acute heart failure populations - Wiley Online Library

ESC HEART FAILURE ESC Heart Failure 2016; 3: 65–70 Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.12092

EDITORIAL

Acute heart failure facts and numbers: acute heart failure populations Julia Searle, Johann Frick and Martin Möckel Division of Emergency and Acute Medicine with Chest Pain Units, Campus Virchow-Klinikum and Campus Charité Mitte, Charité — Universitätsmedizin Berlin, Berlin, Germany

Abstract Acute heart failure (AHF) is a life-threatening emergency, which largely profits from early diagnosis and treatment. The prevalence of AHF is difficult to assess, estimates range between 1 and 12% in the general population. Despite recent therapeutic advances, in-hospital mortality is high with estimates varying from 4 and 18% in different registries. Due to large differences in AHF definitions and selection criteria AHF populations vary in their characteristics and outcomes. This is especially true for randomized clinical trials and the external validity of some of these trials is questionable. Additionally, the timing of data collection and/or initiation of new therapies vary with the setting of trials. The aim of this article is to call attention to the difference in AHF populations and to emphasize the need for research to clearly define these populations. AHF populations from registries and clinical trials are the basis for evidence-based management strategies. It is important that these populations represent the patients in whom these strategies will be applied in routine care. Keywords

Acute Heart Failure; AHF cohort; registry; randomized controlled Trial (RCT); Emergency Department

Introduction Despite all efforts of scientific and medical advances, heart failure (HF) remains a massive clinical and public health problem with high morbidity and mortality and a high frequency of hospitalizations.1 Most hospitalizations for HF occur in the context of acute heart failure (AHF), which the ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 define as a ‘term used to describe the rapid onset of, or change in, symptoms and signs of HF.’2 Acute heart failure is not a disease but a syndrome with a range of precipitants, causes, underlying conditions, and acuteness; the time from the onset of symptoms to presentation and urgency can vary widely. Whilst the differentiation of the underlying cause of AHF is extremely important for patient management, clinical studies, which form the scientific basis of such management strategies, lack a clear definition of the condition AHF. Patients with AHF enrolled in clinical trials are, on the one hand, screened for in a wide spectre of settings and from a large cohort of patients with AHF-related signs and symptoms. On the other hand, they are highly selected by applying a large array of exclusion criteria to secure patient safety

and feasibility. Typically, patients with acute dyspnoea and known or suspected heart failure are recruited, often after initial stabilization, to assess diagnostic and treatment options for patients who are typically admitted via an emergency department with diverse presentation patterns, underlying pathophysiology, and patient characteristics. Depending on healthcare system-related and hospital-related processes, patient characteristics vary between different countries and study sites.3 Likewise, patient characteristics in AHF-registries, which are the basis for most of our scientific knowledge on AHF, are largely dependent on the setting of data collection. This article shows facts and numbers of patients with AHF from different settings. This will include the presentation of AHF data from two tertiary care emergency departments to show the characteristics of unselected patients with AHF early after their presentation to a hospital. We will emphasize how setting and timing of data collection and patient recruitment affect patient characteristics, and what impact patient selection in clinical trials has on the external validity of AHF studies and related guidelines. The aim of this article is to call attention to the differences in AHF populations, and to emphasize the need for research to clearly define these populations.

