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Randomized clinical trials are the foundation of evidence-based medicine and central to practice guidelines and patient care decisions. Nonetheless, randomized trials in heart failure (HF) populations have become increasingly difficult to conduct and are frequently associated with slow patient enrollment, highly selected populations, extensive data collection, and high costs. The traditional model for HF trials has become particularly difficult to execute in the United States, where challenges to site-based research have frequently led to modest U.S. representation in global trials. In this context, the TRANSFORM-HF (Torsemide Comparison with Furosemide for Management of Heart Failure) trial aims to overcome traditional trial challenges and compare the effects of torsemide versus furosemide among patients with HF in the United States. Loop diuretic agents are regularly used by most patients with HF and practice guidelines recommend optimal use of diuretic agents as key to a successful treatment strategy. Long-time clinical experience has contributed to dominant use of furosemide for loop diuretic therapy, although preclinical and small clinical studies suggest potential advantages of torsemide. However, due to the lack of appropriately powered clinical outcome studies, there is insufficient evidence to conclude that torsemide should be routinely recommended over furosemide. Given this gap in knowledge and the fundamental role of loop diuretic agents in HF care, the TRANSFORM-HF trial was designed as a prospective, randomized, event-driven, pragmatic, comparative-effectiveness study to definitively compare the effect of a treatment strategy of torsemide versus furosemide on long-term mortality, hospitalization, and patient-reported outcomes among patients with HF. (TRANSFORM-HF: ToRsemide compArisoN With furoSemide FORManagement of Heart Failure [TRANSFORM-HF]; NCT03296813 )

Background We assessed the prevalence and clinical characteristics of patients with acute decompensated heart failure (ADHF) who live alone and how they were different from patients who lived with someone else. Methods We analyzed patients in the REHAB-HF Trial. Patients were ≥60 years with preserved or reduced ejection fraction who were hospitalized with ADHF. Results Of 202 patients, 67 (33.2%) lived alone. Patients who lived alone had a mean age of 72.4±7.8 years, 64% (n=43) of whom were female, 52% (n=35) were non-white and had a mean 6.1±5.5 comorbidities. Patients living alone were largely similar in baseline characteristics, comorbid burden and prescribed medications to patients living with someone else. However, patients living alone were more likely to be female than patients living with someone else (63% [n=43] vs. 49% [n=66], p=0.04). Patients living alone had severe impairments in physical function and QoL. Cognitive dysfunction was present in 81% of those living alone. However, after adjusting for sex, no differences in physical function, depression, cognitive dysfunction or QoL were noted between patients who lived alone or those who lived with someone else. Conclusions In this diverse population of older ADHF patients, 33% lived alone (versus 26% in the general population). Those living alone were more often female, non-white, and had >6 comorbidities. Treatment strategies for older ADHF patients should consider the potential impact of social determinants.

Multiple newer medications benefit patients with heart failure with reduced ejection fraction (HFrEF). While these therapies benefit the broad population with HFrEF, the efficacy and safety of these therapies have been less well characterized in patients with significant comorbidities. Common comorbidities of high interest in heart failure (HF) include diabetes mellitus, chronic kidney disease (CKD), atrial fibrillation, and obesity, and each has potential implications for clinical management. As the burden of comorbidities increases in HF populations, risk-benefit assessments of HF therapies in the context of different comorbidities are increasingly relevant for clinical practice. This review summarizes data regarding the core HFrEF therapies in the context of comorbidities, with specific attention to sodium-glucose cotransporter 2 inhibitors, sacubitril/valsartan, mineralocorticoid receptor antagonists (MRAs), and beta-blockers. In general, studies support consistent treatment effects with regard to clinical outcome benefits in the presence of comorbidities. Likewise, safety profiles are relatively consistent irrespective of comorbidities, with the exception of heightened risk of hyperkalemia with MRA therapy in patients with severe CKD. In conclusion, while HF management is complex in the context of multiple comorbidities, the totality of evidence strongly supports guideline-directed medical therapies as foundational for improving outcomes in these high-risk patients.

Background: Hospitalization for heart failure (HF) is associated with increased risk of death among patients with chronic HF. The degree to which hospitalization for HF is a distinct biologic entity with independent prognostic value versus a marker of higher risk chronic HF patients is unclear. Methods: After excluding patients with new-onset HF, the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) included 4205 patients hospitalized for worsening chronic HF with reduced or preserved ejection fraction. The present analysis compared patients by presence or absence of prior HF hospitalization within 12 months and by timing of prior HF hospitalization relative to index hospitalization. Associations with 180-day all-cause mortality were assessed, including adjustment for 27 prespecified clinical factors. Results: Overall, 2241 (53.3%) patients had a HF hospitalization within the prior 12 months and 1964 (46.7%) did not. Mortality rates at 180 days were 15.5% and 11.9%, respectively. In unadjusted analyses, prior HF hospitalization was associated with increased risk of 180-day mortality (HR, 1.35 [95% CI, 1.14–1.59]; P P =0.064). Similarly, after adjustment, compared with patients without prior hospitalization, prior HF hospitalization was not associated with mortality, irrespective of timing (0–4 months: HR, 1.10 [95% CI, 0.87–1.39], P =0.41; 4–8 months: HR, 0.95 [95% CI, 0.70–1.27]; P =0.72; 8–12 months: HR, 1.06 [95% CI, 0.74–1.51], P =0.77; >12 months: HR, 0.81 [95% CI, 0.63–1.06], P =0.12). Conclusions: In this cohort of patients hospitalized for worsening HF, prior HF hospitalization was not associated with 180-day mortality after comprehensively accounting for patient characteristics measured during the index patient visit. Clinical confounders measured at the point-of-care may explain previously observed associations between prior HF hospitalization and mortality, and these clinical factors may be a more direct means of predicting patient survival. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00475852.

