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Journal of Cardiac Failure Vol. 19 No. 6 2013 Consensus Statement Acute Decompensated Heart Failure: Update on New and Emerging Evidence and Directions for Future Research MICHAEL M. GIVERTZ, MD,1 JOHN R. TEERLINK, MD,2 NANCY M. ALBERT, RN, PhD,3 CHERYL A. WESTLAKE CANARY, RN, PhD,5 SEAN P. COLLINS, MD, MSc,6 MONICA COLVIN-ADAMS, MD,7 JUSTIN A. EZEKOWITZ, MD,8 JAMES C. FANG, MD,9 ADRIAN F. HERNANDEZ, MD,10 STUART D. KATZ, MD,11 RAJAN KRISHNAMANI, MD,12 WENDY GATTIS STOUGH, PharmD,13 MARY N. WALSH, MD,14 JAVED BUTLER, MD,15 PETER E. CARSON, MD,16 JOHN P. DIMARCO, MD, PhD,17 RAY E. HERSHBERGER, MD,18 JOSEPH G. ROGERS, MD,10 JOHN A. SPERTUS, MD, MPH,19 WILLIAM G. STEVENSON, MD,1 NANCY K. SWEITZER, MD, PhD,20 W.H. WILSON TANG, MD,4 AND RANDALL C. STARLING, MD, MPH4 Boston, Massachusetts; San Francisco, California; Cleveland, Ohio; Azusa, California; Nashville, Tennessee; Minneapolis, Minnesota; Edmonton, Alberta, Canada; Cleveland, Ohio; Durham, North Carolina; New York, New York; Middletown, Ohio; Buies Creek, North Carolina; Indianapolis, Indiana; Atlanta, Georgia; Washington, DC; Charlottesville, Virginia; Columbus, Ohio; Kansas City, Missouri; and Madison, Wisconsin ABSTRACT Acute decompensated heart failure (ADHF) is a complex clinical event associated with excess morbidity and mortality. Managing ADHF patients is challenging because of the lack of effective treatments that both reduce symptoms and improve clinical outcomes. Existing guideline recommendations are largely based on expert opinion, but several recently published trials have yielded important data to inform both current clinical practice and future research directions. New insight has been gained regarding volume management, including dosing strategies for intravenous loop diuretics and the role of ultrafiltration in patients with heart failure and renal dysfunction. Although the largest ADHF trial to date (ASCENDHF, using nesiritide) was neutral, promising results with other investigational agents have been reported. If these findings are confirmed in phase III trials, novel compounds, such as relaxin, omecamtiv mecarbil, and ularitide, among others, may become therapeutic options. Translation of research findings into quality clinical care can not be overemphasized. Although many gaps in knowledge exist, ongoing studies will address issues around delivery of evidence-based care to achieve the goal of improving the health status and clinical outcomes of patients with ADHF. (J Cardiac Fail 2013;19:371e389) Key Words: Heart failure, clinical trials, diuretics, vasodilators, biomarkers, quality of care, ultrafiltration. 16 From the 1Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; 2Department of Medicine, University of California San Francisco, San Francisco, California; 3Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio; 4 Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio; 5School of Nursing, Azusa Pacific University, Azusa, California; 6 Department of Emergency Medicine, Vanderbilt University, Nashville, Tennessee; 7Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota; 8Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada; 9Division of Cardiovascular Medicine, Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio; 10Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; 11 Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York; 12Advanced Cardiovascular Institute, Middletown, Ohio; 13Department of Clinical Research, Campbell University College of Pharmacy and Health Sciences, Buies Creek, North Carolina; 14The Care Group, Indianapolis, Indiana; 15Division of Cardiology, Department of Medicine, Emory University, Atlanta, Georgia; Georgetown University and Washington DC Veterans Affairs Medical Center, Washington, DC; 17University of Virginia Health System, Charlottesville, Virginia; 18Ohio State University, Columbus, Ohio; 19St. Luke’s Mid America Heart Institute, University of MissourieKansas City, Kansas City, Missouri and 20Department of Medicine, University of Wisconsin, Madison, Wisconsin. Manuscript received April 16, 2013; revised manuscript accepted April 17, 2013. Reprint requests: Michael M. Givertz, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. Tel: 617-732-7367; Fax: 617-264-5265. E-mail: [email protected] This paper was reviewed and approved on March 19, 2013 by the Heart Failure Society of America Executive Council, whose members are listed in the Acknowledgment. See page 384 for disclosure information. 1071-9164/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2013.04.002 371 372 Journal of Cardiac Failure Vol. 19 No. 6 June 2013 Heart failure is a complex syndrome that involves both acute and chronic processes. Acute heart failure has various presentations. It can be characterized by rapidly developing symptoms of new-onset or de novo heart failure, or it can be a gradual worsening of chronic heart failure culminating in acute decompensated heart failure (ADHF), sometimes referred to as ‘‘acute on chronic’’ heart failure. Many different terms have been used in the literature to describe this syndrome, including acute heart failure, acute heart failure syndromes, and ADHF.1 The latter term will be used for this report. Despite ongoing and intense efforts, clinical trials have not yielded therapeutic strategies that improve outcomes in the ADHF population. Many factors may contribute to inadequate trial results, including the heterogeneity of the condition, the likelihood that multiple triggers or pathophysiologic processes exist and differ among individual patients, the timing of patient enrollment, and inherent challenges such as obtaining informed consent and conducting clinical trials in patients who are acutely symptomatic and may have high adverse event rates. As a result, there are limited data to guide patient management. Of the 44 recommendations relevant to ADHF in the 2010 Heart Failure Society of America (HFSA) heart failure guidelines, 3 were supported by strength of evidence A, 8 by strength of evidence B, and 33 by strength of evidence C.2 Similarly, in the American College of Cardiology/ American Heart Association 2009 heart failure guidelines, only 1 of 25 recommendations related to ADHF was a class I, level of evidence A recommendation.3 Despite the paucity of evidence, practicing clinicians routinely seek guidance on the management of patients with ADHF. Since the publication of the 2010 HFSA heart failure guidelines, several trials in ADHF have yielded new data. Although these studies advance knowledge and inform clinical decision making, their results do not warrant a complete revision of the guidelines. The purpose of the present paper is to review new data generated in the broad ADHF population involving therapeutic drugs or strategies, biomarkers, and quality of care initiatives. This paper also highlights gaps in the current evidence base for the diagnosis, prognosis, risk stratification, management and monitoring of ADHF. Future research efforts should focus on these high-priority areas of unmet needs. This paper does not address the management of heart failure in the setting of shock, specific precipitants (eg, acute myocardial infarction or atrial fibrillation), early management with bilevel positive airway pressure, or other agents not approved for use in the United States (eg, levosimendan). Readers interested in these topics should refer to the 2010 HFSA guidelines for further information.2 Epidemiology More than 1 million hospitalizations for heart failure occur annually in the USA.4,5 Heart failure remains a primary cause of hospitalization among older Americans. An analysis from the Centers for Medicare and Medicaid Services (CMS) revealed a risk-adjusted heart failure hospitalization rate of w2,000 per 100,000 person-years among Medicare beneficiaries based on 2008 data.6 A decline in the relative rate of hospitalization from 1998 to 2008 was detected in that study, which the authors primarily attributed to a reduction in the number of unique individuals hospitalized for heart failure rather than to a reduction in repeated hospitalizations. Unfortunately, heart failure is a progressive disease in most patients, and although some therapies slow or reverse progression, only cardiac transplantation is curative for patients with irreversible causes. The prevalence of heart failure is expected to increase in the USA over the next 20 years.7 Moreover, the risk of hospitalization tends to increase as heart failure progresses, and ADHF admissions increase the risk of subsequent readmission and death. If the expected increase actually occurs, the burden of heart failure hospitalization will continue to place a major strain on health care resources. Clinicians, hospital administrators, and patients now have access to CMS publicly reported ‘‘quality metrics’’ for ADHF, including 30-day mortality and readmission rates (www.cms.gov/Medicare/ Quality-Initiatives-Patient-Assessment-Instruments/Hospital QualityInits/OutcomeMeasures.html). It remains hotly debated whether the ideal end points have been defined for ADHF clinical trials and quality metrics.8 Event rates were lower than predicted in the Acute Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial,9 revealing that emerging therapies must have large treatment effects for an ADHF trial to have the power to detect a mortality benefit (even with O5,000 patients enrolled). Therefore, the process to develop new therapies from small mechanistic trials to large outcome trials will be prolonged and expensive. Patient Characteristics In general, patients hospitalized for ADHF are elderly, approximately one-half are women, and 25% are nonwhite.10 The majority (88% in the OPTIMIZE [Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure] registry)11 have a history of chronic heart failure rather than a de novo presentation. These patients typically have multiple comorbidities and moderately elevated systolic blood pressure, and approximately one-half have heart failure with preserved ejection fraction (HF-PEF).10 The majority of patients present with evidence of congestion or volume overload.10,12 Increases in body weight are associated with heart failure hospitalization and begin at least a week before presentation.13 Cardiogenic shock during the initial presentation to the emergency department (ED) is very rare.14,15 ADHF is a heterogeneous syndrome, and more focus on presenting characteristics may allow for better-targeted therapies. Clinical characteristics have been proposed to subcategorize patients with ADHF based on parameters such as blood pressure, degree of congestion, time course Update on Acute Decompensated Heart Failure of symptoms, presence of cardiogenic shock, or concomitant factors, such as acute coronary syndrome or renal dysfunction.16 In recent trials, patients were selected on the basis of 1 or more subcategories, such that the known or expected pharmacologic actions of the drug were matched to patient characteristics.17,18 Patients with ADHF present in a variety of settings, and the initial patient assessment and management may differ depending on the presenting location. Patients may develop acute symptoms in the home environment, prompting the use of emergency medical services (EMS) personnel as first responders, or they may present directly to the ED. Patients routinely managed in heart failure clinics may contact the heart failure clinical team to notify them of worsening symptoms. The decision can be made to bring patients in for urgent clinic evaluations and potential treatment on an outpatient basis depending on the severity of symptoms. In this scenario, an ambulatory center or observation unit may be used for administration of intravenous diuretics and laboratory monitoring. As health care reimbursement models change and Accountable Care Organizations and patient-centered medical home models emerge, a shift toward initial management of patients with ADHF in outpatient clinics or observation units is likely to occur, particularly in the USA.19,20 Recent data show that subclinical changes in intracardiac pressures and thoracic impedance occur days before patients generally seek medical attention owing to escalating symptoms (typically dyspnea or volume overload).21e23 Therefore, the typical patient with chronic heart failure presenting with symptoms that require hospitalization most likely has experienced subclinical changes for days, weeks, or even months. It is anticipated that future treatment strategies will include therapies triggered by monitoring devices even before symptoms occur. Clinical Outcomes Episodes of ADHF are associated with significant shortand long-term morbidity and mortality. In the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trials, patients hospitalized for heart failure had a 3-fold greater risk for all-cause mortality compared with patients who did not have a heart failure hospitalization after adjustment for known baseline predictors of death.24 The in-hospital mortality reported in major registries ranges from 4% to 12%, and it may increase to 20%e25% in high-risk subgroups.10,12,14,25e27 It has not been determined whether the association between an ADHF event and poor prognosis is related to an underlying detrimental process that occurs during the episode, as evidenced by myocardial necrosis, inflammation, or marked