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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.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.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.URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00328692 and NCT00354458. [ABSTRACT FROM AUTHOR]

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.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.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.URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00328692 and NCT00354458. [ABSTRACT FROM AUTHOR]

Background: Contrast left ventriculography is a method of measuring left ventricular function usually performed at the discretion of the invasive cardiologist during cardiac catheterization. We sought to determine variation in the use of left ventriculography in the Veterans Affairs (VA) Health Care System. Methods and Results: We identified adult patients who underwent cardiac catheterization including coronary angiography between 2000 and 2009 in the VA Health Care System. We determined patient and hospital predictors of the use of left ventriculography as well as the variation in use across VA facilities. Results were validated using data from the VA's Clinical Assessment, Reporting, and Tracking (CART) program. Of 457 170 cardiac catheterization procedures among 336 853 patients, left ventriculography was performed on 263 695 (58%) patients. Use of left ventriculography decreased over time (64% in 2000 to 50% in 2009) and varied markedly across facilities (<1->95% of cardiac catheterizations). Patient factors explained little of the large variation in use between facilities. When the cohort was restricted to those with an echocardiogram in the prior 30 days and no intervening event, left ventriculography was still performed in 50% of cases. Conclusions: There is large variation in the use of left ventriculography across VA facilities that is not explained by patient characteristics. [ABSTRACT FROM AUTHOR]

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.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).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.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938. [ABSTRACT FROM AUTHOR]

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.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.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.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852. [ABSTRACT FROM AUTHOR]

There are few sex-specific outcome data in heart failure with preserved ejection fraction.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.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.URL: http://www.clinicaltrials.gov. Unique identifier: NCT000095238. [ABSTRACT FROM AUTHOR]

The article assesses effects of Irbesartan on heart failure (HF) with preserved ejection fraction (PEF) as measured by Minnesota Living with Heart Failure Questionnaire in the Irbesartan in HF with Preserved Systolic Function (I-PRESERVE) trial. It is noted that MLHFQ is a measure of HF as indicated by adverse effects on patients' lives used in clinical trials of HF with reduced ejection. Results showed that Irbesartan did not substantially improve MLHFQ scores over long follow-up period.

The article discusses a study on the effects of cardiac troponin T (cTnT) release on outcomes in patients with acute heart failure (AHF). The patients involved in the study were randomized to receive intravenous rolofylline or placebo. Multivariable analysis revealed that positive cTnT at baseline served as an independent predictor of the composite end point of cardiovascular or renal rehospitalization or mortality at 60 days. The cohort group showed a high prevalence of cTnT elevation.

The article focuses on the benefits of irbesartan in the management of patients with heart failure and preserved ejection fraction. I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Trial) patients' N-terminal pro-brain natriuretic peptide was measured by the authors for their study. They discovered that significant interaction was seen between irbesartan's effect and median split of baseline NT-proBNP, all-cause mortality and the heart failure composite outcome.

The article explores the role of peripheral collagen markers to heart failure and preserved ejection fraction patients' death and hospitalization. The authors focused on the plasma levels of procollagen type I amino-terminal peptide, procollagen type III amino-terminal peptide and osteopontin of Irbesartan in Heart Failure With Preserved Systolic Function participants. They conclude that increased mortality and hospitalization was not caused by increased peripheral collagen turnover markers.

The article presents a survey conducted to understand the current staffing environment of heart failure (HF), transplant, and mechanical circulatory support device (MCSD) programs in the U.S. and abroad. The study involved an online survey for members of the 3 participating American heart organizations who professed interest in HF, heart transplant or both, and was done from March 12 to May 12, 2009. Results revealed that the HF patient population is growing both in the U.S. and abroad and that an adequate number of qualified professionals are needed.

