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Over the past decade, the field of heart failure (HF) has witnessed remarkable progress in drug development, resulting in the approval of numerous groundbreaking drugs by the U.S. Food and Drug Administration. To address some of these challenges, the U.S. Food and Drug Administration has issued guidance documents that have been critical in contemporary HF drug development; however, there are still many challenges in need of investigation. This paper leverages efforts of the Heart Failure Collaboratory and the scientific community to discuss the critical need for innovative trial designs, important concepts in clinical trials in the modern era, and the utilization of big data to accelerate HF drug development. At this inflection point in HF drug development, it is imperative that, as a global scientific community, we foster increased collaboration among researchers, clinicians, patients, and regulatory bodies. Only through such unified efforts can we navigate the complexities of HF, accelerate the development process, and ultimately deliver effective therapies that transform patient outcomes., Competing Interests: Funding Support and Author Disclosures Dr Januzzi has a board position with Imbria Pharma; has received grant support from Abbott, Applied Therapeutics, AstraZeneca, BMS, and Novartis Pharmaceuticals; has received consulting income from Abbott Diagnostics, Beckman-Coulter, Jana Care, Janssen, Novartis, Prevencio, Quidel, and Roche Diagnostics; and has served on clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, CVRx, Medtronic, Pfizer, and Roche Diagnostics. Dr Lindenfeld has received consulting fees from Abbott, Adona, Axon, Alleviant, AstraZeneca, Boston Scienrific, CVRx, Cordio, Edwards Lifesciences, Medtronic, Merck, Orchestra Biomed, VWave, Whiteswell, and Vascular Dynamics; and has received grant funding from AstraZeneca and Volumetrix. Dr Solomon has received research grants from Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Cytokinetics, Eidos, Gossamer, GlaxoSmithKline, Ionis, Lilly, MyoKardia, National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr Bristow has been a consultant for ARCA Biopharma. Dr Abraham has received research grant support from the NHLBI (NIH 1 UG3/UH3 HL140144-01, 08/01/18-07/31/22, “Impact of Low Flow Nocturnal Oxygen Therapy on Hospital Readmission/Mortality in Patients with Heart Failure and Central Sleep Apnea [LOFT-HF]”); has received consulting income from Abbott Vascular, Boehringer Ingelheim, and Zoll Respicardia; has received speaker honoraria from Impulse Dynamics; and has received salary support from V-Wave Medical. Dr O'Connor has done consulting for Abiomed and Merck. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Clinical trials are vital for assessing therapeutic interventions. The associated data monitoring committees (DMCs) safeguard patient interests and enhance trial integrity, thus promoting timely, reliable evaluations of those interventions. We face an urgent need to recruit and train new DMC members. The HFC (Heart Failure Collaboratory), a multidisciplinary public-private consortium of academics, trialists, patients, industry representatives, and government agencies, is working to improve the clinical trial ecosystem. The HFC aims to improve clinical trial efficiency and quality by standardizing concepts, and to help meet the demand for experienced individuals on DMCs by creating a standardized approach to training new members. This paper discusses the HFC's training workshop, and an apprenticeship model for new DMC members. It describes opportunities and challenges DMCs face, along with common myths and best practices learned through previous experiences, with an emphasis on data confidentiality and need for quality independent statistical reporting groups., Competing Interests: Funding Support and Author Disclosures Dr Fleming has received consulting fees from the National Institutes of Health, the World Health Organization, the Food and Drug Administration, and the pharmaceutical and biotech industry in the design, monitoring, and analysis of clinical trials; and he has received fees for serving on several industry-sponsored Data Monitoring Committees (DMCs). Dr Wittes has received compensation for her membership on several DMCs sponsored by industry, government, and not-for-profit organizations; and has received consulting fees from a variety of pharmaceutical and medical device companies. Dr Bristow is the President/CEO/Director at ARCA biopharma. Dr Rockhold has received consulting fees from Intercept, Clover, and Inventprise; has received compensation for serving on several industry-sponsored DMCs; and holds stock in Clover, GSK, Athira, Spence, Adaptic, and Doctor Evidence. Dr Claggett has received consulting fees from Alnylam, Axon, Cardior, Cardurion, CVRx, Cytokinetics, Intellia, and Rocket. Dr Abraham has received consulting fees from Boehringer Ingelheim, Cardionomic, Zoll Respicardia, scPharmaceuticals, Sensible Medical, and Vectorious; has received salary support from V-Wave Medical; and has served as a speaker for Edwards Lifesciences. Dr Lindenfeld has received consulting fees from Abbott, ADI, Alleviant, Amgen, AstraZeneca, Axon, Boston Scientific, Cordio, CVRx, Cytokinetics, Edwards Lifesciences, Medtronic, Merck, VWave, Vascular Dynamics, Vectorious, and Whiteswell; and has received grants from Analog Devices Inc, AstraZeneca, and Volumetrix. Dr DeMets has received consulting fees from the National Institutes of Health, the U.S. Food and Drug Administration, and the pharmaceutical and medical device industry on the design, monitoring, and analysis of clinical trials; and he has received compensation for serving on several recent industry-sponsored data and safety monitoring committees or steering committees including AstraZeneca, Bristol Meyers Squib, GSK, Merck, Boston Scientific, Medtronic, USONA, LivaNova, AnthosTherapy, ARCA biopharma, Duke Clinical Research Institute, and the Population Health Research Institute of Hamilton Ontario. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Polypharmacy is common among patients with heart failure with reduced ejection fraction (HFrEF). However, its impact on the use of optimal guideline-directed medical therapy (GDMT) is not well established., Objectives: This study sought to evaluate the association between polypharmacy and odds of receiving optimal GDMT over time among patients with HFrEF., Methods: The authors conducted a post hoc analysis of the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment) trial. Polypharmacy was defined as receiving ≥5 medications (excluding HFrEF GDMT) at baseline. The outcome of interest was optimal triple therapy GDMT (concurrent administration of a renin-angiotensin-aldosterone blocker and beta-blocker at 50% of the target dose and a mineralocorticoid receptor antagonist at any dose) achieved over the 12-month follow-up. Multivariable adjusted mixed-effect logistic regression models with multiplicative interaction terms (time × polypharmacy) were constructed to evaluate how polypharmacy at baseline modified the odds of achieving optimal GDMT on follow-up., Results: The study included 891 participants with HFrEF. The median number of non-GDMT medications at baseline was 4 (IQR: 3-6), with 414 (46.5%) prescribed ≥5 and identified as being on polypharmacy. The proportion of participants who achieved optimal GDMT at the end of the 12-month follow-up was lower with vs without polypharmacy at baseline (15% vs 19%, respectively). In adjusted mixed models, the odds of achieving optimal GDMT over time were modified by baseline polypharmacy status (P for interaction < 0.001). Patients without polypharmacy at baseline had increased odds of achieving GDMT (OR: 1.16 [95% CI: 1.12-1.21] per 1-month increase; P < 0.001) but not patients with polypharmacy (OR: 1.01 [95% CI: 0.96-1.06)] per 1-month increase)., Conclusions: Patients with HFrEF who are on non-GDMT polypharmacy have lower odds of achieving optimal GDMT on follow-up., Competing Interests: Funding Support and Author Disclosures Dr Pandey has received research support from the National Institute on Aging GEMSSTAR grant (1R03AG067960-01) and the National Institute on Minority Health and Disparities (R01MD017529); grant funding from Applied Therapeutics and Gilead Sciences; honoraria outside of the present study as an advisor/consultant for Tricog Health Inc, Lilly USA, Rivus, Cytokinetics, and Roche Diagnostics; nonfinancial support from Pfizer and Merck; and is a consultant for Palomarin Inc with stock compensation. Dr Segar has received speaker fees from Merck and Co outside the present study. Dr Butler is a consultant for Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, 3live, and Vifor. Dr Fonarow has done consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Eli Lilly, Johnson & Johnson, Medtronic, Merck, Novartis, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Aims: Whether electrocardiographic (ECG) measurements predict mortality in chronic heart failure with reduced ejection fraction (HFrEF) is unknown., Methods and Results: We studied 4880 patients from the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial with a baseline 12-lead ECG. Associations between ECG measurements and mortality were estimated as hazard ratios (HR) and adjusted for the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, N-terminal pro-B-type natriuretic peptide, and index event. Select interactions between ECG measurements, patient characteristics and mortality were examined. Over a median of 10.8 months, there were 824 cardiovascular (CV) deaths (214 sudden) and 1005 all-cause deaths. Median age was 68 years (interquartile range [IQR] 60-76), 24% were women, median ejection fraction was 30% (IQR 23-35), 41% had New York Heart Association class III/IV, and median MAGGIC score was 24 (IQR 19-28). After multivariable adjustment, significant associations existed between heart rate (per 5 bpm: HR 1.02), QRS duration (per 10 ms: HR 1.02), absence of left ventricular hypertrophy (HR 0.64) and CV death, and similarly so with all-cause death (HR 1.02; HR 1.02; HR 0.61, respectively). Contiguous pathologic Q waves were significantly associated with sudden death (HR 1.46), and right ventricular hypertrophy with all-cause death (HR 1.44). The only sex-based interaction observed was for pathologic Q waves on CV (men: HR 1.05; women: HR 1.64, p interaction  = 0.024) and all-cause death (men: HR 0.99; women: HR 1.57; p interaction  = 0.010). Whereas sudden death doubled in females, it did not differ among males (male: HR 1.25, 95% confidence interval [CI] 0.87-1.79; female: HR 2.50, 95% CI 1.23-5.06; p interaction  = 0.141)., Conclusion: Routine ECG measurements provide additional prognostication of mortality in high-risk HFrEF patients, particularly in women with contiguous pathologic Q waves., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Patients with heart failure with reduced ejection fraction (HFrEF) have a high residual risk of adverse outcomes, even when treated with optimal guideline-directed medical therapy and in a clinically stable state. Soluble guanylate cyclase (sGC) stimulators have the potential to lower this risk by modifying the nitric oxide-sGC-cyclic guanosine monophosphate cascade - a pathophysiological pathway that has been targeted with limited success in HFrEF previously. Vericiguat, an sGC stimulator, was shown to improve outcomes in patients with HFrEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. However, this trial included patients with recently worsening disease. In this brief review, we discuss the rationale of evaluating sGC stimulators in lower-risk HFrEF patients. First, all key HFrEF medications have been evaluated in both higher- and lower-risk populations, and the treatment effect is not always consistent across the risk spectrum. Second, pre-clinical studies and post-hoc studies of the VICTORIA trial have suggested that sGC stimulators may have cardioprotective effects - these effects may be more apparent when the medication is initiated earlier in the disease process. Third, the effect of vericiguat on cardiovascular mortality remains uncertain and a trial with a longer follow-up in a lower-risk population may allow better assessment of its effect on cardiovascular mortality. Therefore, there is a pertinent need to investigate the effects of vericiguat in optimally treated, low-risk HFrEF patients (i.e. those without recently worsening heart failure)., (© 2022 European Society of Cardiology.)