neurohormonal activation, or if ADHF is a marker of progressive disease. ADHF episodes are frequent and costly, and they negatively affect overall health status and quality of life. Givertz et al 373 New Data in Management of ADHF Standard therapies for managing ADHF (in addition to background chronic heart failure therapy) primarily include intravenous loop diuretics for patients with evidence of pulmonary and/or systemic venous congestion, vasodilators for patients with acute dyspnea or elevated filling pressures and evidence of vascular volume redistribution, and positive inotropes for patients with low cardiac output and evidence of end-organ dysfunction or damage. However, robust scientific evidence evaluating the safety and efficacy of current treatment strategies were lacking before the completion of several studies designed to address knowledge gaps. In addition, there have been no new drugs approved for the treatment of ADHF since 2001. The management of ADHF requires a multifaceted approach that involves strategies or methods of delivering therapy, as well as drug therapies. Recent data will be examined in the context of these distinctions. Strategies Diuretics. The Diuretic Optimization Strategies Evaluation (DOSE) trial was designed to test low- versus high-dose intravenous furosemide administered as a continuous infusion versus intermittent intravenous boluses as the initial treatment strategy (ie, patients were not treatment resistant).28 This relatively small, prospective, double-blind, controlled trial randomized a total of 308 patients in a 1:1:1:1 fashion with the use of a 22 factorial design (Table 1). In the low-dose strategy, the total intravenous furosemide dose was equal to the total daily oral loop diuretic dose (in furosemide equivalents). For the high-dose arm, patients received a dose that was 2.5 times greater than their total daily oral loop diuretic dose (in furosemide equivalents). The median time to randomization was 14.6 hours.28 No significant difference was observed for efficacy or safety between the groups (Table 1). Some significant differences were noted across secondary end points for the low versus high dose comparison, including a larger decrease in body weight, greater fluid loss, and more dyspnea relief with higher doses. Length of stay and days alive out of the hospital did not differ between groups.28 However, caution should be used in the interpretation of secondary end points, because the primary efficacy outcome did not detect significant between-group differences. The DOSE results suggest that high-dose intravenous furosemide (median 773 mg over 72 hours) was not associated with greater increases in serum creatinine compared with a low-dose strategy (median 358 mg over 72 hours), although more patients experienced an increase in serum creatinine of O0.3 mg/dL at 72 hours in the high-dose (23%) compared with the low-dose (14%) strategy (P 5 .04). The difference in creatinine between the 2 groups had disappeared at 7 days. In earlier retrospective analyses, high-dose diuretics were associated with a greater risk of worsening renal function and subsequent mortality.29e32 Trial Study Arms Population Primary End Point Results 28 DOSE n 5 308 Low- vs high-dose furosemide. Continuous vs intermittent intravenous bolus. 1:1:1:1 22 factorial design. ADHF presented within previous 24 h, $1 sign and $1 symptom of HF, history of chronic HF treated with 80e240 mg/d furosemide (or equivalent) for $1 mo Coprimary: patient global assessment of symptoms measured by a VAS and quantified as the AUC of serial assessments from baseline to 72 h; change in sCr from baseline to 72 h ASCEND-HF9 n 5 7,141 Nesiritide 0.01 mg kg1 min1 with optional 2 mg/kg bolus (from 24 h up to 7 d) vs standard medical therapy Hospitalized for ADHF, dyspnea at rest or with minimal activity, $1 sign and $1 objective measure of ADHF, randomized within 24 h of first IV treatment for ADHF Coprimary: change in self-reported dyspnea at 6 and 24 h; composite of HF rehospitalization or all-cause mortality through day 30 DAD-HF51 n 5 60 Dopamine 5 mg kg1 min1 plus low-dose furosemide (5 mg/h continuous infusion) vs high-dose furosemide (20 mg/h continuous infusion Hospitalized for ADHF with evidence of volume overload and eGFR $30 mL min1 1.73 m2 Incidence of worsening renal function during the first 24 h after randomization, defined as O0.3 mg/dL rise in sCr from baseline to 24 h and O20% decrease in eGFR from baseline to 24 h PROTECT18 n 5 2033 Rolofylline 30 mg vs placebo for up to 3 d Hospitalized for ADHF, persistent dyspnea at rest or with minimal activity, estimated CrCl 20e80 mL/min, BNP $500 pg/mL or NT-proBNP $2,000 pg/mL, IV loop diuretic therapy, and enrollment within 24 h after admission CARRESS42 n 5 188 Ultrafiltration vs stepped pharmacologic care Patients hospitalized with ADHF who develop cardiorenal syndrome (defined as increasing sCr [$0.3 mg/dL] either after hospitalization (within 7 d from admission after receiving intravenous diuretics) or before hospitalization [within 6 wk of the index hospitalization in the setting of escalating doses of outpatient loop diuretics]). Treatment success (moderate or marked improvement in dyspnea at both 24 and 48 h), failure (death or readmission for HF through day 7, worsening symptoms requiring intervention by day 7 or discharge, or persistent worsening renal function), or no change in patient’s condition Combined change in SCr and body weight at 96 h Global assessment of symptoms: bolus AUC 4,236 6 1,440 vs continuous AUC 4,373 6 1,404 (P 5 .47); low dose AUC 4,171 6 1,436 vs high dose AUC 4,430 6 1,401 (P 5 .06). Mean change in sCr: bolus 0.05 mg/dL vs continuous 0.07 mg/dL (P 5 .45); low dose 0.04 mg/dL vs high dose 0.08 mg/dL (P 5 .21). Self-reported dyspnea moderately or markedly better. At 6 h: placebo 42.1% vs nesiritide 44.5%; P 5 .03.* At 24 h: placebo 66.1% vs nesiritide 68.2%; P 5 .007.* Death or rehospitalization for HF at 30 d: placebo 10.1% vs nesiritide 9.4% (HR 0.93, 95% CI 0.8e1.08; P 5 .31). sCr increase O0.3 mg/dL: low-dose dopamine/low-dose furosemide 6.7% vs high-dose furosemide 30%; P 5 .042. O20% decrease in eGFR: low-dose dopamine/low-dose furosemide 10% vs high-dose furosemide 33.3%; P 5 .057. Treatment success: placebo 36% vs rolofylline 40.6%. No change: placebo 44.2% vs rolofylline 37.5%. Treatment failure: placebo 19.8% vs rolofylline 21.8%. OR for rolofylline: 0.92, 95% CI 0.78e1.09; P 5 .35. Change in creatinine level: 0.04 6 0.53 mg/dL in the pharmacologictherapy group vs þ0.23 6 0.70 mg/dL in the ultrafiltration group; P 5 .003. Weight loss: 5.5 6 5.1 kg (12.1 6 11.3 lb) in the pharmacologic-therapy group vs 5.7 6 3.9 kg (12.6 6 8.5 lb) in the ultrafiltration group; P 5 .58. Serious adverse events: 72% in the ultrafiltration group vs 57% in the pharmacologic-therapy group; P 5 .03. 374 Journal of Cardiac Failure Vol. 19 No. 6 June 2013 Table 1. Summary of Recently Completed Trials ADHF, Acute Decompensated Heart Failure; AUC, area under the receiver operating characteristic curve; BNP, B-type natriuretic peptide; CI, confidence interval; CrCl, creatinine clearance; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; HR, hazard ratio; IV, intravenous; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; OR, odds ratio; SBP, systolic blood pressure; sCr, serum creatinine; VAS, visual analog scale. *Did not meet USA regulatory requirement of significance. CV death or HF rehospitalization at 6 and 12 mo 150 mg (increased to 300 mg as tolerated) Aliskiren daily vs placebo ASTRONAUT162,163 n 5 1,639 randomized (n 5 1,615 in final efficacy analysis) Hemodynamically stable patients hospitalized for HF (median 5 d after admission), LVEF #40%, BNP $400 pg/mL or NT-proBNP $1,600 pg/mL, and signs/symptoms of fluid overload Seralaxin 30 mg kg1 d1 vs placebo for 48 h RELAX-AHF61 n 5 1,161 Patients with dyspnea at rest or on minimal exertion, congestion on chest x-ray, BNP $350 ng/L (or NT-proBNP $1,400 ng/L), eGFR 30e75 mL/min1 1.73 m2, and SBP O125 mm Hg 2 primary efficacy end points: change in patient-reported dyspnea from baseline to day 5 (VAS AUC); moderately or markedly improved patient-reported dyspnea at 6, 12, and 24 h (7-point Likert scale) Change in dyspnea to day 5: Seralaxin significantly improved dyspnea compared with placebo by VAS AUC (448 mm h, 95% CI 120e775); P 5 .007. Proportion of patients with moderately or markedly improved dyspnea at all 3 early time points: seralaxin 27% vs placebo 26%; P 5 .70. Days alive out of hospital up to day 60: seralaxin 48.3 vs placebo 47.7; P 5 .37. 180-day mortality: placebo 65 deaths vs seralaxin 42; HR 0.63 (95% CI 0.43e0.93); P 5 .02. CV death or HF hospitalization at 6 mo: aliskiren 24.9% vs placebo 26.5% (HR 0.92, 95% CI 0.76e1.12; P 5 .41); at 12 mo: aliskiren 35% vs placebo 37.3% (HR 0.93, 95% CI 0.79e1.09; P 5 .36) Update on Acute Decompensated Heart Failure Givertz et al 375 In DOSE, there was no significant difference between the low- and high-dose strategies in the clinical composite of death, rehospitalization, or ED visit within 60 days. However, the numbers of patients and events in DOSE were small. The hazard ratio and 95% confidence interval (CI) for the high-dose strategy were 0.83, 0.60e1.16. The findings from DOSE are not likely to substantially change clinical practice, but they may reduce clinicians’ concerns regarding the safety of using high-dose diuretics in ADHF patients, at least up to the doses studied in the trial. Other recent reports also confirm the safety of higher-dose diuretics in ADHF.33,34 In addition, there is no longer a strong rationale for using a continuous infusion of diuretics as an up-front strategy. High-dose therapy may be associated with some clinical advantages regarding response to therapy, but the data are not definitive. There was no evidence that continuous infusions offered an advantage over bolus administration in terms of efficacy or safety, but the study results may be confounded by the rigorous administration of the bolus doses in the clinical trial context, which may not be representative of general clinical practice. In a Cochrane review of earlier studies, a modest benefit of continuous loop diuretic infusion regarding urine output and safety was observed,35 but the studies involved were small and incompletely blinded. Therefore, clinicians should use their clinical judgment and personal preference when determining mode of administration. Hypertonic Saline. In small trials, administration of hypertonic saline (3%) along with high-dose furosemide and sodium and fluid restriction may be associated with greater diuretic and clinical response.36e38 In the SMACHF [Sodium Management in Acute and Chronic Heart Failure] study, 1,927 patients hospitalized for ADHF were randomized to a single-blind strategy of hypertonic saline solution plus 250 mg furosemide (intravenous bolus) twice daily and sodium restriction to 120 mmol (2,760 mg) per day, versus 250 mg furosemide (intravenous bolus) twice daily (without hypertonic saline) and sodium restriction to 80 mmol (1,849 mg) per day. Both groups received fluid restriction to 1,000 mL/d.39 The primary end point was death or first hospitalization for worsening heart failure during a mean follow-up of 57 months. A total of 8% of patients were lost to follow-up. Length of stay was shorter (3.5 days vs 5.5 days; P ! .0001) and creatinine clearance was higher at discharge for patients in the hypertonic saline arm. Readmissions occurred in 18.5% of the hypertonic saline and 120 mmol/d sodium group versus 34.2% of the 80 mmol/d sodium group (P ! .0001). Mortality was also lower in the hypertonic saline group (12.9% vs 23.8%; P ! .0001). These data are intriguing, but they are limited by the lack of blinding, the absence of data on short-term outcomes, the proportion of patients lost to follow-up, and the unknown effect that postdischarge management may have had on the study findings. Additionally, in usual practice, clinicians and patients may find it extremely difficult to limit fluid intake to 1,000 mL daily. 