Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005)

The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology

Authors/Task Force Members, Karl Swedberg, Chairperson, Göteborg (Sweden)* Writing Committee:, John Cleland, Hull (UK), Henry Dargie, Glasgow (UK), Helmut Drexler, Hannover (Germany), Ferenc Follath, Zurich (Switzerland), Michel Komajda, Paris (France), Luigi Tavazzi, Pavia (Italy), Otto A. Smiseth, Oslo (Norway) Other Contributors, Antonello Gavazzi, Bergamo (Italy), Axel Haverich, Hannover (Germany), Arno Hoes, Utrecht (The Netherlands), Tiny Jaarsma, Gronigen (The Netherlands), Jerzy Korewicki, Warsaw (Poland), Samuel Lévy, Marseille (France), Cecilia Linde, Stockholm (Sweden), José-Luis Lopez-Sendon, Madrid (Spain), Markku S. Nieminen, Helsinki (Finland), Luc Piérard, Liège (Belgium), Willem J. Remme, Rhoon (The Netherlands)

* Corresponding author. Chairperson: Karl Swedberg, Sahlgrenska Academy at the Göteborg University, Department of Medicine, Sahlgrenska University Hospital Östra, SE-416 85 Göteborg, Sweden. Tel.: +46 31 3434078; fax: +46 31 258933. E-mail address: karl.swedberg{at}hjl.gu.se

ESC Committee for Practice Guidelines (CPG), Silvia G. Priori (Chairperson) (Italy), Jean-Jacques Blanc (France), Andrzej Budaj (Poland), John Camm (UK), Veronica Dean (France), Jaap Deckers (The Netherlands), Kenneth Dickstein (Norway), John Lekakis (Greece), Keith McGregor (France), Marco Metra (Italy), João Morais (Portugal), Ady Osterspey (Germany), Juan Tamargo (Spain), José Luis Zamorano (Spain)
Document Reviewers, Marco Metra (CPG Review Coordinator) (Italy), Michael Böhm (Germany), Alain Cohen-Solal (France), Martin Cowie (UK), Ulf Dahlström (Sweden), Kenneth Dickstein (Norway), Gerasimos S. Filippatos (Greece), Edoardo Gronda (Italy), Richard Hobbs (UK), John K. Kjekshus (Norway), John McMurray (UK), Lars Rydén (Sweden), Gianfranco Sinagra (Italy), Juan Tamargo (Spain), Michal Tendera (Poland), Dirk van Veldhuisen (The Netherlands), Faiez Zannad (France)

Preamble

Guidelines and Expert Consensus Documents aim to present all the relevant evidence on a particular issue in order to help physicians to weigh the benefits and risks of a particular diagnostic or therapeutic procedure. They should be helpful in everyday clinical decision-making.

A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) and by different organizations and other related societies. This profusion can put at stake the authority and validity of guidelines, which can only be guaranteed if they have been developed by an unquestionable decision-making process. This is one of the reasons why the ESC and others have issued recommendations for formulating and issuing Guidelines and Expert Consensus Documents.

In spite of the fact that standards for issuing good quality Guidelines and Expert Consensus Documents are well defined, recent surveys of Guidelines and Expert Consensus Documents published in peer-reviewed journals between 1985 and 1998 have shown that methodological standards were not complied with in the vast majority of cases. It is therefore of great importance that guidelines and recommendations are presented in formats that are easily interpreted. Subsequently, their implementation programmes must also be well conducted. Attempts have been made to determine whether guidelines improve the quality of clinical practice and the utilization of health resources.

The ESC Committee for Practice Guidelines (CPG) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups, or consensus panels. The chosen experts in these writing panels are asked to provide disclosure statements of all relationships they may have which might be perceived as real or potential conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. The Committee is also responsible for the endorsement of these Guidelines and Expert Consensus Documents or statements.

The Task Force has classified and ranked the usefulness or efficacy of the recommended procedure and/or treatments and the Level of Evidence as indicated in the tables on page 3.

Diagnosis of chronic heart failure

Introduction

Methodology
These Guidelines are based on the Diagnostic and Therapeutic Guidelines published in 1995, 1997, and renewed in 2001,13 which has now been combined into one manuscript. Where new information is available, an update has been performed while other parts are unchanged or adjusted only to a limited extent.

The aim of this report is to provide updated practical guidelines for the diagnosis, assessment, and treatment of heart failure for use in clinical practice, as well as for epidemiological surveys and clinical trials. Particular attention in this update has been allocated to diastolic function and heart failure with preserved left ventricular ejection fraction (PLVEF). The intention has been to merge the previous Task Force report4 with the present update.

The Guidelines are intended as a support for practising physicians and other health care professionals concerned with the management of heart failure patients and to provide advice on how to manage these patients, including recommendations for referral. Documented and published evidence on diagnosis, efficacy, and safety is the main basis for these guidelines. ESC Guidelines are relevant to 49 member-states with diverse economies and therefore recommendations based on cost-effectiveness have been avoided in general. National health policy as well as clinical judgement may dictate the order of priority of implementation. It is recognized that some interventions may not be affordable in some countries for all appropriate patients. The recommendations in these guidelines should therefore always be considered in the light of national policies and local regulatory requirements for the administration of any diagnostic procedure, medicine, or device.

