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Objectives: The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure., Background: Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking., Methods: In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction <35% to receive placebo or bosentan (target dose 125 mg twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or hospitalization for heart failure., Results: Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure., Conclusions: Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The course of patients following admission for acute heart failure (AHF) is of major importance to patients and healthcare providers. We examined predictors and associations of length of stay (LOS), 30-day post-discharge readmission and 90-day post-discharge mortality in 1990 patients enrolled in the PROTECT study., Methods and Results: PROTECT was a randomized study that examined the effect of the adenosine blocker rolofylline in patients within 24 h of admission for AHF with mild to moderate renal impairment. Geographic-region-adjusted multivariable models showed that LOS was only partly explained by the severity of heart failure (HF), comorbidities (diabetes mellitus, renal impairment, ischaemic heart disease) and degree of metabolic dysfunction (cholesterol and albumin) at baseline (adjusted R(2) 0.27). Addition of in-hospital worsening heart failure (WHF) and changes in metabolic markers contributed significantly to prediction of LOS [R(2) difference 0.050, 95% confidence interval (CI) 0.0282-0.072]. Thirty-day HF readmission was associated with more severe HF and previous HF admission but not with LOS (odds ratios 1.00, 95% CI 0.97-1.04). Death within 90 days after discharge was associated with older age, more severe HF, worse renal function, and lower sodium and bicarbonate at admission; LOS was a strong predictor of 90-day post-discharge mortality., Conclusions: In patients admitted for AHF, LOS is not well-predicted by traditional markers of disease severity, but strongly associated with the occurrence of in-hospital WHF. Longer LOS is a strong predictor of early mortality after discharge but not of readmission. These findings may help focus efforts to reduce LOS and post-discharge outcomes on patients' subgroups at increased risk., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Aims: Episodes of acute heart failure (AHF) unfavourably affect multiple organs, which may have an adverse impact on the outcomes. We investigated the prevalence and clinical consequences of abnormal liver function tests (LFTs) in AHF patients enrolled in the PROTECT study., Methods and Results: The LFTs comprised serial assessment of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin at baseline and during follow-up (daily until discharge, on days 7 and 14). The prevalence of abnormal LFTs (above upper limit of normal for AST and ALT or below lower limit of normal for albumin) was: at baseline AST 20%, ALT 12%, albumin 40%; and at day 14: AST 15%, ALT 9%, albumin 26%. Abnormal LFTs at baseline were associated with a higher risk of in-hospital death with odds ratios [95% confidence interval (CI)] of 3.5 (1.7-7.3) for AST, 3.9 (1.8-8.4) for ALT, and 2.8 (1.3-5.9) for albumin (all P < 0.01). Abnormal baseline and discharge LFTs had an unfavourable impact on 180-day mortality with hazard ratios (95% CI) for baseline AST, ALT, and albumin of 1.3 (1.0-1.7), 1.1 (1.0-1.2), 1.4 (1.1-1.8), respectively, and 1.5 (1.1-2.0), 1.5 (1.0-2.2), and 1.6 (1.2-2.1), for discharge AST, ALT, albumin, respectively (all P < 0.05). Analysis of LFTs trajectories (calculated as changes in LFTs over time) revealed that increasing AST and ALT on day 3 as well as decreasing albumin on day 4 were independent prognosticators of 180-day outcome (all P < 0.05)., Conclusions: Abnormal LFTs are frequent in AHF at baseline and during hospital stay and predict worse outcomes. Whether this association is causal and what are the underlying mechanisms involved require further study., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Background: Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction., Methods: After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure., Results: After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001)., Conclusions: In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.).

Aims and Methods: To: (i) describe the baseline characteristics of patients in ATMOSPHERE and the changes in the planned analysis of ATMOSPHERE resulting from the mandated discontinuation of study treatment in patients with diabetes; (ii) compare the baseline characteristics of patients in ATMOSPHERE with those in the Prospective comparison of Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF); and (iii) compare the characteristics of patients with and without diabetes at baseline in ATMOSPHERE., Results: A total of 7063 patients were randomized into ATMOSPHERE April 2009-April 2014 at 755 sites in 43 countries. Their average age was 63 years and 78% were men. ATMOSPHERE patients were generally similar to those in PARADIGM-HF although fewer had diabetes, renal dysfunction, and were treated with a mineralocorticoid receptor antagonist. In ATMOSPHERE, patients with diabetes differed in numerous ways from those without. Patients with diabetes were older and had worse heart failure status but a similar left ventricular ejection fraction (mean 28%); they had a higher body mass index and more co-morbidity, especially hypertension and coronary heart disease. Mean estimated glomerular filtration rate was slightly lower in those with diabetes compared with those without., Conclusion: ATMOSPHERE will determine whether patients with HF and reduced ejection fraction (particularly those without diabetes) benefit from the addition of a direct renin inhibitor to standard background therapy, including an angiotensin-converting enzyme inhibitor, beta-blocker, and a mineralocorticoid receptor antagonist. ATMOSPHERE will also determine whether aliskiren alone is superior to, or at least non-inferior to, enalapril., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Background: Patients with heart failure and preserved ejection fraction (HFpEF) have a poor prognosis, and no therapies have been proven to improve outcomes. It has been proposed that heart failure, including HFpEF, represents overlapping syndromes that may have different prognoses. We present an exploratory study of patients enrolled in the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) using latent class analysis (LCA) with validation using the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study to identify HFpEF subgroups., Methods and Results: In total, 4113 HFpEF patients randomized to irbesartan or placebo were characterized according to 11 clinical features. The HFpEF subgroups were identified using LCA. Event-free survival and effect of irbesartan on the composite of all-cause mortality and cardiovascular hospitalization were determined for each subgroup. Subgroup definitions were applied to 3203 patients enrolled in CHARM-Preserved to validate observations regarding prognosis and treatment response. Six subgroups were identified with significant differences in event-free survival (P < 0.001). Clinical profiles and prognoses of the six subgroups were similar in CHARM-Preserved. The two subgroups with the worst event-free survival in both studies were characterized by a high prevalence of obesity, hyperlipidaemia, diabetes mellitus, anaemia, and renal insufficiency (Subgroup C) and by female predominance, advanced age, lower body mass index, and high rates of atrial fibrillation, valvular disease, renal insufficiency, and anaemia (Subgroup F)., Conclusion: Using a data-driven approach, we identified HFpEF subgroups with significantly different prognoses. Further development of this approach for characterizing HFpEF subgroups is warranted., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Objectives: These studies conducted analyses to examine patient characteristics and outcomes associated with worsening heart failure (WHF)., Background: WHF during an admission for acute heart failure (AHF) represents treatment failure and is a potential therapeutic target for clinical trials of AHF., Methods: Individual patient data from the PROTECT (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) and RELAX-AHF (Relaxin in Acute Heart Failure) phase II and III studies were pooled for analysis., Results: Of 3,691 patients, death or WHF through day 5 occurred in 12.4%, ranging from 9.5% to 14.5% among studies. A multivariable model provided modest discrimination between patients who did or did not develop WHF (C-index = 0.68). After multivariable adjustment, WHF was associated with a mean increase in length of stay of 5.2 days (95% confidence interval [CI]: 4.6 to 5.8 days) and increased risks of 60-day HF or renal failure readmission or cardiovascular death (hazard ratio [HR]: 1.64, 95% CI: 1.34 to 2.01) and 180-day mortality (HR: 1.93, 95% CI: 1.55 to 2.41) (all p < 0.001). The risk of mortality was higher in patients whose WHF required intravenous inotropes or mechanical therapy (HR: 3.03, 95% CI: 2.11 to 4.36) compared with patients whose WHF was treated with intravenous loop diuretic alone (HR: 1.80, 95% CI: 1.36 to 2.36) (both p < 0.001). WHF was associated with larger increases in markers of renal and hepatic dysfunction during the first days of admission, but remained significantly associated with adverse outcomes after adjustment for these changes., Conclusions: WHF during the first 5 days of admission for AHF occurred in approximately 10% to 15% of patients and was associated with longer length of stay and higher risk for readmission and death., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The 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)., Background: Newer renal biomarkers or their derived estimates of renal function have demonstrated long-term prognostic value in chronic heart failure., Methods: CysC 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)., Results: Median 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., Conclusions: Our 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., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Previous heart failure (HF) trials suggested that age influences patient characteristics and outcome; however, under-representation of elderly patients has limited characterization of this cohort. Whether standard prognostic variables have differential utility in various age groups is unclear., Methods and Results: The PROTECT trial investigated 2033 patients (median age 72 years) with acute HF randomized to rolofylline or placebo. Patients were divided into five groups based on the quintiles of age: ≤59, 60-68, 69-74, 75-79, and ≥80 years. Baseline characteristics, medications, and outcomes (30-day death or cardiovascular/renal hospitalization, and death at 30 and 180 days) were explored. The prognostic utility of baseline characteristics for outcomes was investigated in the different groups and in those aged <80 years vs. ≥80 years. With increasing age, patients were more likely to be women with hypertension, AF, and higher EF. Increased age was associated with increased risk of 30- and 180-day outcomes, which persisted after multivariable adjustment (hazard ratio for 180-day death = 1.17; 95% confidence interval 1.11-1.24 for each 5-year increase). The prognostic utility of baseline characteristics such as previous HF hospitalization and serum sodium, systolic blood pressure, and NYHA class was attenuated in the elderly for the endpoint of 180-day mortality. An increase in albumin was associated with a greater reduction in risk in patients aged ≥80 years vs. <80 years., Conclusions: In a large trial of acute HF, there were differences in baseline characteristics and outcomes amongst patients of different ages. Standard prognostic variables exhibit different utility in elderly patients., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Background: The impact of depression on outcome in implantable cardioverter defibrillator (ICD) recipients has not been fully appreciated. We assessed the prevalence of depression and its association with heart failure (HF) outcome among veterans with ICDs., Methods and Results: Patients enrolled between January 2005 and January 2010 in the Outcomes among Veterans with Implantable Defibrillators Registry were studied. We examined the cross-sectional association of depression with severity of HF functional class as well as the association of depression with the composite outcome of mortality or HF hospitalization over a mean follow-up time of 2.7 years. There were 3,862 patients enrolled. Patients with depression (1,162, 43%) were younger (63.1 ± 9.4 years vs 66.6 ± 9.9 years, P < 0.001), more likely to have a history of tobacco or alcohol abuse (P < 0.0001) or atrial fibrillation (P = 0.05) while having a higher ejection fraction (28.3% vs 27.4%, P = 0.03). Depression was associated with advanced HF class at time of implant; odds ratio (OR; vs class I) for class III: 1.65 (confidence interval [CI] 1.17-2.33), class IV: 1.73 (95% CI 1.08-2.76). Death or HF hospitalization was more likely to occur in patients with depression (35.2% vs 32.0%, HR: 1.15 [95% CI 0.99-1.33]). The predictive value of depression was stronger after multivariable adjustment; HR: 1.25 (95% CI 1.05-1.49)., Conclusion: Depression was prevalent among veterans with ICDs. Depression was associated with severity of HF. The predictive value of associated depression was significant after multivariable adjustment., (©2014 Wiley Periodicals, Inc.)

