ASCEND-HF Trial Research Articles

Common Variants on FGD5 Increase Hazard of Mortality or Rehospitalization in Patients With Heart Failure From the ASCEND-HF Trial.

Heart failure remains a global health burden, and patients hospitalized are particularly at risk, but genetic associates for subsequent death or rehospitalization are still lacking. The genetic substudy of the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) was used to perform genome-wide association study and transethnic meta-analysis. The overall trial included the patients of self-reported European ancestry (n=2173) and African ancestry (n=507). The end point was death or heart failure rehospitalization within 180 days. Cox models adjusted for 11 a priori predictors of rehospitalization and 5 genetic principal components were used to test the association between single-nucleotide polymorphisms and outcome. Summary statistics from the 2 populations were combined via meta-analysis with the significance threshold considered P<5×10-8. Common variants (rs2342882 and rs35850039 in complete linkage disequilibrium) located in FGD5 were significantly associated with the primary outcome in both ancestry groups (European Americans: hazard ratio [HR], 1.38; P=2.42×10-6; African ancestry: HR, 1.51; P=4.43×10-3; HR in meta-analysis, 1.41; P=4.25×10-8). FGD5 encodes a regulator of VEGF (vascular endothelial growth factor)-mediated angiogenesis, and in silico investigation revealed several previous genome-wide association study hits in this gene, among which rs748431 was associated with our outcome (HR, 1.20; meta P<0.01). Sensitivity analysis proved FGD5 common variants survival association did not appear to operate via coronary artery disease or nesiritide treatment (P>0.05); and the signal was still significant when changing the censoring time from 180 to 30 days (HR, 1.39; P=1.59×10-5). In this multiethnic genome-wide association study of ASCEND-HF, single-nucleotide polymorphisms in FGD5 were associated with increased risk of death or rehospitalization. Additional investigation is required to examine biological mechanisms and whether FGD5 could be a therapeutic target. URL: https://www. gov; Unique identifier: NCT00475852.

Abstract 11004: Investigator-Reported versus Adjudicated Clinical Events for Worsening Heart Failure

Introduction: Clinical event committee (CEC) adjudication is the gold standard for event reporting in clinical trials. In some instances, investigator-reported events may be an appropriate substitute to reduce operational complexity and costs of heart failure (HF) trials, but the level of agreement between CEC and trial investigators for defining worsening HF (WHF) events is not well described. Methods: The ASCEND-HF trial compared nesiritide vs. placebo among patients hospitalized for HF, regardless of ejection fraction, and adjudicated endpoints through 30-day follow-up. This post-hoc analysis included patients with death or rehospitalization within 30 days. Concordance between the CEC and site investigators for WHF death and rehospitalization was measured using simple kappa (ĸ) statistics. Factors independently associated with discordance were identified using a backward selection model. Results: Over 30-day follow-up, there were 105 investigator-reported WHF deaths and 154 CEC-classified WHF deaths (p&lt;0.001), with a modest level of agreement (ĸ 0.59) ( Figure 1A ). For 30-day WHF rehospitalization, there were 355 events reported by investigators and 426 classified by CEC, with high levels of agreement (ĸ 0.77). Older age was independently associated with higher likelihood of CEC-investigator discordance for WHF death (OR 1.16 [1.01-1.33] per 5-year increase). For WHF rehospitalization, older age (OR 0.91 [0.84-0.98] per 5-year increase) and higher systolic blood pressure (OR 0.82 [0.71-0.94] per 10 mmHg increase) were associated with lower likelihood of discordance. Agreement for WHF endpoints varied by geographic region ( Figure 1B ). Conclusions: CEC and trial investigators had modest rates of agreement for characterizing WHF death and high rates of agreement for WHF rehospitalization. Multiple patient factors were associated with CEC-investigator discordance and levels of agreement for WHF endpoints varied across geographic regions.