Background: Supervised aerobic exercise training (ET) is recommended for stable outpatients with heart failure (HF) with reduced ejection fraction (HFrEF). Frailty, a syndrome characterized by increased vulnerability and decreased physiologic reserve, is common in patients with HFrEF and associated with a higher risk of adverse outcomes. The effect modification of baseline frailty on the efficacy of aerobic ET in HFrEF is not known., Methods: Stable outpatients with HFrEF randomized to aerobic ET versus usual care in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial were included. Baseline frailty was estimated using the Rockwood frailty index (FI), a deficit accumulation-based model of frailty assessment; participants with FI scores >0.21 were identified as frail. Multivariable Cox proportional hazard models with multiplicative interaction terms (frailty × treatment arm) were constructed to evaluate whether frailty modified the treatment effect of aerobic ET on the primary composite end point (all-cause hospitalization or mortality), secondary end points (composite of cardiovascular death or cardiovascular hospitalization, and cardiovascular death or HF hospitalization), and Kansas City Cardiomyopathy Questionnaire score. Separate models were constructed for continuous (FI) and categorical (frail versus not frail) measures of frailty., Results: Among 2130 study participants (age, 59±13 years; 28% women), 1266 (59%) were characterized as frail (FI>0.21). Baseline frailty burden significantly modified the treatment effect of aerobic ET ( P interaction: FI × treatment arm=0.02; frail status [frail versus nonfrail] × treatment arm=0.04) with a lower risk of primary end point in frail (hazard ratio [HR], 0.83 [95% CI, 0.72-0.95]) but not nonfrail (HR, 1.04 [95% CI, 0.87-1.25]) participants. The favorable effect of aerobic ET among frail participants was driven by a significant reduction in the risk of all-cause hospitalization (HR, 0.84 [95% CI, 0.72-0.99]). The treatment effect of aerobic ET on all-cause mortality and other secondary endpoints was not different between frail and nonfrail patients ( P interaction>0.1 for each). Aerobic ET was associated with a nominally greater improvement in Kansas City Cardiomyopathy Questionnaire scores at 3 months among frail versus nonfrail participants without a significant treatment interaction by frailty status ( P interaction>0.2)., Conclusions: Among patients with chronic stable HFrEF, baseline frailty modified the treatment effect of aerobic ET with a greater reduction in the risk of all-cause hospitalization but not mortality.