Background: Higher heart rate is associated with poorer outcomes in patients with heart failure and reduced ejection fraction (HF-REF). Less is known about the association between heart rate and outcomes in patients with heart failure and preserved ejection fraction (HF-PEF). Therefore, we examined the relationship between heart rate and outcomes in the irbesartan in patients with heart failure and preserved systolic function trial (I-Preserve) in patients with an ejection fraction >45% aged >60 years., Methods and Results: Heart rate was analysed as both a categorical (tertiles) and continuous variable. Patients in sinus rhythm (n = 3271) and atrial fibrillation (n = 696) were analysed separately. The outcomes examined were the primary endpoint of the trial (all-cause death or cardiovascular hospitalization), the composite of cardiovascular death or heart failure hospitalization (and its components) and all-cause death alone. Higher heart rate was associated with a significantly higher risk of all outcomes studied for patients in sinus rhythm, even after adjustment for other prognostic variables, including N-terminal pro-B-type natriuretic peptide. Each standard deviation (12.4 bpm) increase in heart rate was associated with an increase in risk of 13% for cardiovascular death or heart failure hospitalization (P = 0.002). No relationship between heart rate and outcomes was observed for patients in atrial fibrillation. Beta-blocker treatment did not reduce the heart rate-risk relationship., Conclusions: In patients with heart failure and preserved ejection fraction, heart rate is in sinus rhythm an independent predictor of adverse clinical outcomes and might be a therapeutic target in this syndrome. Clinical Trial Registration - URL http://www.clinicaltrials.gov. Unique identifier: NCT 0095238., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Aims: The implications of geographical variation are unknown following adjustment for hospital length of stay (LOS) in heart failure (HF) trials that included patients whether or not they had systolic dysfunction. We investigated regional differences in an international acute HF trial., Methods and Results: The PROTECT trial investigated 2033 patients with acute HF and renal dysfunction hospitalized at 173 sites in 17 countries with randomization to rolofylline or placebo. We grouped enrolling countries into six regions. Baseline characteristics, in-hospital management, and outcomes were explored by region. The primary study outcome was 60-day mortality or cardiovascular/renal hospitalization. Secondary outcomes included 180-day mortality. Of 2033 patients, 33% were from Eastern Europe, 19% from Western Europe, 16% from Israel, 15% from North America, 14% from Russia, and 3% from Argentina. Marked differences in baseline characteristics, HF phenotype, in-hospital diuretic and vasodilator strategies, and LOS were observed by region. LOS was shortest in North America and Israel (median 5 days) and longest in Russia (median 15 days). Regional event rates varied significantly. Following multivariable adjustment, region was an independent predictor of the risk of mortality/hospitalization at 60 days, with the lowest risk in Russia (hazard ratio 0.39, 95% confidence interval 0.23-0.64 vs. Western Europe) due to lower rehospitalization; mortality differences were attenuated by 180 days., Conclusions: In an international HF trial, there were differences in baseline characteristics, treatments, LOS, and rehospitalization amongst regions, but little difference in longer term mortality. Rehospitalization differences exist independent of LOS. This analysis may help inform future trial design and should be externally validated., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Background: Inflammation is associated with progression of chronic heart failure (HF). Few data exist on high-sensitivity C-reactive protein (hsCRP) levels and their importance in acute HF., Methods and Results: In this biomarker substudy of the ASCEND-HF trial, we measured hsCRP levels at admission (n = 794), 48-72 hours (n = 677), and 30 days (n = 581) and evaluated their association with outcomes. Levels of hsCRP were considerably elevated at admission (median 12.6 mg/L, interquartile range [IQR] 5.23-30.5) and 48-72 hours (median 11.0 mg/L, IQR 4.87-29.9) and declined only at 30 days (median 4.7 mg/L, IQR 1.83-13.1). Admission hsCRP was not associated with dyspnea improvement at 6 hours (74.1%) and 24 hours (86.2%), in-hospital death or worsening HF (n = 37; 4.7%), 30-day mortality or HF readmission (death: n = 25 [3.2%]; combined death and HF readmission: n = 95 [12.0%]), or 180-day mortality (n = 96; 12.1%). Hospital stay (median 5 days, IQR 3-7) was longer among patients with higher admission hsCRP levels (0.57 days per log2-hsCRP in adjusted models; 95% confidence interval [CI] 0.33-0.81; P < .001). Levels of hsCRP at 48-72 hours did not predict 30-day mortality or HF readmission and were only marginally associated with 180-day mortality. However, higher hsCRP at 30 days among survivors was associated with higher 180-day mortality in models including admission hsCRP (adjusted hazard ratio [HR] per log2-hsCRP: 1.23; 95% CI 1.04-1.45; P = .016). Patients with an hsCRP increase at day 30, defined as >10% increase over baseline value, had higher 180-day mortality risk compared with those with unchanged or decreased 30-day hsCRP (HR 2.29, 95% CI 1.16-4.52; P = .017)., Conclusions: Levels of hsCRP are elevated among patients with acute HF. Increasing levels at 30 days after discharge are associated with higher 180-day mortality., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: Acute decompensated heart failure (ADHF) is associated with significant morbidity and mortality but the relationship between LVEF and outcomes is unclear. We explored the association between LVEF and 30 and 180 day mortality in 7007 ADHF patients enrolled in the Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial., Methods and Results: We explored the association between LVEF and 30 and 180 day mortality in 7007 ADHF patients enrolled in the Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. LVEF was analysed both as a continuous variable and according to three categories: < 40% (LowEF), 40-50% [intermediate EF (IntEF)], and > 50% [preserved ejection fraction (PresEF)]. Of the patients in the trial, 4474 (78.7%) had LowEF, 674 (11.9%) had IntEF, and 539 (9.5%) had PresEF. The unadjusted 30 and 180 day mortality was similar for LowEF (3.7%, 12.3%), IntEF (3.4%, 13.1%), and PresEF (4.3%, 14.1%), respectively (P > 0.05). After multivariable adjustment, the hazard ratio (HR) for 180 day mortality remained similar for the LowEF [HR 0.96, 95% confidence interval (CI) 0.75-1.24; P = 0.77] and IntEF (0.91, 95% CI 0.66-1.3; P = 0.58) compared to PresEF patients. By contrast, when LVEF was evaluated as a continuous measure, it exhibited a U-shaped pattern with mortality. After matching for age and sex, the mortality risk attributed to LVEF was attenuated, as the LVEF increased as a continuous variable over 35%. However, in patients with EF < 35%, the mortality risk continue to increase as the LVEF declined., Conclusions: Among patients with ADHF, the unadjusted mortality rates are similar across LVEF strata. However, after accounting for key patient variables, the mortality risk increases as EF falls below 35%. These data will be useful in planning future studies of ADHF., Clinical Trial Registration: www.clinicaltrials.gov identifier: NCT00475852., (© 2013 The Authors. European Journal of Heart Failure © 2013 European Society of Cardiology.)

