ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012

Abstract

Guidelines summarize and evaluate all available evidence at the time of the writing process, on a particular issue with the aim of assisting physicians 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 are no substitutes, but are complements, for textbooks and cover the European Society of Cardiology (ESC) Core Curriculum topics. Guidelines and recommendations should help physicians to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible physician(s). A large number of Guidelines have been issued in recent years by the ESC as well as by other societies and organizations. 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-surveys/esc-guidelines/about/Pages/rules-writing.aspx). 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 diagnosis, management, and/or prevention 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 recommendation of particular treatment options were weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2. The experts of the writing and reviewing panels filled in declarations of interest forms of all relationships which 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, it is 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 task of developing ESC Guidelines covers not only the 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, 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 Societies of the ESC are encouraged to endorse, translate, and implement the 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, and implementing them into clinical practice. The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and, where appropriate and necessary, the patient's guardian or carer. It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription. Heart failure can be defined as an abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues, despite normal filling pressures (or only at the expense of increased filling pressures).1 For the purposes of these guidelines, HF is defined, clinically, as a syndrome in which patients have typical symptoms (e.g. breathlessness, ankle swelling, and fatigue) and signs (e.g. elevated jugular venous pressure, pulmonary crackles, and displaced apex beat) resulting from an abnormality of cardiac structure or function. The diagnosis of HF can be difficult (see Section 3.6). Many of the symptoms of HF are non-discriminating and, therefore, of limited diagnostic value.2–6 Many of the signs of HF result from sodium and water retention and resolve quickly with diuretic therapy, i.e. may be absent in patients receiving such treatment. Demonstration of an underlying cardiac cause is therefore central to the diagnosis of HF (see Section 3.6). This is usually myocardial disease causing systolic ventricular dysfunction. However, abnormalities of ventricular diastolic function or of the valves, pericardium, endocardium, heart rhythm, and conduction can also cause HF (and more than one abnormality can be present) (see Section 3.5). Identification of the underlying cardiac problem is also crucial for therapeutic reasons, as the precise pathology determines the specific treatment used (e.g. valve surgery for valvular disease, specific pharmacological therapy for LV systolic dysfunction, etc.). The main terminology used to describe HF is historical and is based on measurement of LV ejection fraction (EF). Mathematically, EF is the stroke volume (which is the end-diastolic volume minus the end-systolic volume) divided by the end-diastolic volume. In patients with reduced contraction and emptying of the left ventricle (i.e. systolic dysfunction), stroke volume is maintained by an increase in end-diastolic volume (because the left ventricle dilates), i.e. the heart ejects a smaller fraction of a larger volume. The more severe the systolic dysfunction, the more the EF is reduced from normal and, generally, the greater the end-diastolic and end-systolic volumes. The EF is considered important in HF, not only because of its prognostic importance (the lower the EF the poorer the survival) but also because most clinical trials selected patients based upon EF (usually measured using a radionuclide technique or echocardiography). The major trials in patients with HF and a reduced EF (HF-REF), or ‘systolic HF’, mainly enrolled patients with an EF ≤35%, and it is only in these patients that effective therapies have been demonstrated to date. Other, more recent, trials enrolled patients with HF and an EF >40–45% and no other causal cardiac abnormality (such as valvular or pericardial disease). Some of these patients did not have an entirely normal EF (generally considered to be >50%) but also did not have a major reduction in systolic function either. Because of this, the term HF with ‘preserved’ EF (HF-PEF) was created to describe these patients. Patients with an EF in the range 35–50% therefore represent a ‘grey area’ and most probably have primarily mild systolic dysfunction. The diagnosis of HF-PEF is more difficult than the diagnosis of HF-REF because it is largely one of exclusion, i.e. potential non-cardiac causes of the patient's symptoms (such as anaemia or chronic lung disease) must first be discounted (Table 3).7,8 Usually these patients