Aim We conducted a survey of practitioners' knowledge of the clinical application of the major drug classes in HF, with reference to the European Society of Cardiology guidelines. The aim was to identify areas for practice development through education, which may improve HF morbidity and mortality. Methods We distributed a 14 item questionnaire assessing doctors knowledge of indications and contraindications for the major HF drug classes. Results Total number of responses was 127: Intern (N=21), SHO (N=64), Registrar (N=12), SpR (N=14), Consultant (N=4), GP (N=2). Consultants and GPs were excluded from analysis due to underrepresentation. Median years of practice was 4. Indications were correctly identified in a mean of 78% of responses overall. Of participants who felt comfortable with initiation and up-titration of beta blockers (N=84), only 31% (N=26) correctly identified an optimal target heart rate of less than 70 beats per minute. Forty-five percent (N=50) identified serum potassium and creatinine concentrations generally considered safe as contraindications to the initiation of MRA. Twenty-five percent of respondents (N=28) were unaware of a specialist HF service that catered to their institution, and how to refer to it, but 99% (N=110) felt that their practice would benefit from further education on HF pharmacotherapy. Conclusion Results of this survey suggest a need, and indeed a demand, for further education for clinicians in order to reduce mortality, morbidity, and hospital readmission in HF, as well as their attendant costs., Competing Interests: The authors have no conflicts of interest to declare.

Background: Loop diuretics are commonly used for patients with heart failure (HF) but it remains unknown if one loop diuretic is clinically superior., Hypothesis: Biomarkers and proteomics provide insight to how different loop diuretics may differentially affect outcomes., Methods: Blood and urine were collected from outpatients with HF who were taking torsemide or furosemide for >30 days. Differences were assessed in cardiac, renal, and inflammatory biomarkers and soluble protein panels using the Olink Cardiovascular III and inflammation panels., Results: Of 78 subjects, 55 (71%) were treated with furosemide and 23 (29%) with torsemide, and 25 provided a urine sample (15 treated with furosemide, 10 with torsemide). Patients taking torsemide were older (68 vs 64 years) with a lower mean eGFR (46 vs 54 ml/min/1.73 m 2 ), a higher proportion were women (39% vs 24%) and Black (43% vs 27%). In plasma, levels of hs-cTnT, NT-proBNP, and hsCRP were not significantly different between groups. In urine, there were significant differences in urinary albumin, β-2M, and NGAL, with higher levels in the torsemide-treated patients. Of 184 proteins testing in Olink panels, in plasma, 156 (85%) were higher in patients taking torsemide but none were significantly different after correcting for false discovery., Conclusions: We show differences in urinary biomarkers but few differences in plasma biomarkers among HF patients on different loop diuretics. Olink technology can detect differences in plasma protein levels from multiple biologic domains. These findings raise the importance of defining differences in mechanisms of action of each diuretic in an appropriately powered study., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Background: Palliative care (PC) in advanced heart failure (HF) aims to improve symptoms and quality of life (QOL), in part through medication management. The impact of PC on polypharmacy (>5 medications) remains unknown., Methods and Results: We explored patterns of polypharmacy in the Palliative Care in HF (PAL-HF) randomized controlled trial of standard care vs interdisciplinary PC in advanced HF (N = 150). We describe differences in medication counts between arms at 2, 6, 12, and 24 weeks for HF (12 classes) and PC (6 classes) medications. General linear mixed models were used to evaluate associations between treatment arm and polypharmacy over time. The median age of the patients was 72 years (interquartile range 62-80 years), 47% were female, and 41% were Black. Overall, 48% had ischemic etiology, and 55% had an ejection fraction of 40% or less. Polypharmacy was present at baseline in 100% of patients. HF and PC medication counts increased in both arms, with no significant differences in counts by drug class at any time point between arms., Conclusions: In a trial of patients with advanced HF considered eligible for PC, polypharmacy was universal at baseline and increased during follow-up with no effect of the palliative intervention on medication counts relative to standard care., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Actigraphy-based measurements of physiologic parameters may enable design of patient-centric heart failure (HF) clinical trials. Recently, the Heart Failure Collaboratory focused on recommendations for meaningful change and use of actigraphy as an end point in HF clinical trials. We aimed to evaluate randomized controlled trials (RCTs) that have quantified the impact of HF interventions using actigraphy., Methods: Using a scoping review strategy, we evaluated the use of actigraphy in HF RCTs. Studies were identified through electronic searches of Embase, OVID Medline, PubMed, and Cochrane Review. Data on trial characteristics and results were collected., Results: We identified 11 RCTs with a total of 1,455 participants. The risk of bias across the included trials was high overall. All trials had the primary outcomes reflecting measures of either physical activity (n = 8), sleep (n = 2), or both (n = 1). Five trials evaluated response to pharmacologic therapies compared with placebo, 3 evaluated physical activity interventions, 2 evaluated group or cognitive therapy, and 1 evaluated sleep-ventilation strategy. Sample sizes ranged from 30 to 619 participants. There was significant heterogeneity relating to device type, body placement site, and handling of missing actigraphy data. Duration of monitoring ranged from 48 hours to 12 weeks. None of the studies evaluating pharmacologic therapies (n = 5) demonstrated a significant improvement of actigraphy-based primary end point measurements., Conclusions: There is significant heterogeneity in the use, methodology, and results of actigraphy-based HF RCTs. Our results highlight the need to develop, standardize, and validate actigraphy-specific outcomes for use in HF clinical trials., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In a randomized control trial, Palliative Care in Heart Failure (PAL-HF) improved heart failure-related quality of life, though cost-effectiveness remains unknown. The aim of this study was to evaluate the cost-effectiveness of the PAL-HF trial, which provided outpatient palliative care to patients with advanced heart failure., Methods and Results: Outcomes for usual care and PAL-HF strategies were compared using a Markov cohort model over 36 months from a payer perspective. The model parameters were informed by PAL-HF trial data and supplemented with meta-analyses and Medicare administrative data. Outcomes included hospitalization, place of death, Medicare expenditures, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. Simulated mortality rates were the same for PAL-HF and usual care cohorts, at 89.7% at 36 months. In the base case analysis, the PAL-HF intervention resulted in an incremental gain of 0.03 QALYs and an incremental cost of $964 per patient for an incremental cost-effectiveness ratio of $29,041 per QALY. In 1-way sensitivity analyses, an intervention cost of up to $140 per month is cost effective at $50,000 per QALY. Of 1000 simulations, the PC intervention had a 66.1% probability of being cost effective at a $50,000 willingness-to-pay threshold assuming no decrease in hospitalization. In a scenario analysis, PAL-HF decreased payer spending through reductions in noncardiovascular hospitalizations., Conclusions: These results from this single-center trial are encouraging that palliative care for advanced heart failure is an economically attractive intervention. Confirmation of these findings in larger multicenter trials will be an important part of developing the evidence to support more widespread implementation of the PAL-HF palliative care intervention., (Published by Elsevier Inc.)

