Heart Failure Clinical Trials Research Articles

Sex Differences in Long-term Heart Failure Prognosis: A Comprehensive Meta-Analysis.

Sex differences in the long-term prognosis of heart failure (HF) remain controversial, and there is a lack of comprehensive pooling of the sex differences in outcomes of HF. This study aims to characterize the sex differences in the long-term prognosis of HF and explore whether these differences vary by age, HF course, left ventricular ejection fraction, region, period of study, study design, and follow-up duration. A systematic review was conducted using Medline, Embase, Web of Science, and the Cochrane Library, from January 1, 1990, to March 31, 2024. The primary outcome was all-cause mortality (ACM), and the secondary outcomes included cardiovascular mortality (CVM), hospitalization for HF (HHF), all-cause hospitalization, a composite of ACM and HHF, and a composite of CVM and HHF. Pooled hazard risks (HRs) with corresponding 95% confidence intervals (CIs) were calculated using random effects meta-analysis. 94 studies (comprising 96 cohorts) were included in the meta-analysis, representing 706,247 participants (56.5% were men, the mean age was 71.0 years). Female HF patients had a lower risk of ACM (HR: 0.83, 95% CI: 0.80, 0.85; I2=84.9%), CVM (HR: 0.84, 95% CI: 0.79, 0.89; I2=70.7%), HHF (HR: 0.94, 95% CI: 0.89, 0.98; I2=84.0%), and composite endpoints (ACM+HHF: HR: 0.89, 95% CI: 0.83, 0.95; I2=80.0%; CVM+HHF: HR: 0.85, 95% CI: 0.77, 0.93; I2=87.9%) compared to males. Subgroup analysis revealed that the lower risk of mortality observed in women was more pronounced among individuals with long-course HF (i.e., chronic HF, follow-up duration >2 years) or recruited in the randomized controlled trials. (P for interaction <0.05). Female HF patients had a better prognosis compared to males, with lower risks of ACM, CVM, HHF, and composite endpoints. Despite the underrepresentation of female populations in HF clinical trials, their mortality benefits tended to be lower than in real-world settings. PROSPERO: CRD42024526100.

Management of patients with heart failure and chronic kidney disease.

Chronic kidney disease (CKD) and heart failure are often co-existing conditions due to a shared pathophysiological process involving neurohormonal activation and hemodynamic maladaptation. A wide range of pharmaceutical and interventional tools are available to patients with CKD, consisting of traditional ones with decades of experience and newer emerging therapies that are rapidly reshaping the landscape of medical care for this population. Management of patients with heart failure and CKD requires a stepwise approach based on renal function and the clinical phenotype of heart failure. This is often challenging due to altered drug pharmacokinetics interactions with various degrees of kidney function and frequent adverse effects from the therapy that lead to poor patient tolerance. Despite a great body of clinical evidence and guidelines that have offered various treatment options for patients with heart failure and CKD, respectively, patients with CKD are still underrepresented in heart failure clinical trials, especially for those with advanced CKD and end-stage renal disease (ESRD). Future studies are needed to better understand the generalizability of these therapeutic options among heart failures with different stages of CKD.

Eligibility of Asian and European registry patients for phase III trials in heart failure with reduced ejection fraction.

Traditional approaches to designing clinical trials for heart failure (HF) have historically relied on expertise and past practices. However, the evolving landscape of healthcare, marked by the advent of novel data science applications and increased data availability, offers a compelling opportunity to transition towards a data-driven paradigm in trial design. This research aims to evaluate the scope and determinants of disparities between clinical trials and registries by leveraging natural language processing for the analysis of trial eligibility criteria. The findings contribute to the establishment of a robust design framework for guiding future HF trials. Interventional phase III trials registered for HF on ClinicalTrials.gov as of the end of 2021 were identified. Natural language processing was used to extract and structure the eligibility criteria for quantitative analysis. The most common criteria for HF with reduced ejection fraction (HFrEF) were applied to estimate patient eligibility as a proportion of registry patients in the ASIAN-HF (N=4868) and BIOSTAT-CHF registries (N=2545). Of the 375 phase III trials for HF, 163 HFrEF trials were identified. In these trials, the most frequently encountered inclusion criteria were New York Heart Association (NYHA) functional class (69%), worsening HF (23%), and natriuretic peptides (18%), whereas the most frequent comorbidity-based exclusion criteria were acute coronary syndrome (64%), renal disease (55%), and valvular heart disease (47%). On average, 20% of registry patients were eligible for HFrEF trials. Eligibility distributions did not differ (P=0.18) between Asian [median eligibility 0.20, interquartile range (IQR) 0.08-0.43] and European registry populations (median 0.17, IQR 0.06-0.39). With time, HFrEF trials became more restrictive, where patient eligibility declined from 0.40 in 1985-2005 to 0.19 in 2016-2022 (P=0.03). When frequency among trials is taken into consideration, the eligibility criteria that were most restrictive were prior myocardial infarction, NYHA class, age, and prior HF hospitalization. Based on 14 trial criteria, only one-fifth of registry patients were eligible for phase III HFrEF trials. Overall eligibility rates did not differ between the Asian and European patient cohorts.