do not have a dilated heart and many have an increase in LV wall thickness and increased left atrial (LA) size. Most have evidence of diastolic dysfunction (see Section 4.1.2), which is generally accepted as the likely cause of HF in these patients (hence the term ‘diastolic HF’).7,8 It is important to note that EF values and normal ranges are dependent on the imaging technique employed, method of analysis, and operator. Other, more sensitive measures of systolic function may show abnormalities in patients with a preserved or even normal EF (see Section 4.1.1), hence the preference for stating preserved or reduced EF over preserved or reduced ‘systolic function’.9,10 The terms used to describe different types of HF can be confusing. As described above, 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 3.4 and Table 4), although a patient can be rendered asymptomatic by treatment. In these guidelines, a patient who has never exhibited the typical signs or symptoms of HF is described as having asymptomatic LV systolic dysfunction (or whatever the underlying cardiac abnormality is). Patients who have had HF for some time are often said to have ‘chronic HF’. A treated patient with symptoms and signs, which have remained generally unchanged for at least a month, is said to be ‘stable’. If chronic stable HF deteriorates, the patient may be described as ‘decompensated’ and this may happen suddenly, i.e. ‘acutely’, usually leading to hospital admission, an event of considerable prognostic importance. New (‘de novo’) HF may present acutely, for example as a consequence of acute myocardial infarction or in a subacute (gradual) fashion, for example in a patient who has had asymptomatic cardiac dysfunction, often for an indeterminate period, and may persist or resolve (patients may become ‘compensated’). Although symptoms and signs may resolve in the latter patients, their underlying cardiac dysfunction may not, and they remain at risk of recurrent ‘decompensation’. Occasionally, however, a patient may have HF due to a problem that resolves completely (e.g. acute viral myopericarditis). Some other patients, particularly those with ‘idiopathic’ dilated cardiomyopathy, may also show substantial or even complete recovery of LV systolic function with modern disease-modifying therapy [including an angiotensin-converting enzyme (ACE) inhibitor, beta-blocker, and mineralocorticoid receptor antagonist (MRA)]. ‘Congestive HF’ is a term that is sometimes still used, particularly in the USA, and may describe acute or chronic HF with evidence of congestion (i.e. sodium and water retention). Congestion, though not other symptoms of HF (e.g. fatigue), may resolve with diuretic treatment. 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 (Table 4) has been used to select patients in almost all randomized treatment trials in HF and, therefore, to describe which patients benefit from effective therapies. Patients in NYHA class I have no symptoms attributable to heart disease; those in NYHA classes II, III or IV are sometimes said to have mild, moderate or severe symptoms, respectively. It is important to note, however, that symptom severity correlates poorly with ventricular function, and that although there is a clear relationship between severity of symptoms and survival, patients with mild symptoms may still have a relatively high absolute risk of hospitalization and death.11–13 Symptoms can also change rapidly; for example, a stable patient with mild symptoms can become suddenly breathless at rest with the onset of an arrhythmia, and an acutely unwell patient with pulmonary oedema and NYHA class IV symptoms may improve rapidly with the administration of a diuretic. Deterioration in symptoms indicates heightened risk of hospitalization and death, and is an indication to seek prompt medical attention and treatment. Obviously, improvement in symptoms (preferably to the point of the patient becoming asymptomatic) is one of the two major goals of treatment of HF (the other being to reduce morbidity, including hospital admissions, and mortality). The Killip classification may be used to describe the severity of the patient's condition in the acute setting after myocardial infarction.14 Approximately 1–2% of the adult population in developed countries has HF, with the prevalence rising to ≥10% among persons 70 years of age or older.15 There are many causes of HF, and these vary in different parts of the world (Appendix A). At least half of patients with HF have a low EF (i.e. HF-REF). HF-REF is the best understood type of HF in terms of pathophysiology and treatment, and is the focus of these guidelines. Coronary artery disease (CAD) is the cause of approximately two-thirds of cases of systolic HF, although hypertension and diabetes are probable contributing factors in many cases. There are many other causes of systolic HF (Appendix A), which include previous viral infection (recognized or unrecognized), alcohol abuse, chemotherapy (e.g. doxorubicin or trastuzumab), and ‘idiopathic’ dilated cardiomyopathy (although the cause is thought to be unknown, some of these cases may have a genetic basis).16 HF-PEF seems to have a different epidemiological and aetiological profile from HF-REF.17,18 