This report was drafted by a Writing Group of the Task Force (see title page) appointed by the CPG of the ESC. Within this Task Force, statements of Conflicts of Interests were collected, which are available at the ESC Office. The draft was sent to the Committee and the document reviewers (see title page) and after their input the document was updated, reviewed and then approved for presentation. The summary is based on a full document, which includes more background statements and includes references. This document is available at the ESC website www.escardio.org. The full report should be used when in doubt or when further information is required. An evidenced based approach to the evaluations has been applied including a grading of the evidence for recommendations. However, for the diagnosis, evidence is incomplete and in general based on consensus of expert opinions. Already in the 2001 version, it was decided not to use evidence grading in this part. The same approach has been used here.

Major conclusions or recommendations have been highlighted by Bullets.

Epidemiology

The ESC represents countries with a population of over 900 million, suggesting that there are at least 10 million patients with heart failure in those countries. There are also patients with myocardial systolic dysfunction without symptoms of heart failure and who constitute approximately a similar prevalence.57 The prognosis of heart failure is uniformly poor if the underlying problem cannot be rectified. Half of patients carrying a diagnosis of heart failure will die within 4 years, and in patients with severe heart failure >50% will die within 1 year.8,9 Many patients with heart failure have symptoms and PLVEF.10


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Classes of recommendations
 

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Levels of evidence
 
Studies show that the accuracy of diagnosis by clinical means alone is often inadequate,11,12 particularly in women, elderly, and obese. To study properly the epidemiology and prognosis and to optimize the treatment of heart failure, the uncertainty relating to the diagnosis must be minimized or avoided completely.

Descriptive terms in heart failure

Acute vs. chronic heart failure
The term acute heart failure (AHF) is often used exclusively to mean de novo AHF or decompensation of chronic heart failure (CHF) characterized by signs of pulmonary congestion, including pulmonary oedema. Other forms include hypertensive AHF, pulmonary oedema, cardiogenic shock, high output failure, and right heart failure. (See Guidelines on acute heart failure.13)

CHF often punctuated by acute exacerbations, is the most common form of heart failure. A definition of CHF is suceedingly given.

The present document will concentrate on the syndrome of CHF and leave out aspects on AHF.13 Thus, heart failure, if not stated otherwise, is referring to the chronic state.

Systolic vs. diastolic heart failure
Most heart failures are associated with evidence of left ventricular systolic dysfunction, although diastolic impairment at rest is a common if not universal accompaniment. In most cases, diastolic and systolic heart failures should not be considered as separate pathophysiological entities. Diastolic heart failure is often diagnosed when symptoms and signs of heart failure occur in the presence of a PLVEF (normal ejection fraction) at rest. Predominant diastolic dysfunction is relatively uncommon in younger patients but increases in importance in the elderly. PLVEF is more common in women, in whom systolic hypertension and myocardial hypertrophy with fibrosis are contributors to cardiac dysfunction.10,14

Other descriptive terms in heart failure
Right and left heart failure refer to syndromes presenting predominantly with congestion of the systemic or pulmonary veins. The terms do not necessarily indicate which ventricle is most severely damaged. High- and low-output, forward and backward, overt, treated, and congestive are other descriptive terms still in occasional use; the clinical utility of these terms is descriptive without etiological information and therefore of little use in determining modern treatment for heart failure.

Mild, moderate, or severe heart failure is used as a clinical symptomatic description, where mild is used for patients who can move around with no important limitations of dyspnea or fatigue, severe for patients who are markedly symptomatic and need frequent medical attention and moderate for the remaining patient cohort.

Definition of chronic heart failure

Many definitions of CHF exist1518 but highlight only selective features of this complex syndrome. The diagnosis of heart failure relies on clinical judgement based on a history, physical examination, and appropriate investigations.

Heart failure is a syndrome in which the patients should have the following features: symptoms of heart failure, typically breathlessness or fatigue, either at rest or during exertion, or ankle swelling and objective evidence of cardiac dysfunction at rest (Table 1). The distinctions between cardiac dysfunction, persistent heart failure, heart failure that has been rendered asymptomatic by therapy, and transient heart failure are outlined in Figure 1. A clinical response to treatment directed at heart failure alone is not sufficient for diagnosis, although the patient should generally demonstrate some improvement in symptoms and/or signs in response to those treatments in which a relatively fast symptomatic improvement could be anticipated (e.g. diuretic or nitrate administration).


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Table 1 Definition of heart failure
 


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Figure 1 Relationship between cardiac dysfunction, heart failure, and heart failure rendered asymptomatic.

 
Asymptomatic left ventricular systolic dysfunction is considered as precursor of symptomatic CHF and is associated with high mortality.19 It is important when diagnosed and treatment is available, and the condition is therefore included in these Guidelines.

