Heart Failure Clinical Trials Research Articles

Influence of NT-proBNP on Efficacy of Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

BackgroundN-terminal pro–B-type natriuretic peptide (NT-proBNP) is used for diagnostic and prognostic evaluation in heart failure (HF). Previous clinical trials in heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) have shown potential heterogeneity in the treatment response by baseline NT-proBNP levels. ObjectivesThe purpose of this study was to assess the treatment effect of dapagliflozin across baseline levels of NT-proBNP among patients with HFmrEF or HFpEF. MethodsThis was a post hoc analysis from DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure), a randomized, placebo-controlled trial of dapagliflozin in patients with HFmrEF or HFpEF. Elevated NT-proBNP was part of the inclusion criteria (≥300 ng/L for non–atrial fibrillation or flutter [AFF]; ≥600 ng/L for AFF). Baseline NT-proBNP was categorized in quartiles and additionally analyzed continuously. The primary composite outcome was cardiovascular death or worsening HF events. ResultsAmong the 6,262 included patients (mean: 71.7 years and 3,516 [56%] men), the median baseline concentration of NT-proBNP was 716 (Q1-Q3: 469-1,280) ng/L and 1,399 (Q1-Q3: 962-2,212) ng/L for non-AFF and AFF, respectively. Higher NT-proBNP levels were linearly associated with a greater risk of the primary outcome (adjusted HR for log2NTpro-BNP was 1.53 [95% CI: 1.46-1.62] and Q4 vs Q1: 3.46 [95% CI: 2.48-4.22]; P < 0.001), with consistent results regardless of AFF status. The clinical benefit of dapagliflozin was present irrespective of baseline NT-proBNP concentration (P value for interaction = 0.40 by quartiles and = 0.19 continuously for the primary outcome) and the absolute risk reduction was, therefore, greater with higher NT-proBNP concentrations. The effect on health status and safety of dapagliflozin was similarly consistent across NT-proBNP quartiles. ConclusionsDapagliflozin is safe and improves outcomes irrespective of baseline NT-proBNP concentrations in HFmrEF or HFpEF, with the greatest absolute benefit likely seen in patients with higher NT-proBNP concentrations. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)

Vasodilators for acute heart failure-A protocol for a systematic review of randomized clinical trials with meta-analysis and Trial Sequential Analysis.

BackgroundAbove one million annual hospitalizations occur with a primary diagnosis of acute heart failure in the US, with comparable numbers in Europe. Within 1 year, over a third of patients have died or been re‐hospitalized. Most patients have acutely elevated systemic and/or intra‐cardiac blood pressures as part of the acute heart failure syndrome. Most clinical trials of acute heart failure have aimed at reducing preload and/or afterload through drug‐induced vasodilation. However, recent European guidelines downgraded the treatment recommendation of vasodilators. We aim to assess the beneficial and harmful effects of vasodilators in the treatment of acute heart failure.MethodsThis protocol for a systematic review was undertaken using the recommendations of The Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis Protocols. We plan to include all randomized clinical trials assessing the use of vasodilators in the treatment of AHF. The systematic review will be conducted based on a systematic search of relevant major medical databases without date restrictions, including MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) in addition to clinical trial registries. We will begin the searches in August 2022. All included trials will be assessed and classified at low risk of bias or at high risk of bias. Our conclusions will be based on the results from the primary outcomes with concomitant low risk of bias. Extracted data will be analyzed using Trial Sequential Analysis 0.9.5.10, Review Manager 5.3, and SAS. We will assess the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation. We will register this systematic review at Prospero and aim to update it when new trials are published.DiscussionThis protocol defines the detailed methodology and approach used for a systematic review on whether vasodilation for acute heart failure improves patient outcome. This systematic review will potentially aid clinicians in deciding the optimal treatment of patients admitted with acute heart failure. Furthermore, this review will explore gaps in our knowledge and thus guide future research within acute heart failure.

Polypharmacy in Older Heart Failure Patients: a Multidisciplinary Approach.