376 Journal of Cardiac Failure Vol. 19 No. 6 June 2013 Larger prospective blinded trials are needed to further evaluate this therapeutic approach,39 which can not be recommended for clinical practice at this time. Ultrafiltration. In the Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD) study, ultrafiltration reduced body weight and promoted fluid loss to a greater extent than intravenous diuretics in 200 patients hospitalized for ADHF with signs of volume overload. A reduction in ADHF hospitalizations and unscheduled visits was also observed, but the study was too small to definitively evaluate the effect of ultrafiltration on outcomes.40 Although the results from UNLOAD and earlier studies were encouraging, 2 recent studies raise concerns about the efficacy and safety of using ultrafiltration as a rescue strategy in highrisk patients with ADHF, persistent congestion, and worsening renal function. In an observational study, Patarroyo et al examined clinical outcomes of slow continuous ultrafiltration (SCUF) in 63 patients with ADHF and refractory congestion.41 Although 48 hours of SCUF improved hemodynamics and resulted in further weight loss, renal function did not improve in this high-risk cohort, and almost 60% required hemodialysis during their hospital course. The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS) randomly assigned (Table 1) 188 patients with ADHF, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic care (intravenous diuretics dosed by the investigator to maintain urine output of 3e5 L/d plus intravenous vasodilators or inotropes if needed to achieve target urine output) or ultrafiltration (target fluid removal rate of 200 mL/h).42 The primary end point assessed at 96 hours was the bivariate change from baseline in serum creatinine level and weight. Ultrafiltration resulted in similar weight loss (w12 pounds), but it was inferior to pharmacologic care owing to an increase in creatinine levels (P 5 .003). In addition, more patients in the ultrafiltration group had a serious adverse event (72% vs 57%; P 5 .03). CARRESS enrolled a high-risk population with composite rates of death or rehospitalization at 60 days of 61% and 48% in the ultrafiltration and pharmacologic-therapy groups, respectively (P 5 .12). An ongoing trial, the Aquapheresis Versus Intravenous Diuretics and Hospitalizations for Heart Failure (AVOID-HF, ClinicalTrials.gov identifier NCT01474200; Table 2) will further evaluate the role of ultrafiltration in the management of ADHF. Ultrafiltration is an option that may be considered instead of diuretics for treating volume overload in the setting of ADHF (strength of evidence B, HFSA 2010 guidelines).2 However, major gaps in knowledge remain and include short- and long-term safety, patient impact, and costeffectiveness of this approach compared with diuretic management. In particular, issues related to venous access, systemic anticoagulation and bleeding risks, and acute kidney injury need to be explored in larger patient cohorts. Patients with ADHF who are truly refractory to diuretic therapy also deserve further study. Existing Pharmacologic Therapies Nitrates. Nitrates may be considered for relief of congestive symptoms in patients with ADHF. Information on their use is provided in the full HFSA guidelines, and no new evidence has been generated since the most recent guidelines publication. Readers are referred to the 2010 HFSA guidelines for more information on the role of nitroglycerin and nitroprusside in ADHF, including a detailed discussion of the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) study.2 Additional comparative effectiveness studies of intravenous nitroglycerin in ADHF are being planned. Inotropes. As recommended in the 2010 HFSA guidelines, intravenous inotropes may be considered to relieve symptoms and improve end-organ function in patients with advanced heart failure, reduced left ventricular ejection fraction (LVEF), and LV dilatation. In particular, positive inotropes may be used when patients are hypotensive despite adequate filling pressures, are unresponsive or intolerant to intravenous vasodilators, or display diminished or worsening peripheral perfusion or renal or other endorgan dysfunction.2 No new evidence has been generated since the most recent guidelines publication. Readers are referred to the 2010 HFSA guidelines for detailed information on the use of inotropes in ADHF.2 Nesiritide. Nesiritide (recombinant human B-type natriuretic peptide [BNP]) was approved to relieve dyspnea and to reduce pulmonary capillary wedge pressure in patients with ADHF on the basis of the VMAC study, which was a short-term trial of 498 patients that was not powered to evaluate clinical outcomes.43 Subsequently, 2 metaanalyses brought the safety and efficacy of the drug into question.44,45 The ASCEND-HF trial was designed to prospectively answer the questions raised by the meta-analyses and to respond to the concerns of an expert panel commissioned by the drug sponsor.9,46 The study design and overall results are presented in Table 1. A total of 7,141 patients were randomized 1:1 to nesiritide (0.01 mg kg1 min1 infusion for 24 hours to 7 days, with an optional initial 2 mg/kg intravenous bolus), or placebo. In addition, all patients received standard medical therapy. The use of loop diuretics, positive inotropes, and vasodilators after randomization were similar between groups.9 Self-reported dyspnea improved marginally in the nesiritide group at 6 and 24 hours, but the prespecified criterion for statistical significance (P ! .005) was not met (although analyses required by the European Medicines Agency did achieve significance). Similarly, there was no significant difference in the outcome of death or heart failure hospitalization between treatment groups. There were no between-group differences in the safety end point of the proportion of patients with a O25% decrease in estimated glomerular filtration rate (eGFR) from baseline (31.4% nesiritide vs 29.5% placebo; odds ratio 1.09, 95% CI 0.98e1.21; P 5 .11). Hypotension was reported more frequently in the nesiritide group (26.6% vs 15.3%; August 2013 December 2013 December 2012* DAD-HF II Low-dose dopamine plus low-dose furosemide NCT01060293 vs low-dose furosemide alone vs high-dose furosemide alone Hospitalized with ADHF and evidence of congestion 360 Safety: change in serum cystatin C from ROSE-AHF Low-dose dopamine (2 mg kg1 min1) vs and eGFR 15e60 mL min1 m2 low-dose nesiritide (0.005 mg kg1 min1) randomization to 72 h. NCT01132846 vs placebo Efficacy: Cumulative urinary volume at 72 h. ATOMIC-AHF Omecamtiv mecarbil infusion for 48 h vs placebo Hospitalized for ADHF within 24 h of initiating loop 600 Dyspnea at 48 h NCT01300013 diuretic, dyspnea at rest or with minimal exertion, and elevated BNP or NT-proBNP September 2013 ED, emergency department; other abbreviations as in Table 1. *Last verified May 2010. 544 Time to first rehospitalization or unscheduled outpatient or ED visit for ADHF within 90 d after discharge Hospitalized with ADHF and evidence of congestion 450 Mortality or all-cause hospitalization at 1 y AVOID-HF Aquapheresis therapy (venovenous ultrafiltration) Hospitalized for ADHF with evidence of volume NCT01474200 vs intravenous diuretics overload (estimated excess fluid $10 lb) n Population Treatment Arms Trial Table 2. Summary of Select Ongoing Trials Primary End Point Estimated Study Completion Date (ClinicalTrials.gov) Update on Acute Decompensated Heart Failure Givertz et al 377 P ! .001). The end point findings were consistent across a number of prespecified subgroups.9 What is the current role of nesiritide in light of the ASCEND-HF findings? In patients with signs and symptoms of ADHF within 24 hours after the initial presentation, nesiritide did not provide a meaningful incremental improvement in dyspnea on top of standard therapy at either 6 or 24 hours. Therefore, it is not recommended as an effective therapy in this setting. It is possible that nesiritide may have clinical efficacy in other patient populations or at even lower doses (ROSE-AHF [Renal Optimization Strategies Evaluation in Acute Heart Failure]: Table 2), but that hypothesis remains to be tested. Dopamine. Dopamine is an adrenergic agonist with dose-dependent pharmacologic effects. At low doses (0.5e2.5 mg kg1 min1), dopamine leads primarily to vasodilation through vascular D1-dopaminergic receptor stimulation, thereby increasing renal blood flow and GFR. At medium doses (5e10 mg kg1 min1), dopamine is associated with positive inotropic and chronotropic effects through stimulation of b1-adrenergic receptors.47 High doses of dopamine (O10 to 20 mg kg1 min1) lead to systemic vasoconstriction via stimulation of a-receptors. Lowdose or ‘‘renal-dose’’ dopamine has been used in critical care settings for the prevention or treatment of acute kidney injury, but the available evidence of efficacy is limited.48,49 Although mechanistic data show beneficial renal effects of dopamine in chronic heart failure,50 few studies have evaluated low-dose dopamine specifically in the ADHF population.51 The Dopamine in Acute Decompensated Heart Failure (DAD-HF) trial demonstrated that fewer patients randomized to ‘‘low-dose’’ dopamine (actually 5 mg kg1 min1) and low-dose furosemide experienced an increase in serum creatinine O0.3 mg/dL or a O20% decrease in eGFR from baseline compared with high-dose furosemide, although the number of patients and absolute numbers of events in this study was small (Table 1).51 The DAD-HF II (NCT01060293) and ROSE-AHF (NCT 01132846) trials are ongoing (Table 2). Pharmacologic Agents in Development for ADHF Rolofylline. Rolofylline is an adenosine A1 receptor antagonist that has been studied in the setting of ADHF and renal impairment. It was hypothesized that A1-receptor antagonists would preserve GFR, improve the response to diuretic therapy, and increase sodium excretion by blocking the effects of adenosine on the kidney.52e54 In phase II trials, rolofylline produced greater improvements in dyspnea outcomes, and fewer patients experienced worsening renal function. A trend toward improved clinical outcome was also observed.55 However, these findings were not confirmed in the large 2,033-patient phase III Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to 378 Journal of Cardiac Failure Vol. 19 No. 6 June 2013 Assess Treatment Effect on Congestion and Renal Function (PROTECT) trial (Table 1).18 No difference in the primary clinical composite outcome was observed between the rolofylline and placebo groups. Persistent worsening renal function did not differ between treatment groups,56 and the incidence of death or readmission for cardiovascular or renal causes at 60 days also was similar between groups.18 Furthermore, rolofylline was associated with an increased rate of adverse neurologic events, including seizures and strokes.57 Based on the data, further development of rolofylline and other adenosine receptor antagonists for ADHF was discontinued.58 Relaxin. Relaxin is an endogenous peptide initially discovered as a hormone that is active in pregnancy.59,60 Through stimulation of the relaxin receptor, relaxin decreases inflammation, decreases fibrosis, increases vasodilation, promotes renal blood flow, and increases vascular endothelial growth factor and angiogenesis.59 In a variety of animal models, relaxin prevented ischemia and reperfusion injury, decreased cardiac fibrosis in hypertension and cardiomyopathy, and reduced cell death and contractile dysfunction in myocardial infarction.60 Relaxin was studied in a phase II placebo-controlled dose-ranging study of 234 patients with ADHF, evidence of congestion, mild to moderate renal impairment, and preserved systolic blood pressure (O125 mm Hg).17 The Preliminary Study of Relaxin in Acute Heart Failure (Pre-RELAX-AHF) showed improvements in dyspnea scores for patients treated with relaxin, although hypotension and worsening renal function were observed at higher doses. The study was too small to draw conclusions regarding efficacy or clinical outcomes, but hypothesis-generating observations from the trial suggested favorable effects on clinical end points including cardiovascular death or hospitalization for heart or renal failure.17 The larger RELAX-AHF study61 was designed on the basis of previous data, and enrolled 1,161 ADHF patients within 16 hours of presentation who had dyspnea, congestion, mild-moderate renal insufficiency, and systolic blood pressure O125 mm Hg (Table 1). Patients were randomly assigned to receive an infusion of seralaxin (30 mg kg1 d1) or placebo for 48 hours with primary efficacy end points being dyspnea improvement over 5 days with the use of a visual analog scale (VAS) and over 24 hours with the use of a 7point Likert scale. Compared with placebo, seralaxin improved the dyspnea VAS end point (P 5 .007), but it had no significant effect on the shorter-term end point (P 5 .70). Seralaxin had no significant effect on the secondary end point of death or heart failure readmission at 60 days (P 5 .89), but it was associated with reduced 180-day mortality (P 5 .02). More hypotensive events requiring dose reduction occurred in the seralaxin group (29% vs 18%; P ! .0001), and more adverse events due to renal impairment were observed in the placebo group (9% vs 6%; P 5 .03).61 More data are needed to determine the role of seralaxin in patients with ADHF. Omecamtiv Mecarbil. The development of positive inotropic agents for the treatment of ADHF has had a history marked by early enthusiasm tempered by concerns for toxicity. Although drugs such as dobutamine, milrinone, vesnarinone, enoximone, and levosimendan effectively increase cardiac output, they increase the risk of adverse events, including arrhythmias, ischemia, and hypotension, and, in some cases, mortality.62e67 Omecamtiv mecarbil is the first selective cardiac myosin activator to be studied in humans.68 Through greater binding of myosin to actin during cardiac systole, omecamtiv mecarbil increases the force of myocardial contractions without increasing myocardial oxygen consumption.69 In a phase II, dose-ranging trial in 45 patients with stable heart failure, omecamtiv mecarbil increased LVEF and stroke volume, and decreased end-systolic and end-diastolic volumes. Chest pain, tachycardia, and myocardial ischemia were observed at high plasma concentrations.70 These data were sufficient to proceed with the Acute Treatment With Omecamtiv Mecarbil to Increase Contractility-Acute Heart Failure (ATOMICAHF; NCT01300013; Table 2) study to further evaluate the potential role of omecamtiv mecarbil. Ularitide. Ularitide is a synthetic form of urodilatin, a human natriuretic peptide produced