Aspects of the pathophysiology of the symptoms of heart failure relevant to diagnosis

The origin of the symptoms of heart failure is not fully understood. Increased pulmonary capillary pressure is undoubtedly responsible for pulmonary oedema in part, but studies conducted during exercise in patients with CHF demonstrate only a weak relationship between capillary pressure and exercise performance.20,21 This suggests either that raised pulmonary capillary pressure is not the only factor responsible for exertional breathlessness (e.g. lungwater and plasma albumin) or that current techniques to measure true pulmonary capillary pressure may not be adequate. Variation in the degree of mitral regurgitation will also influence breathlessness.

Possible methods for the diagnosis of heart failure in clinical practice

Symptoms and signs in the diagnosis of heart failure

Breathlessness, ankle swelling, and fatigue are the characteristic symptoms and signs of heart failure but may be difficult to interpret, particularly in elderly patients, in obese, and in women. It should be interpreted carefully and different modes (e.g. effort and nocturnal) should be assessed.



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Figure 2 Algorithm for the diagnosis of heart failure or left ventricular dysfunction.

 
Fatigue is also an essential symptom in heart failure. The origins of fatigue are complex including low cardiac output, peripheral hypoperfusion, skeletal muscle deconditioning, and confounded by difficulties in quantifying this symptom.

Peripheral oedema, raised venous pressure, and hepatomegaly are the characteristic signs of congestion of systemic veins.22,23 Clinical signs of heart failure should be assessed in a careful clinical examination, including observing, palpating, and auscultating the patient.

Symptoms and the severity of heart failure

Once a diagnosis of heart failure has been established, symptoms may be used to classify the severity of heart failure and should be used to monitor the effects of therapy. However, as noted subsequently, symptoms cannot guide the optimal titration of neurohormonal blockers. The New York Heart Association (NYHA) classification is in widespread use (Table 2). In other situations, the classification of symptoms into mild, moderate, or severe is used. Patients in NYHA class I would have to have objective evidence of cardiac dysfunction, have a past history of heart failure symptoms and be receiving treatment for heart failure in order to fulfil the basic definition of heart failure.


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Table 2 New York Heart Association classification of heart failure
 
In acute myocardial infarction, the classification described by Killip26 has been used to describe symptoms and signs.27 It is important to recognize the common dissociation between symptoms and cardiac dysfunction. Symptoms are also similar in patients across different levels of ejection fraction.28 Mild symptoms should not be equated with minor cardiac dysfunction.

Electrocardiogram

Electrocardiographic changes are common in patients suspected of having heart failure whether or not the diagnosis proves to be correct. An abnormal ECG, therefore, has little predictive value for the presence of heart failure. On the other hand, if the ECG is completely normal, heart failure, especially due LV systolic dysfunction, is unlikely. The presence of pathological Q-waves may suggest myocardial infarction as the cause of cardiac dysfunction. A QRS width >120 ms suggests that cardiac dyssynchrony may be present and a target for treatment.

The chest X-ray

Haematology and biochemistry
Routine diagnostic evaluation of patients with CHF includes: complete blood count (Hb, leukocytes, and platelets), S-electrolytes, S-creatinine, S-glucose, S-hepatic enzymes, and urinalysis. Additional tests to evaluate thyroid function should be considered according to clinical findings. In acute exacerbations, acute myocardial infarction is excluded by myocardial specific enzyme analysis.

Natriuretic peptides

As the diagnostic potential of natriuretic peptides is less clear cut when systolic function is normal, there is increasing evidence that their elevation can indicate diastolic dysfunction is present.29,30 Other common cardiac abnormalities that may cause elevated natriuretic peptide levels include left ventricular hypertrophy, valvular heart disease, acute or chronic ischaemia or hypertension,31 and pulmonary embolism.32

In considering the use of BNP and NT-proBNP as diagnostic aids, it should be emphasized that a ‘normal’ value cannot completely exclude cardiac disease, but a normal or low concentration in an untreated patient makes heart failure unlikely as the cause of symptoms.

In clinical practice today, the place of BNP and NT-proBNP is as ‘rule out’ tests to exclude significant cardiac disease. Particularly in primary care but also in certain aspects of secondary care (e.g. the emergency room and clinics.) The cost-effectiveness of the test suggest that a normal result should obviate the need for further cardiological tests such as in the first instance echocardiography as well as more expensive investigations.33

Echocardiography

The access to and use of echocardiography is encouraged for the diagnosis of heart failure. Transthoracic Doppler echocardiography (TDE) is rapid, safe, and widely available.

Assessment of LV diastolic function
Assessment of diastolic function may be clinically useful: (1) to detect abnormalities of diastolic function in patients who present with CHF and normal left ventricular ejection fraction, (2) in determining prognosis in heart failure patients, (3) in providing a non-invasive estimate of left ventricular diastolic pressure, and (4) in diagnosing constrictive pericarditis and restrictive cardiomyopathy.

Diagnostic criteria of diastolic dysfunction
A diagnosis of primary diastolic heart failure requires three conditions to be simultaneously satisfied: (1) presence of signs or symptoms of CHF, (2) presence of normal or only mildly abnormal left ventricular systolic function (LVEF≥45–50%), and (3) evidence of abnormal left ventricular relaxation, diastolic distensibility, or diastolic stiffness.34 Furthermore, it is essential to exclude pulmonary disease.35

At an early stage of diastolic dysfunction, there is typically a pattern of ‘impaired myocardial relaxation’ with a decrease in peak transmitral E-velocity, a compensatory increase in the atrial-induced (A) velocity and therefore a decrease in the E/A ratio.