Background: Prior studies have demonstrated adverse risk associated with baseline and worsening renal function in acute heart failure, but none has modeled the trajectories of change in renal function and their impact on outcomes., Methods and Results: We used linear mixed models of serial measurements of blood urea nitrogen and creatinine to describe trajectories of renal function in 1962 patients with acute heart failure and renal dysfunction enrolled in the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function study. We assessed risk of 180-day mortality and 60-day cardiovascular or renal readmission and used Cox regression to determine association between renal trajectories and outcomes. Compared with patients alive at 180 days, patients who died were older, had lower blood pressure and ejection fraction, and higher creatinine levels at baseline. On average for the entire cohort, creatinine rose from days 1 to 3 and increased further after discharge, with the trajectory dependent on the day of discharge. Blood urea nitrogen, creatinine, and the rate of change in creatinine from baseline were the strongest independent predictors of 180-day mortality and 60-day readmission, whereas the rate of change of blood urea nitrogen from baseline was not predictive of outcomes. Baseline blood urea nitrogen>35 mg/dL and increase in creatinine>0.1 mg/dL per day increased the risk of mortality, whereas stable or decreasing creatinine was associated with reduced risk., Conclusions: Patients with acute heart failure and renal dysfunction demonstrate variable rise and fall in renal indices during and immediately after hospitalization. Risk of morbidity and mortality can be predicted based on baseline renal function and creatinine trajectory during the first 7 days., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00328692 and NCT00354458.

Background: Acute heart failure is a common reason for admission, and outcome is often poor. Improved prognostic risk stratification may assist in the design of future trials and in patient management. Using data from a large randomized trial, we explored the prognostic value of clinical variables, measured at hospital admission for acute heart failure, to determine whether a few selected variables were inferior to an extended data set., Methods and Results: The prognostic model included 37 clinical characteristics collected at baseline in PROTECT, a study comparing rolofylline and placebo in 2033 patients admitted with acute heart failure. Prespecified outcomes at 30 days were death or rehospitalization for any reason; death or rehospitalization for cardiovascular or renal reasons; and, at both 30 and 180 days, all-cause mortality. No variable had a c-index>0.70, and few had values>0.60; c-indices were lower for composite outcomes than for mortality. Blood urea was generally the strongest single predictor. Eighteen variables contributed independent prognostic information, but a reduced model using only 8 items (age, previous heart failure hospitalization, peripheral edema, systolic blood pressure, serum sodium, urea, creatinine, and albumin) performed similarly. For prediction of all-cause mortality at 180 days, the model c-index using all variables was 0.72 and for the simplified model, also 0.72., Conclusions: A few simple clinical variables measured on admission in patients with acute heart failure predict a variety of adverse outcomes with accuracy similar to more complex models. However, predictive models were of only moderate accuracy, especially for outcomes that included nonfatal events. Better methods of risk stratification are required., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00328692 and NCT00354458.

Aims: Differences in manifestation, treatment, and outcomes of acute heart failure between men and women have not been well studied. The objective of this analysis was to characterize differences in clinical presentation, and in-hospital and post-discharge outcomes between sexes in acute heart failure patients., Methods and Results: Clinical profiles, treatment characteristics, and outcomes were compared between sexes in 2033 patients hospitalized for acute heart failure and impaired renal function. Women comprised 33% of the study population and were older, had higher body mass index, LVEF, and systolic blood pressure, and a greater prevalence of diabetes. At baseline, women showed signs and symptoms of congestion comparable with men, but more often had rales, orthopnoea, and worse renal function. Women were less intensively diuresed, as indicated by lower oral and intravenous diuretic doses used, fewer dose increases, and less total weight loss during hospitalization. Furthermore, hospitalization was slightly but significantly prolonged in women (11.04 ± 7.8 vs. 10.65 ± 8.86 days; P = 0.024). Age-adjusted 180-day mortality was lower in women (15.8% vs. 18.5%, hazard ratio 0.74; 95% confidence interval 0.59-0.93, P = 0.010), but multivariable risk-adjusted mortality was similar in both sexes, mainly attributable to lower blood urea nitrogen, higher LVEF, and higher systolic blood pressure in women compared with men., Conclusions: Women with acute heart failure present with a clinical profile different from that of men, with more hypertension, diabetes, and depression, and a preserved LVEF. During hospitalization, they were less intensively diuresed. Nevertheless, risk-adjusted 180-day outcome was similar between sexes.

