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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.)

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: 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.)

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.)

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.

Background: N-terminal B type natriuretic peptide (NT-proBNP) is usually elevated in heart failure (HF) patients with reduced ejection fraction (EF). Less is known about NT-proBNP in HF with preserved EF (HF-PEF). We measured baseline NT-proBNP in 3562 HF-PEF enrolled patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial., Methods and Results: Patients with EF >or=45%, age >or=60 years, and either New York Heart Association (NYHA) II-IV symptoms with HF hospitalization (HFH) within 6 months or NYHA III-IV symptoms with corroborative evidence of HF or structural changes associated with HF-PEF. NT-proBNP (pg/mL) measured centrally using the Elecsys proBNP assay (Roche). Mean age 72 +/- 7 years, 60% were women, the investigator indicated HF etiology was hypertension in 64%; the majority were in NYHA III. Medications included diuretics in 82%, angiotensin-converting enzyme inhibitor in 26%, beta-blocker in 59%, and spironolactone in 15%. Median NT-proBNP was 341 pg/mL (interquartile range 135 to 974 pg/mL) and geometric mean was 354 pg/mL. In multivariate analysis, the baseline characteristics most strongly associated with higher NT-proBNP levels were atrial fibrillation (ratio of geometric mean 2.59, P < .001), NYHA IV symptoms (1.52, P < .001), lower estimated glomerular filtration rate (1.44, P < .001), and HFH hospitalization within 6 months (1.37, P < .001)., Conclusions: Most HF-PEF patients have elevated NT-proBNP levels. The NT-proBNP concentrations were related to baseline characteristics generally associated with worse outcomes for HF patients., (Copyright 2010. Published by Elsevier Inc.)

Background: Current treatment for acute decompensated heart failure (ADHF) is associated with incomplete resolution of symptoms and signs, recurrent symptoms of heart failure in-hospital and after discharge and high mortality. Studies have consistently demonstrated an association between worsening renal function in ADHF and adverse outcomes. Adenosine A(1) receptor antagonists, such as rolofylline, appear in preliminary studies to produce potentially beneficial effects on natriuresis, diuresis, renal blood flow, and glomerular filtration rate. In a previous dose-finding study, rolofylline 30 mg intravenously daily for 3 days was associated with symptom improvement, less worsening of renal function, and trends toward lower 60-day rates of death or readmission for cardiovascular or renal causes., Methods and Results: This manuscript describes the rationale underlying the design of the phase 3 PROTECT (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) trial., Conclusion: Rolofylline 30 mg or matching placebo was given intravenously as a 4-hour continuous infusion on 3 consecutive days and the hospital course was assessed by measurements dyspnea, clinical status, renal function, and subsequent morbidity and mortality in a large population of patients with ADHF with renal impairment.

Background: The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial revealed no significant differences among 1587 symptomatic heart failure patients randomized to warfarin, clopidogrel, or aspirin in time to all-cause death, nonfatal myocardial infarction, or nonfatal stroke. We compared within-trial medical resource use and costs between treatments., Methods and Results: We assigned country-specific costs to medical resources incurred during follow-up. Annualized rates of hospitalizations, inpatient and outpatient procedures, and emergency department visits did not differ significantly between groups. Annualized total costs averaged $5901 (95% confidence interval [CI], $4776-$7520) for the aspirin group, $5646 (95% CI, $4903-$6584) for the clopidogrel group, and $5830 (95% CI, $4838-$7400) for the warfarin group., Conclusions: Consistent with clinical findings, our analyses did not identify significant cost differences between treatments.