in the kidneys. It induces natriuresis and diuresis by binding to specific natriuretic peptide receptors (NPR-A, NPR-B, and others), thereby increasing intracellular cyclic guanosine monophosphate, relaxing smooth muscle cells, and leading to vasodilation and increased renal blood flow. Ularitide has been studied in patients with ADHF in 2 double-blind placebo-controlled proof-of-concept studies, and it was shown to exert beneficial effects on symptoms and hemodynamics.71,72 The Trial of Ularitide’s Efficacy and Safety in Patients With Acute Heart Failure (TRUE-AHF) is an ongoing phase III randomized clinical trial designed to evaluate the role of ularitide as an intravenous infusion in addition to conventional therapy in patients with ADHF (NCT01661634). The primary end point will be a hierarchic clinical composite variable that includes a patient-centered assessment of clinical progress, an assessment of lack of improvement or worsening of HF requiring a prespecified intervention, and death. The study aims to recruit w2,116 patients with ADHF from 190 centers in North America, Europe, and Latin America. Biomarkers Diagnosis. Natriuretic peptides (plasma BNP or Nterminal pro-BNP [NT-proBNP]) are recommended in the current HFSA guidelines to aid in the diagnosis of ADHF in patients with dyspnea and signs and symptoms of heart failure.2 The biomarker field is constantly evolving, and new biomarkers are being investigated. A complete review of all biomarkers undergoing clinical investigation is outside the scope of this paper. In the Biomarkers in Acute Heart Failure (BACH) trial, midregional proeA-type natriuretic peptide (MR-proANP) at a prespecified threshold of 120 pmol/L was noninferior to a BNP level of 100 pg/mL for the diagnosis of ADHF.73 The use of both BNP and Update on Acute Decompensated Heart Failure MR-proANP slightly, but significantly, enhanced the diagnostic performance of BNP. Similarly to BNP and NT-proBNP, MR-proANP levels may be affected by age, race, sex, body mass index, or comorbidities such as atrial fibrillation. Confirmatory studies are needed to establish the role of MR-proANP as a diagnostic tool for ADHF and to determine its advantages over available biomarkers. Currently, MR-proANP is not recommended for use. Prognosis. A number of novel markers predict clinical outcomes in ADHF. The soluble ST2 receptor is a member of the interleukin family, and it is up-regulated in response to myocardial stretch. ST2 levels correlate with New York Heart Association (NYHA) functional class and predict 1-year mortality in patients with ADHF.74,75 Neutrophil gelatinase-associated lipocalin (NGAL) is a marker of acute kidney injury. When investigated in ADHF, higher levels strongly predicted all-cause death or hospital readmission at 30 days,76 although some data indicated that NGAL more accurately reflects underlying renal function rather than cardiac disease.77 A more recent study of serum NGAL found a modest area under the receiver operating characteristic curve (AUC) of 0.67 for prediction of acute kidney injury.78 NGAL was not a significant predictor of acute kidney injury after adjusting for multiple covariates. Furthermore, measuring urinary NGAL 12e24 hours after initial therapy may identify patients at risk for acute kidney injury (P 5 .012) and adverse events at 30 days (P 5 .02).79 However, another study showed only a small rise in urinary NGAL in patients with ADHF who developed acute kidney injury after diuretic therapy.80 A concern with novel biomarker studies is that creatinine is a poor criterion standard for evaluation of acute kidney injury, damping the novel biomarker’s predictive ability. Copeptin is the C-terminal fragment of preprovasopressin. In a secondary analysis of the BACH study, elevated copeptin levels were associated with the highest 90-day mortality (quartile 4 vs quartile 1). Copeptin was an independent predictor of outcome, and it contributed additional prognostic value to existing markers of outcome in that analysis.81 The BACH study also suggested that the prognostic ability of midregion proadrenomedullin (MRproADM) was limited, with AUC !0.60 for a composite outcome at 7, 30, and 90 days. Although MR-proADM had slightly better prognostic ability for survival, even after adjusting for several clinical confounders, it appears to have limited clinical utility. Galectin-3 promotes collagen synthesis and cardiac fibrosis, and it has been identified as an important marker early in the development of heart failure. The majority of evidence with galectin-3 relates to chronic heart failure, although galectin-3 was also elevated in patients with ADHF, and higher levels (O17.8 ng/mL) predicted short- and long-term mortality.82,83 The emerging data suggest that these and other novel biomarkers may be clinically useful for the diagnosis and prognosis of patients with ADHF. For example, a multimarker approach may have greater precision in determining prognosis in chronic heart failure populations84 as well as Givertz et al 379 in acute coronary syndromes.85 Further research is needed to define the specificity and sensitivity of these markers for ADHF, to determine the influence of demographics and comorbidities on their diagnostic and prognostic utility, and to determine the incremental benefit of these markers in the context of current clinical approaches and costs. There are no conclusive data on the role of natriuretic peptides or other biomarkers to guide inpatient heart failure therapy. In particular, the practice of serial biomarker measurement has not been shown to improve outcomes in ADHF. Quality of Care A major component of the economic burden of heart failure is related to hospitalizations.5,86 Understanding the level of quality of health care delivered to patients with ADHF and how quality affects clinical outcomes is imperative. The rate of hospital adherence to national performance measures for patients with heart failure is variable but improving, and targeted interventions to improve adherence to core measures have been successful.10,87 However, the degree to which adherence correlates with improved outcomes has not been well established. Recent mortality and rehospitalization rates in the Veterans Affairs Health Care System have trended in opposite directions with decreasing mortality and increasing odds for readmission at 30 days.88 Similar trends were observed in the Hospital Compare database (www.hospitalcompare.hhs.gov), leading some to question the validity of using readmission rate as a quality measure.89 Measures associated with evidence-based drug therapy at the time of discharge (angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB]; or beta-blockade, an emerging performance measure) have been associated with a lower risk of 60e90-day postdischarge mortality or rehospitalization; however, other standard performance measures were not.90 At 1 year, beta-blocker use at discharge was associated with a lower risk of mortality, but other standard performance measures were not associated with mortality or cardiovascular readmission.91 Recent analyses from the Get With the Guidelines Heart Failure (GWTG-HF) registry that linked quality measures to Medicare claims data showed poor correlations between hospital ranking and 30-day mortality or readmission.92 Another study showed that hospitals enrolled in the GWTG-HF program had greater adherence to the composite CMS core performance measures than other hospitals, but CMS-reported 30-day mortality was similar regardless of participation in GWTG-HF.93 Although the differences in performance measure adherence rates were statistically significant, the absolute differences were small. GWTG-HF hospitals had statistically lower 30-day all-cause readmission rates compared with other hospitals. Although the absolute differences again were quite small (24% vs 24.4%; P 5 .0009), these differences may still translate into substantial reductions in hospital readmissions and costs 380 Journal of Cardiac Failure Vol. 19 No. 6 June 2013 when applied to the large number of annual ADHF hospitalizations within and beyond the USA.93 The evidence is inconclusive to determine the most effective strategies for improving postdischarge outcomes. In a systematic review of interventions to reduce 30-day rehospitalization, interventions centered around the predischarge, postdischarge, and transition phases. A transitional care model may be best.94 In a meta-review of 15 meta-analyses of heart failure disease management programs (averaging 18.5 studies assessed per metaanalysis), all-cause mortality tended to be lower in the intervention group than in the control group.95 Most heart failure disease management programs in the meta-analysis included education, self-care, discharge planning, and medication support; however, interventions were poorly described and varied between studies. In a large randomized study of telemonitoring versus usual care, the addition of a telephone-activated voice-response system to postdischarge care did not improve outcomes.96 The 2012 American College of Cardiology/American Heart Association (ACC/AHA) performance measures were composed of 9 indicators (3 new and 6 revised), including LVEF assessment (inpatient and outpatient measure), symptom and activity measurement, symptom management, patient self-care education, beta-blocker therapy, ACE inhibitor or ARB therapy, counseling about implantable cardioverter-defibrillator therapy, and postdischarge follow-up.97 Although a single intervention does not stand out as being more effective than others, opportunities to improve care exist beyond reliance on standard performance (process or outcome related) measures.92 Some comprehensive process-of-care strategies that deliver provider-targeted education and performance feedback and patient-focused education and self-management strategies were associated with higher rates of rehospitalization but a trend toward lower mortality at 1 year.98 In the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) study, investigators observed no difference in the primary end point of death or heart failure rehospitalization for patients randomized to usual care or to additional support provided by a nurse with specialty training in heart failure.99 Trends toward decreased mortality and an increase in the number of short-term hospitalizations were noted.99 The totality of evidence suggests that heart failure disease management programs reduce heart failure hospitalization and have a varying impact on survival and quality of life, but the effectiveness of specific components of these programs remains to be determined.95,100,101 Early follow-up (within 7 days after discharge) is one mechanism that was associated with lower rates of allcause readmission at 30 days in an observational analysis of Medicare beneficiaries.102 Focused efforts on treating cardiac and noncardiac comorbidities and providing comprehensive disease management have been proposed to improve postdischarge outcomes in patients with ADHF, but the effectiveness of bundled or individual interventions needs to be established through formal evaluation and testing.103 Key components of transition programs that may promote improved outcomes are: 1) ongoing contact with a care manager and interactions before and after discharge; 2) education that includes assuring understanding of content and comprehensive discharge planning, including early follow-up and medication reconciliation and adherence; 3) access to community resources; and 4) provider-to-provider communication and coordination. Rehospitalization rates may also be influenced more by regional patterns of practice (ie, underlying use of hospital services) than by patient factors.104 The number of cardiovascular specialists available to manage ADHF may play a role in this variation. Whether or not targeted process-of-care initiatives will overcome such external factors and beneficially influence rehospitalization rates remains to be determined. More evidence is required to determine the effectiveness of many current strategies intended to reduce readmissions.105 Evidence Gaps: Priorities for Future Research Diagnosis ADHF is a heterogeneous syndrome that encompasses new-onset heart failure, worsening chronic heart failure, heart failure exacerbated by comorbidities,106 nonadherence, or contraindicated drugs or toxins, and reduced or preserved ejection fraction. This heterogeneity may cause delays in making the diagnosis of ADHF and instituting appropriate therapies or processes of care. BNP and NT-proBNP are useful tools when the diagnosis is uncertain, but even extremely high or low values do not always rule in or rule out ADHF and must be interpreted with knowledge of the patient’s clinical picture. Chest radiography also may be helpful to identify patterns consistent with ADHF, although other objective measures are needed. Based on preliminary data, limited bedside echocardiography, combined with ultrasound measures of lung water, may be helpful to differentiate ADHF from non-ADHF causes in patients with undifferentiated dyspnea.107e109 Use of thoracic bioimpedance to determine increases in lung water associated with decompensation have produced mixed results,110e112 although newer devices may be helpful to differentiate hypervolemic and euvolemic patients.113 Most findings, however, are preliminary, and large-scale studies are