We provide a review of considerations when applying principles of optimal pharmacotherapy to older adults with heart failure (HF), an analysis on the pivotal clinical trials focusing on applicability to older adults, and multi-disciplinary strategies to optimize the health of HF patients with polypharmacy. Polypharmacy is very common among patients with HF, due to medications for both HF and non-HF comorbidities. Definitions of polypharmacy were not developed specifically for older adults with HF and may need to be modified in order to meaningfully describe medication burden and promote appropriate medical therapy. This is because clinical practice guidelines for multi-drug HF regimens have unique considerations, given that they improve outcomes and symptoms of HF. Adults older than 65years are well represented in contemporary clinical trials for HF with preserved ejection fraction (HFpEF) and guideline directed medical therapy (GDMT) for HF with reduced ejection fraction (HFrEF). While these trials did not have significant heterogeneity in safety or efficacy across a broad age spectrum, some may have limited representation of adults ≥ 80years old, the sickest older adults, or those with decreased functional status. There is also a lack of data on the safety and efficacy of deprescribing HF medications, and deprescription in otherwise stable patients may lead to clinical destabilization or disease progression. There is therefore innate tension between the well-studied benefits of optimized HF therapy for older adults that must be weighed against the risks of polypharmacy and many unknowns that still exist. Given the strong evidence that optimized HF therapies confer symptomatic and mortality benefits for older adults, it is clear that polypharmacy in this context can be appropriate. A shift in paradigm is therefore needed when evaluating polypharmacy in patients with HF. Instead of assuming all polypharmacy is "good" or "bad," we propose a concerted move, using a multidisciplinary approach, to focus on the "appropriateness" of specific medications, in order to optimize HF medical therapy. Clinicians of all specialties caring for complex older adults with HF must consider goals of care, functional status, and new evidence-based therapies, in order to optimize this polypharmacy for older adults.

Improving clinical trial efficiency using a machine learning-based risk score to enrich study populations.

Prognostic enrichment strategies can make trials more efficient, although potentially at the cost of diminishing external validity. Whether using a risk score to identify a population at increased mortality risk could improve trial efficiency is uncertain. We aimed to assess whether Machine learning Assessment of RisK and EaRly mortality in Heart Failure (MARKER-HF), a previously validated risk score, could improve clinical trial efficiency. Mortality rates and association of MARKER-HF with all-cause death by 1 year were evaluated in four community-based heart failure (HF) and five HF clinical trial cohorts. Sample size required to assess effects of an investigational therapy on mortality was calculated assuming varying underlying MARKER-HF risk and proposed treatment effect profiles. Patients from community-based HF cohorts (n=11 297) had higher observed mortality and MARKER-HF scores than did clinical trial patients (n=13 165) with HF with either reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). MARKER-HF score was strongly associated with risk of 1-year mortality both in the community (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.44-1.52) and clinical trial cohorts with HFrEF (HR 1.41, 95% CI 1.30-1.54), and HFpEF (HR 1.74, 95% CI 1.53-1.98), per 0.1 increase in MARKER-HF. Using MARKER-HF to identify patients for a hypothetical clinical trial assessing mortality reduction with an intervention, enabled a reduction in sample size required to show benefit. Using a reliable predictor of mortality such as MARKER-HF to enrich clinical trial populations provides a potential strategy to improve efficiency by requiring a smaller sample size to demonstrate a clinical benefit.

Cardiac Fibrosis in the Pressure Overloaded Left and Right Ventricle as a Therapeutic Target.

