Reassessing Treatment of Acute Heart Failure Syndromes: the ADHERE Registry

European Heart Journal Supplements (2005) 7 (Supplement B), B13–B19 doi:10.1093/eurheartj/sui008

Reassessing treatment of acute heart failure syndromes: the ADHERE Registry Downloaded from https://academic.oup.com/eurheartjsupp/article/7/suppl_B/B13/603537 by guest on 30 September 2021

Mihai Gheorghiade1* and Gerasimos Filippatos2

1 Division of Cardiology, Northwestern University Feinberg School of Medicine, Galter 10-240, 201 E. Huron Street, Chicago, IL 60611, USA 2 2nd Department of Cardiology, University of Athens Hospital ‘Attikon’, Athens, Greece

KEYWORDS Acute heart failure syndromes (AHFS) are the leading cause of hospitalization in persons Acute disease; aged over 65 years, costing an estimated $12.7 billion per year in the United States congestive heart failure, alone. Acute Decompensated Heart Failure National Registry (ADHERE) was estab- classiﬁcation/epidemiology; lished in the United States in 2001, and now represents the largest database on Hospitalization/statistics acute heart failure in the world, with over 100 000 patients enrolled to date. The and numerical data; ﬁrst analyses of data from the registry are now in the public domain, and offer Patient registry; useful insights into the characteristics, management, and outcomes of AHFS patients. United States The ‘real-life’ patient population represented in ADHERE is older, contains more women, and has a higher incidence and complexity of co-morbidities than individuals studied in clinical trials. Patient management varies substantially, and often does not utilize the full range of technical resources and clinical knowledge available. It is also notable that among patients admitted with worsening chronic heart failure, at least one-third are not receiving well-established life-saving medications. The information gathered so far by ADHERE has highlighted key areas for improvement in the management of both acute and chronic heart failure.

Introduction studies, fuelling an interest in defining optimal treatment and patient management strategies. Acute heart failure syndromes (AHFS) cause almost A key step towards designing relevant research trials to 1 million hospitalizations annually in the United States,1 evaluate treatment of AHFS is the generation of a data- placing an enormous social and financial burden on base of patients hospitalized with heart failure. Acute society. Indeed, heart failure is the leading cause of Decompensated Heart Failure National Registry (ADHERE) hospitalization in persons aged over 65 years, and in is one such database, which was established in October 2003, inpatient management of AHFS cost an estimated 2001 and is now the most extensive acute heart failure $12.7 billion in the United States.2 Although European registry in the world, with more than 100 000 patients data on acute heart failure are limited, the EuroHeart enrolled to date.2,7 The registry is an observational study Failure Survey3–6 and the majority of studies suggest involving more than 275 sites throughout the United that heart failure is also a large and growing public States, under the guidance of the ADHERE Registry health burden throughout this continent. Despite the sub- Scientific Advisory Committee (Table 1 ).7 Patients over stantial survival and financial impact of the disease, there the age of 18 years who are admitted to an acute care are few randomized trials studying the efficacy and safety hospital with a primary or secondary discharge diagnosis of different therapies for AHFS. Over the past few years, of heart failure are eligible for inclusion. Details of the extent of the worldwide public health burden of medical history, clinical presentation, laboratory tests, AHFS has been brought into sharp focus by a number of medical management, and health outcomes are collected from hospital discharge medical records. The database has several goals: first, to describe * Corresponding author. E-mail address: [email protected] demographics and clinical characteristics of AHFS

Table 1 The ADHERE Registry Scientiﬁc Advisory Committee2

Investigator Institution Location

William T. Abraham The Ohio State University Heart Center Columbus, OH Kirkwood F. Adams Jr University of North Carolina Chapel Hill, NC Robert L. Berkowitz Hackensack University Hospital Hackensack, NJ Maria Rosa Costanzo Midwest Heart Specialists Naperville, IL Teresa De Marco University of California San Francisco, CA Charles L. Emerman The Cleveland Clinic Cleveland, OH Gregg C. Fonarow Ahmanson—UCLA Cardiomyopathy Center Los Angeles, CA Marie Galvao Monteﬁore Medical Center Bronx, NY J. Thomas Heywood Loma Linda University Medical Center Loma Linda, CA Downloaded from https://academic.oup.com/eurheartjsupp/article/7/suppl_B/B13/603537 by guest on 30 September 2021 Thierry H. LeJemtel Albert Einstein Hospital Bronx, NY Lynne Warner Stevenson Brigham and Women’s Hospital Boston, MA Clyde W. Yancy University of Texas, Southwestern Medical Center Dallas, TX