Despite therapeutic advances, patients with worsening heart failure (HF) requiring hospitalization have unacceptably high post-discharge mortality and re-admission rates soon after discharge. Evidence suggests a hypercoagulable state is present in patients with HF. Although thromboembolism as a direct consequence of HF is not frequently clinically recognized, it may contribute to mortality and morbidity. Additionally, many patients with HF have concomitant disorders conferring additional thrombotic risk, including atrial fibrillation (AF) and coronary artery disease (CAD). Acute coronary syndrome (ACS), a known consequence of coronary thrombosis, is a common precipitating factor for worsening HF. Coronary thrombosis may also cause sudden death in patients with HF and CAD. Because data are largely derived from observational studies or trials of modest size, guideline recommendations on anticoagulation for HF vary between organizations. The recently presented Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial of HF patients in sinus rhythm suggested anticoagulation reduces the risk of stroke, although rates of the combined primary endpoint (death, ischemic stroke, or intracerebral hemorrhage) were similar for acetylsalicylic acid and warfarin. Newer oral anticoagulants dabigatran, apixaban, and rivaroxaban have successfully completed trials for the prevention of stroke in patients with AF and have shown benefits in the subpopulation of patients with concomitant HF. Positive results of the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) trial of rivaroxaban in ACS are also encouraging. These data suggest there is a need to assess the potential role for these newer agents in the management of patients hospitalized for HF who continue to have a high post-discharge event rate despite available therapies.

Background: The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin., Methods and Results: We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier (P for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48-0.84; P=0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88-1.35; P=0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52-0.89; P=0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02-1.53; P=0.03)., Conclusions: In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included.

Background: The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) randomly assigned 7,141 participants to nesiritide or placebo. Dyspnea improvement was more often reported in the nesiritide group, but there were no differences in 30-day all-cause mortality or heart failure readmission rates. We compared medical resource use, costs, and health utilities between the treatment groups., Methods and Results: There were no significant differences in inpatient days, procedures, and emergency department visits reported for the first 30 days or for readmissions to day 180. EQ-5D health utilities and visual analog scale ratings were similar at 24 hours, discharge, and 30 days. Billing data and regression models were used to generate inpatient costs. Mean length of stay from randomization to discharge was 8.5 days in the nesiritide group and 8.6 days in the placebo group (P = .33). Cumulative mean costs at 30 days were $16,922 (SD $16,191) for nesiritide and $16,063 (SD $15,572) for placebo (P = .03). At 180 days, cumulative costs were $25,590 (SD $30,344) for nesiritide and $25,339 (SD $29,613) for placebo (P = .58)., Conclusions: The addition of nesiritide contributed to higher short-term costs and did not significantly influence medical resource use or health utilities compared with standard care alone., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Hospital readmission is an important clinical outcome of patients with heart failure. Its relation to length of stay for the initial hospitalization is not clear., Methods and Results: We used hierarchical modeling of data from a clinical trial to examine variations in length of stay across countries and across hospitals in the United States and its association with readmission within 30 days of randomization. Main outcomes included associations between country-level length of stay and readmission rates, after adjustment for patient-level case mix; and associations between length of stay and readmission rates across sites in the United States. Across 27 countries with 389 sites and 6848 patients, mean length of stay ranged from 4.9 to 14.6 days (6.1 days in the United States). Rates of all-cause readmission ranged from 2.5% to 25.0% (17.8% in the United States). There was an inverse correlation between country-level mean length of stay and readmission (r=-0.52; P<0.01). After multivariable adjustment, each additional inpatient day across countries was associated with significantly lower risk of all-cause readmission (odds ratio, 0.86; 95% confidence interval, 0.75-0.98; P=0.02) and heart failure readmission (odds ratio, 0.79; 95% confidence interval, 0.69-0.99; P=0.03). Similar trends were observed across US study sites concerning readmission for any cause (odds ratio, 0.92; 95% confidence interval, 0.85-1.00; P=0.06) and readmission for heart failure (odds ratio, 0.90; 95% confidence interval, 0.80-1.01; P=0.07). Across countries and across US sites, longer median length of stay was independently associated with lower risk of readmission., Conclusions: Countries with longer length of stay for heart failure hospitalizations had significantly lower rates of readmission within 30 days of randomization. These findings may have implications for developing strategies to prevent readmission, defining quality measures, and designing clinical trials in acute heart failure., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852.

Objectives: The study sought to investigate the clinical correlates and prognostic role of anemia and changes in hemoglobin in patients hospitalized for acute decompensated heart failure (AHF)., Background: Anemia is related to a poor outcome in patients with heart failure. In addition, an increase in hemoglobin during hospitalization might be a sign of effective decongestion and therefore related to improved outcome., Methods: This is a post hoc analysis of the PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) study in 1,969 patients with AHF and mild to moderate impaired renal function. Hemoglobin levels were measured daily for the first 4 days and at day 7. The endpoint was 180-day all-cause mortality., Results: Anemia at baseline was observed in 50.3% of the patients. During follow-up, 359 patients (18.2%) died. Hemoglobin increased in 69.1% and was associated with a better renal function at baseline and more weight loss, but was associated with a deterioration of renal function (p = 0.01), whereas total dose diuretics was lower in patients with hemoconcentration (p < 0.01). Interaction analysis showed that greater weight loss and better baseline renal function were associated with a more rapid increase in hemoglobin concentration (p < 0.01 for both). The absolute change in hemoglobin (g/dl) independently predicted outcome (hazard ratio: 0.66; 95% confidence interval: 0.51 to 0.86; p = 0.002), whereas baseline hemoglobin levels did not., Conclusions: Patients with AHF and preserved renal function are decongested better, as shown by an increase in hemoglobin. A rapid increase in hemoglobin during the first week is independently associated with a favorable outcome, despite a slight decrease in renal function., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) care takes place in multiple settings, with a variety of providers, and generally involves patients who have multiple comorbidities. This situation is a "perfect storm" of factors that predispose patients to medication errors., Methods and Results: The goals of this paper are to outline potential roles for clinical pharmacists in a multidisciplinary HF team, to document outcomes associated with interventions by clinical pharmacists, to recommend minimum training for clinical pharmacists engaged in HF care, and to suggest financial strategies to support clinical pharmacy services within a multidisciplinary team. As patients transition from inpatient to outpatient settings and between multiple caregivers, pharmacists can positively affect medication reconciliation and education, assure consistency in management that results in improvements in patient satisfaction and medication adherence, and reduce medication errors. For mechanical circulatory support and heart transplant teams, the Centers for Medicare and Medicaid Services considers the participation of a transplant pharmacology expert (e.g., clinical pharmacist) to be a requirement for accreditation, given the highly specialized and complex drug regimens used. Although reports of outcomes from pharmacist interventions have been mixed owing to differences in study design, benefits such as increased use of evidence-based therapies, decreases in HF hospitalizations and emergency department visits, and decreases in all-cause readmissions have been demonstrated. Clinical pharmacists participating in HF or heart transplant teams should have completed specialized postdoctoral training in the form of residencies and/or fellowships in cardiovascular and/or transplant pharmacotherapy, and board certification is recommended. Financial mechanisms to support pharmacist participation in the HF teams are variable., Conclusions: Positive outcomes associated with clinical pharmacist activities support the value of making this resource available to HF teams., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aims: To examine the characteristics associated with early dyspnoea relief during acute heart failure (HF) hospitalization, and its association with 30-day outcomes., Methods and Results: ASCEND-HF was a randomized trial of nesiritide vs. placebo in 7141 patients hospitalized with acute HF in which dyspnoea relief at 6 h was measured on a 7-point Likert scale. Patients were classified as having early dyspnoea relief if they experienced moderate or marked dyspnoea improvement at 6 h. We analysed the clinical characteristics, geographical variation, and outcomes (mortality, mortality/HF hospitalization, and mortality/hospitalization at 30 days) associated with early dyspnoea relief. Early dyspnoea relief occurred in 2984 patients (43%). In multivariable analyses, predictors of dyspnoea relief included older age and oedema on chest radiograph; higher systolic blood pressure, respiratory rate, and natriuretic peptide level; and lower serum blood urea nitrogen (BUN), sodium, and haemoglobin (model mean C index = 0.590). Dyspnoea relief varied markedly across countries, with patients enrolled from Central Europe having the lowest risk-adjusted likelihood of improvement. Early dyspnoea relief was associated with lower risk-adjusted 30-day mortality/HF hospitalization [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.68-0.96] and mortality/hospitalization (HR 0.85; 95% CI 0.74-0.99), but similar mortality., Conclusion: Clinical characteristics such as respiratory rate, pulmonary oedema, renal function, and natriuretic peptide levels are associated with early dyspnoea relief, and moderate or marked improvement in dyspnoea was associated with a lower risk for 30-day outcomes.

