluate hospital variation, hospitals with at least 10 eligible hospitalizations during the study period were assessed., Results: Of 21,078 patients hospitalized with HFrEF during the study period, 495 (2.3%) were prescribed ARNIs at discharge. Patients prescribed ARNIs were younger (median age 65 years vs. 70 years; p < 0.001), had lower ejection fractions (median 23% vs. 25%; p < 0.001), and had higher use of aldosterone antagonists (45% vs. 31%; p < 0.001) at discharge. At the 241 participating hospitals with 10 or more eligible admissions, 125 (52%) reported no discharge prescriptions of ARNIs., Conclusions: Approximately 2.3% of patients hospitalized for HFrEF in a national registry were prescribed ARNI therapy in the first 12 months following Food and Drug Administration approval. Further study is needed to identify and overcome barriers to implementing new evidence into practice, such as ARNI use among eligible patients with HFrEF., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Guidelines recommend continuation or initiation of guideline-directed medical therapy, including angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARB), in hospitalized patients with heart failure with reduced ejection fraction., Methods and Results: Using the Get With The Guidelines-Heart Failure Registry, we linked clinical data from 16 052 heart failure with reduced ejection fraction (ejection fraction ≤40%) patients with Medicare claims data. We divided ACEi/ARB-eligible patients into 4 categories based on admission and discharge ACEi/ARB use: continued (reference group), started, discontinued, or not started on therapy. A multivariable Cox proportional hazard model was used to determine the association between ACEi/ARB category and outcomes. Most, 90.5%, were discharged on ACEi/ARB (59.6% continued and 30.9% newly started). Of those discharged without ACEi/ARB, 1.9% were discontinued, and 7.5% were eligible but not started. Thirty-day mortality was 3.5% for patients continued and 4.1% for patients started on ACEi/ARB. In contrast, 30-day mortality was 8.8% for patients discontinued (adjusted hazard ratio [HR adj ] 1.92; 95% CI 1.32-2.81; P <0.001) and 7.5% for patients not started (HR adj 1.50; 95% CI 1.12-2.00; P =0.006). The 30-day readmission rate was lowest among patients continued or started on therapy. One-year mortality was 28.2% for patients continued and 29.7% for patients started on ACEi/ARB compared to 41.6% for patients discontinued (HR adj 1.35; 95% CI 1.13-1.61; P <0.001) and 41.7% (HR adj 1.28; 95% CI 1.14-1.43; P <0.001) for patients not started on therapy., Conclusions: Compared with continuation, withdrawal of ACEi/ARB during heart failure hospitalization is associated with higher rates of postdischarge mortality and readmission, even after adjustment for severity of illness., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Importance: Elevated levels of cardiac troponins are associated with adverse clinical outcomes among patients with heart failure (HF) and reduced ejection fraction. However, the clinical significance of troponin elevation in the setting of decompensated HF with preserved ejection fraction (HFpEF) is not well established., Objective: To determine the clinical predictors of troponin elevation and its association with in-hospital and long-term outcomes among patients with decompensated HFpEF., Design, Setting, and Participants: Observational analysis of Get With The Guidelines-HF registry participants who were admitted for decompensated HFpEF (ejection fraction ≥50%) from January 2009 through December 2014 and who had quantitative or categorical (elevated vs normal based on institution's reference laboratory) measures of troponin level (troponin T or troponin I, as available)., Main Outcomes and Measures: In-hospital outcomes (mortality, length of stay, and discharge destination) and postdischarge outcomes (30-day mortality, 30-day readmission rate, 1-year mortality)., Results: We included 34 233 patients with HFpEF from 224 sites with measured troponin levels (33.4% men; median age, 79 years): 78.6% (n = 26 896) with troponin I and 21.4% (n = 7319) with troponin T measurements. Among these, 22.6% (n = 7732) had elevation in troponin levels. In adjusted analysis, higher serum creatinine level, black race, older age, and ischemic heart disease were associated with troponin elevation. Elevated troponin was associated with higher odds of in-hospital mortality (odds ratio [OR], 2.19; 95% CI, 1.88-2.56), greater length of stay (length of stay >4 days OR, 1.38; 95% CI, 1.29-1.47), and lower likelihood of discharge to home (OR, 0.65; 95% CI, 0.61-0.71) independent of other clinical predictors and measured confounders. Presence of elevated troponin I levels was also significantly associated with increased risk of 30-day mortality (hazard ratio [HR], 1.59; 95% CI, 1.42-1.80), 30-day all-cause readmission (HR, 1.12; 95% CI, 1.01-1.25), and 1-year mortality HR, 1.35; 95% CI, 1.26-1.45)., Conclusions and Relevance: Troponin elevation among patients with acutely decompensated HFpEF is associated with worse in-hospital and postdischarge outcomes, independent of other predictive variables. Future studies are needed to determine if measurement of troponin levels among patients with decompensated HFpEF may be useful for risk stratification.