Patients with HF-PEF are older and more often female and obese than those with HF-REF. They are less likely to have coronary heart disease and more likely to have hypertension and atrial fibrillation (AF). Patients with HF-PEF have a better prognosis than those with HF-REF (see below).19 In patients with LV systolic dysfunction, the maladaptive changes occurring in surviving myocytes and extracellular matrix after myocardial injury (e.g. myocardial infarction) lead to pathological ‘remodelling’ of the ventricle with dilatation and impaired contractility, one measure of which is a reduced EF.11,20 What characterizes untreated systolic dysfunction is progressive worsening of these changes over time, with increasing enlargement of the left ventricle and decline in EF, even though the patient may be symptomless initially. Two mechanisms are thought to account for this progression. The first is occurrence of further events leading to additional myocyte death (e.g. recurrent myocardial infarction). The other is the systemic responses induced by the decline in systolic function, particularly neurohumoral activation. Two key neurohumoral systems activated in HF are the renin–angiotensin–aldosterone system and sympathetic nervous system. In addition to causing further myocardial injury, these systemic responses have detrimental effects on the blood vessels, kidneys, muscles, bone marrow, lungs, and liver, and create a pathophysiological ‘vicious cycle’, accounting for many of the clinical features of the HF syndrome, including myocardial electrical instability. Interruption of these two key processes is the basis of much of the effective treatment of HF.11,20 Clinically, the aforementioned changes are associated with the development of symptoms and worsening of these over time, leading to diminished quality of life, declining functional capacity, episodes of frank decompensation leading to hospital admission (which is often recurrent and costly to health services), and premature death, usually due to pump failure or a ventricular arrhythmia. The limited cardiac reserve of such patients is also dependent on atrial contraction, synchronized contraction of the left ventricle, and a normal interaction between the right and left ventricles. Intercurrent events affecting any of these [e.g. the development of AF or conduction abnormalities, such as left bundle branch block (LBBB)] or imposing an additional haemodynamic load on the failing heart (e.g. anaemia) can lead to acute decompensation. Before 1990, the modern era of treatment, 60–70% of patients died within 5 years of diagnosis, and admission to hospital with worsening symptoms was frequent and recurrent, leading to an epidemic of hospitalization for HF in many countries.21–23 Effective treatment has improved both of these outcomes, with a relative reduction in hospitalization in recent years of 30–50% and smaller but significant decreases in mortality.21–23 The diagnosis of HF can be difficult, especially in the early stages. Although symptoms bring patients to medical attention, many of the symptoms of HF (Table 5) are non-specific and do not, therefore, help discriminate between HF and other problems. Symptoms that are more specific (i.e. orthopnoea and paroxysmal nocturnal dyspnoea) are less common, especially in patients with milder symptoms, and are, therefore, insensitive.2–6 Many of the signs of HF result from sodium and water retention, and are, therefore, also not specific. Peripheral oedema has other causes as well, and is particularly non-specific. Signs resulting from sodium and water retention (e.g. peripheral oedema) resolve quickly with diuretic therapy (i.e. may be absent in patients receiving such treatment, making it more difficult to assess patients already treated in this way). More specific signs, such as elevated jugular venous pressure and displacement of the apical impulse, are harder to detect and, therefore, less reproducible (i.e. agreement between different doctors examining the same patient may be poor).2–6 Symptoms and signs may be particularly difficult to identify and interpret in obese individuals, in the elderly, and in patients with chronic lung disease.24–26 The patient's medical history is also important. 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.2–5 These points highlight the need to obtain objective evidence of a structural or functional cardiac abnormality that is thought to account for the patient's symptoms and signs, to secure the diagnosis of HF (see below). Once the diagnosis of HF has been made, it is important to establish the cause, particularly specific correctable causes (Appendix A). 