The Rationale for an Acute Heart Failure Syndromes Clinical Trials Network

Journal of Cardiac Failure Vol. 15 No. 6 2009

Clinical Trials: Methods and Design

The Rationale for an Acute Heart Failure Syndromes Clinical Trials Network SEAN P. COLLINS, MD, MSc,1 PHILLIP D. LEVY, MD, MPH,2 CHRISTOPHER J. LINDSELL, PhD,1 PETER S. PANG, MD,3 ALAN B. STORROW, MD,4 CHADWICK D. MILLER, MD,5 ALLEN J. NAFTILAN, MD, PhD,4 VINAY THOHAN, MD,5 WILLIAM T. ABRAHAM, MD,6 BRIAN HIESTAND, MD, MPH,6 GERASIMOS FILIPPATOS, MD,7 DEBORAH B. DIERCKS, MD,8 JUDD HOLLANDER, MD,9 RICHARD NOWAK, MD,10 W. FRANK PEACOCK, MD,11 AND MIHAI GHEORGHIADE, MD3 Cincinnati, Ohio; Detroit, Michigan; Chicago, Illinois; Nashville, Tennessee; Winston-Salem, North Carolina; Columbus, Ohio; Athens, Greece; Sacramento, California; Philadelphia, Pennsylvania; Cleveland, Ohio

ABSTRACT Background: Clinical trials involving novel therapies treating acute heart failure syndromes (AHFS) have shown limited success with regard to both efficacy and safety. As a direct result, outcomes have changed little over time and AHFS remains a disease process associated with largely no change in hospitalization rates (80%), hospital length of stay (median 4.5 days), and in-hospital (4-7%) and 60-day mortality (10%). Despite extensive emergency department (ED) involvement during the initial phase of AHFS management, clinical trials have enrolled patients after the ED phase of management, up to 48 hours after initial therapy, long after many patients have experienced significant beneficial effects of standard therapy. As standard therapy has provided symptomatic improvement in up to 70% of patients in these trials, it is not surprising that investigational agents started after 24 to 48 hours of standard therapy have shown limited clinical efficacy when compared with standard therapy. Methods and Results: The ability to screen, enroll, and randomize in the emergency setting is fundamental. The unique environment, the ethical complexities of enrollment in emergency-based research, and the need for rapid and standardized study-compliant care represent key challenges to active recruitment in AHFS studies. Specifically, the ability to identify and enroll a large cohort of AHFS patients early (!6 hours) in their presentation has been cited as the primary barrier to the appropriate design of clinical trials that includes this early window. Conclusions: In response, we have created a network of dedicated academic physicians with experience in clinical trials and acute management of heart failure who together can surmount this barrier and provide a framework for conducting early trials in AHFS. (J Cardiac Fail 2009;15:467e474) Key Words: Acute heart failure syndromes, clinical trials network, emergency department, cardiology.

In 2005, there were more than 1 million hospital discharges with a primary diagnosis of heart failure, consuming 3% of the total national health care budget.1e3 The introduction of b-blockers and angiotensin-converting enzyme inhibitors have led to tremendous advances in chronic heart failure management. Conversely, clinical trial results for novel therapies treating acute heart failure syndromes (AHFS) have shown limited success with regard to both efficacy and safety.4e7 As a direct result, AHFS remains a disease process with largely no change in hospitalization rates (80%), hospital length of stay (LOS; median 4.5 days), and in-hospital (4% to 7%) and 60-day mortality (10%).5,8e12

From the 1University of Cincinnati, Cincinnati, OH; 2Wayne State University, Detroit, MI; 3Northwestern University, Chicago, IL; 4Vanderbilt University, Nashville, TN; 5Wake Forest University, Winston-Salem, NC; 6 Ohio State University, Columbus, OH; 7Evangelismos Hospital, Athens, Greece; 8University of California-Davis, Sacramento, CA; 9University of Pennsylvania, Philadelphia, PA; 10Henry Ford Hospital, Detroit, MI and 11 The Cleveland Clinic, Cleveland, OH. Manuscript received September 4, 2007; revised manuscript received October 21, 2008; revised manuscript accepted December 22, 2008. Correspondence to: Sean P. Collins, MD, MSc, University of Cincinnati College of Medicine, Department of Emergency Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0769. 1071-9164/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2008.12.013