OBJECTIVES: The authors estimated changes of stressed blood volume (SBV) induced by splanchnic nerve block (SNB) in patients with either decompensated or ambulatory heart failure with reduced ejection fraction (HFrEF). BACKGROUND: The splanchnic vascular capacity is a major determinant of the SBV, which in turn determines cardiac filling pressures and may be modifiable through SNB. METHODS: We analyzed data from 2 prospective, single-arm clinical studies in decompensated HFrEF (splanchnic HF-1; resting hemodynamics) and ambulatory heart failure (splanchnic HF-2; exercise hemodynamics). Patients underwent invasive hemodynamics and short-term SNB with local anesthetics. SBV was simulated using heart rate, cardiac output, central venous pressure, pulmonary capillary wedge pressure, systolic and diastolic systemic arterial and pulmonary artery pressures, and left ventricular ejection fraction. SBV is presented as ml/70 kg body weight. RESULTS: Mean left ventricular ejection fraction was 21 ± 11%. In patients with decompensated HFrEF (n = 11), the mean estimated SBV was 3,073 ±251 ml/70 kg. At 30 min post-SNB, the estimated SBV decreased by 10% to 2,754 ± 386 ml/70 kg (p = 0.003). In ambulatory HFrEF (n = 14) patients, the mean estimated SBV was 2,664 ± 488 ml/70 kg and increased to 3,243 ± 444 ml/70 kg (p < 0.001) at peak exercise. The resting estimated SBV was lower in ambulatory patients with HFrEF than in decompensated HFrEF (p = 0.019). In ambulatory patients with HFrEF, post-SNB, the resting estimated SBV decreased by 532 ± 264 ml/70 kg (p < 0.001). Post-SNB, with exercise, there was no decrease of estimated SBV out of proportion to baseline effects (p = 0.661). CONCLUSIONS: The estimated SBV is higher in decompensated than in ambulatory heart failure. SNB reduced the estimated SBV in decompensated and ambulatory heart failure. The reduction in estimated SBV was maintained throughout exercise. (Splanchnic Nerve Anesthesia in Heart Failure, NCT02669407; Abdominal Nerve Blockade in Chronic Heart Failure, NCT03453151) (J Am Coll Cardiol HF 2021;9:293–300) © 2021 by the American College of Cardiology Foundation.

Our aims are to explore the evidence for egg consumption effects on cardiovascular disease risk factors and the relationship between egg consumption with risk of coronary heart disease, stroke, heart failure, hypertension, and also to briefly discuss cardiovascular implications of egg consumption in individuals with diabetes and chronic kidney disease. Additionally, we provide a framework for health professionals when counseling patients on egg consumption as it relates to cardiovascular disease risk, and highlight areas where evidence is inconclusive and in need of future investigation. The relationship between egg consumption and cardiovascular diseases remains an area of significant debate among health professionals, as historically, eggs have been seen as potentially harmful if consumed frequently. The majority of existing evidence supports that assertion that moderate egg consumption of up to one egg per day in otherwise healthy individuals is not associated with a higher risk of ASCVD. In fact, eggs are a nutritious staple food that can be consumed in moderation in healthy individuals. Diet is all about balance. Moderate egg consumption, i.e., up to one egg per day, is not associated with a higher risk of cardiovascular diseases. Besides, eggs are an affordable food with a high content of many important nutrients.

Older adults with acute decompensated heart failure have persistently poor clinical outcomes. Cognitive impairment (CI) may be a contributing factor. However, the prevalence of CI and the relationship of cognition with other patient-centered factors such a physical function and quality of life (QOL) that also may contribute to poor outcomes are incompletely understood.Older (≥60 years) hospitalized patients with acute decompensated heart failure were assessed for cognition (Montreal Cognitive Assessment [MoCA]), physical function (Short Physical Performance Battery [SPPB], 6-minute walk distance [6MWD]), and QOL (Kansas City Cardiomyopathy Questionnaire, Short Form-12). Among patients (N = 198, 72.1 ± 7.6 years), 78% screened positive for CI (MoCA of26) despite rare medical record documentation (2%). Participants also had severely diminished physical function (SPPB 6.0 ± 2.5 units, 6MWD 186 ± 100 m) and QOL (scores of50). MoCA positively related to SPPB (ß = 0.47, P.001), 6MWD ß = 0.01, P = .006) and inversely related to Kansas City Cardiomyopathy Questionnaire Overall Score (ß = -0.05, P.002) and Short Form-12 Physical Component Score (ß = -0.09, P = .006). MoCA was a small but significant predictor of the results on the SPPB, 6MWD, and Kansas City Cardiomyopathy Questionnaire.Among older hospitalized patients with acute decompensated heart failure, CI is highly prevalent, is underrecognized clinically, and is associated with severe physical dysfunction and poor QOL. Formal screening may reduce adverse events by identifying patients who may require more tailored care.

Background Cardiovascular disease (CVD) hospitalizations declined worldwide during the COVID-19 pandemic. It is unclear how shelter-in-place orders affected acute CVD hospitalizations, illness severity, and outcomes. Hypothesis COVID-19 pandemic was associated with reduced acute CVD hospitalizations (heart failure [HF], acute coronary syndrome [ACS], and stroke [CVA]), and worse HF illness severity. Methods We compared acute CVD hospitalizations at Duke University Health System before and after North Carolina's shelter-in-place order (January 1-March 29 vs. March 30-August 31), and used parallel comparison cohorts from 2019. We explored illness severity among admitted HF patients using ADHERE ("high risk": >2 points) and GWTG-HF (">10%": >57 points) in-hospital mortality risk scores, as well as echocardiography-derived parameters. Results Comparing hospitalizations during January 1-March 29 (N = 1618) vs. March 30-August 31 (N = 2501) in 2020, mean daily CVD hospitalizations decreased (18.2 vs. 16.1 per day, p = .0036), with decreased length of stay (8.4 vs. 7.5 days, p = .0081) and no change in in-hospital mortality (4.7 vs. 5.3%, p = .41). HF hospitalizations decreased (9.0 vs. 7.7 per day, p = .0019), with higher ADHERE ("high risk": 2.5 vs. 4.5%; p = .030), but unchanged GWTG-HF (">10%": 5.3 vs. 4.6%; p = .45), risk groups. Mean LVEF was lower (39.0 vs. 37.2%, p = .034), with higher mean LV mass (262.4 vs. 276.6 g, p = .014). Conclusions CVD hospitalizations, HF illness severity, and echocardiography measures did not change between admission periods in 2019. Evaluating short-term data, the COVID-19 shelter-in-place order was associated with reductions in acute CVD hospitalizations, particularly HF, with no significant increase in in-hospital mortality and only minor differences in HF illness severity.