patients; secondly, to characterize current management Table 2 Clinical characteristics of patients with relatively of hospitalized patients with AHFS; thirdly, to generate preserved vs. impaired systolic function10 hypotheses for randomized controlled trial design; and most importantly, to evaluate and improve the quality Characteristics LVEF P-value of care for these patients. The first analyses of data from the ADHERE Registry entered the public domain in .40% ,40% 2003, and have already provided important insights into (n ¼ 7829) (n ¼ 8245) characteristics and management of patients with AHFS. Age (years) 73.9 69.9 The real value of ADHERE lies in identifying and acting Female sex (%) 63 40 on those findings that can make a significant impact on History of CAD (%) 52 61 ,0.0001 clinical management of AHFS. With this aim in mind, History of MI (%) 47 61 ,0.0001 this paper highlights some of the most important History of 45 41 ,0.0001 insights to have emerged to date. Unless stated diabetes (%) otherwise, figures quoted here refer to patients enrolled Rales on 71 69 0.002 in the registry who were discharged from an acute care presentation (%) hospital between October 2001 and January 2004 Peripheral oedema on 70 64 ,0.0001 (n ¼ 105 388).8 presentation (%) Serum BNP level on 647 918 ,0.0001 presentation (pg/mL)

CAD, coronary artery disease; MI, myocardial infarction. Patient characteristics when managing patients who may suffer from multiple The characteristics of patients included in the ADHERE conditions that contribute to a poor prognosis. database highlight an important caveat: that the populations studied in heart failure clinical trials often differ Systolic function substantially from ‘real-world’ patients with heart failure. For example, the median age of patients enrolled Interestingly, among those patients in whom left ventri- in the registry was 75 years and 52% of patients were cular ejection fraction (LVEF) was measured, only 47% female.2 This is consistent with other recent hospital had LVEF ,40%.2 An analysis of patients enrolled up to surveys but contrasts with the majority of clinical trial January 2003 found that patients with LVEF .40% were participants, both in the United States and Europe, who older, more likely to be female or have diabetes, and tend to be younger and predominantly male.9 less likely to have coronary heart disease or myocardial Similarly, although the majority of patients with signiﬁ- infarction than those with compromised LVEF cant co-existing morbidity may be excluded from clinical (Table 2 ).10 This subgroup of patients presented with trials, a high degree of co-morbidity was shown among an increased incidence of rales, peripheral oedema and patients in the ADHERE database. Many patients had a hypertension, a lower incidence of hypotension, and history of hypertension (72%) or coronary artery disease diminished elevation in B-type natriuretic peptide (BNP) (57%); 44% had diabetes, 35% had a history of hyperlipi- levels. Although the ADHERE data indicate that patients daemia, 31% had atrial ﬁbrillation, and 31% had chronic with relatively preserved systolic function represent obstructive pulmonary disease or asthma. The high almost half of all patients with AHFS, these patients frequency of these diagnoses within the ADHERE database would have been excluded from most recent clinical underscores the complex challenges faced by physicians trials.9 Reassessing treatment of AHFS B15