The article presents a study that determined whether a relationship exists between body mass index (BMI) and outcomes in preserved left ventricular ejection fraction (HFPEF). The study involved 4109 patients in the Irbesartan in Heart Failure (HF) with Preserved Ejection Fraction (I-PRESERVE) trial. Results revealed that there was a U-shaped relationship with the greatest rate of adverse outcomes in the lowest and highest BMI categories, independent of other key prognostic variables.

The article presents a study which aimed to determine the factors that affect the prognosis of patients with heart failure and preserved ejection fraction (HF-PEF), as these determinants are poorly documented. They evaluated the data from the I-PRESERVE trial (Irbesartan in HF-PEF Study). Their results for a large sample of elderly patients with HF-PEF revealed simple clinical, demographic, and biological variables associated with prognosis severity. Very high and very low risk subgroups were also identified.

The article focuses on the development of pharmacological therapies for the treatment of acute heart failure syndromes (AHFS). It discusses various factors attributed to therapy failure including patient heterogeneity, lack of pathophysiological understanding and flaws in the designs of AHFS studies. It also mentions that Phase III studies on drug efficacy should consider all risk boundaries. Moreover, it notes that therapy standardization requires cooperation within the scientific community.

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.

Background: The mode of death has been well characterized in patients with heart failure and a reduced ejection fraction; however, less is known about the mode of death in patients with heart failure and a preserved ejection fraction (HFPEF). The purpose of this study was to examine the mode of death in patients with HFPEF enrolled in the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial and to determine whether irbesartan altered the distribution of mode of death in HFPEF., Methods and Results: All deaths were reviewed by a clinical end-point committee, and the mode of death was assigned by consensus of the members. The annual mortality rate was 5.2% in the I-Preserve trial. There were no significant differences in mortality rate between the placebo and irbesartan groups. The mode of death was cardiovascular in 60% (including 26% sudden, 14% heart failure, 5% myocardial infarction, and 9% stroke), noncardiovascular in 30%, and unknown in 10%. There were no differences in the distribution of mode-specific mortality rates between placebo and irbesartan., Conclusions: Sixty percent of the deaths in patients with HFPEF were cardiovascular, with sudden death and heart failure death being the most common. Treatment with irbesartan did not affect overall mortality or the distribution of mode-specific mortality rates., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Background: Chronic heart failure remains a major cause of mortality and morbidity. The role of antithrombotic therapy in patients with chronic heart failure has long been debated. The objective of this study was to determine the optimal antithrombotic agent for heart failure patients with reduced ejection fractions who are in sinus rhythm., Methods and Results: This prospective, randomized clinical trial of open-label warfarin (target international normalized ratio of 2.5 to 3.0) and double-blind treatment with either aspirin (162 mg once daily) or clopidogrel (75 mg once daily) had a 30-month enrollment period and a minimum of 12 months of treatment. We enrolled 1587 men and women >/=18 years of age with symptomatic heart failure for at least 3 months who were in sinus rhythm and had left ventricular ejection fraction of

The National Heart, Lung, and Blood Institute convened an expert panel April 28 to 29, 2008, to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiological, and clinical literature about AF and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: (1) enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; (2) improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; (3) improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural, and electrical remodeling markers; (4) develop additional animal models reflective of the pathophysiology of human AF; (5) conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and (6) conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.