Eligibility of Asian and European registry patients for phase III trials in heart failure with reduced ejection fraction.

Traditional approaches to designing clinical trials for heart failure (HF) have historically relied on expertise and past practices. However, the evolving landscape of healthcare, marked by the advent of novel data science applications and increased data availability, offers a compelling opportunity to transition towards a data-driven paradigm in trial design. This research aims to evaluate the scope and determinants of disparities between clinical trials and registries by leveraging natural language processing for the analysis of trial eligibility criteria. The findings contribute to the establishment of a robust design framework for guiding future HF trials. Interventional phase III trials registered for HF on ClinicalTrials.gov as of the end of 2021 were identified. Natural language processing was used to extract and structure the eligibility criteria for quantitative analysis. The most common criteria for HF with reduced ejection fraction (HFrEF) were applied to estimate patient eligibility as a proportion of registry patients in the ASIAN-HF (N=4868) and BIOSTAT-CHF registries (N=2545). Of the 375 phase III trials for HF, 163 HFrEF trials were identified. In these trials, the most frequently encountered inclusion criteria were New York Heart Association (NYHA) functional class (69%), worsening HF (23%), and natriuretic peptides (18%), whereas the most frequent comorbidity-based exclusion criteria were acute coronary syndrome (64%), renal disease (55%), and valvular heart disease (47%). On average, 20% of registry patients were eligible for HFrEF trials. Eligibility distributions did not differ (P=0.18) between Asian [median eligibility 0.20, interquartile range (IQR) 0.08-0.43] and European registry populations (median 0.17, IQR 0.06-0.39). With time, HFrEF trials became more restrictive, where patient eligibility declined from 0.40 in 1985-2005 to 0.19 in 2016-2022 (P=0.03). When frequency among trials is taken into consideration, the eligibility criteria that were most restrictive were prior myocardial infarction, NYHA class, age, and prior HF hospitalization. Based on 14 trial criteria, only one-fifth of registry patients were eligible for phase III HFrEF trials. Overall eligibility rates did not differ between the Asian and European patient cohorts.

Implications of trial eligibility in patients with heart failure with mildly reduced or preserved ejection fraction.

Clinical trials in heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) commonly have detailed eligibility criteria. This may contribute to challenges with efficient enrolment and questions regarding the generalizability of trial findings. Patients with HFmrEF/HFpEF from a large US healthcare system were identified through a computable phenotype applied in linked imaging and electronic health record databases. We evaluated shared eligibility criteria from five recent/ongoing HFmrEF/HFpEF trials (PARAGON-HF, EMPEROR-Preserved, DELIVER, FINE-ARTS, and SPIRRIT-HFpEF) and compared clinical and echocardiographic features as well as outcomes between trial-eligible and trial-ineligible patients. Among 5552 patients with HFpEF/HFmrEF, 792 (14%) were eligible for trial consideration, having met all criteria assessed. Causes of ineligibility included lack of recent loop diuretics (37%), significant pulmonary disease (24%), reduced estimated glomerular filtration rate (17%), recent stroke/transient ischaemic attack (13%), or low natriuretic peptides (12%); 53% of ineligible patients had >1 reason for exclusion. Compared with eligible patients, ineligible patients were younger (age 71 vs. 75years, P<0.001) with higher rates of coronary artery disease (66% vs. 59%, P<0.001) and peripheral vascular disease (40% vs. 33%, P<0.001), but less mitral regurgitation, lower E/e' ratio, and smaller left atrial sizes. Both eligible and ineligible patients demonstrated high rates of structural heart disease consistent with HFpEF [elevated left atrial size or left ventricular (LV) hypertrophy/increased LV mass], although this was slightly higher among eligible patients (95% vs. 92%, P=0.001). The two cohorts demonstrated similar LV global longitudinal strain along with a similar prevalence of atrial fibrillation/flutter, hypertension, and obesity. Ineligible patients had similar all-cause mortality (33% vs. 33% at 3years) to those eligible but lower rates of heart failure hospitalization (20% vs. 28% at 3years, P<0.001). Among patients with HFmrEF/HFpEF from a large health system, approximately one in seven were eligible for major trials based on key criteria applied through a clinical computable phenotype. These findings highlight the large proportion of patients with HFmrEF/HFpEF ineligible for contemporary trials for whom the generalizability of trial findings may be questioned and further investigation would be beneficial.