Renal dysfunction of AHFS. Although this suboptimal treatment of congestion appears to provide short-term improvement in symp- Signs of renal dysfunction were apparent in a substantial toms, it could well be a major contributor to the high proportion of patients: 30% had a history of chronic renal readmission rates.12 This is a matter of great concern, insufficiency, 13% had an admitting diagnosis of given the mounting evidence that congestion should be renal insufficiency or failure, and one-fifth of those a major treatment target in patients with AHFS.13 whose serum creatinine was determined had levels .2.0 mg/dL.2 Importantly, compromised renal function was associated with poor prognosis: classification and regression tree analysis of risk factors for in-hospital Work-up and treatment mortality found that the best single predictor for mortality was an admission blood urea nitrogen level Diagnosis and patient management Downloaded from https://academic.oup.com/eurheartjsupp/article/7/suppl_B/B13/603537 by guest on 30 September 2021 of .43 mg/dL.11 Along with low admission systolic Considering the complex physiology underlying the pre- blood pressure, high serum creatinine—another well- sentation of these patients, one noteworthy observation established indicator of poor renal function—was also a from the ADHERE data is the relative lack of comprehen- predictor of in-hospital mortality. sive work-up. In particular, recently developed technolo- gies for deriving diagnostic and prognostic information Congestion seem to be underused. Electrocardiogram, chest radi- ography, assessments of systolic blood pressure, serum Only 2% of patients had a systolic blood pressure (SBP) sodium, and serum creatinine were performed in .90% ,90 mmHg, with 48% of patients classified as normotensive of patients. However, LVEF, BNP levels, and NYHA class (SBP: 90–140 mmHg) and 50% hypertensive (SBP were determined in only 58, 35, and 11% of patients, .140 mmHg). Most patients had signs of congestion on respectively. Increases in LVEF and BNP have been presentation (Table 3 ), and heart failure, recorded in 93% shown to be predictors of increased rehospitalization of patients, was the most common admitting diagnosis. and mortality in patients with AHFS,13 and their use Dyspnoea was the most common symptom, and more than may identify patients with increased mortality risk. one-third of patients experienced dyspnoea at rest while Data from the ADHERE Registry suggest that improve- being examined. In addition, many patients exhibited ments in patient assessment could make an important rales or peripheral oedema, and 75% had pulmonary conges- contribution for optimizing the treatment of the tion on chest X-ray. The majority of patients were severely condition. symptomatic [New York heart association (NYHA) Class III or A surprising finding is that patient management varies IV], and 20% were in atrial fibrillation on admission. The substantially, depending on the hospital department median level of BNP was 667 pg/mL in patients who under- providing treatment—worryingly, this disparity appears went this assessment. to translate into significant differences in patient On discharge, 52% of patients reported that they were outcome.14 Although 78% of patients in the ADHERE asymptomatic, 37% were improved (but still sympto- Registry were initially treated in an emergency depart- matic), ,1% were unchanged, and ,1% were worse. ment (ED), a substantial proportion (21%) were admitted However, congestion was not substantially improved in directly for inpatient care. There was an unexpected many patients during their inpatient stay—one-third had difference in time-to-treatment between patients first lost only 0–5 lb in weight on discharge and 16% had actu- given intravenous vasoactive therapy in the ED (median ally gained weight (Table 4 ). The tendency to discharge time of 1.1 h after admission) and those whose vasoactive patients without significant improvement of congestion therapy was not initiated until admission to an inpatient may reflect a dissociation between patients’ self-assess- unit (median time of 22.2 h after admission). This had ment of their condition and physician-determined signs substantial effects on outcomes: early administration of

Table 3 Signs and symptoms of congestion on presentation Table 4 Body weight change at discharge in patients in patients enrolled in the ADHERE database, October enrolled in the ADHERE database, October 2001–January 2001–January 2004 (n ¼ 105 358)8 2004 (n ¼ 51 013)8