© 2016 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Facts and numbers Numbers on acute heart failure It is difficult to assess the numbers on the prevalence of acute heart failure. ICD-10 coding for heart failure distinguishes between different types of heart failure and the severity of symptoms, but a clear assignment of AHF is difficult. Big data analyses often select patients based on a maximum of three digits of the ICD-code in order to not create too many small subgroups, even though coding of all digits is mandatory in German hospitals. For the emergency department, hospitalization for heart failure is usually equalized as AHF, and I50 is the diagnosis which is chosen to define AHF. Studies on AHF prevalence use different sources for their estimation, as outlined in a publication on the epidemiology of AHF by Rogers.1 These studies include patient-based assessment (self-report) and routine data analyses (first hospitalization for heart failure, hospital discharge or death certificate with ICD code for HF, hospital discharge diagnosis, and administrative databases, e.g. Medicare). In other studies, defined criteria are applied to count patients with heart failure, e.g. the Framingham Congestive Heart Failure Criteria or the Boston criteria for heart failure. These criteria require prospective patient enrolment or a thorough analysis of welldocumented routine data. From all these studies, Roger summarizes an overall prevalence of HF between 1 and 12% in the United States and Europe. The lifetime risk to developing the disease is described as ranging between 20 and 33%.1 Importantly, the prevalence of heart failure dramatically increases with age. The ESC guidelines2 refer to a study by Mosterd et al., estimating an overall prevalence in the population of 1–2% and of >10% in the population of persons of and above the age of 70 years.4 None of these publications provides specific numbers for acute heart failure, indicating the difficulty to group patients into a defined AHF-cohort.

AHF in the emergency department Acute heart failure is a serious and life-threatening condition, and a large proportion of patients are admitted either directly to an intensive care unit or to an emergency department. In a recent single-day snapshot survey of all unplanned hospitalizations due to AHF in 170 French hospitals, 64% of the patients were admitted via an emergency department.5 In ADHERE, a large US-based registry on AHF patients, 78% of patients were admitted via the ED.6 Presentation of AHF in the emergency department can be challenging and atypical. In the CHARITEM study, which analysed routine hospital data from all patients in internal medicine who presented to one of two German tertiary care emergency departments (n = 34.333), the relationship between chief complaint and underlying main diagnosis was assessed.7

Editorial

To evaluate the characteristics of patients with heart failure in the emergency department, we analysed data from all inpatients with a main hospital diagnosis heart failure (ICD-10 code I50, n = 370). We assumed that patients present to the emergency department with an emergency or, at least, with an acute condition, and that the probability of AHF in these patients is high. Doing this, we might have missed patients for whom other codes were used, e.g. in the context of cardiomyopathies as well as patients in whom HF was not coded as the main diagnosis. On the other hand, we might have included patients who presented with a different acute condition, but their HF was coded as the main hospital diagnosis because it became an issue during the further hospital stay. The most frequent chief complaint in inpatients with the main hospital diagnosis of heart failure in our cohort was acute dyspnoea with 65.1%. Another 9.7% of the patients with HF presented with a chief complaint of chest pain. Interestingly, almost one quarter of patients (23.1%) did not have either of these two complaints, but presented with unspecified symptoms. On the other hand, of the hospitalized patients in CHARITEM with dyspnoea (n = 1497), only a moderate proportion of patients had an underlying diagnosis of HF; the top five main hospital diagnoses were chronic obstructive pulmonary disease (16.5%), heart failure (16.1%), pneumonia (5.5%), acute myocardial infarction (5.3%), and atrial fibrillation (4.9%). Table 1 shows the unpublished characteristics of patients with heart failure analysed from the CHARITEM data as compared with all inpatients enrolled in CHARITEM. The median age in the hospitalized patients with HF in the emergency department was 71 years. Women, who represented 41% of the patients with HF, were almost 10 years older than the men (median age: 68 years). The patients with HF had a higher breathing rate, lower oxygen saturation, and higher creatinine values compared with all inpatients, and they had a longer length of hospital stay. The inhospital mortality in the HF group was 8.4%. The median GFR in patients with heart failure was 51 mL/min (34/72) per 1.73 m3. Table 2 shows the full 5-digit ICD-10 codes of the CHARITEM patients with HF. From this coding, especially in the setting of an emergency department, it is difficult to define patients with clear AHF, especially, as symptoms at presentation to the ED are relevant. Therefore, any HF diagnosis in combination with the hospitalization via an ED is counted as AHF. CHARITEM was approved by the ethics committee of the Charité — Universitätsmedizin Berlin. The study complies with the Declaration of Helsinki.