In patients with advanced cardiac disease, there may be a pattern of ‘restrictive filling’, with an elevated peak E-velocity, a short E-deceleration time, and a markedly increased E/A ratio. The elevated peak E-velocity is due to elevated left atrial pressure that causes an increase in the early-diastolic transmitral pressure gradient.36

In patients with an intermediate pattern between impaired relaxation and restrictive filling the E/A ratio and the deceleration time may be normal, a so-called ‘pseudonormalized filling pattern’. This pattern may be distinguished from normal filling by the demonstration of reduced peak E'-velocity by TDI.37

The three filling patterns ‘impaired relaxation’, ‘pseudonormalized filling’, and ‘restrictive filling’ represent mild, moderate, and severe diastolic dysfunction, respectively37 (Figure 3). Thus, by using the combined assessment of transmitral blood flow velocities and mitral annular velocities, it becomes possible to perform staging of diastolic dysfunction during a routine echocardiographic examination. We still lack prospective outcome studies that investigate if assessment of diastolic function by these criteria may improve management of heart failure patients.



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Figure 3 The three filling patterns ‘impaired relaxation’, ‘pseudonormalised filling’, and ‘restrictive filling’ represent mild, moderate, and severe diastolic dysfunction, respectively.37

 
Transoesophageal echocardiography is not recommended routinely and can only be advocated in patients who have an inadequate echo window, in complicated valvular patients, and in patients with suspected dysfunction of mechanical mitral valve prosthesis or when it is mandatory to identify or exclude a thrombus in the atrial appendage.

Repeated echocardiography can be recommended in the follow-up of patients with heart failure only when there is an important change in the clinical status suggesting significant improvement or deterioration in cardiac function.

Additional non-invasive tests to be considered
In patients in whom echocardiography at rest has not provided enough information and in patients with coronary artery disease (e.g. severe or refractory CHF and coronary artery disease), further non-invasive imaging may include stress echocardiography, radio-nuclide imaging, and cardiac magnetic resonance imaging (CMR).

Cardiac magnetic resonance imaging (CMR)

Pulmonary function

Exercise testing

Invasive investigation

Cardiac catheterization
Coronary angiography should be considered in patients with acute or acutely decompensated CHF and in patients with severe heart failure (shock or acute pulmonary oedema) who are not responding to initial treatment. Coronary angiography should also be considered in patients with angina pectoris or any other evidence of myocardial ischaemia if they are not responding to appropriate anti-ischaemic treatment. Revascularization has not been shown to alter prognosis in heart failure in clinical trials and therefore, in the absence of angina pectoris unresponsive to medical therapy, coronary arteriography is not indicated. Coronary angiography is also indicated in patients with refractory heart failure of unknown aetiology and in patients with evidence of severe mitral regurgitation or aortic valve disease.

Monitoring of haemodynamic variables by means of a pulmonary arterial catheter is indicated in patients who are hospitalized for cardiogenic shock or to direct treatment of patients with CHF not responding promptly to initial and appropriate treatment. Routine right heart catheterization should not be used to tailor chronic therapy.

Tests of neuroendocrine evaluations other than natriuretic peptides

Holter electrocardiography: ambulatory ECG and long-time ECG recording (LTER)

Requirements for the diagnosis of heart failure in clinical practice

The echocardiogram is the single most effective tool in widespread clinical use. Other conditions may mimic or exacerbate the symptoms and signs of heart failure and therefore need to be excluded (Table 3). An approach (Figure 2) to the diagnosis of heart failure in symptomatic patients should be performed routinely in patients with suspected heart failure in order to establish the diagnosis. Additional tests (Table 4) should be performed or re-evaluated in cases in which diagnostic doubt persists or clinical features suggest a reversible cause for heart failure.


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Table 3 Assessments to be performed routinely to establish the presence and likely cause of heart failure
 

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Table 4 Additional tests to be considered to support the diagnosis or to suggest alternative diagnoses
 
Figure 2 represents a simplified plan for the evaluation of a patient presenting with symptoms suggestive of heart failure or signs giving suspicion of left ventricular systolic dysfunction. Table 5 provides a management outline connecting the diagnosis component of the guidelines with the treatment section.


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Table 5 Management outline
 
Prognostication


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Table 6 Risk stratification in CHF predictors
 
Treatment of heart failure

Aims of treatment in heart failure

  1. Prevention—a primary objective
    1. Prevention and/or controlling of diseases leading to cardiac dysfunction and heart failure.
    2. Prevention of progression to heart failure once cardiac dysfunction is established.

  2. Maintenance or improvement in quality of life
  3. Improved survival

Prevention of heart failure

When myocardial dysfunction is already present, the first objective is to remove the underlying cause of ventricular dysfunction if possible (e.g. ischaemia, toxic substances, alcohol, drugs, and thyroid disease), providing the benefits of intervention outweigh the risks. When the underlying cause cannot be corrected treatment should be directed at delaying or preventing left ventricular dysfunction that will increase the risk of sudden death and the development of heart failure.