Nitroxyl donating and visualization with a coumarin-based fluorescence probe

Nitroxyl (HNO), the single-electron reduction product of nitric oxide (NO), has attracted great interest in the treatment of congestive heart failure in clinical trials. In this paper, we describe the first coumarin-based compound N-hydroxy-2-oxo-2H-chromene-6-sulfonamide (CD1) as a dualfunctional HNO donor, which can release both an HNO signaling molecule and a fluorescent reporter. Under physiological conditions (pH 7.4 and 37 °C), the CD1 HNO donor can readily decompose with a half-life of ∼90 min. The corresponding stoichiometry HNO from the CD1 donor was confirmed using both Vitamin B12 and phosphine compound traps. In addition to HNO releasing, specifically, the degradation product 2-oxo-2H-chromene-6-sulfinate (CS1) was generated as a fluorescent marker during the decomposition. Therefore, the HNO amount released in situ can be accurately monitored through fluorescence generation. As compared to the CD1 donor, the fluorescence intensity increased by about 4.9-fold. The concentration limit of detection of HNO releasing was determined to be ∼0.13 μM according to the fluorescence generation of CS1 at physiological conditions. Moreover, the bioimaging of the CD1 donor was demonstrated in the cell culture of HeLa cells, where the intracellular fluorescence signals were observed, inferring the site of HNO release. Finally, we anticipate that this novel coumarin-based CD1 donor opens a new platform for exploring the biology of HNO.

Real-world characteristics and use patterns of patients treated with vericiguat: A nationwide longitudinal cohort study in Germany.

Vericiguat reduced clinical endpoints in patients experiencing worsening heart failure in clinical trials, but its implementation outside trials is unclear. This retrospective analysis of longitudinally collected data was based on the IQVIA™ LRx database, which includes ~ 80% of the prescriptions of the 73 million people covered by the German statutory health insurance. Between September 2021 and December 2022, vericiguat was initiated in 2916 adult patients. Their mean age was 73 ± 13 years and 28% were women. While approximately 70% were uptitrated beyond 2.5 mg, only 36% reached 10 mg. Median time to up-titration from 2.5 mg to 5 mg was 17 (quartiles: 11-33) days, and from 2.5 to 10 mg 37 (25-64) days, respectively. In 87% of thepatients, adherence to vericiguat was high as indicated by a medication possession ratio of ≥ 80%, and 67% of thepatients persistently used vericiguat during the first year. Women and older patients reached the maximal dose of 10 mg vericiguat less often and received other substance classes of guideline-recommended therapy (GDMT) less frequently. The proportion of patients receiving four pillars of GDMT increased from 29% before vericiguat initiation to 44% afterwards. In a real-world setting, despite higher age than in clinical trials, adherence and persistence of vericiguat appeared satisfactory across age categories. Initiation of vericiguat was associated with intensification of concomitant GDMT. Nevertheless, barriers to vericiguat up-titration and implementation of other GDMT, applying in particular to women and elderly patients, need to be investigated further.

Trends in use of composite endpoints in clinical trials: A comparison between acute heart failure trials and COVID-19 trials.

Composite endpoints can encode multiple pieces of information and are increasingly adopted in clinical trials. Advocacy for using composite endpoints began decades ago in cardiovascular trials, leading to incorporation of patient-oriented outcomes and consideration of a hierarchical ranking system. The use of composite endpoints in coronavirus disease (COVID-19) trials has evolved similarly. We conducted a literature review to investigate the use of composite endpoints in acute heart failure and COVID-19 clinical trials. The results showed more frequent use of patient-oriented outcomes and ordinal composite endpoints in COVID-19 trials, which might be driven by global consensus on a set of common outcome measures.

