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Aims: The impact of mitral regurgitation (MR) in patients hospitalized for acute heart failure (AHF) is not well established. We assessed the role of MR in patients enrolled in the Relaxin in Acute Heart Failure 2 (RELAX-AHF-2) trial. Methods and results: Patients enrolled in RELAX-AHF-2 with available data regarding MR status were included in this analysis. Baseline characteristics, in-hospital data, and clinical outcomes through 180-day follow-up were evaluated. The impact of moderate/severe MR was assessed. Among 6420 AHF patients with known MR status, 1810 patients (28.2%) had moderate/severe MR. Compared to patients with no/mild MR, those with moderate/severe MR were more likely to have history of heart failure (HF), prior HF hospitalization, more comorbidities, symptoms/signs of HF, lower left ventricular ejection fraction and higher N-terminal pro-B-type natriuretic peptide levels. Moderate/severe MR was associated with longer length of hospital stay, higher rates of residual dyspnoea, increased jugular venous pressure through the index hospitalization and a higher unadjusted risk of the composite of cardiovascular (CV) death or rehospitalization for HF/renal failure (RF) through 180 days (crude hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.03–1.27, p = 0.01). The association between moderate/severe MR and poorer outcomes was not maintained in a multivariable model including several covariates of interest (adjusted HR 1.03, 95% CI 0.91–1.17, p = 0.65). Similar findings were observed for HF/RF rehospitalization alone. Conclusions: In patients with AHF, moderate/severe MR was associated with a worse clinical profile but did not have an independent prognostic impact on clinical outcomes.

Previous studies have suggested that the neutrophil-to-lymphocyte ratio (NLR) is a novel yet readily evaluable inflammatory biomarker that may be useful for determining cardiovascular prognosis during acute episodes. The study investigated the role of NLR in predicting cardiovascular (CV) outcomes in patients with acute heart failure (HF). Individual patient data from the BLAST-AHF (phase 2b study of the biased ligand of the angiotensin 2 type 1 receptor, TRV027), Pre-RELAX-AHF (phase 2b study of recombinant human relaxin-2, serelaxin), and RELAX-AHF (phase 3 study of serelaxin) randomized, placebo-controlled studies for patients with acute HF were pooled for analysis. Dyspnea visual analog scale area under the curve through day 5, worsening HF through day 5, 30-day all-cause mortality, 60-day HF/renal failure rehospitalizations or CV death, 180-day all-cause mortality, and 180-day CV death were assessed. There were several differences in the baseline characteristics of the patients divided by NLR tertile, with patients in the higher NLR having worse clinical characteristics. NLR was an independent predictor of 30-day all-cause mortality (adjusted hazard ratio [HR] per log2 NLR increment: 1.66 [1.22 to 2.25], p = 0.001), 60-day HF/renal failure rehospitalizations or CV death: 1.33 [1.12 to 1.57], p = 0.001), 180-day all-cause mortality (adjusted HR 1.27 [1.08 to 1.50], p = 0.003), and 180-day CV death (adjusted HR 1.24 [1.04 to 1.49], p = 0.018). NLR, a readily available inflammatory biomarker, was associated with independent risk for short- and long-term adverse outcomes in acute HF, surpassing traditional markers, such as natriuretic peptides.

Emergency department (ED) providers play a critical role in the stabilization and diagnostic evaluation of patients presenting with acute heart failure (AHF), and EDs are key areas for establishing current best practices and future considerations for the disposition of and decision making for patients with AHF. These elements include accurate risk assessment; response to initial treatment and shared decision making concerning optimal venue of care; reframing of physicians' risk perceptions for patients presenting with AHF; exploration of alternative venues of care beyond hospitalization; population-level changes in demographics, management and outcomes of HF patients; development and testing of data-driven pathways to assist with disposition decisions in the ED; and suggested outcomes for measuring success.

Background and aims STRONG-HF showed that rapid up-titration of guideline-recommended medical therapy (GRMT), in a high intensity care (HIC) strategy, was associated with better outcomes compared to usual care (UC). The aim of this study was to assess the role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and its changes early during up-titration. Methods A total of 1077 patients hospitalized for acute heart failure (HF) and with a >10% NT-proBNP decrease from screening (i.e. admission) to randomization (i.e. pre-discharge), were included. Patients in HIC were stratified by further NT-proBNP changes from randomization to 1 week later as decreased (≥30% decrease), stable (10% increase). The primary endpoint was 180-day HF readmission or death. Results The effect of HIC vs. UC was independent of baseline NT-proBNP. Patients in the HIC group with stable or increased NT-proBNP were older, with more severe acute HF and worse renal and liver function. Per protocol, patients with increased NT-proBNP received more diuretics and were up-titrated more slowly during the first weeks after discharge. However, by 6 months they reached 70.4% optimal GRMT doses, compared with 80.3% for those with NT-proBNP decrease. As a result, the primary endpoint at 60 and 90 days occurred in 8.3% and 11.1% of patients with increased NT-proBNP vs 2.2% and 4.0% in those with decreased NT-proBNP (p=0.039 and p=0.045, respectively). However, no difference in outcome was found at 180 days (13.5% vs. 13.2%; p=0.93). Conclusions Among patients with acute HF enrolled in STRONG-HF, HIC reduced 180-day HF readmission or death regardless of baseline NT-proBNP. GRMT up-titration early post-discharge utilizing increased NT-proBNP as guidance to increase diuretic therapy and reduce the GRMT up-titration rate resulted in the same 180-day outcomes regardless of early post-discharge NT-proBNP change.

OBJECTIVES: The aim of this study was to investigate the association between systolic blood pressure (SBP) drop, worsening renal function (WRF), and prognosis in patients with acute heart failure (AHF).BACKGROUND: A large drop in SBP early after hospital admission for AHF might be associated with increased risk for WRF and prognosis. However, there is a paucity of data regarding the interaction between WRF and a drop in SBP on clinical outcomes.METHODS: A post hoc analysis among 6,544 patients with AHF enrolled in the RELAX-AHF-2 (Relaxin in Acute Heart Failure-2) trial was performed. Blood pressure was uniformly and repetitively measured. Peak SBP drop was defined as the difference between baseline SBP and lowest SBP documented during the first 48 hours. WRF was defined by an increase in serum creatinine of ≥0.3 mg/dL from baseline to day 5.RESULTS: Peak SBP drop was independently associated with a higher risk for WRF (HR: 1.11 per 10 mm Hg SBP drop; P < 0.001), 5-day worsening heart failure (HR: 1.12 per 10 mm Hg SBP drop; P = 0.006), and 180-day cardiovascular death (HR: 1.09 per 10 mm Hg SBP drop; P = 0.026) after adjustment for potential confounders including baseline SBP. There was no interaction between the prognostic value of early SBP drop according to the presence or absence of WRF.CONCLUSIONS: In patients hospitalized for AHF, a greater early drop in SBP was associated with a higher incidence of WRF, worsening heart failure, and an increased risk for 180-day cardiovascular death. However, the association between SBP drop and prognosis was not influenced by WRF. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778).

