On-treatment analysis of torsemide versus furosemide for patients hospitalized for heart failure: A post-hoc analysis of TRANSFORM-HF.

AIM: The TRANSFORM-HF trial demonstrated no significant outcome differences between torsemide and furosemide following hospitalization for heart failure (HF), but may have been impacted by non-adherence to the randomized diuretic. The current study sought to determine the treatment effect of torsemide versus furosemide using an on-treatment analysis inclusive of all randomized patients except those confirmed non-adherent to study diuretic. METHODS AND RESULTS: TRANSFORM-HF was an open-label, pragmatic randomized trial of 2859 patients hospitalized for HF from June 2018 through March 2022. Patients were randomized to a loop diuretic strategy of torsemide versus furosemide with investigator-selected dosage. This post-hoc on-treatment analysis included all patients alive with either known or unknown diuretic status, and excluded patients confirmed to be non-adherent to study diuretic. This modified on-treatment definition was applied separately at time of hospital discharge and 30-day follow-up. All-cause mortality and hospitalization outcomes were assessed over 12 months. Overall, 2570 (89.9%) and 2374 (83.0%) patients were included in on-treatment analyses at discharge and 30-day follow-up, respectively. There was no significant difference in all-cause mortality between torsemide and furosemide in patients on-treatment at discharge (17.5% vs. 17.8%; hazard ratio [HR] 1.01 [95% confidence interval [CI] 0.83-1.22], p = 0.96) and at 30-day follow-up (14.5% vs. 15.0%; HR 1.02 [95% CI 0.81-1.27], p = 0.90). All-cause mortality or all-cause hospitalization was similar between torsemide and furosemide in patients who were on-treatment at discharge (58.3% vs. 61.3%; HR 0.92 [95% CI 0.82-1.03]) and 30-day follow-up (60.9% vs. 64.4%; HR 0.93 [95% CI 0.82-1.05]). In patients who were on-treatment at 30-day follow-up, there were 677 total hospitalizations in the torsemide group and 686 total hospitalizations in the furosemide group (rate ratio 0.99 [95% CI 0.86-1.14], p = 0.87). CONCLUSIONS: In TRANSFORM-HF, a post-hoc on-treatment analysis did not meaningfully differ from the original trial results. Among those deemed compliant with the assigned diuretic, there remained no significant difference in mortality or hospitalization after HF hospitalization with a strategy of torsemide versus furosemide. CLINICAL TRAIL REGISTRATION: ClinicalTrials.gov Identifier: NCT03296813.

Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers in HIV: Mechanistic Substudy of the REPRIEVE Randomized Clinical Trial.

Importance: Cardiovascular disease (CVD) is increased in people with HIV (PWH) and is characterized by premature noncalcified coronary plaque. In the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), pitavastatin reduced major adverse cardiovascular events (MACE) by 35% over a median of 5.1 years. Objective: To investigate the effects of pitavastatin on noncalcified coronary artery plaque by coronary computed tomography angiography (CTA) and on inflammatory biomarkers as potential mechanisms for MACE prevention. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial enrolled participants from April 2015 to February 2018 at 31 US clinical research sites. PWH without known CVD who were taking antiretroviral therapy and had low to moderate 10-year CVD risk were included. Data were analyzed from April to November 2023. Intervention: Oral pitavastatin calcium, 4 mg per day. Main Outcomes and Measures: Coronary CTA and inflammatory biomarkers at baseline and 24 months. The primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified plaque. Results: Of 804 enrolled persons, 774 had at least 1 evaluable CTA. Plaque changes were assessed in 611 who completed both CT scans. Of 611 analyzed participants, 513 (84.0%) were male, the mean (SD) age was 51 (6) years, and the median (IQR) 10-year CVD risk was 4.5% (2.6-7.0). A total of 302 were included in the pitavastatin arm and 309 in the placebo arm. The mean noncalcified plaque volume decreased with pitavastatin compared with placebo (mean [SD] change, -1.7 [25.2] mm3 vs 2.6 [27.1] mm3; baseline adjusted difference, -4.3 mm3; 95% CI, -8.6 to -0.1; P = .04; 7% [95% CI, 1-12] greater reduction relative to placebo). A larger effect size was seen among the subgroup with plaque at baseline (-8.8 mm3 [95% CI, -17.9 to 0.4]). Progression of noncalcified plaque was 33% less likely with pitavastatin compared with placebo (relative risk, 0.67; 95% CI, 0.52-0.88; P = .003). Compared with placebo, the mean low-density lipoprotein cholesterol decreased with pitavastatin (mean change: pitavastatin, -28.5 mg/dL; 95% CI, -31.9 to -25.1; placebo, -0.8; 95% CI, -3.8 to 2.2). The pitavastatin arm had a reduction in both oxidized low-density lipoprotein (-29% [95% CI, -32 to -26] vs -13% [95% CI, -17 to -9]; P < .001) and lipoprotein-associated phospholipase A2 (-7% [95% CI, -11 to -4] vs 14% [95% CI, 10-18]; P < .001) compared with placebo at 24 months. Conclusions and Relevance: In PWH at low to moderate CVD risk, 24 months of pitavastatin reduced noncalcified plaque volume and progression as well as markers of lipid oxidation and arterial inflammation. These changes may contribute to the observed MACE reduction in REPRIEVE. Trial Registration: ClinicalTrials.gov Identifier: NCT02344290.

