Acute Study Of Clinical Effectiveness Of Nesiritide In Decompensated Heart Failure Research Articles

Prognostic Value of a Multi-mRNA Signature for 1-Year All-Cause Death in Hospitalized Patients With Heart Failure With a Preserved Ejection Fraction.

Heart failure with preserved ejection fraction is a major global public health problem, while effective risk stratification tools are still lacking. We sought to construct a multi-mRNA signature to predict 1-year all-cause death. We selected 30 patients with heart failure with preserved ejection fraction who died during 1-year follow-up and 30 who survived in the discovery set. One hundred seventy-one and 120 patients with heart failure with preserved ejection fraction were randomly selected as a test set and a validation set, respectively. We performed mRNA microarrays in all patients. We constructed a 5-mRNA signature for predicting 1-year all-cause death. The scores of the 5-mRNA signature were significantly associated with the 1-year risk of all-cause death in both the test set (hazard ratio, 2.72 [95% CI, 1.98-3.74]; P<0.001) and the validation set (hazard ratio, 3.95 [95% CI, 2.40-6.48]; P<0.001). Compared with a reference model, which included sex, ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) score, history of HF and NT-proBNP (N-terminal pro-B-type natriuretic peptide), the 5-mRNA signature had a better discrimination capability, with an increased area under the curve from 0.696 to 0.813 in the test set and from 0.712 to 0.848 in the validation set. A composite model integrating the 5-mRNA risk score and variables in the reference model demonstrated an excellent discrimination capability, with an area under the curve of 0.861 (95% CI, 0.784-0.939) in the test set and an area under the curve of 0.859 (95% CI, 0.755-0.963) in the validation set. The net reclassification improvement and integrated discrimination improvement indicated that the composite model significantly improved patient classification compared with the reference model in both sets (P<0.001). The 5-mRNA signature is a promising predictive tool for 1-year all-cause death and shows improved prognostic power over the established risk scores and NT-proBNP in patients with heart failure with preserved ejection fraction.

Prognostic value of Growth differentiation factors 15 in Acute heart failure patients with preserved ejection fraction.

There is an increasing proportion of hospitalized heart failure (HF) patients classified as HF with preserved ejection fraction (HFpEF) around the world. Growth differentiation factor 15 (GDF-15) is a promising biomarker in HFpEF prognostication; however, the majority of the existing data has been derived from the research on undifferentiated HF, whereas the studies focusing on HFpEF are still limited. This study aimed to determine the prognostic power of GDF-15 in the hospitalized patients with HFpEF in a Chinese cohort. We analysed the levels of serum GDF-15 in 380 patients hospitalized for acute onset of HFpEF measured by heart ultrasound at admission in a prospective cohort. The associations of GDF-15 with 1year risk of all-cause death and 1year HF readmission were assessed by the Cox proportional hazards model. Area under the receiver operating characteristic curves was used to compare predictive accuracy. GDF-15 was strongly correlated with 1year HF readmission and 1year all-cause death, with event rates of 24.8%, 40.0%, and 50.0% for 1year HF readmission (P<0.001), respectively, and with 11.2%, 13.6%, and 24.6% for 1year all-cause death (P=0.004) in the corresponding tertile, respectively. In the multivariate linear regression model, GDF-15 had a significantly negative correlation with haemoglobin (P=0.01) and a positive correlation with creatinine (P=0.01), alanine transaminase (P=0.001), and therapy of aldosterone antagonist (P=0.018). The univariate Cox regression model of GDF-15 showed that c-statistic was 0.632 for 1year HF readmission and 0.644 for 1year all-cause death, which were superior to the N-terminal pro-brain natriuretic peptide (NT-proBNP) model with c-statistics of 0.595 and 0.610, respectively. In the multivariable Cox regression model, GDF-15 tertiles independently predicted 1year HF readmission (hazard ratio 2.25, 95% confidence interval: 1.43-3.54, P<0.001) after adjusting for baseline Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) risk score, history of HF, NT-proBNP, and high-sensitivity cardiac troponin T. Compared with the model including all the adjusted variables, the model with the addition of GDF-15 improved predictive power, with c-statistic increasing from 0.643 to 0.657 for 1year HF readmission and from 0.638 to 0.660 for 1year all-cause death. In hospitalized patients with HFpEF, GDF-15 measured within 48h of admission is a strong independent biomarker for 1year HF readmission and even better than NT-proBNP. GDF-15 combined with the traditional indicators provided incremental prognostic value in this population.