Signs/symptoms Proportion of patients (%) Change in body weight at discharge Proportion of patients (%) Any dyspnoea 89 NYHA Class III or IV 87 Decrease of .20 lb (.9 kg) 7 Pulmonary congestion by CXR 75 Decrease of 15–20 lb (6.8–9 kg) 6 Rales 68 Decrease of 10–15 lb (4.5–6.8 kg) 13 Peripheral oedema 66 Decrease of 5–10 lb (2.3–4.5 kg) 24 LVEF ,40% 47 Decrease of 0–5lb(0–2.3 kg) 33 Dyspnoea at rest 34 Increase of 0–5lb(0–2.3 kg) 11 Fatigue 32 Increase of 5–10 lb (2.3–4.5 kg) 3 Increase of .10 lb (.4.5 kg) 2 CXR, chest X-ray. B16 M. Gheorghiade and G. Filippatos intravenous vasoactive therapy in the ED was associated association between high-dose diuretic use and adverse with significantly lower mortality, fewer transfers to outcomes.17–19 Consistent with these findings, a recent the intensive care or critical care unit, and decreased analysis of ADHERE data found that patients who received requirement for invasive procedures. Furthermore, intravenous diuretics had a longer overall length of stay patients who received intravenous vasoactive treatment (P , 0.001) as well as a longer ICU length of stay in the ED had shorter in-hospital and intensive/critical (P , 0.001) and slightly higher mortality (non-significant) care unit median length of stay, and fewer of these than patients who did not receive these drugs.20 A recent patients required prolonged hospitalization. These find- study also found that chronic use of diuretics was associ- ings require further investigation, given that patients ated with increased mortality among patients in ADHERE included in the analysis received a wide range of vaso- who had renal insufficiency or earlier stages of renal active drugs with differing toxicity and efficacy profiles. disease: high creatinine levels and chronic treatment with diuretics were strong independent predictors of Downloaded from https://academic.oup.com/eurheartjsupp/article/7/suppl_B/B13/603537 by guest on 30 September 2021 mortality.21 Moreover, it has been shown that high-dose Use of inotropes isosorbide dinitrate is more effective than high-dose furosemide, in terms of need for mechanical ventilation Previous studies have indicated that the use of inotropic and frequency of myocardial infarction, in patients with agents may be associated with increased risk of adverse pulmonary oedema.22 Although high-dose intravenous events and increased mortality, particularly in patients diuretic use may indicate patients with more severe with preserved left ventricular function.15 Therefore, it heart failure, this finding emphasizes the need for has been recommended that positive inotropes should large-scale randomized, controlled trials of diuretics in only be used in patients who absolutely require inotropic AHFS. Despite the widespread use of diuretics, there support for low cardiac output.13 With this in mind, it is are very few clinical data to support their safety and effi- concerning that 9% of patients in the ADHERE Registry cacy in AHFS. received a positive inotrope (dobutamine or milrinone) The nitrovasodilator nesiritide, a recombinant exact as part of their inpatient care, although only 2% of copy of BNP, was used in 10% of patients in the ADHERE patients were hypotensive. This suggests that .75% of Registry, and a further 11% received either nitroglycerin patients who receive these potentially deleterious drugs or nitroprusside. The mortality associated with nesiritide may have no clinical indication for their use, and under- has been reported to be similar to that of nitroglycerin lines the importance of developing consensus guidelines and lower than that of dobutamine.23,24 Similarly, an analy- for management of patients with AHFS. sis of ADHERE data found that treatment with nesiritide One analysis of ADHERE data provides evidence that within the first 24 h of hospitalization for AHFS was associ- patients with preserved systolic function may respond ated with significantly lower in-hospital mortality than differently to treatment with positive inotropes com- treatment with milrinone or dobutamine, and similar pared with those with impaired LVEF.16 In this subgroup mortality to treatment with nitroglycerin (Figure 1 ).25 analysis, patients with preserved systolic function who received inotropic agents had a significantly longer length of hospital stay (mean: 12.9 vs. 9.6 days; P , 0.0001) and higher mortality rate (19 vs. 14%; P , 0.002) than all Outcomes and quality of care other inotrope-treated patients. Furthermore, among patients with preserved systolic function, those who The median hospital stay for patients in the ADHERE received inotropic agents had more than double the Registry was 4.3 days and in-hospital mortality was 4%. length of stay (12.9 vs. 5.8 days; P , 0.0001) and a nine- This mortality rate is above that reported in several fold increase in mortality rate (19 vs. 2%; P , 0.0001) large heart failure clinical trials [e.g. 2.3% for the compared with those who were not treated with inotropes. As patients with preserved systolic function are often excluded from clinical trials, this suggests that the adverse outcomes associated with these drugs could potentially affect a greater proportion of patients in ‘real-life’ populations than in clinical studies. These data highlight the need to examine the effects of therapies on this important, but perhaps overlooked, patient subgroup. Designing clinical studies with this aim should, therefore, be a key focus of future research.