Background: The inflammatory cytokine IL-6 has been previously implicated in the pathophysiology of acute decompensated heart failure (HF). Prior observations in acute HF patients have suggested that IL-6 may be associated with outcomes and modulated by nesiritide. We aimed to evaluate the associations between serial IL-6 measurements, mortality and rehospitalization in acute HF., Methods and Results: We analyzed the associations between IL-6 in acute HF, readmission, and mortality (30 and 180 days) using a cohort of 883 hospitalized patients from the ASCEND-HF trial (nesiritide vs placebo). Plasma IL-6 was measured at randomization (baseline), 48-72 hours, and 30 days. The median IL-6 was highest at baseline (14.1 pg/mL) and decreased at subsequent time points (7.6 pg/mL at 30 days). In a univariable Cox regression analysis, the baseline IL-6 was associated with 30- and 180-day mortality (hazard ratio per log 1.74, 95% confidence interval 1.09-2.78, P = .021; hazard ratio 3.23, confidence interval 1.18-8.86, P = .022, respectively). However, there was no association after multivariable adjustment. IL-6 at 48-72 hours was found to be independently associated with 30-day mortality (hazard ratio 8.2, confidence interval 1.2-57.5, P= .03), but not 180-day mortality in multivariable analysis that included the ASCEND-HF risk model and amino terminal pro-B-type natriuretic peptide as covariates. In comparison with placebo, nesiritide therapy was not associated with differences in serial IL-6 levels., Conclusions: Although elevated IL-6 levels were associated with higher all-cause mortality in acute HF, no independent association with this outcome was identified at baseline or 30-day measurements. In contrast with prior reports, we did not observe any impact of nesiritide over placebo on serial IL-6 levels., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cardiac rehabilitation is defined as a multidisciplinary program that includes exercise training, cardiac risk factor modification, psychosocial assessment, and outcomes assessment. Exercise training and other components of cardiac rehabilitation (CR) are safe and beneficial and result in significant improvements in quality of life, functional capacity, exercise performance, and heart failure (HF)-related hospitalizations in patients with HF. Despite outcome benefits, cost-effectiveness, and strong practice guideline recommendations, CR remains underused. Clinicians, health care leaders, and payers should prioritize incorporating CR as part of the standard of care for patients with HF., Competing Interests: Funding Support and Author Disclosures Dr. Bozkurt has received consulting fees from Bristol Myers Squibb, scPharmaceuticals, Baxter Healthcare Corporation, Sanofi, and Relypsa; serves on the Clinical Event Committee for the GUIDE-HF trial, sponsored by Abbott Vascular; and serves on the Data and Safety Monitoring Committee of the ANTHEM trial, sponsored by LivaNova. Dr. O’Connor has received grant or research support from Roche Diagnostics, Merck, and Bayer; and has received consulting fees from Merck, Bayer, Bristol Myers Squibb, Windtree Therapeutics, and Arena. Dr. Forman has received funds from the National Institute on Aging and the National Institutes of Health Common Fund through grants R01AG060499, R01AG058883, P30AG024827, and UO1AR071130. Dr. Fonarow has received research funding from the National Institutes of Health; and has received consulting fees from Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen, Medtronic, Merck, and Novartis. Dr. Panjrath has received speaker fees from Pfizer. Dr. Piña has received advisory board fees from Relypsa. Dr. Lindenfeld has received consulting fees from Abbott, AstraZeneca, CVRx, Boehringer Ingelheim, Edwards Lifesciences, Impulse Dynamics, and VWave; and has received grant support from AstraZeneca, Volumetric, and Sensible Medical. Dr. Goldberg has received consulting fees from Respicardia and Abbott; has served on the steering committee of the Remede Pivotal Trial, sponsored by Respicardia; and is the current principal investigator of the REST trial, sponsored by Respicardia. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