Patient-reported and Clinical Outcomes Among Patients Hospitalized for Heart Failure With Reduced Versus Preserved Ejection Fraction

BackgroundDifferences between patients hospitalized for heart failure with reduced ejection fraction (HFrEF) vs HF with preserved EF (HFpEF) are not well-characterized, particularly as pertains to in-hospital decongestion and longitudinal patient-reported outcomes. The objective of this analysis was to compare patient-reported and clinical outcomes between patients hospitalized with HFrEF vs HFpEF. Methods and ResultsThe Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial enrolled 7141 patients hospitalized for HF with reduced or preserved EF. We assessed the association between an EF ≤ 40% vs an EF >40% with in-hospital decongestion, risk of rehospitalization and mortality, and quality of life as measured by the EuroQOL 5 Dimensions (EQ-5D). Among 5800 patients (81%) with complete EF data, 4782 (82%) had an EF ≤40% and 1018 (18%) had an EF >40%. Both groups demonstrated similar rates of decongestion by weight change and urine volume through 24 hours, a similar risk of 30-day mortality and HF rehospitalization, and a similar 180-day mortality. Patients with HFpEF had worse EQ-5D scores at hour 24 (median 0.76, [interquartile range (IQR) 0.51–0.84] vs 0.78 [IQR 0.57–0.84]; P = .01) that persisted through discharge (0.81 [IQR 0.69–0.86] vs 0.83 [IQR 0.71–1.00]; P < .001) and the 30-day follow-up (0.78 [IQR 0.60–0.85] vs 0.83 [IQR 0.71–1.00]; P < .001). After adjustment, these differences were attenuated and not statistically significant. ConclusionsIn this large, multinational cohort of patients hospitalized for HF, patients with an EF ≤ 40% vs an EF >40% experienced similar in-hospital decongestion and postdischarge clinical outcomes. Patients with an EF >40% reported worse in-hospital and postdischarge patient-reported health status, but these measures were similar to HFrEF after accounting for other clinical factors.

Sex Differences in Clinical Course and Patient-Reported Outcomes Among Patients Hospitalized for Heart Failure

ObjectivesThe goal of this study was to evaluate differences in clinical and patient-reported outcomes between women and men hospitalized for acute HF. BackgroundAmong patients hospitalized for heart failure (HF), it is unclear if symptom burden, response to therapy, and patient-reported quality of life (QOL) are different in women as compared with men. MethodsThe ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized 7,141 patients hospitalized for HF with reduced or preserved ejection fraction (EF) to receive nesiritide or placebo in addition to standard care. Clinical endpoints included 30-day mortality and rehospitalization and 180-day mortality. Patient-reported QOL was assessed at baseline, discharge, and 30 days using the EuroQOL 5 dimensions (EQ-5D) survey. ResultsAmong 7,141 total patients, 4,697 (65.8%) were men and 2,444 (34.2%) were women. Among patients with EF ≤40%, women were less likely to receive angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker and beta-blocker therapy, and less likely to have an implantable cardioverter-defibrillator (all p < 0.03). Signs and symptoms of HF were similar between men and women (all p > 0.05), but women experienced less in-hospital weight loss and urine output (all p < 0.01). In unadjusted and adjusted analyses, men and women had similar risk of all mortality and rehospitalization endpoints (all p ≥ 0.41). Women reported lower EQ-5D utility and visual analogue scores at admission, discharge, and 30 days. Women continued to have significantly lower EQ-5D scores at all in-hospital and post-discharge time points after adjustment for clinical characteristics (all p < 0.01). ConclusionsIn this acute HF population, women had similar risk of mortality and rehospitalization as compared with men, but experienced worse patient-reported QOL during and after hospitalization that persisted after adjustment for demographic and clinical factors. Current acute HF management may work similarly in either sex for purposes of preventing clinical events, but may be less equipped to improve patient-reported outcomes in women as compared with men.

Representativeness of a Heart Failure Trial by Race and Sex: Results From ASCEND-HF and GWTG-HF

ObjectivesThis study sought to determine the degree to which U.S. patients enrolled in a heart failure (HF) trial represent patients in routine U.S. clinical practice according to race and sex. BackgroundBlack patients and women are frequently under-represented in HF clinical trials. However, the degree to which black patients and women enrolled in trials represent such patients in routine practice is unclear. MethodsThe ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized patients hospitalized for HF to receive nesiritide or placebo from May 2007 to August 2010 and was neutral for clinical endpoints. This analysis compared non-Hispanic white (n = 1,494) and black (n = 1,012) patients enrolled in ASCEND-HF from the U.S. versus non-Hispanic white and black patients included in a U.S. hospitalized HF registry (i.e., Get With The Guidelines–Heart Failure [GWTG-HF]) during the ASCEND-HF enrollment period and meeting trial eligibility criteria. ResultsAmong 79,291 white and black registry patients, 49,063 (62%) met trial eligibility criteria (white, n = 37,883 [77.2%]; black, n = 11,180 [22.8%]). Women represented 35% and 49% of the ASCEND-HF and trial-eligible GWTG-HF cohorts, respectively. Compared with trial-enrolled patients, trial-eligible GWTG-HF patients tended to be older with higher blood pressure and higher ejection fraction. Trial-eligible patients had higher in-hospital mortality (2.3% vs. 1.3%), 30-day readmission (20.2% vs. 16.8%), and 180-day mortality (21.2% vs. 18.6%) than those enrolled in the trial (all p < 0.02), with consistent mortality findings by race and sex. After propensity score matching, mortality rates were similar; however, trial-eligible patients continued to have higher rates of 30-day readmission (23.1% vs. 17.3%; p < 0.01), driven by differences among black patients and women (all p for interaction ≤0.02). ConclusionsPatients with HF seen in U.S. practice and eligible for the ASCEND-HF trial had worse clinical outcomes than those enrolled in the trial. After accounting for clinical characteristics, trial-eligible real-world patients continued to have higher rates of 30-day readmission, driven by differences among black patients and women. Social, behavioral, and other unmeasured factors may impair representativeness of patients enrolled in HF trials, particularly among racial/ethnic minorities and women. (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure [ASCEND-HF]; NCT00475852)