How to modulate progression from asymptomatic left ventricular dysfunction to heart failure is described on page 1133, Treatment of Asymptomatic Left Ventricular Dysfunction.

Management of chronic heart failure

The therapeutic approach in patients with CHF that is caused by left ventricular systolic dysfunction includes general advice and other non-pharmacological measures, pharmacological therapy, mechanical devices, and surgery. The currently available types of management are outlined in Tables 5 and 7.


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Table 7 Treatment options: general advice and measures, exercise and exercise training, pharmacological therapy, and devices and surgery
 
Non-pharmacological management

General advice and measures
(Class of recommendation I, level of evidence C for non-pharmacological management unless stated otherwise)

Educating patients and family
Patients with CHF and their close relatives should receive general advice.

Weight monitoring
Patients are advised to weigh on a regular basis to monitor weight gain (preferably as part of a regular daily routine, for instance after morning toilet) and, in case of a sudden unexpected weight gain of >2 kg in 3 days, to alert a health care provider or adjust their diuretic dose accordingly (e.g. to increase the dose if a sustained increase in weight is noted).

Dietary measures
Sodium
Controlling the amount of salt in the diet is a problem, that is, more important in advanced than in mild heart failure.

Fluids
Instructions on fluid control should be given to patients with advanced heart failure, with or without hyponatraemia. The exact amount of fluid restriction remains unclear, however. In practice, a fluid restriction of 1.5–2 L/day is advised in advanced heart failure.

Alcohol
Moderate alcohol intake (one beer, 1–2 glasses of wine/day) is permitted other than in case of alcoholic cardiomyopathy when it is prohibited.

Obesity
Treatment of CHF should include weight reduction in obese patients.

Abnormal weight loss
Clinical or subclinical malnutrition is present in ~50% of patients with severe CHF. The wasting of total body fat and lean body mass that accompanies weight loss is called cardiac cachexia. Cardiac cachexia is an important predictor of reduced survival.41

Smoking
Smoking should always be discouraged. The use of smoking cessation aids should be actively encouraged and may include nicotine replacement therapies.

Travelling
High altitudes or very hot or humid places should be discouraged. In general, short air flights are preferable to long journeys by other means of transport.

Sexual activity
It is not possible to dictate guidelines about sexual activity counselling. Recommendations are given to reassure the not severely compromised, but frightened patient, to reassure the partner who is often even more frightened, and perhaps refer the couple for specialist counselling. Little is known about the effects of treatments for heart failure on sexual function.

Advice on immunizations
There is no documented evidence of the effects of immunization in patients with heart failure. Immunization for influenza is widely used.

Drug counselling
Self-management (when practical) of the dose of the diuretic, based on changes in symptoms and weight (fluid balance), should be encouraged. Within pre-specified and individualized limits, patients are able to adjust their diuretics.

Drugs to avoid or beware
The following drugs should be used with caution when co-prescribed with any form of heart failure treatment or avoided:

  1. Non-steroidal anti-inflammatory drugs (NSAIDS) and coxibs
  2. Class I anti-arrhythmic agents (page 1131)
  3. Calcium antagonists (verapamil, diltiazem, and short-acting dihydropyridine derivatives (page 1126)
  4. Tricyclic anti-depressants
  5. Corticosteroids
  6. Lithium

Rest, exercise, and exercise training
Rest
In acute heart failure or destabilization of CHF, physical rest or bed rest is recommended.

Exercise
Exercise improves skeletal muscle function and therefore overall functional capacity. Patients should be encouraged and advised on how to carry out daily physical and leisure time activities that do not induce symptoms. Exercise training programs are encouraged in stable patients in NYHA class II–III. Standardized recommendations for exercise training in heart failure patients by the European Society of Cardiology have been published.42

Pharmacological therapy

Angiotensin-converting enzyme inhibitors

ACE-inhibitors in asymptomatic left ventricular dysfunction

ACE-inhibitors in symptomatic heart failure

Target maintenance dose ranges of ACE-inhibitors shown to be effective in various trials are given in Table 8. Recommended initiating and maintenance dosages of ACE-inhibitors which have been approved for the treatment of heart failure in Europe are presented in Table 9.


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Table 8 Doses of ACE-inhibitors shown to be effective in large, controlled trials of heart failure, or left ventricular dysfunction
 

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Table 9 Recommended ACE-inhibitor maintenance dose ranges for some agents approved for heart failure in Europe*
 
The dose of ACE-inhibitors should always be initiated at the lower dose level and titrated to the target dose. The recommended procedures for starting an ACE-inhibitor are given in Table 10.


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Table 10 The recommended procedure for starting an ACE-inhibitor or an angiotensin receptor blocker
 
Regular monitoring of renal function is recommended: (1) before, 1–2 weeks after each dose increment, and at 3–6 months interval; (2) when the dose of an ACE-inhibitor is increased or other treatments, which may affect renal function, are added (e.g. aldosterone antagonist or angiotensin receptor blocker), (3) in patients with past or present renal dysfunction or electrolyte disturbances more frequent measurements should be made, or (4) during any hospitalization.