Improving Stroke Risk Factor Management Focusing on Health Disparities and Knowledge Gaps.

Stroke is a leading cause of death and disability in the United States and worldwide, necessitating comprehensive efforts to optimize stroke risk factor management. Health disparities in stroke incidence, prevalence, and risk factor management persist among various race/ethnic, geographic, and socioeconomic populations and negatively impact stroke outcomes. This review highlights existing literature and guidelines for stroke risk factor management, emphasizing health disparities among certain populations. Moreover, stroke risk factors for special groups, including the young, the very elderly, and pregnant/peripartum women are outlined. Strategies for stroke risk factor improvement at every level of the health care system are discussed, from the individual patient to providers, health care systems, and policymakers. Improving stroke risk factor management in the context of the social determinants of health, and with the goal of eliminating inequities and disparities in stroke prevention strategies, are critical steps to reducing the burden of stroke and equitably improving public health.

Pitavastatin to Prevent Cardiovascular Disease in HIV Infection.

BACKGROUND: The risk of cardiovascular disease is increased among persons with human immunodeficiency virus (HIV) infection, so data regarding primary prevention strategies in this population are needed. METHODS: In this phase 3 trial, we randomly assigned 7769 participants with HIV infection with a low-to-moderate risk of cardiovascular disease who were receiving antiretroviral therapy to receive daily pitavastatin calcium (at a dose of 4 mg) or placebo. The primary outcome was the occurrence of a major adverse cardiovascular event, which was defined as a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral arterial ischemia, revascularization, or death from an undetermined cause. RESULTS: The median age of the participants was 50 years (interquartile range, 45 to 55); the median CD4 count was 621 cells per cubic millimeter (interquartile range, 448 to 827), and the HIV RNA value was below quantification in 5250 of 5997 participants (87.5%) with available data. The trial was stopped early for efficacy after a median follow-up of 5.1 years (interquartile range, 4.3 to 5.9). The incidence of a major adverse cardiovascular event was 4.81 per 1000 person-years in the pitavastatin group and 7.32 per 1000 person-years in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.48 to 0.90; P = 0.002). Muscle-related symptoms occurred in 91 participants (2.3%) in the pitavastatin group and in 53 (1.4%) in the placebo group; diabetes mellitus occurred in 206 participants (5.3%) and in 155 (4.0%), respectively. CONCLUSIONS: Participants with HIV infection who received pitavastatin had a lower risk of a major adverse cardiovascular event than those who received placebo over a median follow-up of 5.1 years. (Funded by the National Institutes of Health and others; REPRIEVE ClinicalTrials.gov number, NCT02344290.).

Effect of Torsemide Versus Furosemide on Symptoms and Quality of Life Among Patients Hospitalized for Heart Failure: The TRANSFORM-HF Randomized Clinical Trial.