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468 Journal of Cardiac Failure Vol. 15 No. 6 August 2009 The primary driver for this lack of change is unknown. One potential explanation is that it reflects the confluence of improved management in a sicker patient population. Specifically, as patients with heart failure are living longer, they tend to have a greater number of comorbidities, leading to a more complex disease course. An alternative possibility is that a stagnation in acute heart failure treatment exists, which in turn, is a consequence of prevailing clinical trial design.13 Clinical trials have traditionally enrolled highly select patients long after their acute presentation resulting in minimal therapeutic success. As such, there has been limited progress in the identification of effective, novel interventions for AHFS resulting in a limited ability of clinicians to influence associated outcomes. Consequently, there is a need for further investigation and reappraisal of how current AHFS clinical trials are conducted. The Role of the Emergency Department in AHFS Management Approximately 80% of hospital admissions from AHFS originate in the emergency department (ED).14e16 While in the ED, these patients undergo lengthy diagnostic and therapeutic interventions. Improved survival from myocardial infarction, an aging population, and hospital overcrowding have also resulted in an increased ED burden of acute heart failure management. Accordingly, emergency physicians are ideally positioned to have a significant impact on the acute care of these patients. The majority of patients with AHFS who are admitted to the hospital receive a significant amount of their initial care in the ED before admission. This is a direct result of a lack of inpatient bed availability; the delay in inpatient bed availability increases ED LOS. Further, lack of inpatient bed availability has a greater impact on ED LOS than ED treatment or processes.17e19 With previous studies suggesting a mean ED LOS for patients admitted with AHFS to be approximately 5 hours, emergency physicians are delivering both acute and ongoing heart failure care.18 This is compounded by a growing demand for ED services, as highlighted by the Institute of Medicine and the Centers for Disease Control and Prevention, which show a 26% increase in ED visits and a concurrent 10% decrease in the number of EDs between 1993 and 2003.20 Although ED and hospital overcrowding can lead to an overstretching of available resources and potentially limit the extent of care provided, by necessity patients receive a large proportion of their early care in the ED. Because the ED component of treatment often influences the subsequent 24 hours of care21,22 emergency physicians set the stage for acute and ongoing heart failure care. Rationale for ED Enrollment in Therapeutic Trials Definition of AHFS

AHFS has been previously defined as the gradual or rapid onset of heart failure signs and symptoms requiring urgent

therapy.23 Because the ED is the primary avenue through which the vast majority of AHFS patients initially present and are subsequently admitted, it is the location where urgent therapy is delivered. Although 24 to 48 hours after admission remains a critical time period for optimization of ongoing management, the acute phase of disease is largely dissipated; investigation of AHFS treatment during this period, depending on the target of intervention, may therefore lead to a diminished likelihood of anticipated response. Recent data suggest that patients who present to the ED may not be adequately represented in clinical trials. Patients who are enrolled in clinical trials must meet stringent inclusion and exclusion criteria resulting in a study specific population that is derived from, but different, than the general acute heart failure pool. Differences in the demographics and clinical characteristics between AHFS patients as identified by registry data and those enrolled in AHFS clinical trials are highlighted in Table 1. Registry patients tend to be older, female, and more often have preserved systolic function. Capturing ED patients will not only facilitate enrollment of a more representative sample of AHFS patients that is unbiased by admission decisions, it will also allow us to evaluate the impact of early investigational therapy on AHFS symptoms. Patient Selection and Timing of Enrollment

Despite extensive ED involvement during the initial phase of AHFS management, the potential impact of early therapy has not been accounted for in the design of therapeutic trials. The majority of trials have enrolled patients up to 48 hours after initial therapy, well after most patients have experienced significant improvement in symptoms. A recent ED-based prospective, international study of dyspnea suggests that dyspnea improves dramatically within Table 1. Demographics and Clinical Characteristics of Patients Enrolled in Registries and Clinical Trials

Study VMAC 5 EVEREST

Reduced Prior LVEF (% Heart Renal with EF Age Women White Failure Dysfunction !40% or (y) (%) (%) (%) (%) Mean EF) 61 66

31 26

58 85

84 79

21 27

85 Mean EF 27%

70

40

86

73

36

Mean EF 29%

72

52

74

76

30

51

OPTIMIZE 73

52

d

63

d

51

4

VERITAS 74

ADHERE 75 76

ADHERE, Acute Decompensated Heart Failure National Registry; EF, ejection fraction; EVEREST, Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan; LVEF, left ventricular ejection fraction; OPTIMIZE, Organized Program To Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure; VERITAS, The Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Studies; VMAC, Vasodilation in the Management of Acute Congestive Heart Failure.

