2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

Abstract

1. Preamble 3 2. Introduction 7 3. Definition, epidemiology and prognosis 8 3.1 Definition of heart failure 8 3.2 Terminology 9 3.2.1 Heart failure with preserved, mid-range and reduced ejection fraction 9 3.2.2 Terminology related to the time-course of heart failure 9 3.2.3 Terminology related to the symptomatic severity of heart failure 10 3.3 Epidemiology, aetiology and natural history of heart failure 10 3.4 Prognosis 10 4. Diagnosis 10 4.1 Symptoms and signs 10 4.2 Essential initial investigations: natriuretic peptides, electrocardiogram, echocardiography 11 4.3 Algorithm for the diagnosis of heart failure 12 4.3.1 Algorithm for the diagnosis of heart failure in non-acute setting 12 4.3.2 Diagnosis of heart failure with preserved ejection fraction 12 5. Cardiac imaging and other diagnostic tests 14 5.1 Chest X-ray 14 5.2 Transthoracic echocardiography 14 5.2.1 Assessment of left ventricular systolic function 14 5.2.2 Assessment of left ventricular diastolic function 15 5.2.3 Assessment of right ventricular function and pulmonary arterial pressure 15 5.3 Transoesophageal echocardiography 15 5.4 Stress echocardiography 15 5.5 Cardiac magnetic resonance 15 5.6 Single-photon emission computed tomography and radionuclide ventriculography 15 5.7 Positron emission tomography 15 5.8 Coronary angiography 16 5.9 Cardiac computed tomography 16 5.10 Other diagnostic tests 17 5.10.1 Genetic testing in heart failure 17 6. Delaying or preventing the development of overt heart failure or preventing death before the onset of symptoms 18 7. Pharmacological treatment of heart failure with reduced ejection fraction 19 7.1 Objectives in the management of heart failure 19 7.2 Treatments recommended in all symptomatic patients with heart failure with reduced ejection fraction 20 7.2.1 Angiotensin-converting enzyme inhibitors 20 7.2.2 Beta-blockers 20 7.2.3 Mineralocorticoid/aldosterone receptor antagonists 20 7.3 Other treatments recommended in selected patients with symptomatic heart failure with reduced ejection fraction 20 7.3.1 Diuretics 20 7.3.2 Angiotensin receptor neprilysin inhibitor 23 7.3.3 If-channel inhibitor 24 7.3.4 Angiotensin II type I receptor blockers 24 7.3.5 Combination of hydralazine and isosorbide dinitrate 24 7.4 Other treatments with less-certain benefits in patients with symptomatic heart failure with reduced ejection fraction 24 7.4.1 Digoxin and other digitalis glycosides 24 7.4.2 n-3 polyunsaturated fatty acids 25 7.5 Treatments not recommended (unproven benefit) in patients with symptomatic heart failure with reduced ejection fraction 25 7.5.1 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (‘statins') 25 7.5.2 Oral anticoagulants and antiplatelet therapy 25 7.5.3 Renin inhibitors 25 7.6 Treatments not recommended (believed to cause harm) in patients with symptomatic heart failure with reduced ejection fraction 26 7.6.1 Calcium-channel blockers 26 8. Non-surgical device treatment of heart failure with reduced ejection fraction 26 8.1 Implantable cardioverter-defibrillator 26 8.1.1 Secondary prevention of sudden cardiac death 26 8.1.2 Primary prevention of sudden cardiac death 27 8.2 Cardiac resynchronization therapy 28 8.3 Other implantable electrical devices 29 9. Treatment of heart failure with preserved ejection fraction 29 9.1 Effect of treatment on symptoms in heart failure with preserved ejection fraction 30 9.2 Effect of treatment on hospitalization for heart failure in heart failure with preserved ejection fraction 30 9.3 Effect of treatment on mortality in heart failure with preserved ejection fraction 30 9.4 Other considerations 30 10. Arrhythmias and conductance disturbances 30 10.1 Atrial fibrillation 31 10.1.1 Prevention of atrial fibrillation in patients with heart failure 31 10.1.2 Management of new-onset, rapid atrial fibrillation in patients with heart failure 31 10.1.3 Rate control 31 10.1.4 Rhythm control 32 10.1.5 Thromboembolism prophylaxis 33 10.2 Ventricular arrhythmias 33 10.3 Symptomatic bradycardia, pauses and atrio-ventricular block 34 11. Co-morbidities 35 11.1 Heart failure and co-morbidities 35 11.2 Angina and coronary artery disease 35 11.2.1 Pharmacological management 35 11.2.2 Myocardial revascularization 35 11.3 Cachexia and sarcopenia 36 11.4 Cancer 36 11.5 Central nervous system (including depression, stroke and autonomic dysfunction) 37 11.6 Diabetes 37 11.7 Erectile dysfunction 38 11.8 Gout and arthritis 38 11.9 Hypokalaemia and hyperkalaemia 38 11.10 