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

This study investigated the use of natriuretic peptides as inclusion criteria and to develop recommendations regarding their use. B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are commonly used as inclusion criteria for heart failure (HF) clinical trials, but no consensus exists regarding their optimal use for this purpose. A comprehensive search of the Aggregate Analysis of ClincalTrials.gov database identified 3,446 HF trials. Of these, 365 recently completed or ongoing HF clinical trials (10.6%) used either BNP or NT-proBNP as inclusion criteria. A panel of experts discussed current practices and a path forward for the use of natriuretic peptides as inclusion criteria for HF trials. Significant variations existed across trials regarding which natriuretic peptide and which cutoff value were used. Overall, 43% used both natriuretic peptides, 33% used only NT-proBNP, and 24% used only BNP in determining eligibility. Studies using BNP and NT-proBNP concentrations as inclusion criteria had higher cardiovascular event rates and higher concentrations for study entry and were generally associated with higher event rates. Areas of uncertainty included use in certain patient populations in which natriuretic peptides are historically lower (e.g., black patients, obese patients, patients with HF with preserved ejection fraction) or higher (older patients, patients with atrial fibrillation). This paper discusses best practices regarding use of BNP or NT-proBNP in clinical trials and identification of gaps in medical literature, including importance of documentation in ClinicalTrials.gov studies to inform future research efforts., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with heart failure having a low expected probability of arrhythmic death may not benefit from implantable cardioverter defibrillators (ICDs)., Objective: The objective was to validate models to identify cardiac resynchronization therapy (CRT) candidates who may not require CRT devices with ICD functionality., Methods: Heart failure (HF) patients with CRT-Ds and non-CRT ICDs from the National Cardiovascular Data Registry and others with no device from 3 separate registries and 3 heart failure trials were analyzed using multivariable Cox proportional hazards regression for survival with the Seattle Heart Failure Model (SHFM; estimates overall mortality) and the Seattle Proportional Risk Model (SPRM; estimates proportional risk of arrhythmic death)., Results: Among 60,185 patients (age 68.6 ± 11.3 years, 31.9% female) meeting CRT-D criteria, 38,348 had CRT-Ds, 11,389 had non-CRT ICDs, and 10,448 had no device. CRT-D patients had a prominent adjusted survival benefit (HR 0.52, 95% CI 0.50-0.55, P < .0001 versus no device). CRT-D patients with SHFM-predicted 4-year survival ≥81% (median) and a low SPRM-predicted probability of an arrhythmic mode of death ≤42% (median) had an absolute adjusted risk reduction attributable to ICD functionality of just 0.95%/year with the majority of survival benefit (70%) attributable to CRT pacing. In contrast, CRT-D patients with SHFM-predicted survival median had substantially more ICD-attributable benefit (absolute risk reduction of 2.6%/year combined; P < .0001)., Conclusions: The SPRM and SHFM identified a quarter of real-world, primary prevention CRT-D patients with minimal benefit from ICD functionality. Further studies to evaluate CRT pacemakers in these low-risk CRT candidates are indicated., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Palliative care improves quality of life in patients with heart failure. Whether men and women with heart failure derive similar benefit from palliative care interventions remains unknown., Methods: In a secondary analysis of the PAL-HF trial (Palliative Care in Heart Failure), we analyzed differences in quality of life among men and women with heart failure and assessed for differential effects of the palliative care intervention by sex. Differences in clinical characteristics and quality-of-life metrics were compared between men and women at serial time points. The primary outcome was change in Kansas City Cardiomyopathy Questionnaire score between baseline and 24 weeks., Results: Among the 71 women and 79 men, there was a significant difference in baseline Kansas City Cardiomyopathy Questionnaire (24.5 versus 36.2, respectively; P =0.04) but not Functional Assessment of Chronic Illness Therapy-Palliative Care scale (115.7 versus 120.3; P =0.27) scores. Among those who received the palliative care intervention (33 women and 42 men), women's quality-of-life score remained lower than that of men after enrollment. Treated men's scores were significantly higher than those untreated (6-month Kansas City Cardiomyopathy Questionnaire, 68.0 [interquartile range, 52.6-85.7] versus 41.1[interquartile range, 32.0-78.3]; P =0.047), whereas the difference between treated and untreated women was not significantly different ( P =0.39). Rates of death and rehospitalization, as well as the composite end point, were similar between treated and untreated women and men., Conclusions: In the PAL-HF trial, women with heart failure experienced a greater symptom burden and poorer quality of life as compared with men. The change in treated men's Kansas City Cardiomyopathy Questionnaire score between baseline and 24 weeks was significantly higher than those untreated; this trend was not observed in women. Thus, there may be a sex disparity in response to palliative care intervention, suggesting that sex-specific approaches to palliative care may be needed to improve outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0158960.

Background: Amino-terminal pro-B-type natriuretic peptide (NTproBNP) is closely associated with prognosis in acute decompensated heart failure (ADHF). As a result, there has been great interest measuring it during the course of treatment. The prognostic implications in both short-term and follow-up changes in NTproBNP need further clarification., Methods: Baseline, 48-72 hour, and 30-day NTproBNP levels were measured in 795 subjects in the ASCEND-HF trial. Multivariable logistic and Cox-proportional hazards models were used to test the association between static, relative, and absolute changes in NTproBNP with outcomes during and after ADHF., Results: The median NTproBNP at baseline was 5773 (2981-11,579) pg/mL; at 48-72 hours was 3036 (1191-6479) pg/mL; and at 30 days was 2914 (1364-6667) pg/mL. Absolute changes in NTproBNP by 48-72 hours were not associated with 30-day heart failure rehospitalization or mortality (P = .065), relative changes in NTproBNP were nominally associated (P = .046). In contrast, both absolute and relative changes in NTproBNP from baseline to 48-72 hours and to 30 days were closely associated with 180-day mortality (P < .02 for all) with increased discrimination compared to the multivariable models with baseline NTproBNP (P <.05 for models with relative and absolute change at both time points)., Conclusions: Although the degree of absolute change in NTproBNP was dependent on baseline levels, both short-term absolute and relative changes in NTproBNP were independently and incrementally associated with long-term clinical outcomes. Changes in NTproBNP levels at 30-days were particularly well associated with long-term clinical outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: We examined the modifying effects of social support on depressive symptoms and health-related quality of life (QoL) in patients receiving coping skills training (CST)., Method: We considered the modifying effects of social support in the Coping Effectively with Heart Failure clinical trial, which randomized 179 heart failure (HF) patients to either 4 months of CST or usual care enhanced by HF education (HFE). CST involved training in specific coping techniques, whereas HFE involved education about HF self-management. Social support was assessed by the Enhancing Recovery in Coronary Heart Disease (ENRICHD) Social Support Inventory, QoL was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ), and depression was assessed with the Beck Depression Inventory-II (BDI-II)., Results: Linear regression models revealed a significant Intervention Group × Baseline Social Support interaction for change in KCCQ total scores (p = .006) and BDI-II scores (p < .001). Participants with low social support assigned to the CST intervention showed large improvements in KCCQ scores (M = 11.2, 95% CI [5.7, 16.8]), whereas low-social-support patients assigned to the HFE controls showed no significant change (M = -0.8, 95% CI [-7.2, 5.6]). Similarly, BDI-II scores in participants with low social support in the CST group showed large reductions (M = -8.7, 95% CI [-11.3, -6.1]) compared with low-social-support HFE participants (M = -3.0, 95% CI [-6.0, -0.1])., Conclusions: HF patients with low social support benefit substantially from telephone-based CST interventions. Targeting HF patients with low social support for behavioral interventions could prove to be a cost-effective strategy for improving QoL and reducing depression. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