Rationale for an Acute Heart Failure Syndromes Clinical Trials Network

6 hours of ED treatment, and by 24 hours it is less than 40% of its original magnitude.24 Because many trials require dyspnea for inclusion, enrolling patients 24 to 48 hours into their hospital course selects only those patients with residual dyspnea despite standard therapy. Further, in those patients with continued symptoms, initial therapy (diuretics and inotropes) may have deleterious downstream effects. Previous studies of diuretics suggest not only an association with adverse outcomes, but perhaps a direct cause and effect.25e30 In particular, the development of in-hospital renal dysfunction, a common consequence of overdiuresis, has been associated with increased in-hospital mortality.31e33 Achievement of symptomatic improvement should not be at the expense of worsened morbidity and mortality. We hypothesize that the medication regimen and the ‘‘route one travels’’ to symptomatic improvement is important and may play a role in preserving renal function and hibernating myocardium while avoiding a significant decline in blood pressure. Critical to this hypothesis is an understanding that trial design and timing are as important as the type of intervention. For agents targeting symptom improvements, patients should be enrolled when symptoms are maximal, minimizing concomitant therapy, if the effect of a novel agent is to be determined. For optimal success, the effect of acute therapy on symptoms and outcomes should be matched with an enrollment strategy that targets patients at the appropriate phase of the heart failure disease continuum. A previous consensus statement has identified a patient’s position in the heart failure disease continuum according to 3 distinct phases (Fig 1).23 Stage A trials are designed to investigate symptoms existent on acute presentation, when the duration of the intervention is expected to be 24 to 48 hours. Clinical parameters available a short time after presentation (blood pressure, renal function, serum sodium) facilitate early stratification. Stage B trials, on the other hand, would be conducted during hospitalization and would target patients that continue to have symptoms despite initial therapy, aiming to achieve euvolemia, setting the stage for initiation of longer term therapeutic regimens known to impact long-

Stage A

Time Frame:

< 48 hours

Possible Endpoints: Hemodynamic parameters Dyspnea scores Mechanical ventilation rates ICU admission rates Mortality Creatinine Serum Sodium Hospital LOS



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term outcomes (eg, oral b-blockers and angiotensinconverting enzyme inhibitors). Stage C trials focus on improving postdischarge outcomes. Although novel therapies have been developed as Stage A agents, clinical trial design has studied them as Stage B interventions, perhaps from perceived difficulty in clinical trial implementation in the ED. By discounting initial ED treatment, there is potential for mismatching target enrollment populations with stagespecific symptoms and outcomes. Evidence for this can be seen in data available from prior studies, which demonstrate symptomatic improvement with standard therapy in up to 70% of patients.4,5 As a result, trials that have, by design, studied an investigational agent expected to be effective in Stage A, to see if it works better than standard therapy in the remaining 30% of patients who have significant persistent symptoms, have yielded de facto Stage B trials, making it difficult to demonstrate a clinically relevant impact. Both Stage A and B trials are needed to study acute and residual symptoms, respectively. However, it is not surprising those investigational agents that should be effective in Stage A, when started after the first 24 hours of care, have shown only limited clinical improvement in symptomatology when compared with standard therapy. Several key principles underlay focused enrollment of the ED AHFS population. First, agents designed to provide acute hemodynamic improvement and symptom relief should be administered when symptoms are most severe (ie, Stage A). This principle is inconsistent with the study design of most AHFS clinical trials, which have focused on patients with persistent symptoms despite standard therapy. Second, the timing of enrollment and the intervention studied should be dictated not only by the severity of symptoms and type of clinical end point targeted (eg, dyspnea, renal function, mortality), but also the likelihood of endpoint occurrence during the specified stage of intervention. It is apparent that therapeutic agents are not being matched with the proper ‘‘stage’’ of AHFS presentation. There is an optimal time point for enrolling patients in Stage A studies, which we suggest is earlier than that

Stage B

Stage C

48 hours to discharge

Outpatient

Hospital LOS Mortality Serum sodium, creatinine Residual dyspnea resolution Hospital readmission rates

Mortality ED revisit rates Hospital readmission rates Quality of Life Indicators

Fig. 1. Continuum of acute heart failure stages for clinical trials.