Machine learning to define phenotypes and outcomes of patients hospitalized for heart failure with preserved ejection fraction: Findings from ASCEND-HF

Heart Failure with Preserved Ejection Fraction (HFpEF) is a heterogenous disease with few therapies proven to provide clinical benefit. Machine learning can characterize distinct phenotypes and compare outcomes among patients with HFpEF who are hospitalized for acute HF. We applied hierarchical clustering using demographics, comorbidities, and clinical data on admission to identify distinct clusters in hospitalized HFpEF (ejection fraction >40%) in the ASCEND-HF trial. We separately applied a previously developed latent class analysis (LCA) clustering method and compared in-hospital and long-term outcomes across cluster groups. Of 7141 patients enrolled in the ASCEND-HF trial, 812 (11.4%) were hospitalized for HFpEF and met the criteria for complete case analysis. Hierarchical Cluster 1 included older women with atrial fibrillation (AF). Cluster 2 had elevated resting blood pressure. Cluster 3 had young men with obesity and diabetes. Cluster 4 had low resting blood pressure. Mortality at 180 days was lowest among Cluster 3 (KM event-rate 6.2 [95% CI: 3.5, 10.9]) and highest among Cluster 4 (18.8 [14.6, 24.0], P < .001). Twenty four-hour urine output was higher in Cluster 3 (2700mL [1800, 3975]) than Cluster 4 (2100mL [1400, 3055], P < .001). LCA also identified four clusters: A) older White or Asian women, B) younger men with few comorbidities, C) older individuals with AF and renal impairment, and D) patients with obesity and diabetes. Mortality at 180 days was lowest among LCA Cluster B (KM event-rate 5.5 [2.0, 10.3]) and highest among LCA Cluster C (26.3 [19.2, 35.4], P < .001). In patients hospitalized for HFpEF, cluster analysis demonstrated distinct phenotypes with differing clinical profiles and outcomes.

Unsupervised Machine Learning To Define Acute Hfpef Phenotypes: Findings From Ascend-hf

Introduction : Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition with distinct phenotypes. Prior studies have used cluster analysis to group patients with chronic ambulatory HFpEF by shared characteristics. Data are limited regarding different HFpEF phenotypes in the hospitalized setting. Hypothesis We hypothesized that distinct clusters of patients hospitalized for HFpEF would have unique baseline characteristics and distinct clinical outcomes. Methods : We applied an unsupervised machine learning analysis to group patients hospitalized with HFpEF in the ASCEND-HF trial into distinct phenotypes. Groups were made via hierarchical clustering after variable reduction on a set of 39 baseline variables including demographics, medical comorbidities, and clinical data at the time of admission. Cox regression models were used to evaluate the association between HFpEF phenotypes and 180-day mortality. Results : Overall, 812 patients with EF >40% were included. Hierarchical clustering identified 4 phenotypes that had distinct baseline characteristics and outcomes (Figure). Cluster 1 was older, predominantly White/Asian, female, and had high rates of atrial fibrillation. Cluster 2 had high rates of hypertension, the highest systolic blood pressure, and lowest heart rate. Cluster 3 was the youngest, predominantly male, had a high proportion of Black patients, and had the highest BMI and diabetes prevalence. Cluster 4 had a high the lowest systolic blood pressure, a high heart rate, and high natriuretic peptide concentrations. Cluster 4 (chosen as the reference group) demonstrated the highest 180-day mortality, followed by Cluster 1 (HR= 0.68 [95% CI: 0.42-1.09]), Cluster 2 (HR=0.45 [95% CI: 0.25-0.79]), and Cluster 3 (HR=0.31 [95% CI: 0.16-0.59]) (Overall p-value =0.007). Conclusions : In this clinical trial cohort of patients hospitalized for HFpEF, cluster analysis incorporating demographic, vital sign, laboratory, and comorbidity data demonstrated distinct patient phenotypes with differing clinical profiles and outcomes. These clusters may inform patient selection for future clinical trials and may facilitate matching investigational therapies to patients more likely to benefit. : Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition with distinct phenotypes. Prior studies have used cluster analysis to group patients with chronic ambulatory HFpEF by shared characteristics. Data are limited regarding different HFpEF phenotypes in the hospitalized setting. We hypothesized that distinct clusters of patients hospitalized for HFpEF would have unique baseline characteristics and distinct clinical outcomes. : We applied an unsupervised machine learning analysis to group patients hospitalized with HFpEF in the ASCEND-HF trial into distinct phenotypes. Groups were made via hierarchical clustering after variable reduction on a set of 39 baseline variables including demographics, medical comorbidities, and clinical data at the time of admission. Cox regression models were used to evaluate the association between HFpEF phenotypes and 180-day mortality. : Overall, 812 patients with EF >40% were included. Hierarchical clustering identified 4 phenotypes that had distinct baseline characteristics and outcomes (Figure). Cluster 1 was older, predominantly White/Asian, female, and had high rates of atrial fibrillation. Cluster 2 had high rates of hypertension, the highest systolic blood pressure, and lowest heart rate. Cluster 3 was the youngest, predominantly male, had a high proportion of Black patients, and had the highest BMI and diabetes prevalence. Cluster 4 had a high the lowest systolic blood pressure, a high heart rate, and high natriuretic peptide concentrations. Cluster 4 (chosen as the reference group) demonstrated the highest 180-day mortality, followed by Cluster 1 (HR= 0.68 [95% CI: 0.42-1.09]), Cluster 2 (HR=0.45 [95% CI: 0.25-0.79]), and Cluster 3 (HR=0.31 [95% CI: 0.16-0.59]) (Overall p-value =0.007). : In this clinical trial cohort of patients hospitalized for HFpEF, cluster analysis incorporating demographic, vital sign, laboratory, and comorbidity data demonstrated distinct patient phenotypes with differing clinical profiles and outcomes. These clusters may inform patient selection for future clinical trials and may facilitate matching investigational therapies to patients more likely to benefit.

