ESC Guidelines for the Diagnosis and Treatment of Chronic Heart Failure

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ESC Guidelines

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

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

Authors/Task Force Members: Karl Swedberg, Chairperson,*Goteborg (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, Hann-over (Germany), Arno Hoes, Utrecht (The Netherlands),Tiny Jaarsma, Gronigen (The Netherlands), Jerzy Korewicki, Warsaw (Poland),Samuel Levy, Marseille (France), Cecilia Linde, Stockholm (Sweden),Jose-Luis Lopez-Sendon, Madrid (Spain), Markku S. Nieminen, Helsinki(Finland), Luc Pierard, Liege (Belgium), Willem J. Remme,Rhoon (The Netherlands)

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),

Joao Morais (Portugal), Ady Osterspey (Germany), Juan Tamargo (Spain), Jose Luis Zamorano (Spain)

Document Reviewers, Marco Metra (CPG Review Coordinator) (Italy), Michael Bohm (Germany), Alain Cohen-Solal

(France), Martin Cowie (UK), Ulf Dahlstrom (Sweden), Kenneth Dickstein (Norway), Gerasimos S. Filippatos

(Greece), Edoardo Gronda (Italy), Richard Hobbs (UK), John K. Kjekshus (Norway), John McMurray (UK),

Lars Ryden (Sweden), Gianfranco Sinagra (Italy), Juan Tamargo (Spain), Michal Tendera (Poland),

Dirk van Veldhuisen (The Netherlands), Faiez Zannad (France)

Online publish-ahead-of-print 18 May 2005

Table of Contents

Preamble . . . . . . . . . . . . . . . . . . . . . . . . 1116Diagnosis of chronic heart failure . . . . . . . . . . 1116

Introduction . . . . . . . . . . . . . . . . . . . . . 1116

Methodology . . . . . . . . . . . . . . . . . . . . 1116Epidemiology . . . . . . . . . . . . . . . . . . . . . 1117Descriptive terms in heart failure . . . . . . . . . 1117

Acute vs. chronic heart failure . . . . . . . . . 1117Systolic vs. diastolic heart failure . . . . . . . 1118Other descriptive terms in heart failure . . . . 1118Definition of chronic heart failure . . . . . . . 1118

Aspects of the pathophysiology of the symptomsof heart failure relevant to diagnosis . . . . . . . 1119Possible methods for the diagnosis of heartfailure in clinical practice . . . . . . . . . . . . . 1119

& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: [email protected]

* Corresponding author. Chairperson: Karl Swedberg, SahlgrenskaAcademy at the Goteborg University, Department of Medicine,

Sahlgrenska University Hospital Ostra, SE-416 85 Goteborg, Sweden.

Tel.: 46 31 3434078; fax: 46 31 258933.

E-mail address: [email protected]

European Heart Journal (2005) 26, 11151140

doi:10.1093/eurheartj/ehi204

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Symptoms and signs in the diagnosis of heartfailure . . . . . . . . . . . . . . . . . . . . . . . 1119Symptoms and the severity of heart failure . . 1120Electrocardiogram . . . . . . . . . . . . . . . . 1120The chest X-ray . . . . . . . . . . . . . . . . . . 1120Haematology and biochemistry . . . . . . . . . 1120Natriuretic peptides . . . . . . . . . . . . . . . 1120Echocardiography . . . . . . . . . . . . . . . . . 1120

Additional non-invasive tests to be considered 1121Pulmonary function . . . . . . . . . . . . . . . . 1122Exercise testing . . . . . . . . . . . . . . . . . . 1122Invasive investigation . . . . . . . . . . . . . . 1122Tests of neuroendocrine evaluations otherthan natriuretic peptides . . . . . . . . . . . . 1122Holter electrocardiography: ambulatory ECGand long-time ECG recording (LTER) . . . . . . 1122Requirements for the diagnosis of heart failurein clinical practice . . . . . . . . . . . . . . . . 1122Prognostication . . . . . . . . . . . . . . . . . . 1122

Treatment of heart failure . . . . . . . . . . . . . 1122Aims of treatment in heart failure . . . . . . . . 1122

Prevention of heart failure . . . . . . . . . . . . . 1123Management of chronic heart failure . . . . . . . 1123Non-pharmacological management . . . . . . . . 1124

General advice and measures . . . . . . . . . . 1124Rest, exercise, and exercise training . . . . . 1125

Pharmacological therapy . . . . . . . . . . . . . . 1125Angiotensin-converting enzyme inhibitors . . . 1125Diuretics . . . . . . . . . . . . . . . . . . . . . . 1126Potassium-sparing diuretics . . . . . . . . . . . 1126Beta-adrenoceptor antagonists . . . . . . . . . 1127Aldosterone receptor antagonists . . . . . . . . 1128Angiotensin II receptor blockers . . . . . . . . 1128Cardiac glycosides . . . . . . . . . . . . . . . . 1128Vasodilator agents in chronic heart failure . . 1129

Positive inotropic therapy . . . . . . . . . . . . 1130Anti-thrombotic agents . . . . . . . . . . . . . 1130Anti-arrhythmics . . . . . . . . . . . . . . . . . 1131Oxygen therapy . . . . . . . . . . . . . . . . . . 1131

Surgery and devices . . . . . . . . . . . . . . . . . 1131Revascularization procedures, mitral valvesurgery, and ventricular restoration . . . . . . 1131Revascularization . . . . . . . . . . . . . . . . . 1131Mitral valve surgery . . . . . . . . . . . . . . . 1131Left ventricular restoration . . . . . . . . . . . 1131Pacemakers . . . . . . . . . . . . . . . . . . . . 1132Implantable cardioverter defibrillators . . . . 1132Heart replacement therapies: hearttransplantation, ventricular assist devices,and artificial heart . . . . . . . . . . . . . . . . 1132Ultrafiltration . . . . . . . . . . . . . . . . . . . 1132Choice and timing of pharmacological therapy 1133Management of heart failure with preservedleft ventricular ejection fraction . . . . . . . . 1134