International audience; Background: Prior analyses suggest an association between formula-based plasma volume (PV) estimates and outcomes in heart failure (HF). We assessed the association between estimated PV status by the Duarte-ePV and Kaplan Hakim (KH-ePVS) formulas, and in-hospital and postdischarge clinical outcomes, in the ASCEND-HF trial.Methods and results: The KH-ePVS and Duarte-ePV were calculated on admission. We assessed associations with in-hospital worsening HF, 30-day composite cardiovascular mortality or HF rehospitalization and 180-day all-cause mortality. There were 6373 (89.2%), and 6354 (89.0%) patients who had necessary characteristics to calculate KH-ePVS and Duarte-ePV, respectively. There was no association between PV by either formula with in-hospital worsening HF. KH-ePVS showed a weak correlation with N-terminal prohormone BNP, and with measures of decongestion such as body weight change and urine output (r < 0.3 for all). Duarte-ePV was trending toward an association with worse 30-day (adjusted odds ratio 1.07, 95% confidence interval [CI] 1.00-1.15, P = .058), but not 180-day outcomes (adjusted hazard ratio 1.03, 95% CI 0.97-1.09, P = .289). A continuous KH-ePVS of >0 (per 10-unit increase) was associated with improved 30-day outcomes (adjusted odds ratio 0.75, 95% CI 0.62-0.91, P = .004). The continuous KH-ePVS was not associated with 180-day outcomes (adjusted hazard ratio 1.05, 95% CI 0.98-1.12, P = .139).Conclusions: Baseline PV estimates had a weak association with in-hospital measures of decongestion. The Duarte-ePV trended toward an association with early clinical outcomes in decompensated HF, and may improve risk stratification in HF.

We examined the relationship between pain severity and outcomes in patients with heart failure with reduced ejection fraction (HFrEF) in the HF-ACTION randomized controlled trial. Trends of health-related quality of life (HRQoL) measures grouped by patients' self-reported baseline bodily pain severity were compared using correlation tests, and the association between pain severity and clinical outcomes (including a primary composite endpoint of all-cause mortality and all-cause hospitalization) was assessed using multivariable adjusted analyses. Of the 2310 patients, 22.9% reported no pain, 45.8% very mild/mild, 24.9% moderate, and 6.4% severe/very severe. Greater pain severity was associated with worse HRQoL measures (EuroQoL-5D-3L and Kansas City Cardiomyopathy Questionnaire; both p < 0.0001). Compared to those reporting no pain, patients reporting severe/very severe pain had greater risk for the primary endpoint (adjusted hazard ratio 1.42, 95% confidence interval 1.11-1.83, p = 0.01). In patients with HFrEF, greater pain severity was associated with worse HRQoL and clinical outcomes. Trial Registration: NCT00047437.

Multiple medications are proven to reduce morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), but data regarding personalized approaches to optimize medication dosing remain limited. Current treatment guidelines recommend up-titration to target or maximally tolerated doses of these medications, yet use and dosing remain suboptimal in clinical practice. Body surface area (BSA) is a readily available clinical metric, used for dosing many medications, closely associated with blood pressure, renal function, and vascular congestion, and may influence efficacy, safety, and tolerability of HFrEF medications. In this review, we examine the rationale, strengths/weaknesses, and potential utility of BSA as a means of optimizing HFrEF medication use and dosing.

Background: Women with heart failure report worse health-related quality of life, on average, than men. Whether this is due to true differences in care or that women and men interpret and respond to survey questions differently is unknown. In this study, we investigate potential gender-based differential item functioning (DIF) on the Kansas City Cardiomyopathy Questionnaire (KCCQ) Physical Limitations (PL) domain.Methods: Using data from Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION), a multicenter, randomized controlled trial of exercise training in patients with chronic heart failure with reduced ejection fraction (1670 men, 661 women), we assessed gender DIF using item response theory (IRT)–based Wald test and ordinal logistic regression. Both methods evaluated how men and women responded to each KCCQ item after adjusting for their physical limitation status.Results: A 5-item version of the KCCQ PL domain was evaluated to satisfy statistical assumptions of DIF methodology. No KCCQ items exhibited statistically significant DIF using the IRT-based Wald method, and two items exhibited DIF using the ordinal logistic regression method (KCCQ1e: Climbing a flight of stairs without stopping; KCCQ1f: Hurrying or jogging) (pConclusions: To accurately measure patient-reported outcomes, it is important to evaluate potential biases that may influence the ability to compare patient subgroups. The magnitude of DIF on the 5-item KCCQ PL domain was negligible.

The trends of implantable cardioverter defibrillator (ICD) use in patients with a durable left ventricular assist device (LVAD) remain uncertain. We used the National Inpatient Sample to identify hospitalizations between 2009 and 2018 in which patients received a new LVAD or had a pre-existing one. Procedure codes were then used to identify hospitalizations in which a new ICD was implanted. In 34,113 hospitalizations for new and/or replacement LVADs, an ICD was implanted in 1297 (3.8%). The rate of ICD implantation along with an LVAD declined from 2009 to 2018 (annual percent change: -23.2%; P-trend0.001). Independent factors associated with concurrent ICD implantation in patients receiving LVAD were younger age, White (compared with Black) race, and in-hospital cardiac arrest. Concurrent ICD implantation was associated with a longer hospital stay (adjusted mean difference: 4.48 days) and higher inflation-adjusted costs (adjusted mean difference: $31,679), but lower in-hospital mortality rates (adjusted odds ratio: 0.29; P0.001), compared with LVAD placement alone. Amongst 95,583 hospitalizations of patients with a pre-existing LVAD, an ICD was placed in 616 (0.64%). There was no change in the rate of ICD implantation from 2009 to 2018 in patients with a pre-existing LVAD (annual percent change: -10.34%; P = 0.18).

We aimed to investigate the impact of obstructive coronary artery disease (CAD) in patients with acute decompensated heart failure (ADHF), and examine potential differences in prognostic utility for heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF).The Atherosclerosis Risk in Communities study conducted hospital surveillance of ADHF from 2005 to 2014. Obstructive CAD was defined as ≥50% or ≥75% stenosis, respectively, for the left main and other major epicardial arteries. Adjusted associations between obstructive CAD and 30-, 60-, and 90-day mortality were analysed. A total of 934 (4146 weighted) patients admitted with ADHF (mean age 72 years, 46% women, 30% Black, 30% HFpEF) had available angiography (61% performed in hospital). Obstructive CAD was more prevalent with HFrEF than HFpEF, whether at the left main (15% vs. 11%), left anterior descending (LAD) (48% vs. 30%), left circumflex (37% vs. 32%), right coronary (42% vs. 32%), or multiple coronary arteries (45% vs. 33%). In-hospital revascularization was performed in 25% and 22% of patients with HFrEF and HFpEF, respectively. Obstructive CAD was associated with higher adjusted mortality, particularly with left main or LAD involvement, and had a more pronounced association with 90-day mortality in HFrEF (odds ratio [OR] 2.77; 95% confidence interval [CI] 1.53-5.02) than HFpEF (OR 0.94; 95% CI 0.36-2.41) (p-interaction = 0.05).Patients hospitalized with ADHF and coexisting obstructive CAD have higher short-term mortality, warranting the need for effective interventions and secondary prevention.