Emergency Department Visits Versus Hospital Readmissions Among Patients Hospitalized for Heart Failure

BackgroundWorsening heart failure (HF) often requires hospitalization but in some cases may be managed in the outpatient or emergency department (ED) settings. The predictors and clinical significance of ED visits without admission vs hospitalization are unclear. MethodsThe ASCEND-HF trial included 2661 US patients hospitalized for HF with reduced or preserved ejection fraction. Clinical characteristics were compared between patients with a subsequent all-cause ED visit (with ED discharge) within 30 days vs all-cause readmission within 30 days. Factors associated with each type of care were assessed in multivariable models. Multivariable models landmarked at 30 days evaluated associations between each type of care and subsequent 150-day mortality. ResultsThrough 30-day follow-up, 193 patients (7%) had ED discharge, 459 (17%) had readmission, and 2009 (76%) had neither urgent visit. Patients with ED discharge vs readmission were similar with respect to age, sex, systolic blood pressure, ejection fraction, and coronary artery disease, whereas ED discharge patients had a modestly lower creatinine (P < .01). Among patients with either event within 30 days, a higher creatinine and prior HF hospitalization were associated with a higher likelihood of readmission, as compared with ED discharge (P < .02). Landmarked at 30 days, rates of death during the subsequent 150 days were 21.0% for patients who were readmitted and 11.4% for patients discharged from the ED. Compared with patients who were readmitted, ED discharge was independently associated with lower 150-day mortality (adjusted hazard ratio 0.58, 95% confidence interval 0.36–0.92, P = .02). ConclusionsIn this cohort of US patients hospitalized for HF, worse renal function and prior HF hospitalization were associated with a higher likelihood of early postdischarge readmission, as compared with ED discharge. Although subsequent mortality was high after discharge from the ED, this risk of mortality was significantly lower than patients who were readmitted to the hospital.

Is There Any Interaction Between Sex and Renal Function Change During Hospital Stay in Patients Hospitalized With Acute Heart Failure?

BackgroundRenal dysfunction is a strong predictor of outcomes in patients with acute heart failure (AHF). However, less is known about how sex may influence the prognostic import of renal function in AHF. Methods and ResultsIn a post hoc analysis of the ASCEND-HF trial including 5377 patients with AHF (33% female), patients were categorized into 3 groups based on the changes in renal function during their hospital stay. Worsening, stable, and improving renal functions were defined as a ≥20% decrease, a <20% change, and a ≥20% increase in the estimated glomerular filtration rate, respectively. The primary outcome was the composite of 30-day all-cause mortality or HF rehospitalization. The median baseline and discharge estimated glomerular filtration rate were 58.4 and 56.9 mL/min/1.73 m2, respectively. Worsening, stable, and improving renal function was observed in 31.9%, 63.2, and 4.9% of patients, respectively. Worsening renal function was associated with adverse outcomes at 30 days (adjusted hazard ratio [aHR] 1.47, 95% confidence interval [CI] 1.22–1.76). This association existed in both males and females (aHR 1.42 and aHR 1.56, respectively, both P < .01). There was an interaction between renal function changes and sex (P = .025), because improving renal function was associated with better outcomes in men (aHR 0.29, 95% CI 0.13–0.66) as compared with women (aHR 1.18, 95% CI 0.59–2.35). There was no interaction between the ejection fraction and renal function in association with subsequent outcomes. ConclusionsIrrespective of sex, worsening renal function was associated with poorer outcomes at 30 days in patients with AHF. More studies are warranted to further delineate the possible sex differences in this setting.