Heart failure treatment in the elderly . . . . . . 1134ACE inhibitors and ARBs . . . . . . . . . . . . . 1135Diuretic therapy . . . . . . . . . . . . . . . . . 1135Beta-blockers . . . . . . . . . . . . . . . . . . . 1135Cardiac glycosides . . . . . . . . . . . . . . . . 1135Vasodilator agents . . . . . . . . . . . . . . . . 1135Arrhythmias . . . . . . . . . . . . . . . . . . . . 1135

Ventricular arrhythmias . . . . . . . . . . . . . 1136Atrial fibrillation . . . . . . . . . . . . . . . . . 1136

Symptomatic systolic left ventricular dysfunctionand concomitant angina or hypertension . . . . 1136

Care and follow-up . . . . . . . . . . . . . . . . . . . 1136References . . . . . . . . . . . . . . . . . . . . . . . 1136

Preamble

Guidelines and Expert Consensus Documents aim topresent all the relevant evidence on a particular issue inorder to help physicians to weigh the benefits and risksof a particular diagnostic or therapeutic procedure. Theyshould be helpful in everyday clinical decision-making.

A great number of Guidelines and Expert ConsensusDocuments have been issued in recent years by theEuropean Society of Cardiology (ESC) and by differentorganizations and other related societies. This profusioncan put at stake the authority and validity of guidelines,which can only be guaranteed if they have been deve-loped by an unquestionable decision-making process.This is one of the reasons why the ESC and others have

issued recommendations for formulating and issuingGuidelines and Expert Consensus Documents.

In spite of the fact that standards for issuing goodquality Guidelines and Expert Consensus Documents arewell defined, recent surveys of Guidelines and ExpertConsensus Documents published in peer-reviewed jour-nals between 1985 and 1998 have shown that methodo-logical standards were not complied with in the vastmajority of cases. It is therefore of great importancethat guidelines and recommendations are presented informats that are easily interpreted. Subsequently, theirimplementation programmes must also be well con-ducted. Attempts have been made to determine

whether guidelines improve the quality of clinical prac-tice and the utilization of health resources.The ESC Committee for Practice Guidelines (CPG)

supervises and coordinates the preparation of newGuidelines and Expert Consensus Documents producedby Task Forces, expert groups, or consensus panels. Thechosen experts in these writing panels are asked toprovide disclosure statements of all relationships theymay have which might be perceived as real or potentialconflicts of interest. These disclosure forms are kept onfile at the European Heart House, headquarters of theESC. The Committee is also responsible for the endorse-ment of these Guidelines and Expert ConsensusDocuments or statements.

The Task Force has classified and ranked the usefulnessor efficacy of the recommended procedure and/or treat-ments and the Level of Evidence as indicated in thetables on page 3.

Diagnosis of chronic heart failure

Introduction

Methodology

These Guidelines are based on the Diagnostic andTherapeutic Guidelines published in 1995, 1997, and

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renewed in 2001,13 which has now been combined intoone manuscript. Where new information is available, anupdate has been performed while other parts areunchanged or adjusted only to a limited extent.

The aim of this report is to provide updated practicalguidelines for the diagnosis, assessment, and treatmentof heart failure for use in clinical practice, as well asfor epidemiological surveys and clinical trials. Particular

attention in this update has been allocated to diastolicfunction and heart failure with preserved left ventricularejection fraction (PLVEF). The intention has been tomerge the previous Task Force report4 with the presentupdate.

The Guidelines are intended as a support for practisingphysicians and other health care professionals concernedwith the management of heart failure patients and toprovide advice on how to manage these patients, includingrecommendations for referral. Documented and publishedevidence on diagnosis, efficacy, andsafety is themain basisfor these guidelines. ESC Guidelines are relevant to 49member-states with diverse economies and therefore

recommendations based on cost-effectiveness have beenavoided in general. National health policy as well as clini-cal judgement may dictate the order of priority ofimplementation. It is recognized that some interventionsmay not be affordable in some countriesfor allappropriatepatients. The recommendations in these guidelines shouldtherefore always be considered in the light of nationalpolicies and local regulatory requirements for the admini-stration of any diagnostic procedure, medicine, or device.

This report was drafted by a Writing Group of the TaskForce (see title page) appointed by the CPG of the ESC.Within this Task Force, statements of Conflicts ofInterests were collected, which are available at the ESCOffice. The draft was sent to the Committee and the

document reviewers (see title page) and after theirinput the document was updated, reviewed and thenapproved for presentation. The summary is based on afull document, which includes more background state-ments and includes references. This document is avai-lable at the ESC website www.escardio.org. The fullreport should be used when in doubt or when furtherinformation is required. An evidenced based approachto the evaluations has been applied including a gradingof the evidence for recommendations. However, for thediagnosis, evidence is incomplete and in general basedon consensus of expert opinions. Already in the 2001version, it was decided not to use evidence grading inthis part. The same approach has been used here.

Major conclusions or recommendations have beenhighlighted by Bullets.

Epidemiology

. Much is now known about the epidemiology of heartfailure in Europe but the presentation and aetiologyare heterogeneous and less is known about differencesamong countries.

The ESC represents countries with a population of over 900million, suggesting that there are at least 10 million

patients with heart failure in those countries. There arealso patients with myocardial systolic dysfunction withoutsymptoms of heart failure and who constitute approxi-mately a similar prevalence.57 The prognosis of heart

failure is uniformly poor if the underlying problem cannotbe rectified. Half of patients carrying a diagnosis of heartfailure will die within 4 years, and in patients withsevere heart failure .50% will die within 1 year.8,9 Manypatients with heart failure have symptoms and PLVEF.10

Studies show that the accuracy of diagnosis by clinicalmeans alone is often inadequate,11,12 particularly inwomen, elderly, and obese. To study properly the epide-miology and prognosis and to optimize the treatment ofheart failure, the uncertainty relating to the diagnosismust be minimized or avoided completely.