Is Time of the Essence? The Impact of Time of Hospital Presentation in Acute Heart Failure: Insights From ASCEND-HF Trial

ObjectivesAs the largest acute heart failure (AHF) trial conducted to date, the global ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial database presented an opportunity to systematically describe the relationship among time of hospital presentation, clinical profile, inpatient management, and outcomes among patients admitted with AHF. BackgroundTime of hospital presentation has been shown to impact outcomes among patients hospitalized with many conditions. However, the association among time of presentation and patient characteristics, management, and clinical outcomes among patients hospitalized with AHF has not been well characterized. MethodsA post hoc analysis of the ASCEND-HF trial was performed, which enrolled 7,141 patients hospitalized for AHF. Patients were divided based on when they presented to the hospital; regular hours were defined as 9 am to 5 pm, Monday through Friday, and off hours were defined as 5 pm to 9 am, Monday through Friday and weekends. Clinical characteristics and outcomes were compared by time of presentation. ResultsOverall, 3,298 patients (46%) presented during off hours. Off-hour patients were more likely to have orthopnea (80% vs. 74%, respectively) and rales (56% vs. 49%, respectively) than regular-hour patients. Off-hour patients were more likely to receive intravenous (IV) nitroglycerin (18% vs. 11%, respectively) and IV loop diuretics (92% vs. 86%, respectively) as initial therapy and reported greater relief from dyspnea at 24 h (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.04 to 1.24; p = 0.01) than regular-hour patients. After adjustment, off-hour presentation was associated with significantly lower 30-day mortality (OR: 0.74; 95% CI: 0.57 to 0.96; p = 0.03) and 180-day mortality (hazard ratio [HR]: 0.82; 95% CI: 0.72 to 0.94; p = 0.01) but similar 30-day rehospitalization rates (p = 0.40). ConclusionsIn this AHF trial, patients admitted during off hours exhibited a distinct clinical profile, experienced greater dyspnea relief, and had lower post-discharge mortality than regular-hour patients. These findings have implications for future AHF trials.

Interaction of Body Mass Index on the Association Between N-Terminal-Pro-b-Type Natriuretic Peptide and Morbidity and Mortality in Patients With Acute Heart Failure: Findings From ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure).

BackgroundHigher body mass index (BMI) is associated with lower circulating levels of N‐terminal‐pro‐b‐type natriuretic peptide (NT‐proBNP). The Interaction between BMI and NT‐proBNP with respect to clinical outcomes is not well characterized in patients with acute heart failure.Methods and ResultsA total of 686 patients from the biomarker substudy of the ASCEND‐HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated HF ) clinical trial with documented NT‐proBNP levels at baseline were included in the present analysis. Patients were classified by the World Health Organization obesity classification (nonobese: BMI <30 kg/m2, Class I obesity: BMI 30–34.9 kg/m2, Class II obesity BMI 35–39.9 kg/m2, and Class III obesity BMI ≥40 kg/m2). We assessed baseline characteristics and 30‐ and 180‐day outcomes by BMI class and explored the interaction between BMI and NT‐proBNP for these outcomes. Study participants had a median age of 67 years (55, 78) and 71% were female. NT‐proBNP levels were inversely correlated with BMI (P<0.001). Higher NT‐proBNP levels were associated with higher 180‐day mortality (adjusted hazard ratio for each doubling of NT‐proBNP, 1.40; 95% confidence interval, 1.16, 1.71; P<0.001), but not 30‐day outcomes. The effect of NT‐proBNP on 180‐day death was not modified by BMI class (interaction P=0.24).ConclusionsThe prognostic value of NT‐proBNP was not modified by BMI in this acute heart failure population. NT‐proBNP remains a useful prognostic indicator of long‐term mortality in acute heart failure even in the obese patient.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852.

Sudden cardiac death after acute heart failure hospital admission: insights from ASCEND-HF.