needed to determine the additive value of these tests in the acute setting. Ongoing studies will determine if other biomarkers or noninvasive tools will offer advantages to the existing approach to ADHF diagnosis. Scores have been developed that use NT-proBNP and clinical characteristics to diagnose ADHF. The Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) acute heart failure score had a sensitivity of 96% and a specificity of 84% for the diagnosis of ADHF at a cutoff of $6 points (Table 3).114 A mathematical model that included NT-proBNP as a continuous variable, patient Update on Acute Decompensated Heart Failure Table 3. PRIDE Score Predictor Value Elevated NT-proBNP (O450 pg/mL for age !50 y and O900 pg/mL for age $50 y) Interstitial edema on chest x-ray Orthopnea Lack of fever Current loop diuretic use Age O75 y Rales on lung exam Lack of cough Total possible points 4 2 2 2 1 1 1 1 14 Adapted from Baggish et al. Am Heart J 2006;151:48e54.114 age, and pretest probability of ADHF also enhanced the diagnosis of ADHF, particularly among patients where the physician’s clinical diagnosis was uncertain.115 PrðAHFÞ 5 1=1 þ exp ð8 þ 0:011 age 5:9 ptprob 2:3 lntbnp þ 0:82 ptprob lntbnpÞ where Pr(AHF) is posttest probability for acute heart failure, ptprob is patient’s pretest probability, and lntbnp is log (to base 10) of NT-proBNP value. Early patient identification is a critical area for future research efforts. Rapid patient identification may facilitate faster institution of therapies that improve patient symptoms and well-being, and it may also allow for more expedient identification of treatable precipitating factors. In an analysis from ADHERE (Acute Decompensated Heart Failure National Registry), delayed measurement of natriuretic peptides and delayed administration of intravenous diuretics were strongly associated and linked to a modest increase of in-hospital mortality independently from other prognostic factors.116 Whether faster or more optimal management of precipitating factors (ischemia, pulmonary disease, or arrhythmias) would improve ADHF outcomes has yet to be determined, and research in this area is warranted. Pathophysiology Despite significant clinical research efforts, novel effective pharmacologic therapies that improve outcomes for patients with ADHF remain to be identified. Many aspects of ADHF pathophysiology are poorly understood. Dyspnea, a patient-centered outcome, has been hard to quantify and to link to specific objective physiologic or patient outcomes.117 Multiple pathophysiologic processes are likely to be present, given the heterogeneity of the syndrome,118 increasing the challenge of identifying therapeutic targets and treatments that apply to the broad population of patients with ADHF. There is an inadequate understanding of why patients with chronic heart failure deteriorate, and more work is needed to identify these mechanisms. Future research efforts that focus on patient subsets selected on the basis of suspected pathophysiology may be more successful at identifying targeted treatments more effective than the more inclusive methods that have traditionally been used.16,118,119 Givertz et al 381 The contribution of cardiorenal syndrome to the pathophysiology of ADHF has garnered significant interest in recent years. Many researchers have established that worsening renal function (using a variety of definitions) was a predictor of mortality and morbidity in patients with both acute and chronic heart failure.32,120e122 However, evidence is lacking to determine the interplay (or interaction) between the kidney and the heart in cardiorenal syndrome, ie, whether the kidney contributes to heart failure pathophysiology, poor cardiac function results in renal impairment, or it is some combination of both. Two analyses confirmed the central role that elevated systemic venous pressure plays in worsening renal function in ADHF.123,124 Investigators highlighted the important role of vascular redistribution.125 In additional analyses, worsening renal function was associated with cardiovascular mortality and heart failure hospitalizations, and it was also associated with greater reductions in body weight, natriuretic peptides, and blood pressure, factors that generally predict favorable outcomes.126 Furthermore, transient (vs persistent) worsening renal function during treatment of ADHF may actually be associated with improved outcomes when related to aggressive diuresis.34 In addition, several drug classes that improve survival and reduce morbidity in chronic heart failure may also increase serum creatinine, namely, ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists. These data illustrate the complexity of cardiorenal interactions. Clearly, more data are needed to fully characterize the pathophysiologic role of the cardiorenal syndrome in ADHF. Ongoing research is examining the role of dopamine and nesiritide to preserve renal function when treating ADHF (ROSE-AHF). Heart failure with preserved ejection fraction accounts for almost one-half of all ADHF admissions, yet its underlying pathophysiology is understood even less than heart failure with reduced ejection fraction (HF-REF).127 Although limited data exist to characterize patients with ADHF and preserved ejection fraction, registry data suggest that postdischarge mortality and rehospitalization rates are similar to those of patients with reduced ejection fraction,128 although the risk of noncardiac mortality and rehospitalization is higher in HF-PEF patients.129 The majority of completed or ongoing studies of HF-PEF have not been conducted in the setting of ADHF. Although it is unlikely that therapies for the acute setting will differ substantially among HF-PEF and HF-REF patients, achieving a better understanding of the pathophysiology may allow postdischarge therapies to be specifically tailored to HF-PEF. For example, systemic or pulmonary arterial hypertension may play a greater role in decompensation among patients with HF-PEF and serve as an appropriate target for therapy. Risk Stratification: Predicting Early Versus Later Events Several prognostic models have been developed from clinical trials or registries in ADHF.130e134 Other scores derived from chronic heart failure (Seattle Heart Failure 382 Journal of Cardiac Failure Vol. 19 No. 6 June 2013 Model)135 or transplant referral populations (Heart Failure Survival Score)136 were validated in advanced heart failure populations referred for cardiac transplant,137 though not in the ADHF setting. A novel model has been developed that estimates the combined end point of death and failure to achieve a favorable health status, and it may identify ADHF patients before discharge who may be good candidates for either advanced therapies or palliative care.138 Risk stratification may be a valuable tool in the setting of ADHF. Patients identified as high risk for short- or longterm mortality or rehospitalization may benefit from aggressive optimization of drug or device therapy, focused disease management initiatives, or therapies targeting comorbidities or risk factor modification. A stratified treatment approach for patients with ADHF based on risk scores has not been tested in clinical trials and is an area where research is warranted. Clinical Measures of Patient Improvement Measures of efficacy should be both clinically relevant and meaningful to patients. Several outcomes have been used to evaluate the efficacy of therapeutic agents for ADHF. In clinical trials, dyspnea is a common end point because it is generally the symptom that prompts patients to seek medical attention. Despite this, clinically meaningful improvements in dyspnea in clinical trials are difficult to demonstrate, particularly on top of standard diuretic therapy. In secondary analyses of both the Pre-RELAX-AHF study139 and the PROTECT trial,140 early dyspnea relief was associated with more favorable outcomes. In the RELAX-AHF study (Table 1), treatment with serelaxin improved dyspnea at 5 days, but it had no effect on cardiovascular death or heart failure readmission.61 The optimal method and timing of dyspnea assessment in clinical trials is controversial,141 although in the clinical setting it is routinely assessed by physical examination and by querying patients regarding their degree of breathlessness. Whether dyspnea is the most relevant end point to judge patient response in clinical practice (or in clinical trials) has been debated.117,142e144 More research is needed to fill the evidence gap that exists between dyspnea improvement, overall health status, and clinical outcomes. Functional measures, such as 6-minute walk or patient-reported health status measures, or refinements to dyspnea assessment that include response to exertion also may be informative ways to judge patient response to ADHF therapies in the clinical setting. Monitoring Devices. The majority of published and ongoing trials of telemonitoring in heart failure were conducted in patients with chronic heart failure. The use of existing or similar devices to prevent recurrent episodes of heart failure in the setting of ADHF has not been well studied. When noninvasive externally applied impedance cardiography (ICG) was studied in 212 patients in the PREDICT (Prospective Evaluation and Identification of Cardiac Decompensation by ICG Test) study, it identified patients at increased near-term risk for recurrent decompensation.145 Other variables were also important: patient visual analog scale of distress, NYHA functional class, and systolic blood pressure. Furthermore, data from other studies indicated that internally implanted devices that measured intrathoracic impedance values were not highly sensitive to predict hospital admissions,146 and they did not reduce heart failure hospitalizations,147 although studies to date have generally been underpowered. In contrast, the observational Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure (PARTNERS-HF) study showed that internal cardiac device diagnostic data (driven to a large extent by high fluid indices) independently predicted subsequent heart failure hospitalization with pulmonary congestion in patients with NYHA functional class III/IV heart failure who received a cardiac resynchronization therapy defibrillator device with impedance monitoring capabilities (Optivol; Medtronic).148 Implantable hemodynamic monitoring systems are currently being investigated for use in heart failure and are capable of monitoring pulmonary artery pressures (CardioMEMS) or left atrial pressures (Heartpod; St Jude Medical). In the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Functional Class III Heart Failure Patients (CHAMPION) trial, the 270 patients randomized to the CardioMEMS device had a lower rate of heart failure-related hospitalizations at 6 and 15 months than the 280 patients in the control group.21 The Heartpod device was studied in the Hemodynamically Guided Home Self-Therapy in Severe Heart Failure Patients (HOMEOSTASIS) observational pilot trial. The investigators found that individualized therapy guided by left atrial pressures was associated with reduced left atrial pressures, improved NYHA functional class, and increased LVEF and resulted in higher doses of ACE inhibitors/ ARBs and beta-blockers.149 The Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy (LAPTOP-HF) study is a larger randomized study evaluating the safety and efficacy (heart failure hospitalization) of the Heartpod device in patients with NYHA functional class III heart failure. Although these implantable device studies are not being conducted specifically in the ADHF population, if the devices are approved, they will likely be used clinically in this setting during hospitalization of patients with the devices. Whether used to prevent acute decompensation or in patients currently undergoing treatment for ADHF, a key element of improved outcomes will be how aggressively and thoroughly clinicians respond to data abnormalities. Therefore, studies in the setting of ADHF are warranted so that information on how to interpret the data in this setting can be generated. Noninvasive monitoring of left ventricular end-diastolic pressure (LVEDP) has also been studied as a mechanism to guide treatment and prevent heart failure rehospitalization. Update on Acute Decompensated Heart Failure In a small study of 50 patients hospitalized for ADHF, patients randomized to daily noninvasive monitoring of LVEDP with the use of the Vericor monitor (CVP Diagnostics) had lower estimated LVEDP at discharge and lower rates of rehospitalizations for heart failure at 1, 3, 6, and 12 months. However, the study was too small to draw conclusions regarding clinical outcomes.150 In the future, noninvasive tools that assess congestion and/or other sensitive factors of decompensation and guide treatment of ADHF may be most useful to the primary health care providers of ADHF patients, including emergency physicians, cardiologists, internists, and hospitalists.151 Biomarkers. The majority of biomarker-guided therapy studies were performed in the chronic heart failure population. The Pro-B-Type Natriuretic Peptide Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study reported a reduction in cardiovascular events among 151 patients with chronic heart failure at a single center who were randomized to NT-proBNP-guided therapy compared with standard care.152 Whether