Given the emerging recognition of left atrial structure and function as an important marker of disease in heart failure with preserved ejection fraction (HF-pEF), we investigated the association between left atrial volume and function with markers of disease severity and cardiac structure in HF-pEF. We studied 100 patients enrolled in the PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) trial who underwent cardiac magnetic resonance (CMR), cardiopulmonary exercise testing, and blood collection before randomization. Maximal left atrial volume index (LAVi; N = 100), left atrial emptying fraction (LAEF; N = 99; including passive and active components (LAEFP, LAEFA; N = 80, 79, respectively) were quantified by CMR. After adjustment for multiple testing, maximal LAVi was only associated with age (ρ = 0.39), transmitral filling patterns (medial E/e' ρ = 0.43), and N-terminal pro-BNP (NT-proBNP; ρ = 0.65; all p<0.05). Lower LAEF was associated with older age, higher transmitral E/A ratio and higher NT-proBNP. Peak VO2 and VE/VCO2 slope were not associated with left atrial structure or function. After adjustment for age, sex, transmitral E/A ratio, CMR LV mass, LV ejection fraction, and creatinine clearance, NT-proBNP remained associated with maximal LAVi (β = 0.028, p = 0.0007) and total LAEF (β = -0.033, p = 0.001). Passive and active LAEF were most strongly associated with age and NT-proBNP, but not gas exchange or other markers of ventricular structure or filling properties. Left atrial volume and emptying function are associated most strongly with NT-proBNP and diastolic filling properties, but not significantly with gas exchange, in HFpEF. Further research to explore the relevance of left atrial structure and function in HF-pEF is warranted., Competing Interests: The authors have declared that no competing interests exist.

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is more common in women than in men; data characterizing sex differences in the management and outcomes of HFpEF patients presenting to the emergency department (ED) are limited., Methods and Results: Using Acute Decompensated Heart Failure National Registry Emergency Module data linked to Medicare claims, we conducted a retrospective analysis of acute HF patients in the ED, identifying HFpEF (ejection fraction [EF] ≥40%) patients and stratifying by sex to compare baseline characteristics, ED therapies, hospital length of stay (LOS), in-hospital mortality, and post-discharge outcomes. Of 4161 HFpEF patients, 2808 (67%) were women, who were more likely to be older and hypertensive, but less likely to be diabetic or smokers (all P < .01). Women more often presented with systolic blood pressure >140 mm Hg (62.5% vs 56.4%; P = .0001) and higher EF. There were no sex differences in ED therapies, adjusted 30- and 180-day all-cause mortality, in-hospital mortality, or 30- and 180-day readmissions. After adjustment, women had longer LOS (0.40 days, 95% confidence interval [CI] 0.10-0.70; P = .008)., Conclusions: Women with HFpEF presenting to the ED were more likely to have elevated systolic blood pressure, but overall ED management strategies were similar to those in men. We observed adjusted differences in hospital LOS, but no differences in 30- and 180-day outcomes., (Copyright © 2016. Published by Elsevier Inc.)

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., Competing Interests: Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. No other disclosures were reported.