The incidence of and factors associated with sudden cardiac death (SCD) early after an acute heart failure (HF) hospital admission have not been well defined. We assessed SCD and ventricular arrhythmias in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial, which included patients with acute HF with reduced or preserved ejection fraction. SCD, resuscitated SCD (RSCD), and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) were adjudicated from randomization through 30 days and were combined into a composite endpoint. Baseline characteristics associated with this composite were determined by logistic regression. RSCD and VT/VF were included as time-dependent variables in a Cox model evaluating the association of these variables with 180-day all-cause mortality. Among 7011 patients, the 30-day all-cause mortality rate was 3.8%; SCD accounted for 17% of these deaths. The 30-day composite event rate was 1.8% (n = 121). Ten patients had more than one event with 30-day Kaplan-Meier event rates of 0.6% for SCD [95% confidence interval (CI) 0.5%-0.9%, n = 43], 0.4% for RSCD (95% CI 0.2%-0.5%, n = 24), and 0.9% for VT/VF (95% CI 0.7%-1.2%, n = 64). In the multivariable model, chronic obstructive pulmonary disease, history of VT, male sex, and longer QRS duration were associated with SCD, RSCD, or VT/VF. A RSCD or VT/VF event was associated with higher 180-day mortality (adjusted hazard ratio 6.6, 95% CI 4.8-9.1, P < 0.0001). Approximately 2% of patients admitted for acute HF experienced SCD, RSCD, or VT/VF within 30 days of admission, and SCD accounted for 17% of all deaths within 30 days.

Past, present, and future of acute heart failure clinical trials-a high-risk population in search of a strategy.

Past, present, and future of acute heart failure clinical trials-a high-risk population in search of a strategy.

301 - The Burden of Non-Cardiac Comorbidities in Acute Heart Failure: Insights From ASCEND-HF

Background: Non-cardiac comorbidities are common in heart failure (HF) but the association between non-cardiac comorbidities (NCC) and outcomes in acute HF has not been well-characterized. Purpose: To determine the prevalence and prognostic implications of NCC in acute HF patients enrolled in Acute Study of Clinical Effectiveness of Nesiritide in Decompensated HF (ASCEND-HF) clinical trial. Methods: A post-hoc study analyzed 7070 patients admitted with complete comorbidity profiles irrespective of ejection fraction (EF). The following eleven NCC were collected at baseline: alcohol abuse, anemia, cancer, cerebrovascular disease, chronic respiratory disease, depression, diabetes mellitus, end-stage renal disease, liver disease, peripheral arterial disease, and smoking. Patients were grouped as having 0, 1, 2, 3, and ≥4 NCC. Prevalence of comorbidity was assessed across groups in patients with preserved EF (i.e. >40%) and reduced EF (i.e. ≤40%). The association between the burden of NCC and the composite of 30-day mortality or HF hospitalization and 180-day mortality were assessed with 0 NCC as the reference group. Results: Patients had a mean age of 65 ± 14 years and 66% were male. The prevalence of 0, 1, 2, 3, and ≥4 NCC were 9%, 26%, 30%, 20%, and 15% respectively (Figure). Significantly higher levels of comorbidity were seen in patients from North America/Western Europe compared to patients from Central Europe/Asia Pacific. Patients with preserved EF had a higher comorbidity burden overall. After adjustment, a greater number of NCC was associated with increased risk of 30-day mortality/ HF hospitalization in patients with 2 (Odds Ratio [OR] 2.09; 95% CI 1.16–3.76), 3 (OR 2.47; 95% CI 1.33–4.56), and ≥4 NCC (OR 3.32; 95% CI 1.74–5.99). The presence of 2 and 3 NCC approached significance with respect to 180-day mortality, while ≥4 NCC was associated with significantly higher rates of 180-day mortality (Hazard Ratio [HR] 2.44, 95% CI 1.53–3.88). Conclusion(s): The prevalence of NCC is high in patients with acute HF. The presence of 2 or more NCC is strongly associated with increased risk of death or hospitalization for worsening HF.

Hospitalization for Recently Diagnosed Versus Worsening Chronic Heart Failure: From the ASCEND-HF Trial