Objectives The goal of this study was to determine whether a 6-hour lung ultrasound (LUS)-guided strategy-of-care improves pulmonary congestion over usual management in the emergency department (ED) setting. A secondary goal was to explore whether early targeted intervention leads to improved outcomes. Background Targeting pulmonary congestion in acute heart failure remains a key goal of care. LUS B-lines are a semi-quantitative assessment of pulmonary congestion. Whether B-lines decrease in patients with acute heart failure by targeting therapy is not well known. Methods A multicenter, single-blind, ED-based, pilot trial randomized 130 patients to receive a 6-hour LUS-guided treatment strategy versus structured usual care. Patients were followed up throughout hospitalization and 90 days’ postdischarge. B-lines ≤15 at 6 h was the primary outcome, and days alive and out of hospital (DAOOH) at 30 days was the main exploratory outcome. Results No significant difference in the proportion of patients with B-lines ≤15 at 6 hours (25.0% LUS vs 27.5% usual care; P = 0.83) or the number of B-lines at 6 hours (35.4 ± 26.8 LUS vs 34.3 ± 26.2 usual care; P = 0.82) was observed between groups. There were also no differences in DAOOH (21.3 ± 6.6 LUS vs 21.3 ± 7.1 usual care; P = 0.99). However, a significantly greater reduction in the number of B-lines was observed in LUS-guided patients compared with those receiving usual structured care during the first 48 hours (P = 0.04). Conclusions In this pilot trial, ED use of LUS to target pulmonary congestion conferred no benefit compared with usual care in reducing the number of B-lines at 6 hours or in 30 days DAOOH. However, LUS-guided patients had faster resolution of congestion during the initial 48 hours. (B-lines Lung Ultrasound–Guided ED Management of Acute Heart Failure Pilot Trial; NCT03136198 )

Aims Lung ultrasound B‐lines are the sonographic sign of pulmonary congestion and can be used in the differential diagnosis of dyspnoea to rule in or rule out acute heart failure (AHF). Our aim was to assess the prognostic value of B‐lines, integrated with echocardiography, in patients admitted to a cardiology department, independently of the initial clinical presentation, thus in patients with and without AHF, and in AHF with reduced and preserved ejection fraction (HFrEF and HFpEF). Methods and results We enrolled consecutive patients admitted for various cardiac conditions. Patients were classified into three groups: (i) acute HFrEF; (ii) acute HFpEF; and (iii) non‐AHF. All patients underwent an echocardiogram coupled with lung ultrasound at admission, according to standardized protocols. We followed up 1021 consecutive inpatients (69 ± 12 years) for a median of 14.4 months (interquartile range 4.6–24.3) for death and rehospitalization for AHF. During the follow‐up, 126 events occurred. Admission B‐lines > 30, ejection fraction 2.8 m/s, and tricuspid annular plane systolic excursion 30 had a strong predictive value in HFpEF and non‐AHF, but not in HFrEF. Conclusions Ultrasound B‐lines can detect subclinical pulmonary interstitial oedema in patients thought to be free of congestion and provide useful information not only for the diagnosis but also for the prognosis in different cardiac conditions. Their added prognostic value among standard echocardiographic parameters is more robust in patients with HFpEF compared with HFrEF.

Objective: Experts recommended that direct discharge without hospitalization (DDWH) for emergency departments (EDs) able to observe acute heart failure (AHF) patients should be 40%, and these discharged patients should fulfil the following outcome standards: 30-day all-cause mortality 40%. Considering DDWH patients altogether, outcomes A/C were above the recommended standards (4.3%/29.4%), while outcome B was nearly met (B = 10.1%). When analyzing individual EDs, 58.1% of them achieved the outcome B standard, while outcomes A/C standards were barely achieved (19.3%/9.7%). We observed clinically relevant linear/quadratic relationships between higher DDWH and worse outcomes B (weighted R-2 = 0.184/0.322) and C (weighted R-2 = 0.430/0.624), but not with outcome A (weighted R-2 = 0.002/0.022). Conclusions: The EDs of this nationwide cohort do not fulfil the standards for AHF patients with DDWH. High DDWH rates negatively impact ED revisit or hospitalization but not mortality. This may represent an opportunity for improvement in better selecting patients for early ED discharge and in ensuring early follow-up after ED discharge. (c) 2020 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.

Objectives The primary objective was to identify well-tolerated doses of cimlanod in patients with acute heart failure (AHF). Secondary objectives were to identify signals of efficacy, including biomarkers, symptoms, and clinical events. Background Nitroxyl (HNO) donors have vasodilator, inotropic and lusitropic effects. Bristol-Myers Squibb-986231 (cimlanod) is an HNO donor being developed for acute heart failure (AHF). Methods This was a phase IIb, double-blind, randomized, placebo-controlled trial of 48-h treatment with cimlanod compared with placebo in patients with left ventricular ejection fraction ≤40% hospitalized for AHF. In part I, patients were randomized in a 1:1 ratio to escalating doses of cimlanod or matching placebo. In part II, patients were randomized in a 1:1:1 ratio to either of the 2 highest tolerated doses of cimlanod from part I or placebo. The primary endpoint was the rate of clinically relevant hypotension (systolic blood pressure Results In part I (n = 100), clinically relevant hypotension was more common with cimlanod than placebo (20% vs. 8%; relative risk [RR]: 2.45; 95% confidence interval [CI]: 0.83 to 14.53). In part II (n = 222), the incidence of clinically relevant hypotension was 18% for placebo, 21% for cimlanod 6 μg/kg/min (RR: 1.15; 95% CI: 0.58 to 2.43), and 35% for cimlanod 12 μg/kg/min (RR: 1.9; 95% CI: 1.04 to 3.59). N-terminal pro–B-type natriuretic peptide and bilirubin decreased during infusion of cimlanod treatment compared with placebo, but these differences did not persist after treatment discontinuation. Conclusions Cimlanod at a dose of 6 μg/kg/min was reasonably well-tolerated compared with placebo. Cimlanod reduced markers of congestion, but this did not persist beyond the treatment period. (Evaluate the Safety and Efficacy of 48-Hour Infusions of HNO (Nitroxyl) Donor in Hospitalized Patients With Heart Failure [STANDUP AHF]; NCT03016325 )

Objectives This study sought to better understand the discrepant results of 2 trials of serelaxin on acute heart failure (AHF) and short-term mortality after AHF by analyzing causes of death of patients in the RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF-2) trial. Background Patients with AHF continue to suffer significant short-term mortality, but limited systematic analyses of causes of death in this patient population are available. Methods Adjudicated cause of death of patients in RELAX-AHF-2, a randomized, double-blind, placebo-controlled trial of serelaxin in patients with AHF across the spectrum of ejection fraction (EF), was analyzed. Results By 180 days of follow-up, 11.5% of patients in RELAX-AHF-2 died, primarily due to heart failure (HF) (38% of all deaths). Unlike RELAX-AHF, there was no apparent effect of treatment with serelaxin on any category of cause of death. Older patients (≥75 years) had higher rates of mortality (14.2% vs. 8.8%) and noncardiovascular (CV) death (27% vs. 19%) compared to younger patients. Patients with preserved EF (≥50%) had lower rates of HF-related mortality (30% vs. 40%) but higher non-CV mortality (36% vs. 20%) compared to patients with reduced EF. Conclusions Despite previous data suggesting benefit of serelaxin in AHF, treatment with serelaxin was not found to improve overall mortality or have an effect on any category of cause of death in RELAX-AHF-2. Careful adjudication of events in the serelaxin trials showed that older patients and those with preserved EF had fewer deaths from HF or sudden death and more deaths from other CV causes and from noncardiac causes. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778 )

Aims: Whether risk of worsening renal function (WRF) during acute heart failure (AHF) hospitalization or the association between in-hospital WRF and post-discharge outcomes vary according to left ventricular ejection fraction (LVEF) is uncertain. We assessed incidence of WRF, factors related to its development and impact of WRF on post-discharge outcomes across the spectrum of LVEF in patients enrolled in RELAX-AHF-2.Methods and results: A total of 6112 patients who had LVEF measured on admission and renal function determined prospectively during hospitalization were included. WRF, defined as a rise in serum creatinine ≥0.3 mg/dL from baseline through day 5, occurred in 1722 patients (28.2%). Incidence increased progressively from lowest to highest LVEF quartile (P < 0.001). After baseline adjustment, WRF risk in Q4 (LVEF >50%) remained significantly greater than in Q1 (LVEF ≤29%; hazard ratio 1.2, 95% confidence interval 1–1.43; P = 0.050). Age and comorbidity burden including chronic kidney disease increased as LVEF increased. Neither admission haemodynamic abnormalities, extent of diuresis during hospitalization nor residual congestion explained the increased incidence of WRF in patients with higher LVEF. Serelaxin treatment and diuretic responsiveness were associated with reduced risk of WRF in all LVEF quartiles. WRF in patients in the upper three LVEF quartiles increased risk of post-discharge events.Conclusions: Worsening renal function incidence during AHF hospitalization increases progressively with LVEF. Greater susceptibility of patients with higher LVEF to WRF appears more related to their advanced age and worse underlying kidney function rather than haemodynamic or treatment effects. WRF is associated with increased risk of post-discharge events except in patients in the lowest LVEF quartile.