Background: A subset of patients hospitalized with acute heart failure experiences in-hospital worsening heart failure, defined as persistent or worsening signs or symptoms requiring an escalation of therapy., Methods: We analyzed data from the Acute Decompensated Heart Failure National Registry (ADHERE) linked to Medicare claims to develop and validate a risk model for in-hospital worsening heart failure. Our definition of in-hospital worsening heart failure included events such as escalation of medical therapy (eg, inotropic medications) >12hours after admission. We considered candidate risk prediction variables routinely assessed at admission, including age, medical history, biomarkers, and renal function. We used logistic regression with robust standard errors to generate a risk model in a 66% random derivation sample; we validated the model in the remaining 34%. We evaluated the calibration and discrimination of the model in both samples., Results: We evaluated 23,696 patients hospitalized with acute heart failure. Baseline characteristics were well matched in the derivation and validation samples, and the occurrence of in-hospital worsening heart failure was similar in both samples (15.4% and 15.6%, respectively). In the multivariable model, the strongest predictors of in-hospital worsening heart failure were increased troponin and creatinine. The model was well calibrated and had good discrimination in the derivation sample (c statistic, 0.74) and validation sample (c statistic, 0.72)., Conclusions: The ADHERE worsening heart failure risk model is a clinical tool with good discrimination for use in patients hospitalized with acute heart failure to identify those at increased risk for in-hospital worsening heart failure. This tool may be useful to target treatment strategies for patients at high risk for in-hospital worsening heart failure., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: This study assessed the comparative frequency of precipitating clinical factors leading to hospitalization among heart failure (HF) patients with reduced, borderline, and preserved ejection fraction (EF) BACKGROUND: There are few data assessing the comparative frequency of clinical factors leading to HF among hospitalized among patients with reduced, borderline, and preserved EF., Methods: We analyzed the factors potentially contributing to HF hospitalization among 99,825 HF admissions from 305 hospitals in the Get With The Guidelines-HF (GWTG-HF) database between January 2005 and September 2013 and assessed their association with length of stay and in-hospital mortality., Results: Mean patient age was 72.6 ± 14.2 years, 49% were female, and mean EF was 39.3 ± 17.2%. Common factors included pneumonia/respiratory process (28.2%), arrhythmia (21.7%), medication noncompliance (15.8%), worsening renal failure (14.7%), and uncontrolled hypertension (14.5%). In patients with borderline EF (EF 40% to 49%), pneumonia was associated with longer hospital stay, whereas dietary and medication noncompliance were associated with reduced length of stay. In patients with preserved EF (EF ≥50% or qualitative assessment of normal or mild dysfunction), pneumonia, weight gain, and worsening renal function were independently associated with longer lengths of stay. Worsening renal function and pneumonia were independently associated with higher in-hospital mortality in all HF groups, and acute pulmonary edema was associated with higher mortality in reduced EF. Dietary noncompliance (14.7%) was associated with reduced mortality for all groups but reached statistical significance in the subgroups of reduced (odds ratio [OR]: 0.65; 95% confidence interval [CI]: 0.46 to 0.91) and preserved systolic function (OR: 0.52; 95% CI: 0.33 to 0.83). Patients presenting with ischemia had a higher mortality rate (OR: 1.31; 95% CI: 1.02 to 1.69; and 1.72; 95% CI: 1.27 to 2.33, respectively, in the 2 groups)., Conclusions: Potential precipitating factors among patients hospitalized with HF vary by EF group and are independently associated with clinical outcomes., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

There are limited data describing outcomes associated with an elevated heart rate in patients with heart failure with reduced ejection fraction (HFrEF) in routine clinical practice. We identified patients with HFrEF at Duke University Hospital undergoing echocardiograms and heart rate assessments without paced rhythms or atrial fibrillation. Outcomes (all-cause mortality or hospitalization and medical costs per day alive) were assessed using electronic medical records, hospital cost accounting data, and national death records. Patients were stratified by heart rate (<70 and ≥70 beats/min) and compared using generalized linear models specified with gamma error distributions and log links for costs and proportional hazard models for mortality/hospitalization. Of 722 eligible patients, 582 patients (81%) were treated with β blockers. The median heart rate was 81 beats/min (25th and 75th percentiles 69 to 96) and 527 patients (73%) had a heart rate ≥70 beats/min. After multivariate adjustment, a heart rate ≥70 beats/min was associated with increased 1-year all-cause mortality or hospitalization, hazard ratio 1.37 (95% CI 1.07 to 1.75) and increased medical costs per day alive, cost ratio 2.03 (95% CI 1.53 to 2.69). In conclusion, at a large tertiary care center, despite broad use of β blockers, a heart rate ≥70 beats/min was observed in 73% of patients with HFrEF and associated with worse 1-year outcomes and increased direct medical costs per day alive., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Furosemide is the most commonly used loop diuretic in patients with heart failure (HF) despite data suggesting potential pharmacologic and antifibrotic benefits with torsemide. We investigated patients with HF in Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure who were discharged on either torsemide or furosemide. Using inverse probability weighting to account for the nonrandom selection of diuretic, we assessed the relation between choice of diuretic at discharge with 30-day mortality or HF hospitalization and 180-day mortality. Of 7,141 patients in the trial, 4,177 patients were included in this analysis, of which 87% (n = 3,620) received furosemide and 13% (n = 557) received torsemide. Torsemide-treated patients had lower ejection fraction and blood pressure and higher creatinine and natriuretic peptide level compared with furosemide. Torsemide was associated with similar outcomes on unadjusted analysis and nominally lower events on adjusted analysis (30-day mortality/HF hospitalization odds ratio 0.89, 95% CI 0.62 to 1.29, p = 0.55 and 180-day mortality hazard ratio 0.86, 95% CI 0.63 to 1.19, p = 0.37). In conclusion, these data are hypothesis-generating and randomized comparative effectiveness trials are needed to investigate the optimal diuretic choice., (Copyright © 2016 Elsevier Inc. All rights reserved.)