470 Journal of Cardiac Failure Vol. 15 No. 6 August 2009 traditionally used in AHFS clinical trials. It is the time when a patient has not shown immediate improvement to initial therapy and thus may benefit from investigational therapy. Waiting longer than this, however, increases the likelihood that a patient will: have a delayed resolution of their symptoms with additional standard therapy, be considered a standard therapy failure or receive therapy too late to disrupt underlying processes that contribute to renal or myocardial dysfunction. In essence, the effect of delayed enrollment is to reduce the likelihood of an investigational therapy performing well because patients either can’t improve significantly or will not further improve. End Points for Stage A Clinical Trial Design

By alleviating congestion and preserving myocardial and renal function, we hypothesize that early therapy may have a beneficial effect on near-term outcomes such as need for respiratory support, intensive care unit admission, and inhospital mortality. Previous data suggest that appropriate early therapy provides rapid symptomatic improvement while concurrently minimizing renal dysfunction and subsequent adverse events.30,34,35 Key to such an approach is alignment of the mechanism of the therapeutic agent with the underlying disease process. Thus, we also hypothesize that early enrollment strategies will permit the identification of AHFS patient subsets such as those who are hypertensive or hyponatremic that are more likely to benefit from specific early treatment (ie, intravenous vasodilators and vasopressin antagonists, respectively). Improving signs and symptoms may additionally set the stage for optimization of congestion during the inpatient phase of care. Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) and Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) demonstrated substantial improvement in symptoms with both standard and investigational therapy.4,5 We would expect the earlier use of such investigational therapy would have a similar if not greater effect. The potential benefit of early enrollment and early therapy has been suggested by the noninvasive positive pressure ventilation and high-dose nitrate trials.30,34,36,37 Because of such a dramatic improvement in outcomes among these acutely ill patients, superiority was demonstrated with a relatively small number of patients. It is plausible, therefore, that delayed enrollment may have contributed to the limited beneficial effects demonstrated in recent clinical trial of vasopressin antagonists and novel intravenous vasodilators.4,5,38 Based on the aforementioned data, we hypothesize that earlier initiation of vasodilator and vasopressin antagonist therapy in the ED would be expected to not only improve symptoms quicker than standard therapy, but also avoid the potentially detrimental effects of other rescue therapy such as high-dose diuretics and inotropes. An early enrollment strategy also permits a more comprehensive understanding of how early treatment

contributes to, or prevents, renal dysfunction, myocardial injury, extended in-hospital LOS, and other more protracted end points. We hypothesize that short- and intermediate-term outcomes (5 days through 30 days) such as in-hospital mortality, delayed or prolonged intubation, LOS, and early recidivism are more likely to be related to acute treatment and its impact on clinical variables such as blood pressure, serum sodium, renal function, myocardial preservation, and congestion.8,39e41 The limited available data support this assertion.30,34,35 Conversely, long-term outcomes (60 days, 180 days) are largely related to underlying disease and behavioral issues such as medication nonadherence and dietary indiscretion.42,43 Interventions aimed at education, dietary and medication assessment, discharge planning, and close outpatient follow-up reduce AHFS long-term outcomes and readmissions.44 Translation of Clinical Trial Data to ED Practice

Failure to capture patients in the ED setting has the potential to limit the acceptance of a medication or intervention by emergency physicians. To facilitate implementation, outcome level data are needed that suggest that an adjunct or intervention needs to be used in a timely fashion while the patient is in the ED and improves clinically relevant endpoints (such as patient symptoms or outcomes), before it achieves wide acceptance. These criteria emanate from a culture of competing resources that is abundant in every ED. The number of interventions that can be accomplished by an ED team in any given period is relatively constant. Thus, providing a therapy to one patient may deprive another patient of nursing or physician time for other interventions. As a result, emergency physicians are encouraged to carefully choose their patient interventions. This may lead to positive inpatient clinical trial data being not accepted as an ‘‘ED therapy’’ due to lack of ED relevant data. However, successful inpatient trials may serve as the foundation for properly designed ED-based trials. Emergency Management and Research Group in Acute Heart Failure (EMERG-HF)

Until recently, the ability to identify and enroll a large cohort of AHFS patients early (!6 hours) in their presentation has been cited as the primary barrier to the design of clinical trials that includes this early window. We have therefore created a network of dedicated academic physicians with experience in clinical trials and acute management of heart failure who together can surmount these challenges and provide a framework for what has been an unexplored hypothesis in acute heart failure trial design. An early enrollment strategy requires the ability to screen, enroll, and randomize in the emergency setting. The unique environment, the ethical complexities of enrollment in emergency-based research, and the need for rapid and standardized study-compliant care represent key challenges to active recruitment in AHFS studies. ED