International audience; Aims: Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast to those in HF with reduced ejection fraction (HFrEF). We explore how the neutral results in larger HF trials may be attributable to chance and/or the dilution of statistical power.Methods and results: Using simulations, we examined the probability that a positive finding in a Phase 2 trial would result in the study of a truly effective medicine in a Phase 3 trial. We assessed the similarity of clinical trial and registry patient populations. We conducted a meta-analysis of paired Phase 2 and 3 trials in HFrEF and acute HF examining the associations of trial phase and size with placebo event rates and treatment effects for HF events and death. We estimated loss in trial power attributable to dilution with increasing trial size. Appropriately powered Phase 3 trials should have yielded ∼35% positive results. Patient populations in Phase 3 trials are similar to those in Phase 2 trials but both differ substantially from the populations of 'real-life' registries. We observed decreasing placebo event rates and smaller treatment effects with increasing trial size, especially for HF events (and less so for mortality). This was more pronounced in trials in acute HF patients.Conclusions: The selection of more positive Phase 2 trials for further development does not explain the failure of HFpEF and acute HF medicine development. Increasing sample size may lead to reduced event rates and smaller treatment effects, resulting in a high rate of neutral Phase 3 trials.

Background Heart failure (HF) necessitates frequent transport by emergency medical services (EMS), but few studies have been conducted to evaluate predictors of EMS use and of multiple EMS transports that are amenable to intervention. Objectives To characterize prehospital clinical status of community-dwelling adults with reported HF who used EMS across 8 years and to evaluate predictors of EMS use and multiple EMS transports. Methods Data were from a database in a large Midwestern county. Descriptive statistics, logistic and negative binomial regression were used for analysis. Results EMS transports were evaluated for 6582 adults with 16,905 transports. The most common chief complaints were respiratory problems, feeling sick, and chest pain. Shortness of breath, chest pain, level of consciousness, age, gender, race, and hospital site predicted multiple transports. Conclusions Clinicians need to educate patients with HF about ways to manage shortness of breath and chest pain and when to activate EMS.

Background Patients with heart failure (HF) with concomitant ischemic heart disease (IHD) have not been well characterized. We examined survival of patients with ischemic HF syndrome (IHFS), defined as presentation with acute HF and concomitant features suggestive of IHD. Methods Patients were included if they presented with acute HF to hospitals in Ontario, Canada. IHD was defined by any of the following criteria: angina/chest pain, prior myocardial infarction (MI), or troponin elevation that was above the upper limit of normal (mild) or suggestive of cardiac injury. Deaths were determined after hospital presentation. Results Of 5353 patients presenting with acute HF, 4088 (76.4%) exhibited features of IHFS. Patients with IHFS demonstrated a higher rate of 30-day (hazard ratio [HR], 1.89; 95% confidence interval [CI], 1.33-2.68) and 1-year death (HR, 1.16, 95% CI, 1.00-1.35) compared with those with nonischemic HF. Troponin elevation demonstrated the strongest association with mortality. Mildly elevated troponin was associated with increased hazard over 30-day (HR, 1.77; 95% CI, 1.12-2.81) and 1-year (HR, 1.63; 95% CI, 1.38-1.93) mortality. Troponins indicative of cardiac injury were associated with increased hazard of death over 30 days (HR, 2.33; 95% CI, 1.63-3.33) and 1 year (HR, 1.40; 95% CI, 1.21-1.61). The association between elevated troponin and higher mortality at 30 days was similar in left ventricular ejection fraction subcategories of HF with reduced ejection fraction, HF with mildly reduced ejection fraction, or HF with preserved ejection fraction (P interaction = 0.588). After multivariable adjustment, prior MI and angina were not associated with higher mortality risk. Conclusions In acute HF, elevated troponin, but not prior MI or angina, was associated with a higher risk of 30-day and 1-year mortality irrespective of left ventricular ejection fraction. Resume Contexte Les patients presentant une insuffisance cardiaque et une cardiopathie ischemique (CI) concomitante ne sont pas bien caracterises. Nous avons examine les donnees sur la survie de patients atteints d’un syndrome d’insuffisance cardiaque ischemique (SICI), caracterise par la presence d’une insuffisance cardiaque aigue et de manifestations concomitantes evoquant une CI. Methodologie Les donnees examinees concernaient des patients atteints d’insuffisance cardiaque aigue recus en consultation dans des hopitaux de l’Ontario, au Canada. Un patient etait repute atteint de CI s’il repondait a l’un des criteres suivants : angine/douleur thoracique, antecedents d’infarctus du myocarde (IM) ou elevation de la concentration de troponine se situant au-dela de la limite superieure de la normale (cas leger) ou evoquant une lesion cardiaque. La determination des deces a ete effectuee en aval des consultations hospitalieres. Resultats Parmi 5 353 patients atteints d’insuffisance cardiaque aigue recus en consultation, 4 088 (76,4 %) presentaient des caracteristiques de SICI. Chez les patients atteints d’un SICI, un taux plus eleve de mortalite a 30 jours (rapport des risques instantanes [RRI] : 1,89, intervalle de confiance [IC] a 95 % : 1,33-2,68) et a 1 an (RRI : 1,16, IC a 95 % : 1,00-1,35) a ete note comparativement aux patients atteints d’insuffisance cardiaque non ischemique. L’elevation de la concentration de troponine presentait la plus forte association avec la mortalite. Une legere elevation de la concentration de troponine se trouvait associee a un risque accru de mortalite a 30 jours (RRI : 1,77, IC a 95 % : 1,12-2,81) et a 1 an (RRI : 1,63, IC a 95 % : 1,38-1,93). Les concentrations de troponine temoignant de lesions cardiaques etaient associees a une augmentation du risque de mortalite a 30 jours (RRI : 2,33, IC a 95 % : 1,63-3,33) et a 1 an (RRI : 1,40, IC a 95 % : 1,21-1,61). L’association entre une concentration elevee de troponine et une augmentation du taux de mortalite a 30 jours etait semblable dans les sous-categories d’insuffisance cardiaque avec fraction d’ejection ventriculaire gauche reduite, legerement reduite ou preservee (p = 0,588 pour l’interaction). Apres correction multivariee, les antecedents d’IM et d’angine n’etaient pas associes a un risque accru de mortalite. Conclusions Dans un contexte d’insuffisance cardiaque aigue, l’elevation de la concentration de troponine etait associee a un risque plus eleve de mortalite a 30 jours et a 1 an independamment de la fraction d’ejection ventriculaire gauche; les antecedents d’IM ou d’angine ne l’etaient toutefois pas.