Descriptive terms in heart failure

Acute vs. chronic heart failure

The term acute heart failure (AHF) is often used exclu-sively to mean de novo AHF or decompensation ofchronic heart failure (CHF) characterized by signs of pul-monary congestion, including pulmonary oedema. Otherforms include hypertensive AHF, pulmonary oedema,cardiogenic shock, high output failure, and right heartfailure. (See Guidelines on acute heart failure.13)

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

Levels of evidence

Level of Evidence A Data derived from multiplerandomized clinical trials or

meta-analysesLevel of Evidence B Data derived from a single

randomized clinical trialor large non-randomized studies

Level of Evidence C Consensus of opinion of theexperts and/or small studies,reprospective studies, registries

Classes of recommendations

Class I Evidence and/or general agreement that agiven diagnostic procedure/treatment isbeneficial, useful, and effective

Class II Conflicting evidence and/or a divergence ofopinion about the usefulness/efficacy of thetreatment

Class IIa Weight of evidence/opinion is in favour ofusefulness/efficacyClass IIb Usefulness/efficacy is less well established

by evidence/opinionClass III Evidence or general agreement that the

treatment is not useful/effective and insome cases may be harmful

Use of Class III is discouraged by the ESC.

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

Systolic vs. diastolic heart failure

Most heart failures are associated with evidence of leftventricular systolic dysfunction, although diastolicimpairment at rest is a common if not universal accompa-niment. In most cases, diastolic and systolic heartfailures should not be considered as separate patho-physiological entities. Diastolic heart failure is oftendiagnosed when symptoms and signs of heart failureoccur in the presence of a PLVEF (normal ejection frac-tion) at rest. Predominant diastolic dysfunction is rela-tively uncommon in younger patients but increases inimportance in the elderly. PLVEF is more common inwomen, in whom systolic hypertension and myocardialhypertrophy with fibrosis are contributors to cardiacdysfunction.10,14

Other descriptive terms in heart failure

Right and left heart failure refer to syndromes presentingpredominantly with congestion of the systemic or pul-monary veins. The terms do not necessarily indicatewhich ventricle is most severely damaged. High- andlow-output, forward and backward, overt, treated, andcongestive are other descriptive terms still in occasionaluse; the clinical utility of these terms is descriptivewithout etiological information and therefore of littleuse in determining modern treatment for heart failure.

Mild, moderate, or severe heart failure is used as a

clinical symptomatic description, where mild is used forpatients who can move around with no important limita-tions of dyspnea or fatigue, severe for patients who aremarkedly symptomatic and need frequent medical atten-tion and moderate for the remaining patient cohort.

Definition of chronic heart failure

. Heart failure should never be the only diagnosis.

Many definitions of CHF exist1518 but highlight onlyselective features of this complex syndrome. The diag-nosis of heart failure relies on clinical judgement basedon a history, physical examination, and appropriateinvestigations.

Heart failure is a syndrome in which the patientsshould have the following features: symptoms of heartfailure, typically breathlessness or fatigue, either atrest or during exertion, or ankle swelling and objectiveevidence of cardiac dysfunction at rest (Table 1 ). Thedistinctions between cardiac dysfunction, persistentheart failure, heart failure that has been renderedasymptomatic by therapy, and transient heart failureare outlined in Figure 1. A clinical response to treatmentdirected at heart failure alone is not sufficient for diagno-sis, although the patient should generally demonstratesome improvement in symptoms and/or signs in response

to those treatments in which a relatively fast sympto-matic improvement could be anticipated (e.g. diureticor nitrate administration).

Asymptomatic left ventricular systolic dysfunctionis considered as precursor of symptomatic CHF and is

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

Table 1 Definition of heart failure

I. Symptoms of heart failure (at rest or during exercise)and

II. Objective evidence (preferably by echocardiography)of cardiac dysfunction (systolic and/or diastolic)

(at rest) and (in cases where the diagnosis is in doubt)and

III. Response to treatment directed towards heart failure

Criteria I. and II. should be fulfilled in all cases.

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associated with high mortality.19 It is important whendiagnosed and treatment is available, and the conditionis therefore included in these Guidelines.

Aspects of the pathophysiology of thesymptoms of heart failure relevantto diagnosis

The origin of the symptoms of heart failure is not fullyunderstood. Increased pulmonary capillary pressure isundoubtedly responsible for pulmonary oedema in part,but studies conducted during exercise in patients withCHF demonstrate only a weak relationship betweencapillary pressure and exercise performance.20,21 Thissuggests either that raised pulmonary capillary pressureis not the only factor responsible for exertional breath-lessness (e.g. lungwater and plasma albumin) or thatcurrent techniques to measure true pulmonary capi-llary pressure may not be adequate. Variation in the

degree of mitral regurgitation will also influencebreathlessness.

Possible methods for the diagnosis of heartfailure in clinical practice

Symptoms and signs in the diagnosis ofheart failure

. Symptoms and signs are important as they alert theobserver to the possibility that heart failure exists.

The clinical suspicion of heart failure must be con-firmed by more objective tests particularly aimed atassessing cardiac function (Figure 2 ).

Breathlessness, ankle swelling, and fatigue are thecharacteristic symptoms and signs of heart failure butmay be difficult to interpret, particularly in elderlypatients, in obese, and in women. It should be inter-preted carefully and different modes (e.g. effort andnocturnal) should be assessed.

Fatigue is also an essential symptom in heart failure.The origins of fatigue are complex including low cardiac

output, peripheral hypoperfusion, skeletal muscle decon-ditioning, and confounded by difficulties in quantifyingthis symptom.

Peripheral oedema, raised venous pressure, and hepa-tomegaly are the characteristic signs of congestion ofsystemic veins.22,23 Clinical signs of heart failure shouldbe assessed in a careful clinical examination, includingobserving, palpating, and auscultating the patient.

Symptoms and the severity of heart failure

. There is a poor relationship between symptoms and the

severity of cardiac dysfunction.10,24

However, symp-toms may be related to prognosis particularly if persist-ing after therapy.25

Once a diagnosis of heart failure has been established,symptoms may be used to classify the severity of heartfailure and should be used to monitor the effects oftherapy. However, as noted subsequently, symptomscannot guide the optimal titration of neurohormonalblockers. The New York Heart Association (NYHA) classifi-cation is in widespread use (Table 2 ). In other situations,the classification of symptoms into mild, moderate, orsevere is used. Patients in NYHA class I would have tohave objective evidence of cardiac dysfunction, have a

past history of heart failure symptoms and be receivingtreatment for heart failure in order to fulfil the basicdefinition of heart failure.