Heart failure (HF) is a complex, multifactorial and heterogeneous syndrome with substantial mortality and morbidity. Over the last few decades, numerous attempts have been made to develop targeted therapies that may attenuate the known pathophysiological pathways responsible for causing the progression of HF. However, therapies developed with this objective have sometimes failed to show benefit. The pathophysiological construct of HF with numerous aetiologies suggests that interventions with broad mechanisms of action which simultaneously target more than one pathway maybe more effective in improving the outcomes of patients with HF. Indeed, current therapeutics with clinical benefits in HF have targeted a wider range of intermediate phenotypes. Despite extensive scientific breakthroughs in HF research recently, questions persist regarding the ideal therapeutic targets which may help achieve maximum benefit. In this review, we evaluate the mechanism of action of current therapeutic strategies, the pathophysiological pathways they target and highlight remaining knowledge gaps regarding the mode of action of these interventions.

Mobile health (mHealth) platforms can affect health behaviors but have not been rigorously tested in randomized trials.We sought to evaluate the effectiveness of a pragmatic mHealth intervention in patients with heart failure (HF) and diabetes (DM).We conducted a multicenter randomized trial in 187 patients with both HF and DM to assess an mHealth intervention to improve physical activity and medication adherence compared to usual care. The primary endpoint was change in mean daily step count from baseline through 3 months. Other outcomes included medication adherence, health-related quality of life and metabolomic profiling.The mHealth group had an increase in daily step count of 151 steps/day at 3 months, whereas the usual-care group had a decline of 162 steps/day (least squares mean between-group difference = 313 steps/day; 95% CI: 8 619; P = 0.044). Medication adherence, measured using the Voils Adherence Questionnaire, did not change from baseline to 3 months (LS-mean change -0.08 in mHealth vs -0.15 in usual care; P = 0.47). The mHealth group had an improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score compared to the usual-care group (LS-mean difference = 5.5 points, 95% CI: 1.4, 9.6; P = 0.009). Thirteen metabolites, primarily medium- and long-chain acylcarnitines, changed differently between treatment groups from baseline to 3 months (P0.05).In patients with HF and DM, a 3-month mHealth intervention significantly improved daily physical activity, health-related quality of life and metabolomic markers of cardiovascular health but not medication adherence.Heart failure (HF) and diabetes (DM) have overlapping biological and behavioral risk factors. We conducted a multicenter randomized, clinical trial in 187 patients with both HF (regardless of ejection fraction) and DM to assess whether an mHealth intervention could improve physical activity and medication adherence. The mHealth group had an increase in mean daily step count and quality of life but not in medication adherence. Medium- and long-chain acylcarnitines changed differently in treatment groups from baseline to 3 months (P0.05). These data have important implications for designing effective lifestyle interventions in HF and DM.

Purpose We aimed to 1) describe characteristics of patients with heart failure with preserved ejection fraction (HFpEF) enrolled in RELAX stratified by normal or elevated baseline serum uric acid (sUA) level; 2) evaluate the association between sUA level and surrogate clinical measures; and 3) assess associations between changes in sUA level over time and changes in surrogate clinical measures. Methods We analyzed 212 patients with HFpEF and normal or elevated (>6 mg/dL) baseline sUA measurements from the RELAX trial. Variables examined included clinical characteristics, cardiopulmonary exercise testing, 6-minute walk testing, quality of life, echocardiography, and serum biomarker testing. Baseline characteristics between groups were compared and scatter plots with quadratic regression lines and linear regression modeling were used to assess the relationship between baseline sUA and clinical measures. Kaplan–Meier curves were used to describe composite death or cardiovascular/renal hospitalization. Results The prevalence of elevated baseline sUA was 68.9%. Patients with elevated sUA had more baseline comorbidities and poorer functional status on cardiopulmonary exercise testing than those without. After adjustment, significant associations between baseline sUA levels and cystatin C, N-terminal pro B-type natriuretic peptide, high-sensitivity troponin I, and high-sensitivity C-reactive protein were identified. Higher baseline sUA was also associated with worsening peak VO2, 6-minute walk testing, and left ventricular mass. No significant association was found between baseline sUA levels and the composite of death or cardiovascular/renal hospitalization at 24 weeks. Conclusion sUA is an important marker of comorbidities and functional status in patients with HFpEF. Clinical trials of sUA-lowering therapies in patients with HFpEF are promising.

There is no clear consensus on a lower cutoff value for normal left ventricular ejection fraction (EF) and the prognostic implications of low normal EF (LNEF) are poorly understood, particularly in Blacks. Therefore, we investigated the association of LNEF and incident heart failure (HF) in a community-based cohort of Blacks. We studied 3,669 participants (mean age 54 years, 63% women) of the Jackson Heart Study without prevalent HF or coronary heart disease (CHD). Participants were divided into three groups: (1) Reduced EF (

The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on renal outcomes in patients with type 2 diabetes at high cardiovascular risk are modest or neutral. However, GLP-1RAs may confer clinical benefits in those at high risk of progressive renal function loss. We examined the effects of once-weekly exenatide (EQW) on estimated glomerular filtration rate (eGFR) slope and urinary albumin:creatinine ratio (UACR) as a function of baseline UACR in 3503 EXSCEL participants (23.7%) with eGFR data available and 2828 participants (19.2%) with UACR change data available. EQW improved eGFR slope assessed via mixed model repeated measures, compared with placebo, in participants with baseline UACR >100 mg/g (0.79 mL/min/1.73 m2/year [95% confidence interval {CI} 0.24–1.34]) and UACR >200 mg/g (1.32 mL/min/1.73 m2/year [95% CI 0.57–2.06]), but not at lower UACR thresholds. EQW reduced UACR, compared with placebo, assessed via analysis of covariance, consistently across subgroups with baseline UACR >30 mg/g (28.2% reduction), baseline UACR >100 mg (22.5% reduction) and baseline UACR >200 mg (34.5% reduction). This post hoc EXSCEL analysis suggests that EQW reduces UACR, with improvement in eGFR slope specifically in participants with elevated baseline UACR.