BACKGROUND: Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than furosemide remains unknown. As prespecified secondary end points, the TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) compared the effect of torsemide versus furosemide on patient-reported outcomes among patients with HF. METHODS: TRANSFORM-HF was an open-label, pragmatic, randomized trial of 2859 patients hospitalized for HF (regardless of ejection fraction) across 60 hospitals in the United States. Patients were randomly assigned in a 1:1 ratio to a loop diuretic strategy of torsemide or furosemide with investigator-selected dosage. This report examined effects on prespecified secondary end points, which included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; assessed as adjusted mean difference in change from baseline; range, 0-100 with 100 indicating best health status; clinically important difference, ≥5 points) and Patient Health Questionnaire-2 (range, 0-6; score ≥3 supporting evaluation for depression) over 12 months. RESULTS: Baseline data were available for 2787 (97.5%) patients for KCCQ-CSS and 2624 (91.8%) patients for Patient Health Questionnaire-2. Median (interquartile range) baseline KCCQ-CSS was 42 (27-60) in the torsemide group and 40 (24-59) in the furosemide group. At 12 months, there was no significant difference between torsemide and furosemide in change from baseline in KCCQ-CSS (adjusted mean difference, 0.06 [95% CI, -2.26 to 2.37]; P=0.96) or the proportion of patients with Patient Health Questionnaire-2 score ≥3 (15.1% versus 13.2%: P=0.34). Results for KCCQ-CSS were similar at 1 month (adjusted mean difference, 1.36 [95% CI, -0.64 to 3.36]; P=0.18) and 6-month follow-up (adjusted mean difference, -0.37 [95% CI, -2.52 to 1.78]; P=0.73), and across subgroups by ejection fraction phenotype, New York Heart Association class at randomization, and loop diuretic agent before hospitalization. Irrespective of baseline KCCQ-CSS tertile, there was no significant difference between torsemide and furosemide on change in KCCQ-CSS, all-cause mortality, or all-cause hospitalization. CONCLUSIONS: Among patients discharged after hospitalization for HF, a strategy of torsemide compared with furosemide did not improve symptoms or quality of life over 12 months. The effects of torsemide and furosemide on patient-reported outcomes were similar regardless of ejection fraction, previous loop diuretic use, and baseline health status. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03296813.

Supervised Exercise Training for Chronic Heart Failure With Preserved Ejection Fraction: A Scientific Statement From the American Heart Association and American College of Cardiology.

Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure; its prevalence is increasing, and outcomes are worsening. Affected patients often experience severe exertional dyspnea and debilitating fatigue, as well as poor quality of life, frequent hospitalizations, and a high mortality rate. Until recently, most pharmacological intervention trials for HFpEF yielded neutral primary outcomes. In contrast, trials of exercise-based interventions have consistently demonstrated large, significant, clinically meaningful improvements in symptoms, objectively determined exercise capacity, and usually quality of life. This success may be attributed, at least in part, to the pleiotropic effects of exercise, which may favorably affect the full range of abnormalities-peripheral vascular, skeletal muscle, and cardiovascular-that contribute to exercise intolerance in HFpEF. Accordingly, this scientific statement critically examines the currently available literature on the effects of exercise-based therapies for chronic stable HFpEF, potential mechanisms for improvement of exercise capacity and symptoms, and how these data compare with exercise therapy for other cardiovascular conditions. Specifically, data reviewed herein demonstrate a comparable or larger magnitude of improvement in exercise capacity from supervised exercise training in patients with chronic HFpEF compared with those with heart failure with reduced ejection fraction, although Medicare reimbursement is available only for the latter group. Finally, critical gaps in implementation of exercise-based therapies for patients with HFpEF, including exercise setting, training modalities, combinations with other strategies such as diet and medications, long-term adherence, incorporation of innovative and more accessible delivery methods, and management of recently hospitalized patients are highlighted to provide guidance for future research.

Supervised Exercise Training for Chronic Heart Failure With Preserved Ejection Fraction: A Scientific Statement From the American Heart Association and American College of Cardiology.

Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure; its prevalence is increasing, and outcomes are worsening. Affected patients often experience severe exertional dyspnea and debilitating fatigue, as well as poor quality of life, frequent hospitalizations, and a high mortality rate. Until recently, most pharmacological intervention trials for HFpEF yielded neutral primary outcomes. In contrast, trials of exercise-based interventions have consistently demonstrated large, significant, clinically meaningful improvements in symptoms, objectively determined exercise capacity, and usually quality of life. This success may be attributed, at least in part, to the pleiotropic effects of exercise, which may favorably affect the full range of abnormalities-peripheral vascular, skeletal muscle, and cardiovascular-that contribute to exercise intolerance in HFpEF. Accordingly, this scientific statement critically examines the currently available literature on the effects of exercise-based therapies for chronic stable HFpEF, potential mechanisms for improvement of exercise capacity and symptoms, and how these data compare with exercise therapy for other cardiovascular conditions. Specifically, data reviewed herein demonstrate a comparable or larger magnitude of improvement in exercise capacity from supervised exercise training in patients with chronic HFpEF compared with those with heart failure with reduced ejection fraction, although Medicare reimbursement is available only for the latter group. Finally, critical gaps in implementation of exercise-based therapies for patients with HFpEF, including exercise setting, training modalities, combinations with other strategies such as diet and medications, long-term adherence, incorporation of innovative and more accessible delivery methods, and management of recently hospitalized patients are highlighted to provide guidance for future research.