or not biomarker-guided therapy improves outcomes in the setting of ADHF has not been determined. New evidence evaluating this concept is lacking, and more studies are critically needed to advance the field in this area. Home-based monitoring of biomarkers is another potential strategy that may be useful to identify and treat episodes of worsening heart failure before a patient’s signs and symptoms progress to the point that hospitalization is required. The Heart Failure Outpatient Monitoring Evaluation (HOME; NCT01347567) study is enrolling w375 patients hospitalized or treated as an outpatient with ADHF. Participants will be randomized into 1 of 3 arms: BNP home finger-stick monitoring plus health management (investigator will use BNP data to guide management, along with weight, signs, and symptoms), health management alone (BNP levels will be obtained, but results will be blinded to investigator and subject; investigator will use weight, signs, and symptoms to manage care), or usual care. The primary end point is heart failure-related mortality, heart failure readmission, intravenous diuretic or augmented oral diuretic therapy in the ED, or unplanned outpatient treatments for ADHF. The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT; NCT01685840) study is also enrolling subjects with ADHF to determine the efficacy of a strategy of NT-proBNP-guided therapy compared with usual care in high-risk patients with left ventricular systolic dysfunction. The primary outcome measure is the time to cardiovascular death or heart failure hospitalization; all-cause mortality will also be assessed. Processes of Care in the Hospital Setting A wide variation in quality of care for ADHF persists across the USA.153 Although multiple initiatives that involve processes of care and outcomes in ADHF have been an intense area of research in recent years, more Givertz et al 383 work is needed to determine the best approaches. Developing standard algorithms and processes to rapidly assess, triage, and implement early therapy in patients in prehospital and ED-based settings (ambulance, ED, or observation units) is one approach where formal testing is warranted. Collaborations among prehospital personnel, cardiologists, hospital-based clinicians, heart failure specialists, and emergency physicians are needed to ensure a smooth transition of care. Preliminary data suggest that collaborative care can result in successful implementation of protocoldriven therapy.154 Creating networks and integration between emergency personnel and hospital-based personnel decreased treatment delays in patients with acute coronary syndromes.155 Whether similar strategies, such as door-todiuretic time or triage of heart failure admissions in the ED, would be feasible and/or effective to improve outcomes in ADHF is unknown. Additional parameters beyond the door-to-diuretic time (preferably !90 min) could include: 1) clinical assessment of volume status and readiness for discharge on a twicedaily basis; 2) assessment of precipitating factors and measurement of electrolytes and renal function at least every 48 hours in patients receiving intravenous diuretics; 3) assessment of LVEF if not done in the past year; and 4) initiation of an ACE inhibitor (or ARB) and beta-blocker therapy in patients with HF-REF and no contraindications. Further studies are needed to determine if these measures improve quality, reduce length of stay, and favorably affect longer-term outcomes in ADHF. The key evidence gap in this arena is in clarifying the contributions of the individual components of these interventions to determine which are the most effective. Specific predischarge strategies are critically important in enhancing patient knowledge and adherence to postdischarge expectations. Some examples are education (clinician and patient), medication optimization and reconciliation, and plans for postdischarge follow-up. Risk-stratified readmission models that are widely available and have the potential to identify high-risk patients who may benefit from aggressive postdischarge follow-up and management need to be formally evaluated. Examples include the readmission score (http://readmissionscore.org/heart_failure.php) or the score developed by Philbin and DiSalvo based on administrative data.156,157 The optimal method of follow-up (in-home, heart failure clinic, telephone) for patients may depend on geography and the availability of clinicians, as well as the underlying physical, emotional, social (including informed caregivers and family), and/or economic risk of an individual patient. New knowledge in these areas would be highly clinically relevant. Finally, more work is needed to address palliative care and end of life issues, particularly as advanced therapies such as mechanical circulatory support are considered for broader patient populations.158,159 Although palliative care should be integrated throughout the course of heart failure care, an episode of ADHF may act as a trigger for 384 Journal of Cardiac Failure Vol. 19 No. 6 June 2013 clinicians to assess whether or not goals of care have been addressed and to implement symptom-focused and end of life care as appropriate.160 A recent study showed that palliative care consultation can be provided in the heart failure clinic after discharge and can result in reduced symptoms and improved quality of life.161 Conclusion Recently completed trials answered questions regarding the safety and efficacy of diuretic strategies, vasodilator therapies, and ultrafiltration. Completed trials with neutral or negative results, though disappointing, contribute to overall knowledge pertaining to clinical characteristics and outcomes, and they are informative for the design of future trials. The results of ongoing trials of new therapeutic agents and devices that monitor clinical status will determine if effective and safe therapies are on the horizon. In the future, attempts may be made to match patient clinical characteristics with the expected pharmacologic mechanism of action for new agents or devices, rather than taking the traditional ‘‘all comers’’ approach. Successful translation of this approach into a greater ability to detect effective therapies remains to be seen. The timing of intervention will also be tested to determine the optimal pace and location of treatment. At present, initiatives to improve processes and quality of care may offer the best opportunity to improve patient outcomes. Although advances have been realized, many opportunities remain to reduce the burden of ADHF. Acknowledgments The authors acknowledge Bart Galle, PhD, for his contributions to the development of this manuscript, and the HFSA Executive Committee (Thomas Force, MD, JoAnn Lindenfeld, MD, John C. Burnett, Jr, MD, John Chin, MD, Steven R. Houser, PhD, Joseph Hill, MD, PhD, Sharon A. Hunt, MD, Barry M. Massie, MD, Mandeep R. Mehra, MD, Sara C. Paul, RN, MSN, Mariann Piano, RN, PhD, Heather J. Ross, MD, James E. Udelson, MD, and Michael R. Zile, MD) for their review and critique of this paper. Disclosures Michael M. Givertz: consultant or advisory board: Merck, Cardioxyl. John R. Teerlink: consultant or advisory board: Amgen, Corthera, Cytokinetics, Novartis, Gambro; research grants: Amgen, Corthera, Cytokinetics, Novartis, Affymax, St Jude. Randall C. Starling: sponsored research: Johnson & Johnson, Scios; stock options: CardioMEMS; steering committee: Biocontrol INOVATE-HF, NHLBI Heart Failure Network; advisory board: Medtronic; all details posted on Cleveland Clinic website. Nancy M. Albert: honoraria or speaker’s bureau: BG Medicine, Medtronic; consultant or advisory board: BG Medicine, Gambro. Sean P. Collins: consultant or advisory board: The Medicines Company, Novartis, Radiometer, Trevena; research grants: Medtronic. Justin A. Ezekowitz: research grants: Amgen, Johnson & Johnson, Alere. James C. Fang: consultant or advisory board: Medtronic; research grants: Medtronic. Adrian F. Hernandez: honoraria or speaker’s bureau: Corthera, BMS; research grants: Amylin, Portola, Janssen. Wendy Gattis Stough: consultant: Medtronic. Mary N. Walsh: consultant or advisory board: United Healthcare, Eli Lilly; officer, trustee, or director: American College of Cardiology. Javed Butler: consultant of advisory board: Stemira, Medtronic, Trevena, Gambro, Ono, Bayer, Harvest; research grants: NIH, HRSA, European Union; ethical trial: Medtronic, Otsuka; DSMB or steering committee: Amgen, Celladon, Corthera, Novatis, BG Medicine. John P. Dimarco: consultant: Medtronic, St Jude; speaker: Boston Scientific. John A. Spertus: consultant or advisory board: Genentech, United Healthcare, Janssen, Amgen; equity interests or stock options: Health Outcomes; royalties or intellectual property rights: KCCQ, SAQ, PAQ; research grants: Genentech, Lilly, EvaHeart, Amorcyte, ACCF. W. H. Wilson Tang: research grants: NIH, Abbott Laboratories. References 1. Felker GM, Adams KF Jr, Konstam MA, O’Connor CM, Gheorghiade M. The problem of decompensated heart failure: nomenclature, classification, and risk stratification. Am Heart J 2003; 145:S18e25. 2. Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, et al. HFSA 2010 comprehensive heart failure practice guideline. J Card Fail 2010;16:e1e194. 3. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009;53: e1e90. 4. Hall M, Levant S, DeFrances C. Hospitalization for congestive heart failure: United States, 2000e2010. NCHS Data Brief 2012;108:1e8. 5. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statisticsd2012 update: a report from the American Heart Association. Circulation 2012;125: e2e220. 6. Chen J, Normand SL, Wang Y, Krumholz HM. National and regional trends in heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998e2008. JAMA 2011;306:1669e78. 7. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 2011;123:933e44. 8. Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization for heart failure: problems and perspectives. J Am Coll Cardiol 2013;61:391e403. 9. O’Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365: 32e43. 10. Fonarow GC, Abraham WT, Albert NM, Gattis Stough W, Gheorghiade M, Greenberg BH, et al. Influence of a performance- Update on Acute Decompensated Heart Failure 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. improvement initiative on quality of care for patients hospitalized with heart failure: results of the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF). Arch Intern Med 2007;167:1493e502. Fonarow GC, Abraham WT, Albert NM, Gattis WA, Gheorghiade M, Greenberg B, et al. Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF): rationale and design. Am Heart J 2004;148:43e51. Follath F, Yilmaz MB, Delgado JF, Parissis JT, Porcher R, Gayat E, et al. Clinical presentation, management and outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF). Intensive Care Med 2011;37:619e26. Chaudhry SI, Wang Y, Concato J, Gill TM, Krumholz HM. Patterns of weight change preceding hospitalization for heart failure. Circulation 2007;116:1549e54. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola VP, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J 2006;27:2725e36. Collins SP, Lindsell CJ, Storrow AB, Fermann GJ, Levy PD, Pang PS, et al. Early changes in clinical characteristics after emergency department therapy for acute heart failure syndromes: identifying patients who do not respond to standard therapy. Heart Fail Rev 2012;17:387e94. Mebazaa A, Gheorghiade M, Pina IL, Harjola VP, Hollenberg SM, Follath F, et al. Practical recommendations for prehospital and early in-hospital management of patients presenting with acute heart failure syndromes. Crit Care Med 2008;36:S129e39. Teerlink JR, Metra M, Felker GM, Ponikowski P, Voors AA, Weatherley BD, et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet 2009;373:1429e39. Massie BM, O’Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, et al. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010;363:1419e28. Fermann GJ, Collins SP. Observation units in the management of acute heart failure syndromes. Curr Heart Fail Rep 2010;7: 125e33. Ezekowitz JA, Kaul P, Bakal JA, Quan H, McAlister FA. Trends in heart failure care: has the incident diagnosis of heart failure shifted from the hospital to the emergency department and outpatient clinics? Eur J Heart Fail 2011;13:142e7. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR, Stevenson LW, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658e66. Zile MR, Bennett TD, St John SM, Cho YK, Adamson PB, Aaron MF, et al. Transition from chronic compensated to acute decompensated heart failure: pathophysiological insights obtained from continuous monitoring of intracardiac pressures. Circulation 2008;118:1433e41. Small RS, Wickemeyer W, Germany R, Hoppe B, Andrulli J, Brady PA, et al. Changes in intrathoracic impedance are associated with subsequent risk of hospitalizations for acute decompensated heart failure: clinical utility of implanted device monitoring without a patient alert. J Card Fail 2009;15:475e81. Solomon SD, Dobson J, Pocock S, Skali H, McMurray JJ, Granger CB, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation 2007;116:1482e7. Cleland JG, Swedberg K, Follath F, Komajda M, Cohen-Solal A, Aguilar JC, et al. The EuroHeart Failure survey programmeda survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J 2003;24:442e63. Komajda M, Follath F, Swedberg K, Cleland J, Aguilar JC, CohenSolal A, et al. The EuroHeart Failure Survey programmeda survey 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. Givertz et al 385 on the quality of care among patients with heart failure in Europe. Part 2: treatment. Eur Heart J 2003;24:464e74. Adams KF Jr, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149:209e16. