Search

Aims: The objective of this study was to examine associations between elevated depressive symptoms and increased risk of adverse clinical events patients with heart failure and reduced ejection fraction (HFrEF), as well as the potential contribution of health behaviours., Methods and Results: One hundred forty-two men and women with HFrEF were enrolled through heart failure (HF) clinics and followed over time. At baseline and 6 months, depressive symptoms were assessed by the Beck Depression Inventory-II (BDI-II) and HFrEF disease activity by B-type natriuretic peptide (BNP). The Self-Care of Heart Failure Index (SCHFI) was used to assess HF self-care behaviours. Proportional hazards regression models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. Over a median follow-up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10-point higher baseline BDI-II score was associated with a 35% greater risk of death or cardiovascular hospitalization. Higher baseline BDI-II scores were associated with poorer HF self-care maintenance behaviours (R = -0.30, P < 0.001) and fewer daily steps (R = -0.19, P = 0.04), suggesting that elevated depressive symptoms may diminish important health behaviours. Increases in plasma BNP over 6 months were associated with worse outcomes. Changes in BDI-II and plasma BNP over 6 months were positively related (R = 0.25, P = 0.004)., Conclusions: This study confirms that elevated depressive symptoms are associated with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Poor health behaviours may contribute to the adverse association of elevated depressive symptoms with the increased hazard of adverse clinical outcomes., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients., Methods and Results: Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin-angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12-1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78-1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86-1.02) (interaction P = .51)., Conclusions: Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients., Competing Interests: Declaration of Competing Interest K.F.D. has received financial support to attend educational meetings from Cytokinetics during the conduct of the study, personal fees from AstraZeneca, consulting fees from Us2.ai and research grants to his institution from AstraZeneca and Boehringer Ingelheim outside the submitted work. J.J.V.M. has received funding to his institution from Amgen and Cytokinetics for his participation in the Steering Committee for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities related to these trials; has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; has received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners (GCTP). R.D. has received research grants and other payment or honoraria from Amgen. G.M.F. has received grant funding to his institution from American Heart Association, Amgen, Bayer, Bristol Myers Squibb, CSL-Behring, Cytokinetics, Merck, Myokardia, and National Institutes of Health; has received consulting fees from Abbott, American Regent, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cardionomic, Cytokinetics, Medtronic, Myovant, Novartis, Reprieve, Sequana, Windtree Therapeutics, and WhiteSwell; and has participated on Data Safety Monitoring boards or advisory boards for EBR Systems, LivaNova, Medtronic, Siemens, Rocket Pharma, and V-Wave. M.M. has received funding to his institution from Amgen and Cytokinetics as participant to the Executive Committee during the trial and for patients’ enrolment; has received consulting fees for participation to advisory boards from AstraZeneca, Bayer, and Boehringer Ingelheim; has received personal fees as member of Executive or Data Monitoring Committees of sponsored clinical trials from LivaNova and Vifor Pharma; has received speaker fees from Abbott Vascular and Edwards Therapeutics for speeches at sponsored meetings; and has participated on Data Safety Monitoring boards for Actelion. S.D.S. has received grant funding to his institution from Actelion, Alnylam, Amgen, AstraZeneca, Bayer, Bellerophon, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis Pharmaceuticals, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has received consulting fees from Abbott, Action, Akros, Alnylam, American Regent, Amgen, Anacardio, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardior, Cardurion, CellProthera, Corvia, Cytokinetics, Daiichi Sankyo, Dinaqor, GlaxoSmithKline, Janssen, Lexicon, Lilly, Merck, Moderna, Myokardia, Novartis, Puretech Health, Quantum Genomics, Roche, Sanofi Pasteur, Sarepta, Tenaya, Theracos, and Tremeau. K.F.A. has received research grants from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim Pharmaceuticals Inc., Eli Lilly USA, LivaNova USA, Merck, Novartis, and Otsuka; acted as a consultant to Amgen, Cytokinetics, Inc., Novartis, Roche Diagnostics, Relypsa, and Windtree Therapeutics. M.B. has received funds from the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project No. 322900939) and personal fees from Abbott, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cytokinetics, Medtronic, Novartis, ReCor, Servier, Vifor Pharma, and Boehringer Ingelheim. A.R.G. reports consulting fees for clinical trials from Amgen, Novartis, KOWA, and Bayer outside the submitted work; personal payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk outside the submitted work; support for attending meetings and/or travel from Pfizer, AstraZeneca, and Boehringer Ingelheim; and leadership or fiduciary role as President, Bulgarian Society of Cardiology 2020-22. J.G.H. has received grants and consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, and Pfizer; has received personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, and Pfizer; and is Co-Chair of the Heart Failure Pathway Group of the Province of Alberta, Heart Failure lead at University of Calgary, and in the Canadian Cardiovascular Society Guidelines and Development Committees. M.L. has received grant funding and personal fees from Amgen; has received honoraria from Novartis; and has served as the New Zealand Chairperson for Cardiac Society Australia and New Zealand. P.P. has received research grants to his institution from Amgen and Vifor Pharma; and has received consulting fees or honoraria from Abbott Vascular, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Cibiem, Coridea, Impulse Dynamics, Novartis, Pfizer, Renal Guard Solutions, Servier, and Vifor Pharma. M.B.Y. reports funding to his institution from Amgen, Bayer, Novartis, and Dalcor Pharmaceuticals outside the submitted work. F.Z. reports consulting fees from Cardior, Cereno pharmaceutical, Cellprothera, Owkin, Novo Nordisk, Vifor, and Fresenius; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer and Bayer; payment for expert testimony from Cardiorentis; stock or stock options in Cereno pharmaceutical; and steering committee personal fees from Applied Therapeutics, Amgen, Bayer, Boehringer, CVRx, Novartis, and Merck. B.L.C. has received consulting fees from Amgen, Cardurion, Corvia, Myokardia, and Novartis. Z.M.M. has no conflicts of interest to disclose. S.A.A. is an employee and shareholder of Amgen. P.H.D., S.B.H., S.K., and F.I.M. are employees and shareholders of Cytokinetics. J.R.T. has received personal fees as Chairperson of the GALACTIC-HF Executive Committee from Amgen and Cytokinetics; has received personal fees for research contracts and/or consulting fees from 3ive Labs, Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Medtronic, Merck, Novartis, Verily, ViCardia, and Windtree Therapeutics; has served as Secretary and Treasurer of Heart Failure Society of America; and is currently President-Elect of the Heart Failure Society of America. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: We sought to determine whether circulating modifiers of endothelial function are associated with cardiac structure and clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF)., Methods: We measured 25 proteins related to endothelial function in 99 patients from the GUIDE-IT study. Protein levels were evaluated for association with echocardiographic parameters and the incidence of all-cause death and hospitalization for heart failure (HHF)., Results: Higher concentrations of angiopoietin 2 (ANGPT2), vascular endothelial growth factor receptor 1 (VEGFR1) and hepatocyte growth factor (HGF) were significantly associated with worse function and larger ventricular volumes. Over time, decreases in ANGPT2 and, to a lesser extent, VEGFR1 and HGF, were associated with improvements in cardiac size and function. Individuals with higher concentrations of ANGPT2, VEGFR1 or HGF had increased risks for a composite of death and HHF in the following year (HR 2.76 (95% CI 1.73-4.40) per 2-fold change in ANGPT2; HR 1.76 (95% CI 1.11-2.79) for VEGFR1; and HR 4.04 (95% CI 2.19-7.44) for HGF)., Conclusions: Proteins related to endothelial function associate with cardiac size, cardiac function and clinical outcomes in patients with HFrEF. These results support the concept that endothelial function may be an important contributor to the progression to and the recovery from HFrEF., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Omecamtiv mecarbil improves cardiovascular outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Consistency of drug benefit across race is a key public health topic., Objectives: The purpose of this study was to evaluate the effect of omecamtiv mecarbil among self-identified Black patients., Methods: In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) patients with symptomatic HF, elevated natriuretic peptides, and left ventricular ejection fraction (LVEF) ≤35% were randomized to omecamtiv mecarbil or placebo. The primary outcome was a composite of time to first event of HF or cardiovascular death. The authors analyzed treatment effects in Black vs White patients in countries contributing at least 10 Black participants., Results: Black patients accounted for 6.8% (n = 562) of overall enrollment and 29% of U.S. enrollment. Most Black patients enrolled in the United States, South Africa, and Brazil (n = 535, 95%). Compared with White patients enrolled from these countries (n = 1,129), Black patients differed in demographics, comorbid