Myocardial fibrosis is a remodeling process of the extracellular matrix (ECM) following cardiac stress. “Replacement fibrosis” is a term used to describe wound healing in the acute phase of an injury, such as myocardial infarction. In striking contrast, ECM remodeling following chronic pressure overload insidiously develops over time as “reactive fibrosis” leading to diffuse interstitial and perivascular collagen deposition that continuously perturbs the function of the left (L) or the right ventricle (RV). Examples for pressure-overload conditions resulting in reactive fibrosis in the LV are systemic hypertension or aortic stenosis, whereas pulmonary arterial hypertension (PAH) or congenital heart disease with right sided obstructive lesions such as pulmonary stenosis result in RV reactive fibrosis. In-depth phenotyping of cardiac fibrosis has made it increasingly clear that both forms, replacement and reactive fibrosis co-exist in various etiologies of heart failure. While the role of fibrosis in the pathogenesis of RV heart failure needs further assessment, reactive fibrosis in the LV is a pathological hallmark of adverse cardiac remodeling that is correlated with or potentially might even drive both development and progression of heart failure (HF). Further, LV reactive fibrosis predicts adverse outcome in various myocardial diseases and contributes to arrhythmias. The ability to effectively block pathological ECM remodeling of the LV is therefore an important medical need. At a cellular level, the cardiac fibroblast takes center stage in reactive fibrotic remodeling of the heart. Activation and proliferation of endogenous fibroblast populations are the major source of synthesis, secretion, and deposition of collagens in response to a variety of stimuli. Enzymes residing in the ECM are responsible for collagen maturation and cross-linking. Highly cross-linked type I collagen stiffens the ventricles and predominates over more elastic type III collagen in pressure-overloaded conditions. Research has attempted to identify pro-fibrotic drivers causing fibrotic remodeling. Single key factors such as Transforming Growth Factor β (TGFβ) have been described and subsequently targeted to test their usefulness in inhibiting fibrosis in cultured fibroblasts of the ventricles, and in animal models of cardiac fibrosis. More recently, modulation of phenotypic behaviors like inhibition of proliferating fibroblasts has emerged as a strategy to reduce pathogenic cardiac fibroblast numbers in the heart. Some studies targeting LV reactive fibrosis as outlined above have successfully led to improvements of cardiac structure and function in relevant animal models. For the RV, fibrosis research is needed to better understand the evolution and roles of fibrosis in RV failure. RV fibrosis is seen as an integral part of RV remodeling and presents at varying degrees in patients with PAH and animal models replicating the disease of RV afterload. The extent to which ECM remodeling impacts RV function and thus patient survival is less clear. In this review, we describe differences as well as common characteristics and key players in ECM remodeling of the LV vs. the RV in response to pressure overload. We review pre-clinical studies assessing the effect of anti-fibrotic drug candidates on LV and RV function and their premise for clinical testing. Finally, we discuss the mode of action, safety and efficacy of anti-fibrotic drugs currently tested for the treatment of left HF in clinical trials, which might guide development of new approaches to target right heart failure. We touch upon important considerations and knowledge gaps to be addressed for future clinical testing of anti-fibrotic cardiac therapies.

Editorial introductions.

Current Opinion in Cardiology was launched in 1985. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of cardiology is divided into 14 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Ali J. MarianAli J. MarianDr Ali J. Marian joined the faculty at the Department of Medicine (Cardiology) at Baylor College of Medicine, USA, in 1992 and was recruited to The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases at UTHealth, USA, in 2006. His colleagues nationally and internationally recognize him for his research achievements and expertise in genetics of cardiomyopathies. He received the Young Investigator Award from the American College of Cardiology, the Junior Faculty Award for research from the American Federation of Medical Research, the Award for Excellence in Research at Baylor College of Medicine, the Established Investigator Award by the American Heart Association, the Clinician-Scientist Award in Translational Research from Burroughs Wellcome Fund and the Best Editor Award from the American Heart Association. Dr Marian is an Associate Editor of Cardiovascular Research and Section Editor on Genetics for Current Opinion in Cardiology and Current Atherosclerosis Reports. He was a Deputy Editor of Circulation Research, Associate Editor for Circulation and an Associate Editor for European Journal of Clinical Investigation. He received the Best Editor Award from the American Heart Association for his work for Circulation Research. Dr Marian has co-authored ∼ 200 manuscripts in peer-reviewed journals. He has served as a reviewer for > 100 National Institute of Health, American Heart Association and other organizations study sections. Dr Marian's research is supported by grants from NHLBI-NIH, Leducq Foundation Trans-Atlantic Network of Excellence and local foundations. Rebecca CogswellRebecca CogswellDr Cogswell completed internal medicine residency, chief residency, and cardiology fellowship at the University of California, San Francisco, USA. While at UCSF, she also completed a year of advanced clinical research training. She then went on to complete Advanced Heart Failure fellowship at the University of Minnesota, USA. She has been on faculty at the University of Minnesota since 2013 and is presently the Medical Director of Mechanical Circulatory Support Program. Dr Cogswell's research focus is the skeletal muscle changes that occur in end stage heart failure. Specifically, she is interested in what these changes can reveal about optimal timing of advanced heart failure therapies and using these measures to predict outcomes after mechanical circulatory support. She has built a left ventricular assist device database at the University of Minnesota and is collaborating with other centers towards answering several clinical questions in the contemporary continuous flow LVAD population. She is presently the Advanced Heart Failure fellowship director and is an active reviewer for Journal of Heart Lung Transplant and Circulation Heart Failure. She is a principle investigator for several heart failure and LVAD related clinical trials. In 2017, she was appointed to the Medtronic Heart Failure Advisory Board. In addition, she developed and directs to the Infiltrative Cardiomyopathies Clinic at the University of Minnesota. Gene KimGene KimDr Kim is a cardiologist with the Advanced heart failure, Cardiac transplant, and Mechanical Circulatory Support Program at the University of Chicago Medicine, USA. He is an Assistant Professor of Medicine and the Advanced Heart Failure Fellowship Program Director. His medical school, residency, and fellowship training were completed at the University of Chicago. Dr Kim's research interests include the genetic and epigenetic regulation of heart failure and arrhythmogenesis with publications on the role of microRNAs in cardiomyopathy. His interests also include myocardial recovery, extracellular matrix in failing myocardium, and the role of inflammation and angiogenesis in LVAD patients. He has published over 80 articles and book chapters and is an investigator in numerous clinical trials.