The coronavirus disease-2019 (COVID-19) pandemic has profoundly changed clinical care and research, including the conduct of clinical trials, and the clinical research ecosystem will need to adapt to this transformed environment. The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory and the Academic Research Consortium, composed of academic investigators from the United States and Europe, patients, the U.S. Food and Drug Administration, the National Institutes of Health, and industry members. A series of meetings were convened to address the challenges caused by the COVID-19 pandemic, review options for maintaining or altering best practices, and establish key recommendations for the conduct and analysis of clinical trials for cardiovascular disease and heart failure. This paper summarizes the discussions and expert consensus recommendations., Central Illustration, Highlights • The COVID-19 pandemic has profoundly affected patient care and the conduct of clinical trials. • HF-ARC scientific expert panel developed recommendations for the conduct and analysis of heart failure trials during the pandemic. • The HF-ARC consensus recommendations support ongoing clinical trials and strengthen the clinical trial ecosystem, which should have sustained benefits in the future.

Machine learning and artificial intelligence are generating significant attention in the scientific community and media. Such algorithms have great potential in medicine for personalizing and improving patient care, including in the diagnosis and management of heart failure. Many physicians are familiar with these terms and the excitement surrounding them, but many are unfamiliar with the basics of these algorithms and how they are applied to medicine. Within heart failure research, current applications of machine learning include creating new approaches to diagnosis, classifying patients into novel phenotypic groups, and improving prediction capabilities. In this paper, we provide an overview of machine learning targeted for the practicing clinician and evaluate current applications of machine learning in the diagnosis, classification, and prediction of heart failure.

Cluster randomized trials (CRTs) refer to experiments with randomization carried out at the cluster or the group level. While numerous statistical methods have been developed for the design and analysis of CRTs, most of the existing methods focused on testing the overall treatment effect across the population characteristics, with few discussions on the differential treatment effect among subpopulations. In addition, the sample size and power requirements for detecting differential treatment effect in CRTs remain unclear, but are helpful for studies planned with such an objective. In this article, we develop a new sample size formula for detecting treatment effect heterogeneity in two-level CRTs for continuous outcomes, continuous or binary covariates measured at cluster or individual level. We also investigate the roles of two intraclass correlation coefficients (ICCs): the adjusted ICC for the outcome of interest and the marginal ICC for the covariate of interest. We further derive a closed-form design effect formula to facilitate the application of the proposed method, and provide extensions to accommodate multiple covariates. Extensive simulations are carried out to validate the proposed formula in finite samples. We find that the empirical power agrees well with the prediction across a range of parameter constellations, when data are analyzed by a linear mixed effects model with a treatment-by-covariate interaction. Finally, we use data from the HF-ACTION study to illustrate the proposed sample size procedure for detecting heterogeneous treatment effects.

The role of obesity in the pathogenesis of heart failure (HF), and in particular HF with preserved ejection fraction (HFpEF), has drawn significant attention in recent years. The prevalence of both obesity and HFpEF has increased worldwide over the past decades and when present concomitantly suggests an obese-HFpEF phenotype. Anthropometrics, including body mass index (BMI), waist circumference (WC), and waist-hip-ratio (WHR), are associated with incident HFpEF. However, the cardiovascular effects of obesity may actually be driven by the distribution of fat, which can accumulate in the epicardial, visceral, and subcutaneous compartments. Regional fat can be quantified using noninvasive imaging techniques, including computed tomography (CT), magnetic resonance imaging (MRI), and dual-energy X-ray absorptiometry (DXA). Regional variations in fat accumulation are associated with different HFpEF risk profiles, whereby higher epicardial and visceral fat have a much stronger association with HFpEF risk compared with elevated subcutaneous fat. Thus, regional adiposity may serve a pivotal role in the pathophysiology of HFpEF contributing to decreased cardiopulmonary fitness, impaired left ventricular compliance, upregulation of local and systemic inflammation, promotion of neurohormonal dysregulation, and increased intra-abdominal pressure and vascular congestion. Strategies to reduce total and regional adiposity have shown promise, including intensive exercise, dieting, and bariatric surgery programs, but few studies have focused on HFpEF-related outcomes among obese. Further understanding the role these variable fat depots play in the progression of HFpEF and HFpEF-related hospitalizations may provide therapeutic targets in treating the obese-HFpEF phenotype. This article is protected by copyright. All rights reserved.

OptiVol (Medtronic PLC, Minneapolis, MN) is a diagnostic feature of some cardiac implantable electronic devices (CIEDs) based on changes in thoracic impedance (TI) over time. Changes in TI can predict heart failure (HF) hospitalizations and mortality in HF populations. However, the utility of this feature is unknown in patients with a left ventricular assist device (LVAD). To determine if OptiVol and TI correlate with clinical HF events in a population of LVAD patients, hospitalization outcomes were collected retrospectively from the electronic health records at a single academic medical center in 80 LVAD patients with an OptiVol-capable CIED. Demographics, medical history, and available clinical data were reviewed and reported. The primary outcomes of interest were TI and OptiVol trends before and after hospitalization, and association of trends before and after these events was evaluated. Most patients had a HeartMate II LVAD and most CIEDs were defibrillators, and 23 (29%) had at least one HF hospitalization during the study period. HF hospitalizations were preceded by signs of volume overload in Optivol (60%) and TI (78%) with recovery of these measures post hospitalization in 33% and 25% of patients, respectively. Monitoring of TI and OptiVol may be one effective component of HF management in LVAD patients as part of a comprehensive program.

Cardiovascular disease has an increased prevalence among patients with idiopathic pulmonary fibrosis (IPF). Cardiovascular disease and IPF share similar symptoms with overlapping demographics and risk factors for disease development. Common cellular mediators leading to disease development and progression have been identified in both the cardiovascular and pulmonary organ systems. In this context, discovery of new therapeutic targets and medical therapies could be mutually beneficial across cardiopulmonary diseases. Here we present (1) a clinical review of IPF for the cardiovascular clinician and (2) common cellular mechanisms responsible for fibrosis in the heart and lungs and (3) highlight future research considerations and the potential role of novel therapeutic agents which may be mutually beneficial in cardiac and pulmonary fibrosis.