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

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In acute myocardial infarction, the classificationdescribed by Killip26 has been used to describe symptomsand signs.27 It is important to recognize the common dis-sociation between symptoms and cardiac dysfunction.

Symptoms are also similar in patients across differentlevels of ejection fraction.28 Mild symptoms should notbe equated with minor cardiac dysfunction.

Electrocardiogram

. A normal electrocardiogram (ECG) suggests that thediagnosis of CHF should be carefully reviewed.

Electrocardiographic changes are common in patients sus-pected of having heart failure whether or not the diagnosisproves 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, isunlikely. The presence of pathological Q-waves maysuggest myocardial infarction as the cause of cardiacdysfunction. A QRS width .120 ms suggests that cardiacdyssynchrony may be present and a target for treatment.

The chest X-ray

. Chest X-ray should be part of the initial diagnosticwork-up in heart failure. It is useful to detect cardio-megaly and pulmonary congestion; however, it hasonly predictive value in the context of typical signsand symptoms and in abnormal ECG.

Haematology and biochemistry

Routine diagnostic evaluation of patients with CHFincludes: complete blood count (Hb, leukocytes, andplatelets), S-electrolytes, S-creatinine, S-glucose,S-hepatic enzymes, and urinalysis. Additional tests toevaluate thyroid function should be considered accordingto clinical findings. In acute exacerbations, acute myo-cardial infarction is excluded by myocardial specificenzyme analysis.

Natriuretic peptides

. Plasma concentrations of certain natriuretic peptidesor their precursors, especially BNP and NT-proBNP, arehelpful in the diagnosis of heart failure.

. A low-normal concentration in an untreated patientmakes heart failure unlikely as the cause of symptoms.

. BNP and NT-proBNP have considerable prognostic

potential, although evaluation of their role in treat-ment monitoring remains to be determined.

As the diagnostic potential of natriuretic peptides is lessclear cut when systolic function is normal, there isincreasing evidence that their elevation can indicatediastolic dysfunction is present.29,30 Other commoncardiac abnormalities that may cause elevated natriure-tic peptide levels include left ventricular hypertrophy,valvular heart disease, acute or chronic ischaemia orhypertension,31 and pulmonary embolism.32

In considering the use of BNP and NT-proBNP as diag-nostic aids, it should be emphasized that a normalvalue cannot completely exclude cardiac disease, but a

normal or low concentration in an untreated patientmakes 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 significantcardiac disease. Particularly in primary care but also incertain aspects of secondary care (e.g. the emergencyroom and clinics.) The cost-effectiveness of the testsuggest that a normal result should obviate the needfor further cardiological tests such as in the firstinstance echocardiography as well as more expensiveinvestigations.33

Echocardiography

. Echocardiography is the preferred method for thedocumentation of cardiac dysfunction at rest.

. The most important measurement of ventricular func-tion is the left ventricular ejection fraction (LVEF) fordistinguishing patients with cardiac systolic dysfunctionfrom patients with preserved systolic function.

The access to and use of echocardiography is encouragedfor the diagnosis of heart failure. Transthoracic Dopplerechocardiography (TDE) is rapid, safe, and widelyavailable.

Assessment of LV diastolic function

Assessment of diastolic function may be clinically useful:(1) to detect abnormalities of diastolic function inpatients who present with CHF and normal left ventri-cular ejection fraction, (2) in determining prognosis inheart failure patients, (3) in providing a non-invasiveestimate of left ventricular diastolic pressure, and (4)in diagnosing constrictive pericarditis and restrictivecardiomyopathy.

Diagnostic criteria of diastolic dysfunction

A diagnosis of primary diastolic heart failure requiresthree conditions to be simultaneously satisfied: (1) pre-sence of signs or symptoms of CHF, (2) presence of

Table 2 New York Heart Association classification of heartfailure

Class I No limitation: ordinary physical exercise does notcause undue fatigue, dyspnoea, or palpitations

Class II Slight limitation of physical activity: comfortableat rest but ordinary activity results in fatigue,palpitations, or dyspnoea

Class III Marked limitation of physical activity: comfortableat rest but less than ordinary activity results insymptoms

Class IV Unable to carry out any physical activity withoutdiscomfort: symptoms of heart failure are presenteven at rest with increased discomfort with anyphysical activity

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normal or only mildly abnormal left ventricular systolicfunction (LVEF ! 4550%), and (3) evidence of abnormalleft ventricular relaxation, diastolic distensibility, ordiastolic stiffness.34 Furthermore, it is essential toexclude pulmonary disease.35

At an early stage of diastolic dysfunction, there is typi-cally a pattern of impaired myocardial relaxation with adecrease in peak transmitral E-velocity, a compensatory

increase in the atrial-induced (A) velocity and thereforea decrease in the E/A ratio.

In patients with advanced cardiac disease, there maybe a pattern of restrictive filling, with an elevatedpeak E-velocity, a short E-deceleration time, and a mark-edly increased E/A ratio. The elevated peak E-velocity isdue to elevated left atrial pressure that causes anincrease in the early-diastolic transmitral pressuregradient.36

In patients with an intermediate pattern betweenimpaired relaxation and restrictive filling the E/A ratioand the deceleration time may be normal, a so-calledpseudonormalized filling pattern. This pattern may be

distinguished from normal filling by the demonstrationof reduced peak E0-velocity by TDI.37

The three filling patterns impaired relaxation, pseu-donormalized filling, and restrictive filling representmild, moderate, and severe diastolic dysfunction,respectively37 (Figure 3 ). Thus, by using the combinedassessment of transmitral blood flow velocities and mitralannular velocities, it becomes possible to perform stagingof diastolic dysfunction during a routine echocardio-graphic examination. We still lack prospective outcomestudies that investigate if assessment of diastolic func-tion by these criteria may improve management ofheart failure patients.