Women With Heart Failure In The CardiAMP Cell Therapy Trial

<h3>Introduction</h3> Ischemic heart disease affects 48 million women in the US. The prevalence of heart failure (HF) is similar among women and men, but a majority of the newly diagnosed HF patients in the United States each year are women. Women with HF and reduced left ventricular ejection fraction are more symptomatic and have similar outcomes as men. Despite similar need for treatment, women represent only roughly 1 of every 5 patients enrolled in clinical trials for heart failure. A novel personalized approach to cell-based management of NYHA class II-III ischemic HF is being employed in the ongoing CardiAMP Cell Therapy HF trial (NCT02438306). An important screening criterion consists of a cell "potency" assay (CPA), whereby prospective subjects must demonstrate bone marrow quality having sufficient CD34+ cells, among other cell markers, to be included in the trial. The purpose of this analysis was to determine if there may be differences in the potential for female HF patients to meet the study CPA screening criterion and therefore be included in the trial. <h3>Methods</h3> For the CPA, bone marrow quality characteristics were evaluated using a biomarker panel, including determination of CD34+ cell concentration by flow cytometry. Of the 154 patients screened thus far, 138 (89.6%) are men. Average age is 63.7± 4.9 years for females and 66.5±11.5 for males. <h3>Results</h3> Concentration of CD34+ cells (Table) did not differ significantly between males and females (p=0.354). Females met the CPA criterion at a higher rate than males (75% vs 65%). All subjects who passed the CPA were successfully randomized into the cell therapy treatment or control arms per protocol. <h3>Conclusions</h3> Women continue to be under enrolled in this HF trial. Preliminary results suggest that women may be more likely than men to meet the CPA criterion for study eligibility. Additional analyses are underway to evaluate other demographic measures that may be associated with bone marrow quality for autologous treatment of heart failure. While the trial continues to enroll, the importance of including more women into this and other HF research programs is vital to understand and improve outcomes for all patients.

Satisfaction With Access To Health Services In West Virginia Despite Covid-19

IntroductionCenters for Disease Control and Prevention reported COVID-19 significantly impacts health services for chronic health conditions including patients with cardiovascular disease. This study was conducted as an immediate follow-up on study participants who enrolled in the heart failure (HF) clinical trial (1R15NR018547-01) testing home palliative care coaching for patients with HF and their family caregivers in rural Appalachia.HypothesisCOVID-19 impacts HF patients and their caregivers’ (1) overall quality of life (QoL) and health satisfaction, and (2) access to health care and community services.MethodsThis is a descriptive study conducted between August 2020 to March 2021, using a structured telephone survey with open-ended questions. The questions include demographic queries, frequency of health services use, overall quality of life and health during social distancing and the COVID-19 pandemic.ResultsOf 13 participants enrolled in the study, the majority were white (85%) and married (61.5%). HF patients were predominantly male (83%), and caregivers were female (85.7%). The mean age of HF patients was 63 (SD=16.8) and family caregivers was 60.7 (SD=12.9) years. Twenty-three percent of participant couldn't financially make ends meet, while another 23.1% reported having barely enough. On a scale of 1-5, the patients were satisfied with their overall QoL (Mean = 3.83 (SD=1.17), but half of caregivers reported average and poor QoL (Mean = 3.17 (SD=0.98). However, 70% of caregivers were satisfied with their health (Mean=3.71 (SD=1.25), while half of the patients reported neutral satisfaction or dissatisfaction with their health (Mean=3.17 (SD=0.98). All patients were able to attend in-person appointments. Notably, 50% of patients reported phone calls and 33% used telehealth for their appointments. A majority of patients reported calling (83%) and receiving calls (67%) from their doctors or nurses. The reasons for calls were related to health issues, lab reports, medications, and dose adjustments. Three patients reported emergency room (ER) visits and two had HF-related hospital admissions. One caregiver had an ER visit. Overall, a few participants (15%) used community services, including hospice and visiting nurses and found them useful. About 70% of participants reported sufficient healthcare, while one-third (30%) did not and reported difficulty in getting medications and rescheduling appointments after cancellation.ConclusionsCOVID-19 has an impact on QoL and health of patients with HF and their family caregivers. These families need care coordination from their healthcare providers to maintain HF home care. Many families need help with their prescriptions, monitoring and managing symptoms, scheduling appointments, and preventing unwarranted hospitalizations.