conditions, received higher rates of medical therapy and lower rates of device therapies, and experienced higher overall event rates. The effect of omecamtiv mecarbil was consistent in Black vs White patients, with no difference in the primary endpoint (HR = 0.83 vs 0.88, P-interaction = 0.66), similar improvements in heart rate and N-terminal pro-B-type natriuretic peptide, and no significant safety signals. Among endpoints, the only nominally significant treatment-by-race interaction was the placebo-corrected change in blood pressure from baseline in Black vs White patients (+3.4 vs -0.7 mm Hg, P for interaction = 0.02)., Conclusions: GALACTIC-HF enrolled more Black patients than other recent HF trials. Black patients treated with omecamtiv mecarbil had similar benefit and safety compared with White counterparts., Competing Interests: Funding Support and Author Disclosures The GALACTIC-HF trial was funded by Amgen (Thousand Oaks, California, USA), Cytokinetics, Inc (South San Francisco, California, USA), and Servier Laboratories (Suresnes, France). Prof Lanfear has received research funding or support from the National Institutes of Health (P50MD017351), Amgen, AstraZeneca, Eli Lilly, and SomaLogic; and has acted as consultant to ACI Clinical (Abbott Laboratories), Cytokinetics, Duke Clinical Research Institute (CONNECT-HF), Illumina, Janssen, Martin Pharmaceuticals, Ortho Clinical Diagnostics, Otsuka, and Vicardia. Dr Adams has received research grants from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim Pharmaceuticals Inc, Eli Lilly USA, LivaNova USA, Merck, Novartis, and Otsuka; and acted as a consultant to Amgen, Cytokinetics Inc, Novartis, Roche Diagnostics, Relypsa, and Windtree Therapeutics. Dr Anand has received personal fees from Amgen during the conduct of the study; and has received personal fees from ARCA Biopharma, Boehringer Ingelheim, Boston Scientific, Novartis, and Zensun outside the submitted work. Dr Fang serves on the Board of Directors for the Heart Failure Society of America; and has received consulting fees from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics Inc, Novartis, and Windtree Therapeutics. Dr Diaz has received research grants and/or consulting fees from Amgen, Cytokinetics Inc, and Servier Laboratories. Dr Felker has received grant funding to his institution from Amgen, Bayer, Cytokinetics Inc, Merck, and MyoKardia; has received consulting fees from Abbott, American Regent, Amgen, AstraZeneca, Becton Dickinson, Boehringer Ingelheim, Bristol-Myers Squibb, Cardionomic, Cytokinetics Inc, Medtronic, Novartis, and Sequana; and has served on the Board of Directors for the Heart Failure Society of America. Dr McMurray has received consulting fees paid to his institution from Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardialysis, Cardurion, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Merck, Novartis, Pfizer, and Theracos. Dr Metra has received honoraria from AstraZeneca, Abbott Vascular, Amgen, and Edwards Therapeutics; and personal fees for presentations/participation on a Data Safety Monitoring Board/Advisory Board from Actelion, Amgen, LivaNova, Servier, Vifor Pharma, and Windtree Therapeutics. Dr Solomon has received grants from Celladon, Eidos, Ionis, Lone Star Heart, Mesoblast, National Institutes of Health/National Heart, Lung, and Blood Institute, and Sanofi Pasteur; has received grants and personal fees from Alnylam, Amgen, AstraZeneca, Bayer, Bellerophon, Bristol-Myers Squibb, Cytokinetics Inc, Gilead, GlaxoSmithKline, MyoKardia, Novartis, and Theracos; and has received personal fees from Akros, AoBiome, Arena, Cardiac Dimensions, Cardior, Cardurion, Corvia, Daiichi-Sankyo, Dinaqor, Ironwood, Janssen, Merck, Moderna, Quantum Genomics, Roche, Takeda, and Tenaya. Dr Claggett has received consulting fees from Amgen, Cardurion, Corvia, and MyoKardia. Drs Heitner, Kupfer, and Malik are employed by and receive stock options from Cytokinetics, Inc. Dr Teerlink has received personal fees as Chairperson of the GALACTIC-HF Executive Committee from Amgen and Cytokinetics; has received personal fees for research contracts and/or consulting fees from 3ive Labs, Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardurion, Medtronic, Merck, Novartis, Verily, ViCardia, and Windtree Therapeutics; has served as Secretary and Treasurer of the Heart Failure Society of America; and is currently President-Elect of the Heart Failure Society of America. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is predictive of both outcomes and response to treatment in patients with heart failure with reduced ejection fraction (HFrEF). The aim of this study was to examine the effect of the cardiac myosin activator omecamtiv mecarbil according to baseline NT-proBNP level in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure trial (GALACTIC-HF)., Methods and Results: The primary outcome was the composite of a worsening heart failure event (urgent clinic visit, emergency department visit, or hospitalization) or cardiovascular death. We prespecified analysis of the effect of treatment according to baseline NT-proBNP (≤ median, > median), excluding individuals with atrial fibrillation/flutter (AF/AFL). Of the 8232 patients analysed, 8206 had an available baseline NT-proBNP measurement. Among the 5971 patients not in AF/AFL, the median (Q1-Q3) NT-proBNP level was 1675 (812-3579) pg/ml. Hazard ratios (HR) for the effect of omecamtiv mecarbil, compared with placebo, for the primary endpoint in patients without AF/AFL were: ≤ median 0.94 (95% confidence interval [CI] 0.80-1.09), > median 0.81 (0.73-0.90) (p-interaction = 0.095); for the overall population (including patients with AF/AFL) the HRs were ≤ median 1.01 (0.90-1.15) and > median 0.88 (0.80-0.96) (p-interaction = 0.035). There was an interaction between treatment and NT-proBNP, examined as a continuous variable, with greater effect of omecamtiv mecarbil on the primary outcome in patients with a higher baseline NT-proBNP (p-interaction = 0.086)., Conclusions: In GALACTIC-HF, the benefit of omecamtiv mecarbil appeared to be larger in patients with higher baseline NT-proBNP levels, especially in patients without AF/AFL., Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02929329; EudraCT number, 2016-002299-28., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Previous studies have suggested that the neutrophil-to-lymphocyte ratio (NLR) is a novel yet readily evaluable inflammatory biomarker that may be useful for determining cardiovascular prognosis during acute episodes. The study investigated the role of NLR in predicting cardiovascular (CV) outcomes in patients with acute heart failure (HF). Individual patient data from the BLAST-AHF (phase 2b study of the biased ligand of the angiotensin 2 type 1 receptor, TRV027), Pre-RELAX-AHF (phase 2b study of recombinant human relaxin-2, serelaxin), and RELAX-AHF (phase 3 study of serelaxin) randomized, placebo-controlled studies for patients with acute HF were pooled for analysis. Dyspnea visual analog scale area under the curve through day 5, worsening HF through day 5, 30-day all-cause mortality, 60-day HF/renal failure rehospitalizations or CV death, 180-day all-cause mortality, and 180-day CV death were assessed. There were several differences in the baseline characteristics of the patients divided by NLR tertile, with patients in the higher NLR having worse clinical characteristics. NLR was an independent predictor of 30-day all-cause mortality (adjusted hazard ratio [HR] per log 2 NLR increment: 1.66 [1.22 to 2.25], p = 0.001), 60-day HF/renal failure rehospitalizations or CV death: 1.33 [1.12 to 1.57], p = 0.001), 180-day all-cause mortality (adjusted HR 1.27 [1.08 to 1.50], p = 0.003), and 180-day CV death (adjusted HR 1.24 [1.04 to 1.49], p = 0.018). NLR, a readily available inflammatory biomarker, was associated with independent risk for short- and long-term adverse outcomes in acute HF, surpassing traditional markers, such as natriuretic peptides., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: β-Blockers (BBs) are mainstay therapy for heart failure with reduced ejection fraction. However, individual patient responses to BB vary, which may be partially due to genetic variation. The goal of this study was to derive and validate the first polygenic response predictor (PRP) for BB survival benefit in heart failure with reduced ejection fraction patients., Methods: Derivation and validation analyses were performed in n=1436 total HF patients of European descent and with ejection fraction <50%. The PRP was derived in a random subset of the Henry Ford Heart Failure Pharmacogenomic Registry (n=248) and then validated in a meta-analysis of the remaining patients from Henry Ford Heart Failure Pharmacogenomic Registry (n=247), the TIME-CHF (Trial of Intensified Versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure; n=431), and HF-ACTION trial (Heart Failure: a Controlled Trial Investigating Outcomes of Exercise Training; n=510). The PRP was constructed from a genome-wide analysis of BB×genotype interaction predicting time to all-cause mortality, adjusted for Meta-Analysis Global Group in Chronic Heart Failure score, genotype, level of BB exposure, and BB propensity score., Results: Five-fold cross-validation summaries out to 1000 single-nucleotide polymorphisms identified optimal prediction with a 44 single-nucleotide polymorphism score and cutoff at the 30th percentile. In validation testing (n=1188), greater BB exposure was associated with reduced all-cause mortality in patients with low PRP score (n=251; hazard ratio, 0.19 [95% CI, 0.04-0.51]; P =0.0075) but not high PRP score (n=937; hazard ratio, 0.84 [95% CI, 0.53-1.3]; P =0.448)-a difference that was statistically significant ( P interaction, 0.0235). Results were consistent regardless of atrial fibrillation, ejection fraction (≤40% versus 41%-50%), or when examining cardiovascular death., Conclusions: Among patients of European ancestry with heart failure with reduced ejection fraction, a PRP distinguished patients who derived substantial survival benefit from BB exposure from a larger group that did not. Additional work is needed to prospectively test clinical utility and to develop PRPs for other population groups and other medications.