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.)

Background: Medical treatment for acute heart failure (AHF) has not changed substantially over the last four decades. Emergency department (ED)-based evidence for treatment is limited. Outcomes remain poor, with a 25% mortality or re-admission rate within 30days post discharge. Targeting pulmonary congestion, which can be objectively assessed using lung ultrasound (LUS), may be associated with improved outcomes., Methods: BLUSHED-AHF is a multicenter, randomized, pilot trial designed to test whether a strategy of care that utilizes a LUS-driven treatment protocol outperforms usual care for reducing pulmonary congestion in the ED. We will randomize 130 ED patients with AHF across five sites to, a) a structured treatment strategy guided by LUS vs. b) a structured treatment strategy guided by usual care. LUS-guided care will continue until there are ≤15 B-lines on LUS or 6h post enrollment. The primary outcome is the proportion of patients with B-lines ≤ 15 at the conclusion of 6 h of management. Patients will continue to undergo serial LUS exams during hospitalization, to better understand the time course of pulmonary congestion. Follow up will occur through 90days, exploring days-alive-and-out-of-hospital between the two arms. The study is registered on ClinicalTrials.gov (NCT03136198)., Conclusion: If successful, this pilot study will inform future, larger trial design on LUS driven therapy aimed at guiding treatment and improving outcomes in patients with AHF., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Previous systematic reviews have indicated that exercise-based cardiac rehabilitation (ExCR) for patients with heart failure (HF) has a beneficial effect on health-related quality-of-life (HRQoL) and exercise capacity. However, there is uncertainty regarding potential differential effects of ExCR across HF patient subgroups., Objectives: The authors sought to undertake an individual participant data (IPD) meta-analysis to: 1) assess the impact of ExCR on HRQoL and exercise capacity in patients with HF; and 2) investigate differential effects of ExCR according to a range of patient characteristics: age, sex, ethnicity, New York Heart Association functional class, ischemic etiology, ejection fraction, and exercise capacity., Methods: A single dataset was produced, comprising randomized trials where ExCR (delivered for 3 weeks or more) was compared with a no exercise control group. Each trial provided IPD on HRQoL or exercise capacity (or both), with follow-up of 6 months or more. One- and 2-stage meta-analysis models were used to investigate the effect of ExCR overall and the interactions between ExCR and participant characteristics., Results: IPD was obtained from 13 trials for 3,990 patients, predominantly (97%) with reduced ejection fraction HF. Compared with the control group, there was a statistically significant difference in favor of ExCR for HRQoL and exercise capacity. At 12-month follow-up, improvements were seen in 6-min walk test (mean 21.0 m; 95% confidence interval: 1.57 to 40.4 m; p = 0.034) and Minnesota Living With HF score (mean improvement 5.9; 95% confidence interval: 1.0 to 10.9; p = 0.018). No consistent evidence was found of differential intervention effects across patient subgroups., Conclusions: These results, based on an IPD meta-analysis of randomized trials, confirm the benefit of ExCR on HRQoL and exercise capacity and support the Class I recommendation of current international clinical guidelines that ExCR should be offered to all HF patients. (Exercise Training for Chronic Heart Failure [ExTraMATCH II]: protocol for an individual participant data meta-analysis; PROSPERO: international database of systematic reviews CRD42014007170)., (Copyright © 2019. Published by Elsevier Inc.)

Aims: To undertake an individual patient data (IPD) meta-analysis to assess the impact of exercise-based cardiac rehabilitation (ExCR) in patients with heart failure (HF) on mortality and hospitalisation, and differential effects of ExCR according to patient characteristics: age, sex, ethnicity, New York Heart Association functional class, ischaemic aetiology, ejection fraction, and exercise capacity., Methods and Results: Randomised trials of exercise training for at least 3 weeks compared with no exercise control with 6-month follow-up or longer, providing IPD time to event on mortality or hospitalisation (all-cause or HF-specific). IPD were combined into a single dataset. We used Cox proportional hazards models to investigate the effect of ExCR and the interactions between ExCR and participant characteristics. We used both two-stage random effects and one-stage fixed effect models. IPD were obtained from 18 trials including 3912 patients with HF with reduced ejection fraction. Compared to control, there was no statistically significant difference in pooled time to event estimates in favour of ExCR although confidence intervals (CIs) were wide [all-cause mortality: hazard ratio (HR) 0.83, 95% CI 0.67-1.04; HF-specific mortality: HR 0.84, 95% CI 0.49-1.46; all-cause hospitalisation: HR 0.90, 95% CI 0.76-1.06; and HF-specific hospitalisation: HR 0.98, 95% CI 0.72-1.35]. No strong evidence was found of differential intervention effects across patient characteristics., Conclusion: Exercise-based cardiac rehabilitation did not have a significant effect on the risk of mortality and hospitalisation in HF with reduced ejection fraction. However, uncertainty around effect estimates precludes drawing definitive conclusions., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

The prevalence of heart failure continues to grow, and this is accompanied by an increase in hospitalization for acute heart failure. Hospitalization for heart failure results in a trajectory shift of the syndrome and is associated with worsening outcomes, increased mortality risk, and high costs. Numerous clinical trials over the past 2 decades have had limited success, with no single agent shown to improve mortality risk. The lack of success is multifactorial and in part related to inadequate targets and end points selected for intervention, underscoring the need to better understand and define the pathophysiology of acute heart failure. To better inform future drug development, this review critically explores the short-term end points and outcomes that previous phase III acute heart failure trials have examined., (Copyright © 2018 Elsevier Inc. All rights reserved.)