Background: This study evaluated the efficacy and safety of levosimendan, a positive inotropic drug with vasodilator effects, given intravenously to patients with acutely decompensated heart failure (ADHF)., Methods: We performed 2 sequential trials, the first to develop a new measure of efficacy in 100 patients, and the second to use this measure to evaluate levosimendan in an additional 600 patients. Patients admitted with ADHF received placebo or intravenous levosimendan for 24 h in addition to standard treatment. The primary endpoint was a composite that evaluated changes in clinical status during the first 5 days after randomization., Results: In the 600-patient trial, more levosimendan than placebo patients (58 vs. 44) were improved at all 3 pre-specified time points (6 h, 24 h, and 5 days), whereas fewer levosimendan patients (58 vs. 82) experienced clinical worsening (p = 0.015 for the difference between the groups). These differences were apparent, despite more frequent intensification of adjunctive therapy in the placebo group (79 vs. 45 patients). Improvements in patient self-assessment and declines in B-type natriuretic peptide levels with levosimendan persisted for 5 days and were associated with reduced length of stay (p = 0.009). Similar findings were present in the 100-patient pilot trial. Levosimendan was associated with more frequent hypotension and cardiac arrhythmias during the infusion period and a numerically higher risk of death across the 2 trials (49 of 350 on a regimen of levosimendan vs. 40 of 350 on a regimen of placebo at 90 days, p = 0.29)., Conclusions: In patients with ADHF, intravenous levosimendan provided rapid and durable symptomatic relief. As dosed in this trial, levosimendan was associated with an increased risk of adverse cardiovascular events. (Evaluation of Intravenous Levosimendan Efficacy in the Short Term Treatment of Decompensated Chronic Heart Failure; NCT00048425)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: There are few sex-specific outcome data in heart failure with preserved ejection fraction., Methods and Results: We assessed sex differences in baseline characteristics and outcomes among 4128 patients with heart failure with preserved ejection fraction in the Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial. Women (n=2491) with heart failure with preserved ejection fraction were ≈1 year older (72±7 years versus 71±7 years) and more likely to be obese (46% versus 35%) and have chronic kidney disease (34% versus 26%) and hypertension (91% versus 85%) than men but less likely to have an ischemic cause (19% versus 34%), atrial fibrillation (27% versus 33%), or chronic obstructive pulmonary disease (8% versus 13%) (all P<0.001). During a mean of 49.5 months, there were 881 deaths (447 in women, 434 in men; risk ratio, 0.64; 95% CI, 0.56-0.74) and 5776 hospitalizations (3239 in women, 2537 in men; risk ratio, 0.80; 95% CI, 0.76-0.84). Women had lower risk of all-cause events (deaths and hospitalizations), even after adjusting for baseline characteristics (adjusted hazards ratio, 0.81; 95% CI, 0.73-0.89). However, the sex-related difference in risk of all-cause events was modified in the presence or absence of atrial fibrillation, renal dysfunction, stable angina pectoris, or advanced New York Heart Association class symptoms., Conclusions: In patients with typical heart failure with preserved ejection fraction, there were prominent sex differences in baseline characteristics and outcomes. Women had better overall prognosis, although the presence of 4 common baseline characteristics seemed to moderate this finding.

Aims: This double-blind, randomized, parallel, placebo-controlled investigation evaluated the effects of cross-linked polyelectrolyte (CLP) on serum potassium and measures of congestion in patients with heart failure (HF) and chronic kidney disease (CKD)., Methods and Results: The primary endpoint was change in serum potassium over time. Exploratory endpoints included: weight, physician and patient assessment of exertional dyspnoea, effect on N-terminal pro brain natriuretic peptide (NT-proBNP) levels, New York Heart Association (NYHA) classification, 6 min walk test (6MWT), and quality of life by Kansas City Cardiomyopathy Questionnaire (KCCQ). Serum potassium was similar in CLP (n =59) and placebo (n =52) groups throughout the 8-week study. Weight loss was greater in the CLP than in the placebo group at Weeks 1 (P =0.014) and 2 (P =0.004), and this trend continued until the end of the study. After 8 weeks, by physician assessment, the percentage of patients experiencing marked or disabling dyspnoea tended to be lower in the CLP than in the placebo group (7.3% vs. 23.9%, P =0.128). Fewer patients in the CLP than in the placebo group had NT-proBNP levels >1000 pg/mL at Week 4 (P =0.039) and Week 8 (P =0.065). The proportion of patients improving by at least one NYHA functional class over the study was higher in the CLP than in the placebo group (48.8% vs. 17.4%; P =0.002). Effects on 6MWT at Week 8 (p =0.072) and quality of life (overall KCCQ score) at Week 4 (p =0.005) and 8 (P =0.062) all favoured the CLP cohort. Four treatment-unrelated deaths occurred in the CLP group and none in the placebo group (P =0.056)., Conclusion: In advanced, symptomatic HF with CKD, CLP is associated with beneficial clinical effects without significant serum potassium changes., Trial Registration: NCT01265524.

Aims: In patients with acute heart failure (AHF), early worsening heart failure (WHF) predicts a significant proportion of post-discharge readmissions and mortality. We aimed to identify the predictors of 7-day heart failure events or death in patients hospitalized with AHF., Methods and Results: A predictive model and risk score for the short-term primary composite endpoint of 7-day death, HF rehospitalization, or WHF was created using variables collected within 24 h of admission from patients with complete data (n = 2015) enrolled in the PROTECT trial of AHF patients. The 7-day composite was experienced by 294 patients (14.6%), with a mortality rate of 1.8% (n = 37), HF rehospitalization rate of 0.5% (n = 9), and WHF rate of 13.1% (n = 264). In multivariable analyses, the strongest predictor of short-term morbidity and mortality was higher blood urea nitrogen (BUN) concentration. Additional independent predictors of a worse outcome were lower serum albumin, cholesterol, and systolic blood pressure, as well as higher heart rate and respiratory rate. Model coefficients were converted to an additive risk score for predicting the 7-day composite endpoint with a total point range of 0-100. The risk score allowed discrimination of a wide spectrum of risk (4.8% risk with score ≤35, to 28.7% risk with score >55)., Conclusions: Using the PROTECT 7-day risk model and score, the main determinants of an adverse outcome for AHF patients included impaired metabolic status, neurohormonal activation, and reduced cardiac performance, gauged by BUN, serum albumin and cholesterol levels, systolic blood pressure, heart rate, and respiratory rate.

Background: It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm., Methods: We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause., Results: The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P=0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P=0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P=0.82)., Conclusions: Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized. (Funded by the National Institute of Neurological Disorders and Stroke; WARCEF ClinicalTrials.gov number, NCT00041938.).