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial. Here we describe the baseline characteristics of participants in GALACTIC-HF and how these compare with other contemporary trials., Methods and Results: Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic-guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non-white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N-terminal pro-B-type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC-HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m 2 (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594)., Conclusions: GALACTIC-HF enrolled a well-treated, high-risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Underuse of hydralazine/nitrate (HYD/NIT) in black patients with heart failure and reduced ejection fraction (HFrEF) has been previously described, but whether this important treatment gap persists in contemporary practice is unknown. Sacubitril/valsartan has become a part of guideline-directed medical therapy for HFrEF but data on utilization of this therapy in black patients is lacking. This study addressed these issues by assessing the frequency of HYD/NIT and sacubitril/valsartan use in black patients with HFrEF in the Change the Management of Patients with Heart Failure Registry, a multicenter cohort study. The association of race with utilization rates of these agents was also evaluated. Clinical and medication data at baseline and during 12 months of follow-up from black and nonblack registry patients without documented contraindications or intolerance to the medications of interest were analyzed. Data were available from December 2015 to October 2017, in 4,848 HFrEF patients, of whom 853 were black (18%) and 3995 were nonblack. Black patients were younger, more likely to be female, and had lower ejection fractions compared with nonblacks. Only 11% of black patients were receiving HYD/NIT therapy at baseline and 13% at 1 year. The percentage of black patients treated at baseline with sacubitril/valsartan was also low at 18% and remained unchanged at 1 year. After adjustment for covariates, race was independently associated with HYD/NIT use (odds ratio 8.32; 95% confidence interval 6.12 to 11.3; p < 0.0001), but not for sacubitril/valsartan. In conclusion, study findings demonstrate a marked persistent treatment gap for HYD/NIT and similar poor utilization of sacubitril/valsartan in black patients with HFrEF despite current guideline recommendations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial demonstrated that a strategy to "guide" application of guideline-directed medical therapy (GDMT) by reducing amino-terminal pro-B-type natriuretic peptide (NT-proBNP) was not superior to GDMT alone., Objectives: The purpose of this study was to examine the prognostic meaning of NT-proBNP changes following heart failure (HF) therapy intensification relative to the goal NT-proBNP value of 1,000 pg/ml explored in the GUIDE-IT trial., Methods: A total of 638 study participants were included who were alive and had available NT-proBNP results 90 days after randomization. Rates of subsequent cardiovascular (CV) death/HF hospitalization or all-cause mortality during follow-up and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall scores were analyzed., Results: A total of 198 (31.0%) subjects had an NT-proBNP ≤1,000 pg/ml at 90 days with no difference in achievement of NT-proBNP goal between the biomarker-guided and usual care arms. NT-proBNP ≤1,000 pg/ml by 90 days was associated with longer freedom from CV/HF hospitalization or all-cause mortality (p < 0.001 for both) and lower adjusted hazard of subsequent HF hospitalization/CV death (hazard ratio: 0.26; 95% confidence interval: 0.15 to 0.46; p < 0.001) and all-cause mortality (hazard ratio: 0.34; 95% confidence interval: 0.15 to 0.77; p = 0.009). Regardless of elevated baseline concentration, an NT-proBNP ≤1,000 pg/ml at 90 days was associated with better outcomes and significantly better KCCQ overall scores (p = 0.02)., Conclusions: Patients with heart failure with reduced ejection fraction whose NT-proBNP levels decreased to ≤1,000 pg/ml during GDMT had better outcomes. These findings may help to understand the results of the GUIDE-IT trial. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure., Methods: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days., Results: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups., Conclusions: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.)., (Copyright © 2019 Massachusetts Medical Society.)

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

The term "inotrope" is familiar and intimately connected with pharmaceuticals clinically used for treatment of low cardiac output with cardiogenic shock. Traditional inotropic agents exert their effect by modulating calcium signaling in the myocardium. Their use is associated with poor long-term outcomes. Newer molecules in development intend to break from calcium mediation and the associated detrimental long-term effects by targeting distinct mechanisms of action to improve cardiac performance. Thus, "inotropy" does not sufficiently describe the range of potential novel pharmaceutical products. To enhance communication around and evaluation of current, emerging, and potential therapies, this review proposes a novel nuanced and holistic framework to categorize pharmacological agents that improve myocardial performance based on 3 myocardial mechanisms: calcitropes, which alter intracellular calcium concentrations; myotropes, which affect the molecular motor and scaffolding; and mitotropes, which influence energetics. Novel chemical entities can easily be incorporated into this structure, distinguishing themselves based on their mechanisms and clinical outcomes., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial prospectively compared the efficacy of an N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided heart failure treatment strategy (target NT-proBNP level <1,000 pg/ml) with optimal medical therapy alone in high-risk patients with heart failure and reduced ejection fraction. When the study was stopped for futility, 894 patients had been enrolled., Objectives: The purpose of this study was to assess treatment-related quality-of-life (QOL) and economic outcomes in the GUIDE-IT trial., Methods: The authors prospectively collected a battery of QOL instruments at baseline and 3, 6, 12, and 24 months post-randomization (collection rates 90% to 99% of those eligible). The principal pre-specified QOL measures were the Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and the Duke Activity Status Index (DASI). Cost data were collected for 735 (97%) U.S., Results: Baseline variables were well balanced in the 446 patients randomized to the NT-proBNP-guided therapy and 448 to usual care. Both the KCCQ and the DASI improved over the first 6 months, but no evidence was found for a strategy-related difference (mean difference [biomarker-guided - usual care] at 24 months of follow-up 2.0 for DASI [95% confidence interval (CI): -1.3 to 5.3] and 1.1 for KCCQ [95% CI: -3.7 to 5.9]). Total winsorized costs averaged $5,919 higher in the biomarker-guided strategy (95% CI: -$1,795, +$13,602) over 15-month median follow-up., Conclusions: A strategy of NT-proBNP-guided HF therapy had higher total costs and was not more effective than usual care in improving QOL outcomes in patients with heart failure and a reduced ejection fraction. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840)., (Copyright © 2018 American College of Cardiology Foundation. All rights reserved.)