Aims Concentrations of insulin‐like growth factor binding protein‐7 (IGFBP7) have been linked to abnormal cardiac structure and function in patients with chronic heart failure (HF), but cardiovascular correlates of the biomarker in patients with more acute presentations are lacking. We aimed to determine the relationship between IGFBP7 concentrations and cardiac structure and to evaluate the impact of IGFBP7 on the diagnosis of acute HF among patients with acute dyspnoea. Methods and results In this pre‐specified subgroup analysis of the International Collaborative of N‐terminal pro‐B‐type Natriuretic Peptide Re‐evaluation of Acute Diagnostic Cut‐Offs in the Emergency Department (ICON‐RELOADED) study, we included 271 patients with and without acute HF. All patients presented to an emergency department with acute dyspnoea, had blood samples for IGFBP7 measurement, and detailed echocardiographic evaluation. Higher IGFBP7 concentrations were associated with numerous cardiac abnormalities, including increased left atrial volume index (LAVi; r = 0.49, P

AIMS Although left ventricular ejection fraction (LVEF) is routinely used to categorize patients with heart failure (HF), whether it predicts outcomes after hospitalization for acute heart failure (AHF) is uncertain. Consequently, we assessed the relationship between LVEF and cardiovascular (CV) outcomes in a large, well characterized cohort of patients hospitalized for AHF. METHODS AND RESULTS The 6128 patients from the RELAX-AHF-2 trial who had LVEF measured during AHF hospitalization were separated into LVEF quartiles and the relationship between LVEF and a composite of CV mortality and rehospitalization for HF or renal failure through 180 days was assessed. We found progressively lower risk for this composite outcome as LVEF increased (hazard ratio 0.95, 95% confidence interval 0.93-0.98 per 5% LVEF increase, P

Background: For patients with acute heart failure (AHF), a substantial diuresis after administration of loop diuretics is generally associated with better clinical outcomes but may cause creatinine to rise, suggesting a decline in renal function. We investigated the interaction between diuretic response and worsening renal function (WRF) on clinical outcomes in patients with AHF. Methods: In two cohorts of patients with AHF (PROTECT, n=1,698 and RELAX-AHF-2, n=5,586 in current analysis), the prognostic impact of WRF (creatinine ≥0.3 mg/dL increase baseline-day 4, sensitivity analyses were performed incorporating baseline renal function) by diuretic response (kg weight loss per 40 mg furosemide equivalent from baseline-day 4) was investigated with regards to (CV) death or cardiovascular/renal hospitalisation using subpopulation treatment effect pattern (STEPP) plots and survival analyses. Results: WRF occurred in 286 (16.8%) patients in PROTECT and 1,031 (18.5%) patients in RELAX-AHF-2. Patients with WRF had higher left ventricular ejection fraction and lower estimated glomerular filtration rate at baseline (P Conclusion: In two large cohorts of patients with AHF, WRF in the first 4 days was not associated with worse outcomes when patients had a good diuretic response. The occurrence of WRF in patients with AHF should therefore be considered in the context of diuretic response.

BackgroundFor patients with acute heart failure (AHF), substantial diuresis after administration of loop diuretics is generally associated with better clinical outcomes but may cause creatinine to rise, suggesting renal function decline. We investigated the interaction between diuretic response and worsening renal function (WRF) on clinical outcomes in patients with AHF.Methods and resultsIn two AHF cohorts (PROTECT, n= 1698 and RELAX-AHF-2, n= 5586 in current analysis), the prognostic impact of WRF (creatinine ≥0.3mg/dl increase baseline-day 4; sensitivity analyses incorporated baseline renal function) by diuretic response (kg weight loss/40 mg furosemide equivalent baseline-day 4) was investigated with regard to (cardiovascular) death or cardiovascular/renal hospitalization using subpopulation treatment effect pattern plots (STEPP) and survival analyses. WRF occurred in 286 (16.8%) and 1031 (18.5%) patients in PROTECT and RELAX-AHF-2, respectively. Patients with WRF had higher left ventricular ejection fraction and lower estimated glomerular filtration rate at baseline (p&nbsp

Background: We conducted a secondary analysis of changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 over 30 days in a randomized trial of self-care coaching versus structured usual care in patients with acute heart failure who were discharged from the emergency department. Methods: Patients in 15 emergency departments completed the KCCQ-12 at emergency department discharge and at 30 days. We compared change in KCCQ-12 scores between the intervention and usual care arms, adjusted for enrollment KCCQ-12 and demographic characteristics. We used linear regression to describe changes in KCCQ-12 summary scores and logistic regression to characterize clinically meaningful KCCQ-12 subdomain changes at 30 days. Results: There were 350 patients with both enrollment and 30-day KCCQ summary scores available; 166 allocated to usual care and 184 to the intervention arm. Median age was 64 years (interquartile range, 55–70), 37% were female participants, 63% were Black, median KCCQ-12 summary score at enrollment was 47 (interquartile range, 33–64). Self-care coaching resulted in significantly greater improvement in health status compared with structured usual care (5.4-point greater improvement, 95% CI, 1.12–9.68; P =0.01). Improvements in health status in the intervention arm were driven by improvements within the symptom frequency (adjusted odds ratio, 1.62 [95% CI, 1.01–2.59]) and quality of life (adjusted odds ratio, 2.39 [95% CI, 1.46–3.90]) subdomains. Conclusions: In this secondary analysis, patients with acute heart failure who received a tailored, self-care intervention after emergency department discharge had clinically significant improvements in health status at 30 days compared with structured usual care largely due to improvements within the symptom frequency and quality of life subdomains of the KCCQ-12. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02519283.

Vasodilators are commonly recommended to treat acute heart failure (AHF), yet they are infrequently used. This review aims to evaluate the clinical utility of traditional, historical, and novel vasodilators in the treatment of AHF. No traditional vasodilator (i.e., nitroglycerin) therapy definitely improves short- or long-term outcomes. Despite repeated efforts to develop new pharmacologic treatments, no novel therapy outperforms traditional management. At the present time, we continue to recommend traditional vasodilators, such as nitroglycerin. The use of select vasodilators in the treatment of AHF improves hemodynamics and provides short-term relief; however, data regarding long-term benefits is lacking.

Acute heart failure accounts for over one million hospital discharges annually. Current guidelines suggest treatments for AHF should begin “without delay” but this time interval has not been clearly defined. Data suggest that certain treatments such as earlier treatment with diuretics and vasodilators may improve patient symptom relief, morbidity, and mortality. Secondary analyses of clinical trials of novel treatments under development have not shown similar results. The data are equivocal regarding the impact of early treatment in AHF on in-hospital and long-term morbidity and mortality. Improved clinical trial designs will help answer when and if “early” treatment should begin and whether it impacts short- and long-term outcomes in AHF.

Among patients with acute dyspnea, concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T, and insulin-like growth factor binding protein-7 predict cardiovascular outcomes and death. Understanding the optimal means to interpret these elevated biomarkers in patients presenting with acute dyspnea remains unknown.Concentrations of NT-proBNP, high-sensitivity cardiac troponin T, and insulin-like growth factor binding protein-7 were analyzed in 1448 patients presenting with acute dyspnea from the prospective, multicenter International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department (ICON-RELOADED) Study. Eight biogroups were derived based upon patterns in biomarker elevation at presentation and compared for differences in baseline characteristics. Of 441 patients with elevations in all 3 biomarkers, 218 (49.4%) were diagnosed with acute heart failure (HF). The frequency of acute HF diagnosis in this biogroup was higher than those with elevations in 2 biomarkers (18.8%, 44 of 234), 1 biomarker (3.8%, 10 of 260), or no elevated biomarkers (0.4%, 2 of 513). The absolute number of elevated biomarkers on admission was prognostic of the composite end point of mortality and HF rehospitalization. In adjusted models, patients with one, 2, and 3 elevated biomarkers had 3.74 (95% confidence interval [CI], 1.26-11.1, P = .017), 12.3 (95% CI, 4.60-32.9, P.001), and 12.6 (95% CI, 4.54-35.0, P.001) fold increased risk of 180-day mortality or HF rehospitalization.A multimarker panel of NT-proBNP, hsTnT, and IGBFP7 provides unique clinical, diagnostic, and prognostic information in patients presenting with acute dyspnea. Differences in the number of elevated biomarkers at presentation may allow for more efficient clinical risk stratification of short-term mortality and HF rehospitalization.