Background: The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was used in a large, multinational, randomized, placebo-controlled trial to measure adverse effects of heart failure with preserved ejection fraction (HF-PEF) on patients' lives and the effects of irbesartan., Methods and Results: Patients with symptomatic HF-PEF were randomly assigned to irbesartan (up to 300 mg daily) or placebo. The MLHFQ was administered at baseline (n=3605), month 6 (n=3137), month 14 (n=2904), and the end of study (median, 56 months, n=2205). Baseline MLHFQ scores of 43±21 indicated that HF-PEF had a substantial adverse effects. Estimated retest reliability was 0.80. Baseline MLHFQ scores were associated with other measures of the severity of heart failure including symptoms, signs of congestion, cardiac structure, and time to hospitalizations or deaths attributed to heart failure. Slight improvement in shortness of breath or fatigue was associated with significant improvement in MLHFQ scores (-5.9 and -5.0, P<0.0001). Compared with placebo, further improvement in MLHFQ scores was not observed with irbesartan after 6 months (mean adjusted difference, 0.4; 95% confidence interval, -0.8 to 1.7), 14 months (0.5; 95% confidence interval, -0.9 to 1.8), or the end of study (2.0; 95% confidence interval, -4.1 to 0.01)., Conclusions: The MLHFQ scores are a reliable, valid, and sensitive measure of the adverse impact of HF-PEF on patients' lives. Irbesartan did not substantially improve MLHFQ scores during a long period of follow-up. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Background: Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes., Objective: The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure., Methods: The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days., Results: Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group., Conclusions: Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A(1)-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure.

Background: The purpose of this study was to examine the prevalence of abnormalities in cardiac structure and function present in patients with heart failure and a preserved ejection fraction (HFPEF) and to determine whether these alterations in structure and function were associated with cardiovascular morbidity and mortality., Methods and Results: The Irbesartan in HFPEF trial (I-PRESERVE) enrolled 4128 patients; echocardiographic determination of left ventricular (LV) volume, mass, left atrial (LA) size, systolic function, and diastolic function were made at baseline in 745 patients. The primary end point was death or protocol-specific cardiovascular hospitalization. A secondary end point was the composite of heart failure death or heart failure hospitalization. Associations between baseline structure and function and patient outcomes were examined using univariate and multivariable Cox proportional hazard analyses. In this substudy, LV hypertrophy or concentric remodeling was present in 59%, LA enlargement was present in 66%, and diastolic dysfunction was present in 69% of the patients. Multivariable analyses controlling for 7 clinical variables (including log N-terminal pro-B-type natriuretic peptide) indicated that increased LV mass, mass/volume ratio, and LA size were independently associated with an increased risk of both primary and heart failure events (all P<0.05)., Conclusions: Left ventricular hypertrophy or concentric remodeling, LA enlargement, and diastolic dysfunction were present in the majority of patients with HFPEF. Left ventricular mass and LA size were independently associated with an increased risk of morbidity and mortality. The presence of structural remodeling and diastolic dysfunction may be useful additions to diagnostic criteria and provide important prognostic insights in patients with HFPEF.

Background: Cardiac troponin T (cTnT) elevation is common and is a predictor of outcomes in patients with acute heart failure (AHF). The degree and progression of cTnT release during hospitalization of patients with AHF is unclear. We evaluated the incidence of cTnT release during AHF hospitalization and the relationship of cTnT release with outcomes., Methods and Results: The Placebo-controlled Randomized study of the selective A(1) adenosine receptor antagonist rolofylline for patients hospitalized with acute heart failure and volume Overload to assess Treatment Effect on Congestion and renal funcTion (PROTECT) pilot study was a multicenter, double-blind study of patients with AHF. Measurements of cTnT were collected at randomization and days 2, 3, 4, and 7. Patients were classified on the basis of their serum cTnT levels at baseline: positive (>0.03 ng/mL), detectable (>0.01 ng/mL), and negative (≤0.01 ng/mL). A detectable cTnT level developed during the study (after baseline) was classified as cTnT conversion: 288 patients were included; 172 (60%) patients had detectable cTnT levels and 97 (34%) had positive values (>0.03 ng/mL) at baseline. Of the 116 patients with negative troponin at baseline, 24 (21%) had elevated cTnT levels by day 7. On multivariable analysis, positive cTnT at baseline was an independent predictor of the composite end point of cardiovascular/renal rehospitalization or death at 60 days (hazard ratio, 1.84; 95% confidence interval, 1.04-3.26; P=0.036). Kaplan-Meier curves showed similar worse outcomes in patients with troponin conversion and positive troponin at baseline., Conclusions: There was a high prevalence of baseline cTnT elevation in this cohort; 21% of those negative at baseline converted to detectable levels by day 7. Positive troponin at baseline, and conversion to positive levels, were associated with worse outcomes at 60 days. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00328692 and NCT00354458.

Background: In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in high-risk hypertensive participants, risk of new-onset heart failure (HF) was higher in the amlodipine (2.5-10 mg/d) and lisinopril (10-40 mg/d) arms compared with the chlorthalidone (12.5-25 mg/d) arm. Similar to other studies, mortality rates following new-onset HF were very high (≥50% at 5 years), and were similar across randomized treatment arms. After the randomized phase of the trial ended in 2002, outcomes were determined from administrative databases., Methods and Results: With the use of national databases, posttrial follow-up mortality through 2006 was obtained on participants who developed new-onset HF during the randomized (in-trial) phase of ALLHAT. Mean follow-up for the entire period was 8.9 years. Of 1761 participants with incident HF in-trial, 1348 died. Post-HF all-cause mortality was similar across treatment groups, with adjusted hazard ratios (95% confidence intervals) of 0.95 (0.81-1.12) and 1.05 (0.89-1.25), respectively, for amlodipine and lisinopril compared with chlorthalidone, and 10-year adjusted rates of 86%, 87%, and 83%, respectively. All-cause mortality rates were also similar among those with reduced ejection fractions (84%) and preserved ejection fractions (81%), with no significant differences by randomized treatment arm., Conclusions: Once HF develops, risk of death is high and consistent across randomized treatment groups. Measures to prevent the development of HF, especially blood pressure control, must be a priority if mortality associated with the development of HF is to be addressed. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique identifier: NCT00000542.

Background: Older patients often receive less guideline-concordant care for heart failure than younger patients., Objective: To determine whether age differences in heart failure care are explained by patient, provider, and health system characteristics and/or by chart-documented reasons for non-adherence to guidelines., Design and Patients: Retrospective cohort study of 2,772 ambulatory veterans with heart failure and left ventricular ejection fraction <40% from a 2004 nationwide medical record review program (the VA External Peer Review Program)., Main Measures: Ambulatory use of ACE inhibitors, angiotensin receptor blockers (ARBs), and beta blockers., Results: Among 2,772 patients, mean age was 73 +/- 10 years, 87% received an ACE inhibitor or ARB, and 82% received a beta blocker. When patients with explicit chart-documented reasons for not receiving these drugs were excluded, 95% received an ACE inhibitor or ARB and 89% received a beta blocker. In multivariable analyses controlling for a variety of patient and health system characteristics, the adjusted odds ratio for ACE-inhibitor and ARB use was 0.43 (95% CI 0.24-0.78) for patients age 80 and over vs. those age 50-64 years, and the adjusted odds ratio for beta blocker use was 0.66 (95% CI 0.48-0.93) between the two age groups. The magnitude of these associations was similar but not statistically significant after excluding patients with chart-documented reasons for not prescribing ACE inhibitors or ARBs and beta blockers., Conclusions: A high proportion of veterans receive guideline-recommended medications for heart failure. Older veterans are consistently less likely to receive these drugs, although these differences were no longer significant when accounting for patients with chart-documented reasons for not prescribing these drugs. Closely evaluating reasons for non-prescribing in older adults is essential to assessing whether non-treatment represents good clinical judgment or missed opportunities to improve care.