Objectives: The goal of this study was to test the effects of long-chain omega-3 fatty acid supplementation on omega-3 levels, depressive symptoms, and other psychosocial factors, as well as other chronic heart failure (CHF)-related functional measures., Background: Patients with CHF and depression had low blood omega-3 concentrations that were associated with an elevated risk of mortality., Methods: This study was a randomized, double-blind, placebo-controlled pilot clinical trial using a 400/200 eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) fish oil at 2 g and an almost pure EPA at 2 g, compared with a matched placebo, daily for 12 weeks for patients with CHF and major depressive disorder. Statistical analyses included the intention-to-treat population and "completers" (defined as participants consuming ≥70% of the capsules and completing the final endpoint evaluation between 10 and 14 weeks)., Results: A total of 108 patients with CHF and major depressive disorder and a score ≥18 on the Hamilton Depression Scale who were randomized at 1:1:1 to the 3 interventions at 3 enrolling centers from June 12, 2014, to May 19, 2016; 80 (74.1%) qualified as completers. Intention-to-treat analyses revealed that the levels of all omega-3 variables were significantly elevated in the omega-3 groups, whereas the placebo group showed little change; there were no between-group differences with overall depression measurements. Per-protocol exploratory analyses showed that scores on the social functioning measurement of the 36-item Short Form Health Survey improved notably in the 400/200 EPA/DHA (p = 0.040) and EPA (p = 0.10) groups compared with the placebo group. Spearman correlation analysis indicated that increased omega-3 indices were associated with improved cognitive depressive symptoms., Conclusions: Omega-3 supplementation resulted in significant increases in omega-3 levels in red blood cell counts, corresponding to a particular compound of omega-3. Changes in cognitive depressive symptoms and social function were in favor of the omega-3 supplementation. Further studies with larger sample sizes are necessary to confirm the benefits of omega-3 supplementation on modifying psychosocial factors for patients with CHF. (Omega-3 Supplementation for Co-Morbid Depression and Heart Failure Treatment [OCEAN]; NCT02057406)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background In heart failure (HF) with reduced ejection fraction, 2 clinical trials, the BEST (β-Blocker Evaluation of Survival Trial) and HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), have reported an effectiveness interaction between the ADRB1 (β-1 adrenergic receptor) Arg389Gly polymorphism and β-blockers (BBs). HF-ACTION additionally reported a dose-related interaction of unclear origin. If confirmed and pharmacogenetically resolved, these findings may have important implications for HF with reduced ejection fraction precision therapy. We used uniform methodology to investigate BB dose-ADRB1 Arg389Gly polymorphism interaction with major clinical end points in BEST/bucindolol and HF-ACTION/other BB databases. Methods This was a retrospective analysis of prospectively designed DNA substudies from BEST (N=1040) and HF-ACTION (N=957). Subjects were genotyped for ADRB1 Arg389Gly and ADRA2C (α2C adrenergic receptor) Ins322-325Del. BB dose was defined as either no/low dose or high dose, according to total daily dose of either bucindolol (BEST subjects) or other BB (HF-ACTION subjects) standardized to carvedilol equivalents. The main outcome of interest was all-cause mortality, and CV mortality/HF hospitalization was a secondary outcome. Results Subjects in each trial had less all-cause mortality with high- versus no/low-dose BB if they had ADRB1 Arg389Arg (BEST: hazard ratio [HR]=0.40, P=0.002; HF-ACTION: HR=0.45, P=0.005) but not Arg389Gly genotype (both P>0.2). Among gene-dose groups, there was a differential favorable treatment effect of 46% for high-dose bucindolol with ADRB1 Arg389Arg versus Gly carrier genotype (HR, 0.54; P=0.018), but not for no/low-dose bucindolol. In contrast, HF-ACTION Arg389Arg genotype subjects taking no/low-dose BB had greater all-cause mortality compared with 389Gly carriers (HR, 1.83; P=0.015), whereas all-cause mortality did not vary by genotype among subjects taking high-dose BB (HR, 0.84; P=0.55). Conclusions The enhanced HF with reduced ejection fraction efficacy of bucindolol in the ADRB1 Arg389Arg versus 389Gly carrier genotypes occurs at high dose. Other BBs taken at low dose have reduced efficacy for Arg389Arg genotype subjects compared with 389Gly carriers, suggesting a greater relative treatment effect at high dose. These data support guideline recommendations to use high, clinical trial target doses of all BBs to treat HF with reduced ejection fraction.

Natriuretic peptides (NPs) are recommended by international guidelines to exclude non-heart failure causes of acute dyspnea and to assess prognosis. NPs are commonly used as an entry criterion for clinical trials, to minimize enrollment of misdiagnosed patients, or to ensure enrollment of a sufficiently at-risk population. NP values used to select trial populations to date have been inconsistent across studies. Future trials should consider using standardized thresholds for NP levels, with protocol-specified adaptations appropriate for the specific study and patient population to account for factors that can influence the NP level. NPs have been used as an endpoint for proof-of-concept or phase 2 clinical trials, although it is important to remember that positive results in early phase studies may be unstable due to small numbers and the play of chance, and they are not always reproducible in phase 3 trials. Likewise, failure to reduce NP in phase 2 may not necessarily indicate that a drug will be ineffective on clinical outcomes in phase 3. NP guided therapy has been intensively studied, but the clinical outcome benefits of this approach remain uncertain. Neprilysin inhibitors have stimulated further exploration of the NP system and how it influences, and is potentially influenced by, heart failure therapies. This paper discusses the utility of NPs in the current clinical research and practice environment and addresses areas in need of further research from the perspectives of academic clinical trialists, clinicians, biostatisticians, regulators, and pharmaceutical industry scientists who participated in the 13th Global Cardiovascular Clinical Trialists Forum., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study sought to determine the relationship between growth differentiation factor (GDF)-15 and clinical outcomes in ambulatory patients with heart failure and reduced ejection fraction (HFrEF)., Background: The prognostic utility of GDF-15, a member of the transforming growth factor-β cytokine family, among patients with HF is unclear., Methods: We assessed GDF-15 levels in 910 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial, a randomized clinical trial of exercise training in patients with HFrEF. Median follow-up was 30 months. Cox proportional hazard models assessed the relationships between GDF-15 and clinical outcomes., Results: The median GDF-15 concentration was 1,596 pg/ml. Patients in the highest tertile of GDF-15 were older and had measurements of more severe HF (higher N-terminal pro-B-type natriuretic peptide [NT-proBNP] concentrations and lower peak oxygen uptake on cardiopulmonary exercise testing [CPX]). GDF-15 therapy was a significant predictor of all-cause death (unadjusted hazard ratio [HR]: 2.03 when GDF-15 was doubled; p < 0.0001). This association persisted after adjustment for demographic and clinical and biomarkers including high sensitivity troponin T (hs-TnT) and NT-proBNP (HR: 1.30 per doubling of GDF-15; p = 0.029). GDF-15 did not improve discrimination (as measured by changes in c-statistics and the integrated discrimination improvement) in addition to baseline variables, including hs-TnT and NT-proBNP or variables found in CPX testing., Conclusions: In demographically diverse, well-managed patients with HFrEF, GDF-15 therapy provided independent prognostic information in addition to established predictors of outcomes. These data support a possible role for GDF-15 in the risk stratification of patients with chronic HFrEF. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Cardiovascular (CV) reactivity to psychological stress has been implicated in the development and exacerbation of cardiovascular disease (CVD). Although high CV reactivity traditionally is thought to convey greater risk of CVD, the relationship between reactivity and clinical outcomes is inconsistent and may depend on the patient population under investigation. The present study examined CV reactivity in patients with heart failure (HF) and its potential association with long-term clinical outcomes., Methods: One hundred ninety-nine outpatients diagnosed with HF, with ejection fraction ≤40%, underwent an evaluation of blood pressure (BP) and heart rate reactivity to a laboratory-based simulated public-speaking stressor. Cox proportional hazards regression models were used to examine the prospective association between BP and heart rate reactivity on a combined end point of death or CV hospitalization over a 5-year median follow-up period., Results: Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) reactivity, quantified as continuous variables, were inversely related to risk of death or CV hospitalization (Ps < .01) after controlling for established risk factors, including HF disease severity and etiology. In similar models, heart rate reactivity was unrelated to outcome (P = .12). In models with tertiles of reactivity, high SBP reactivity, compared with intermediate SBP reactivity, was associated with lower risk (hazard ratio [HR] = .498, 95% CI .335-.742, P =.001), whereas low SBP reactivity did not differ from intermediate reactivity. For DBP, high reactivity was marginally associated with lower risk compared with intermediate DBP reactivity (HR = .767, 95% CI .515-1.14, P =.193), whereas low DBP reactivity was associated with greater risk (HR = 1.49, 95% CI 1.027-2.155, P =.0359). No relationship of heart rate reactivity to outcome was identified., Conclusions: For HF patients with reduced ejection fraction, a robust increase in BP evoked by a laboratory-based psychological challenge was associated with lower risk for adverse CVD events and may be a novel and unique marker of left ventricular systolic reserve that is accompanied by a more favorable long-term prognosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Importance: The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ("guided therapy") with inconsistent results., Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF)., Design, Settings, and Participants: The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP-guided strategy or usual care., Interventions: Patients were randomized to either an NT-proBNP-guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/mL. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group., Main Outcomes and Measures: The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events., Results: The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79-1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65-1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups., Conclusions and Relevance: In high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy was not more effective than a usual care strategy in improving outcomes., Trial Registration: clinicaltrials.gov Identifier: NCT01685840.