Rewarding Site-Based Research: A Step Towards Improving The Ecosystem Of Heart Failure Clinical Trials

Rewarding Site-Based Research: A Step Towards Improving The Ecosystem Of Heart Failure Clinical Trials

Role of vericiguat in management of patients with heart failure with reduced ejection fraction after worsening episode.

Worsening heart failure (HF) is a vulnerable period in which the patient has a markedly high risk of death or HF hospitalization (up to 10% and 30%, respectively, within the first weeks after episode). The prognosis of HF patients can be improved through a comprehensive approach that considers the different neurohormonal systems, with the early introduction and optimization of the quadruple therapy with sacubitril-valsartan, beta-blockers, mineralocorticoid receptor antagonists, and inhibitors. Despite that, there is a residual risk that is not targeted with these therapies. Currently, it is recognized that the cyclic guanosine monophosphate deficiency has a negative direct impact on the pathogenesis of HF, and vericiguat, an oral stimulator of soluble guanylate cyclase, can restore this pathway. The effect of vericiguat has been explored in the VICTORIA study, the largest chronic HF clinical trial that has mainly focused on patients with recent worsening HF, evidencing a significant 10% risk reduction of the primary composite endpoint of cardiovascular death or HF hospitalization (number needed to treat 24), after adding vericiguat to standard therapy. This benefit was independent of background HF therapy. Therefore, optimization of treatment should be performed as earlier as possible, particularly within vulnerable periods, considering also the use of vericiguat.

Novel Trial Designs in Heart Failure: Using Digital Health Tools to Increase Pragmatism.

Heart failure is an important clinical and public health issue. There is an urgent need to improve the efficiency of clinical trials in heart failure to rapidly identify new therapies and evidence-based implementation strategies for currently existing therapies. Electronic health (eHealth) platforms and digital health tools are being integrated into heart failure care. In this manuscript, we review opportunities to use these tools to potentially improve the design of and reduce the complexity of clinical trials in heart failure. The PRECIS-2 tool outlines clinical trial design domains that are targets for pragmatism. We believe incorporating pragmatic design elements with the aid of eHealth platforms and digital health tools into clinical trials may help address the current complexity of clinical trials in heart failure and improve efficiency. In the manuscript, we provide examples from recent clinical trials across clinical trial design domains. We believe the current adoption of eHealth platforms and digital health tools is an opportunity improve the design of heart failure clinical trials. We specifically believe these tools can enhance pragmatism in clinical trials and reduce delays in generating high-quality evidence for new heart failure therapeutics.

Underrepresentation of Women in Reduced Ejection Heart Failure Clinical Trials With Improved Mortality or Hospitalization

BackgroundThere are established sex-specific differences in heart failure with reduced ejection fraction (HFrEF) outcomes. Randomized clinical trials (RCTs) based on cardiovascular outcome benefits, typically either reduced cardiovascular mortality or hospitalization for heart failure (HHF), influence current guidelines for therapy. ObjectivesThe authors evaluate the representation of women in HFrEF RCTs that observed reduced all-cause or cardiovascular mortality or HHF. MethodsWe queried Cumulative Index to Nursing and Allied Health Literature, Excerpta Medica dataBASE, Medical Literature Analysis and Retrieval System Online, and PubMed for HFrEF RCTs that reported a statistically significant benefit of intervention resulting in improved mortality or HHF published from 1980 to 2021. We estimated representation using the participation-to-prevalence ratio (PPR). A PPR of 0.8 to 1.2 was considered representative. ResultsThe final analysis included 33 RCTs. Women represented only 23.2% of all enrolled participants (n = 24,366/104,972), ranging from 11.4% to 40.1% per trial. Overall PPR was 0.58, with per-trial PPR estimates ranging from 0.29 to 1.00. Only 5 trials (15.2%) had a PPR of women representative of the disease population. Representation did not change significantly over time. The proportion of women in North American trials was significantly greater than trials conducted in Europe (P = 0.03). The proportion of women was greater in industry trials compared to government-funded trials (P = 0.05). ConclusionsWomen are underrepresented in HFrEF RCTs that have demonstrated mortality or HHF benefits and influence current guidelines. Representation is key to further delineation of sex-specific differences in major trial results. Sustained efforts are warranted to ensure equitable and appropriate inclusion of women in HFrEF trials.