Improving Enrollment of Underrepresented Racial and Ethnic Populations in Heart Failure Trials

Despite bearing a disproportionate burden of heart failure (HF), Black and Hispanic individuals have been poorly represented in HF clinical trials. Underrepresentation in clinical trials limits the generalizability of the findings to these populations and may even introduce uncertainties and hesitancy when translating trial data to the care of people from underrepresented groups. The Heart Failure Collaboratory, a consortium of stakeholders convened to enhance HF therapeutic development, has been dedicated to improving recruitment strategies for patients from diverse and historically underrepresented groups. Despite federal policies from the US Food and Drug Administration and National Institutes of Health aimed at improving trial representation, gaps in trial enrollment proportionate to the racial and ethnic composition of the HF population have persisted. Increasing trial globalization with limited US enrollment is a major driver of these patterns. Additional barriers to representative enrollment include inequities in care access, logistical issues in participation, restrictive enrollment criteria, and English language requirements. Strategies for improving diverse trial enrollment include methodical study design and site selection, diversification of research leadership and staff, broadening of eligibility criteria, community and patient engagement, and broad stakeholder commitment. In contemporary HF trials, diverse trial enrollment is not only feasible but can be efficiently achieved to improve the generalizability and translation of trial knowledge to clinical practice.

Heart failure clinical trial enrollment at a rural satellite hospital

IntroductionHeart failure is a clinical condition that notably affects the lives of patients in rural areas. Partnering of a rural satellite hospital with an urban academic medical center may provide geographically underrepresented populations with heart failure an opportunity to access to controlled clinical trials (CCTs). MethodsWe report our experience in screening, consenting and enrolling subjects at the VCU Health Community Memorial Hospital (VCU-CMH) in rural South Hill, Virginia, that is part of the larger VCU Health network, with the lead institution being VCU Health Medical College of Virginia Hospitals (VCU-MCV), Richmond, VA. Subjects were enrolled in a clinical trial sponsored by the National Institutes of Health and assigned to treatment with an anti-inflammatory drug for heart failure or placebo. We used the electronic health record and remote guidance and oversight from the VCU-MCV resources using a close-loop communication network to work with local resources at the facility to perform screening, consenting and enrollment. ResultsOne hundred subjects with recently decompensated heart failure were screened between January 2019 and August 2021, of these 61 are enrolled to date: 52 (85%) at VCU-MCV and 9 (15%) at VCU-CMH. Of the subjects enrolled at VCU-CMH, 33% were female, 77% Black, with a mean age of 52 ± 10 years. ConclusionThe use of a combination of virtual/remote monitoring and guidance of local resources in this trial provides an opportunity for decentralization and access of CCTs for potential novel treatment of heart failure to underrepresented individuals from rural areas. Trial registrationClinicalTrials.gov: NCT03797001

Developments in Exercise Capacity Assessment in Heart Failure Clinical Trials and the Rationale for the Design of METEORIC-HF.