Transoesophageal echocardiography is not recom-mended routinely and can only be advocated in patientswho have an inadequate echo window, in complicatedvalvular patients, and in patients with suspected dysfunc-tion of mechanical mitral valve prosthesis or when it ismandatory to identify or exclude a thrombus in theatrial appendage.

Repeated echocardiography can be recommended in

the follow-up of patients with heart failure only whenthere is an important change in the clinical statussuggesting significant improvement or deterioration incardiac function.

Additional non-invasive tests to be considered

In patients in whom echocardiography at rest has notprovided enough information and in patients withcoronary artery disease (e.g. severe or refractory CHFand coronary artery disease), further non-invasiveimaging may include stress echocardiography, radio-nuclide imaging, and cardiac magnetic resonanceimaging (CMR).

Cardiac magnetic resonance imaging (CMR)

. CMR is a versatile, highly accurate, and reproducibleimaging technique for the assessment of left andright ventricular volumes, global function, regionalwall motion, myocardial thickness, thickening, myocar-dial mass, and cardiac valves.38,39 The method is wellsuited for detection of congenital defects, massesand tumours, valvular, and pericardial disease.

Figure 3 The three filling patterns impaired relaxation, pseudonormalised filling, and restrictive filling represent mild, moderate, and severe

diastolic dysfunction, respectively.37

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Pulmonary function

. Measurements of lung function are of little value indiagnosing CHF. However, they are useful in excludingrespiratory causes of breathlessness. Spirometry canbe useful to evaluate the extent of obstructiveairways disease which is a common comorbidity inpatients with heart failure.

Exercise testing

. In clinical practice, exercise testing is of limited valuefor the diagnosis of heart failure. However, a normalmaximal exercise test in a patient not receiving treat-ment for heart failure excludes heart failure as a diag-nosis. The main applications of exercise testing in CHFare focused more on functional and treatment assess-ment and on prognostic stratification.

Invasive investigation

. Invasive investigation is generally not required toestablish the presence of CHF but may be importantin elucidating the cause or to obtain prognosticinformation.

Cardiac catheterization

Coronary angiography should be considered in patientswith acute or acutely decompensated CHF and in patientswith severe heart failure (shock or acute pulmonaryoedema) who are not responding to initial treatment.Coronary angiography should also be considered inpatients with angina pectoris or any other evidence of

myocardial ischaemia if they are not responding to appro-priate anti-ischaemic treatment. Revascularization hasnot been shown to alter prognosis in heart failure inclinical trials and therefore, in the absence of anginapectoris unresponsive to medical therapy, coronaryarteriography is not indicated. Coronary angiographyis also indicated in patients with refractory heartfailure of unknown aetiology and in patients withevidence of severe mitral regurgitation or aortic valvedisease.

Monitoring of haemodynamic variables by means of apulmonary arterial catheter is indicated in patients whoare hospitalized for cardiogenic shock or to direct treat-ment of patients with CHF not responding promptly to

initial and appropriate treatment. Routine right heartcatheterization should not be used to tailor chronictherapy.

Tests of neuroendocrine evaluations other thannatriuretic peptides

. Tests of neuroendocrine activation are not rec-ommended for diagnostic or prognostic purposes inindividual patients.

Holter electrocardiography: ambulatory ECG andlong-time ECG recording (LTER)

. Conventional Holter monitoring is of no value in thediagnosis of CHF, though it may detect and quantifythe nature, frequency and duration of atrial and ventri-cular arrhythmias which could be causing or exacer-bating symptoms of heart failure. Recording LTER

should be restricted to patients with CHF and symp-toms suggestive of an arrhythmia.

Requirements for the diagnosis of heart failure inclinical practice

. To satisfy the definition of heart failure, symptoms ofheart failure and objective evidence of cardiac dysfunc-tion must be present (Table 1 ). The assessment ofcardiac function by clinical criteria alone is unsatisfac-tory. Cardiacdysfunctionshould be assessed objectively.

The echocardiogram is the single most effective tool inwidespread clinical use. Other conditions may mimic or

exacerbate the symptoms and signs of heart failure andtherefore need to be excluded (Table 3 ). An approach(Figure 2 ) to the diagnosis of heart failure in sympto-matic patients should be performed routinely in patientswith suspected heart failure in order to establish thediagnosis. Additional tests (Table 4 ) should be performedor re-evaluated in cases in which diagnostic doubt per-sists or clinical features suggest a reversible cause forheart failure.

Figure 2 represents a simplified plan for the evaluationof a patient presenting with symptoms suggestive ofheart failure or signs giving suspicion of left ventricularsystolic dysfunction. Table 5 provides a management

outline connecting the diagnosis component of the guide-lines with the treatment section.

Prognostication

. The problem of defining prognosis in heart failure iscomplex for many reasons: several aetiologies, fre-quent comorbidities, limited ability to explore theparacrine pathophysiological systems, varying indivi-dual progression and outcome (sudden vs. progressiveheart failure death), and efficacy of treatments.Moreover, several methodological limitations weakenmany prognostic studies. The variables more consist-

ently indicated as independent outcome predictorsare reported in Table 6.

Treatment of heart failure

Aims of treatment in heart failure

(i) Preventiona primary objectivea. Prevention and/or controlling of diseases leading

to cardiac dysfunction and heart failure.b. Prevention of progression to heart failure once

cardiac dysfunction is established.

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(ii) Maintenance or improvement in quality of life(iii) Improved survival

Prevention of heart failure. The development of ventricular dysfunction and heart

failure may be delayed or prevented by treatmentof conditions leading to heart failure, in particularin patients with hypertension and/or coronaryartery disease (Class of recommendation I, level ofevidence A).40

. The prevention of heart failure should always be aprimary objective.

When myocardial dysfunction is already present, the firstobjective is to remove the underlying cause of

ventricular dysfunction if possible (e.g. ischaemia, toxicsubstances, alcohol, drugs, and thyroid disease), provid-ing the benefits of intervention outweigh the risks. Whenthe underlying cause cannot be corrected treatmentshould be directed at delaying or preventing left ventri-cular dysfunction that will increase the risk of suddendeath and the development of heart failure.