BackgroundIt is unclear how patients hospitalized for acute heart failure (HF) who are long-term chronic HF survivors differ from those with more recent HF diagnoses. ObjectivesThe goal of this study was to evaluate the influence of HF chronicity on acute HF patient profiles and outcomes. MethodsThe ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized 7,141 hospitalized patients with acute HF with reduced or preserved ejection fraction (EF) to receive nesiritide or placebo in addition to standard care. The present analysis compared patients according to duration of HF diagnosis before index hospitalization by using pre-specified cutoffs (0 to 1 month [i.e., “recently diagnosed”], >1 to 12 months, >12 to 60 months, and >60 months). ResultsOverall, 5,741 (80.4%) patients had documentation of duration of HF diagnosis (recently diagnosed, n = 1,536; >1 to 12 months, n = 1,020; >12 to 60 months, n = 1,653; and >60 months, n = 1,532). Across HF duration groups, mean age ranged from 64 to 66 years, and mean ejection fraction ranged from 29% to 32%. Compared with patients with longer HF duration, recently diagnosed patients were more likely to be women with nonischemic HF etiology, higher baseline blood pressure, better baseline renal function, and fewer comorbidities. After adjustment, compared with recently diagnosed patients, patients with longer HF duration were associated with more persistent dyspnea at 24 h (>1 to 12 months, odds ratio [OR]: 1.20; 95% confidence interval [CI]: 0.97 to 1.48; >12 to 60 months, OR: 1.34; 95% CI: 1.11 to 1.62; and >60 months, OR: 1.31; 95% CI: 1.08 to 1.60) and increased 180-day mortality (>1 to 12 months, hazard ratio [HR]: 1.89; 95% CI: 1.35 to 2.65; >12 to 60 months, HR: 1.82; 95% CI: 1.33 to 2.48; and >60 months, HR: 2.02; 95% CI: 1.47 to 2.77). The influence of HF duration on mortality was potentially more pronounced among female patients (interaction p = 0.05), but did not differ according to age, race, prior ischemic heart disease, or ejection fraction (all interactions, p ≥ 0.23). ConclusionsIn this acute HF trial, patient profile differed according to duration of the HF diagnosis. A diagnosis of HF for ≤1 month before hospitalization was independently associated with greater early dyspnea relief and improved post-discharge survival compared to patients with chronic HF diagnoses. The distinction between de novo or recently diagnosed HF and worsening chronic HF should be considered in the design of future acute HF trials. (A Study Testing the Effectiveness of Nesiritide in Patients With Acute Decompensated Heart Failure; NCT00475852)

April 2016 at a glance. Focus on cardiac remodeling, biomarkers and treatment.

Mohamed et al. show the long-term effects of volume overload induced by aortacaval shunt in mice followed by serial echocardiography until the development of reduced left ventricular ejection fraction (LVEF) and heart failure (HF). Transition to HF was characterized by reduced sarcomeric titin phosphorylation, a cause of increased sarcomeric stiffness, activation of calcium/calmodulin-dependent protein kinase II, decreased protein kinase B (Akt) phosphorylation, high oxidative stress, and increased apoptosis. These changes were worsened in Akt-deficient mice showing the critical role of this kinase.1 Tenascin-C is a large glycoprotein which appears in the extracellular matrix following tissue injury or tumor formation. Yokokawa et al. have measured it in 123 patients with dilated cardiomyopathy undergoing endomyocardial biopsy. Patients with high myocardial tenascin had worse cardiac remodeling and poorer outcomes. Diabetes and HF severity were independent determinants of its content.2 Suematsu et al. have compared valsartan and LCZ696 with a control group in streptozotocin induced diabetic mice. Compared with control and with valsartan groups, administration of LCZ696 improved LVEF and reduced LV ANP mRNA, the LV fibrotic area and TGF-β levels.3 Atrial flutter-related tachycardiomyopathy is a specific form of cardiac remodeling. Brembilla-Perot et al. report the 6 months follow-up of 1269 patients who underwent radiofrequency ablation for atrial flutter. A marked improvement in LVEF was shown in 56% of the patients who had a reduced LVEF before ablation. An ischemic etiology and prescription of antiarrhythmic drugs were associated with a lower likelihood of LVEF improvement. Patients who improved their LVEF had similar outcomes as those with a normal LVEF at baseline whereas those with a persistent low LVEF post-ablation had an almost 3-fold higher mortality rate.4 Ovchinnikova et al. have measured circulating microRNAs in 137 patients with acute HF, 20 with chronic HF, 8 with dyspnea caused by COPD exacerbation, and 41 healthy controls. Plasma levels of miRNAs were decreased in the patients with acute HF compared with all the other groups with 15 of the 226 miRNAs measured that showed a larger than a 4-fold difference. Among them, 12 were different also in the validation cohort and a prognostic value was shown for 7 of them so that their further drop within 48 hours after admission was associated with an increased risk of 180-day mortality.5 Another study shows that liver function exams were abnormal in up to 40% of the patients with acute HF enrolled in ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) and increased serum bilirubin had prognostic value also at multivariable analysis.6 Sleep-disordered breathing (SDB) is found in over half of the patients with HF and is associated with reduced quality of life and poor prognosis. Pearse and Cowie have reviewed the classification, pathophysiology, prognosis and treatment options for patients with HF and SDB. The results of the most recent trials, including SERVE-HF, are discussed.7 The effects of chronic subcutaneous (SQ) BNP administration were evaluated by McKie et al. in a double-blind, placebo controlled study in patients with asymptomatic LV dysfunction who underwent plasma volume expansion at baseline and after 12 weeks. Compared with placebo, chronic SQ, twice daily, BNP administration was associated with an increase in urinary sodium and cGMP excretion and in urine flow with a tendency to a different glomerular filtration rate response to volume expansion and to a lower LV mass.8

Liver function tests in patients with acute heart failure and associated outcomes: insights from ASCEND-HF.