Acute heart failure in registries A large number of AHF registries have been set up worldwide. Pang et al. recently published an educational consensus paper for which an international group of experts had convened to ESC Heart Failure 2016; 3: 65–70 DOI: 10.1002/ehf2.12092

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Table 1 Patient characteristics in the emergency department of hospitalized patients with heart failure (ICD-10 codes I50) from the CHARITEM trial All inpatients (n = 13.536)

Variable Age* Female Chief complaint at presentation Dyspnoea Chest pain Abdominal pain Headache None of these Respiratory rate Oxygen saturation* Creatinine (mg/dL)* Length of hospital stay* ICU stay Mortality

Inpatients with HF (ICD-10 code I50) (n = 370)

67 (53/75) 45.9%

71 (65/80) 40.8%

11.1% 13.9% 8.9% 2.3% 63.8% 16 (15/18)/min 97 (95/98)% 0.95 (0.8/1.2) 5 (3/9) days 18.2% 4.7%

65.1% 9.7% 1.4% — 23.8% 18 (16/22)/min 94 (90/97)% 1.29 (1.0/1.7) 7 (4/13) 30.8% 8.4%

Women with HF (n = 151)

Men with HF (n = 218)

77 (69/85) —

68 (62/76) —

64.2% 6.6% 2.0% — 27.2% 19 (16/23)/min 94 (89/97)% 1.3 (1.0/1.8) 8 (4/13) 31.8% 9.9%

66.1% 11.5% 0.9% — 21.5% 18 (15/21)/min 95 (91/97)% 1.3 (1.0/1.7) 7 (4/14) 30.2% 7.3%

*Median (interquartile range). Table 2 5-digit ICD-10 codes for the patients in CHARITEM ICD-10 code I50.00 I50.01 I50.12 I50.13 I50.14 I50.19 I50.9 Total

Text

Number of patients with HF in CHARITEM

Primary right ventricular heart failure Secondary right ventricular heart failure Left ventricular heart failure with symptoms at moderate exercise Left ventricular heart failure with symptoms at mild exercise Left ventricular heart failure with symptoms at rest Left ventricular heart failure, not specified Heart failure, not specified

2.2% (n = 8) 21.6% (n = 80) 3.5% (n = 13) 19.7% (n = 73) 42.2% (n = 156) 2.2% (n = 8) 8.6% (n = 32) n = 370

Table 3 Inclusion criteria of exemplary AHF registries based in the USA, Europe, and Japan Registry ADHERE

Origin 6,9

USA

OPTIMIZE-HF10

USA

ATTEND11

Japan

12

EHFS II

30 European countries

ESC-HF pilot13

12 European countries

Definition of AHF cited from the publication or the study registry Inclusion criteria: •Age greater than or equal to 18 years at the time of admission to the hospital •Received or is eligible to receive a principal hospital discharge diagnosis of HF •Decompensated HF is present as determined clinically by the patient care team Exclusion criteria: •HF is present as a comorbid condition, but is not a principal focus of diagnosis or treatment during this hospitalization episode Inclusion criteria: •Hospitalized for episode of worsening heart failure as primary cause of admission or significant heart failure symptoms that develop during the hospitalization when the initial reason for admission was not heart failure •Systolic dysfunction (LVEF < 40%) or heart failure symptoms in the setting of preserved systolic function (diastolic dysfunction) Exclusion criteria: •This study has no exclusion criteria. https://clinicaltrials.gov/ct2/show/NCT00344513?term=OPTIMIZE-HF&rank=1 Inpatients with AHFS who met the modified Framingham criteria, which only includes variables estimated at admission (….) are eligible for the study EHFS II recruited patients admitted to the hospital (emergency area, internal medicine/cardiology wards, CCU, or ICU) with dyspnoea and verification of HF (new-onset AHF or ADCHF) based on: Symptoms (dyspnoea) and signs (i.e. rales, hypotension, hypoperfusion, right ventricular HF) of HF and lung congestion on chest X-ray The following patients were entered in the survey: All outpatients with chronic HF diagnosed according to the clinical judgement of the responsible cardiologist at the participating centres Patients admitted to hospital for acute HF, for whom an intravenous therapy (inotropes, vasodilators, or diuretics) was needed All patients had to be aged over 18 years

AHF, acute heart failure; LVEF, left ventricular ejection fraction; AFHS, acute heart failure syndrome; CCU, coronary care unit; ICU, intensive care unit; ADCHF, acutely decompensated congestive heart failure.

