Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the ENABLE Trials.

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.

Abnormal liver function tests in acute heart failure: relationship with clinical characteristics and outcome in the PROTECT study.

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.

Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure.

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.).

Patient journey after admission for acute heart failure: length of stay, 30-day readmission and 90-day mortality.

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.

The Aliskiren Trial to Minimize OutcomeS in Patients with HEart failure trial (ATMOSPHERE): revised statistical analysis plan and baseline characteristics.

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.

Characterization of subgroups of heart failure patients with preserved ejection fraction with possible implications for prognosis and treatment response.

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.

Facilitation of a Multihospital Community of Practice to Increase Enrollment in the Hospital to Home National Quality Improvement Initiative.

BACKGROUND: Hospital to Home (H2H) is a national quality improvement (QI) initiative composed of three recommended hospital interventions to improve the transition of care for hospitalized patients with heart disease. A study was conducted to determine if enrollment of Department of Veterans Affairs (VA) hospitals in H2H and adoption of the recommended interventions would both increase following facilitation of an existing Heart Failure (HF) provider-based community of practice (COP) within the VA health care system. The VA HF COP includes more than 800 VA providers and other VA staff from VA inpatient medical centers. METHODS: In 2010, 122 VA hospitals were randomized to facilitation using the VA HF COP (intervention) or no facilitation (control). COP members from intervention hospitals were invited to periodic teleconferences promoting H2H and received multiple e-mails asking members to report interest and then progress in H2H implementation. RESULTS: Among the 61 hospitals randomized to HF COP facilitation, 33 (54%) enrolled in H2H, compared with 6 (10%) of 61 control hospitals (p<.001) at five months after randomization. Of 38 intervention hospitals responding to the follow-up survey, 13 stated they had initiated 22 QI projects as a result of the H2H campaign. Another 7 hospitals had planned H2H projects. Of 20 control hospitals that responded, 5 had initiated 9 projects as a result of H2H, and no additional hospitals had plans to do so. CONCLUSIONS: Facilitation using the VA HF COP was successful in increasing enrollment in the H2H initiative and providing implementation support for recommended QI projects. Multihospital provider groups are a potentially valuable tool for implementation of national QI campaigns.

Worsening Heart Failure Following Admission for Acute Heart Failure: A Pooled Analysis of the PROTECT and RELAX-AHF Studies.

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.

The Hospitalization Burden and Post-Hospitalization Mortality Risk in Heart Failure With Preserved Ejection Fraction: Results From the I-PRESERVE Trial (Irbesartan in Heart Failure and Preserved Ejection Fraction).

OBJECTIVES: The aim of this study was to investigate prognosis in patients with heart failure (HF) with preserved ejection fraction and the causes of hospitalization and post-hospitalization mortality. BACKGROUND: Although hospitalizations in patients with HF with preserved ejection fraction are common, there are limited data from clinical trials on the causes of admission and the influence of hospitalizations on subsequent mortality risk. METHODS: Patients (n = 4,128) with New York Heart Association functional class II to IV HF and left ventricular ejection fractions >45% were enrolled in I-PRESERVE (Irbesartan in Heart Failure and Preserved Ejection Fraction). A blinded events committee adjudicated cardiovascular hospitalizations and all deaths using predefined and standardized definitions. The risk for death after HF, any-cause, or non-HF hospitalization was assessed using time-dependent Cox proportional hazard models. RESULTS: A total of 2,278 patients had 5,863 hospitalizations during the 49 months of follow-up, of which 3,585 (61%) were recurrent hospitalizations. For any-cause hospitalizations, 26.5% of patients died during follow-up, with an incident mortality rate of 11.1 deaths per 100 patient-years (PYs) and an adjusted hazard ratio of 5.32 (95% confidence interval: 4.21 to 6.23). Overall, 53.6% of hospitalizations were classified as cardiovascular and 43.7% as noncardiovascular, with 2.7% not classifiable. HF was the largest single cause of initial (17.6%) and overall (21.1%) hospitalizations, although, after HF hospitalization, a substantially higher proportion of readmissions were due to primary HF causes (40%). HF hospitalization occurred in 685 patients, with 41% deaths during follow-up, an incident mortality rate of 19.3 deaths per 100 PYs. The adjusted hazard ratio was 2.93 (95% confidence interval: 2.40 to 3.57) relative to patients who were not hospitalized for HF and was greater in those with longer durations of hospitalization. There were 1,593 patients with only non-HF hospitalizations, 21% of whom died during follow-up, with an incident mortality rate of 8.7 deaths per 100 PYs and an adjusted hazard ratio of 4.25 (95% confidence interval: 3.27 to 5.32). The risk for death was highest in the first 30 days and declined over time for all hospitalization categories. Patients not hospitalized for HF or for any cause had observed incident mortality rates of 3.8 and 1.3 deaths per 100 PYs, respectively. CONCLUSIONS: In I-PRESERVE, HFpEF patients hospitalized for any reason, and especially for HF, were at high risk for subsequent death, particularly early. The findings support the need for careful attention in the post-discharge time period including attention to comorbid conditions. Among those hospitalized for HF, the high mortality rate and increased proportion of readmissions due to HF (highest during the first 30 days), suggest that this group would be an appropriate target for investigation of new interventions.