Little is known about the impact of accountable care organizations (ACO) on hospitalized heart failure (HF) patients, a high-cost and high-risk population.We linked Medicare fee-for-service claims from 2013 to 2015 with data from American Heart Association Get With The Guidelines-HF registry to compare HF care, post-discharge outcomes, and total annual Medicare spending by ACO status at discharge.Using adjusted Cox models and accounting for competing risks of death, we compared all-cause mortality and readmission at 1 year by ACO status with reporting of hazard ratios (HR) and 99% confidence intervals (CI).The study included 45,259 HF patients from 300 hospitals, with 21.1% assigned to an ACO. Patient characteristics were similar between the two groups with a few exceptions. The ACO patients lived in geographic areas with higher median income ($54400 [IQR $48600-65900] vs $52300 [$45900-61200], P.0001). Compliance with four HF-specific quality measures was modestly higher in the ACO group (80% vs 76%, P.0001). In adjusted analysis, ACO status was associated with similar all-cause readmission (HR: 1.03; 99% CI: 0.99, 1.07) but lower risk of 1-year mortality (HR: 0.85; 99% CI: 0.85, 0.90) compared with non-ACO status. Median Medicare spending in the calendar year of hospitalization was similar (ACO $42,737 [IQR $23,011-72,667] vs non-ACO $42,586 [$22,896-72,518], P = 0.06).Among Medicare patients hospitalized for HF, participation in an ACO was associated with similar rates of all-cause readmission and no associated cost reductions compared with non-ACO status. There was a lower risk of 1-year mortality associated with ACO participation, which warrants further evaluation.

Background: Patients with heart failure (HF) have multiple coexisting comorbidities. The temporal trends in the burden of comorbidities and associated risk of mortality among patients with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are not well established. Methods: HF-related hospitalizations were sampled by stratified design from 4 US areas in 2005 to 2014 by the community surveillance component of the ARIC study (Atherosclerosis Risk in Communities). Acute decompensated HF was classified by standardized physician review and a previously validated algorithm. An ejection fraction Results: A total of 5460 hospitalizations (24 937 weighted hospitalizations) classified as acute decompensated HF had available ejection fraction data (53% female, 68% white, 53% HFrEF, 47% HFpEF). The average number of comorbidities was higher for patients with HFpEF versus HFrEF, both for women (5.53 versus 4.94; P P P -trendP for interaction by HF type=0.02). The associated mortality risk per 1 higher comorbidity also increased significantly over time for patients with HFpEF and HFrEF, as well ( P for interaction with time=0.002 and 0.02, respectively) Conclusions: The burden of comorbidities among hospitalized patients with acute decompensated HFpEF and HFrEF has increased over time, as has its associated mortality risk. Higher burden of comorbidities is associated with higher risk of mortality, with a stronger association noted among patients with HFpEF versus HFrEF.

Background Hypertensive diseases in pregnancy have been associated with altered cardiac structure and function, yet these associations have not been systematically investigated in larger populations including African Americans. We evaluated the relationships between hypertensive diseases in pregnancy with cardiac structure and function later in life in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Methods We investigated 1013 African American women sibships with echocardiographic measurements from the GENOA study (Phase II, 2000-05; Jackson, MS). Women were classified as self-reported nulliparous (n = 61), a history of normotensive pregnancies (n = 780), a history of a hypertensive pregnancies (n = 152), or a history of preeclampsia (n = 20). We compared adjusted associations among these 4 groups with echocardiographic measurements of cardiac structure and function using generalized estimating equations, accounting for familial clustering. Results Among 1013 women with echocardiographic data (mean age 62 ± 9.5 years), women with a history of hypertensive pregnancy had lower left ventricular ejection fraction (LVEF) (P = 0.043) compared to nulliparous women and higher left atrial systolic dimension (LASD) compared to women with a history of normotensive pregnancies (P = 0.010), After adjusting for cardiovascular risk factors. There were no statistically significant differences in other echocardiographic parameters among these groups. Conclusions A history of hypertension in pregnancy is associated with lower LVEF later in life, compared to nulliparous women and higher LASD compared to women with a history of normotensive pregnancies. However, given the multiple comparisons considered, this finding should be interpreted cautiously and requires further study.

Background An early report of recipient heart transplantation outcomes under the new U.S. heart allocation system introduced in late 2018 found a lower post-transplant survival rate compared with that of the prior system. Objectives The aim of this study was to examine recipient survival under the new system by using an updated dataset. Methods The 2015 to 2019 United Network for Organ Sharing registry was queried for adult heart transplant recipients, stratified according to whether the subjects were listed and underwent transplant before or after October 18, 2018, when the new allocation system was implemented. The association between allocation system and recipient mortality was analyzed by using the Kaplan-Meier method and multivariable Cox proportional hazards regression. Results A total of 7,119 recipients met inclusion criteria: 6,004 (84%) and 1,115 (16%) listed and undergoing transplant in the old and new allocation systems, respectively. This registry update included 576 new-system recipients, more than double the amount previously analyzed. Recipients from the new system were more likely to be bridged to transplant with temporary mechanical circulatory support devices instead of durable left ventricular assist devices and had longer graft ischemic times. After adjustment, the new system was not associated with poorer survival on Kaplan-Meier survival analysis (log-rank test; p = 0.075) or multivariable Cox proportional hazards modeling (adjusted hazard ratio: 1.18; 95% confidence interval: 0.90 to 1.55). Conclusions The short-term survival of recipients listed and receiving a transplant under the old and new allocation systems seems to be comparable. The modification to the allocation system has resulted in several changes to the clinical profiles of patients undergoing transplants that must be closely monitored in the coming years.

The role of percutaneous coronary interventions in addition to medical therapy for patients with stable coronary artery disease continues to be debated in routine clinical practice, despite more than 2 decades of randomized controlled trials. The residual uncertainty arises from particular challenges facing revascularization trials. Which endpoint do doctors care about, and which do patients care about? Which participants should be enrolled? What background medical therapy should we use? When is placebo control relevant? In this paper, we discuss how these questions can be approached and examine the merits and disadvantages of possible options. Engaging multiple stakeholders, including patients, researchers, regulators, and funders, to ensure the design elements are methodologically valid and clinically meaningful should be an aspirational goal in the development of future trials.