Hyperlipidaemia 38 11.11 Hypertension 38 11.12 Iron deficiency and anaemia 39 11.13 Kidney dysfunction (including chronic kidney disease, acute kidney injury, cardio-renal syndrome, and prostatic obstruction) 40 11.14 Lung disease (including asthma and chronic obstructive pulmonary disease) 41 11.15 Obesity 41 11.16 Sleep disturbance and sleep-disordered breathing 41 11.17 Valvular heart disease 42 11.17.1 Aortic stenosis 42 11.17.2 Aortic regurgitation 42 11.17.3 Mitral regurgitation 42 11.17.4 Tricuspid regurgitation 42 12. Acute heart failure 43 12.1 Definition and classification 43 12.2 Diagnosis and initial prognostic evaluation 44 12.3 Management 48 12.3.1 Identification of precipitants/causes leading to decompensation which need urgent management 48 12.3.2 Criteria for hospitalization in ward vs. intensive/coronary care unit 49 12.3.3 Management of the early phase 49 12.3.4 Management of patients with cardiogenic shock 54 12.4 Management of evidence-based oral therapies 54 12.5 Monitoring of clinical status of patients hospitalized due to acute heart failure 55 12.6 Criteria for discharge from hospital and follow-up in high-risk period 55 12.7 Goals of treatment during the different stages of management of acute heart failure 55 13. Mechanical circulatory support and heart transplantation 56 13.1 Mechanical circulatory support 56 13.1.1 Mechanical circulatory support in acute heart failure 56 13.1.2 Mechanical circulatory support in end-stage chronic heart failure 56 13.2 Heart transplantation 58 14. Multidisciplinary team management 59 14.1 Organization of care 59 14.2 Discharge planning 61 14.3 Lifestyle advice 61 14.4 Exercise training 61 14.5 Follow-up and monitoring 61 14.6 The older adult, frailty and cognitive impairment 62 14.7 Palliative/end-of-life care 62 15. Gaps in evidence 63 16. To do and not to do messages from the Guidelines 64 17. Web Addenda 65 18. Appendix 1 66 19. References 66 Guidelines summarize and evaluate all available evidence on a particular issue at the time of the writing process, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate. A great number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organisations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC website (http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines). ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated. Members of this Task Force were selected by the ESC to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for management (including diagnosis, treatment, prevention and rehabilitation) of a given condition according to ESC Committee for Practice Guidelines (CPG) policy. A critical evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk-benefit ratio. Estimates of expected health outcomes for larger populations were included, where data exist. The level of evidence and the strength of the recommendation of particular management options were weighed and graded according to predefined scales, as outlined in Tables 1.1 and 1.2. The experts of the writing and reviewing panels provided declarations of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. These forms were compiled into one file and can be found on the ESC website (http://www.escardio.org/guidelines). Any changes in declarations of interest that arise during the writing period must be notified to the ESC and updated. The Task Force received its entire financial support from the ESC without any involvement from the healthcare industry. The ESC CPG supervises and coordinates the preparation of new Guidelines produced by task forces, expert groups or consensus panels. The Committee is also responsible for the endorsement process of these Guidelines. The ESC Guidelines undergo extensive review by the CPG and external experts. After appropriate revisions the Guidelines are approved by all the experts involved in the Task Force. The finalized document is approved by the CPG for publication in the European Heart Journal. The Guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating. The task of developing ESC Guidelines covers not only integration of the most recent research, but also the creation of educational tools and implementation programmes for the recommendations. To implement the guidelines, condensed pocket guidelines versions, summary slides, booklets with essential messages, summary cards for non-specialists, and an electronic version for digital applications (smartphones, etc.) are produced. These versions are abridged and thus, if needed, one should always refer to the full text version, which is freely available on the ESC website. The National Cardiac Societies of the ESC are encouraged to endorse, translate and implement all ESC Guidelines. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations. Surveys and registries are needed to verify that real-life daily practice is in keeping with what is recommended in the guidelines, thus completing the loop between clinical research, writing of guidelines, disseminating them and implementing them into clinical practice. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies. However, the ESC Guidelines do not override in any way whatsoever the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and the patient's caregiver where appropriate and/or necessary. It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription. The aim of all the ESC Guidelines is to help health professionals to make decisions in their everyday life based on the best available evidence. We will soon be celebrating the 30th anniversary of clinical trials that for the first time incontrovertibly demonstrated that the miserable outcome of patients with heart failure (HF) can be markedly improved.2 Since then, in the area of HF management we have witnessed and celebrated numerous highs, which have definitely outnumbered several lows, all of which have allowed us to unravel the pathophysiology of this clinical syndrome, but more importantly has led to better care of our patients.3 In the year 2016, no one would any longer dispute that, by applying all evidence-based discoveries, HF is now becoming a preventable and treatable disease. a new term for patients with HF and a left ventricular ejection fraction (LVEF) that ranges from 40 to 49% — ‘HF with mid-range EF (HFmrEF)’; we believe that identifying HFmrEF as a separate group will stimulate research into the underlying characteristics, pathophysiology and treatment of this population; clear recommendations on the diagnostic criteria for HF with reduced EF (HFrEF), HFmrEF and HF with preserved EF (HFpEF); a new algorithm for the diagnosis of HF in the non-acute setting based on the evaluation of HF probability; recommendations aimed at prevention or delay of the development of overt HF or the prevention of death before the onset of symptoms; indications for the use of the new compound sacubitril/valsartan, the first in the class of angiotensin receptor neprilysin inhibitors (ARNIs); modified indications for cardiac resynchronization therapy (CRT); the concept of an early initiation of appropriate therapy going along with relevant investigations in acute HF that follows the ‘time to therapy’ approach already well established in acute coronary syndrome (ACS); a new algorithm for a combined diagnosis and treatment approach of acute HF based on the presence/absence of congestion/hypoperfusion. This document is the result of extensive interactions between the Task Force, the review team and the ESC Committee for Practice Guidelines. It represents a consensus of opinion of all of the experts involved in its development. Concurrently to the development of the 2016 ESC Guidelines on HF, the group writing the “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure” independently developed its recommendations on new pharmacotherapy for Heart Failure. Both working groups/Task Force independently surveyed the evidence, arrived at similar conclusions, and constructed similar, but not identical, recommendations. Given the concordance, the respective organizations simultaneously issued aligned recommendations on the use of these new treatments to minimize confusion and improve the care of patients with HF. HF is a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. The current definition of HF restricts itself to stages at which clinical symptoms are apparent. Before clinical symptoms become apparent, patients can present with asymptomatic structural or functional cardiac abnormalities [systolic or diastolic left ventricular (LV) dysfunction], which are precursors of HF. Recognition of these precursors is important because they are related to poor outcomes, and starting treatment at the precursor stage may reduce mortality in patients with asymptomatic systolic LV dysfunction4, 5 (for details see Section 6). Demonstration of an underlying cardiac cause is central to the diagnosis of HF. This is usually a myocardial abnormality causing systolic and/or diastolic ventricular dysfunction. However, abnormalities of the valves, pericardium, endocardium, heart rhythm and