Background: Rolofylline, an adenosine A(1) receptor antagonist, facilitates diuresis and preserves renal function in patients with acute heart failure (AHF) with renal impairment. Although not powered around any specific hypothesis, this pilot study was designed to identify an efficacious dose while refining inclusion criteria and end points., Methods: A total of 301 patients hospitalized for AHF with an estimated creatinine clearance of 20 to 80 mL/min and elevated natriuretic peptide levels were enrolled within 24 hours of presentation to placebo or rolofylline 10, 20, or 30 mg administered as 4-hour infusions for 3 days in addition to intravenously administered loop diuretics. Post hoc analyses for end points chosen for subsequent Phase III studies were performed., Results: Compared with placebo, rolofylline produced trends toward greater proportions of patients with marked or moderately improved dyspnea and fewer patients with worsening heart failure or renal function. Serum creatinine increased in patients receiving placebo and remained stable or tended to decrease in those receiving rolofylline. On day 14 the absolute differences between placebo and rolofylline for change in creatinine increased with increasing rolofylline dose, reflecting the lesser increase in creatinine in rolofylline-treated patients (r = -0.12, P = .030). Treatment with 30 mg, the dose selected for the pivotal trials, was associated with a trend toward reduced 60-day mortality or readmission for cardiovascular or renal cause (hazard ratio, 0.55; 95% confidence interval, 0.28-1.04)., Conclusion: These results demonstrate that adenosine A(1) receptor blockade with rolofylline can prevent renal impairment in patients with AHF and may positively affect acute symptoms and 60-day outcome. A 2000-patient trial of this agent is now under way.

Background: Although 40% to 50% of patients with chronic heart failure (HF) have relatively preserved systolic function (PSF), few trials have been conducted in this population and treatment guidelines do not include evidence-based recommendations., Methods and Results: The Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) is enrolling 4100 subjects with HF-PSF to evaluate whether 300 mg irbesartan is superior to placebo in reducing mortality and prespecified categories of cardiovascular hospitalizations. The principal inclusion criteria are age > or =60 years, heart failure symptoms, an ejection fraction > or =45%, and either hospitalization for heart failure within 6 months or corroborative evidence of heart failure or the substrate for diastolic heart failure. Additional secondary end points include cardiovascular mortality, cause-specific mortality and morbidity, change in New York Heart Association functional class, quality of life, and N-terminal pro-BNP measurements. Follow-up will continue until 1440 patients experience a primary end point. Substudies will evaluate changes in echocardiographic measurements and serum collagen markers., Conclusion: I-PRESERVE is the largest trial in this understudied area and will provide crucial information on the characteristics and course of the syndrome, as well as the efficacy of the angiotensin receptor blocker irbesartan.

Silent cerebral infarction in heart failure as reported by Siachos et al is significantly higher than reports of symptomatic cerebral infarction. Are we underestimating the occurrence of silent cerebral infarction, or can this finding be accounted for by concomitant conditions?

Background: Endothelin receptor antagonism produces favorable short-term hemodynamic effects in heart failure, but the clinical effects of longer term therapy have not been evaluated., Methods and Results: Three hundred and seventy patients with symptoms of heart failure at rest or on minimal exertion and a left ventricular ejection fraction <35% were randomly assigned (double-blind) to placebo (n = 126) or the endothelin receptor antagonist bosentan, titrated slowly (n = 121) or rapidly (n = 123) to a target dose of 500 mg twice daily. Treatment with the study drug was to be maintained for 26 weeks, whereas background medications for heart failure were kept constant. Safety concerns led to early termination of the trial when only 174 patients had had an opportunity to complete 26 weeks of therapy. Bosentan exerted no apparent benefit when all randomized patients were analyzed (P = .709). However, in the first 174 patients who were recruited at least 26 weeks before study termination and who could therefore be followed for the planned duration of the trial, patients in the bosentan groups were more likely to be improved (26% versus 19%) and were less likely to be worse (28% versus 43%), P = .045. When compared with placebo-treated patients, bosentan-treated patients had a increased risk of heart failure during the first month of treatment but a decreased risk of heart failure during the fourth, fifth, and sixth months of therapy. The major noncardiac adverse effects of bosentan included an increase in hepatic transaminases (in 15.6% of patients) and a decrease in hemoglobin (of about 1 g/L)., Conclusion: Although bosentan exerted no favorable effects in the overall study, our findings suggest that the clinical responses to endothelin antagonism with bosentan in patients with severe chronic heart failure may be dependent on the duration of treatment.

Background: Decompensated heart failure (HF) is among the most common indications for hospitalization in the United States, but little is known about features on admission that predict adverse events. We used data from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study to develop a model that would predict outcomes in patients with decompensated HF., Methods and Results: OPTIME-CHF randomized 949 patients hospitalized with decompensated HF for 48 to 72 hours of infusion of either milrinone or placebo. We used multivariable modeling to evaluate variables on admission that would be predictive of 60-day mortality or the composite of death or rehospitalization at 60 days. Variables at presentation that predicted death at 60 days were increased age, lower systolic blood pressure, New York Heart Association class IV symptoms, elevated blood urea nitrogen (BUN), and decreased sodium. Predictors of the composite of death or rehospitalization within 60 days were the number of HF hospitalizations in the preceding 12 months, elevated BUN, lower systolic blood pressure, decreased hemoglobin, and a history of percutaneous coronary intervention (PCI). The discriminatory power of the model was substantial for the mortality model (c-index .77) but less for the composite endpoint (c-index .69)., Conclusions: Risk stratification of patients with decompensated HF may be accomplished using easily assessed clinical variables. Further research into the validity of this model in independent samples will potentially aid in the development of risk stratification strategies.