Impact of worsening renal function in patients with incident heart failure across the spectrum of ejection fraction: a population-based longitudinal study

Abstract Background Renal dysfunction is a common occurrence in patients with heart failure (HF) and may impact on HF treatment and outcomes. HF clinical trial data suggest that worsening renal function (WRF) is associated with worse prognosis, however many of the medications used in HF cause a short-term decline in renal function that may improve in the longer-term. The real-world incidence and implications of WRF following an initial diagnosis of HF across the spectrum of ejection have not been well-characterised. Purpose The present study was designed to establish the incidence and outcomes associated with WRF in patients with incident HF on the risk of mortality and HF hospitalisation (hHF) in a real-world setting. Methods Electronic health records were linked to echocardiography data between 2016 to 2021 to define incident HF with reduced/mildly reduced/preserved EF (HFrEF/HFmrEF/HFpEF). Incidence of WRF at 6 months was determined as a composite endpoint of (i) having two consecutive eGFR declined by 40% or greater; (ii) having an eGFR &amp;lt;15 mL/min/1.73m^2; (iii) on sustained dialysis; or (iv) receiving kidney transplantation. Incidence of hHF and all-cause mortality were compared in HF patients with versus without WRF. We performed a stratified analysis according to baseline renal function (eGFR: &amp;gt;60, 45-59, 30-44, 15-29, or &amp;lt;15 mL/min/1.73m2). Results 4254 individuals were identified, 1100 HFrEF, 650 HFmrEF, 1252 HFpEF, and 1252 HF with unknown EF. Within 6 months of HF diagnosis, 592 patients died and 349 had WRF. Baseline eGFR &amp;lt;60 was present in 32% of individuals with HFrEF, 32% in HFpEF, 27% in HFmrEF, and 37% in HF with unknown EF. The incidence of WRF was similar in HFrEF (20.7 [95% CI: 16.9 – 25.1] per 100 person-years) and in HF with unknown EF (20.9 [17.1 – 25.3]), but was significantly lower in HFmrEF (13.6 [9.8 – 18.4]) and HFpEF (16.8 [13.7 – 20.5]). Patients with WRF were more likely to be female (adjusted hazard ratio [aHR]: 1.32 [1.06 – 1.64], p=0.014), having diabetes (1.34 [1.07 – 1.69], p = 0.012), and with lower baseline renal function (eGFR categories 45-59, 30-44, 15-29, or &amp;lt;15 compared with &amp;gt;60: aHR 1.75 [1.29 – 2.38], p&amp;lt;0.001; 1.64 [1.12 – 2.42], p=0.012; 5.65 [4.06 – 7.87], p&amp;lt;0.001; 90.74 [63.2 – 130.28], p&amp;lt;0.001). Individuals with WRF had significantly higher incidence of subsequent hHF (HR adjusted for age, sex, baseline renal function, and diabetes: 1.79 [1.35 – 2.39], p&amp;lt;0.001) and all-cause death (2.18 [1.66 – 2.88], p&amp;lt;0.001), compared to those without WRF. This was driven by patients diagnosed with HFrEF (2.46 [1.45 – 4.18], p&amp;lt;0.001) or HFpEF (3.45 [2.21 – 5.40], p&amp;lt;0.001), but was not seen in HFmrEF (1.91 [0.91 – 3.99], p=0.086) or HF within unknown EF (1.28 [0.65 – 2.52], p=0.484). Conclusion WRF is an important and common consequence following initial diagnosis of HF across the spectrum of EF with associated severe clinical outcomes in HF. Priority should be given to prevention of WRF in patients with incident HF.Impact of WRF on Clinical Outcomes

Abstract 12936: Quality of Life Assessments as Inclusion Criteria in Heart Failure Clinical Trials