Prognostic Role of Prior Heart Failure Hospitalization Among Patients Hospitalized for Worsening Chronic Heart Failure.

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. 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. 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<0.01). After adjustment, the point estimate was attenuated and the association not statistically significant (HR, 1.18 [95% CI, 0.99-1.40]; 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). 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.

Interleukin-6 and Outcomes in Acute Heart Failure: An ASCEND-HF Substudy

BackgroundThe inflammatory cytokine IL-6 has been previously implicated in the pathophysiology of acute decompensated heart failure (HF). Prior observations in acute HF patients have suggested that IL-6 may be associated with outcomes and modulated by nesiritide. We aimed to evaluate the associations between serial IL-6 measurements, mortality and rehospitalization in acute HF. Methods and ResultsWe analyzed the associations between IL-6 in acute HF, readmission, and mortality (30 and 180 days) using a cohort of 883 hospitalized patients from the ASCEND-HF trial (nesiritide vs placebo). Plasma IL-6 was measured at randomization (baseline), 48–72 hours, and 30 days. The median IL-6 was highest at baseline (14.1 pg/mL) and decreased at subsequent time points (7.6 pg/mL at 30 days). In a univariable Cox regression analysis, the baseline IL-6 was associated with 30- and 180-day mortality (hazard ratio per log 1.74, 95% confidence interval 1.09–2.78, P = .021; hazard ratio 3.23, confidence interval 1.18–8.86, P = .022, respectively). However, there was no association after multivariable adjustment. IL-6 at 48–72 hours was found to be independently associated with 30-day mortality (hazard ratio 8.2, confidence interval 1.2–57.5, P= .03), but not 180-day mortality in multivariable analysis that included the ASCEND-HF risk model and amino terminal pro-B-type natriuretic peptide as covariates. In comparison with placebo, nesiritide therapy was not associated with differences in serial IL-6 levels. ConclusionsAlthough elevated IL-6 levels were associated with higher all-cause mortality in acute HF, no independent association with this outcome was identified at baseline or 30-day measurements. In contrast with prior reports, we did not observe any impact of nesiritide over placebo on serial IL-6 levels.

Plasma Volume Status and Its Association With In-Hospital and Postdischarge Outcomes in Decompensated Heart Failure

BackgroundPrior 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 ResultsThe 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). ConclusionsBaseline 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.

A Novel In-hospital Congestion Score to Risk Stratify Patients Admitted for Worsening Heart Failure (from ASCEND-HF).

Patients hospitalized for heart failure (HF) remain at high risk for early readmission. A post hoc analysis was performed of the biomarker substudy of the ASCEND-HF trial. An in-hospital congestion score was derived using orthopnea, pedal edema, and NT-proBNP levels. Its added prognostic value beyond traditional risk factors was assessed by determining the net reclassification index (NRI). Study participants (n = 884) had a median age (years) of 67 (55-77), 68% were male, and the median (25th-75th) ejection fraction (%) was 26 (20-40). After adjustment, increasing congestion score was associated with 30-day all-cause mortality or HF hospitalization (odds ratio = 1.51, 95% confidence interval [CI] 1.28-1.77, p < 0.001) and 180-day all-cause mortality (hazard ratio = 1.48, 95% CI 1.28-1.72, p < 0.001). However, adding the congestion score to the multivariable model did not significantly impact the NRI. A higher in-hospital congestion score portended a poor short-term prognosis but did not significantly reclassify risk.