We aimed to characterize abnormal liver function tests in patients with heart failure (HF), as they are commonly encountered yet poorly defined. We used data from ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) to characterize associations with baseline liver function tests (LFTs). Each LFT was analysed as both a continuous and dichotomous variable [normal vs. abnormal; bilirubin >1.0 mg/dL; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >35 mmol/L]. Logistic regression assessed the association of LFTs and 30-day all-cause mortality and HF rehospitalization, and Cox proportional hazards assessed the association with 180-day all-cause mortality among patients alive at a 30-day landmark. In ASCEND-HF, 4228 (59%) had complete admission LFT data. Of these, 42% had abnormal bilirubin, 22% had abnormal ALT, and 30% had abnormal AST. Patients with abnormal LFTs were younger, had lower body mass index, and lower left ventricular ejection fraction. In multivariable models, increased total bilirubin was associated with increased 30-day mortality or HF rehospitalization [hazard ratio (HR) 1.17 per 1 mg/dL increase, 95% confidence interval (CI) 1.04, 1.32; P = 0.012], but not with an increase in 180-day mortality (HR 1.10, 95% CI 0.97, 1.25; P = 0.13) per 1 mg/dl increase. Compared with normal bilirubin levels, abnormal bilirubin was associated with increased 30-day mortality or HF rehospitalization (HR 1.24, 95% CI 1.00, 1.54; P = 0.048) and 180-day mortality (HR 1.32, 95% CI 1.08, 1.62; P = 0.007). We found no association with AST or ALT and outcomes. Greater than 40% of patients hospitalized with acute HF had abnormal LFTs. After multivariable adjustment, only elevated bilirubin was independently associated with worse clinical outcomes and may represent an important prognostic variable.

Prognostic Value of Baseline and Changes in Circulating Soluble ST2 Levels and the Effects of Nesiritide in Acute Decompensated Heart Failure

ObjectivesThe study sought to investigate the association between soluble growth stimulation expressed gene 2 (sST2) level and adverse outcomes in acute heart failure (HF). BackgroundSeveral studies have demonstrated the prognostic utility of sST2 levels in HF. MethodssST2 levels were measured in sequential baseline and follow-up (48 to 72 h and 30 days) plasma samples from 858 acute HF subjects enrolled in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial biomarker substudy and were related to in-hospital and post-discharge clinical outcomes. ResultsHigher sST2 levels were associated with increased death risk at 180 days (baseline hazard ratio [HR]: 2.21; follow-up HR: 2.64; both p < 0.001). These results were not independent of covariates and aminoterminal pro–B-type natriuretic peptide for baseline sST2 (HR: 1.29, p = 0.243), but were borderline significant for follow-up sST2 (HR: 1.61, p = 0.051). Subjects with persistently high (>60 ng/ml) sST2 levels at follow-up had higher 180-day death rates than those with lower follow-up sST2 levels (adjusted HR: 2.91, p = 0.004). Neither baseline nor follow-up sST2 levels were associated with dyspnea improvement. Changes in sST2 from baseline were less in the nesiritide versus placebo group at follow-up, but were similar at 30 days. ConclusionsElevated levels of sST2 were associated with an increased risk of adverse clinical events in acute HF, but prognostic value of baseline sST2 diminished after adjusting for clinical covariates and aminoterminal pro–B-type natriuretic peptide. In those with elevated baseline sST2 levels, persistently elevated sST2 levels at follow-up were associated with increased mortality risk. In addition, nesiritide did not demonstrate an incremental impact on sST2 levels over standard therapy.

Circulating Kidney Injury Molecule-1 Levels in Acute Heart Failure: Insights From the ASCEND-HF Trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure)

ObjectivesThis study sought to determine the relationship of KIM-1 levels with adverse clinical outcomes in acute decompensated heart failure (ADHF). BackgroundKidney injury molecule (KIM)-1 is a biomarker expressed by the nephron in acute tubular injury, and is a sensitive and specific marker for early acute kidney injury. Although commonly measured in urine, KIM-1 levels are also detectable in plasma, but its clinical and prognostic utility in ADHF is unknown. MethodsBaseline, 48- to 72-h, and 30-day KIM-1 plasma levels were measured in 874 subjects in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial. Multivariable logistic and Cox models were used to assess the relationship between KIM-1 levels and outcomes during and after ADHF. ResultsThe median circulating KIM-1 level at baseline was 375.4 pg/ml (interquartile range [IQR]: 237.0 to 633.1 pg/ml), at 48 to 72 h was 373.7 pg/ml (IQR: 220.3 to 640.5 pg/ml), and at 30 days was 382.6 pg/ml (IQR: 236.5 to 638.0 pg/ml). There were no associations between KIM-1 levels and any 30-day outcomes. In univariable analysis, both baseline and follow-up KIM-1 were associated with greater 180-day mortality risk. However, after adjusting for blood urea nitrogen or creatinine in addition to established risk predictors from ASCEND-HF, higher KIM-1 at all time points during hospitalization was not associated with in-hospital or post-discharge outcomes (all p > 0.05), but KIM-1 levels measured at 30 days were associated independently with 180-day mortality (hazard ratio: 1.49; p = 0.04). ConclusionsIn our study cohort, circulating KIM-1 at baseline and during hospitalization was not associated with adverse clinical outcomes in ADHF after adjusting for standard indices of kidney function.