Background: Heart failure with preserved ejection fraction (HFPEF) is a common and increasing public health problem. Myocardial fibrosis is a key pathological feature of HFPEF. Peripheral collagen markers may reflect this excess fibrosis; however, the relation of these markers to prognosis in patients with HFPEF has not as yet been determined., Methods and Results: This substudy of the Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) trial measured plasma levels of procollagen type I amino-terminal peptide, procollagen type III amino-terminal peptide, and osteopontin in 334 patients with HFPEF. Measurements were performed at baseline and 6 months after randomization to placebo or irbesartan 300 mg/day. The relation of baseline collagen markers to the I-PRESERVE primary end point (all-cause death and hospitalization for prespecified cardiovascular causes) was evaluated by single and multivariable analysis. Similar evaluations were performed for all-cause death alone as well as heart failure events (death or hospitalization because of heart failure). Increased plasma levels of collagen markers at baseline were associated with increased frequency of the study primary end point for all collagen markers. For each 10-μg/L increase in procollagen type I amino-terminal peptide, the hazard ratio (HR) for the primary end point was 1.09 (95% CI, 1.052 to 1.13; P<0.0001); for each 10-μg/L increase in procollagen type III amino-terminal peptide procollagen type I amino-terminal peptide, the HR was 2.47 (95% CI, 0.97 to 6.33; P=0.059); and for each 10-nmol/L increase in osteopontin, the HR was 1.084 (95% CI, 1.026 to 1.15; P=0.004). No variable remained significant as an independent predictor when introduced into a multivariable model. Both treatment groups tended to reduce collagen markers, with the reduction significantly greater for placebo versus irbesartan for procollagen type III amino-terminal peptide only (P=0.0185)., Conclusions: Increased peripheral collagen turnover markers were not independently associated with increased mortality and cardiovascular hospitalization in an HFPEF population on multivariable analysis but were associated on single-variable analysis. These findings provide some support to the hypothesis that pathological fibrosis in the heart, and possibly the peripheral vasculature, may be contributory to adverse clinical outcomes in patients with HFPEF., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Background: Plasma concentrations of natriuretic peptides (NPs) are associated with morbidity and mortality in patients with systolic heart failure (HF). However, the role of NP as a prognostic marker in patients with HF and preserved ejection fraction (HFpEF) has not been studied in a large cohort of well-characterized patients. Moreover, it is unclear whether treatments have a differential effect on morbidity and mortality across the spectrum of NP levels., Methods and Results: N-terminal pro-brain natriuretic peptide (NT-proBNP) was measured at baseline in 3480 patients in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Trial). In a multivariable Cox regression model, NT-proBNP above the median of 339 pg/mL was independently associated with an increased risk of the primary end point of all-cause mortality and prespecified cardiovascular hospitalizations (adjusted hazard ratio [HR], 1.79; 95% CI, 1.56 to 2.10; P<0.001); all-cause mortality (adjusted HR, 2.04; 95% CI, 1.68 to 2.47; P<0.001); and a composite of HF events, including death due to worsening HF or sudden death or hospitalization due to worsening HF (adjusted HR, 1.77; 95% CI, 1.43 to 2.20; P<0.001). There were significant interactions between the effect of irbesartan and median split of baseline NT-proBNP for the primary outcome (P=0.005), all-cause mortality (P=0.05), and the HF composite outcome (P<0.001). Use of irbesartan was associated with improved outcomes in patients with NT-proBNP below, but not above, the median. After adjusting for 20 baseline covariates, irbesartan still had a beneficial effect on the primary outcome (HR, 0.74; 95% CI, 0.60 to 90; P=0.003), all-cause mortality (HR, 0.75; 95% CI, 0.56 to 0.99; P=0.046), and HF composite outcome (HR, 0.57; 95% CI, 0.41 to 0.80; P=0.001) in patients with NT-proBNP below the median., Conclusions: The unexpected benefit of irbesartan in lower-risk patients with HFpEF in this post hoc analysis may indicate effects on early, but not later, high-risk stages of the disease. These findings question the strategy of using elevated plasma concentrations of NP as a patient selection criterion in HFpEF trials. More studies are needed to support or contest this practice. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Objectives: This study sought to assess the effects of rolofylline on renal function in patients with acute heart failure (AHF) and renal dysfunction randomized in PROTECT (Placebo-Controlled Randomized Study of the Selective A(1) Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function)., Background: Small studies have indicated that adenosine A(1) receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF., Methods: A total of 2,033 patients with AHF, volume overload, estimated creatinine clearance between 20 and 80 ml/min, and elevated natriuretic peptide levels were randomized (2:1) within 24 h of hospital presentation to rolofylline 30 mg/day or intravenous placebo for up to 3 days. Creatinine was measured daily until discharge or day 7 and on day 14. Persistent worsening renal function was defined as an increase in serum creatinine ≥0.3 mg/dl at both days 7 and 14, or initiation of hemofiltration or dialysis or death by day 7., Results: At baseline, mean ± SD estimated creatinine clearance was 51.0 ± 20.5 ml/min in the placebo group and 50.4 ± 20.0 ml/min in the rolofylline group. Changes in creatinine and estimated creatinine clearance were similar between placebo- and rolofylline-treated patients during hospitalization and at day 14. After 4 days, mean body weight was reduced by 2.6 and 3.0 kg in placebo and rolofylline patients, respectively (p = 0.005). Persistent worsening renal function occurred in 13.7% of the placebo group and 15.0% of the rolofylline group (odds ratio vs. placebo: 1.11 [95% confidence interval: 0.85 to 1.46]; p = 0.44)., Conclusions: In this large, phase III clinical trial, the adenosine A(1) receptor antagonist rolofylline did not prevent persistent worsening renal function in AHF patients with volume overload and renal dysfunction. (A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function [PROTECT-1], NCT00328692; and [PROTECT-2], NCT00354458)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Obesity is a major risk factor for incident heart failure (HF). Paradoxically, in HF with reduced left ventricular ejection fraction (HFREF), a high body mass index (BMI) appears to be beneficial. Approximately 50% of HF patients have a preserved left ventricular ejection fraction (HFPEF). However, there are few data regarding the relationship between BMI and outcomes in HFPEF., Methods and Results: Baseline characteristics and cardiovascular outcomes were assessed in the 4109 patients (mean age, 72 years; mean follow-up, 49.5 months) in the Irbesartan in HF with Preserved Ejection Fraction (I-PRESERVE) trial. Based on the BMI distribution, 5 BMI categories were defined: <23.5, 23.5 to 26.4, 26.5 to 30.9, 31 to 34.9, and ≥35 kg/m(2). Most patients (71%) had a BMI ≥26.5, 21% had a BMI between 23.5 and 26.4, and 8% had a BMI <23.5 kg/m(2). Patients with higher BMI were younger, more often women, and more likely to have hypertension and diabetes and higher left ventricular ejection fraction. Patients with BMI of 26.5 to 30.9 kg/m(2) had the lowest rate for the primary composite outcome (death or cardiovascular hospitalization) and were used as reference group. After adjustment for 21 risk variables including age, sex, and N-terminal pro-brain natriuretic peptide, the hazard ratio for the primary outcome was increased in patients with BMI <23.5 (hazard ratio, 1.27; 95% confidence interval, 1.04 to 1.56; P=0.019) and in those with BMI ≥35 kg/m(2) (hazard ratio, 1.27; 95% confidence interval, 1.06 to 1.52; P=0.011) compared with the referent group. A similar relationship was found for all-cause mortality and for HF hospitalization., Conclusions: Obesity is common in HFPEF patients and is accompanied by multiple differences in clinical characteristics. Independent of other key prognostic variables, there was a U-shaped relationship, with the greatest rate of adverse outcomes in the lowest and highest BMI categories., Clinical Trial Registration- Url: http://www.clinicaltrials.gov. Unique identifier: NCT000095238.