Prognostic Implications of Changes in Amino-Terminal Pro–B-Type Natriuretic Peptide in Acute Decompensated Heart Failure: Insights From ASCEND-HF

BackgroundAmino-terminal pro–B-type natriuretic peptide (NTproBNP) is closely associated with prognosis in acute decompensated heart failure (ADHF). As a result, there has been great interest measuring it during the course of treatment. The prognostic implications in both short-term and follow-up changes in NTproBNP need further clarification. MethodsBaseline, 48–72 hour, and 30-day NTproBNP levels were measured in 795 subjects in the ASCEND-HF trial. Multivariable logistic and Cox-proportional hazards models were used to test the association between static, relative, and absolute changes in NTproBNP with outcomes during and after ADHF. ResultsThe median NTproBNP at baseline was 5773 (2981–11,579) pg/mL; at 48–72 hours was 3036 (1191–6479) pg/mL; and at 30 days was 2914 (1364–6667) pg/mL. Absolute changes in NTproBNP by 48–72 hours were not associated with 30-day heart failure rehospitalization or mortality (P = .065), relative changes in NTproBNP were nominally associated (P = .046). In contrast, both absolute and relative changes in NTproBNP from baseline to 48–72 hours and to 30 days were closely associated with 180-day mortality (P < .02 for all) with increased discrimination compared to the multivariable models with baseline NTproBNP (P <.05 for models with relative and absolute change at both time points). ConclusionsAlthough the degree of absolute change in NTproBNP was dependent on baseline levels, both short-term absolute and relative changes in NTproBNP were independently and incrementally associated with long-term clinical outcomes. Changes in NTproBNP levels at 30-days were particularly well associated with long-term clinical outcomes.

Circulating Cardiac Troponin I Levels Measured by a Novel Highly Sensitive Assay in Acute Decompensated Heart Failure: Insights From the ASCEND-HF Trial

Circulating cardiac troponin levels (cTn), representative of myocardial injury, are commonly elevated in heart failure (HF) and related to adverse clinical events. However, whether cTn represents a spectrum of risk in HF is unclear. Baseline, 48-72-hour, and 30-day plasma cTnI was measured with the use of a new highly sensitive assay in 900 subjects with acute decompensated HF (ADHF) in ASCEND-HF. Multivariable models determined the relationship between cTnI and outcomes. The median (interquartile range) cTnI was 16.4 (9.3-31.6) ng/L at baseline, 14.1 (7.8-29.7) ng/L at 48-72 hours, and 11.6 (6.8-22.5) ng/L at 30 days. After additional adjustment for N-terminal pro-B-type natriuretic peptide (NT-proBNP) to established risk predictors, both baseline (odds ratio [OR] 1.25; P = .03) and 48-72-hour (OR 1.43; P = .001) cTnI were associated with higher risk for death or worsening HF before discharge. However, only cTnI at 30 days was associated with 180-day death (hazard ratio 1.25; P = .007). There were no curvilinear associations between changing cTnI and clinical outcomes. Circulating cTnI level was associated with clinical outcomes in ADHF, but these observations diminished with additional adjustment for NT-proBNP. Although they likely represent a spectrum of risk in ADHF, these findings question the implications of changing cTnI levels during treatment.

Characterization of hemodynamically stable acute heart failure patients requiring a critical care unit admission: Derivation, validation, and refinement of a risk score

Most patients with acute heart failure (AHF) admitted to critical care units (CCUs) are low acuity and do not require CCU-specific therapies, suggesting that they could be managed in a lower-cost ward environment. This study identified the predictors of clinical events and the need for CCU-specific therapies in patients with AHF. Model derivation was performed using data from patients in the ASCEND-HF trial cohort (n=7,141), and the Acute Heart Failure Emergency Management community-based registry (n=666) was used to externally validate the model and to test the incremental prognostic utility of 4 variables (heart failure etiology, troponin, B-type natriuretic peptide [BNP], ejection fraction) using net reclassification index and integrated discrimination improvement. The primary outcome was an in-hospital composite of the requirement for CCU-specific therapies or clinical events. The primary composite outcome occurred in 545 (11.4%) derivation cohort participants (n=4,767) and 7 variables were predictors of the primary composite outcome: body mass index, chronic respiratory disease, respiratory rate, resting dyspnea, hemoglobin, sodium, and blood urea nitrogen (c index=0.633, Hosmer-Lemeshow P=.823). In the validation cohort (n=666), 87 (13.1%) events occurred (c index=0.629, Hosmer-Lemeshow P=.386) and adding ischemic heart failure, troponin, and B-type natriuretic peptide improved model performance (net reclassification index 0.79, 95% CI 0.046-0.512; integrated discrimination improvement 0.014, 95% CI 0.005-0.0238). The final 10-variable clinical prediction model demonstrated modest discrimination (c index=0.702) and good calibration (Hosmer-Lemeshow P=.547). We derived, validated, and improved upon a clinical prediction model in an international trial and a community-based cohort of AHF. The model has modest discrimination; however, these findings deserve further exploration because they may provide a more accurate means of triaging level of care for patients with AHF who need admission.