How to modulate progression from asymptomatic leftventricular dysfunction to heart failure is described onpage 1133, Treatment of Asymptomatic Left VentricularDysfunction.

Management of chronic heart failure

The therapeutic approach in patients with CHF that iscaused by left ventricular systolic dysfunction includes

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

Assessments Diagnosis of heart failure Suggests alternativeor additional diagnosis

Necessary for Supports Opposes

Appropriate symptoms (If absent)Appropriate signs (If absent)Cardiac dysfunction on Imaging

(usually echocardiography) (If absent)

Response of symptoms or signsto therapy

(If absent)

ECG (If Normal)Chest X-ray If pulmonary

congestion orcardiomegaly

(If normal) Pulmonary disease

Full blood count Anaemia/secondarypolycythaemia

Biochemistry and urinalysis Renal or hepaticdisease/diabetes

Plasma concentration ofnatriuretic peptidesin untreated patients

(where available)

(If elevated) (If normal) Can be normal intreated patients

of some importance; of great importance.

Table 4 Additional tests to be considered to support the diagnosis or to suggest alternative diagnoses

Tests Diagnosis of heart failure Suggests alternative oradditional diagnosis

Supports Opposes

Exercise test (If impaired) (If normal)Pulmonary function tests Pulmonary diseaseThyroid function tests Thyroid diseaseInvasive investigation

and angiography

Coronary artery

disease, ischaemiaCardiac output (If depressed at rest) (If normal; especially

during exercise)Left atrial pressure

(pulmonary capillarywedge pressure)

(If elevated at rest) (If normal; in absenceof therapy)

of some importance; of great importance.

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general advice and other non-pharmacological measures,pharmacological therapy, mechanical devices, andsurgery. The currently available types of managementare outlined in Tables 5 and 7.

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 receivegeneral advice.

Weight monitoring

Patients are advised to weigh on a regular basis tomonitor weight gain (preferably as part of a regulardaily routine, for instance after morning toilet) and,in case of a sudden unexpected weight gain of.2 kg in3 days, to alert a health care provider or adjust theirdiuretic dose accordingly (e.g. to increase the dose if asustained increase in weight is noted).

Dietary measures

Sodium. Controlling the amount of salt in the diet is aproblem, that is, more important in advanced than inmild heart failure.

Fluids. Instructions on fluid control should be given topatients with advanced heart failure, with or withouthyponatraemia. The exact amount of fluid restrictionremains unclear, however. In practice, a fluid restrictionof 1.52 L/day is advised in advanced heart failure.

Alcohol. Moderate alcohol intake (one beer, 12 glassesof wine/day) is permitted other than in case of alcoholiccardiomyopathy when it is prohibited.

Table

6

RiskstratificationinCHFpredictors

Demographicandhistorical

C

linical

Electrophysiolog

ic

Functional/exertional

Blood

Centralhaemodyn

amic

Advancedage123125

H

ighheartrate

149

BroadQRS95,

127

VO2

max

(mL/kg

permin,1014)128130

High

serum

BNP31,

131

Low

LVEF124,

132134

Coronaryaetiology

123,

135

Persistentlow

BP123

Low

heartrate

variability

136,

137

HighVE/VCO2

ratio

138

High

serum

norepinephrine

139,

140

Increasedleftventricular

volumes1

41,

142

Diabetes1

43

N

YHAfunctional

ClassIIIIV123,

124,

144

Complexventric

ular

rhythms

110,

13

9

Low

6minwalking

ability

145,

146

Low

serum

sodium123,

147

Low

cardiacindex

123

Resuscitated

suddendeath110

Low

body-massindex

148

T-wavealternan

s134

High

serum

cre

atinine123,

147,

150

Highleftventricul

arfilling

pressure

123,

124

Race

126

Ventilatoryrhythm

High

serum

bilirubine147

Restrictivemitral

fillingpattern

153,

154

andrate

Anae

mia155

Impairedright

ve

ntricular

disturbances1

51,

152

High

serum

troponin158

function

156,

157

High

serum

uricacid160

Cardiothoracicrat

io139,

159

CHF

chronicheartfailure;BP

bloodpressure;NYHA

New

YorkHeartAssociation;VE

ventilationvolumepermin;VCO2

v

entilationofCO2;BNP

brainnatriureticpepti

de;LVEF

leftventri-

cularejectionfraction.

Strong.

Table 5 Management outline

Establish that the patient has heart failure (in accordance withthe definition presented on page 1122, diagnosis section)

Ascertain presenting features: pulmonary oedema, exertionalbreathlessness, fatigue, peripheral oedema

Assess severity of symptomsDetermine aetiology of heart failure

Identify precipitating and exacerbating factorsIdentify concomitant diseases relevant to heart failure and itsmanagement

Estimate prognosis based on page 1124, Table 6.Assess complicating factors (e.g. renal dysfunction, arthritis)Counsel patient and relativesChoose appropriate managementMonitor progress and manage accordingly

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Obesity

Treatment of CHF should include weight reduction inobese patients.

Abnormal weight loss

Clinical or subclinical malnutrition is present in 50% ofpatients with severe CHF. The wasting of total body fatand lean body mass that accompanies weight loss is

called cardiac cachexia. Cardiac cachexia is an importantpredictor of reduced survival.41

Smoking

Smoking should always be discouraged. The use ofsmoking cessation aids should be actively encouragedand may include nicotine replacement therapies.

Travelling

High altitudes or very hot or humid places should be dis-couraged. In general, short air flights are preferable tolong journeys by other means of transport.

Sexual activity

It is not possible to dictate guidelines about sexualactivity counselling. Recommendations are given to reas-sure the not severely compromised, but frightenedpatient, to reassure the partner who is often even morefrightened, and perhaps refer the couple for specialistcounselling. Little is known about the effects of treat-ments for heart failure on sexual function.

Advice on immunizations

There is no documented evidence of the effects of immu-nization in patients with heart failure. Immunization forinfluenza is widely used.