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364:797e805. Heywood JT, Fonarow GC, Costanzo MR, Mathur VS, Wigneswaran JR, Wynne J, et al. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail 2007;13:422e30. Peacock WF, Costanzo MR, De Marco T, Lopatin M, Wynne J, Mills RM, et al. Impact of intravenous loop diuretics on outcomes of patients hospitalized with acute decompensated heart failure: insights from the ADHERE registry. Cardiology 2009;113:12e9. Hasselblad V, Gattis Stough W, Shah MR, Lokhnygina Y, O’Connor CM, Califf RM, et al. Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE trial. Eur J Heart Fail 2007;9:1064e9. Butler J, Forman DE, Abraham WT, Gottlieb SS, Loh E, Massie BM, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 2004;147:331e8. Yilmaz MB, Gayat E, Salem R, Lassus J, Nikolaou M, Laribi S, et al. Impact of diuretic dosing on mortality in acute heart failure using a propensity-matched analysis. Eur J Heart Fail 2011;13:1244e52. Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation 2010;122:265e72. Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database Syst Rev 2005:CD003178. Paterna S, Di Pasquale P, Parrinello G, Fornaciari E, Di GF, Fasullo S, et al. Changes in brain natriuretic peptide levels and bioelectrical impedance measurements after treatment with high-dose furosemide and hypertonic saline solution versus high-dose furosemide alone in refractory congestive heart failure: a double-blind study. J Am Coll Cardiol 2005;45:1997e2003. Licata G, Di Pasquale P, Parrinello G, Cardinale A, Scandurra A, Follone G, et al. Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as bolus in refractory congestive heart failure: longterm effects. Am Heart J 2003;145:459e66. Paterna S, Di Pasquale P, Parrinello G, Amato P, Cardinale A, Follone G, et al. Effects of high-dose furosemide and small-volume hypertonic saline solution infusion in comparison with a high dose of furosemide as a bolus, in refractory congestive heart failure. Eur J Heart Fail 2000;2:305e13. Paterna S, Fasullo S, Parrinello G, Cannizzaro S, Basile I, Vitrano G, et al. Short-term effects of hypertonic saline solution in acute heart failure and long-term effects of a moderate sodium restriction in patients with compensated heart failure with New York Heart Association class III (class C) (SMAC-HF study). Am J Med Sci 2011;342: 27e37. Costanzo MR, Guglin ME, Saltzberg MT, Jessup ML, Bart BA, Teerlink JR, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49:675e83. Patarroyo M, Wehbe E, Hanna M, Taylor DO, Starling RC, Demirjian S, et al. Cardiorenal outcomes after slow continuous ultrafiltration therapy in refractory patients with advanced decompensated heart failure. J Am Coll Cardiol 2012;60:1906e12. 386 Journal of Cardiac Failure Vol. 19 No. 6 June 2013 42. Bart BA, Goldsmith SR, Lee KL, Givertz MM, O’Connor CM, Bull DA, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012;367:2296e304. 43. VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002;287:1531e40. 44. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487e91. 45. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA 2005;293:1900e5. 46. Scios. Panel of cardiology experts provides recommendations to Scios regarding NATRECOR. 2005. Available at: http://www sciosinc com/scios/pr_1118721302. 47. Westfall TC, Westfall DP. Adrenergic agonists and antagonists. In: Brunton LL, Chabner B, Knollman B, editors. Goodman & Oilman’s The Pharmacological Basis of Therapeutics. l2th ed. New York: McGraw-Hill; 2011. p. 277e334. 48. Kellum JA, Decker M. Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med 2001;29:1526e31. 49. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J, Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Lancet 2000; 356:2139e43. 50. Elkayam U, Ng TM, Hatamizadeh P, Janmohamed M, Mehra A. Renal vasodilatory action of dopamine in patients with heart failure: magnitude of effect and site of action. Circulation 2008;117:200e5. 51. Giamouzis G, Butler J, Starling RC, Karayannis G, Nastas J, Parisis C, et al. Impact of dopamine infusion on renal function in hospitalized heart failure patients: results of the Dopamine in Acute Decompensated Heart Failure (DAD-HF) trial. J Card Fail 2010;16: 922e30. 52. Gottlieb SS, Brater DC, Thomas I, Havranek E, Bourge R, Goldman S, et al. BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation 2002;105:1348e53. 53. Vallon V, Miracle C, Thomson S. Adenosine and kidney function: potential implications in patients with heart failure. Eur J Heart Fail 2008;10:176e87. 54. Slawsky MT, Givertz MM. Rolofylline: a selective adenosine 1 receptor antagonist for the treatment of heart failure. Expert Opin Pharmacother 2009;10:311e22. 55. Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM, O’Connor CM, Metra M, et al. The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment. J Card Fail 2008;14:631e40. 56. Voors AA, Dittrich HC, Massie BM, DeLucca P, Mansoor GA, Metra M, et al. Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). J Am Coll Cardiol 2011;57:1899e907. 57. Teerlink JR, Iragui VJ, Mohr JP, Carson PE, Hauptman PJ, Lovett DH, et al. The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT. Drug Saf 2012;35:233e44. 58. Givertz MM. Adenosine A1 receptor antagonists at a fork in the road. Circ Heart Fail 2009;2:519e22. 59. Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M. Relaxin: review of biology and potential role in treating heart failure. Curr Heart Fail Rep 2010;7:75e82. 60. Du XJ, Bathgate RA, Samuel CS, Dart AM, Summers RJ. Cardiovascular effects of relaxin: from basic science to clinical therapy. Nat Rev Cardiol 2010;7:48e58. 61. Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2013;381:29e39. 62. Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 2002;287:1541e7. 63. Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial. JAMA 2007;297:1883e91. 64. O’Connor CM, Gattis WA, Uretsky BF, Adams KF Jr, McNulty SE, Grossman SH, et al. Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J 1999;138:78e86. 65. Cohn JN, Goldstein SO, Greenberg BH, Lorell BH, Bourge RC, Jaski BE, et al, Vesnarinone Trial Investigators. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. N Engl J Med 1998;339:1810e6. 66. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, et al, PROMISE Study Research Group. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991;325:1468e75. 67. Cowley AJ, Skene AM, Enoximone Investigators. Treatment of severe heart failure: quantity or quality of life? A trial of enoximone. Br Heart J 1994;72:226e30. 68. Teerlink JR, Clarke CP, Saikali KG, Lee JH, Chen MM, Escandon RD, et al. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study. Lancet 2011;378:667e75. 69. Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K, et al. Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science 2011;331:1439e43. 70. Cleland JG, Teerlink JR, Senior R, Nifontov EM, McMurray JJ, Lang CC, et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a doubleblind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 2011;378:676e83. 71. Mitrovic V, Luss H, Nitsche K, Forssmann K, Maronde E, Fricke K, et al. Effects of the renal natriuretic peptide urodilatin (ularitide) in patients with decompensated chronic heart failure: a double-blind, placebo-controlled, ascending-dose trial. Am Heart J 2005;150: 1239.e2ee8. 72. Mitrovic V, Seferovic PM, Simeunovic D, Ristic AD, Miric M, Moiseyev VS, et al. Haemodynamic and clinical effects of ularitide in decompensated heart failure. Eur Heart J 2006;27:2823e32. 73. Maisel A, Mueller C, Nowak R, Peacock WF, Landsberg JW, Ponikowski P, et al. Mid-region pro-hormone markers for diagnosis and prognosis in acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol 2010;55:2062e76. 74. Rehman SU, Mueller T, Januzzi JL Jr. Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure. J Am Coll Cardiol 2008;52:1458e65. 75. Januzzi JL Jr, Peacock WF, Maisel AS, Chae CU, Jesse RL, Baggish AL, et al. Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Proe Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol 2007;50:607e13. 76. Maisel AS, Mueller C, Fitzgerald R, Brikhan R, Hiestand BC, Iqbal N, et al. Prognostic utility of plasma neutrophil gelatinaseassociated lipocalin in patients with acute heart failure: the NGAL Evaluation Along With B-Type Natriuretic Peptide in Acutely Update on Acute Decompensated Heart Failure 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. Decompensated Heart Failure (GALLANT) trial. Eur J Heart Fail 2011;13:846e51. Shrestha K, Borowski AG, Troughton RW, Thomas JD, Klein AL, Tang WH. Renal dysfunction is a stronger determinant of systemic neutrophil gelatinase-associated lipocalin levels than myocardial dysfunction in systolic heart failure. J Card Fail 2011;17:472e8. Breidthardt T, Socrates T, Drexler B, Noveanu M, Heinisch C, Arenja N, et al. Plasma neutrophil gelatinase-associated lipocalin for the prediction of acute kidney injury in acute heart failure. Crit Care 2012;16:R2. Collins SP, Hart KW, Lindsell CJ, Fermann GJ, Weintraub NL, Miller KF, et al. Elevated urinary neutrophil gelatinase-associated lipocalcin after acute heart failure treatment is associated with worsening renal function and adverse events. Eur J Heart Fail 2012;14: 1020e9. Dupont M, Shrestha K, Singh D, Awad A, Kovach C, Scarcipino M, et al. Lack of significant renal tubular injury despite acute kidney injury in acute decompensated heart failure. Eur J Heart Fail 2012;14: 597e604. Maisel A, Xue Y, Shah K, Mueller C, Nowak R, Peacock WF, et al. Increased 90-day mortality in patients with acute heart failure with elevated copeptin: secondary results from the Biomarkers in Acute Heart Failure (BACH) study. Circ Heart Fail 2011;4: 613e20. Shah RV, Chen-Tournoux AA, Picard MH, van Kimmenade RR, Januzzi JL. Galectin-3, cardiac structure and function, and longterm mortality in patients with acutely decompensated heart failure. Eur J Heart Fail 2010;12:826e32. van Kimmenade RR, Januzzi JL Jr, Ellinor PT, Sharma UC, Bakker JA, Low AF, et al. Utility of amino-terminal proebrain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure. J Am Coll Cardiol 2006;48:1217e24. Ky B, French B, Levy WC, Sweitzer NK, Fang JC, Wu AH, et al. Multiple biomarkers for risk prediction in chronic heart failure. Circ Heart Fail 2012;5:183e90. Sabatine MS, Morrow DA, de Lemos JA, Gibson CM, Murphy SA, Rifai N, et al. Multimarker approach to risk stratification in nonST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation 2002;105:1760e3. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med 2009;360:1418e28. Fonarow GC, Yancy CW, Heywood JT. Adherence to heart failure quality-of-care indicators in US hospitals: analysis of the ADHERE registry. Arch Intern Med 2005;165:1469e77. Heidenreich PA, Sahay A, Kapoor JR, Pham MX, Massie B. Divergent trends in survival and readmission following a hospitalization for heart failure in the Veterans Affairs Health Care System 2002 to 2006. J Am Coll Cardiol 2010;56:362e8. Gorodeski EZ, Starling RC, Blackstone EH. Are all readmissions bad readmissions? N Engl J Med 2010;363:297e8. Fonarow GC, Abraham WT, Albert NM, Stough WG, Gheorghiade M, Greenberg BH, et al. Association between performance measures and clinical outcomes for patients hospitalized with heart failure. JAMA 2007;297:61e70. Patterson ME, Hernandez AF, Hammill BG, Fonarow GC, Peterson ED, Schulman KA, et al. Process of care performance measures and long-term outcomes in patients hospitalized with heart failure. Med Care 2010;48:210e6. Hernandez AF, Fonarow GC, Liang L, Heidenreich PA, Yancy C, Peterson ED. The need for multiple measures of hospital quality: results from the Get With the GuidelineseHeart Failure Registry of the American Heart Association. Circulation 2011;124:712e9. Heidenreich PA, Hernandez AF, Yancy CW, Liang L, Peterson ED, Fonarow GC. Get With the Guidelines program participation, process of care, and outcome for medicare patients hospitalized with heart failure. Circ Cardiovasc Qual Outcomes 2012;5:37e43. Givertz et al 387 94. Hansen LO, Young RS, Hinami K, Leung A, Williams MV. Interventions to reduce 30-day rehospitalization: a systematic review. Ann Intern Med 2011;155:520e8. 95. Savard LA, Thompson DR, Clark AM. A meta-review of evidence on heart failure disease management programs: the challenges of describing and synthesizing evidence on complex interventions. Trials 2011;12:194. 96. Chaudhry SI, Mattera JA, Curtis JP, Spertus JA, Herrin J, Lin Z, et al. Telemonitoring in patients with heart failure. N Engl J Med 2010; 363:2301e9. 97. Bonow RO, Ganiats TG, Beam CT, Blake K, Casey DE Jr, Goodlin SJ, et al. ACCF/AHA/AMA-PCPI 2011 performance measures for adults with heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures and the American Medical AssociationPhysician Consortium for Performance Improvement. J Am Coll Cardiol 2012;59:1812e32. 98. Mudge A, Denaro C, Scott I, Bennett C, Hickey A, Jones MA. The paradox of readmission: effect of a quality improvement program in hospitalized patients with heart failure. J Hosp Med 2010;5:148e53. 