Aims Our aim was to assess the dynamic changes of pulmonary congestion (PC) through variations of sonographic B-lines, in addition to conventional clinical, biohumoral and echocardiographic findings, to improve prognostic stratification of patients admitted for acute heart failure with reduced and preserved ejection fraction (HFrEF, HFpEF). Methods In this multicenter, prospective, observational study, lung ultrasound was performed in all patients at admission and before discharge by trained investigators, blinded to clinical findings and outcomes. Results We enrolled 208 consecutive patients admitted for acute heart failure (125 HFrEF, 83 HFpEF, mean age 75.9±11.7 years, 36% females, mean ejection fraction 38%). After 180-day follow-up, 38 composite endpoint events occurred (cardiovascular deaths or HF re-hospitalisations). In a multivariate model, B-lines at discharge had independent prognostic value in the overall population together with NT-proBNP, moderate-to-severe mitral regurgitation (MR) and inferior vena cava diameter at admission. When dividing the population in HFrEF and HFpEF, B-lines at discharge was the only independent parameter to predict events in all subgroups. At ROC analysis, a cut-off of B-lines>15 at discharge displayed the highest accuracy in predicting adverse events (AUC=0.80, p15 at discharge, improved event classification (integrated discrimination improvement=4%, p=0.01; continuous net reclassification improvement=22.8%, p=0.04). Conclusions The presence of residual subclinical sonographic PC at discharge predicts adverse events in the whole spectrum of acute HF patients, independently of conventional biohumoral and echocardiographic parameters. The dynamic evaluation of pulmonary decongestion during hospital stay can further improve patient risk stratification. Funding Acknowledgement Type of funding source: None

Fulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe diffuse cardiac inflammation often leading to death resulting from cardiogenic shock, ventricular arrhythmias, or multiorgan system failure. Historically, FM was almost exclusively diagnosed at autopsy. By definition, all patients with FM will need some form of inotropic or mechanical circulatory support to maintain end-organ perfusion until transplantation or recovery. Specific subtypes of FM may respond to immunomodulatory therapy in addition to guideline-directed medical care. Despite the increasing availability of circulatory support, orthotopic heart transplantation, and disease-specific treatments, patients with FM experience significant morbidity and mortality as a result of a delay in diagnosis and initiation of circulatory support and lack of appropriately trained specialists to manage the condition. This scientific statement outlines the resources necessary to manage the spectrum of FM, including extracorporeal life support, percutaneous and durable ventricular assist devices, transplantation capabilities, and specialists in advanced heart failure, cardiothoracic surgery, cardiac pathology, immunology, and infectious disease. Education of frontline providers who are most likely to encounter FM first is essential to increase timely access to appropriately resourced facilities, to prevent multiorgan system failure, and to tailor disease-specific therapy as early as possible in the disease process.

Aims The goal of this study was to determine the number of scans needed for novice learners to attain proficiency in B‐line quantification compared with expert interpretation. Methods and results This was a prospective, multicentre observational study of novice learners, physicians and non‐physicians from three academic institutions. Learners received a 2 h lung ultrasound (LUS) training session on B‐line assessment, including lecture, video review to practice counting and hands‐on patient scanning. Learners quantified B‐lines using an eight‐zone scanning protocol in patients with suspected acute heart failure. Ultrasound (US) machine settings were standardized to a depth of 18 cm and clip length of 6 s, and tissue harmonics and multibeam former were deactivated. For quantification, the intercostal space with the greatest number of B‐lines within each zone was used for scoring. Each zone was given a score of 0–20 based on the maximum number of B‐lines counted during one respiratory cycle. The B‐line score was determined by multiplying the percentage of the intercostal space filled with B‐lines by 20. We compared learner B‐line counts with a blinded expert reviewer (five US fellowship‐trained faculty with > 5 years of clinical experience) for each lung zone scanned; proficiency was defined as an intraclass correlation of > 0.7. Learning curves for each learner were constructed using cumulative sum method for statistical analysis. The Wilcoxon rank‐sum test was used to compare the number of scans required to reach proficiency between different learner types. Twenty‐nine learners (21 research associates, 5 residents and 3 non‐US‐trained emergency medicine faculty) scanned 2629 lung zones with acute pulmonary oedema. After a mean of 10.8 (standard deviation 14.0) LUS zones scanned, learners reached the predefined proficiency standard. The number of scanned zones required to reach proficiency was not significantly different between physicians and non‐physicians (P = 0.26), learners with no prior US experience vs. > 25 prior patient scans (P = 0.64) and no prior vs. some prior LUS experience (P = 0.59). The overall intraclass correlation for agreement between learners and experts was 0.74 and 0.80 between experts. Conclusions Our results show that after a short, structured training, novice learners are able to achieve proficiency for quantifying B‐lines on LUS after scanning 11 zones. These findings support the use of LUS for B‐line quantification by non‐physicians in clinical and research applications.

Background Contemporary reconsideration of diagnostic N-terminal pro–B-type natriuretic peptide (NT-proBNP) cutoffs for diagnosis of heart failure (HF) is needed. Objectives This study sought to evaluate the diagnostic performance of NT-proBNP for acute HF in patients with dyspnea in the emergency department (ED) setting. Methods Dyspneic patients presenting to 19 EDs in North America were enrolled and had blood drawn for subsequent NT-proBNP measurement. Primary endpoints were positive predictive values of age-stratified cutoffs (450, 900, and 1,800 pg/ml) for diagnosis of acute HF and negative predictive value of the rule-out cutoff to exclude acute HF. Secondary endpoints included sensitivity, specificity, and positive (+) and negative (−) likelihood ratios (LRs) for acute HF. Results Of 1,461 subjects, 277 (19%) were adjudicated as having acute HF. The area under the receiver-operating characteristic curve for diagnosis of acute HF was 0.91 (95% confidence interval [CI]: 0.90 to 0.93; p Conclusions In acutely dyspneic patients seen in the ED setting, age-stratified NT-proBNP cutpoints may aid in the diagnosis of acute HF. An NT-proBNP

Introduction TRV027, a 'biased' ligand of the angiotensin II type 1 receptor (AT1R), did not affect a composite clinical outcome at 30 days in a phase 2b acute heart failure (AHF) trial (BLAST-AHF).Methods Post-hoc analyses from BLAST-AHF (n = 618) examined the effects of TRV027 by baseline systolic blood pressure (SBP) on changes in renal function and 180-day outcomes. Interactions between baseline SBP and select endpoints were identified utilizing a subpopulation treatment effect pattern plots (STEPP) analysis, then grouping of patients by SBP tertile: = 127 to = 140 mmHg.Results A trend towards increased creatinine in the first 3 days was noted in the lower SBP tertile, while in those in the higher two tertiles, TRV027, especially the 1 mg/h dose, reduced creatinine at days 5 and 30. Beneficial effects on 180-day all-cause mortality and cardiovascular (CV) death or readmission were observed in the two higher SBP tertiles (SBP >= 127 mmHg) in the TRV027 1 mg/h dose group (all-cause mortality HR 0.39, 95% CI 0.14-1.06, p = 0.056; CV death or HF/RF rehospitalization HR 0.53, 95% CI 0.28-1.01, p = 0.049), while more adverse outcomes were observed in patients in the lower SBP tertile.Conclusions This post-hoc analysis of the BLAST-AHF study suggests contrasting effects of TRV027 by baseline SBP, with trends towards lower 180-day event rates in patients enrolled with higher baseline SBP, especially when given lower doses of TRV027.