Research Opportunities in Stroke Prevention for Atrial Fibrillation: A Report From a National Heart, Lung, and Blood Institute Virtual Workshop.

Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas: (1) improving risk stratification tools for stroke and intracranial hemorrhage; (2) addressing challenges with oral anticoagulants; and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closure/excision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.

3-Dimensional Strain Analysis of Hypertrophic Cardiomyopathy: Insights From the NHLBI International HCM Registry.

BACKGROUND: Abnormal global longitudinal strain (GLS) has been independently associated with adverse cardiac outcomes in both obstructive and nonobstructive hypertrophic cardiomyopathy. OBJECTIVES: The goal of this study was to understand predictors of abnormal GLS from baseline data from the National Heart, Lung, and Blood Institute (NHLBI) Hypertrophic Cardiomyopathy Registry (HCMR). METHODS: The study evaluated comprehensive 3-dimensional left ventricular myocardial strain from cine cardiac magnetic resonance in 2,311 patients from HCMR using in-house validated feature-tracking software. These data were correlated with other imaging markers, serum biomarkers, and demographic variables. RESULTS: Abnormal median GLS (> -11.0%) was associated with higher left ventricular (LV) mass index (93.8 ± 29.2 g/m2 vs 75.1 ± 19.7 g/m2; P < 0.0001) and maximal wall thickness (21.7 ± 5.2 mm vs 19.3 ± 4.1 mm; P < 0.0001), lower left (62% ± 9% vs 66% ± 7%; P < 0.0001) and right (68% ± 11% vs 69% ± 10%; P < 0.01) ventricular ejection fractions, lower left atrial emptying functions (P < 0.0001 for all), and higher presence and myocardial extent of late gadolinium enhancement (6 SD and visual quantification; P < 0.0001 for both). Elastic net regression showed that adjusted predictors of GLS included female sex, Black race, history of syncope, presence of systolic anterior motion of the mitral valve, reverse curvature and apical morphologies, LV ejection fraction, LV mass index, and both presence/extent of late gadolinium enhancement and baseline N-terminal pro-B-type natriuretic peptide and troponin levels. CONCLUSIONS: Abnormal strain in hypertrophic cardiomyopathy is associated with other imaging and serum biomarkers of increased risk. Further follow-up of the HCMR cohort is needed to understand the independent relationship between LV strain and adverse cardiac outcomes in hypertrophic cardiomyopathy.

Effect of Torsemide vs Furosemide After Discharge on All-Cause Mortality in Patients Hospitalized With Heart Failure: The TRANSFORM-HF Randomized Clinical Trial.