Use of intravenous diuretics and vasoactive therapy

During their inpatient stay, 88% of patients in ADHERE were treated with intravenous diuretics. However, despite the ability of these drugs to provide rapid symp- Figure 1 Comparison of in-hospital mortality in patients treated with tomatic improvement, several studies have found an nesiritide vs. nitroglycerin, milrinone, or dobutamine.25 Reassessing treatment of AHFS B17 placebo group in the Outcomes of a Prospective Trial of treatments, and outcomes. In the short time since its Intravenous Milrinone for Exacerbations of Chronic Heart inception, the ADHERE database has already revolution- Failure (OPTIME CHF) trial, who received standard care ized the way we think about heart failure and its as deemed appropriate by their physician26]. Again, this management. Along with European initiatives, such as may reflect the selective nature of clinical trial inclusion the EuroHeart Failure Survey programme3–6 and Etude criteria—which often exclude patients with co-existing d’observation Francaise de l’Insuffisance Cardiaque disease—and emphasizes the value of studies on non- Aigue¨ (EFICA),31 ADHERE has brought several important restricted populations, such as the ADHERE Registry. issues surrounding AHFS into sharp focus (Table 5 ). Performance measured by Joint Commission on First, ADHERE has taught us that patients admitted Accreditation of Healthcare Organizations (JCAHO) with acute heart failure belong to a heterogeneous popu- quality of care indicators was often substandard and lation. Most clinical trials are based on patients with varied substantially among sites. These quality of care compensated systolic dysfunction and few co-morbidities. Downloaded from https://academic.oup.com/eurheartjsupp/article/7/suppl_B/B13/603537 by guest on 30 September 2021 indicators were developed to identify standards of accep- The ADHERE data show that 53% of patients with AHFS table care in patients hospitalized with heart failure. have relatively preserved systolic function. Moreover, Left ventricular function was measured in 82% of patients these patients tend to be older, predominantly female, (JCAHO indicator HF-2), but only 63% of eligible patients and are more likely to have a history of hypertension or received an angiotensin-converting enzyme inhibitor diabetes. A multidisciplinary approach—involving control (ACE-I) on discharge (HF-3), and just 28 and 31% of of hypertension, diabetes, and renal failure—is therefore patients received a complete set of discharge instruc- essential to the ultimate treatment of heart failure. tions (HF-1) and smoking cessation counselling (where Secondly, it is apparent that treatment of AHFS could appropriate, HF-4), respectively.27 These data highlight be improved substantially. Advanced prognostic and a clear need to develop treatment guidelines and com- diagnostic techniques that are now available are under- municate these widely in order to standardize and utilized, and patient management varies considerably improve quality of care. from site to site across the United States, and between hospital departments. Up to 7% of patients are receiving positive inotropes, drugs that are associated with an Long-term patient management increased incidence of poor outcomes, without any As indicated by the poor performance on JCAHO HF-3, the use of chronic heart failure medications is disappointingly Table 5 Key issues highlighted by ADHERE low. US practice guidelines advocate the prescription of ACE-Is and beta-blockers in all patients with chronic heart Patient characteristics failure who do not have contraindications for their † Unlike clinical trial populations, ‘real-life’ patients with 28,29 use. Despite these recommendations, the use of pre- AHFS are a heterogeneous population: they tend to be hospitalization chronic heart failure medications among relatively old, normo- or hypertensive, and have a high ADHERE patients was relatively low. Most of the patients incidence of co-morbidities including diabetes, atrial (70%) were on diuretics as outpatients. However, only 53% fibrillation, coronary artery disease, hypertension, and were on either ACE-Is or angiotensin-receptor blockers renal dysfunction (ARBs) and only 48% were on beta-blockers. Considering † Over 50% of patients have a LVEF .40%—but patients that 75% of patients had a history of heart failure, with preserved systolic function are rarely included in clinical trials this suggests that about one-third of eligible individuals † Renal dysfunction is a common finding and a major are not receiving these medications in the outpatient predictor of poor prognosis setting, despite their substantial benefits being well- Diagnosis and treatment documented. Even after hospitalization for AHFS, prescri- † Despite the complex physiology underlying presentation, ption of ACE-Is and beta-blockers remains comparatively work-up is not always complete and the available low. While 86% of patients were prescribed diuretics, only diagnostic technology is under-utilized 69% were given either ACE-Is or ARBs, and only 59% received † Congestion is not well treated and warrants greater beta-blockers. A recent study found that in-hospital clinical focus initiation of beta-blocker therapy increased the rate of † Treatment requires a multidisciplinary approach use at 60 days after randomization without increasing † Many patients with no apparent clinical indication received side-effects or length of stay.30 In light of this finding, positive inotropes, even though these drugs are associated prescription of chronic heart failure therapies is clearly an with increased mortality area where there is room for achieving significant improve- Outcomes and quality of care ments in current practice that could provide substantial † Performance on JCAHO quality of care indicators requires long-term benefits for patients. substantial improvement † Many patients receive treatment which affords temporary relief but may ultimately contribute to the high The lessons learned so far readmission rates Long-term patient management Patient registries are recognized as vital tools in the drive † The implementation of basic life-saving chronic heart to understand and optimally manage AHFS, providing failure therapies is not optimal (e.g. beta-blockers) comprehensive data on patient characteristics, B18 M. Gheorghiade and G. Filippatos clinical indication to support their use. It is clear that M.G. has acted as a consultant to GlaxoSmithKline Ltd more trials and definitive guidelines are needed to estab- and Otsuka America Pharmaceutical, Inc., and currently lish and promote best practice in the management and holds research grants from Scios Inc. treatment of patients with AHFS. Thirdly, the medical profession is failing to provide life- saving therapies for patients with chronic heart failure. References While ADHERE shows that the majority of patients are symptomatically improved on discharge, body weight 1. American Heart Association. 2003 Heart and Stroke Statistical was not decreased in about half of the patients, and a Update. Dallas, TX: American Heart Association; 2002. 32,33 2. Fonarow GC. The Acute Decompensated Heart Failure National similar proportion face readmission within 6 months. 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