Background: Heart failure (HF) developing in hypertensive patients may occur with preserved or reduced left ventricular ejection fraction (PEF [>or=50%] or REF [<50%]). In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 42 418 high-risk hypertensive patients were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin, providing an opportunity to compare these treatments with regard to occurrence of hospitalized HFPEF or HFREF., Methods and Results: HF diagnostic criteria were prespecified in the ALLHAT protocol. EF estimated by contrast ventriculography, echocardiography, or radionuclide study was available in 910 of 1367 patients (66.6%) with hospitalized events meeting ALLHAT criteria. Cox regression models adjusted for baseline characteristics were used to examine treatment differences for HF (overall and by PEF and REF). HF case fatality rates were examined. Of those with EF data, 44.4% had HFPEF and 55.6% had HFREF. Chlorthalidone reduced the risk of HFPEF compared with amlodipine, lisinopril, or doxazosin; the hazard ratios were 0.69 (95% confidence interval [CI], 0.53 to 0.91; P=0.009), 0.74 (95% CI, 0.56 to 0.97; P=0.032), and 0.53 (95% CI, 0.38 to 0.73; P<0.001), respectively. Chlorthalidone reduced the risk of HFREF compared with amlodipine or doxazosin; the hazard ratios were 0.74 (95% CI, 0.59 to 0.94; P=0.013) and 0.61 (95% CI, 0.47 to 0.79; P<0.001), respectively. Chlorthalidone was similar to lisinopril with regard to incidence of HFREF (hazard ratio, 1.07; 95% CI, 0.82 to 1.40; P=0.596). After HF onset, death occurred in 29.2% of participants (chlorthalidone/amlodipine/lisinopril) with new-onset HFPEF versus 41.9% in those with HFREF (P<0.001; median follow-up, 1.74 years); and in the chlorthalidone/doxazosin comparison that was terminated early, 20.0% of HFPEF and 26.0% of HFREF patients died (P=0.185; median follow-up, 1.55 years)., Conclusions: In ALLHAT, with adjudicated outcomes, chlorthalidone significantly reduced the occurrence of new-onset hospitalized HFPEF and HFREF compared with amlodipine and doxazosin. Chlorthalidone also reduced the incidence of new-onset HFPEF compared with lisinopril. Among high-risk hypertensive men and women, HFPEF has a better prognosis than HFREF.

Background: Admission measures of renal function (blood urea nitrogen [BUN], estimated glomerular filtration rate [eGFR]) in patients hospitalized for worsening heart failure are predictors of in-hospital outcomes. Less is known about the changes and relationships among these variables and the postdischarge survival rate., Methods and Results: In a retrospective analysis of 949 patients from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure, we investigated the relation between admission values and changes in BUN and eGFR and rate of death by 60 days after discharge. On admission, median eGFR was 51 mL min(-1) 1.73 m(-2) (interquartile range, 37 to 70 mL min(-1) 1.73 m(-2)), and BUN was 25 mg/dL (interquartile range, 17 to 41 mg/dL). On average, there was a 1.1-mL min(-1) 1.73 m(-2) decrease in eGFR and a 4.7-mg/dL increase in BUN from admission to discharge. By discharge, 12% of patients had a >25% decrease in eGFR, and 39% had a >25% increase in BUN. Although both lower admission eGFR and higher admission BUN were associated with higher risk of death by 60 days after discharge, multivariable-adjusted Cox proportional-hazards analysis showed that BUN was a stronger predictor of death by 60 days than was eGFR (chi(2), 11.6 and 0.6 for BUN and eGFR, respectively). Independently of admission values, an increase of >or=10 mg/dL in BUN during hospitalization was associated with worse 60-day survival rate: BUN (per 5-mg/dL increase) had a hazard ratio of 1.08 (95% CI, 1.01 to 1.16). Although milrinone treatment led to a minor improvement in renal function by discharge, the 60-day death and readmission rates were similar between the milrinone and placebo groups., Conclusions: A substantial number of patients admitted with heart failure have worsening renal function during hospitalization. Higher admission BUN and increasing BUN during hospitalization, independently of admission values, are associated with a worse survival rate. Use of milrinone in these high-risk patients does not improve outcomes despite minor improvements in the renal function.