Heart failure with reduced ejection fraction (HFrEF) is a highly morbid condition for which exercise intolerance is a major manifestation. However, methods to assess exercise capacity in HFrEF vary widely in clinical practice and in trials. We describe advances in exercise capacity assessment in HFrEF and a comparative analysis of how various therapies available for HFrEF impact exercise capacity. Current guideline-directed medical therapy has indirect effects on cardiac performance with minimal impact on measured functional capacity. Omecamtiv mecarbil is a novel selective cardiac myosin activator that directly increases cardiac contractility and in a phase 3 cardiovascular outcomes study significantly reduced the primary composite end point of time to first heart failure event or cardiovascular death in patients with HFrEF. The objective of the METEORIC-HF trial (Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility in Heart Failure) is to assess the effect of omecamtiv mecarbil versus placebo on multiple components of functional capacity in HFrEF. The primary end point is to test the effect of omecamtiv mecarbil compared with placebo on peak oxygen uptake as measured by cardiopulmonary exercise testing after 20 weeks of treatment. METEORIC-HF will provide state-of-the-art assessment of functional capacity by measuring ventilatory efficiency, circulatory power, ventilatory anaerobic threshold, oxygen uptake recovery kinetics, daily activity, and quality-of-life assessment. Thus, the METEORIC-HF trial will evaluate the potential impact of increased myocardial contractility with omecamtiv mecarbil on multiple important measures of functional capacity in ambulatory patients with symptomatic HFrEF. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT03759392.

Natriuretic peptide-based inclusion criteria in heart failure with preserved ejection fraction clinical trials: insights from PARAGON-HF.

Natriuretic peptides (NPs) are now routinely incorporated as key inclusion criteria in clinical trials of heart failure with preserved ejection fraction (HFpEF) as objective measures of risk. An early amendment in PARAGON-HF required all participants to have elevated NP concentrations, but some were enrolled pre-amendment, providing a unique opportunity to understand the influence of enrolment pathway in HFpEF clinical trials. Among 4796 participants in PARAGON-HF, 193 (4.0%) did not meet the final NP-based enrolment criteria (N-terminal pro-B-type natriuretic peptide >300 pg/ml for patients in sinus rhythm or >900 pg/ml for patients in atrial fibrillation/flutter). These patients had lower rates of the primary endpoint of total heart failure hospitalizations and cardiovascular death as compared with patients meeting final enrolment criteria (8.6 [6.7-11.2] events per 100 patient-years vs. 14.0 [13.4-14.7] events per 100 patient-years; p=0.01). The rate ratio for the treatment effect comparing sacubitril/valsartan with valsartan was 0.85 (95% confidence interval 0.74-0.99; p=0.04) in those who met final criteria. Natriuretic peptides are an important tool in HFpEF clinical trials to objectively affirm diagnoses and enrich clinical event rates.

Representation of women in heart failure clinical trials: Barriers to enrollment and strategies to close the gap

Heart failure is a significant public health burden that differentially impacts women. Important sex- and gender-based differences in HF risk factors, presentation, and treatment exist, and the generation of high-quality evidence is critical to elucidate these differences. Despite the remarkable growth of the heart failure clinical research enterprise over the last four decades, women remain underrepresented in heart failure clinical trials relative to the population prevalence of heart failure in women. This disparity has resulted in significant knowledge gaps regarding the optimal care of women with heart failure. In this review, we summarize the existing literature regarding the participation of women in heart failure clinical trials. Additionally, we explain the evidence surrounding sex- and gender-specific barriers to enrollment in heart failure clinical trials and describe interventions that should be implemented throughout the clinical trial lifespan to achieve sex and gender parity.

Prevention of Heart Failure by Expression of Neuregulin-1-Beta1 in Cardiomyocytes Using Adeno-Associated Virus

Heart failure (HF) is a leading cause of death worldwide, and effective treatments for HF are lacking. Infusion of the growth factor neuregulin-1 (NRG-1) is a promising therapy currently undergoing clinical trials for HF. NRG-1 activates growth factor receptors on cardiomyocytes (predominantly ErbB4, but also ErbB3) to confer protection. Clinically, NRG-1 infusion therapy is limited because it is dose-limited by liver damage and systemic delivery of a potent growth factor has the capacity to promote oncogenesis.

Consensus clustering approaches in the analysis of wearables and biosensors

Wearables and biosensors allow for the passive and non-invasive collection of complimentary data for clinical trials. In specific, wearables and biosensors are useful in the area of cardiovascular disease and heart failure as they can serve as proxies for measures of physical activity and quality of life. In a recent heart failure clinical trial, wearable device data capturing information regarding physical activity and activity intensity was captured for approximately 220 patients across a total of 28 days. This data was then analyzed utilizing a consensus clustering approach in which the patients were assigned to four separate clusters. Activity intensity and activity duration data were described by cluster, in addition to baseline medical history data. Differences were identified in the clinical phenotypes of different clusters of patients. The analytical work here represents an approach that can be utilized when looking to analyze wearable and biosensor data to detect whether potential heterogeneous clinical clusters of patients exist.