Rationale for an Acute Heart Failure Syndromes Clinical Trials Network

enrollment in acute coronary syndromes trials has shown that early enrollment is not only feasible, but beneficial. Several trials have demonstrated improved outcomes when patients are enrolled in the ED compared with delayed enrollment after ED management.64-66 When guideline-based therapies are started in the ED, hospitals are more likely to have better composite quality improvement scores compared with hospitals whose EDs do not use guideline-driven care.67 Moreover, because 80% of hospital admissions for AHFS originate in the ED, issues of compliance and poor social behaviors are not unique to ED patients with AHFS. Compliance and follow-up in several large-scale ED-based AHFS trials has been shown to be similar to studies initiated later in the hospital course.45,47,57,68 The EMERG-HF collaborative network was formed to facilitate early enrollment in acute heart failure trials. EMERG-HF members are composed equally of cardiologists and emergency physicians who have directed numerous cardiovascular trials, and, specifically, acute ED cardiovascular trials and are leaders in emergency medicine research.45,47,57,58,69e71 Our strength as a unified entity of collaborating heart failure clinicians to recruit patients is unparalleled in ED-based research. Members of the group have demonstrated a unique ability to design and conduct trials that recruit patients early in their treatment course, capturing the impact of ED treatment on patient symptomatology.34,57,68 Of major importance is our ability to provide seamless transition from ED to inpatient and followup care through an existing framework of collaboration with expert heart failure cardiologists. Although early enrollment is critical, a longitudinal care structure is a key component to outcomes-based AHFS research. An active ED-cardiology alliance is thus an essential prerequisite for network participation. EMERG-HF, therefore, is poised to be a focal point for the conduction of ED-based clinical trials from inception through recruitment of patients to analysis and publication. This AHFS clinical trial network is codirected by a heart failure cardiologist and emergency physician at each participating institution. These 2 physicians lead an interdisciplinary team of emergency physicians, cardiologists, nurses, and study assistants who assist with patient identification and enrollment. Research nurses and emergency physicians take call to aid in patient identification, consent, and randomization; this reflects the role of the emergency physician in the initial identification and treatment of the AHFS patient in clinical practice. Similarly, the cardiovascular team takes responsibility for patient transition from the ED to the cardiology service, ensuring continuity of the research process for the patient with treatment provided by specialists responsible for patient care. This model has been successful in previous ED-based diagnostic and therapeutic cardiovascular trials.45,68,72 This model can also be easily incorporated in the National Institutes of Health Clinical and Translational Science Awards emergency care subnetwork that is being developed.



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Patient Enrollment in Stage A AHFS Trials Patient Identification

It should be recognized that one of the limitations of early enrollment is inappropriate patient identification. This is a ‘‘real-world’’ situation that occurs daily in the treatment of patients with AHFS. It is important to test the effectiveness of new therapies in a ‘‘real-world’’ setting where they might be prescribed for patients who ultimately do not have the disease. Objective classification schemes, highly specific for acute heart failure, play an extremely important role in patient identification. The use of several signs of congestion (jugular venous distension, rales, pulmonary edema on chest radiograph) along with reliable markers of ventricular dysfunction (natriuretic peptides) would minimize misclassification. Inclusion criteria would rely on objective evidence available within the first 1 to 2 hours of ED presentation and may include: 1. Dyspnea at rest, for example, using the provocative dyspnea assessment 24,73 2. BNP O500 or radiographic evidence of congestion 3. At least 1 of the following 2 criteria a. Prior medical history of heart failure (eg, prior hospitalization for AHFS) b. Clinical evidence of heart failure, including jugular venous distension, rales, or crackles, or pitting edema. However, caution must be exercised to avoid identifying a highly select group of patients and limiting the generalizability of study results. Unique Issues for Stage A AHFS Clinical Trials

Screening and identification of ED patients for clinical trials may occur via several research models. One model uses study assistants to screen the medical record as well as interview patients regarding their reason for ED presentation. After patients are identified, a research nurse or principal investigator would then be contacted to confirm subject eligibility. A second method uses research nurses to screen, identify, and enroll patients. The advent of electronic medical records facilitates the process of screening patients, identifying pertinent medical history and prior test results (ejection fraction, valvular disease) and enables rapid identification and patient enrollment. Although there is often one designated principal investigator, a team of ED faculty typically assists with patient identification, enrollment, and study-related questions. The issue of informed consent for AHFS patients can be difficult, but this is not seen as an impediment to ED participation in clinical trials. Processes for satisfying regulatory issues in ED-based studies have become wellestablished over the last decade. In the vast majority of situations, consent is obtained from the patient or their legally authorized representative. Although rare in AHFS patients, exception from informed consent may be necessary when an investigation occurs in patients who are clinically