99. Jaarsma T, van der Wal MH, Lesman-Leegte I, Luttik ML, Hogenhuis J, Veeger NJ, et al. Effect of moderate or intensive disease management program on outcome in patients with heart failure: Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH). Arch Intern Med 2008;168:316e24. 100. McAlister FA, Stewart S, Ferrua S, McMurray JJ. Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials. J Am Coll Cardiol 2004;44:810e9. 101. Whellan DJ, Hasselblad V, Peterson E, O’Connor CM, Schulman KA. Metaanalysis and review of heart failure disease management randomized controlled clinical trials. Am Heart J 2005;149: 722e9. 102. Hernandez AF, Greiner MA, Fonarow GC, Hammill BG, Heidenreich PA, Yancy CW, et al. Relationship between early physician follow-up and 30-day readmission among Medicare beneficiaries hospitalized for heart failure. JAMA 2010;303:1716e22. 103. Gheorghiade M, Peterson ED. Improving postdischarge outcomes in patients hospitalized for acute heart failure syndromes. JAMA 2011; 305:2456e7. 104. Epstein AM, Jha AK, Orav EJ. The relationship between hospital admission rates and rehospitalizations. N Engl J Med 2011;365: 2287e95. 105. Bradley EH, Curry L, Horwitz LI, Sipsma H, Thompson JW, Elma M, et al. Contemporary evidence about hospital strategies for reducing 30-day readmissions: a national study. J Am Coll Cardiol 2012;60:607e14. 106. Fonarow GC, Abraham WT, Albert NM, Stough WG, Gheorghiade M, Greenberg BH, et al. Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF. Arch Intern Med 2008;168:847e54. 107. Secko MA, Lazar JM, Salciccioli LA, Stone MB. Can junior emergency physicians use E-point septal separation to accurately estimate left ventricular function in acutely dyspneic patients? Acad Emerg Med 2011;18:1223e6. 108. Nazerian P, Vanni S, Zanobetti M, Polidori G, Pepe G, Federico R, et al. Diagnostic accuracy of emergency Doppler echocardiography for identification of acute left ventricular heart failure in patients with acute dyspnea: comparison with Boston criteria and N-terminal prohormone brain natriuretic peptide. Acad Emerg Med 2010;17: 18e26. 109. Volpicelli G, Caramello V, Cardinale L, Mussa A, Bar F, Frascisco MF. Bedside ultrasound of the lung for the monitoring of acute decompensated heart failure. Am J Emerg Med 2008;26: 585e91. 110. Kamath SA, Drazner MH, Tasissa G, Rogers JG, Stevenson LW, Yancy CW. Correlation of impedance cardiography with invasive hemodynamic measurements in patients with advanced heart failure: 388 Journal of Cardiac Failure Vol. 19 No. 6 June 2013 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. the Bioimpedance Cardiography (BIG) substudy of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. Am Heart J 2009;158:217e23. Tanino Y, Shite J, Paredes OL, Shinke T, Ogasawara D, Sawada T, et al. Whole body bioimpedance monitoring for outpatient chronic heart failure follow up. Circ J 2009;73:1074e9. Wang DJ, Gottlieb SS. Impedance cardiography: more questions than answers. Curr Cardiol Rep 2006;8:180e6. Piccoli A, Codognotto M, Cianci V, Vettore G, Zaninotto M, Plebani M, et al. Differentiation of cardiac and noncardiac dyspnea using bioelectrical impedance vector analysis (BIVA). J Card Fail 2012;18:226e32. Baggish AL, Siebert U, Lainchbury JG, Cameron R, Anwaruddin S, Chen A, et al. A validated clinical and biochemical score for the diagnosis of acute heart failure: the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Acute Heart Failure Score. Am Heart J 2006;151:48e54. Steinhart B, Thorpe KE, Bayoumi AM, Moe G, Januzzi JL Jr, Mazer CD. Improving the diagnosis of acute heart failure using a validated prediction model. J Am Coll Cardiol 2009;54: 1515e21. Maisel AS, Peacock WF, McMullin N, Jessie R, Fonarow GC, Wynne J, et al. Timing of immunoreactive B-type natriuretic peptide levels and treatment delay in acute decompensated heart failure: an ADHERE (Acute Decompensated Heart Failure National Registry) analysis. J Am Coll Cardiol 2008;52:534e40. West RL, Hernandez AF, O’Connor CM, Starling RC, Califf RM. A review of dyspnea in acute heart failure syndromes. Am Heart J 2010;160:209e14. Felker GM, Pang PS, Adams KF, Cleland JG, Cotter G, Dickstein K, et al. Clinical trials of pharmacological therapies in acute heart failure syndromes: lessons learned and directions forward. Circ Heart Fail 2010;3:314e25. Metra M, Felker GM, Zaca V, Bugatti S, Lombardi C, Bettari L, et al. Acute heart failure: multiple clinical profiles and mechanisms require tailored therapy. Int J Cardiol 2010;144:175e9. Forman DE, Butler J, Wang Y, Abraham WT, O’Connor CM, Gottlieb SS, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol 2004;43:61e7. Klein L, Massie BM, Leimberger JD, O’Connor CM, Pina IL, Adams KF Jr, et al. Admission or changes in renal function during hospitalization for worsening heart failure predict postdischarge survival: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF). Circ Heart Fail 2008;1:25e33. Metra M, Nodari S, Parrinello G, Bordonali T, Bugatti S, Danesi R, et al. Worsening renal function in patients hospitalised for acute heart failure: clinical implications and prognostic significance. Eur J Heart Fail 2008;10:188e95. Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO, Starling RC, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009;53:589e96. Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009; 53:582e8. Fallick C, Sobotka PA, Dunlap ME. Sympathetically mediated changes in capacitance: redistribution of the venous reservoir as a cause of decompensation. Circ Heart Fail 2011;4:669e75. Blair JE, Pang PS, Schrier RW, Metra M, Traver B, Cook T, et al. Changes in renal function during hospitalization and soon after discharge in patients admitted for worsening heart failure in the placebo group of the EVEREST trial. Eur Heart J 2011;32:2563e72. Udelson JE. Heart failure with preserved ejection fraction. Circulation 2011;124:e540e3. 128. Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol 2007;50:768e77. 129. Zile MR, Gaasch WH, Anand IS, Haass M, Little WC, Miller AB, et al. Mode of death in patients with heart failure and a preserved ejection fraction: results from the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial. Circulation 2010;121:1393e405. 130. Felker GM, Leimberger JD, Califf RM, Cuffe MS, Massie BM, Adams KF Jr, et al. Risk stratification after hospitalization for decompensated heart failure. J Card Fail 2004;10:460e6. 131. O’Connor CM, Abraham WT, Albert NM, Clare R, Gattis Stough W, Gheorghiade M, et al. Predictors of mortality after discharge in patients hospitalized with heart failure: an analysis from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF). Am Heart J 2008;156:662e73. 132. O’Connor CM, Hasselblad V, Mehta RH, Tasissa G, Califf RM, Fiuzat M, et al. Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score. J Am Coll Cardiol 2010;55:872e8. 133. Peterson PN, Rumsfeld JS, Liang L, Albert NM, Hernandez AF, Peterson ED, et al. A validated risk score for in-hospital mortality in patients with heart failure from the American Heart Association Get With the Guidelines program. Circ Cardiovasc Qual Outcomes 2010;3:25e32. 134. Hsieh M, Auble TE, Yealy DM. Validation of the Acute Heart Failure Index. Ann Emerg Med 2008;51:37e44. 135. Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD, Cropp AB, et al. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation 2006;113:1424e33. 136. Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95:2660e7. 137. Goda A, Williams P, Mancini D, Lund LH. Selecting patients for heart transplantation: comparison of the Heart Failure Survival Score (HFSS) and the Seattle Heart Failure Model (SHFM). J Heart Lung Transpl 2011;30:1236e43. 138. Allen LA, Gheorghiade M, Reid KJ, Dunlay SM, Chan PS, Hauptman PJ, et al. Identifying patients hospitalized with heart failure at risk for unfavorable future quality of life. Circ Cardiovasc Qual Outcomes 2011;4:389e98. 139. Metra M, Teerlink JR, Felker GM, Greenberg BH, Filippatos G, Ponikowski P, et al. Dyspnoea and worsening heart failure in patients with acute heart failure: results from the Pre-RELAX-AHF study. Eur J Heart Fail 2010;12:1130e9. 140. Metra M, O’Connor CM, Davison BA, Cleland JG, Ponikowski P, Teerlink JR, et al. Early dyspnoea relief in acute heart failure: prevalence, association with mortality, and effect of rolofylline in the PROTECT study. Eur Heart J 2011;32:1519e34. 141. Ezekowitz JA, Hernandez AF, O’Connor CM, Starling RC, Proulx G, Weiss MH, et al. Assessment of dyspnea in acute decompensated heart failure: insights from ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) on the contributions of peak expiratory flow. J Am Coll Cardiol 2012;59: 1441e8. 142. Allen LA, Hernandez AF, O’Connor CM, Felker GM. End points for clinical trials in acute heart failure syndromes. J Am Coll Cardiol 2009;53:2248e58. 143. Gheorghiade M, Ruschitzka F. Beyond dyspnoea as an endpoint in acute heart failure trials. Eur Heart J 2011;32:1442e5. 144. Teerlink JR. Dyspnea as an end point in clinical trials of therapies for acute decompensated heart failure. Am Heart J 2003;145:S26e33. 145. Packer M, Abraham WT, Mehra MR, Yancy CW, Lawless CE, Mitchell JE, et al. Utility of impedance cardiography for the Update on Acute Decompensated Heart Failure 146. 147. 148. 149. 150. 151. 152. 153. 154. identification of short-term risk of clinical decompensation in stable patients with chronic heart failure. J Am Coll Cardiol 2006;47: 2245e52. Conraads VM, Tavazzi L, Santini M, Oliva F, Gerritse B, Yu CM, et al. Sensitivity and positive predictive value of implantable intrathoracic impedance monitoring as a predictor of heart failure hospitalizations: the SENSE-HF trial. Eur Heart J 2011;32:2266e73. van Veldhuisen DJ, Braunschweig F, Conraads V, Ford I, Cowie MR, Jondeau G, et al. Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with heart failure. Circulation 2011; 124:1719e26. Whellan DJ, Ousdigian KT, Al-Khatib SM, Pu W, Sarkar S, Porter CB, et al. Combined heart failure device diagnostics identify patients at higher risk of subsequent heart failure hospitalizations: results from PARTNERS HF (Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure) study. J Am Coll Cardiol 2010;55:1803e10. Ritzema J, Troughton R, Melton I, Crozier I, Doughty R, Krum H, et al. Physician-directed patient self-management of left atrial pressure in advanced chronic heart failure. Circulation 2010;121:1086e95. Sharma GV, Woods PA, Lindsey N, O’Connell C, Connolly L, Joseph J, et al. Noninvasive monitoring of left ventricular enddiastolic pressure reduces rehospitalization rates in patients hospitalized for heart failure: a randomized controlled trial. J Card Fail 2011; 17:718e25. Givertz MM. Hemodynamic monitoring to guide treatment of acute heart failure. J Card Fail 2011;17:726e8. Januzzi JL Jr, Rehman SU, Mohammed AA, Bhardwaj A, Barajas L, Barajas J, et al. Use of amino-terminal proeB-type natriuretic peptide to guide outpatient therapy of patients with chronic left ventricular systolic dysfunction. J Am Coll Cardiol 2011;58:1881e9. Bernheim SM, Grady JN, Lin Z, Wang Y, Wang Y, Savage SV, et al. National patterns of risk-standardized mortality and readmission for acute myocardial infarction and heart failure. Update on publicly reported outcomes measures based on the 2010 release. Circ Cardiovasc Qual Outcomes 2010;3:459e67. Storrow AB, Collins SP, Lyons MS, Wagoner LE, Gibler WB, Lindsell CJ. Emergency department observation of heart failure: 155. 156. 157. 158. 159. 160. 161. 162. 163. Givertz et al 389 preliminary analysis of safety and cost. Congest Heart Fail 2005; 11:68e72. Rokos IC, French WJ, Koenig WJ, Stratton SJ, Nighswonger B, Strunk B, et al. Integration of pre-hospital electrocardiograms and ST-elevation myocardial infarction receiving center (SRC) networks: impact on Door-to-balloon times across 10 independent regions. JACC Cardiovasc Interv 2009;2:339e46. Keenan PS, Normand SL, Lin Z, Drye EE, Bhat KR, Ross JS, et al. An administrative claims measure suitable for profiling hospital performance on the basis of 30-day all-cause readmission rates among patients with heart failure. Circ Cardiovasc Qual Outcomes 2008;1: 29e37. Philbin EF, DiSalvo TG. Prediction of hospital readmission for heart failure: development of a simple risk score based on administrative data. J Am Coll Cardiol 1999;33:1560e6. Petrucci RJ, Benish LA, Carrow BL, Prato L, Hankins SR, Eisen HJ, et al. Ethical considerations for ventricular assist device support: a 10-point model. ASAIO J 2011;57:268e73. Entwistle JW, Sade RM, Petrucci RJ. The ethics of mechanical support: the need for new guidelines. Ann Thorac Surg 2011;92: 1939e42. Goodlin SJ. Palliative care in congestive heart failure. J Am Coll Cardiol 2009;54:386e96. Evangelista LS, Lombardo D, Malik S, Ballard-Hernandez J, Motie M, Liao S. Examining the effects of an outpatient palliative care consultation on symptom burden, depression, and quality of life in patients with symptomatic heart failure. J Card Fail 2012; 18:894e9. Gheorghiade M, Albaghdadi M, Zannad F, Fonarow GC, Bohm M, Gimpelewicz C, et al. Rationale and design of the multicentre, randomized, double-blind, placebo-controlled Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT). Eur J Heart Fail 2011;13: 100e6. Gheorghiade M, Bohm M, Greene SJ, Fonarow GC, Lewis EF, Zannad F, et al. Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. JAMA 2013; 309:1125e35.