Diuretics
Loop diuretics, thiazides, and metolazone

Detailed recommendations and major side effects are outlined in Tables 11 and 12.


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Table 11 Diuretics
 

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Table 12 Diuretics (oral): dosages and side effects
 
Potassium-sparing diuretics

Beta-adrenoceptor antagonists

Initiation of therapy
The initial dose should be small and increased slowly and progressively to the target dose used in the large clinical trials. Up-titration should be adapted to individual responses.

During titration, beta-blockers may reduce heart rate excessively, temporarily induce myocardial depression, and exacerbate symptoms of heart failure. Table 13 gives the recommended procedure for the use of beta-blockers in clinical practice and contraindications.


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Table 13 The recommended procedure for starting a beta-blocker
 
Table 14 shows the titration scheme of the drugs used in the most relevant studies.


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Table 14 Initiating dose, target dose, and titration scheme of beta-blocking agents as used in recent large, controlled trials
 
Aldosterone receptor antagonists
Administration and dosing considerations for aldosterone antagonists are provided in Table 15.


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Table 15 Administration and dosing considerations with aldosterone antagonists (spironolactone, eplerenone)
 
Angiotensin II receptor blockers
For patients with left ventricular systolic dysfunction:In NYHA class III patients remaining symptomatic despite therapy with diuretics, ACE-inhibitors, and beta-blockers, there is no definite evidence for the recommendation of next addition; an ARB or an aldosterone antagonist to reduce further heart failure hospitalizations or mortality.

Concerns raised by initial studies about a potential negative interaction between ARBs and beta-blockers have not been confirmed by recent studies in post-myocardial infarction or CHF (Class of recommendation I, level of evidence A).65,68

Dosing
Initiation and monitoring of ARBs, which are outlined in Table 10, are similar to procedures for ACE-inhibitors. Available ARBs and the recommended dose levels are shown in Table 16.


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Table 16 Currently available angiotensin II receptor antagonists
 
Cardiac glycosides

Digoxin
The usual daily dose of oral digoxin is 0.125–0.25 mg if serum creatinine is in the normal range (in the elderly 0.0625–0.125 mg, occasionally 0.25 mg).

Vasodilator agents in chronic heart failure

Hydralazine-isosorbide dinitrate

Nitrates

Alpha-adrenergic blocking drugs

Calcium antagonists

As long-term safety data with felodipine and amlodipine indicate a neutral effect on survival, they may offer a safe alternative for the treatment of concomitant arterial hypertension or angina not controlled by nitrates and beta-blockers.

Nesiritide
Nesiritide, a recombinant human brain or B-type natriuretic peptide (BNP), has been shown to be efficacious in improving subjective dyspnoea score as well as inducing significant vasodilation when administered intravenous to patients with acute heart failure. Clinical experience with nesiritide is still limited. Nesiritide may cause hypotension and some patients are non-responders.

Positive inotropic therapy

Anti-thrombotic agents

Patients with CHF are at high risk of thromboembolic events. Factors predisposing to thromboembolism are low cardiac output with relative stasis of blood in dilated cardiac chambers, poor contractility, regional wall motion abnormalities, and atrial fibrillation. There is little evidence to support the concomitant treatment with an ACE-inhibitor and aspirin in heart failure.8183

In general, the rates of thromboembolic complications in heart failure are sufficiently low to limit the evaluation of any potential beneficial effect of anti-coagulation/anti-thrombotic therapy in these patients.

Anti-arrhythmics
Anti-arrhythmic drugs other than beta-blockers are generally not indicated in patients with CHF. In patients with atrial fibrillation (rarely flutter), non-sustained, or sustained ventricular tachycardia treatment with anti-arrhythmic agents may be indicated.

Class I anti-arrhythmics

Class II anti-arrhythmics

Class III anti-arrhythmics

Routine administration of amiodarone in patients with heart failure is not justified (Class of recommendation III, level of evidence A).89,90

Oxygen therapy

Surgery and devices

Revascularization procedures, mitral valve surgery, and ventricular restoration

Revascularization

Mitral valve surgery

Left ventricular restoration
LV aneurysmectomy

Cardiomyoplasty

Partial left ventriculectomy (Batista operation)

External ventricular restoration

Pacemakers

Bi-ventricular pacing improves symptoms, exercise capacity, and reduces hospitalizations.9194 A beneficial effect on the composite of long-term mortality or all-cause hospitalization has recently been demonstrated, as well as a significant effect on mortality.171