conduction can also cause HF (and more than one abnormality is often present). Identification of the underlying cardiac problem is crucial for therapeutic reasons, as the precise pathology determines the specific treatment used (e.g. valve repair or replacement for valvular disease, specific pharmacological therapy for HF with reduced EF, reduction of heart rate in tachycardiomyopathy, etc). The main terminology used to describe HF is historical and is based on measurement of the LVEF. HF comprises a wide range of patients, from those with normal LVEF [typically considered as ≥50%; HF with preserved EF (HFpEF)] to those with reduced LVEF [typically considered as <40%; HF with reduced EF (HFrEF)] (Table 3.1). Patients with an LVEF in the range of 40–49% represent a ‘grey area’, which we now define as HFmrEF (Table 3.1). Differentiation of patients with HF based on LVEF is important due to different underlying aetiologies, demographics, co-morbidities and response to therapies.6 Most clinical trials published after 1990 selected patients based on LVEF [usually measured using echocardiography, a radionuclide technique or cardiac magnetic resonance (CMR)], and it is only in patients with HFrEF that therapies have been shown to reduce both morbidity and mortality. The diagnosis of HFpEF is more challenging than the diagnosis of HFrEF. Patients with HFpEF generally do not have a dilated LV, but instead often have an increase in LV wall thickness and/or increased left atrial (LA) size as a sign of increased filling pressures. Most have additional ‘evidence’ of impaired LV filling or suction capacity, also classified as diastolic dysfunction, which is generally accepted as the likely cause of HF in these patients (hence the term ‘diastolic HF’). However, most patients with HFrEF (previously referred to as ‘systolic HF’) also have diastolic dysfunction, and subtle abnormalities of systolic function have been shown in patients with HFpEF. Hence the preference for stating preserved or reduced LVEF over preserved or reduced ‘systolic function’. In previous guidelines it was acknowledged that a grey area exists between HFrEF and HFpEF.7 These patients have an LVEF that ranges from 40 to 49%, hence the term HFmrEF. Identifying HFmrEF as a separate group will stimulate research into the underlying characteristics, pathophysiology and treatment of this group of patients. Patients with HFmrEF most probably have primarily mild systolic dysfunction, but with features of diastolic dysfunction (Table 3.1). Patients without detectable LV myocardial disease may have other cardiovascular causes for HF (e.g. pulmonary hypertension, valvular heart disease, etc.). Patients with non-cardiovascular pathologies (e.g. anaemia, pulmonary, renal or hepatic disease) may have symptoms similar or identical to those of HF and each may complicate or exacerbate the HF syndrome. In these guidelines, the term HF is used to describe the symptomatic syndrome, graded according to the New York Heart Association (NYHA) functional classification (see Section 3.2.3 and Web Table 3.2), although a patient can be rendered asymptomatic by treatment. In these guidelines, a patient who has never exhibited the typical symptoms and/or signs of HF and with a reduced LVEF is described as having asymptomatic LV systolic dysfunction. Patients who have had HF for some time are often said to have ‘chronic HF’. A treated patient with symptoms and signs that have remained generally unchanged for at least 1 month is said to be ‘stable’. If chronic stable HF deteriorates, the patient may be described as ‘decompensated’ and this may happen suddenly or slowly, often leading to hospital admission, an event of considerable prognostic importance. New-onset (‘de novo’) HF may also present acutely, for example, as a consequence of acute myocardial infarction (AMI), or in a subacute (gradual) fashion, for example, in patients with a dilated cardiomyopathy (DCM), who often have symptoms for weeks or months before the diagnosis becomes clear. Although symptoms and signs of HF may resolve, the underlying cardiac dysfunction may not, and patients remain at the risk of recurrent ‘decompensation’. Occasionally, however, a patient may have HF due to a problem that resolves completely (e.g. acute viral myocarditis, takotsubo cardiomyopathy or tachycardiomyopathy). Other patients, particularly those with ‘idiopathic’ DCM, may also show substantial or even complete recovery of LV systolic function with modern disease-modifying therapy [including