Diversity in modern heart failure trials: Where are we, and where are we going

Over the last three decades, increased attention has been given to the representation of historically underrepresented groups within the landscape of pivotal clinical trials. However, recent events (i.e., coronavirus pandemic) have laid bare the potential continuation of historic inequities in available clinical trials and studies aimed at the care of broad patient populations. Anecdotally, cardiovascular disease (CVD) has not been immune to these disparities. Within this review, we examine and discuss recent landmark CVD trials, with a specific focus on the representation of Blacks within several critically foundational heart failure clinical trials tied to contemporary treatment strategies and drug approvals. We also discuss solutions for inequities within the landscape of cardiovascular trials. Building a more diverse clinical trial workforce coupled with intentional efforts to increase clinical trial diversity will advance equity in cardiovascular care.

Abstract 9517: Under-Utilization of Conventional Guideline-Directed Medical Therapy Among Patients Eligible for the Recent Large-Scale Clinical Trials of Heart Failure With Reduced Ejection Fraction

Introduction: Recent large-scale clinical trials of novel heart failure (HF) agents (angiotensin receptor-neprilysin inhibitor, sodium-glucose cotransporter 2 inhibitor, and ivabradine) emphasize the use of baseline conventional guideline-directed medical therapy (GDMT; angiotensin-converting enzyme inhibitor, beta-blocker and mineral corticosteroid receptor antagonist); however, its use among real-world trial-eligible patients remains unclear. Objectives: To evaluate the prescription rate of GDMT and its association with long-term outcomes in patients that met enrollment criteria of recent large-scale clinical trials within hospitalized HF patients. Methods: We examined 1631 consecutive patients with HF with reduced ejection fraction (HFrEF) discharged after an episode of acute heart failure in the multicenter registry in Japan. We assessed the use of GDMT among patients that met PARADIGM-HF/ DAPA-HF enrollment criteria and SHIFT enrollment criteria. We then examined the association between the use of GDMT and long-term outcomes within each enrollment criteria. Results: Overall, 63.2% (n=1030) and 34.9% (n=569) of the patients met the enrollments criteria of PARADIGM/DAPA-HF and SHIFT trials. Within each patient subset, 32.5% (n=335) and 29.2% (n=166) had full GDMT, respectively. Although 82.6% (n=470) of patients that met SHIFT enrollment criteria received beta-blockers, only 21.3% (n=121) and 4.4% (n=25) patients were on &gt;50% or higher dose (recommended dose). The use of GDMT was associated with lower rates of 2-year mortality and HF readmission in both of these populations (HR 0.85, 95% CI 0.81-0.89; HR 0.90, 95% CI 0.85-0.95, respectively). Conclusions: The underutilization of GDMT was observed among patients meeting the enrollment criteria of novel trials within Japanese multicenter registry of HF patients. Further effort to optimize the conventional GDMT before initiating novel therapeutics needs to be implemented.

Abstract 9476: Global Representation of Leaders, Collaborators, and Enrolled Participants in Heart Failure Clinical Trials: A Systematic Bibliometric Review

Introduction: The geographic representation of investigators and participants in heart failure (HF) randomized clinical trials (RCTs) may not reflect the global burden of disease. Objectives: We assessed the geographic diversity of RCT leaders and explored associations with the geographic representation of enrolled participants among impactful HF RCTs. Methods: We searched MEDLINE, EMBASE, and CINAHL for HF RCTs published in journals with impact factor ≥ 10 between January 2000 and June 2020. We used the Jonckheere-Terpstra test to assess temporal trends and multivariable logistic regression models to explore associations between predictors and outcomes. Results: There were 414 eligible RCTs. Only 80 of 828 trial leaders (9.7%; 95% CI: 7.8% to 11.8%), and 453 of 4656 collaborators (9.7%; 95% CI: 8.8% to 10.6%) were from outside Europe and North America, with no change in temporal trends. The adjusted odds of trial leadership outside Europe and North America were lower with industry funding (aOR: 0.33; 95% CI: 0.15 to 0.75; P = 0.008). Among 157,416 participants in whom geography was reported, only 14.5% (95% CI: 14.3% to 14.7%) were enrolled outside Europe and North America, but odds of enrolment were ten-fold greater with trial leadership outside Europe and North America (aOR: 10.0; 95% CI 5.6-19.0; P &lt; 0.001). Conclusions: Regions disproportionately burdened with HF are under-represented in HF trial leadership, collaboration, and enrolment. RCT leadership outside Europe and North America is independently associated with participant enrolment in under-represented regions. Increasing research capacity outside Europe and North America could enhance trial diversity and generalizability.