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. In view of the difficulty in grading the evidence for diagnostic tests, all diagnostic recommendations have been given an arbitrary evidence level of C. The echocardiogram and electrocardiogram (ECG) are the most useful tests in patients with suspected HF. The echocardiogram provides immediate information on chamber volumes, ventricular systolic and diastolic function, wall thickness, and valve function.7–10,27–34 This information is crucial in determining appropriate treatment (e.g. an ACE inhibitor and beta-blocker for systolic dysfunction or surgery for aortic stenosis). Echocardiography is discussed in detail later (see Section 4). The ECG shows the heart rhythm and electrical conduction, i.e. whether there is sinoatrial disease, atrioventricular (AV) block, or abnormal intraventricular conduction (see Table 7). These findings are also important for decisions about treatment (e.g. rate control and anticoagulation for AF, pacing for bradycardia, or CRT if the patient has LBBB) (see Section 9.2 on treatment). The ECG may also show evidence of LV hypertrophy or Q waves (indicating loss of viable myocardium), giving a possible clue to the aetiology of HF. HF is very unlikely (likelihood <2%) in patients presenting acutely and with a completely normal ECG.2,3,35–38 In patients with a non-acute presentation, a normal ECG has a somewhat lower negative predictive value (likelihood <10–14%). The information provided by these two tests will permit an initial working diagnosis and treatment plan in the majority of patients. Routine biochemical and haematological investigations are also important, partly to determine whether renin–angiotensin–aldosterone blockade can be initiated safely (renal function and potassium) and to exclude anaemia (which can mimic or aggravate HF) and because they provide other, useful information (see Section 3.6.6). Other tests are generally only required if the diagnosis remains unclear (e.g. if echocardiographic images are suboptimal or if an unusual cardiac cause, or a non-cardiac cause, of the patient's condition is suspected) or if further evaluation of the underlying cause of the patient's cardiac problem is indicated (e.g. perfusion imaging or angiography in suspected CAD or endomyocardial biopsy in certain infiltrating diseases of the myocardium). Special tests are discussed in more detail in Sections 4 and 5. Because the signs and symptoms of HF are so non-specific, many patients with suspected HF referred for echocardiography are not found to have an important cardiac abnormality. Where the availability of echocardiography is limited, an alternative approach to diagnosis is to measure the blood concentration of a natriuretic peptide, a family of hormones secreted in increased amounts when the heart is diseased or the load on any chamber is increased (e.g. by AF, pulmonary embolism, and some non-cardiovascular conditions, including renal failure).39–42 Natriuretic peptide levels also increase with age, but may be reduced in obese patients.26 A normal natriuretic peptide level in an untreated patient virtually excludes significant cardiac disease, making an echocardiogram unnecessary (investigation for a non-cardiac cause of the patient's problems is likely to be more productive in such patients).39,42 The use of natriuretic peptides as a ‘rule-out’ test in the diagnosis of HF is discussed in detail elsewhere.39–50 Multiple studies have examined the threshold concentration that excludes HF for the two most commonly used natriuretic peptides, B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP).43–50 The exclusion threshold differs for patients presenting with acute onset or worsening of symptoms (e.g. to a hospital emergency department) and those presenting with a more gradual onset of symptoms. For patients presenting with acute onset or worsening of symptoms, the optimal exclusion cut-off point is 300 pg/mL for NT-proBNP and 100 pg/mL for BNP. In one other study, mid-regional atrial (or A-type) natriuretic peptide (MR-proANP), at a cut-off point of 120 pmol/L, was shown to be non-inferior to these thresholds for BNP and NT-proBNP in the acute setting.51 For patients presenting in a non-acute way, the optimum exclusion cut-off point is 125 pg/mL for NT-proBNP and 35 pg/mL for BNP. The sensitivity and specificity of BNP and NT-proBNP for the diagnosis of HF are lower in non-acute patients.43–50 A chest X-ray is of limited use in the diagnostic work-up of patients with suspected HF. It is probably most useful in identifying an alternative, pulmonary explanation for a patient's symptoms and signs. It may, however, show pulmonary venous congestion or oedema in a patient with HF. It is important to note that significant LV systolic dysfunction may be present without cardiomegaly on the chest X-ray. In addition to standard biochemical [sodium, potassium, creatinine/estimated glomerular filtration rate (eGFR)] and haematological tests (haemoglobin, haematocrit, ferritin, leucocytes, and platelets), it is useful to measure thyroid-stimulating hormone (thyrotropin) as thyroid disease can mimic or aggravate HF (Table 8). Blood glucose is also worth measuring as undiagnosed diabetes is common in patients with HF. Liver enzymes may also be abnormal in HF (important if considering amiodarone or warfarin). As well as a pre-treatment check, biochemical monitoring is important after the initiation of renin–angiotensin system blockers, while the dose is being up-titrated (see Section 7.2) and during longer term follow-up, especially if an intercurrent illness leading to sodium and water loss occurs (e.g. diarrhoea and vomiting) or another drug that affects sodium and water homeostasis or renal function is started or the dose altered [e.g. non-steroidal anti-inflammatory