The infection caused by severe acute respiratory syndrome coronavirus-2, or COVID-19, can result in myocardial injury, heart failure, and arrhythmias. In addition to the viral infection itself, investigational therapies for the infection can interact with the cardiovascular system. As cardiologists and cardiovascular service lines will be heavily involved in the care of patients with COVID-19, our division organized an approach to manage these complications, attempting to balance resource utilization and risk to personnel with optimal cardiovascular care. The model presented can provide a framework for other institutions to organize their own approaches and can be adapted to local constraints, resource availability, and emerging knowledge.

Background Ivabradine is guideline-recommended to reduce heart failure (HF) hospitalization in patients with stable chronic HF with reduced ejection fraction (EF). Ivabradine initiation following acute HF has had limited evaluation, and there are few randomized data in US patients. The PredischaRge initiation of Ivabradine in the ManagEment of Heart Failure (PRIME-HF) study was conducted to address predischarge ivabradine initiation in stabilized acute HF patients. Methods PRIME-HF was an investigator-initiated, randomized, open-label study of predischarge initiation of ivabradine versus usual care. Eligible patients were hospitalized for acute HF but stabilized, with EF ≤35%, on maximally tolerated β-blocker and in sinus rhythm with heart rate ≥70 beats/min. Ivabradine was acquired per routine care. The primary end point was the proportion of patients on ivabradine at 180 days. Additional end points included heart rate change, patient-reported outcomes, β-blocker use/dose, and safety events (symptomatic bradycardia and hypotension). Results Overall, 104 patients (36% women, 64% African American) were randomized, and the study was terminated early because of funding limitations. At 180 days, 21 of 52 (40.4%) of patients randomized to predischarge initiation were treated with ivabradine compared with 6 of 52 (11.5%) randomized to usual care (odds ratio 5.19, 95% CI 1.88-14.33, P = .002). The predischarge initiation group experienced greater reduction in heart rate through 180 days (mean −10.0 beats/min, 95% CI −15.7 to −4.3 vs 0.7 beats/min, 95% CI −5.4 to 6.7, P = .011). Patient-reported outcomes, β-blocker use/dose, and safety events were similar (all P > .05). Conclusions Ivabradine initiation prior to discharge among stabilized HF patients increased ivabradine use at 180 days and lowered heart rates without reducing β-blockers or increasing adverse events. As the trial did not achieve the planned enrollment, additional studies are needed.

Background: EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective. Methods: Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions. Results: Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 ( P =0.061) to 0.85 ( P =0.008) and the ACM HR from 0.86 ( P =0.016) to 0.81 ( P =0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection. Conclusions: EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01144338.

AIMS In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF), high-dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low-dose spironolactone (25 mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long-acting active metabolites of spironolactone [canrenone and 7α-thiomethylspironolactone (7α-TMS)] in the high-dose group could have contributed to these neutral results. METHODS AND RESULTS In patients randomized to high-dose spironolactone not previously treated with spironolactone (high-dose-naive, n = 112), concentrations of canrenone and 7α-TMS increased at 48 and 96 h compared to baseline, and between 48 and 96 h (all P

Background The rate-limiting step in STEMI diagnosis often is the availability of a 12-lead electrocardiogram (ECG) and its interpretation. The potential may exist to speed the availability of 12-lead ECG information by using commonly available mobile technologies. We sought to test whether combining serial smartphone single-lead ECGs to create a virtual 12-lead ECG can accurately diagnose STEMI. Methods Consenting patients presenting with symptoms consistent with a possible STEMI had contemporaneous standard 12-lead and smartphone ‘12-lead equivalent’ ECG (produced by electronically combining serial single-lead ECGs) recordings obtained. Matched ECGs were evaluated qualitatively and quantitatively by a panel of blinded readers and classified as STEMI/STEMI equivalent (LBBB), Not-STEMI, or uninterpretable. Interpretable ECG pairs were graded as showing good, fair, or poor correlation. Results Two hundred four subjects (age = 60 years, males = 57%, STEMI activation = 45%) were enrolled from 5 international sites. Smartphone ECG quality was graded as good in 151 (74.0%), fair in 32 (15.7%), poor in 8 (3.9%), and uninterpretable in 13 (6.4%). A STEMI/STEMI equivalent diagnosis was identified by standard 12-lead ECG in 57/204 (27.9%) recordings. For all interpretable pairs of smartphone ECGs compared with standard ECGs (n = 190), the sensitivity, specificity, and positive and negative predictive values for STEMI/STEMI equivalent by smartphone were 0.89, 0.84, 0.70 and 0.95, respectively. Conclusions A ‘12-lead equivalent’ ECG obtained from multiple serial single-lead ECGs from a smartphone can identify STEMI with good correlation to a standard 12-lead ECG. This technology holds promise to improve outcomes in STEMI by enhancing the reach and speed of diagnosis and thereby early treatment.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity with complex pathophysiology and manifestations. Phenomapping is the process of applying statistical learning techniques to patient data to identify distinct subgroups based on patterns in the data. Phenomapping has emerged as a technique with potential to improve the understanding of different HFpEF phenotypes. Phenomapping efforts have been increasing in HFpEF over the past several years using a variety of data sources, clinical variables, and statistical techniques. This review summarizes methodologies and key takeaways from these studies, including consistent discriminating factors and conserved HFpEF phenotypes. We argue that phenomapping results to date have had limited implications for clinical care and clinical trials, given that the phenotypes, as currently described, are not reliably identified in each study population and may have significant overlap. We review the inherent limitations of aggregating and utilizing phenomapping results. Lastly, we discuss potential future directions, including using phenomapping to optimize the likelihood of clinical trial success or to drive discovery in mechanisms of the disease process of HFpEF.