ESC Heart Failure 2016; 3: 65–70 DOI: 10.1002/ehf2.12092

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3.2 (1.9) h

AHF requiring parenteral antihypertensive therapy Elevated SBP ≥ 160 mm Hg Sitting dyspnoea score ≥50 on a 0–100 mm visual analog scale (VAS) and a physician’s clinical diagnosis of AHF with pulmonary congestion by chest auscultation

7.8 (4.6) h

AHF within previous 16 h, dyspnoea at rest or with minimum exertion, pulmonary congestion on chest radiographBNP ≥ 350 ng/L NT-proBNP ≥ 1400 ng/L 2 GFR 30—75 mL/min/1.73 m SBP > 125 mm Hg Treatment with at least 40 mg i.v. furosemide or its equivalent before screening

1 Enrolment after hemodynamic stabilization [defined as systolic blood pressure 110 mm Hg or greater for at least 6 h and no use of intravenous vasodilators (except nitrates) or intravenous inotropes from the time of hospital presentation to randomization].AHF, acute heart failure; SD, standard deviation; GFR, glomerular filtration rate [Modification of Diet in Renal Disease (MDRD)]; BNP, B-type natriuretic peptide; NT-proBNP, N-terminal pro B-type natriuretic peptide; LVEF, left ventricular ejection fraction; ED, emergency department.

All patients presenting to one of two tertiary care EDs who were hospitalized and had a main hospital diagnosis of heart failure (ICD-10 code I50)

46.3% — 63% 53.7 (13.1)

1

60 (13.9)

History of chronic HF (defined as requiring standard therapy for 30 days or longer prior to the index hospitalization)LVEF ≤ 40% Elevated levels of BNP ≥400 pg/mL or NT-proBNP ≥1600 pg/mL at admissionSigns and symptoms of fluid overload that required hospitalization

—

59.2% 56.0 (29.4) 78.8% 67.3 (20.0)

71.1 (12.9) 64.7 (12.4)

CHARITEM7 ASTRONAUT17 PRONTO16

71.6 (11.7)

Many patients with acute heart failure present with specific precipitants, which include ACS, arrhythmias, and infection. Typical cases with precipitants have been published online (http://www.eusem.org/onlinecontent/ and http://www. escardio.org/The-ESC/Communities/Acute-CardiovascularCare-Association-%28ACCA%29/Education-and-research/ patients-cases) in addition to a consensus paper.8

Age in years (mean/SD) Men GFR (mL/min per 3 1.73 m ) Time until randomization or intervention Inclusion criteria as outlined in the method section

Acute heart failure precipitants and infection

RELAX-AHF15

Clinical trials have the same problem to apply standard criteria for the definition of AHF. Platz et al. were recently able to show that trials use inconsistent criteria for the definition of pulmonary oedema, which is one of the key findings in AHF.14 The composition of representative AHF cohorts is further hampered by the inclusion and exclusion criteria, which are not only applied to select a uniform cohort, but also to secure patient safety and feasibility of the trial. The differences in enrolment criteria and timing again, results in differences in the study populations, as shown in Table 4. As a result of the enrolment criteria, only small subsamples of the large population of patients with AHF are eligible to participate in clinical trials. Wang et al. tried to identify potentially eligible patients for a large AHF RCT, Relax-AHF,15 in the ADHERE registry. They found that only around 2 in 10 patients fulfilled the inclusion and exclusion criteria.18 Figure 1 shows the result of a screening effort to find eligible patients for a large, international multicentre RCT on patients with AHF, in which our emergency departments participated. Only 3% of all patients who were screened for eligibility were enrolled. So far, the issue of the external validity of clinical trials is not well addressed in publications and guidelines. Calls for specific ‘To whom this research applies’ boxes as suggested by Rothwell,19 indicating which patients are likely to profit from evidence-based therapies, are mainly unheard.