Background: Patient-reported quality of life (QoL) assessments, such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) or Minnesota Living with Heart Failure Questionnaire (MLHFQ), reflect an individual’s health status and symptom severity at a given timepoint, and may have utility as inclusion criteria in heart failure (HF) clinical trials. Method: The Heart Failure Collaboratory-Academic Research Consortium, a group of stakeholders including patients, investigators, and representatives from government and industry, convened to review data from multiple HF clinical trials discuss the use of patient reported QoL-based inclusion criteria in clinical trials of HF. Result: Patient-reported QoL assessments, such as the KCCQ, have high test-retest reliability and, in contrast with the physician-assigned New York Heart Association (NYHA) class, are not subject to clinician bias or influenced by knowledge of prognostic variables such as Left Ventricular Ejection Fraction (LVEF) or N-terminal pro B-type Natriuretic Peptide (NT-proBNP). The U.S. FDA has qualified KCCQ as an effective clinical outcomes assessment for HF, and recent clinical trials that demonstrated substantial reductions in morbidity and mortality also showed improvements in KCCQ scores, provided patients had a decrement at baseline. However, KCCQ use is limited by both complicated clinical interpretability, with total symptom score consisting of aggregate scores from different physical and symptomatic domains and uncertainty around the threshold of clinically important difference, and by its length, with average completion time of 5 to 8 minutes. Conclusion: Patient-reported functional assessments have potential as inclusion criteria in clinical trials of HF by ensuring the enrollment of patients with a diminished QoL who have the potential to improve in response to therapeutic intervention, especially in clinical trials with QoL-based endpoints.

Abstract 18005: Underrepresentation of Women in Clinical Trials of Heart Failure With Reduced Ejection Fraction

Background: There are established sex-specific differences in heart failure with reduced ejection fraction (HFrEF) outcomes. Randomized clinical trials (RCTs) based on cardiovascular outcome benefits, typically either reduced cardiovascular mortality or hospitalization for heart failure (HHF), and influence current guidelines for therapy. Objectives: To evaluate the representation of women in HFrEF RCTs that observed reduced all-cause or cardiovascular mortality or HHF. Methods: We queried Excerpta Medica dataBASE, Medical Literature Analysis and Retrieval System Online, Cumulative Index to Nursing and Allied Health Literature, and PubMed for HFrEF RCTs that reported a statistically significant benefit of intervention resulting in improved mortality or HHF published from 1980 to 2021. We estimated representation using the participation-to-prevalence ratio (PPR). PPR was calculated based on the proportion of women with HFrEF in the Framingham cohort (40%). A PPR of 0.8 to 1.2 was considered representative. Results: The final analysis included 33 RCTs. All trials except two were mentioned in the 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America Guidelines for the Management of Heart Failure. Women represented 23.2% of enrolled participants (n = 24,363/ 104,972), ranging from 11.4% to 40.1% per-trial. Overall PPR was 0.58, with per-trial estimates ranging from 0.29 - 1.00. Five trials (15.2%) had a PPR of women representative of the disease population. Representation didn’t change significantly by the decade examined. The proportion of women in North American and Multiregional trials was significantly greater than in trials conducted in Europe (p = 0.04). The proportion of women was greater in industry trials compared to government-funded trials (p = 0.05). Conclusions: Women are underrepresented in HFrEF RCTs that have demonstrated mortality or HHF benefits, which may affect the sex-specific generalizability of major trial results. Sustained efforts are warranted to ensure equitable and appropriate inclusion of women in HFrEF trials.

Abstract 17493: Racial/Ethnic Under-Representation in Early Phase Clinical Trials

Introduction: There is severe underrepresentation of racial and ethnic groups in many cardiovascular clinical trials. Early-phase clinical trials examine the action and safety limits of treatment and thus, underrepresentation may have particularly deleterious effects. Hypothesis: Ethnic and Racial groups are underrepresented in early-phase trials. Methods: Using the clinicaltrials.gov database, we examined the racial and ethnic representation in Phases 1, 2, 3, and 4 in completed heart failure clinical trials (N=89) with reported results from 2016-2021. We examined the proportion of trials with a representation equal or greater than % U.S. Census population (12% for African American (AA), 19% for Hispanic/Latino (HL), and 7% for Asian (AN)) and determined the median trial representation percentage for AA, HL, and AN groups. Using Chi-square analysis we compared the percent representation across the trial phases. Results: We found that 49%, 91%, and 87% Phase 1 and 2 trials have a lower AA, HL, and AN representation, respectively, compared to that in the U.S. Population (Table 1). HL and AN representation in Phase 1 and 2 trials is particularly low. There is significant variation in AA, HL, and AN representation across all trial phases(p&lt;0.001). Conclusions: Significant underrepresentation of racial and ethnic groups persist in contemporary Phase 1 and 2 trials. Efforts to create a standard for collecting and reporting demographics along with increasing racial and ethnic group representation closer to US population may reduce the risk of future adverse events.