Objectives The objectives were to reassess use of amino-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations for diagnosis and prognosis of acute heart failure (HF) in patients with acute dyspnea. Background NT-proBNP facilitates diagnosis, prognosis, and treatment in patients with suspected or proven acute HF. As demographics of such patients are changing, previous diagnostic NT-proBNP thresholds may need updating. Additionally, value of in-hospital NT-proBNP prognostic monitoring for HF is less understood. Methods In a prospective, multicenter study in the United States and Canada, patients presenting to emergency departments with acute dyspnea were enrolled, with demographic, medication, imaging, and clinical course information collected. NT-proBNP analysis will be performed using the Roche Diagnostics Elecsys proBNPII immunoassay in blood samples obtained at baseline and at discharge (if hospitalized). Primary end points include positive predictive value of previously established age-stratified NT-proBNP thresholds for the adjudicated diagnosis of acute HF and its negative predictive value to exclude acute HF. Secondary end points include sensitivity, specificity, and positive and negative likelihood ratios for acute HF and, among those with HF, the prognostic value of baseline and predischarge NT-proBNP for adjudicated clinical end points (including all-cause death and hospitalization) at 30 and 180 days. Results A total of 1,461 dyspneic subjects have been enrolled and are eligible for analysis. Follow-up for clinical outcome is ongoing. Conclusions The International Collaborative of N-terminal pro–B-type Natriuretic Peptide Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department study offers a contemporary opportunity to understand best diagnostic cutoff points for NT-proBNP in acute HF and validate in-hospital monitoring of HF using NT-proBNP.

Aims: Currently, no acute heart failure (AHF) therapy definitively improves outcomes. Reducing morbidity and mortality from acute heart failure (AHF) remains an unmet need. TRV027 is a novel ` biased' ligand of the angiotensin II type 1 receptor (AT1R), selectively antagonizing the negative effects of angiotensin II, while preserving the potential pro-contractility effects of AT1R stimulation. BLAST-AHF was designed to determine the safety, efficacy, and optimal dose of TRV027 to advance into future studies.Methods and results: BLAST-AHF was a multi-centre, international, randomized, double-blind, placebo-controlled, parallel group, phase IIb dose-ranging study, enrolling patients with AHF into 4 groups: placebo, 1, 5, or 25mg/h of TRV027. Treatment was by IV infusion for 48-96 h. The primary composite endpoint was comprised of the following: (i) time from baseline to death through day 30, (ii) time from baseline to heart failure re-hospitalization through day 30, (iii) the first assessment time point following worsening heart failure through day 5, (iv) change in dyspnea visual analogue scale (VAS) score calculated as the area under the curve (AUC) representing the change from baseline over time from baseline through day 5, and (v) length of initial hospital stay (in days) from baseline. Analyses were by modified intention-to-treat. Overall, 621 patients were enrolled. After 254 patients, a pre-specified interim analysis resulted in several protocol changes, including a lower blood pressure inclusion criterion as well as a new allocation scheme of 2: 1: 2: 1, overweighting both placebo, and the 5mg/h dose. TRV027 did not confer any benefit over placebo at any dose with regards to the primary composite endpoint or any of the individual components. There were no significant safety issues with TRV027.Conclusion: In this phase IIb dose-ranging AHF study, TRV027 did not improve clinical status through 30-day follow-up compared with placebo.

Acute heart failure (HF) is a major public health problem with substantial associated economic costs. Because most patients who present to hospitals are admitted irrespective of their level of risk, novel approaches to manage acute HF are needed, such as the use of same-day access clinics for outpatient diuresis and observation units from the emergency department. Current published data lacks a comprehensive overview of the present state of acute HF management in various clinical settings. This review summarizes the strengths and limitations of acute HF care in the outpatient and emergency department settings. Finally, a variety of innovative technologies that have the potential to improve acute HF management are discussed.

Background Signs and symptoms of heart failure can occur at any time. Differences between acute heart failure (AHF) patients who present at nighttime vs daytime and their outcomes have not been well studied. Our objective was to determine if there are differences in baseline characteristics and clinical outcomes between AHF patients presenting during daytime vs nighttime hours within an international, clinical trial.Methods This is a post hoc analysis of the RELAX AHF trial, which randomized 1,161 AHF patients to serelaxin vs placebo, both in addition to usual AHF therapy. Prespecified end points of the primary trial were used: dyspnea, 60-day heart failure/renal failure rehospitalization or cardiovascular (CV) death, and 180-day CV death. Both unadjusted and adjusted analyses for outcomes stratified by daytime vs nighttime presentation were performed.Results Of the 1,161 RELAX-AHF patients, 775 (66.8%) patients presented during daytime and 386 (33.2%) at nighttime. Baseline characteristics were largely similar, although daytime patients were more likely to be male, have greater baseline body weight, have higher New York Heart Association class, have history of atrial fibrillation, and have more peripheral edema compared with nighttime patients. No differences in dyspnea relief or 60-day outcomes were observed. However, daytime presentation was associated with greater risk for 180-day CV death after adjustment (hazard ratio 2.28, 95% CI 1.34-3.86; c statistic = 0.82, 95% CI 0.78-0.86).Conclusion In this secondary analysis of the RELAX-AHF trial, baseline characteristics suggest that daytime-presenting patients may have more gradual worsening of chronic HF. Patients with AHF who presented at night had less risk for 180-day CV death, but similar risk for 60-day CV death or rehospitalization and symptom improvement for patients who presented during the daytime.

Patients admitted for acute heart failure (AHF) experience high rates of in-hospital and post-discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin-2, a hormone with vasodilatory and end-organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX-AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all-cause and cardiovascular mortality by 37% through day 180. RELAX-AHF-2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX-AHF-2 is a multicentre, randomized, double-blind, placebo-controlled, event-driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild-to-moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all-cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in-hospital length of stay during index AHF. The results from RELAX-AHF-2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.

Aims We evaluated the added prognostic value of a multi-time point-based multimarker panel of biomarkers in patients with acute heart failure (AHF). Methods and results Seven circulating biomarkers [NT-proBNP, high sensitivity cardiac troponin T (hs-cTnT), soluble ST2 (sST2), growth differentiation factor 15 (GDF-15), cystatin-C, galectin-3, and high sensitivity C-reactive protein (hs-CRP)] were measured at baseline and on days 2, 5, 14, and 60 in 1161 patients enrolled in the RELAX-AHF trial. Patients with BNP ≥350 ng/L or NT-proBNP ≥1400 ng/L, mild to moderate renal impairment, and systolic blood pressure >125 mmHg were included in the trial. Time-dependent Cox regression analysis was utilized to evaluate the incremental value of serial measurement of biomarkers. Added value of individual biomarkers and their combination, on top of a pre-specified baseline model, was quantified with the gain in the C-index. Serial biomarker evaluation showed incremental predictive value over baseline measurements alone for the prediction of 180-day cardiovascular mortality except for galectin-3. While a repeat measurement as early as day 2 was adequate for NT-proBNP and cystatin-C in terms of maximizing discriminatory accuracy, further measurements on days 14 and 60 provided added value for hs-cTnT, GDF-15, sST2, and hs-CRP. Individual biomarker additions on top of the baseline model showed additional prognostic value. The greatest prognostic gain was, however, attained with the combination of NT-proBNP, hs-cTnT, GDF-15, and sST2, which yielded 0.08 unit absolute increment in the C-index to 0.87 (95% confidence interval 0.83–0.91]. Conclusion In patients with AHF and mild to moderate renal impairment, a multimarker approach based on a panel of serially evaluated biomarkers provides the greatest prognostic improvement unmatched by a single time point-based single marker strategy.