Importance: Although furosemide is the most commonly used loop diuretic in patients with heart failure, some studies suggest a potential benefit for torsemide. Objective: To determine whether torsemide results in decreased mortality compared with furosemide among patients hospitalized for heart failure. Design, Setting, and Participants: TRANSFORM-HF was an open-label, pragmatic randomized trial that recruited 2859 participants hospitalized with heart failure (regardless of ejection fraction) at 60 hospitals in the United States. Recruitment occurred from June 2018 through March 2022, with follow-up through 30 months for death and 12 months for hospitalizations. The final date for follow-up data collection was July 2022. Interventions: Loop diuretic strategy of torsemide (n = 1431) or furosemide (n = 1428) with investigator-selected dosage. Main Outcomes and Measures: The primary outcome was all-cause mortality in a time-to-event analysis. There were 5 secondary outcomes with all-cause mortality or all-cause hospitalization and total hospitalizations assessed over 12 months being highest in the hierarchy. The prespecified primary hypothesis was that torsemide would reduce all-cause mortality by 20% compared with furosemide. Results: TRANSFORM-HF randomized 2859 participants with a median age of 65 years (IQR, 56-75), 36.9% were women, and 33.9% were Black. Over a median follow-up of 17.4 months, a total of 113 patients (53 [3.7%] in the torsemide group and 60 [4.2%] in the furosemide group) withdrew consent from the trial prior to completion. Death occurred in 373 of 1431 patients (26.1%) in the torsemide group and 374 of 1428 patients (26.2%) in the furosemide group (hazard ratio, 1.02 [95% CI, 0.89-1.18]). Over 12 months following randomization, all-cause mortality or all-cause hospitalization occurred in 677 patients (47.3%) in the torsemide group and 704 patients (49.3%) in the furosemide group (hazard ratio, 0.92 [95% CI, 0.83-1.02]). There were 940 total hospitalizations among 536 participants in the torsemide group and 987 total hospitalizations among 577 participants in the furosemide group (rate ratio, 0.94 [95% CI, 0.84-1.07]). Results were similar across prespecified subgroups, including among patients with reduced, mildly reduced, or preserved ejection fraction. Conclusions and Relevance: Among patients discharged after hospitalization for heart failure, torsemide compared with furosemide did not result in a significant difference in all-cause mortality over 12 months. However, interpretation of these findings is limited by loss to follow-up and participant crossover and nonadherence. Trial Registration: ClinicalTrials.gov Identifier: NCT03296813.

Transforming Atrial Fibrillation Research to Integrate Social Determinants of Health: A National Heart, Lung, and Blood Institute Workshop Report.

Importance: Only modest attention has been paid to the contributions of social determinants of health to atrial fibrillation (AF) risk factors, diagnosis, symptoms, management, and outcomes. The diagnosis of AF provides unique challenges exacerbated by the arrhythmia's often paroxysmal nature and individuals' disparate access to health care and technologies that facilitate detection. Social determinants of health affect access to care and management decisions for AF, increasing the likelihood of adverse outcomes among individuals who experience systemic disadvantages. Developing effective approaches to address modifiable social determinants of health requires research to eliminate the substantive inequities in health care delivery and outcomes in AF. Observations: The National Heart, Lung, and Blood Institute convened an expert panel to identify major knowledge gaps and research opportunities in the field of social determinants of AF. The workshop addressed the following social determinants: (1) socioeconomic status and access to care; (2) health literacy; (3) race, ethnicity, and racism; (4) sex and gender; (5) shared decision-making in systemically disadvantaged populations; and (6) place, including rurality, neighborhood, and community. Many individuals with AF have multiple adverse social determinants, which may cluster in the individual and in systemically disadvantaged places (eg, rural locations, urban neighborhoods). Cumulative disadvantages may accumulate over the life course and contribute to inequities in the diagnosis, management, and outcomes in AF. Conclusions and Relevance: Workshop participants identified multiple critical research questions and approaches to catalyze social determinants of health research that address the distinctive aspects of AF. The long-term aspiration of this work is to eradicate the substantive inequities in AF diagnosis, management, and outcomes across populations.

Machine learning evaluation of LV outflow obstruction in hypertrophic cardiomyopathy using three-chamber cardiovascular magnetic resonance.

Left ventricular outflow tract obstruction (LVOTO) is common in hypertrophic cardiomyopathy (HCM), but relationships between anatomical metrics and obstruction are poorly understood. We aimed to develop machine learning methods to evaluate LVOTO in HCM patients and quantify relationships between anatomical metrics and obstruction. This retrospective analysis of 1905 participants of the HCM Registry quantified 11 anatomical metrics derived from 14 landmarks automatically detected on the three-chamber long axis cine CMR images. Linear and logistic regression was used to quantify strengths of relationships with the presence of LVOTO (defined by resting Doppler pressure drop of > 30 mmHg), using the area under the receiver operating characteristic (AUC). Intraclass correlation coefficients between the network predictions and three independent observers showed similar agreement to that between observers. The distance from anterior mitral valve leaflet tip to basal septum (AML-BS) was most highly correlated with Doppler pressure drop (R2 = 0.19, p < 10-5). Multivariate stepwise regression found the best predictive model included AML-BS, AML length to aortic valve diameter ratio, AML length to LV width ratio, and midventricular septal thickness metrics (AUC 0.84). Excluding AML-BS, metrics grouped according to septal hypertrophy, LV geometry, and AML anatomy each had similar associations with LVOTO (AUC 0.71, 0.71, 0.68 respectively, p = ns), significantly less than their combination (AUC 0.77, p < 0.05 for each). Anatomical metrics derived from a standard three-chamber CMR cine acquisition can be used to highlight risk of LVOTO, and suggest further investigation if necessary. A combination of geometric factors is required to provide the best risk prediction.