Clinical guidelines recommend titration of angiotensin converting enzyme inhibitors (ACEi) and beta-blockers among patients with heart failure with reduced ejection fraction (HFrEF) to maximally tolerated doses. Patient characteristics associated with dose titration and clinical outcomes subsequent to dose titration remain poorly characterized.Among 1999 ambulatory patients with chronic HFrEF in the HF-ACTION trial, use and dosing of ACEi and evidence-based beta-blockers were examined at baseline and 6-month follow-up. Multivariable logistic regression models were used to assess factors associated with dose escalation (medication initation or dosing increase) or dose de-escalation (medication discontinuation or dosing decrease). Cox proportional hazard regression models were used to examine associations between dose trajectory group (stable target, stable sub-target, dose escalation, and dose de-escalation) and subsequent mortality and hospitalization outcomes.For both ACEi and beta-blockers, hospitalization for heart failure in the 6 months prior to enrollment (odds ratio [OR] 2.32 [95% confidence interval 1.58-3.42]) for ACEi; 1.42 [1.05-1.9] for beta-blockers) and higher systolic blood pressure (OR 1.01 [1.00-1.03] per 1 mmHg increase for ACEi; 1.01 [1.00-1.02] for beta-blockers) were associated with dose escalation. Hospitalization 6 months prior to enrollment for any cause (including HF or non-HF causes) was associated with dose de-escalation (OR 1.60 [1.14-2.25] for ACEi; 1.67 [1.20-2.33] for beta-blockers). After adjustment for patient characteristics, compared with stable target dosing, dose de-escalation of either medication was associated with greater all-cause mortality (adjusted hazard ratio [aHR] 1.64 [1.11-2.42] for ACEi; 1.62 [1.04-2.53] for beta-blockers). Compared with stable target dosing, both dose de-escalation (aHR 1.98 [1.36-2.87]) and stable sub-target dosing (aHR 1.49 [1.18-1.87]) of beta-blockers were associated with greater cardiovascular mortality or hospitalization for heart failure.Among outpatients with chronic HFrEF, patient characteristics including recent hospitalization status and blood pressure were associated with odds of subsequent escalation and de-escalation of ACEi and beta-blocker therapy. Compared with patients receiving guildeline-recommended target doses, dose de-escalation of either medication and sub-target dosing of beta-blockers were associated with greater morbidity and mortality over long-term follow-up.

Background: Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized). Methods: Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations, quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model. Results: In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8 [24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01–2.20], 1.37 [0.94–1.99], and 1.48 [1.00–2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.32–8.59], P =0.03; 4.80 [95% CI, 0.00–9.61], P =0.05; 4.66 [95% CI, 0.32–9.01], P =0.04; 4.85 [95% CI, 0.77–8.92], P =0.02; and 4.40 points [95% CI, 0.33–8.48], P =0.03, respectively). Conclusions: Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained through 90 days. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT0415775.

Randomized controlled trials (RCTs) may report outcomes different from those prespecified on trial registration websites, protocols, and statistical analysis plans (SAPs). This study sought to investigate prevalence and characteristics of heart failure (HF) RCTs that report outcomes different from those prespecified.MEDLINE via PubMed was searched to include phase II-IV HF RCTs in nine high-impact journals from 2010 to 2020. Outcomes reported in trial publications were compared with pre-specified outcomes in protocols, registration websites, and SAPs. Chi-squared or Fisher exact test were used to analyze correlations between trial characteristics and inconsistencies. Among 216 trials, 32 inconsistencies were observed in 28 trials (13.0%). Among 32 inconsistencies, 2 (6.3%) pertained to omission of prespecified primary outcomes, 4 (12.5%) pertained to omission of prespecified secondary outcomes, 2 (6.3%) pertained to changing prespecified primary outcomes to secondary outcomes, and 2 (6.3%) pertained to changing pre-specified secondary outcomes to primary outcomes. Three inconsistencies (9.4%) pertained to addition of new primary outcomes, 17 (53.1%) pertained to addition of new secondary outcomes, and 2 (6.3%,) pertained to change in timing of assessment of primary outcomes. Majority of the inconsistencies favored statistically significant findings., Seventy-eight (36.1%) were registered retrospectively. Single-center recruitment was associated with outcome inconsistencies (β=-0.14; 95% CI, -0.22 - -0.01,p=0.035).More than one in ten trials reported outcomes inconsistent with those specified in trial registration websites, SAPs, and protocols. An action plan is warranted to minimize selective reporting and improve transparency.

The sodium–glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09–1.68; P = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment.

Aims: This prespecified analysis of the FIDELIO-DKD trial compared the effects of finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, on cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) by history of heart failure (HF). Methods and results: Patients with T2D and CKD (urine albumin-to-creatinine ratio ≥30–5000 mg/g and estimated glomerular filtration rate [eGFR] ≥25–2), without symptomatic HF with reduced ejection fraction (New York Heart Association II–IV) and treated with optimized renin–angiotensin system blockade were randomized to finerenone or placebo. The composite cardiovascular (CV) outcome (CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for HF) and composite kidney outcome (kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death) were analysed by investigator-reported medical history of HF. Of 5674 patients, 436 (7.7%) had a history of HF. Over a median follow-up of 2.6 years, the effect of finerenone compared with placebo on the composite CV outcome was consistent in patients with and without a history of HF (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50–1.06 and HR 0.90, 95% CI 0.77–1.04, respectively; interaction p = 0.33). The effect of finerenone on the composite kidney outcome did not differ by history of HF (HR 0.79, 95% CI 0.52–1.20 and HR 0.83, 95% CI 0.73–0.94, respectively; interaction p = 0.83). Conclusion: In FIDELIO-DKD, finerenone improved cardiorenal outcome in patients with CKD and T2D irrespective of baseline HF history.

PURPOSE OF REVIEW: Solid organ transplantation (SOT) has become a widely accepted therapy for end-stage disease across the spectrum of thoracic and abdominal organs. With contemporary advances in medical and surgical therapies in transplantation, candidates for SOT are increasingly older with a larger burden of comorbidities, including cardiovascular disease (CVD). CVD, in particular, is a leading cause of morbidity and mortality in SOT candidates with end-stage disease of noncardiac organs [1]. RECENT FINDINGS: Identification of coronary artery disease (CAD), heart failure, and valvular disease are important in noncardiac SOT to ensure both appropriate peri-transplant management and equitable organ allocation. Although the American College of Cardiology (ACC) and the American Heart Association (AHA) have published guidelines and recommendations for the perioperative cardiovascular evaluation of patients undergoing noncardiac surgery, the implications of both symptomatic and asymptomatic CVD differ in patients with end-stage organ failure being considered for SOT when compared to the general population. SUMMARY: Herein, we review the epidemiology, diagnosis, and evidence for the management of CVD in kidney and liver transplantation, combining current guidelines from the 2012 ACC/AHA scientific statement on cardiac disease evaluation in SOT with more contemporary evidenced-based algorithms.