This study examined whether insulin-like growth factor binding protein-7 (IGFBP7) would aid in the diagnosis and prognosis of acute heart failure (HF) beyond N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration.IGFBP7 is associated with impaired ventricular relaxation and worse prognosis.The ICON-RELOADED (International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department) study was a prospective, multicenter clinical trial that enrolled subjects presenting with dyspnea. Six-month prognosis for death or repeat hospitalization was obtained.Among 1,449 patients, 274 (18.9%) were diagnosed with acute HF. Those with IGFBP7 concentrations in the highest quartile were older, male, had hypertension and HF, had lower estimated glomerular filtration rate (eGFR) and lowest ejection fraction (41 ± 20%; all p 0.001). Independent predictors of IGFBP7 were age, male sex, history of diabetes, history of HF, and eGFR. Median concentrations of NT-proBNP (2,844 ng/ml vs. 99 ng/ml) and IGFBP7 (146.1 ng/ml vs. 86.1 ng/ml) were higher in those with acute HF (both; p 0.001). Addition of IGFBP7 to NT-proBNP concentrations improved discrimination, therefore increasing the area under the receiver operating curve for diagnosis of acute HF (from 0.91 to 0.94; p 0.001 for differences). Addition of IGFBP7 to a complete model of independent predictors of acute HF improved model calibration. IGFBP7 significantly reclassified acute HF diagnosis beyond NT-proBNP (net reclassification index: +0.25). Higher logAmong patients with acute dyspnea, concentrations of IGFBP7 add to NT-proBNP for diagnosis of acute HF and provide added prognostic utility for short-term risk.

Aims All phase 3 studies in patients with acute heart failure (AHF) and HF with preserved ejection fraction (HFpEF) have failed in the last decades. We explore the likelihood that the negative results are due to chance and/or to study size and dilution of statistical power. Methods and results First, using simulations, we examined the probability that a positive finding in phase 2 would result in studying truly effective drugs in phase 3. We simulated phase 2 studies under six scenarios where the range of true relative risk (RR) for an outcome of interest varied from 0.5 (major benefit) to 1.15 (some harm). The proportion of simulated studies where the RR Figure 1. Power at two-sided 0.05 significance level to detect an effect size of hazard ratio of 0.65 (left) or 0.8 (right) with a placebo event rate of 10% (top) and 20% (bottom) at N=100 at various treatment effect dilutions with increasing sample size. Conclusion These data suggest that it is unlikely that the very high rate of negative AHF phase III trials can be explained by chance alone. Potentially, our tendency to increase sample size does not necessarily increase statistical power, due to more heterogenous populations leading to reduced event rates and treatment effects.

Background Increased activity of insulin-like growth factor–binding protein-7 (IGFBP7) is associated with cellular senescence, tissue aging, and obesity. Prior studies in chronic heart failure (HF) have linked IGFBP7 to impaired myocardial relaxation. The role of IGFBP7 measurement in acute HF remains unclear. Purpose To examine whether concentrations of IGFBP7 in patients presenting with dyspnea to the emergency department (ED) will aid in the diagnosis and prognosis of acute HF beyond N-terminal pro- B type natriuretic peptide (NT-proBNP). Methods The ICON-RELOADED (International Collaborative of NT-proBNP- Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department) study was a prospective, multicenter clinical trial conducted at 19 sites in North America that enrolled subjects ≥22 years of age presenting to ED with complaints of dyspnea. Subjects were blindly adjudicated for the diagnosis of acute HF. A blood sample was taken at enrollment. Six-month prognosis for death/repeat hospitalization was obtained. IGFBP7 was measured using a pre-clinical research use only assay. Results Among 1449 patients (n=274 with acute HF), those with IGFBP7 concentrations in the highest quartile (>123.7 ng/mL) were older, more likely to be male and to have a history of hypertension and HF (all p ROC curve for diagnosis of acute HF Conclusions Among patients with acute dyspnea, concentrations of IGFBP7 add to NT-proBNP for diagnosis of acute HF and provide added prognostic utility for short-term risk. Acknowledgement/Funding Funding for this study was provided by Roche Diagnostics (Risch-Rotkreuz, Switzerland).

Background: Identifying low-risk acute heart failure patients safe for discharge from the emergency department is a major unmet need. Methods AND RESULTS: A prospective, observational, multicenter pilot study targeting lower risk acute heart failure patients to determine whether hsTnT (high-sensitivity troponin T) identifies emergency department acute heart failure patients at low risk for rehospitalization and mortality. hsTnT was drawn at baseline and 3 hours. Phone follow-up occurred at 30 and 90 days. The primary end point composite of all-cause mortality, rehospitalization, and emergency department visits at 90 days (changed from 30 days because of lack of mortality events), analyzed using logistic regression. Secondary end points: 30- and 90-day all-cause mortality. hsTnT values less than the 99th percentile were defined as low hsTnT. Out of 527 enrolled patients, 499 comprised the initial analysis set. Of these, 332 had both 0- and 3-hour hsTnT drawn, of whom 319 completed 30 day follow-up. The average age was 62, 60% male, and 57% black. Median hsTnT was 26.4 ng/L (interquartile range, 15.1–44.3). There were 99 (21%) 30-day composite events, 13 (2.7%) deaths at 30 days, and 25 deaths (8.2%) at 90 days. Serial hsTnT values below the 99th percentile were not associated with a lower risk for the 90-day primary composite end point (odds ratio, 0.79; 95% CI, 0.42–1.50; P =0.4736). However, no deaths occurred in the low hsTnT group at 30 days with 1 death at 90 days. Conclusions: hsTnT did not identify patients at low risk for the primary outcome of rehospitalization, emergency department visits, and mortality at 90 days. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02592135.

Aims Neurohormonal activation characterizes chronic heart failure (HF) and is a well-established therapeutic target. Neurohormonal activation may also play a key role in acute HF (AHF). We aim to describe the association between plasma renin activity (PRA) and three AHF outcomes: (i) worsening HF or death through day 5 of hospitalization; (ii) HF rehospitalization or death through day 30; and (iii) all-cause death through day 30. Methods and results A secondary analysis of the BLAST-AHF trial was performed. Eligible patients had a history of HF, elevated natriuretic peptides, signs and symptoms of HF, systolic blood pressure >120 mmHg, and an estimated glomerular filtration rate between 20-75 mL/min/1.73 m(2). The primary trial was neutral, with no differential effect of study drug by PRA levels. Baseline PRA levels were grouped into tertiles. Adjusted Cox proportional hazard model determined the association of PRA levels with outcomes (alpha set at P

Improved risk stratification of acute heart failure in the emergency department may inform physicians' decisions regarding patient admission or early discharge disposition. We aimed to validate the previously-derived Emergency Heart failure Mortality Risk Grade for 7-day (EHMRG7) and 30-day (EHMRG30-ST) mortality.We conducted a multicenter, prospective validation study of patients with acute heart failure at 9 hospitals. We surveyed physicians for their estimates of 7-day mortality risk, obtained for each patient before knowledge of the model predictions, and compared these with EHMRG7 for discrimination and net reclassification improvement. We also prospectively examined discrimination of the EHMRG30-ST model, which incorporates all components of EHMRG7 as well as the presence of ST-depression on the 12-lead ECG.We recruited 1983 patients seeking emergency department care for acute heart failure. Mortality rates at 7 days in the 5 risk groups (very low, low, intermediate, high, and very high risk) were 0%, 0%, 0.6%, 1.9%, and 3.9%, respectively. At 30 days, the corresponding mortality rates were 0%, 1.9%, 3.9%, 5.9%, and 14.3%. Compared with physician-estimated risk of 7-day mortality (PER7; c-statistic, 0.71; 95% CI, 0.64-0.78) there was improved discrimination with EHMRG7 (c-statistic, 0.81; 95% CI, 0.75-0.87; P=0.022 versus PER7) and with EHMRG7 combined with physicians' estimates (c-statistic, 0.82; 95% CI, 0.76-0.88; P=0.003 versus PER7). Model discrimination increased nonsignificantly by 0.014 (95% CI, -0.009-0.037) when physicians' estimates combined with EHMRG7 were compared with EHMRG7 alone ( P=0.242). The c-statistic for EHMRG30-ST alone was 0.77 (95% CI, 0.73-0.81) and 30-day model discrimination increased nonsignificantly by addition of physician-estimated risk to 0.78 (95% CI, 0.73-0.82; P=0.187). Net reclassification improvement with EHMRG7 was 0.763 (95% CI, 0.465-1.062) when assessed continuously and 0.820 (0.560-1.080) using risk categories compared with PER7.A clinical model allowing simultaneous prediction of mortality at both 7 and 30 days identified acute heart failure patients with a low risk of events. Compared with physicians' estimates, our multivariable model was better able to predict 7-day mortality and may guide clinical decisions.URL: https://www.clinicaltrials.gov . Unique identifier: NCT02634762.