angiotensin-converting enzyme inhibitor (ACEI), beta-blocker, mineralocorticoid receptor antagonist (MRA), ivabradine and/or CRT]. ‘Congestive HF’ is a term that is sometimes used, and may describe acute or chronic HF with evidence of volume overload. Many or all of these terms may be accurately applied to the same patient at different times, depending upon their stage of illness. The NYHA functional classification (Web Table 3.2) has been used to describe the severity of symptoms and exercise intolerance. However, symptom severity correlates poorly with many measures of LV function; although there is a clear relationship between the severity of symptoms and survival, patients with mild symptoms may still have an increased risk of hospitalization and death.8-10 Sometimes the term ‘advanced HF’ is used to characterize patients with severe symptoms, recurrent decompensation and severe cardiac dysfunction.11 The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) classification describes stages of HF development based on structural changes and symptoms (Web Table 3.3).12 The Killip classification may be used to describe the severity of the patient's condition in the acute setting after myocardial infarction (see Section 12).13 The prevalence of HF depends on the definition applied, but is approximately 1–2% of the adult population in developed countries, rising to ≥10% among people >70 years of age.14-17 Among people >65 years of age presenting to primary care with breathlessness on exertion, one in six will have unrecognized HF (mainly HFpEF).18, 19 The lifetime risk of HF at age 55 years is 33% for men and 28% for women.16 The proportion of patients with HFpEF ranges from 22 to 73%, depending on the definition applied, the clinical setting (primary care, hospital clinic, hospital admission), age and sex of the studied population, previous myocardial infarction and the year of publication.17, 18, 20-30 Data on temporal trends based on hospitalized patients suggest that the incidence of HF may be decreasing, more for HFrEF than for HFpEF.31, 32 HFpEF and HFrEF seem to have different epidemiological and aetiological profiles. Compared with HFrEF, patients with HFpEF are older, more often women and more commonly have a history of hypertension and atrial fibrillation (AF), while a history of myocardial infarction is less common.32, 33 The characteristics of patients with HFmrEF are between those with HFrEF and HFpEF,34 but further studies are needed to better characterize this population. The aetiology of HF is diverse within and among world regions. There is no agreed single classification system for the causes of HF, with much overlap between potential categories (Table 3.4). Many patients will have several different pathologies—cardiovascular and non-cardiovascular—that conspire to cause HF. Identification of these diverse pathologies should be part of the diagnostic workup, as they may offer specific therapeutic opportunities. Many patients with HF and ischaemic heart disease (IHD) have a history of myocardial infarction or revascularization. However, a normal coronary angiogram does not exclude myocardial scar (e.g. by CMR imaging) or impaired coronary microcirculation as alternative evidence for IHD. In clinical practice, a clear distinction between acquired and inherited cardiomyopathies remains challenging. In most patients with a definite clinical diagnosis of HF, there is no confirmatory role for routine genetic testing, but genetic counselling is recommended in patients with hypertrophic cardiomyopathy (HCM), ‘idiopathic’ DCM or arrhythmogenic right ventricular cardiomyopathy (ARVC) (see Section 5.10.1), since the outcomes of these tests may have clinical implications. Over the last 30 years, improvements in treatments and their implementation have improved survival and reduced the hospitalization rate in patients with HFrEF, although the outcome often remains unsatisfactory. The most recent European data (ESC-HF pilot study) demonstrate that 12-month all-cause mortality rates for hospitalized and stable/ambulatory HF patients were 17% and 7%, respectively, and the 12-month hospitalization rates were 44% and 32%, respectively.35 In patients with HF (both hospitalized and ambulatory), most deaths are due to cardiovascular causes, mainly sudden death and worsening HF. All-cause mortality is generally higher in HFrEF than HFpEF.35, 36 Hospitalizations are often due to non-cardiovascular causes, particularly in patients with HFpEF. Hospitalization for cardiovascular