Abstract 13158: Hospitalization for De Novo versus Worsening Chronic Heart Failure: Insights From the ASCEND-HF Trial

Introduction: Heart failure (HF) is a heterogeneous syndrome and individual patient survival varies widely. It is unclear how hospitalized acute HF (AHF) patients who are long-term chronic HF survivors differ from those with more recent HF diagnoses. Methods: The ASCEND-HF trial randomized 7,141 hospitalized AHF patients with reduced or preserved ejection fraction (EF) to nesiritide or placebo in addition to standard care. The present analysis compared patients by duration of HF diagnosis prior to index hospitalization using pre-specified cutpoints (0-1 month [i.e. “ de novo ”], &gt;1-12 months, &gt;12-60 months, &gt;60 months). Results: Overall, 5,741 (80.4%) patients had documentation of duration of HF diagnosis ( de novo , N=1536; &gt;1-12 months, N=1020; &gt;12-60 months, N=1653; &gt;60 months, N=1532). Mean age ranged from 64-66 years and mean EF from 29-32% across all HF duration groups. Compared to patients with longer HF duration, de novo patients were more likely to have non-ischemic HF etiology, fewer comorbidities, lower natriuretic peptide levels, and better baseline functional status (all P-value &lt;0.01). After adjustment, compared to de novo patients, longer HF duration was associated with more persistent dyspnea at 24 hours and increased 180-day mortality (Table). The influence of HF duration on mortality did not differ by age, gender, race, etiology of HF, or EF (all P-value for interaction ≥0.05). Conclusion: In this large AHF trial cohort, patient profile differed by duration of the HF diagnosis. De novo HF diagnosis was independently associated with greater early dyspnea relief and improved post-discharge survival compared to those with chronic HF diagnoses.

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Highlights From the <i>Circulation</i> Family of Journals

Insufficient reduction in heart rate during hospitalization despite beta-blocker treatment in acute decompensated heart failure: insights from the ASCEND-HF trial.

Heart failure (HF) can be associated with a higher resting heart rate (HR), and an elevated HR is associated with adverse long-term events. However, the mechanistic and causal role of HR in HF is unclear. This study aimed to investigate changes in HR during hospitalization, and the association between discharge HR and clinical outcomes as well as an interaction with beta-blocker therapy in patients with acute decompensated HF (ADHF). We studied 2906 patients with an LVEF ≤35%, without AF, who were enrolled in the ASCEND-HF trial. A total of 2492 (85.8%) patients had a HR ≥70 b.p.m. at baseline and 1580 (54.4%) patients were on beta-blocker treatment. Although HR was gradually reduced from baseline to discharge (85.5 ± 15.9 b.p.m. at baseline, 81.7 ± 14.1 b.p.m. at 24 h from treatment initiation, and 79.1 ± 12.2 b.p.m. at discharge), 80.2% of the patients still had a HR ≥70 b.p.m. at discharge. Patients with a HR ≥70 b.p.m. at discharge had significantly lower survival rates than those with a HR <70 b.p.m. (adjusted hazard ratio 1.02, 95% confidence interval 1.01-1.04, P = 0.002). Moreover, HR at discharge had a curvilinear association with mortality, and had no significant interaction effect with beta-blocker therapy at discharge (P = 0.82). Despite current beta-blocker therapy, many patients with hospitalized ADHF with reduced LVEF have relatively high discharge HR, and discharge HR is associated with higher mortality. Further studies are warranted to determine the optimal strategy for HR control to improve outcomes.