Worsening heart failure during hospitalization for acute heart failure: Insights from the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF)

Despite initial in-hospital treatment of acute heart failure (HF), some patients experience worsening HF (WHF). There are limited data about the outcomes and characteristics of patients who experience in-hospital WHF. We assessed the characteristics and outcomes of patients with and without WHF in the ASCEND-HF trial. Worsening HF was defined as at least 1 symptom or sign of new, persistent, or WHF requiring additional intravenous inotropic/vasodilator or mechanical therapy during index hospitalization. We assessed the relationship between WHF and 30-day mortality, 30-day mortality or HF hospitalization, and 180-day mortality. We also assessed whether there was a differential association between early (days 1-3) vs late (day ≥4) WHF and outcomes. Of 7,141 patients with acute HF, 354 (5%) experienced WHF. Patients with WHF were more often male and had a history of atrial fibrillation or diabetes, lower blood pressure, and higher creatinine. After risk adjustment, WHF was associated with increased 30-day mortality (odds ratio 13.37, 95% CI 9.85-18.14), 30-day mortality or HF rehospitalization (odds ratio 6.78, 95% CI 5.25-8.76), and 180-day mortality (hazard ratio 3.90, 95% CI 3.14-4.86) (all P values < .0001). There was no evidence of a difference in outcomes between early and late WHF (all P values for comparison ≥ .2). Worsening HF during index hospitalization was associated with worse 30- and 180-day outcomes. Worsening HF may represent an important patient-centered outcome in acute HF and a focus of future treatments.

Comparative Assessment of Short-Term Adverse Events in Acute Heart Failure With Cystatin C and Other Estimates of Renal Function: Results From the ASCEND-HF Trial

ObjectivesThe purpose of this study was to investigate the predictive values of baseline and changes in cystatin C (CysC) and its derived equations for short-term adverse outcomes and the effect of nesiritide therapy on CysC in acute decompensated heart failure (ADHF). BackgroundNewer renal biomarkers or their derived estimates of renal function have demonstrated long-term prognostic value in chronic heart failure. MethodsCysC levels were measured in sequential plasma samples from 811 subjects with ADHF who were enrolled in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) biomarker sub-study (randomized to nesiritide therapy vs. placebo), and followed for all-cause death (180 days) and recurrent hospital stay (30 days). ResultsMedian CysC levels were 1.49 (interquartile range [IQR]: 1.20 to 1.96) mg/l at baseline, 1.56 (IQR: 1.28 to 2.13) mg/l at 48 to 72 h, and 1.58 (IQR: 1.24 to 2.11) mg/l at 30 days. Higher baseline (but not follow-up) CysC levels were associated with increased risk of 30-day adverse events and less improvement in dyspnea after 24 h as well as 180-day mortality, although not incremental to blood urea nitrogen. Worsening renal function (defined as a 0.3 mg/l increase in CysC) occurred in 161 of 701 (23%) patients, but it was not predictive of adverse events. Changes in CysC levels were similar between the nesiritide and placebo groups. ConclusionsOur findings confirmed the prognostic value of baseline CysC levels in the setting of ADHF. However, worsening renal function based on CysC rise was not predictive of adverse events. Nesiritide did not worsen renal function compared with placebo.

Acute decompensated heart failure patients admitted to critical care units: Insights from ASCEND-HF