Implantable cardioverter defibrillators

In patients with documented sustained ventricular tachycardia or ventricular fibrillation, the ICD is highly effective in treating recurrences of these arrhythmias, either by anti-tachycardia pacing or cardioversion/defibrillation, thereby reducing morbidity and the need for rehospitalization. The selection criteria, the limited follow-up and increased morbidity associated with ICD-implantation and the low cost-effectiveness make it inappropariate to extend the findings into a general population with CHF. The COMPANION trial included patients with left ventricular systolic dysfunction, wide QRS complex suggesting dyssynchrony and heart failure and showed that implantation of an ICD in combination with resynchronization in patients with severe heart failure reduced mortality and morbidity (See under Resynchronization).93 However, CRT-D was not superior to CRT alone in terms of reducing mortality and therefore the treatment associated with lower morbidity and cost may be preferred for the majority of patients. CRT-D should be reserved for patients considered at very high risk of sudden death despite medical treatment and CRT alone. The cost-effectiveness of this treatment needs to be established.98 In the SCD-HeFT trial, 2521 patients with CHF and LVEF≤35% were randomized to placebo, amiodarone, or single-lead ICD implantation. After a median follow-up of 45.5 months, there was a significant reduction in mortality by ICD therapy; HR 0.77 (97.5% CI: 0.62–0.96; P=0.007).90 There was no difference between placebo and amiodarone on survival.

Several recent meta-analyses estimated the effect of ICD implantation on all-cause mortality in symptomatic patients with reduced ejection fraction.83,99,100 As the effectiveness with ICD is time-dependent,101 anticipated duration of treatment is important to establish cost-effectiveness. Accordingly, the age of the patient and non-cardiac comorbidity must also be taken into account. Treatment of patients in NYHA class IV is not well established unless associated with CRT in the context of dyssynchrony. There is no evidence that patients with DCM obtain proportionally less benefit but as the prognosis of this group is generally better, the absolute benefits may be less.83

Heart replacement therapies: heart transplantation, ventricular assist devices, and artificial heart
Heart transplantation

Patients who should be considered for heart transplantation are those with severe symptoms of heart failure with no alternative form of treatment and with a poor prognosis. The introduction of new treatments has probably modified the prognostic significance of the variables traditionally used to identify heart transplant candidates i.e. VO2 max (see prognostication page 1122). The patient must be willing and capable to undergo intensive medical treatment, and be emotionally stable so as to withstand the many uncertainties likely to occur both before and after transplantation. The contraindications for heart transplantation are shown in Table 17.


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Table 17 Contraindications for heart transplantation
 
Besides shortage of donor hearts, the main problem of heart transplantation is rejection of the allograft, which is responsible for a considerable percentage of deaths in the first postoperative year. The long-term outcome is limited predominantly by the consequences of immuno-suppression (infection, hypertension, renal failure, malignancy, and by transplant coronary vascular disease).102

Ventricular assist devices and artificial heart

Ultrafiltration

Choice and timing of pharmacological therapy
The choice of pharmacological therapy in the various stages of heart failure that is caused by systolic dysfunction is displayed in Table 18. Before initiating therapy, the correct diagnosis needs to be established and considerations should be given to the Management Outline presented in Table 5.


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Table 18 CHF—choice of pharmacological therapy in left ventricular systolic dysfunction
 
Asymptomatic left ventricular systolic dysfunction
In general, the lower the ejection fraction, the higher the risk of developing heart failure or sudden death. Treatment with an ACE-inhibitor is recommended in patients with reduced LVEF if indicated by a substantial reduction in LVEF (see section on echocardiography in the Diagnosis section) (recommendation page 1120).

Beta-blockers should be added to the therapy in patients with asymptomatic left ventricular dysfunction, especially if following an acute myocardial infarction (recommendation page 1127).

Symptomatic left ventricular systolic dysfunction: heart failure NYHA class II (Figure 4)
Without signs of fluid retention
ACE-inhibitor (recommendation page 1126). Titrate to the target dose used in large controlled trials (Table 8). Add a beta-blocker (recommendation page 1127) and titrate to target dosages used in large controlled trials (Table 14).



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Figure 4 Pharmacological therapy of symptomatic CHF that is equally systolic left ventricular dysfunction. The algorithm should primarily be viewed as an example of how decisions on therapy can be made depending on the progression of heart failure severity. A patient in NYHA Class II can be followed with proposals of decision-making steps. Individual adjustments must be taken into consideration.

 
With signs of fluid retention
Diuretics in combination with an ACE-inhibitor followed by a beta-blocker. First, the ACE-inhibitor and diuretic should be co-administered. When symptomatic improvement occurs (i.e. fluid retention disappears), the optimal dose of the ACE-inhibitor should be maintained followed by a beta-blocker. The dose of diuretic can be adjusted based on patient stability. To avoid hyperkalaemia, any potassium-sparing diuretic should be omitted from the diuretic regimen before introducing an ACE-inhibitor. However, an aldosterone antagonist may be added if hypokalaemia persists. Add a beta-blocker and titrate to target dosages used in large controlled trials (Table 13). Patients in sinus rhythm receiving cardiac glycosides and who have improved from severe to mild heart failure should continue cardiac glycoside therapy (recommendation page 1128) In patients who remain symptomatic and in patients who deteriorate, the addition of an ARB should be considered (recommendation page 1128).