Heart failure is well recognized as a major public health concern not only due to severe and frequent adverse health outcomes but also related to the major financial burden this syndrome presents with advancing age in Western societies. Despite the dire need for more efficacious therapies and better application of existing advances, treatment gaps persist, and outcomes in heart failure remain poor, with continually high mortality and morbidity. Treatment guidelines provide one strategy for advancing quality of care in patients with heart failure. This approach, with well-known potential strengths and weaknesses, has both adherents and detractors. Heart failure treatment guidelines have been in sharp focus recently due to updates that address the United States Food and Drug Administration (FDA) approval in 2015 of two new pharmacologic therapies for heart failure with reduced ejection fraction: sacubitril-valsartan and ivabradine. Our commentary will revisit issues in guideline methodology and discuss these in the context of the updates addressing the FDA approval of new pharmacologic agents for heart failure with reduced ejection fraction., (© 2017 Pharmacotherapy Publications, Inc.)

Background: The oral vasopressin-2 receptor antagonist tolvaptan causes aquaresis in patients with volume overload, potentially facilitating decongestion and improving the clinical course of patients with acute heart failure (AHF)., Objectives: The TACTICS-HF (Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure) study was conducted to address the acute use of tolvaptan to improve congestion in AHF., Methods: The TACTICS-HF study randomized patients (n = 257) within 24 h of AHF presentation in a prospective, double blind, placebo-controlled trial. Patients were eligible regardless of ejection fraction, and were randomized to either 30 mg of tolvaptan or placebo given at 0, 24, and 48 h, with a fixed-dose furosemide regimen as background therapy. The primary endpoint was the proportion of patients considered responders at 24 h. Secondary endpoints included symptom improvement, changes in renal function, and clinical events., Results: Dyspnea relief by Likert scale was similar between groups at 8 h (25% moderately or markedly improved with tolvaptan vs. 28% placebo; p = 0.59) and at 24 h (50% tolvaptan vs. 47% placebo; p = 0.80). Need for rescue therapy was also similar at 24 h (21% tolvaptan, 18% placebo; p = 0.57). The proportion defined as responders at 24 h (primary study endpoint) was 16% for tolvaptan and 20% for placebo (p = 0.32). Tolvaptan resulted in greater weight loss and net fluid loss compared with placebo, but tolvaptan-treated patients were more likely to experience worsening renal function during treatment. There were no differences in in-hospital or post-discharge clinical outcomes., Conclusions: In patients hospitalized with AHF, dyspnea, and congestion, the addition of tolvaptan to a standardized furosemide regimen did not improve the number of responders at 24 h, despite greater weight loss and fluid loss. (Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure [TACTICS-HF]; NCT01644331)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) is a chronic disease that compromises patients' quality of life (QoL). Interventions designed to reduce distress and improve disease self-management are needed. We evaluated the efficacy of a telephone-based coping skills training (CST) intervention., Methods and Results: This randomized clinical trial involved 180 HF outpatients with reduced ejection fraction. Participants ranged in age from 29 to 87 years (mean=58 years); 27% were women, and 47% were nonwhite. Participants were randomized to either a CST intervention or heart failure education, both delivered over 16 weeks. The primary outcomes were (1) postintervention effects on QoL and HF disease biomarkers (both with α=0.01), and (2) a composite measure of time to death or first hospitalization (with α=0.03) over a median follow-up period of 3 years. CST resulted in greater improvements in QoL compared with heart failure education (P<0.01), including the Kansas City Cardiomyopathy Questionnaire (P=0.009), depressive symptoms (P=0.027), and the 6-minute walk test (P=0.012). However, it did not differentially improve HF disease biomarkers or reduce risk of all-cause hospitalizations or death (hazard ratio=0.84 [95% confidence interval, 0.59-1.12]). Interestingly, exploratory analyses showed that participants randomized to CST experienced a reduction in the composite end point of worsening HF hospitalization or death during the 3-year follow-up period (hazard ratio=0.65 [95% confidence interval, 0.44-0.98]; P=0.040)., Conclusions: CST improved QoL in patients with HF. Monitoring and improving QoL is emerging as an important aspect of the clinical management of HF that can reduce disease burden and may help improve clinical outcomes in this vulnerable patient population., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00873418., Competing Interests: None., (© 2017 American Heart Association, Inc.)

Background: Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil., Methods: In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials.gov, number NCT01786512., Findings: From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fixed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18-32, p<0·0001), stroke volume 3·6 mL (0·5-6·7, p=0·0217), left ventricular end-systolic diameter -1·8 mm (-2·9 to -0·6, p=0·0027), left ventricular end-diastolic diameter -1·3 mm, (-2·3 to 0·3, p=0·0128), heart rate -3·0 beats per min (-5·1 to -0·8, p=0·0070), and N-terminal pro B-type natriuretic peptide concentration in plasma -970 pg/mL (-1672 to -268, p=0·0069). The frequency of adverse clinical events did not differ between groups., Interpretation: Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter., Funding: Amgen., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aims: Many patients with heart failure and reduced EF remain at high risk for hospitalization despite evidence-based therapy. Digoxin may decrease hospitalization; however, uncertainty persists concerning its proper administration and effect on mortality. This study investigated whether using dose response concepts to re-evaluate the relationship between serum digoxin concentration and key mortality outcomes in patients with reduced EF in the Digitalis Investigation Group trial would help clarify efficacy and safety., Methods and Results: Multivariable Cox proportional hazards modelling and propensity score adjustment assessed the relationship between serum digoxin concentration (≥0.5 ng/mL) as a continuous variable and mortality outcomes. In patients treated with digoxin, a significant linear association was found between serum concentration and all-cause mortality [adjusted hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.14-1.38, P < 0.001 per 0.5 ng/mL increase in serum concentration]. Based on this relationship, a bidirectional association was found between digoxin therapy and all-cause mortality when compared with placebo. The lowest serum concentrations (0.5-0.7 ng/mL) were associated with the lowest risk of all-cause mortality (adjusted HR 0.77, 95% CI 0.67-0.89, P < 0.001) while high serum concentrations (1.6-2.0 ng/mL) were associated with increased mortality (adjusted HR 1.33, 95% CI 1.12-1.58, P = 0.001). Consistent with this finding, lower serum concentrations (0.5-0.7 ng/mL) were associated with reduced death from worsening heart failure and a neutral effect on cardiovascular death not due to worsening heart failure., Conclusion: These findings favour targeting serum concentrations from 0.5 to 0.7 ng/mL when dosing digoxin in patients with heart failure and reduced EF., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Introduction: Impaired endothelial function, as assessed by brachial artery flow-mediated dilation (FMD), is an established risk factor for cardiovascular events. FMD is impaired in heart failure (HF) patients, but less is known about hyperemic brachial artery flow. We investigated the relationship between FMD and hyperemic flow with adverse clinical outcomes in HF patients., Methods: Brachial artery FMD and hyperemic flow were assessed in 156 patients (70.5 % Male; 45.5% Caucasian; mean age (± SD) = 56.2 (±12.4) years) with HF and reduced left ventricular ejection fraction (LVEF). Cox proportional hazard models were used to assess the potential explanatory association of FMD and hyperemic flow with the composite outcome of death or cardiovascular hospitalization over a median 5-year follow-up period., Results: Both FMD and hyperemic flow were negatively correlated with age, but unrelated to sex, race, body mass index, LVEF or N-terminal pro-B-Type natriuretic peptide (NT-ProBNP). Reduced hyperemic flow, but not FMD, was associated with an increased risk of death or cardiac hospitalization after controlling for traditional risk factors., Conclusion: The association of reduced hyperemic flow with increased risk of adverse clinical outcomes suggests that micro-vascular function may be an important prognostic marker in patients with HF., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Congestion is a primary reason for hospitalization in patients with acute heart failure (AHF). Despite inpatient diuretics and vasodilators targeting decongestion, persistent congestion is present in many AHF patients at discharge and more severe congestion is associated with increased morbidity and mortality. Moreover, hospitalized AHF patients may have renal insufficiency, hyponatremia, or an inadequate response to traditional diuretic therapy despite dose escalation. Current alternative treatment strategies to relieve congestion, such as ultrafiltration, may also result in renal dysfunction to a greater extent than medical therapy in certain AHF populations. Truly novel approaches to volume management would be advantageous to improve dyspnea and clinical outcomes while minimizing the risks of worsening renal function and electrolyte abnormalities. One effective new strategy may be utilization of aquaretic vasopressin antagonists. A member of this class, the oral vasopressin-2 receptor antagonist tolvaptan, provides benefits related to decongestion and symptom relief in AHF patients. Tolvaptan may allow for less intensification of loop diuretic therapy and a lower incidence of worsening renal function during decongestion. In this article, we summarize evidence for decongestion benefits with tolvaptan in AHF and describe the design of the Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure Study (TACTICS) and Study to Evaluate Challenging Responses to Therapy in Congestive Heart Failure (SECRET of CHF) trials., (© 2015 American Heart Association, Inc.)