Objectives: There have been no published recommendations about staffing needs for a heart failure (HF) clinic or an office setting focused on heart transplant. The goal of this survey was to understand the current staffing environment of HF, transplant, and mechanical circulatory support device (MCSD) programs in the United States and abroad. This report identifies current staffing patterns but does not endorse a particular staffing model., Methods: An online survey, jointly sponsored by the American College of Cardiology Foundation (ACCF), American Heart Association (AHA), and the Heart Failure Society of America (HFSA), was sent to the members of all 3 organizations who had identified themselves as interested in HF, heart transplant, or both, between March 12, 2009, and May 12, 2009., Results: The overall response rate to the 1,823 e-mail surveys was 23%. There were 257 unique practices in the United States (81% of total sites) and 58 international sites (19%); approximately 30% of centers were in a cardiovascular group practice and 30% in a medical school hospital setting. The large majority of practices delivered HF care in both an inpatient and outpatient environment, and slightly more centers were implanting MCSDs (47%) than performing cardiac transplantation (39%). Most practices (43%) were small, with <4 staff members, or small- to medium-sized (34%), with 4 to 10 staff members, with only 23% being medium (11-20 staff) or large programs (>20 staff). On average, a U.S. HF practice cared for 1,641 outpatients annually. An average HF program with transplant performed 10 transplants. Although larger programs were able to perform more transplants and see more outpatient HF visits, their clinician staffing volume tended to double for approximately every 500 to 700 additional HF visits annually. The average staffing utilization was 2.65 physician full-time equivalents (FTEs), 2.21 nonphysician practitioner (nurse practitioner or physician assistant) FTEs, and 2.61 nurse coordinator FTEs annually., Conclusions: The HF patient population is growing in number in the United States and internationally, and the clinicians who provide the highly skilled and time-consuming care to this population are under intense scrutiny as a result of focused quality improvement initiatives and reduced financial resources. Staffing guidelines should be developed to ensure that an adequate number of qualified professionals are hired for a given practice volume. These survey results are an initial step in developing such standards., (Copyright © 2011. Published by Elsevier Inc.)

Background: The determinants of prognosis in patients with heart failure and preserved ejection fraction (HF-PEF) are poorly documented., Methods and Results: We evaluated data from 4128 patients in the I-PRESERVE trial (Irbesartan in Heart Failure with Preserved Ejection Fraction Study). Multivariable Cox regression models were developed using 58 baseline demographic, clinical, and biological variables to model the primary outcome of all-cause mortality or cardiovascular hospitalization (1505 events), all-cause mortality (881 events), and HF death or hospitalization (716 events). Log N-terminal pro-B-type natriuretic peptide, age, diabetes mellitus, and previous hospitalization for HF were the most powerful factors associated with the primary outcome and with the HF composite. For all-cause mortality, log N-terminal pro-B-type natriuretic peptide, age, diabetes mellitus, and left ventricular EF were the strongest independent factors. Other independent factors associated with poor outcome included quality of life, a history of chronic obstructive lung disease, log neutrophil count, heart rate, and estimated glomerular filtration rate. The models accurately stratified the actual 3-year rate of outcomes from 8.1% to 59.9% (primary outcome) 2.7% to 36.5% (all-cause mortality), and 2.1% to 38.9% (HF composite) for the lowest to highest septiles of predicted risks., Conclusions: In a large sample of elderly patients with HF and preserved EF enrolled in I-Preserve, simple clinical, demographic, and biological variables were associated with outcome and identified subgroups at very high and very low risk of events.

Guidelines have rather quickly assumed a central role in health care delivery in the U.S. They have become the foundation on which performance measures are built and, therefore, a major player in assessing the quality of care provided by individuals and institutions, the ramifications of which involve reputation, reimbursement, and litigation. We are concerned, however, that in our enthusiasm for collectively endorsing these guidelines, we are marginalizing the importance of physician judgment and inadvertently risking the conversion of guidelines into "cookbooks." We believe that this editorial, while unequivocally acknowledging the fundamental importance of guidelines, simultaneously provides a critically important perspective on the potential for misuse of both guidelines and performance measures. Further, we hope that publication of this commentary will help temper enthusiasm for overzealous conversion of guidelines into performance measures, thereby restoring the vital role of physician judgment and insight into patient management.

Guidelines have rather quickly assumed a central role in health care delivery in the U.S. They have become the foundation on which performance measures are built and, therefore, a major player in assessing the quality of care provided by individuals and institutions, the ramifications of which involve reputation, reimbursement, and litigation. We are concerned, however, that in our enthusiasm for collectively endorsing these guidelines, we are marginalizing the importance of physician judgment and inadvertently risking the conversion of guidelines into "cookbooks." We believe that this viewpoint, while unequivocally acknowledging the fundamental importance of guidelines, simultaneously provides a critically important perspective on the potential for misuse of both guidelines and performance measures. Further, we hope that publication of this viewpoint will help temper enthusiasm for overzealous conversion of guidelines into performance measures, thereby restoring the vital role of physician judgment and insight into patient management., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The direct effects of adenosine A1 receptor antagonists on haemodynamic parameters in patients with acute heart failure (HF) remain largely unknown., Methods and Results: We evaluated the haemodynamic effects of the AA(1)RA rolofylline in 59 HF patients with concomitant renal impairment (estimated creatinine clearance 20-80 mL/min). Placebo or rolofylline 30 mg was administered as a 4 h infusion followed by intravenous (i.v.) loop diuretic administration. Haemodynamic measurements were carried out hourly up to 8 h post-dosing by pulmonary artery catheterization. Urine output, fractional excretion of sodium, potassium, urea, and uric acid, and blood urea nitrogen (BUN) and creatinine levels were also measured. In both groups, the changes from baseline in all haemodynamic indices except mean pulmonary artery pressure (PAP) were not clinically significant. Mean [95% confidence interval (CI)] PAP showed a placebo-adjusted decrease with rolofylline of -1.5 (-4.1, 1.1)mmHg at Hour 4 and -3.5 mmHg (95% CI: -6.2, -0.2) at Hour 8. There was a significant increase with rolofylline in diuresis [placebo-corrected mean (95% CI) change of 68 (20, 116)mL/h at Hour 2-4 and 103 (21, 185)mL/h at Hour 4-8] and in fractional excretion of sodium, potassium, and uric acid. Placebo-corrected changes in plasma levels of creatinine and BUN with rolofylline were non-significant., Conclusion: Single administration of rolofylline in patients with HF and impaired renal function produced a slight decrease in mean PAP and consistently increased diuresis and natriuresis without compromising renal function, both before and after administration of i.v. loop diuretics.

Background: Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure., Methods: We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient's clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes., Results: Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists., Conclusions: Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.).

This paper details the substance and recommendations arising from a meeting convened by the National Heart, Lung, and Blood Institute in August 2009, to assess the challenges and opportunities of emergency department management of acute heart failure syndrome (AHFS). The assembled faculty represented a large cross section of medical professionals spanning the medical management continuum of patients presenting with acute heart failure and included heart failure cardiologists, emergency physicians, laboratory medicine specialists, nurses, and bench scientists. Their recommendations include proposals regarding the design and conduct of emergency department-based clinical trials, suggestions regarding the development of improved methods for early detection and monitoring of AHFS, and potential needs for expanding translational and applied AHFS focused research and biotechnology. We anticipate that this review will serve as a starting point for future investigations across the spectrum of funding sources., (Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)