causes did not change from 2000 to 2010, whereas those with non-cardiovascular causes increased.31 Estimation of prognosis for morbidity, disability and death helps patients, their families and clinicians decide on the appropriate type and timing of therapies (in particular, decisions about a rapid transition to advanced therapies) and assists with planning of health and social services and resources. Numerous prognostic markers of death and/or HF hospitalization have been identified in patients with HF (Web Table 3.5). However, their clinical applicability is limited and precise risk stratification in HF remains challenging. In recent decades, several multivariable prognostic risk scores have been developed for different populations of patients with HF,36-41 and some are available as interactive online applications. Multivariable risk scores may help predict death in patients with HF, but remain less useful for the prediction of subsequent HF hospitalizations.37, 38 A systematic review examining 64 prognostic models37 along with a meta-analysis and meta-regression study of 117 prognostic models38 revealed only a moderate accuracy of models predicting mortality, whereas models designed to predict the combined endpoint of death or hospitalization, or only hospitalization, had an even poorer discriminative ability. Symptoms are often non-specific and do not, therefore, help discriminate between HF and other problems (Table 4.1).42-46 Symptoms and signs of HF due to fluid retention may resolve quickly with diuretic therapy. Signs, such as elevated jugular venous pressure and displacement of the apical impulse, may be more specific, but are harder to detect and have poor reproducibility.18, 46, 47 Symptoms and signs may be particularly difficult to identify and interpret in obese individuals, in the elderly and in patients with chronic lung disease.48-50 Younger patients with HF often have a different aetiology, clinical presentation and outcome compared with older patients.51, 52 A detailed history should always be obtained. HF is unusual in an individual with no relevant medical history (e.g. a potential cause of cardiac damage), whereas certain features, particularly previous myocardial infarction, greatly increase the likelihood of HF in a patient with appropriate symptoms and signs.42-45 At each visit, symptoms and signs of HF need to be assessed, with particular attention to evidence of congestion. Symptoms and signs are important in monitoring a patient's response to treatment and stability over time. Persistence of symptoms despite treatment usually indicates the need for additional therapy, and worsening of symptoms is a serious development (placing the patient at risk of urgent hospital admission and death) and merits prompt medical attention. The plasma concentration of natriuretic peptides (NPs) can be used as an initial diagnostic test, especially in the non-acute setting when echocardiography is not immediately available. Elevated NPs help establish an initial working diagnosis, identifying those who require further cardiac investigation; patients with values below the cut-point for the exclusion of important cardiac dysfunction do not require echocardiography (see also Section 4.3 and Section 12). Patients with normal plasma NP concentrations are unlikely to have HF. The upper limit of normal in the non-acute setting for B-type natriuretic peptide (BNP) is 35 pg/mL and for N-terminal pro-BNP (NT-proBNP) it is 125 pg/mL; in the acute setting, higher values should be used [BNP < 100 pg/mL, NT-proBNP < 300 pg/mL and mid-regional pro A-type natriuretic peptide (MR-proANP) < 120 pmol/L]. Diagnostic values apply similarly to HFrEF and HFpEF; on average, values are lower for HFpEF than for HFrEF.54, 55 At the mentioned exclusionary cut-points, the negative predictive values are very similar and high (0.94–0.98) in both the non-acute and acute setting, but the positive predictive values are lower both in the non-acute setting (0.44–0.57) and in the acute setting (0.66–0.67).54, 56-61 Therefore, the use of NPs is recommended for ruling-out HF, but not to establish the diagnosis. There are numerous cardiovascular and non-cardiovascular causes of elevated NPs that may weaken their diagnostic utility in HF. Among them, AF, age and renal failure are the most important factors impeding the interpretation of NP measurements.55 On the other hand, NP levels may be disproportionally low in obese patients62 (see also Section 12.2 and Table 12.2). An abnormal electrocardiogram (E