472 Journal of Cardiac Failure Vol. 15 No. 6 August 2009 unstable and may lack the capacity to provide informed consent. Of final consideration is the potential impact that clinical trial enrollment may impart on ED LOS. It is possible for enrollment in a clinical trial to prolong ED LOS and measures to minimize this such as utilization of an observation or research unit should be considered. Though rapid admission might be prevented by a need to provide protocolguided care in the ED, such an approach may paradoxically improve throughput because of a defined transition driven by the research study itself.

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Conclusion 14.

Acute heart failure syndromes, by definition, require urgent therapy that occurs in the ED for the vast majority of patients. Despite extensive ED involvement during the initial phase of AHFS management, the impact of early therapy has not been accounted for in the design of therapeutic trials. Late enrollment, well after ED therapeutics have been administered, bypasses a unique window of opportunity for clinical trial design. The unique ED environment was previously thought to be an impediment to patient enrollment in acute clinical trials. Not only have those concerns been assuaged, large-scale AHFS trials can and should be conducted in the ED. Enrolling patients while in the ED, at the time of initial therapy when symptoms are still present, is a novel and needed strategy for AHFS trial design. EMERG-HF provides a framework within which such studies can be conducted.

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References 1. O’Connell JB, Bristow M. Economic impact of heart failure in the United States: a time for a different approach. J Heart Lung Trans 1994;13:S107e12. 2. Stevenson LW, Braunwald E. Recognition and management of patients with heart failure. In: Goldman L, Braunwald E, editors. Primary cardiology. Philadelphia: WB Saunders; 1998. p. 310e29. 3. American Heart Association. Heart disease and stroke statisticsd2005 update. Dallas, TX: AHA; 2004. 4. Gheorghiade M, Konstam MA, Burnett JC Jr, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA 2007;297:1332e43. 5. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002; 287:1531e40. 6. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA 2007;297:1883e91. 7. Luca LD, Fonarow GC, Mebazaa A, et al. Acute heart failure syndromes: clinical scenarios and pathophysiologic targets for therapy. Acute Cardiac Care 2007;12:10e21. 8. Gheorghiade M, Abraham WT, Albert NM, et al. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA 2006;296:2217e26. 9. Cleland JG, Swedberg K, Follath F, et al. The EuroHeart Failure survey programmeda survey on the quality of care among patients with

21.

22.

23.

24.

25. 26.

27.

28.

29.

heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J 2003;24:442e63. Adams KF Jr, Fonarow GC, Emerman CL, 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. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 2002;287:1541e7. Reis SE, Holubkov R, Edmundowicz D, et al. Treatment of patients admitted to the hospital with congestive heart failure: specialty-related disparities in practice patterns and outcomes. J Am Coll Cardiol 1997; 30:733e8. Yancy CW. Climbing the mountain of acute decompensated heart failure: the EVEREST Trials. JAMA 2007;297:1374e6. Graff L, Orledge J, Radford MJ, Wang Y, Petrillo M, Maag R. Correlation of the Agency for Health Care Policy and Research congestive heart failure admission guideline with mortality: peer review organization voluntary hospital association initiative to decrease events (PROVIDE) for congestive heart failure. Ann Emerg Med 1999;34:429e37. Polanczyk CA, Rohde LE, Philbin EA, Di Salvo TG. A new casemix adjustment index for hospital mortality among patients with congestive heart failure. Med Care 1998;36:1489e99. Smith WR, Poses RM, McClish DK, et al. Prognostic judgments and triage decisions for patients with acute congestive heart failure. Chest 2002;121:1610e7. Han JH, Zhou C, France DJ, et al. The effect of emergency department expansion on emergency department overcrowding. Acad Emerg Med 2007;14:338e43. Wu AH, Harrison A, Maisel AS. Reduced readmission rate for alternating diagnoses of heart failure and pulmonary disease after implementation of B-type natriuretic peptide testing. Eur J Heart Fail 2004;6:309e12. Dolcourt B, Bilkovski R, Waiting for a bed: do prolonged ED waits translate to adverse outcomes. In: Society of Academic Emergency Medicine. Chicago; 2007. p. S84. IOM. Hospital-based emergency care: at the breaking point. Washington, D.C: National Academies Press; 2006. p. 1e296. Pines JM, Hollander JE. Emergency department crowding is associated with poor care for patients with severe pain. Ann Emerg Med 2008;51:1e5; discussion 6e7. Sacchetti A, Ramoska E, Moakes ME, McDermott P, Moyer V. Effect of ED management on ICU use in acute pulmonary edema. Am J Emerg Med 1999;17:571e4. Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: current state and framework for future research. Circulation 2005;112:3958e68. Pang PS, Tavares M, Collins SP, Peacock WF, Hamdy A, Cleland JGF, Gheorghiade M, for the URGENT Investigators. The early assessment of dyspnea in patients with acute heart failure syndromesdThe Ularitide Global Evaluation in Acute Decompensated Heart Failure (URGENT) study. In: European Society of Cardiology; 2008; Milan. Jhund PS, McMurray JJ, Davie AP. The acute vascular effects of frusemide in heart failure. Br J Clin Pharmacol 2000;50:9e13. Gottlieb SS, Brater DC, Thomas I, 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. Weinfeld MS, Chertow GM, Stevenson LW. Aggravated renal dysfunction during intensive therapy for advanced chronic heart failure. Am Heart J 1999;138:285e90. Cooper HA, Dries DL, Davis CE, Shen YL, Domanski MJ. Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation 1999;100:1311e5. Hasselblad V, Gattis Stough W, Shah MR, 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.