Implementing the National Heart, Lung, and Blood Institute's Strategic Vision in the Division of Cardiovascular Sciences-2022 Update.

Spurred by the 2016 release of the National Heart, Lung, and Blood Institute's Strategic Vision, the Division of Cardiovascular Sciences developed its Strategic Vision Implementation Plan-a blueprint for reigniting the decline in cardiovascular disease (CVD) mortality rates, improving health equity, and accelerating translation of scientific discoveries into better cardiovascular health (CVH). The 6 scientific focus areas of the Strategic Vision Implementation Plan reflect the multifactorial nature of CVD and include (1) addressing social determinants of CVH and health inequities, (2) enhancing resilience, (3) promoting CVH and preventing CVD across the lifespan, (4) eliminating hypertension-related CVD, (5) reducing the burden of heart failure, and (6) preventing vascular dementia. This article presents an update of strategic vision implementation activities within Division of Cardiovascular Sciences. Overarching and cross-cutting themes include training the scientific workforce and engaging the extramural scientific community to stimulate transformative research in cardiovascular sciences. In partnership with other NIH Institutes, Federal agencies, industry, and the extramural research community, Division of Cardiovascular Sciences strategic vision implementation has stimulated development of numerous workshops and research funding opportunities. Strategic Vision Implementation Plan activities highlight innovative intervention modalities, interdisciplinary systems approaches to CVD reduction, a life course framework for CVH promotion and CVD prevention, and multi-pronged research strategies for combatting COVID-19. As new knowledge, technologies, and areas of scientific research emerge, Division of Cardiovascular Sciences will continue its thoughtful approach to strategic vision implementation, remaining poised to seize emerging opportunities and catalyze breakthroughs in cardiovascular sciences.

Spectrum of National Institutes of Health-Funded Research in Cardio-Oncology: A Basic, Clinical, and Observational Science Perspective.

Advances in cancer treatments have led to nearly 17 million survivors in the US today. Cardiovascular complications attributed to cancer treatments are the leading cause of morbidity and mortality in cancer survivors. In response, NCI and NHLBI held 2 workshops and issued funding opportunities to strengthen research on cardiotoxicity. A representative portfolio of NIH grants categorizing basic, interventional, and observational projects is presented. Compared with anthracyclines, research on radiation therapy and newer treatments is underrepresented. Multidisciplinary collaborative research that considers the cardiotoxicity stage and optimizes the balance between cardiovascular risk and cancer-treatment benefit might support continued improvements in cancer outcomes.

Tolerability of Sacubitril/Valsartan in Patients With Advanced Heart Failure: Analysis of the LIFE Trial Run-In.

BACKGROUND: The LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) trial, which evaluated sacubitril/valsartan in patients with advanced heart failure (HF) with reduced ejection fraction and recent New York Heart Association functional class IV symptomatology, did not require tolerance to a renin angiotensin system antagonist before initiating sacubitril/valsartan, thus affording an opportunity to study the tolerability of sacubitril/valsartan in advanced HF with reduced ejection fraction. OBJECTIVES: The goal of this analysis of the LIFE trial is to characterize the tolerability of initiating sacubitril/valsartan in patients with chronic advanced HF with reduced ejection fraction. METHODS: In the LIFE trial, 445 subjects with advanced HF entered an unblinded run-in period of 3-7 days with sacubitril/valsartan 24/26 mg twice a day. The authors compared characteristics of subjects completing and failing run-in, performed multivariable analysis of clinical parameters associated with run-in failure, and developed a predictive model for short-term intolerance to sacubitril/valsartan. RESULTS: Of 445 subjects entering run-in, 73 (18%) were intolerant of sacubitril/valsartan. Reasons for intolerance included systolic blood pressure <90 mm Hg (59%), symptoms of hypotension/dizziness with systolic blood pressure >90 mm Hg (19%), and renal dysfunction (creatinine >2.0 mg/dL) (12%). Multivariable predictors of intolerance included lower mean arterial pressure, lower serum chloride, presence of an implantable cardioverter-defibrillator and/or cardiac resynchronization device, moderate or greater mitral regurgitation, nonuse of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at the screening visit, and use of insulin at screening. Subjects with 4 or more predictors had a 48.9% probability of sacubitril/valsartan intolerance. CONCLUSIONS: Intolerance to low doses of sacubitril/valsartan is common in patients with advanced chronic HF with reduced ejection fraction and may be predicted by the presence of certain risk factors. (EntrestoTM [LCZ696] in Advanced Heart Failure [LIFE Study] [HFN-LIFE] NCT02816736).