Background: Current heart failure (HF) risk prediction models do not consider how individual patient assessments occur in incremental steps; furthermore, each additional diagnostic evaluation may add cost, complexity, and potential morbidity., Methods and Results: Using a cohort of well-treated ambulatory HF patients with reduced ejection fraction who had complete clinical, laboratory, health-related quality of life, imaging, and exercise testing data, we estimated incremental prognostic information provided by 5 assessment categories, performing an additional analysis on those with available N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. We compared the incremental value of each additional assessment (quality of life screen, laboratory testing, echocardiography, and exercise testing) to baseline clinical assessment for predicting clinical outcomes (all-cause mortality, all-cause mortality/hospitalization, and cardiovascular death/HF hospitalizations), gauging incremental improvements in prognostic ability with more information using area under the curve and reclassification improvement (net reclassification index), with and without NT-proBNP availability. Of 2331 participants, 1631 patients had complete clinical data; of these, 1023 had baseline NT-proBNP. For prediction of all-cause mortality, models with incremental assessments sans NT-proBNP showed improvements in C-indices (0.72 [clinical model alone]-0.77 [complete model]). Compared with baseline clinical assessment alone, net reclassification index improved from 0.035 (w/laboratory data) to 0.085 (complete model). These improvements were significantly attenuated for models in the subset with measured NT-proBNP data (c-indices: 0.80 [w/laboratory data]-0.81 [full model]); net reclassification index improvements were similarly marginal (0.091→0.096); prediction of other clinical outcomes had similar findings., Conclusions: In chronic HF patients with reduced ejection fraction, the marginal benefit of complex prognostic evaluations should be weighed against potential patient discomfort and cost escalation., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437., (© 2015 American Heart Association, Inc.)

Optimizing management of patients with heart failure remains quite challenging despite many significant advances in drug and device therapy for this syndrome. Although a large body of evidence from robust clinical trials supports multiple therapies, utilization of these well-established treatments remains inconsistent and outcomes suboptimal in "real-world" patients with heart failure. Disease management programs may be effective, but are difficult to implement due to cost and logistical issues. Another approach to optimizing therapy is to utilize biomarkers to guide therapeutic choices. Natriuretic peptides provide additional information of significant clinical value in the diagnosis and estimation of risk inpatients with heart failure. Ongoing research suggests a potential important added role for natriuretic peptides in heart failure. Guiding therapy based on serial changes in these biomarkers may be an effective strategy to optimize treatment and achieve better outcomes in this syndrome. Initial, innovative, proof-of-concept studies have provided encouraging results and important insights into key aspects of this strategy, but well designed, large-scale, multicenter, randomized, outcome trials are needed to definitively establish this novel approach to management. Given the immense and growing public health burden of heart failure, identification of cost-effective ways to decrease the morbidity and mortality due to this syndrome is critical.

Heart failure is a syndrome with a pathophysiological basis that can be traced to dysfunction in several interconnected molecular pathways. Identification of biomarkers of heart failure that allow measurement of the disease on a molecular level has resulted in enthusiasm for their use in prognostication and selection of appropriate therapies. However, despite considerable amounts of information available on numerous biomarkers, inconsistent research methodologies and lack of clinical correlations have made bench-to-bedside translations rare and left the literature with countless publications of varied quality. There is a need for a systematic and collaborative approach aimed at definitively studying the clinical benefits of novel biomarkers. In this review, on the basis of input from academia, industry, and governmental agencies, we propose a systematized approach based on adherence to specific quality measures for studies looking to augment current prediction model or use biomarkers to tailor therapeutics. We suggest that study quality, rather than results, should determine publication and propose a system for grading biomarker studies. We outline the need for collaboration between clinical investigators and statisticians to introduce more advanced statistical methodologies into the field of biomarkers that would allow for data from a large number of variables to be distilled into clinically actionable information. Lastly, we propose the creation of a heart failure biomarker consortium that would allow for a comprehensive list of biomarkers to be concomitantly analyzed in a pooled sample of randomized clinical trials and hypotheses to be generated for testing in biomarker-guided trials. Such a consortium could collaborate in sharing samples to identify biomarkers, undertake meta-analyses on completed trials, and spearhead clinical trials to test the clinical utility of new biomarkers., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Hyponatremia is a known complication in patients with heart failure (HF). HF patients with severe congestion, hyponatremia, and renal insufficiency are difficult to manage and may have worse outcomes. A main cause of hyponatremia is inappropriately elevated level of plasma arginine vasopressin (AVP), which causes water retention at the collecting duct. AVP antagonists have thus been developed to increase aquaresis and serum sodium levels in patients with euvolemic and hypervolemic hyponatremia. Although tolvaptan, an AVP-2 receptor antagonist, did not show outcomes benefit in patients with decompensated HF, prospective studies are ongoing to evaluate its optimal role in targeted HF patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Myocardial galectin-3 is upregulated upon cardiac stressors such as angiotensin II and pressure overload leading to cardiac remodeling and heart failure. The expression level of galectin-3 mirrors the progression and severity of heart failure and therefore, galectin-3 is being used as a biomarker for heart failure. However, as galectin-3 is causally involved in pathological myocardial fibrosis it has been suggested that galectin-3 also actively contributes to heart failure development. In this review we discuss how galectin-3 could be a target for therapy in heart failure. Currently, attempts are being made to target or inhibit galectin-3 using natural or pharmaceutical inhibitors with the aim to ameliorate heart failure. Available experimental evidence suggests that galectin-3 inhibition indeed may represent a novel tool to treat heart failure. A strong interaction with aldosterone, another strong pro-fibrotic factor, has been described. Clinical studies are needed to prove if galectin-3 may be used to install specific treatment regimens.