Abstract 14640: Community Socioeconomic Distress is Associated With Poor Access to Heart Failure Clinical Trials in the United States

Introduction: Clinical trials have historically lacked representation from minorities and individuals from lower socioeconomic backgrounds. Little is known about the role geographic access plays in recruiting diverse populations for clinical trials. Objectives: Given disparities in clinical trial enrollment, we sought to analyze how access to heart failure trials varies across demographic groups. Methods: We queried clinicaltrials.gov for trials classified under “heart failure” that are recruiting and enrolling adult patients. Trial site addresses were obtained using Google Maps. We calculated drive times from each US census tract to the closest trial site using ArcGIS Pro v3.1. Demographic information and urban / rural statuses for census tracts were obtained from the US Census Bureau. Distressed Community Index (DCI) scores (0 = no distress, 100 = severe distress) based on metrics including education level, poverty, and unemployment were collected. Data were analyzed using Python v3.8. Results: We identified 954 heart failure trials with 644 unique sites in the US. About 54% of the rural population lives more than 30 minutes from a trial site compared to 22% of the urban population (OR 0.23; p &lt; 0.001). Analysis of DCI scores covering 328 million people revealed that drive times increase with higher socioeconomic distress ( p &lt; 0.001; Figure). In both urban and rural settings, median drive times for individuals in the top 10% of distressed communities (56 min urban and 79 rural) are more than three times those of individuals in the lowest 10% of distressed communities (18 min urban and 23 rural). A larger proportion of non-white minorities live less than 30 minutes from a trial site compared to the white population (77% vs. 60%; OR 2.23; p &lt; 0.001). Conclusions: Increased socioeconomic distress is associated with worse access to heart failure trial sites for both urban and rural populations. Geographic barriers should be addressed to improve diversity in trials.

Istaroxime: A Novel Therapeutic Agent for Acute Heart Failure.

Acute decompensated heart failure (ADHF) is a multifactorial process that is associated with high morbidity and mortality. Treatment with inotropes can rapidly improve hemodynamic status; however, their use has been associated with increased mortality and incidence of arrhythmias. Istaroxime is a first-in-class intravenous agent currently undergoing clinical trials for acute heart failure. It has the unique mechanism of action of both Na+/K+ ATPase inhibition and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a stimulation. Notably, its action on sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a improves calcium handling, which is known to be abnormal in heart failure. Clinical trials have shown that istaroxime has beneficial hemodynamic effects; in particular, its ability to increase systolic blood pressure without causing significant increases in heart rate or clinically significant arrhythmias differentiates it from inotropes currently utilized for ADHF treatment, such as milrinone. While initial studies are encouraging, additional trials are needed to assess outcomes and to compare their performance to standard inotropes in patients hospitalized with ADHF. This article will review the relevant preclinical and clinical trials for istaroxime, as well as the relevant pharmacology.

Examining the Landscape of Surrogate Outcomes in Clinical Trials of Heart Failure With Preserved Ejection Fraction (HFpEF) Patients: A Narrative Review

Examining the Landscape of Surrogate Outcomes in Clinical Trials of Heart Failure With Preserved Ejection Fraction (HFpEF) Patients: A Narrative Review

Improving cardiovascular outcomes for patients with heart failure in sub-Saharan Africa: conference proceedings of the 2022 Nigerian Cardiovascular Symposium.

The Nigerian Cardiovascular Symposium is an annual conference held in partnership with cardiologists in Nigeria and the diaspora to provide updates in cardiovascular medicine and cardiothoracic surgery with the aim of optimising cardiovascular care for the Nigerian population. This virtual conference (due to the COVID-19 pandemic) has created an opportunity for effective capacity building of the Nigerian cardiology workforce. The objective of the conference was for experts to provide updates on current trends, clinical trials and innovations in heart failure, selected cardiomyopathies such as hypertrophic cardiomyopathy and cardiac amyloidosis, pulmonary hypertension, cardiogenic shock, left ventricular assist devices and heart transplantation. Furthermore, the conference aimed to equip the Nigerian cardiovascular workforce with skills and knowledge to optimise the delivery of effective cardiovascular care, with the hope of curbing 'medical tourism' and the current 'brain drain' in Nigeria. Challenges to optimal cardiovascular care in Nigeria include workforce shortage, limited capacity of intensive care units, and availability of medications. This partnership represents a key first step in addressing these challenges. Future action items include enhanced collaboration between cardiologists in Nigeria and the diaspora, advancing participation and enrollment of African patients in global heart failure clinical trials, and the urgent need to develop heart failure clinical practice guidelines for Nigerian patients.