Rationale for an Acute Heart Failure Syndromes Clinical Trials Network 30. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998;351:389e93. 31. Damman K, Navis G, Voors AA, et al. Worsening renal function and prognosis in heart failure: systematic review and meta-analysis. J Card Fail 2007;13:599e608. 32. Krumholz HM, Chen YT, Vaccarino V, et al. Correlates and impact on outcomes of worsening renal function in patients O or 5 65 years of age with heart failure. Am J Cardiol 2000;85:1110e3. 33. Smith GL, Vaccarino V, Kosiborod M, et al. Worsening renal function: what is a clinically meaningful change in creatinine during hospitalization with heart failure? J Card Fail 2003;9:13e25. 34. Levy P, Compton S, Welch R, et al. Treatment of severe decompensated heart failure with high-dose intravenous nitroglycerin: a feasibility and outcome analysis. Ann Emerg Med 2007;50:144e52. 35. Peacock W, Fonarow GC, Emerman CL, Mills RM, Wynne J. Impact of early initiation of intravenous therapy for acute decompensated heart failure on outcomes in ADHERE. Cardiology 2006;107:44e51. 36. Collins SP, Mielniczuk LM, Whittingham HA, Boseley ME, Schramm DR, Storrow AB. The use of noninvasive ventilation in emergency department patients with acute cardiogenic pulmonary edema: a systematic review. Ann Emerg Med 2006;48:260e9, 9 e1e4. 37. Masip J, Roque M, Sanchez B, Fernandez R, Subirana M, Exposito JA. Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis. JAMA 2005;294: 3124e30. 38. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007;297:1319e31. 39. Gheorghiade M, Rossi JS, Cotts W, et al. Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial. Arch Intern Med 2007;167: 1998e2005. 40. Lucas C, Johnson W, Hamilton MA, et al. Freedom from congestion predicts good survival despite previous class IV symptoms of heart failure. Am Heart J 2000;140:840e7. 41. Cowie MR, Komajda M, Murray-Thomas T, Underwood J, Ticho B. Prevalence and impact of worsening renal function in patients hospitalized with decompensated heart failure: results of the prospective outcomes study in heart failure (POSH). Eur Heart J 2006;27: 1216e22. 42. Vinson JM, Rich MW, Sperry JC, Shah AS, McNamara T. Early readmission of elderly patients with congestive heart failure. J Am Geriatr Soc 1990;38:1290e5. 43. Krumholz HM, Amatruda J, Smith GL, et al. Randomized trial of an education and support intervention to prevent readmission of patients with heart failure. J Am Coll Cardiol 2002;39:83e9. 44. Rich MW, Beckham V, Wittenberg C, Leven CL, Freedland KE, Carney RM. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med 1995;333:1190e5. 45. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161e7. 46. Harrison A, Morrison LK, Krishnaswamy P, et al. B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea. Ann Emerg Med 2002;39: 131e8. 47. Maisel A, Hollander JE, Guss D, et al. Primary results of the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT). A multicenter study of B-type natriuretic peptide levels, emergency department decision making, and outcomes in patients presenting with shortness of breath. J Am Coll Cardiol 2004;44:1328e33. 48. Januzzi JL, van Kimmenade R, Lainchbury J, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.