Background: Patients with American College of Cardiology/American Heart Association stage C/D heart failure experience substantial morbidity and mortality, but available interventions beyond standard medical and device therapies are limited. Nesiritide relieves dyspnea and reduces pulmonary congestion, but its risk profile is uncertain. Pilot data suggested a potential benefit of nesiritide given as serial outpatient infusions., Methods and Results: The Second Follow-Up Serial Infusions of Nesiritide (FUSION II) trial was a randomized, double-blind, placebo-controlled trial of outpatient serial nesiritide infusions for patients with American College of Cardiology/American Heart Association stage C/D heart failure. Patients with 2 recent heart failure hospitalizations, ejection fraction <40%, and New York Heart Association class IV symptoms, or New York Heart Association class III symptoms with creatinine clearance <60 mL/min, were randomized to nesiritide (2-microg/kg bolus plus 0.01-microg/kg-per-minute infusion for 4 to 6 hours) or matching placebo, once or twice weekly for 12 weeks. All patients were treated to optimal goals with evidence-based medical/device therapy facilitated by careful disease management during the study. The primary end point was time to all-cause death or cardiovascular or renal hospitalization at 12 weeks. A total of 911 patients were randomized and treated. The primary end point occurred in 36.8% and 36.7% of the placebo and nesiritide groups, respectively (hazard ratio, 1.03; 95% confidence interval, 0.82 to 1.3; log-rank test P=0.79). There were no statistically significant differences between groups in any of the secondary end points, including the number of cardiovascular or renal hospitalizations, the number of days alive and out of the hospital, change in Kansas City Cardiomyopathy Questionnaire score, or cardiovascular death. Adverse events were similar between groups; nesiritide was associated with more hypotension but less predefined worsening renal function., Conclusions: Serial outpatient nesiritide infusions do not provide a demonstrable clinical benefit over intensive outpatient management of patients with advanced American College of Cardiology/American Heart Association stage C/D heart failure.

Background: Substantial evidence suggests that anemia is an independent risk factor for worse outcomes in patients with heart failure (HF). The Study of Anemia in Heart Failure Trial (STAMINA-HeFT) is the largest multicenter, randomized, double-blind, placebo-controlled trial to date evaluating the effect of treating anemia in HF., Methods and Results: Patients (N=319) with symptomatic HF, left ventricular ejection fraction < or = 40%, and hemoglobin > or = 9.0 g/dL and < or = 12.5 g/dL were randomized (double-blind) to placebo (N=157) or darbepoetin alfa (N=162) subcutaneously every 2 weeks for 1 year (target hemoglobin, 14.0+/-1.0 g/dL). The primary end point was change from baseline to week 27 in treadmill exercise time. Secondary end points were change from baseline in New York Heart Association class and quality of life at week 27. An additional prespecified efficacy analysis included the time to death by any cause or first HF-related hospitalization by 1 year. At baseline, the median (interquartile range) hemoglobin was 11.4 (10.9, 12.0) g/dL. At week 27, darbepoetin alfa treatment increased median (interquartile range) hemoglobin by 1.8 (1.1, 2.5) g/dL (placebo, 0.3 [-0.2, 1.0] g/dL; P<0.001). Of the patients treated with darbepoetin alfa, 85% achieved 2 consecutive hemoglobin levels of 14.0+/-1.0 g/dL during the study and experienced a hemoglobin increase of > or = 1.0 g/dL from baseline. By intent-to-treat analysis, darbepoetin alfa treatment did not significantly improve exercise duration, New York Heart Association class, or quality of life score compared with placebo. A nonsignificant trend was observed toward a lower risk of all-cause mortality or first HF hospitalization in darbepoetin alfa-treated patients compared with placebo (hazard ratio, 0.68; 95% CI, 0.43, 1.08; P=0.10). Occurrences of adverse events were similar in both treatment groups., Conclusions: In this study of patients with symptomatic HF and anemia, treatment with darbepoetin alfa was not associated with significant clinical benefits. Darbepoetin alfa treatment was well tolerated and effectively raised hemoglobin. A trend of lower risk of morbidity and mortality was observed.