Background: The role of anticoagulation in patients with chronic heart failure has long been an area of interest and controversy. Traditionally the goal of anticoagulation has been to prevent embolic events, but recent trials also demonstrated that oral anticoagulation also prevents vascular events in patients with prior myocardial infarction, who constitute the majority of heart failure patients. Although antiplatelet agents also reduce postinfarction vascular events, few data are available in heart failure patients, and some evidence suggests that aspirin may also have the potential to worsen heart failure morbidity and mortality, possibly by interfering with the effects of angiotensin-converting enzyme inhibitors. Methods and results The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial was undertaken to determine the optimal antithrombotic agent for heart failure patients. WATCH was a prospective-randomized trial in which symptomatic heart failure patients in sinus rhythm with ejection fractions < or =35% taking angiotensin-converting enzyme inhibitors (unless not tolerated) and diuretics were randomized to open-label warfarin (target International Normalized Ratio 2.5-3.0) or double-blind antiplatelet therapy with aspirin 162 mg or clopidogrel 75 mg. Two primary comparisons were specified: anticoagulation with warfarin versus antiplatelet therapy with aspirin and antiplatelet therapy with clopidogrel versus antiplatelet therapy with aspirin. The primary outcome is the composite of death from all causes, nonfatal myocardial infarction, and nonfatal stroke analyzed as time to first event using the intent-to-treat approach. The secondary endpoint was the broader composite of death from all causes, nonfatal myocardial infarction, non-fatal stroke, and hospitalizations for worsening heart failure, unstable angina pectoris, and systemic or pulmonary artery embolic events. Additional prespecified analyses include heart failure events, coronary events, and resource utilization., Conclusions: Although the trial was designed to enter 4500 patients, it was terminated 18 months prematurely in June 2003 by the VA Cooperative Study Program because of poor enrollment with a resulting reduction of its power to achieve its original objective. This manuscript describes the study rationale, protocol design, and the baseline characteristics of the 1587 patients who were entered into the study. The WATCH trial will help define the optimal approach to antithrombotic therapy in the contemporary management of patients with chronic heart failure resulting from left ventricular systolic dysfunction.

Background: Recent large randomized, controlled trials (BEST [Beta-blocker Evaluation of Survival Trial], CIBIS-II [Cardiac Insufficiency Bisoprolol Trial II], COPERNICUS [Carvedilol Prospective Randomized Cumulative Survival Study], and MERIT-HF [Metoprolol Randomized Intervention Trial in Congestive Heart Failure]) have addressed the usefulness of beta-blockade in the treatment of advanced heart failure. CIBIS-II, COPERNICUS, and MERIT-HF have shown that beta-blocker treatment with bisoprolol, carvedilol, and metoprolol XL, respectively, reduce mortality in advanced heart failure patients, whereas BEST found a statistically nonsignificant trend toward reduced mortality with bucindolol. We conducted a post hoc analysis to determine whether the response to beta-blockade in BEST could be related to differences in the clinical and demographic characteristics of the study populations. We generated a sample from BEST to resemble the patient cohorts studied in CIBIS-II and MERIT-HF to find out whether the response to beta-blocker therapy was similar to that reported in the other trials. These findings are further compared with COPERNICUS, which entered patients with more severe heart failure., Methods: To achieve conformity with the entry criteria for CIBIS-II and MERIT-HF, the BEST study population was adjusted to exclude patients with systolic blood pressure <100 mm Hg, heart rate <60 bpm, and age >80 years (exclusion criteria employed in those trials). The BEST comparison subgroup (BCG) was further modified to more closely reflect the racial demographics reported for patients enrolled in CIBIS-II and MERIT-HF. The association of beta-blocker therapy with overall survival and survival free of cardiac death, sudden cardiac death, and progressive pump failure in the BCG was assessed., Results: In the BCG subgroup, bucindolol treatment was associated with significantly lower risk of death from all causes (hazard ratio (HR)=0.77 [95% CI=0.65, 0.92]), cardiovascular death (HR=0.71 [0.58, 0.86]), sudden death (HR=0.77 [0.59, 0.999]), and pump failure death (HR=0.64 [0.45, 0.91])., Conclusions: Although not excluding the possibility of differences resulting from chance alone or to different properties among beta-blockers, this study suggests the possibility that different heart failure population subgroups may have different responses to beta-blocker therapy.