Drug counselling

Self-management (when practical) of the dose of thediuretic, based on changes in symptoms and weight(fluid balance), should be encouraged. Within pre-speci-fied and individualized limits, patients are able toadjust 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 oravoided:

(i) Non-steroidal anti-inflammatory drugs (NSAIDS) andcoxibs

(ii) Class I anti-arrhythmic agents (page 1131)(iii) Calcium antagonists (verapamil, diltiazem, and

short-acting dihydropyridine derivatives (page 1126)(iv) Tricyclic anti-depressants(v) Corticosteroids

(vi) Lithium

Rest, exercise, and exercise training

Rest

In acute heart failure or destabilization of CHF, physicalrest or bed rest is recommended.

Exercise

Exercise improves skeletal muscle function and thereforeoverall functional capacity. Patients should be encouragedand advised on how to carry out daily physical and leisuretime activities that do not induce symptoms. Exercisetraining programs are encouraged in stable patientsin NYHA class IIIII. Standardized recommendationsfor exercise training in heart failure patients by theEuropean Society of Cardiology have been published.42

Pharmacological therapy

Angiotensin-converting enzyme inhibitors

. Angiotensin-converting enzyme (ACE) inhibitors arerecommended as first-line therapy in patients with areduced left ventricular systolic function expressed asa subnormal ejection fraction, i.e. ,4045% with orwithout symptoms (see non-invasive imaging; page1121 Diagnosis section) (Class of recommendation I,level of evidence A).

. ACE-inhibitors should be uptitrated to the dosages

shown to be effective in the large, controlled trials inheart failure (Class of recommendation I, level of evi-dence A), and not titrated based on symptomaticimprovement alone (Class of recommendation I, levelof evidence C).

ACE-inhibitors in asymptomatic left ventricular

dysfunction

. Asymptomatic patients with a documented left ventri-cular systolic dysfunction should be treated with anACE-inhibitor to delay or prevent the development ofheart failure. ACE-inhibitors also reduce the risk of

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

Non-pharmacological managementGeneral advice and measuresExercise and exercise training

Pharmacological therapy

ACE-inhibitorsDiureticsBeta-adrenoceptor antagonistsAldosterone receptor antagonistsAngiotensin receptor antagonistsCardiac glycosidesVasodilator agents (nitrates/hydralazine)Positive inotropic agentsAnti-coagulationAnti-arrhythmic agentsOxygen

Devices and surgeryRevascularization (catheter interventions and/or surgery),Other forms of surgery (mitral valve repair)Bi-ventricular (multi-site) pacing

Implantable cardioverter defibrillator (ICD)Heart transplantation, ventricular assist devices, andartificial heart

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myocardial infarction and sudden death in this setting(Class of recommendation I, level of evidence A).4346

ACE-inhibitors in symptomatic heart failure

. All patients with symptomatic heart failure that iscaused by systolic left ventricular dysfunction shouldreceive an ACE-inhibitor (Class of recommendation I,

level of evidence A).47

. ACE-inhibition improves survival, symptoms, functionalcapacity, and reduces hospitalization in patients withmoderate and severe heart failure and left ventricularsystolic dysfunction.

. ACE-inhibitors should be given as the initial therapy inthe absence of fluid retention. In patients with fluidretention, ACE-inhibitors should be given togetherwith diuretics (Class of recommendation I, level of evi-dence B).47,48

. ACE inhibition should be initiated in patients with signsor symptoms of heart failure, even if transient, afterthe acute phase of myocardial infarction, even if the

symptoms are transient to improve survival and toreduce reinfarctions and hospitalizations for heartfailure (Class of recommendation I, level of evidenceA).44,45,49

. Asymptomatic patients with a documented left ventri-cular systolic dysfunction benefit from long-term ACE-inhibitor therapy (Class of recommendation I, level ofevidence A).4346

. Important adverse effects associated with ACE-inhibi-tors are cough, hypotension, renal insufficiency, hyper-kalaemia, syncope, and angioedema. Angiotensinreceptor blockers may be used as an effective alterna-tive in patients who develop cough or angioedemaon an ACE-inhibitor (Class of recommendation I, level

of evidence A). Changes in systolic and diastolic bloodpressure and increases in serum creatinine are usuallysmall in normotensive patients.

. ACE-inhibitor treatment is contra-indicated in the pre-sence of bilateral renal artery stenosis and angioedemaduring previous ACE-inhibitor therapy (Class of rec-ommendation III, level of evidence A).

Target maintenance dose ranges of ACE-inhibitors shownto be effective in various trials are given in Table 8.

Recommended initiating and maintenance dosages ofACE-inhibitors which have been approved for the treat-ment of heart failure in Europe are presented in Table 9.

The dose of ACE-inhibitors should always be initiated atthe lower dose level and titrated to the target dose. Therecommended procedures for starting an ACE-inhibitorare given in Table 10.

Regular monitoring of renal function is recommended:

(1) before, 1

2 weeks after each dose increment, and at36 months interval; (2) when the dose of an ACE-inhibi-tor is increased or other treatments, which may affectrenal function, are added (e.g. aldosterone antagonistor angiotensin receptor blocker), (3) in patients withpast or present renal dysfunction or electrolyte disturb-ances more frequent measurements should be made, or(4) during any hospitalization.

Diuretics

Loop diuretics, thiazides, and metolazone

. Diuretics are essential for symptomatic treatmentwhen fluid overload is present and manifest as pulmon-ary congestion or peripheral oedema. The use of diure-tics results in rapid improvement of dyspnoea andincreased exercise tolerance (Class of recommendationI, level of evidence A).50,51

. There are no controlled randomized trials thathave assessed the effect on symptoms or survival ofthese agents. Diuretics should always be administeredin combination with ACE-inhibitors and beta-blockersif tolerated (Class of recommendation I, level ofevidence C).

Detailed recommendations and major side effects are

outlined in Tables 11 and 12.