There is increasing recognition of the relationship between diabetes and heart failure (HF). Comorbid diabetes is associated with worse outcomes in patients with HF, and death from HF forms a large burden of mortality among patients with diabetes and atherosclerotic cardiovascular disease. However, there is evidence of harm relating to the risk of HF outcomes from several antihyperglycemic therapies. The absence of well-powered randomized controlled studies has resulted in significant treatment variations in the glycemic management in patients with coexisting diabetes and HF. However, there is emerging evidence from recent clinical trials suggesting that sodium-glucose-co-transporter-2 inhibitors may be used as a therapy to improve HF outcomes. In order to understand the current state of knowledge, we reviewed the evolving evidence of antihyperglycemic therapies and present strategies to optimize these therapies in patients with diabetes and HF. This analysis is based on discussions among scientists, clinical trialists, industry sponsors, and regulatory representatives who attended the 12th Global Cardiovascular Clinical Trialists Forum, Washington, DC, December 1 to 3, 2016., (Copyright © 2018. Published by Elsevier Inc.)

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

Background: Mitochondrial dysfunction and energy depletion in the failing heart are innovative therapeutic targets in heart failure management. Elamipretide is a novel tetrapeptide that increases mitochondrial energy; however, its safety, tolerability, and therapeutic effect on cardiac structure and function have not been studied in heart failure with reduced ejection fraction., Methods and Results: In this double-blind, placebo-controlled, ascending-dose trial, patients with heart failure with reduced ejection fraction (ejection fraction, ≤35%) were randomized to either a single 4-hour infusion of elamipretide (cohort 1 [n=8], 0.005; cohort 2 [n=8], 0.05; and cohort 3 [n=8], 0.25 mg·kg -1 ·h -1 ) or placebo control (n=12). Safety and efficacy were assessed by clinical, laboratory, and echocardiographic assessments performed at pre-, mid- and end-infusion and 6-, 8-, 12- and 24-hours postinfusion start. Peak plasma concentrations of elamipretide occurred at end-infusion and were undetectable by 24 hours postinfusion. There were no serious adverse events. Blood pressure and heart rate remained stable in all cohorts. Compared with placebo, a significant decrease in left ventricular end-diastolic volume (-18 mL; P =0.009) and end-systolic volume (-14 mL; P =0.005) occurred at end infusion in the highest dose cohort., Conclusions: This is the first study to evaluate elamipretide in heart failure with reduced ejection fraction and demonstrates that a single infusion of elamipretide is safe and well tolerated. High-dose elamipretide resulted in favorable changes in left ventricular volumes that correlated with peak plasma concentrations, supporting a temporal association and dose-effect relationship. Further study of elamipretide is needed to determine long-term safety and efficacy., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02388464., (© 2017 American Heart Association, Inc.)

Background: Most patients with acute heart failure (AHF) admitted to critical care units (CCUs) are low acuity and do not require CCU-specific therapies, suggesting that they could be managed in a lower-cost ward environment. This study identified the predictors of clinical events and the need for CCU-specific therapies in patients with AHF., Methods: Model derivation was performed using data from patients in the ASCEND-HF trial cohort (n=7,141), and the Acute Heart Failure Emergency Management community-based registry (n=666) was used to externally validate the model and to test the incremental prognostic utility of 4 variables (heart failure etiology, troponin, B-type natriuretic peptide [BNP], ejection fraction) using net reclassification index and integrated discrimination improvement. The primary outcome was an in-hospital composite of the requirement for CCU-specific therapies or clinical events., Results: The primary composite outcome occurred in 545 (11.4%) derivation cohort participants (n=4,767) and 7 variables were predictors of the primary composite outcome: body mass index, chronic respiratory disease, respiratory rate, resting dyspnea, hemoglobin, sodium, and blood urea nitrogen (c index=0.633, Hosmer-Lemeshow P=.823). In the validation cohort (n=666), 87 (13.1%) events occurred (c index=0.629, Hosmer-Lemeshow P=.386) and adding ischemic heart failure, troponin, and B-type natriuretic peptide improved model performance (net reclassification index 0.79, 95% CI 0.046-0.512; integrated discrimination improvement 0.014, 95% CI 0.005-0.0238). The final 10-variable clinical prediction model demonstrated modest discrimination (c index=0.702) and good calibration (Hosmer-Lemeshow P=.547)., Conclusions: We derived, validated, and improved upon a clinical prediction model in an international trial and a community-based cohort of AHF. The model has modest discrimination; however, these findings deserve further exploration because they may provide a more accurate means of triaging level of care for patients with AHF who need admission., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: In patients with acute heart failure, early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and, potentially, myocardial injury, thereby favorably affecting patients' long-term prognosis., Methods: In this double-blind trial, we randomly assigned 2157 patients with acute heart failure to receive a continuous intravenous infusion of either ularitide at a dose of 15 ng per kilogram of body weight per minute or matching placebo for 48 hours, in addition to accepted therapy. Treatment was initiated a median of 6 hours after the initial clinical evaluation. The coprimary outcomes were death from cardiovascular causes during a median follow-up of 15 months and a hierarchical composite end point that evaluated the initial 48-hour clinical course., Results: Death from cardiovascular causes occurred in 236 patients in the ularitide group and 225 patients in the placebo group (21.7% vs. 21.0%; hazard ratio, 1.03; 96% confidence interval, 0.85 to 1.25; P=0.75). In the intention-to-treat analysis, there was no significant between-group difference with respect to the hierarchical composite outcome. The ularitide group had greater reductions in systolic blood pressure and in levels of N-terminal pro-brain natriuretic peptide than the placebo group. However, changes in cardiac troponin T levels during the infusion did not differ between the two groups in the 55% of patients with paired data., Conclusions: In patients with acute heart failure, ularitide exerted favorable physiological effects (without affecting cardiac troponin levels), but short-term treatment did not affect a clinical composite end point or reduce long-term cardiovascular mortality. (Funded by Cardiorentis; TRUE-AHF ClinicalTrials.gov number, NCT01661634 .).