Variable

Acute heart failure in clinical studies

Table 4 Basic patients and trial characteristics for selected multicentre, randomized trials in patients with AHF compared with secondary hospital data in CHARITEM. Numbers are given for the intervention group only

provide guidance for AHF care.8 The authors analyse a large set of AHF registries with respect to origin, setting, patient characteristics, treatment, and outcome. The registries use very different criteria to define acute heart failure as outlined in Table 3. Due to the variety in settings and inclusion criteria, patient characteristics vary between the registries. The mean age of patients ranges between 69 and 79 years, whilst the proportion of women ranges between 37 and 62%. Inhospital mortality also varies widely with proportions between 3.8 and 17.8%.8 In summary, AHF cohorts in international registries are extremely varied and do not describe comparable patient groups, owing not only to the different healthcare systems, but also to different patient selection based on different definitions of AHF.

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Figure 1 Screening results for a large, international, multicentre randomized clinical trial on patients with AHF from 1 March 2014 until 31 July 2015. Only 3% (n = 9) of all patients screened for eligibility (n = 352) were enrolled. *Other (n = 45) includes patients who met the following exclusion criteria: surgical intervention or neurological events within the previous 30 days, terminal stage of a malignant disease, infiltration in chest X-ray, restricted medication, aortic valve stenosis, participation in another study, patient not willing or not able to give informed consent, body weight > 160 kg, and patients without acute dyspnoea. RCT, randomized controlled trial. Screening for a large AHF-RCT in the Emergency Department Blood pressure out of range for inclusion 13%

GFR out of range for inclusion

21% 2%

No pulmonary congestion 3%

NT-proBNP too low

3%

Too little or no furosemide administered prior to randomization Inclusion not possible within the given time frame (16h from admission) ACS within previous 30 days

5%

10%

19%

Enrolment Heart rate >130 bpm other*

10% 15%

Decompensation and AHF, secondary to tachycardia or myocardial infarction, are mostly regarded to be straightforward, and treatment of the underlying disease is clear. Infection, specifically of the lower respiratory tract, may not be as obvious as other precipitants and are a challenge for the primary treatment, as patients with pneumonia will profit from very early antibiotic therapy and volume therapy rather than from decongestion and diuretic medication.20 Therefore, a prospective, international study (IMPACT: ClinicalTrials.gov, NCT02392689) randomizing patients who present acutely with proANP levels above 300 (or BNP > 350 or NT-proBNP > 1800) to be diagnosed with additional procalcitonin vs. the clinical standard including WBC and CRP is on its way.

Future challenges We need to rethink the research on patients with acute heart failure. The majority of studies on acute heart failure are a domain of cardiologists. These studies are designed, planned, and conducted by cardiologists on cardiology wards, and presented at cardiology congresses. The actual medical care reality is different. The majority of patients with AHF are admitted via emergency departments. Patient outcome have been shown to improve with an early initiation of i.v. therapies with diuretics and vasoactive medication.6 Mentz et al. also emphasize the importance of early patient recruitment for the success of clinical trials.21 Future registries and trials should carefully define their selection criteria and assess new diagnostic and treatment strategies in patients with AHF very early after their presentation to the hospital’s emergency departments. This also requires

that emergency departments are set up with resources that allow for high quality research in complex trials despite their very high work load.

Conclusions Current populations with AHF from registries and clinical trials are the basis for evidence-based management strategies for patients with AHF. Due to varying criteria to define AHF, these populations have different characteristics and outcomes. Additionally, the timing of data collection and/or initiation of new therapies vary with the setting of trials.

Acknowledgements JS and JF report research grants from Novartis, Thermofisher BRAHMS, and Roche Diagnostics; MM received research grants from Novartis, Thermofisher BRAHMS, and Roche Diagnostics, and lecture fees from these companies.

Conflict of Interest None declared.

Funding This current work received no funding. ESC Heart Failure 2016; 3: 65–70 DOI: 10.1002/ehf2.12092

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