Collins et al

473

International Collaborative of NT-proBNP Study. Eur Heart J 2006; 27:330e7. Mueller C, Laule-Kilian K, Schindler C, et al. Cost-effectiveness of Btype natriuretic peptide testing in patients with acute dyspnea. Arch Intern Med 2006;166:1081e7. Burger AJ, Horton DP, LeJemtel T, et al. Effect of nesiritide (B-type natriuretic peptide) and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: the PRECEDENT study. Am Heart J 2002;144: 1102e8. Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. N Engl J Med 2000;343: 246e53. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol 2006;47:76e84. 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. 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. Collins SP, Hinckley WR, Storrow AB. Critical review and recommendations for nesiritide use in the emergency department. J Emerg Med 2005;29:317e29. Silvers SM, Howell JM, Kosowsky JM, Rokos IC, Jagoda AS. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Ann Emerg Med 2007;49:627e69. Peacock WFt, Holland R, Gyarmathy R, et al. Observation unit treatment of heart failure with nesiritide: results from the proaction trial. J Emerg Med 2005;29:243e52. Peacock WFt, Young J, Collins S, Diercks D, Emerman C. Heart failure observation units: optimizing care. Ann Emerg Med 2006;47: 22e33. Storrow AB, Collins SP, Lyons MS, Wagoner LE, Gibler WB, Lindsell CJ. Emergency department observation of heart failure: preliminary analysis of safety and cost. Congest Heart Fail 2005;11: 68e72. Hamm CW, Goldmann BU, Heeschen C, Kreymann G, Berger J, Meinertz T. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med 1997;337:1648e53. Kim F, Olsufka M, Longstreth WT Jr, et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation 2007;115:3064e70. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368e77. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581e7. Morrow DA, Antman EM, Sayah A, et al. Evaluation of the time saved by prehospital initiation of reteplase for ST-elevation myocardial infarction: results of The Early Retavase-Thrombolysis in Myocardial Infarction (ER-TIMI) 19 trial. J Am Coll Cardiol 2002; 40:71e7. Hourigan CT, Mountain D, Langton PE, et al. Changing the site of delivery of thrombolytic treatment for acute myocardial infarction from the coronary care unit to the emergency department greatly reduces door to needle time. Heart (British Cardiac Society) 2000; 84:157e63.

474 Journal of Cardiac Failure Vol. 15 No. 6 August 2009 66. Corfield AR, Graham CA, Adams JN, Booth I, McGuffie AC. Emergency department thrombolysis improves door to needle times. Emerg Med J 2004;21:676e80. 67. Mehta RH, Newby LK, Patel Y, et al. The impact of emergency department structure and care processes in delivering care for nonST-segment elevation acute coronary syndromes. Am Heart J 2006; 152:648e60. 68. Collins Sp PW, Kontos M, Diercks D, Hiestand B, Hogan C, Mueller C, et al. Heart Failure and Audicor Technology for Rapid Diagnosis and Initial Treatment of ED Patients with Suspected Heart Failure (HEARD-IT). In: Society of Academic Emergency Medicine; 2007; Chicago. 69. Hollander JE. The management of cocaine-associated myocardial ischemia. N Engl J Med 1995;333:1267e72. 70. Storrow AB, Collins S, Disalvo T, Han J. Improving Heart Failure Risk Stratification in the ED. Stratify 1R01HL088459-01. Vanderbilt University: NHLBI; 2007. 71. Storrow AB, Gibler WB. Chest pain centers: diagnosis of acute coronary syndromes. Ann Emerg Med 2000;35:449e61.

72. Roe MT, Christenson RH, Ohman EM, et al. A randomized, placebocontrolled trial of early eptifibatide for non-ST-segment elevation acute coronary syndromes. Am Heart J 2003;146:993e8. 73. Pang PS, Cleland JG, Teerlink JR, et al. A proposal to standardize dyspnoea measurement in clinical trials of acute heart failure syndromes: the need for a uniform approach. Eur Heart J 2008;29:816e24. 74. McMurray JJ, Teerlink JR, Cotter G, et al. Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials. JAMA 2007;298: 2009e19. 75. Fonarow GC, Heywood JT, Heidenreich PA, Lopatin M, Yancy CW. Temporal trends in clinical characteristics, treatments, and outcomes for heart failure hospitalizations, 2002 to 2004: findings from Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2007;153:1021e8. 76. Fonarow GC, Stough WG, Abraham WT, 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.