BackgroundLittle is known about global patterns of critical care unit (CCU) care and the relationship with outcomes in patients with acute decompensated heart failure (ADHF). Whether a ward or a CCU admission is associated with better outcomes is unclear. MethodsPatients in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial were initially hospitalized in a ward or CCU (coronary or intensive care unit). Sites were geographically classified: Asia-Pacific (AP), Central Europe (CE), Latin America (LA), North America (NA), and Western-Europe (WE). The primary outcome of 30-day all-cause mortality or all-cause hospital readmission was adjusted using a two-stage multivariable logistic regression model with a generalized estimated equation that took sites within each country as a nested random factor. ResultsOverall, 1944 (38.2%) patients were admitted to a CCU and 3150 (61.8%) to a ward, and this varied by region: 50.6% AP, 63.3% CE, 60.7% WE, 22.1% LA, and 28.6% NA. The 30-day death or readmission rate was 15.2% in ward patients and 17.0% in CCU patients (risk-adjusted Odds Ratio [OR] 1.44: 95% CI, 1.14–1.82). Compared with CCU patients in NA (24.1% 30-day event rate), the primary outcomes were: AP (10.4%, Odds Ratio [OR] 0.63; 95% confidence Interval [CI], 0.35 to 1.15), CE (10.4%, OR 0.56: 95% CI, 0.31 to 1.02), LA (22.4%, OR 0.60: 95% CI, 0.11 to 3.32), and WE (11.2%, OR 0.63, 95% CI, 0.25 to 1.56). No regional differences in 30-day mortality were observed; however, 30-day readmission rates were highest in NA sites. ConclusionsManagement of patients with ADHF varies significantly, and after adjustment, CCU care was associated with higher risk of early mortality, not explained by international differences. These findings may help to improve the early decisions regarding risk stratification of patients hospitalized with ADHF.

Hypotension During Hospitalization for Acute Heart Failure Is Independently Associated With 30-Day Mortality

Background— Outcomes associated with episodes of hypotension while hospitalized with acute decompensated heart failure are not well understood. Methods and Results— Using data from Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), we assessed factors associated with in-hospital hypotension and subsequent 30-day outcomes. Patients were classified as having symptomatic or asymptomatic hypotension. Multivariable logistic regression was used to determine factors associated with in-hospital hypotension, and Cox proportional hazards models were used to assess the association between hypotension and 30-day outcomes. We also tested for treatment interaction with nesiritide on 30-day outcomes and the association between in-hospital hypotension and renal function at hospital discharge. Overall, 1555 of 7141 (21.8%) patients had an episode of hypotension, of which 73.1% were asymptomatic and 26.9% were symptomatic. Factors strongly associated with in-hospital hypotension included randomization to nesiritide (odds ratio, 1.98; 95% confidence interval [CI], 1.76–2.23; P &lt;0.001), chronic metolazone therapy (odds ratio, 1.74; 95% CI, 1.17–2.60; P &lt;0.001), and baseline orthopnea (odds ratio, 1.31; 95% CI, 1.13–1.52; P =0.001) or S3 gallop (odds ratio, 1.21; 95% CI, 1.06–1.40; P =0.006). In-hospital hypotension was associated with increased hazard of 30-day mortality (hazard ratio, 2.03; 95% CI, 1.57–2.61; P &lt;0.001), 30-day heart failure hospitalization or mortality (hazard ratio, 1.58; 95% CI, 1.34–1.86; P &lt;0.001), and 30-day all-cause hospitalization or mortality (hazard ratio, 1.40; 95% CI, 1.22–1.61; P &lt;0.001). Nesiritide had no interaction on the relationship between hypotension and 30-day outcomes (interaction P =0.874 for death, P =0.908 for death/heart failure hospitalization, P =0.238 death/all-cause hospitalization). Conclusions— Hypotension while hospitalized for acute decompensated heart failure is an independent risk factor for adverse 30-day outcomes, and its occurrence highlights the need for modified treatment strategies. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00475852.

Differences in Treatment, Outcomes, and Quality of Life Among Patients With Heart Failure in Canada and the United States

The aim of this study was to compare clinical outcomes, resource utilization, and health-related quality of life between Canadian and U.S. patients enrolled in ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure). A further aim was to supplement the within-trial analysis with a contemporaneous population-based comparison of all patients hospitalized with primary diagnoses of heart failure (HF) in the 2 countries. Little is known about intercountry differences in outcomes of patients with HF in Canada and the United States. Trial patients consisted of 465 Canadian and 2,684 U.S. patients enrolled in ASCEND-HF. Population-level cohorts consisted of 1.9 million U.S. and 81,016 Canadians hospitalized for HF in 2007 and2008. Canadian patients in ASCEND-HF were older, were more likely to be white, and had lower body weights and blood pressures than U.S. patients. Canadians also had lower baseline-adjusted odds of 30-day mortality (odds ratio: 0.46; 95% confidence interval: 0.23 to 0.92) and better health-related quality of life than U.S. patients. In both countries, trial patients differed significantly from population-level cohorts. In contrast to ASCEND-HF, unadjusted in-hospital mortality at the population level was significantly lower in the United States (3.4%) compared with Canada (11.1%) (p< 0.01). Intercountry differences in outcomes of patients hospitalized with HF differed significantly between trial and population cohorts. Further study on how cardiac care is delivered in the 2 countries and how it influences the results of clinical trials and population-level outcomes, especially in the long term, is warranted. (A Study Testing the Effectiveness of Nesiritide in Patients With Acute Decompensated Heart Failure; NCT00475852).