Acute heart failure in elderly patients: worse outcomes and differential utility of standard prognostic variables. Insights from the PROTECT trial.

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.

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.

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.

A prediction model for sudden cardiac death in patients with heart failure and preserved ejection fraction.

AIMS: Sudden cardiac death (SCD) accounts for ∼ 25% of all deaths in heart failure with preserved ejection fraction (HFpEF). However, strategies to identify HFpEF patients at a higher risk of SCD have not been developed. METHODS AND RESULTS: We studied 4128 patients with HFpEF enrolled in the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial. All SCDs were adjudicated by a clinical endpoint committee. Cumulative incidences of SCD were estimated counting other deaths as competing risks. Cox regression analysis was used to generate a risk model for SCD. During a mean follow-up of 4.1 years, 231 (5.6%) patients died suddenly and 650 (15.7%) died non-suddenly. A multivariable model in 3480 patients including age, gender, history of diabetes and myocardial infarction, LBBB on ECG, and the natural logarithm of NT-proBNP identified a subgroup of 837 (24%) patients with ≥10% cumulative incidence of SCD over 5 years, accounting for other deaths as competing risk (Harrell's C index 0.75). The 5-year cumulative incidences of SCD in the higher and lower risk groups were 11% and 4%, respectively. In the higher risk group, 32% of deaths were SCD compared with 26% in the entire I-PRESERVE cohort. CONCLUSIONS: A multivariable prediction model identified patients with HFpEF who have a ≥10% risk of SCD over 5 years, similar to the risk of SCD in the Sudden Cardiac Death in Heart Failure (SCD-Heft) trial. This model may be useful for selecting patients with HFpEF for SCD prevention trials.

History of atrial fibrillation as a risk factor in patients with heart failure and preserved ejection fraction.

BACKGROUND: Atrial fibrillation (AFib) is common in heart failure (HF) with preserved ejection fraction (HFpEF). Current AFib stroke risk prediction models include the presence of HF but do not specifically include HFpEF as a risk factor. Whether a history of AFib should be used to identify patients with HFpEF who are at risk has not been established. METHODS AND RESULTS: Baseline characteristics and outcomes of patients with HFpEF in the Irbesartan in Heart Failure with Preserved Ejection Fraction Trial were analyzed in relation to AFib. At baseline, 1209 (29.3%) had a history of AFib. Of these 557 (13.5%) had history of AFib alone, whereas 670 (16.2%) had both a history and AFib on ECG; 2901 (70.3%) had neither. There were no significant differences in the risk of stroke between the 2 groups with a history of AFib who did or did not have AFib present on baseline ECG. During a median follow-up of 53 months, a fatal or nonfatal stroke occurred in 6.5% (79/1209) patients with history of AFib compared with 3.9% (114/2901) with no AFib. Having a history of AFib was independently associated with higher risk of stroke (hazard ratio, 2.2; 95% confidence interval, 1.6-3.2; P<0.0001) compared with those with no history of AFib. CONCLUSIONS: In patients with HFpEF, a history of AFib was common and independently associated with increased risk of stroke, regardless of whether AFib was present on ECG. Patients with HFpEF and a history of AFib should be considered at risk. Further studies are needed to determine whether this risk can be safely reduced. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT000095238.

Relationship between heart rate and mortality and morbidity in the irbesartan patients with heart failure and preserved systolic function trial (I-Preserve).

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.

International differences in clinical characteristics, management, and outcomes in acute heart failure patients: better short-term outcomes in patients enrolled in Eastern Europe and Russia in the PROTECT trial.

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.

Depression and outcome among veterans with implantable cardioverter defibrillators with or without cardiac resynchronization therapy capability.

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.

High-sensitivity C-reactive protein in acute heart failure: insights from the ASCEND-HF trial.

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.

The relationship between left ventricular ejection fraction and mortality in patients with acute heart failure: insights from the ASCEND-HF Trial.

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.

Predictors of postdischarge outcomes from information acquired shortly after admission for acute heart failure: a report from 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 (PROTECT) Study.

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.

Renal function trajectories and clinical outcomes in acute heart failure.

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.