There are over 1 million hospitalizations for heart failure (HF) annually in the United States alone, and a similar number has been reported in Europe. Recent clinical trials investigating novel therapies in patients with hospitalized HF (HHF) have been negative, and the post-discharge event rate remains unacceptably high. The lack of success with HHF trials stem from problems with understanding the study drug, matching the drug to the appropriate HF subgroup, and study execution. Related to the concept of study execution is the importance of including appropriate study sites in HHF trials. Often overlooked issues include consideration of the geographic region and the number of patients enrolled at each study center. Marked differences in baseline patient co-morbidities, serum biomarkers, treatment utilization and outcomes have been demonstrated across geographic regions. Furthermore, patients from sites with low recruitment may have worse outcomes compared to sites with higher enrollment patterns. Consequently, sites with poor trial enrollment may influence key patient end points and likely do not justify the costs of site training and maintenance. Accordingly, there is an unmet need to develop strategies to identify the right study sites that have acceptable patient quantity and quality. Potential approaches include, but are not limited to, establishing a pre-trial registry, developing site performance metrics, identifying a local regionally involved leader and bolstering recruitment incentives. This manuscript summarizes the roundtable discussion hosted by the Food and Drug Administration between members of academia, the National Institutes of Health, industry partners, contract research organizations and academic research organizations on the importance of selecting optimal sites for successful trials in HHF.

Heart rate not only predicts outcome but may also be a therapeutic target in patients with chronic heart failure. Several classes of pharmacological agents can be used to modulate heart rate, including beta-blockers, ivabradine, digoxin, amiodarone, and verapamil. Choice of agent will depend on heart rhythm, co-morbidities, and disease phenotype. Beneficial and harmful interactions may also exist. The aim of this paper is to summarize the current body of knowledge regarding the relevance of heart rate as a prognostic factor (risk marker) and particularly as a therapeutic target (risk factor) in patients with chronic heart failure, with a special focus on ivabradine, a novel agent that is currently the only available purely bradycardic agent., (First published online by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013.)

Background: Galectin-3 (Gal-3) is a marker of myocardial fibrosis, and elevated levels are associated with adverse outcomes. Mineralocorticoid receptor antagonists (MRAs) modulate cardiac fibrosis in heart failure (HF) patients and have been shown to improve long-term outcomes. We examined whether treatment effects from MRA use differed by Gal-3 levels in ambulatory heart failure patients enrolled in HF-ACTION., Methods and Results: HF-ACTION was a randomized controlled trial of exercise training versus usual care in patients with HF due to LV systolic dysfunction (New York Heart Association functional class II-IV, left ventricular ejection fraction ≤ 0.35, median follow-up 2.5 years). Galectin-3 was assessed at baseline in 895 patients. The end point was all-cause mortality or all-cause hospitalization (ACM+ACH); all-cause mortality (ACM) was a key secondary end point. A differential association of MRA use by increasing Gal-3 concentration was tested with the use of interaction terms in Cox proportional hazards models, adjusted for covariates previously identified in this cohort as well as age, sex, and race. Inverse propensity-weighted (IPW) methods were also used to assess this association. Approximately one-half (n = 401) of the patients were on an MRA. There was no significant interaction for the associations of Gal-3 levels and MRA use for either end point (adjusted interaction P = .76 for ACM+ACH; P = .26 for ACM). There was no evidence of improved outcomes for patients on an MRA compared with those not on MRA for either end point (hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.85-1.23, P = .8; and HR = 1.15, 95% CI [0.82-1.61], P = .4; respectively). IPW analysis was consistent with the results of the adjusted analysis., Conclusion: Our study showed no evidence of interaction between Gal-3 and treatment effect of MRA. Whether biomarkers may be used to predict which patients may benefit from an mineralocorticoid receptor antagonist in HF requires further investigation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: ST2 is involved in cardioprotective signaling in the myocardium and has been identified as a potentially promising biomarker in heart failure (HF). We evaluated ST2 levels and their association with functional capacity and long-term clinical outcomes in a cohort of ambulatory patients with HF enrolled in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study-a multicenter, randomized study of exercise training in HF., Methods and Results: HF-ACTION randomized 2331 patients with left ventricular ejection fraction <0.35 and New York Heart Association class II to IV HF to either exercise training or usual care. ST2 was analyzed in a subset of 910 patients with evaluable plasma samples. Correlations and Cox models were used to assess the relationship among ST2, functional capacity, and long-term outcomes. The median baseline ST2 level was 23.7 ng/mL (interquartile range, 18.6-31.8). ST2 was modestly associated with measures of functional capacity. In univariable analysis, ST2 was significantly associated with death or hospitalization (hazard ratio, 1.48; P<0.0001), cardiovascular death or HF hospitalization (hazard ratio, 2.14; P<0.0001), and all-cause mortality (hazard ratio, 2.33; P<0.0001; all hazard ratios for log2 ng/mL). In multivariable models, ST2 remained independently associated with outcomes after adjustment for clinical variables and amino-terminal pro-B-type natriuretic peptide. However, ST2 did not add significantly to reclassification of risk as assessed by changes in the C statistic, net reclassification improvement, and integrated discrimination improvement., Conclusions: ST2 was modestly associated with functional capacity and was significantly associated with outcomes in a well-treated cohort of ambulatory patients with HF although it did not significantly affect reclassification of risk., Clinical Trial Information: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.

Background: The value of family history (FH) is well established, but its sensitivity to detect familial dilated cardiomyopathy (FDC) has been infrequently examined., Methods: A genetic ancillary study was created as a component of the HF-ACTION trial, a multicenter, prospective, randomized clinical trial of exercise in patients with heart failure and an ejection fraction <35%. A FH-based study using a structured questionnaire mailed to all consenting individuals was incorporated into the genetic ancillary. FH responses were analyzed for dilated cardiomyopathy (DCM) in family members., Results: Of the 741 individuals with data available, 358 (48.3%) had nonischemic and 383 (51.6%) had ischemic etiology, and of these 164 (45.8%) and 201 (52.4%), respectively, returned evaluable questionnaires. Of those with nonischemic etiology, 14/164 (8.5%) reported at least one first-degree family member with DCM or an enlarged heart; another 21/164 (12.8%) reported a FH of "cardiomyopathy," a less specific term to indicate DCM., Conclusion: At least 8.5% of patients with nonischemic etiology in the HF-ACTION genetic ancillary study provided FH indicating familial DCM, information important to inform further genetic analyses of this cohort and to plan other studies., (© 2013 Wiley Periodicals, Inc.)

Aims: In the Digitalis Investigation Group (DIG) trial, digoxin reduced mortality or hospitalization due to heart failure (HF) in several pre-specified high-risk subgroups of HF patients, but data on protocol-specified 2-year outcomes were not presented. In the current study, we examined the effect of digoxin on HF death or HF hospitalization and all-cause death or all-cause hospitalization in high-risk subgroups during the protocol-specified 2 years of post-randomization follow-up., Methods and Results: In the DIG trial, 6800 ambulatory patients with chronic HF, normal sinus rhythm, and LVEF ≤45% (mean age 64 years, 26% women, 17% non-whites) were randomized to receive digoxin or placebo. The three high-risk groups were defined as NYHA class III-IV symptoms (n = 2223), LVEF <25% (n = 2256), and cardiothoracic ratio (CTR) >55% (n = 2345). In all three high-risk subgroups, compared with patients in the placebo group, those in the digoxin group had a significant reduction in the risk of the 2-year composite endpoint of HF mortality or HF hospitalization: NYHA III-IV [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.57-0.75; P < 0.001], LVEF <25% (HR 0.61; 95% CI 0.53-0.71; P < 0.001), and CTR >55% (HR 0.65; 95% CI 0.57-0.75; P < 0.001). Digoxin-associated HRs (95% CI) for 2-year all-cause mortality or all-cause hospitalization for subgroups with NYHA III-IV, LVEF <25%, and CTR >55% were 0.88 (0.80-0.97; P = 0.012), 0.84 (0.76-0.93; P = 0.001), and 0.85 (0.77-0.94; P = 0.002), respectively., Conclusions: Digoxin improves outcomes in chronic HF patients with NYHA class III-IV, LVEF <25%, or CTR >55%, and should be considered in these patients.