Assessing race and ethnicity differences in outcomes based on GDMT and target NT-proBNP in patients with heart failure with reduced ejection fraction: An analysis of the GUIDE-IT study.

BACKGROUND: The GUIDE-IT trial was, a multicenter, randomized, parallel group, unblinded study that randomized patients to having heart failure therapy titrated to achieve an NT-proBNP <1000 pg/mL or to usual clinical care. METHODS AND RESULTS: We performed pre-specified subgroup analysis to look for the race and ethnicity-based differences in clinical outcomes of patients who were able to achieve GDMT or target NT-proBNP concentration of ≤1000 pg/mL at 90 days of follow-up. There were 894 patients enrolled in GUIDE-IT study. Of these, 733 participants had available data on 90-day guideline directed triple therapy and 616 on NT-proBNP. 35% of the patients were Black and 6% were Hispanic. Black patients were younger, had more comorbidities, lower EF, and higher NYHA class compared with non-Black. Adjusting for 90-day NT-proBNP and important baseline covariates, Black patients were at a higher risk than non-Black patients for HF hospitalization [HR, 2.19; 95% CI, 1.51-3.17; p < 0.0001], but at a similar risk for mortality [HR, 0.85.; 95% CI, 0.44-1.66; p = 0.64]. Similar results were seen adjusting for 90-day GDMT [HF hospitalization: Black vs non-Black, HR: 1.97; 1.41-2.77, P < 0.0001; mortality: HR: 0.70; 0.39-1.26, p = 0.23]. There were no significant differences between Hispanic and non-Hispanic patients with respect to heart failure hospitalization, cardiovascular or all-cause mortality. Over the study period, Black and Hispanic patients experienced smaller changes in physical function and quality of life as measured by the Kansas City Cardiomyopathy Questionnaire overall score. CONCLUSION: Compared to non-Black patients, Black patients in GUIDE-IT study had a higher risk of heart failure hospitalization, but a comparable risk of mortality, despite improved use of GDMT and achievement of similar biomarker targets.

National Heart, Lung, and Blood Institute: Social Determinants of Health Research, Fiscal Year 2008-2020.

INTRODUCTION: Social determinants of health influence the prevention, treatment, and progression of chronic diseases, including heart, lung, blood, and sleep diseases and conditions. Healthy People 2020 classifies Social Determinants of Health into 5 subcategories: (1) Neighborhood and Built Environment, (2) Education, (3) Economic Stability, (4) Social and Community Context, and (5) Health and Health Care. This study's goal is to characterize the National Heart, Lung, and Blood Institute's Fiscal Year 2008-2020 funding in overall Social Determinants of Health research and in the Healthy People 2020 subcategories. METHODS: The Social Determinants of Health Research, Condition, and Disease Categorization code was used to identify funded grants in this area. Natural language processing methods further categorized grants into the 5 Healthy People 2020 Social Determinants of Health subcategories. RESULTS: There were 915 (∼4.3%) social determinants of health‒funded grants from 2008 to 2020 representing $1,034 billion in direct costs. Most grants were relevant to cardiovascular diseases (n=653), with a smaller number relevant to lung diseases (n=186), blood diseases (n=47), and translational and implementation science (n=29). Grants fit multiple Social Determinants of Health subcategories with the majority identified as Health and Health Care (62%) and Economic Stability (61%). The number of National Heart, Lung, and Blood Institute social determinants of health grants awarded increased by 127% from Fiscal Year 2008 to Fiscal Year 2020. CONCLUSIONS: This study identifies Social Determinants of Health grants funded by the National Heart, Lung, and Blood Institute during 2008‒2020. Enhancing the understanding of these determinants and developing effective interventions will ultimately help to advance the mission of the National Heart, Lung, and Blood Institute.