Effect of ivabradine in heart failure: a meta-analysis of heart failure patients with reduced versus preserved ejection fraction.

In clinical trials of heart failure reduced ejection fraction (HFrEF), ivabradine seemed to be an effective heart rate lowering agent associated with lower risk of cardiovascular death. In contrast, ivabradine failed to improve cardiovascular outcomes in heart failure preserved ejection fraction (HFpEF) despite the significant effect on heart rate. This meta-analysis is the first to compare the effects of ivabradine on heart rate and mortality parameters in HFpEF versus HFrEF. We screened three databases: PubMed, Embase, and Cochrane Library. The outcomes of these studies were mortality, reduction in heart rate, and left ventricular function improvement. We compared the efficacy of ivabradine treatment in HFpEF versus HFrEF. Heart rate analysis of pooled data showed decrease in both HFrEF (-17.646beats/min) and HFpEF (-11.434beats/min), and a tendency to have stronger bradycardic effect in HFrEF (p= 0.094) in randomized clinical trials. Left ventricular ejection fraction analysis revealed significant improvement in HFrEF (5.936, 95% CI: [4.199-7.672], p< 0.001) when compared with placebo (p< 0.001). We found that ivabradine significantly improves left ventricular performance in HFrEF, at the same time it exerts a tendency to have improved bradycardic effect in HFrEF. These disparate effects of ivabradine and the higher prevalence of non-cardiac comorbidities in HFpEF may explain the observed beneficial effects in HFrEF and the unchanged outcomes in HFpEF patients after ivabradine treatment.

Estimating treatment effect of tafamidis on hospitalisation in NYHA class III ATTR-CM patients in the presence of death using principal stratification

Abstract Background Hospitalisation has been widely used as a measure of morbidity in clinical trials for chronic heart failure. As previously reported in the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), the observed frequency of cardiovascular (CV)-related hospitalisations favoured tafamidis over placebo in all analyses except in the NYHA Class III baseline subgroup with a relative risk of 1.41 [95% CI: 1.05, 1.90]1. However, the evaluation of the causal effect of treatment on hospitalisation is complicated in the presence of death as death precludes further hospitalisation and thus limits the evaluation of hospitalisation rates between groups. This confounding effect of death is particularly relevant in NYHA Class III participants who had higher mortality rates compared to Class I or II participants. Purpose This aim of this study was to assess the impact of the confounding effect of death on CV-related hospitalisation. Methods The effect of tafamidis treatment on CV-related hospitalisations was defined and compared in the subset of participants from either treatment arm who were alive at the end of the study (ie, Month 30); however the subset of participants who survive on the tafamidis arm would be expected to have different characteristics from the subset of participants who survive on the control arm and thus these analyses do not estimate the causal effect. To address this possible survivor bias, we additionally conducted a post hoc principal stratification analysis. Principal stratification is a statistical method to adjust for post treatment events, in this case mortality, by classifying participants according to their potential to survive under each treatment arm. Specifically, we sought to estimate the principal strata effect on CV-related hospitalisations in NYHA Class III participants who would survive irrespective of treatment assignment. Sensitivity analyses were performed to assess the model assumptions. Results The analysis within the subset of participants who survived at Month 30 demonstrated a relative risk of 1.1 (95% CI: 0.56, 2.16) between tafamidis and placebo. The principal stratification analyses of subjects who would survive to 30 months irrespective of treatment estimated a 0.75 (95% CI: 0.44, 1.23) relative risk between tafamidis and placebo, suggesting a 25% reduction in frequency of CV-related hospitalisations in the tafamidis arm. Conclusion The initial data reported in ATTR-ACT likely underestimated the true effect of tafamidis on CV-related hospitalisations due to the confounding effect of death. The analysis of treatment group among observed survivors estimated a smaller relative risk for NYHA Class III; however, this analysis does not fully address the possible survivor bias. The survivor average causal effect, which adjusts for the survival bias demonstrated a reduction in the frequency of CV-related hospitalisation in the tafamidis treated arm for NYHA Class III participants. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Pfizer