Worsening heart failure (Figure 3)
Frequent causes of worsening heart failure are shown in Table 19. Patients in NYHA class III that have improved from NYHA class IV during the preceding 6 months or are currently NYHA class IV should receive low-dose spironolactone (12.5–50 mg daily recommendation page 1128). Cardiac glycosides are often added. Loop diuretics can be increased in dose, and combinations of diuretics (a loop diuretic with a thiazide) are often helpful. Cardiac resynchronization therapy should be considered if there is evidence of left ventricular dyssynchrony. Heart transplantation, coronary revascularization, aneurysmectory, or valve surgery may play a limited role.


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Table 19 Most frequent causes of worsening heart failure
 
End-stage heart failure (patients who persist in NYHA IV despite optimal treatment and proper diagnosis (Figure 4)
Patients should be (re)considered for heart transplantation if appropriate. In addition to the pharmacological treatments outlined in earlier sections, temporary inotropic support (intravenous sympathomimetic agents, dopaminergic agonists and/or phosphodiesterase agents) can be used in end-stage heart failure, but always should be considered as an interim approach to further treatment that will benefit the patient.

For patients on the waiting list for transplantation bridging procedures, circulatory support with intra-aortic balloon pumping or ventricular assist devices, haemofiltration or dialysis may sometimes be necessary. These should be used only in the context of a strategic plan for the long-term management of the patient.

Palliative treatment in terminal patients should always be considered and may include the use of opiates for the relief of symptoms.

Management of heart failure with preserved left ventricular ejection fraction
Although recent epidemiological studies suggest that in the elderly, the percentage of patients hospitalized with heart failure-like symptoms and PLVEF may be as high as 35–45%, there is uncertainty about the prevalence of diastolic dysfunction in patients with heart failure symptoms and a normal systolic function in the community. There is still little evidence from clinical trials or observational studies on how to treat heart failure with PLVEF.

Heart failure with PLVEF and heart failure due to diastolic dysfunction are not synonymous. The former diagnosis implies the evidence of preserved LVEF and not that left ventricular diastolic dysfunction has been demonstrated.

The diagnosis of isolated diastolic heart failure requires evidence of abnormal diastolic function, which may be difficult to assess. Precipitating factors should be identified and corrected, in particular tachy-arrhythmias should be prevented and sinus rhythm restored whenever possible. Rate control is important. Treatment approach is similar to patients without heart failure.106

Pharmacological therapy of heart failure with PLVEF or diastolic dysfunction
The following recommendations are largely speculative because of the limited data available in patients with PLVEF or diastolic dysfunction (in general, Class of recommendation IIa, level of evidence C).

There is no clear evidence that patients with primary diastolic heart failure benefit from any specific drug regimen.

  1. ACE-inhibitors may improve relaxation and cardiac distensibility directly and may have long-term effects through their anti-hypertensive effects and regression of hypertrophy and fibrosis.
  2. Diuretics may be necessary when episodes with fluid overload are present, but should be used cautiously so as not to lower preload excessively and thereby reduce stroke volume and cardiac output.
  3. Beta-blockade could be instituted to lower heart rate and increase the diastolic filling period.
  4. Verapamil-type calcium antagonists may be used for the same reason.107 Some studies with verapamil have shown a functional improvement in patients with hypertrophic cardiomyopathy.108
  5. A high dose of an ARB may reduce hospitalizations.109

Heart failure treatment in the elderly

Heart failure occurs predominantly among elderly patients with a median age of about 75 years in community studies. Ageing is frequently associated with co-morbidity. Frequent concomitant diseases are hypertension, renal failure, obstructive lung disease, diabetes, stroke, arthritis, and anaemia. Such patients also receive multiple drugs, which includes the risk of unwanted interactions and may reduce compliance. In general, these patients in general have been excluded from randomized trials. Relief of symptoms rather than prolongation of life may be the most important goal of treatment for many older patients.

ACE-inhibitors and ARBs
ACE-inhibitors and ARBs are effective and well-tolerated in elderly patients in general.

Diuretic therapy
In the elderly, thiazides are often ineffective because of reduced glomerular filtration rate. In elderly patients, hyperkalaemia is more frequently seen with a combination of aldosterone antagonsist and ACE-inhibitors or NSAIDs and coxibs.

Beta-blockers
Beta-blocking agents are surprisingly well tolerated in the elderly if patients with such contraindications as sick sinus node, AV-block and obstructive lung disease are excluded. Beta-blockade should not be withheld because of increasing age alone.

Cardiac glycosides
Elderly patients may be more susceptible to adverse effects of digoxin. Initially, low dosages are recommended in patients with elevated serum creatinine.

Vasodilator agents
Venodilating drugs, such as nitrates and the arterial dilator hydralazine and the combination of these drugs, should be administered carefully because of the risk of hypotension.

Arrhythmias

Ventricular arrhythmias

Atrial fibrillation

Symptomatic systolic left ventricular dysfunction and concomitant angina or hypertension

Specific recommendations in addition to general treatment for heart failure because of systolic left ventricular dysfunction. If angina is present

  1. optimize existing therapy, e.g. beta-blockade
  2. add long-acting nitrates
  3. if not successful, add amlodipine or felodipine
  4. consider coronary revascularization.

If hypertension is present

Care and follow-up

See also Table 20.


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Table 20 Recommended components of care and following programmes (class level of evidence C)
 

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