Hospitals may not support programs that improve the quality of care delivered to heart failure patients because these programs lower readmission rates and empty beds, and therefore further diminish already-declining revenues. A conflict between the highest quality of care and financial solvency does not serve the interests of patients, physicians, hospitals, or payers. In principle, resolution of this conflict is simple: reimbursement systems should reward higher quality care. In practice, resolving the conflict is not simple. A recent roundtable discussion sponsored by the Heart Failure Society of America identified 4 major challenges to the design and implementation of reimbursement schemes that promote higher quality care for heart failure: defining quality, accounting for differences in disease severity, crafting novel payment mechanisms, and overcoming professional parochialism. This article describes each of these challenges in turn.

Objectives: The risks and benefits of beta-blockade with bucindolol were assessed in heart failure (HF) patients with Class IV symptoms within the Beta-blocker Evaluation of Survival Trial (BEST)., Background: beta-blockade is accepted therapy for mild to moderate HF, but its safety and efficacy in advanced HF have not been established., Methods: BEST recruited 2708 HF patients; of these, 226 with Class IV symptoms (n=114 randomized to bucindolol, n=112 to placebo) formed the basis of this study. All-cause death, HF hospitalization, and drug discontinuations occurring early during therapy (< or =6 months) and overall during follow-up were assessed. Compared with Class III, Class IV patients were older and had higher plasma norepinephrine levels, prevalence of coronary disease, S3 gallops, and lower ejection fractions, but characteristics of the 2 Class IV treatment groups were similar., Results: During a mean of 1.6 years, 49% Class IV patients died, and 54% were hospitalized for HF. Bucindolol increased the combined endpoint of death or HF hospitalization within the first 6 months (hazard ratio [HR]=1.7, 95% confidence interval [CI]=1.1-2.7) and did not result in benefit overall (HR=1.2, 95% CI=0.9-1.6). HF hospitalization alone within 6 months was increased by bucindolol (HR=1.7), and an early adverse trend for death was seen (HR=1.6) with no benefit overall (HR=1.1). Bucindolol was discontinued more frequently than placebo for worsening HF (11% versus 4%) and hypotension (3% versus 0%)., Conclusions: Class IV HF patients in BEST were at high risk. Bucindolol did not reduce death or HF hospitalization and was associated with early hazard.

Background: Worsening renal function in patients hospitalized for heart failure portends a poor prognosis. However, criteria used to define worsening renal function are arbitrary, and the implications of different definitions remain unclear. We therefore compared the prognostic importance of various definitions of worsening renal function in 1,002 patients hospitalized for congestive heart failure (CHF)., Methods and Results: The patient population was 49% female, aged 67 +/- 15 years. Twenty-three percent had a prior history of renal failure, 73% had known depressed ejection fraction, and 63% had known CHF. On admission to the hospital, 47% were receiving ACE inhibitors, 22% beta-blockers, 70% diuretics and 6% NAID's. 72% developed increased serum creatinine during the hospitalization, with 20% developing an increase of > or = 0.5 mg/dL. Worsening renal function predicted both in-hospital mortality and length of stay > 10 days. Even an increased creatinine of 0.1 mg/dL was associated with worse outcome. Sensitivity for death decreased from 92% to 65% as the threshold for increased creatinine was raised from 0.1 to 0.5 mg/dL, with specificity increasing from 28% to 81%. At a threshold of a 0.3 mg/dL increase, sensitivity was 81% and specificity was 62% for death and 64% and 65% for length of stay >10 days. Adding a requirement of final creatinine of > or = 1.5 mg/dL improved specificity., Conclusions: This analysis demonstrates that any detectable decrease in renal function is associated with increased mortality and prolonged hospital stay. This suggests that therapeutic interventions which improve renal function might be beneficial.