Background: Previous studies have associated reduced hemoglobin levels with increased adverse events in heart failure. It is unclear, however, whether this relation is explained by underlying kidney disease, treatment differences, or associated comorbidity., Methods and Results: We examined the associations between hemoglobin level, kidney function, and risks of death and hospitalization in persons with chronic heart failure between 1996 and 2002 within a large, integrated, healthcare delivery system in northern California. Longitudinal outpatient hemoglobin and creatinine levels and clinical and treatment characteristics were obtained from health plan records. Glomerular filtration rate (GFR; mL.min(-1).1.73 m(-2)) was estimated from the Modification of Diet in Renal Disease equation. Mortality data were obtained from state death files; heart failure admissions were identified by primary discharge diagnoses. Among 59,772 adults with heart failure, the mean age was 72 years and 46% were women. Compared with that for hemoglobin levels of 13.0 to 13.9 g/dL, the multivariable-adjusted risk of death increased with lower hemoglobin levels: an adjusted hazard ratio (HR) of 1.16 and 95% confidence interval (CI) of 1.11 to 1.21 for hemoglobin levels of 12.0 to 12.9 g/dL; HR, 1.50 and 95% CI, 1.44 to 1.57 for 11.0 to 11.9 g/dL; HR, 1.89 and 95% CI, 1.80 to 1.98 for 10.0 to 10.9; HR, 2.31 and 95% CI, 2.18 to 2.45 for 9.0 to 9.9; and HR, 3.48 and 95% CI, 3.25 to 3.73 for <9.0 g/dL. Hemoglobin levels > or = 17.0 g/dL were associated with an increased risk of death (adjusted HR, 1.42; 95% CI, 1.24 to 1.63). Compared with those with a GFR > or = 60 mL . min(-1).1.73 m(-2), persons with a GFR <45 mL.min(-1).1.73 m(-2) had an increased mortality risk: adjusted HR, 1.39 and 95% CI, 1.34 to 1.44 for 30 to 44; HR, 2.28 and 95% CI, 2.19 to 2.39 for 15 to 29; HR, 3.26 and 95% CI, 3.05 to 3.49 for <15; and HR, 2.44 and 95% CI, 2.28 to 2.61 for those on dialysis. Relations were similar for the risk of hospitalization. The findings did not differ among patients with preserved or reduced systolic function, and hemoglobin level was an independent predictor of outcomes at all levels of kidney function., Conclusions: Very high (> or = 17 g/dL) or reduced (<13 g/dL) hemoglobin levels and chronic kidney disease independently predict substantially increased risks of death and hospitalization in heart failure, regardless of the level of systolic function. Randomized trials are needed to evaluate whether raising hemoglobin levels can improve outcomes in chronic heart failure.

Background: The dissemination of clinical practice guidelines often has not been accompanied by desired improvements in guideline adherence. This study evaluated interventions for implementing a new practice guideline advocating the use of beta-blockers for heart failure patients., Methods and Results: This was a randomized controlled trial involving heart failure patients (n=169) with an ejection fraction < or =45% and no contraindications to beta-blockers. Patients' primary providers were randomized in a stratified design to 1 of 3 interventions: (1) control: provider education; (2) provider and patient notification: computerized provider reminders and patient letters advocating beta-blockers; and (3) nurse facilitator: supervised nurse to initiate and titrate beta-blockers. The primary outcome, the proportion of patients who were initiated or uptitrated and maintained on beta-blockers, analyzed by intention to treat, was achieved in 67% (36 of 54) of patients in the nurse facilitator group compared with 16% (10 of 64) in the provider/patient notification and 27% (14 of 51) in the control groups (P<0.001 for the comparisons between the nurse facilitator group and both other groups). The proportion of patients on target beta-blocker doses at the study end (median follow-up, 12 months) was also highest in the nurse facilitator group (43%) compared with the control (10%) and provider/patient notification groups (2%) (P<0.001). There were no differences in adverse events among groups., Conclusions: The use of a nurse facilitator was a successful approach for implementing a beta-blocker guideline in heart failure patients. The use of provider education, clinical reminders, and patient education was of limited value in this setting.