drugs (NSAIDs) or diuretics]. Many routine laboratory tests provide valuable prognostic information (see Section 6). An algorithm for the diagnosis of HF or LV dysfunction is shown in Figure 1. In patients presenting to hospital as an emergency with suspected HF and acute onset of symptoms, early echocardiography is recommended (and immediate echocardiography in shocked or severely haemodynamically compromised patients). If a natriuretic peptide is measured, a high exclusion cut-off point should be used.39–50 In patients presenting non-emergently in primary care, or to a hospital outpatient clinic, with slow onset of symptoms (and signs) suggestive of HF, an ECG and natriuretic peptide measurement may be used as a means of identifying patients who most need echocardiography (an echocardiogram is indicated if the natriuretic peptide level is above the exclusion threshold/ECG is abnormal). In these patients, a lower exclusion natriuretic peptide cut-off point should be used to prevent a ‘false-negative’ diagnosis of HF.39–50 Patients with a high pre-test likelihood of HF, such as those with a history of myocardial infarction, may be referred directly for echocardiography. Imaging plays a central role in the diagnosis of HF and in guiding treatment. Of the several imaging modalities available, echocardiography is the method of choice in patients with suspected HF for reasons of accuracy, availability (including portability), safety, and cost.27–34 It may be complemented by other modalities, chosen according to their ability to answer specific clinical questions and taking account of contraindications to, and risks of, specific tests (see Table 9).9,10,52–60 All imaging examinations, regardless of type, should be performed only by individuals competent and experienced in the specific technique.32 Echocardiography is a term used here to refer to all cardiac ultrasound imaging techniques, including two-dimensional/three-dimensional echocardiography, pulsed and continuous wave Doppler, colour flow Doppler, and tissue Doppler imaging (TDI).8,27–34,61–64 Echocardiography provides information about cardiac anatomy (e.g. volumes, geometry, mass) and function (e.g. LV function and wall motion, valvular function, right ventricular function, pulmonary artery pressure, pericardium). LVEF is not an index of contractility as it depends on volumes, preload, afterload, heart rate, and valvular function, and is not the same as stroke volume. Stroke volume may be maintained by LV dilation in a patient with HF-REF, whereas it may be reduced in patients with HF-PEF and concentric LV hypertrophy. EF may also be preserved (and stroke volume reduced) in patients with significant mitral regurgitation. Thus EF must be interpreted in its clinical context. The recommended echocardiographic method for measurement of EF is the apical biplane method of discs (the modified Simpson's rule).8,27–34,61 However, because this method relies on accurate tracing of the endocardial border, use of a contrast agent to better delineate the endocardial border is recommended when image quality is suboptimal (i.e. where <80% of the endocardial border is adequately visualized).61 The Teichholz and Quinones methods of calculating EF from linear dimensions may result in inaccuracies, particularly in patients with regional LV dysfunction; the same is true for another technique for assessing LV systolic function—fractional shortening. These and visual assessment of EF (‘eye-balling’) are not recommended.61 Three-dimensional echocardiography of adequate quality further improves the quantification of ventricular volumes and EF calculation.62 The LV wall motion score index may be an acceptable alternative to EF but is not widely used. Other indices of LV systolic function include AV plane systolic excursion, systolic tissue Doppler velocities, and measurements of deformation (strain and strain rate). Deformation imaging is more sensitive than EF in detecting minor changes in LV systolic function. However, issues of reproducibility and standardization currently limit the routine clinical use of deformation imaging. Stroke volume and cardiac output can also be calculated by measuring the velocity time integral at the LV outflow tract area. The most common echocardiographic abnormalities seen in patients with HF and their clinical significance are presented in Table 10. LV diastolic dysfunction is thought to be the underlying pathophysiological abnormality in patients with HF-PEF, and thus its identification is fundamental to the diagnosis of this type of HF (Table 11).7,8,27–34,63,64 The Doppler echocardiographic diastolic indices commonly measured in patients with HF are shown in Table 11. Of note, normal values for functional echocardiographic indices of LV diastolic dysfunction may also depend on age, heart rate, and body size.63,64 Importantly, no single echocardiographic parameter is sufficiently accurate and reproducible to be used in isolation to make a diagnosis of LV diastolic dysfunction. Therefore, a comprehensive echocardiographic examination incorporating all relevant two-dimensional and Doppler data is recommended.8,63,64 This should include the evaluation of both structural (LV hypertrophy, LA dilatio