The TRUE-AHF is a randomized, double-blind, parallel-group, placebo-controlled trial which is evaluating the effects of a 48-h infusion of ularitide (15 ng/kg/min) on the short- and long-term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long-term follow-up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event-driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in-hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE-AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure., Trial Registration: NCT01661634., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue on the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17, 2016, represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions., (© 2017 American Heart Association, Inc.)

Background: Classification of acute decompensated heart failure (ADHF) is based on subjective criteria that crudely capture disease heterogeneity. Improved phenotyping of the syndrome may help improve therapeutic strategies., Objective: To derive cluster analysis-based groupings for patients hospitalized with ADHF, and compare their prognostic performance to hemodynamic classifications derived at the bedside., Methods: We performed a cluster analysis on baseline clinical variables and PAC measurements of 172 ADHF patients from the ESCAPE trial. Employing regression techniques, we examined associations between clusters and clinically determined hemodynamic profiles (warm/cold/wet/dry). We assessed association with clinical outcomes using Cox proportional hazards models. Likelihood ratio tests were used to compare the prognostic value of cluster data to that of hemodynamic data., Results: We identified four advanced HF clusters: 1) male Caucasians with ischemic cardiomyopathy, multiple comorbidities, lowest B-type natriuretic peptide (BNP) levels; 2) females with non-ischemic cardiomyopathy, few comorbidities, most favorable hemodynamics; 3) young African American males with non-ischemic cardiomyopathy, most adverse hemodynamics, advanced disease; and 4) older Caucasians with ischemic cardiomyopathy, concomitant renal insufficiency, highest BNP levels. There was no association between clusters and bedside-derived hemodynamic profiles (p = 0.70). For all adverse clinical outcomes, Cluster 4 had the highest risk, and Cluster 2, the lowest. Compared to Cluster 4, Clusters 1-3 had 45-70% lower risk of all-cause mortality. Clusters were significantly associated with clinical outcomes, whereas hemodynamic profiles were not., Conclusions: By clustering patients with similar objective variables, we identified four clinically relevant phenotypes of ADHF patients, with no discernable relationship to hemodynamic profiles, but distinct associations with adverse outcomes. Our analysis suggests that ADHF classification using simultaneous considerations of etiology, comorbid conditions, and biomarker levels, may be superior to bedside classifications.

Congestion is a major reason for hospitalization in acute heart failure (HF). Therapeutic strategies to manage congestion include diuretics, vasodilators, ultrafiltration, vasopressin antagonists, mineralocorticoid receptor antagonists, and potentially also novel therapies such as gut sequesterants and serelaxin. Uncertainty exists with respect to the appropriate decongestion strategy for an individual patient. In this review, we summarize the benefit and risk profiles for these decongestion strategies and provide guidance on selecting an appropriate approach for different patients. An evidence-based initial approach to congestion management involves high-dose i.v. diuretics with addition of vasodilators for dyspnoea relief if blood pressure allows. To enhance diuresis or overcome diuretic resistance, options include dual nephron blockade with thiazide diuretics or natriuretic doses of mineralocorticoid receptor antagonists. Vasopressin antagonists may improve aquaresis and relieve dyspnoea. If diuretic strategies are unsuccessful, then ultrafiltration may be considered. Ultrafiltration should be used with caution in the setting of worsening renal function. This review is based on discussions among scientists, clinical trialists, and regulatory representatives at the 9th Global Cardio Vascular Clinical Trialists Forum in Paris, France, from 30 November to 1 December 2012., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies. This document summarizes the proceedings from this meeting., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Understanding of chronic heart failure (HF) has progressed from the concept of a purely hemodynamic disorder to that of a syndrome that results from dysfunction in interconnected molecular pathways. As a result, the focus of research investigations and clinical care has shifted to measurement and modification of maladaptive molecular processes. Accumulating evidence shows that molecular biomarkers provide a window into the pathophysiology of chronic HF and therefore have important therapeutic implications. However, the use of biomarkers in the treatment of HF remains in its infancy. This is partly a result of shortcomings in research studies and a dearth of biomarker-guided clinical trials. In this review, we summarize the potential therapeutic implications of promising biomarkers that uniquely capture the molecular dysfunction that occurs in chronic HF. We discuss the need for strict statistical standards in biomarker studies, provide an overview of biomarker-guided clinical trial design, and discuss the therapeutic potential of a multimarker-based strategy.

Objectives: This study was designed to test the hypothesis of whether amlodipine reduces the risk for death in patients with heart failure due to a nonischemic cardiomyopathy., Background: A pre-specified subgroup analysis in an earlier, large-scale, placebo-controlled study suggested that amlodipine might reduce the risk for death in patients with heart failure due to a nonischemic cardiomyopathy., Methods: To evaluate this hypothesis, 1654 patients with severe heart failure due to a nonischemic cardiomyopathy (ejection fraction <30%) were randomly assigned to amlodipine (target dose: 10 mg/d) or placebo added to conventional therapy for heart failure for a median of 33 months., Results: There were 278 deaths in the amlodipine group and 262 deaths in the placebo group (hazard ratio: 1.09; 95% confidence interval [CI]: 0.92 to 1.29; p = 0.33). The differences between the 2 groups in the risks for cardiovascular death and hospitalization were also not significant. When the results from patients with a nonischemic cardiomyopathy in both the earlier trial and in the current study were combined, there was no evidence of a favorable or unfavorable effect of amlodipine on mortality (hazard ratio: 0.97; 95% CI: 0.83 to 1.13; p = 0.66). Both trials, however, observed higher frequencies of peripheral edema and pulmonary edema and lower frequencies of uncontrolled hypertension and chest pain in patients treated with amlodipine., Conclusions: These results of the current trial, viewed together with the results from the earlier study, indicate that amlodipine does not exert favorable effects on the clinical course of patients with heart failure, regardless of the presence or absence of underlying coronary artery disease. These findings indicate the need for great caution when striking benefits are observed in subgroups of patients or in trials not primarily designed to assess such effects., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)