Importance Up to 20% of patients who present to the emergency department (ED) with acute heart failure (AHF) are discharged without hospitalization. Compared with rates in hospitalized patients, readmission and mortality are worse for ED patients. Objective To assess the impact of a self-care intervention on 90-day outcomes in patients with AHF who are discharged from the ED. Design, Setting, and Participants Get With the Guidelines in Emergency Department Patients With Heart Failure was an unblinded, parallel-group, multicenter randomized trial. Patients were randomized 1:1 to usual care vs a tailored self-care intervention. Patients with AHF discharged after ED-based management at 15 geographically diverse EDs were included. The trial was conducted from October 28, 2015, to September 5, 2019. Interventions Home visit within 7 days of discharge and twice-monthly telephone-based self-care coaching for 3 months. Main Outcomes and Measures The primary outcome was a global rank of cardiovascular death, HF-related events (unscheduled clinic visit due to HF, ED revisit, or hospitalization), and changes in the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) summary score (SS) at 90 days. Key secondary outcomes included the global rank outcome at 30 days and changes in the KCCQ-12 SS score at 30 and 90 days. Intention-to-treat analysis was performed for the primary, secondary, and safety outcomes. Per-protocol analysis was conducted including patients who completed a home visit and had scheduled outpatient follow-up in the intervention arm. Results Owing to slow enrollment, 479 of a planned 700 patients were randomized: 235 to the intervention arm and 244 to the usual care arm. The median age was 63.0 years (interquartile range, 54.7-70.2), 302 patients (63%) were African American, 305 patients (64%) were men, and 178 patients (37%) had a previous ejection fraction greater than 50%. There was no significant difference in the primary outcome between patients in the intervention vs usual care arm (hazard ratio [HR], 0.89; 95% CI, 0.73-1.10;P = .28). At day 30, patients in the intervention arm had significantly better global rank (HR, 0.80; 95% CI, 0.64-0.99;P = .04) and a 5.5-point higher KCCQ-12 SS (95% CI, 1.3-9.7;P = .01), while at day 90, the KCCQ-12 SS was 2.7 points higher (95% CI, −1.9 to 7.2;P = .25). Conclusions and Relevance The self-care intervention did not improve the primary global rank outcome at 90 days in this trial. However, benefit was observed in the global rank and KCCQ-12 SS at 30 days, suggesting that an early benefit of a tailored self-care program initiated at an ED visit for AHF was not sustained through 90 days. Trial Registration ClinicalTrials.gov Identifier:NCT02519283

Background Heart failure (HF) with preserved ejection fraction (HFpEF) is more common in women than in men; data characterizing sex differences in the management and outcomes of HFpEF patients presenting to the emergency department (ED) are limited. Methods and Results Using Acute Decompensated Heart Failure National Registry Emergency Module data linked to Medicare claims, we conducted a retrospective analysis of acute HF patients in the ED, identifying HFpEF (ejection fraction [EF] ≥40%) patients and stratifying by sex to compare baseline characteristics, ED therapies, hospital length of stay (LOS), in-hospital mortality, and post-discharge outcomes. Of 4161 HFpEF patients, 2808 (67%) were women, who were more likely to be older and hypertensive, but less likely to be diabetic or smokers (all P 140 mm Hg (62.5% vs 56.4%; P = .0001) and higher EF. There were no sex differences in ED therapies, adjusted 30- and 180-day all-cause mortality, in-hospital mortality, or 30- and 180-day readmissions. After adjustment, women had longer LOS (0.40 days, 95% confidence interval [CI] 0.10–0.70; P = .008). Conclusions Women with HFpEF presenting to the ED were more likely to have elevated systolic blood pressure, but overall ED management strategies were similar to those in men. We observed adjusted differences in hospital LOS, but no differences in 30- and 180-day outcomes.

Objectives The aim of this study was to determine if a baseline high-sensitivity troponin T (hsTnT) value ≤99th percentile upper reference limit (0.014 μg/l [“low hsTnT”]) identifies patients at low risk for adverse outcomes. Background Approximately 85% of patients who present to emergency departments with acute heart failure are admitted. Identification of patients at low risk might decrease unnecessary admissions. Methods A post-hoc analysis was conducted from the RELAX-AHF (Serelaxin, Recombinant Human Relaxin-2, for Treatment of Acute Heart Failure) trial, which randomized patients within 16 h of presentation who had systolic blood pressure >125 mm Hg, mild to moderate renal impairment, and N-terminal pro–brain natriuretic peptide ≥1,600 ng/l to serelaxin versus placebo. Linear regression models for continuous endpoints and Cox models for time-to-event endpoints were used. Results Of the 1,076 patients with available baseline hsTnT values, 107 (9.9%) had low hsTnT. No cardiovascular (CV) deaths through day 180 were observed in the low-hsTnT group compared with 79 CV deaths (7.3%) in patients with higher hsTnT. By univariate analyses, low hsTnT was associated with lower risk for all 5 primary outcomes: 1) days alive and out of the hospital by day 60; 2) CV death or rehospitalization for heart failure or renal failure by day 60; 3) length of stay; 4) worsening heart failure through day 5; and 5) CV death through day 180. After multivariate adjustment, only 180-day CV mortality remained significant (hazard ratio: 0.0; 95% confidence interval: 0.0 to 0.736; p = 0.0234; C-index = 0.838 [95% confidence interval: 0.798 to 0.878]). Conclusions No CV deaths through day 180 were observed in patients with hsTnT levels ≤0.014 μg/l despite high N-terminal pro–brain natriuretic peptide levels. Low baseline hsTnT may identify patients with acute heart failure at very low risk for CV mortality.

Background The acute heart failure (AHF) Syndromes International Working Group proposed that dyspnea be assessed under standardized, incrementally provocative maneuvers and called for studies to assess the feasibility of this approach. We sought to assess the feasibility and statistical characteristics of a novel provocative dyspnea severity score (pDS) versus the traditional dyspnea visual analog scale (DVAS) in an AHF trial. Methods At enrollment, 24, 48 and 72hours, 230 ROSE-AHF patients completed a DVAS. Dyspnea was then assessed with 5-point Likert dyspnea scales administered during 4 stages (A: upright-with O 2 , B: upright-without O 2 , C: supine-without O 2 and D: exercise-without O 2 ). Patients with moderate or less dyspnea were eligible for the next stage. Results At enrollment, oxygen withdrawal and supine provocation were highly feasible (≥97%), provoking more severe dyspnea (≥1 Likert point) in 24% and 42% of eligible patients, respectively. Exercise provocation had low feasibility with 38% of eligible patients unable to exercise due to factors other than dyspnea. A pDS was constructed from Likert scales during the 3 feasible assessment conditions (A-C). Relative to DVAS, the distribution of the pDS was more skewed with a high "ceiling effect" at enrollment (23%) limiting sensitivity to change. Change in pDS was not related to decongestion or 60-day outcomes. Conclusions Although oxygen withdrawal and supine provocation are feasible and elicit more severe dyspnea, exercise provocation had unacceptable feasibility in this AHF cohort. The statistical characteristics of a pDS based on feasible provocation measures do not support its potential as a robust dyspnea assessment tool in AHF.