PROGNOSTIC VALUE OF RIGHT-SIDED VOLUME OVERLOAD IN PATIENTS PRESENTING WITH ACUTE HEART FAILURE: INSIGHTS FROM ASCEND-HF

Elevated jugular venous pressure (JVP) and peripheral edema predict worse outcomes in chronic heart failure (HF) patients. We studied these findings in acute HF in the ASCEND-HF trial of nesiritide vs. placebo. Of 7,141 ASCEND-HF patients, 7,135 patients had complete data on baseline JVP and

THE RELATIONSHIP BETWEEN BODY WEIGHT CHANGE DURING HOSPITALIZATION FOR ACUTE HEART FAILURE AND PATIENT CHARACTERISTICS, MARKERS OF CONGESTION, AND OUTCOMES: FINDINGS FROM ASCEND-HF

The clinical course of body weight change during hospitalization for acute heart failure (HF) and its relationship with outcomes have not been well-characterized. A post-hoc analysis was performed of the ASCEND-HF trial, which enrolled patients admitted for acute HF. Spearman rank correlations of

Dichotomous Relationship Between Age and 30-Day Death or Rehospitalization in Heart Failure Patients Admitted With Acute Decompensated Heart Failure: Results From the ASCEND-HF Trial

BackgroundYounger age as an independent predictor of death or all-cause rehospitalization at 30 days post-randomization for hospitalized heart failure (HF) patients has not been well described. Methods and ResultsASCEND-HF enrolled 7141 hospitalized acute HF patients (categorized by age: <45, 45 to <55, 55 to <65, 65 to <75, and ≥75 years) and followed them for 30 days to assess clinical outcomes, which included death or rehospitalization. Patients 45 to <55 years had the lowest percentages of death (1.4%) and total rehospitalizations (10.7%); percentages increased for younger (3.0% and 12.2%, respectively, for age <45 y) and older (5.8% and 12.5%, respectively, for age ≥75 y) patients. For those rehospitalized, the total HF-induced readmissions were highest in the youngest (68%) and declined with increasing age (P = .03). Although patients ≥55 years of age were more likely to die or be rehospitalized within 30 days of randomization for each additional 10 years of life, those <55 years of age had a significant reduction in death or HF rehospitalization for each 10-year increase in age (similar findings for death and HF rehospitalization). ConclusionsThere is a dichotomous relationship between age and risk of death or rehospitalization, and death or HF rehospitalization—risk decreases as age increases up to age 55 years, then increases after age 55 years.

Increased mortality with elevated plasma endothelin-1 in acute heart failure: an ASCEND-HF biomarker substudy.

Endothelin-1 (ET-1) is an endogenous vasoconstrictor implicated in pulmonary and systemic hypertension, as well as ventricular dysfunction, through effects on vascular smooth muscle, the kidneys, and cardiomyocytes. We aimed to determine the association between serial ET-1 levels and acute heart failure patient outcomes. We measured plasma ET-1 at baseline, 48-72 h, and 30 days in a cohort of 872 patients hospitalized with acute heart failure from the ASCEND-HF trial (randomized to nesiritide vs. placebo), and its association with 30-day mortality, 180-day mortality, in-hospital death or worsening heart failure, and 30-day mortality or rehospitalization. Median ET-1 was 7.6 [interquartile range (IQR) 5.9-10] pg/mL at baseline, 6.3 (IQR 4.9-8.1) pg/mL at 48-72 h, and 5.9 (IQR 4.7-7.9) pg/mL at 30 days (P < 0.001). Baseline and 48-72 h ET-1 were found to be independently associated with 180-day mortality in a multivariable analysis [hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.3-2.0, P < 0.001 and HR 1.5, 95% CI 1.2-1.9, P = 0.001, respectively, log-transformed]. ET-1 that was measured at 48-72 h was also independently associated with death or worsening heart failure prior to discharge [odds ratio (OR) 1.6, 95% CI 1.03-2.4, P = 0.03]. These independent associations remained significant after including NT-proBNP in the multivariable analysis. We observed an independent association between elevated ET-1 and short-term in-hospital clinical outcomes and 180-day mortality in hospitalized patients with acute heart failure ET-1 provided additional prognostic information which was incremental to that yielded by NT-proBNP.