Objectives: The aim of this study was to assess the effects of serelaxin on short-term changes in markers of organ damage and congestion and relate them to 180-day mortality in patients with acute heart failure., Background: Hospitalization for acute heart failure is associated with high post-discharge mortality, and this may be related to organ damage., Methods: The Pre-RELAX-AHF (Relaxin in Acute Heart Failure) phase II study and RELAX-AHF phase III study were international, multicenter, double-blind, placebo-controlled trials in which patients hospitalized for acute heart failure were randomized within 16 h to intravenous placebo or serelaxin. Each patient was followed daily to day 5 or discharge and at days 5, 14, and 60 after enrollment. Vital status was assessed through 180 days. In RELAX-AHF, laboratory evaluations were performed daily to day 5 and at day 14. Plasma levels of biomarkers were measured at baseline and days 2, 5, and 14. All-cause mortality was assessed as a safety endpoint in both studies., Results: Serelaxin reduced 180-day mortality, with similar effects in the phase II and phase III studies (combined studies: N = 1,395; hazard ratio: 0.62; 95% confidence interval: 0.43 to 0.88; p = 0.0076). In RELAX-AHF, changes in markers of cardiac (high-sensitivity cardiac troponin T), renal (creatinine and cystatin-C), and hepatic (aspartate transaminase and alanine transaminase) damage and of decongestion (N-terminal pro-brain natriuretic peptide) at day 2 and worsening heart failure during admission were associated with 180-day mortality. Serelaxin administration improved these markers, consistent with the prevention of organ damage and faster decongestion., Conclusions: Early administration of serelaxin was associated with a reduction of 180-day mortality, and this occurred with fewer signs of organ damage and more rapid relief of congestion during the first days after admission., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo., Methods: RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806., Findings: 1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120-775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events [60-day Kaplan-Meier estimate, 13·0%]; serelaxin, 76 events [13·2%]; hazard ratio [HR] 1·02 [0·74-1·41], p=0·89] or days alive out of the hospital up to day 60 (placebo, 47·7 [SD 12·1] days; serelaxin, 48·3 [11·6]; p=0·37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42-0·93; p=0·019)., Interpretation: Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality., Funding: Corthera, a Novartis affiliate company., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The combination of angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic receptor blockers remains the essential component of heart failure (HF) pharmacotherapy. However, individual patient responses to these pharmacotherapies vary widely. The variability in response cannot be explained entirely by clinical characteristics, and genetic variation may play a role. The purpose of this review is to examine our current state of understanding of beta-blocker and ACE inhibitor pharmacogenetics in HF., Methods and Results: Beta-blocker and ACE inhibitor pharmacogenetic studies performed in patients with HF were identified from the Pubmed database from 1966 to July 2011. Thirty beta-blocker and 10 ACE inhibitor pharmacogenetic studies in patients with HF were identified. The ACE deletion variant was associated with greater survival benefit from ACE inhibitors and beta-blockers compared with the ACE insertion. Ser49 in the beta-1 adrenergic receptor, the insertion in the alpha-2C adrenergic receptor, and Gln41 in G-protein-coupled receptor kinase 5 are associated with greater survival benefit from beta-blockers, compared with Gly49, the deletion, and Leu41, respectively. However, many of these associations have not been validated., Conclusions: The HF pharmacogenetic literature is still in its very early stages, but there are promising candidate genetic variants that may identify which HF patients are most likely to benefit from beta-blockers and ACE inhibitors and patients that may require additional therapies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Coping Effectively with Heart Failure (COPE-HF) is an ongoing randomized clinical trial funded by the National Institutes of Health to evaluate if a coping skills training (CST) intervention will result in improved health status and quality of life as well as reduced mortality and hospitalizations compared with a heart failure education (HFE) intervention., Methods and Results: Two hundred heart failure (HF) patients recruited from the Duke University Medical Center and the University of North Carolina Hospital system will be randomized to a CST intervention (16 weekly 30-minute telephone counseling sessions including motivational interviewing and individually tailored cognitive behavioral therapy) or to an HFE intervention (16 weekly 30-minute telephone sessions including education and symptom monitoring). Primary outcomes will include postintervention effects on HF biomarkers (B-type natriuretic peptide, ejection fraction) and quality of life, as well as long-term clinical outcomes (hospitalizations and death). Secondary analyses will include an evaluation of treatment effects across subpopulations, and potential mechanisms by which CST may improve clinical outcomes., Conclusions: COPE-HF is a proof-of-concept study that should provide important insights into the health benefits of a CST intervention designed to enhance HF self-management, improve health behaviors, and reduce psychologic distress., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to assess the impact of changes in symptoms of depression over a 1-year period on subsequent clinical outcomes in heart failure (HF) patients., Background: Emerging evidence shows that clinical depression, which is prevalent among patients with HF, is associated with a poor prognosis. However, it is uncertain how changes in depression symptoms over time may relate to clinical outcomes., Methods: One-hundred forty-seven HF outpatients with ejection fraction of less than 40% were assessed for depressive symptoms using the Beck Depression Inventory (BDI) at baseline and again 1 year later. Cox proportional hazards regression analyses, controlling for established risk factors, were used to evaluate how changes in depressive symptoms were related to a combined primary end point of death or cardiovascular hospitalization over a median follow-up period of 5 years (with a range of 4 to 7 years and no losses to follow-up)., Results: The 1-year change in symptoms of depression, as indicated by higher BDI scores over a 1-year interval (1-point BDI change hazard ratio [HR]: 1.07, 95% confidence interval [CI]: 1.02 to 1.12, p = 0.007), was associated with death or cardiovascular hospitalization after controlling for baseline depression (baseline BDI HR: 1.1, 95% CI: 1.06 to 1.14, p < 0.001) and established risk factors, including HF cause, age, ejection fraction, plasma N-terminal pro-B-type natriuretic peptide level, and prior hospitalizations., Conclusions: Worsening symptoms of depression are associated with a poorer prognosis in HF patients. Routine assessment of symptoms of depression in HF patients may help to guide appropriate medical management of these patients who are at increased risk for adverse clinical outcomes., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Elevated cardiac troponin T is a well-documented marker of cardiomyocyte damage and poor prognosis in patients with heart failure. We prospectively evaluated the relationship between this marker and hematopoietic disturbances in heart failure., Methods: Data were analyzed from 254 patients in the UNITE-HF Biomarker Registry, a prospective, observational, multicenter study of the clinical and biomarker correlates of anemia in heart failure. Logistic regression modeling assessed relationships between detectable troponin T and indices of hematologic function including anemia and red cell distribution width., Results: Anemia (hemoglobin≤12 g/dL) was present in 65 of the 254 study patients, and detectable troponin T was found in 39. Anemia was a significant independent predictor of detectable troponin T in models that considered a number of clinical characteristics including renal function, functional class, heart rate, and systolic blood pressure (odds ratio 2.57, 95% CI 1.09-6.09, P=.032). Likewise, detectable troponin T was directly and independently related to red cell distribution width in similar multivariable analyses (odds ratio 1.36 per unit increase, 95% CI 1.08-1.71, P=.008)., Conclusions: Anemia and increasing red cell distribution width were independently associated with elevated troponin T, a marker of cardiomyocyte injury or death in patients with heart failure., (Copyright © 2010 Mosby, Inc. All rights reserved.)

The B-type natriuretic peptide (BNP) and the amino-terminal fragment of proBNP (NT-proBNP) are increased in heart failure in proportion to severity of symptoms, degree of left ventricular dysfunction, and elevation of cardiac filling pressures. These natriuretic peptides (NPs) are increasingly used for diagnostic and prognostic purposes in acute heart failure. While NP levels on admission provide independent prognostic information, serial determinations during hospitalization and at discharge better reflect adequacy of treatment and prognosis. The addition of BNP and NT-proBNP to usual clinical decision making enhances detection of high-risk patients who need aggressive follow-up and adjustment of treatment.

The ability to measure the appearance of cardiac specific forms of troponin in the blood represents a major advance in the clinical assessment of patients with many types of cardiovascular disease, especially acute coronary syndromes. In this review we focus on the utility of troponin in heart failure where this biomarker has emerged as an independent predictor of prognosis providing information beyond clinical assessment and measurement of b-type natriuretic peptides. The novel clinical role of troponin in a variety of states associated with myocardial injury, including chemotherapy and patients with cardiovascular risk factors, is discussed.