Potassium-sparing diuretics

. Potassium-sparing diuretics should only be prescribedif hypokalaemia persists despite ACE inhibition, or insevere heart failure despite the combination ACEinhibition and low-dose spironolactone (Class of rec-ommendation I, level of evidence C). In patients whoare unable to tolerate even low doses of aldosterone

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

Studies of mortality Drug Target dose Mean daily dose

Studies in CHFCONSENSUS Trial Study Group, 198748 Enalapril 20 mg b.i.d. 18.4 mgV-HeFT II, 1991161 Enalapril 10 mg b.i.d. 15.0 mgThe SOLVD Investigators, 1991162 Enalapril 10 mg b.i.d. 16.6 mgATLAS, 1999163 Lisinopril High dose: 32.535 mg daily

Low dose: 2.55 mg dailyStudies after MI LV dysfunction with or without HF

SAVE, 199244 Captopril 50 mg t.i.d. 127 mgAIRE, 199349 Ramipril 5 mg b.i.d. (not available)TRACE, 199545 Trandolapril 4 mg daily (not available)

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antagonists due to hyperkalaemia and renal dysfunc-tion, amiloride or triamterene may be used (Class of rec-ommendation IIb, level of evidence C).

. Potassium supplements are generally ineffective in thissituation (Class of recommendation III, level of evi-dence C).

. The use of all potassium-sparing diuretics should bemonitored by repeated measurements of serum creati-nine and potassium. A practical approach is to measureserum creatinine and potassium every 57 days afterinitiation of treatment until the values are stable. -Thereafter, measurements can be made every 36months.

Beta-adrenoceptor antagonists

. Beta-blockers should be considered for the treatmentof all patients (in NYHA class IIIV) with stable, mild,moderate, and severe heart failure from ischaemic ornon-ischaemic cardiomyopathies and reduced LVEF onstandard treatment, including diuretics, and ACE-inhibitors, unless there is a contraindication (Class ofrecommendation I, level of evidence A).5258

. Beta-blocking therapy reduces hospitalizations (all,

cardiovascular, and heart failure), improves the func-tional class and leads to less worsening of heartfailure. This beneficial effect has been consistentlyobserved in subgroups of different age, gender, func-tional class, LVEF, and ischaemic or non-ischaemicaetiology (Class of recommendation I, level ofevidence A).

. In patients with left ventricular systolic dysfunction,with or without symptomatic heart failure, followingan acute myocardial infarction long-term beta-block-ade is recommended in addition to ACE inhibition toreduce mortality (Class of recommendation I, level ofevidence B).59

. Differences in clinical effects may be present betweendifferent beta-blockers in patients with heartfailure.60,61 Accordingly, only bisoprolol, carvedilol,metoprolol succinate and nebivolol can be rec-ommended (Class of recommendation I, level of evi-dence A).

Initiation of therapy

The initial dose should be small and increased slowly andprogressively to the target dose used in the large clinicaltrials. Up-titration should be adapted to individualresponses.

Table 9 Recommended ACE-inhibitor maintenance doseranges for some agents approved for heart failure in Europe

Drug Initiating dose Maintenancedose

Documented effects on mortality/hospitalizationCaptopril 6.25 mg t.i.d. 2550 mg t.i.d.Enalapril 2.5 mg daily 10 mg b.i.d.Lisinopril 2.5 mg daily 5

20 mg daily

Ramipril 1.252.5 mgdaily

2.55 mg b.i.d.

Trandolapril 1 mg daily 4 mg daily

Manufacturers or regulatory recommendations.

Table 10 The recommended procedure for starting anACE-inhibitor or an angiotensin receptor blocker

Review the need for and dose of diuretics and vasodilatorsAvoid excessive diuresis before treatment. Consider reducing

or withholding diuretics, if being used, for 24 hIt may be advisable to start treatment in the evening, when

supine, to minimize the potential negative effect on bloodpressure, although there are no data in heart failure tosupport this (Level of Evidence C). When initiated in themorning, supervision for several hours with blood pressurecontrol is advisable in risk patients with renal dysfunctionor low blood pressure

Start with a low dose (Table 9) and build-up to maintenancedosages shown to be effective in large trials (Table 8)

If renal function deteriorates substantially, stop treatmentAvoid potassium-sparing diuretics during initiation of therapyAvoid NSAIDs and coxibsCheck blood pressure, renal function, and electrolytes

12 weeks after each dose increment, at 3 months, and

subsequently at 6 regular monthly intervals

The following patients should be referred for specialist care:Cause of heart failure unknownSystolic blood pressure ,100 mmHgSerum creatinine .150 mmol/LSerum sodium ,135 mmol/LSevere heart failureValve disease as primary cause

Table 11 Diuretics

Initial diuretic treatmentLoop diuretics or thiazides. Always administered

in addition to an ACE-inhibitorIf GFR,30 mL/min, do not use thiazides, except as

therapy prescribed synergistically with loop diureticsInsufficient response:

Increase dose of diureticCombine loop diuretics and thiazidesWith persistent fluid retention: administer loop diuretics

twice dailyIn severe heart failure add metolazone with frequent

measurement of creatinine and electrolytesPotassium-sparing diuretics: triamterene, amiloride and

spironolactoneUse only if hypokalaemia persists after initiation of

therapy with ACE, inhibitors and diureticsStart one-week low-dose administration; check serum

potassium and creatinine after 57 days and titrateaccordingly. Recheck every 57 days until potassiumvalues are stable

GFR glomerular filtration rate.

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

Table 14 shows the titration scheme of the drugs usedin the most relevant studies.

Aldosterone receptor antagonists

. Aldosterone antagonists are recommended in addition

to ACE-inhibitors, beta-blockers and diuretics inadvanced heart failure (NYHA IIIIV) with systolic dys-function to improve survival and morbidity (Class ofrecommendation I, level of evidence B).62

. Aldosterone antagonists are recommended in additionto ACE-inhibitors and beta-blockers in heart failureafter myocardial infarction with left ventricular systo-lic dysfunction and signs of heart failure or diabetesto reduce mortality and morbidity (Class of recommen-dation I, level of evidence B).63

Administration and dosing considerations for aldosteroneantagonists are provided in Table 15.

Angiotensin II receptor blockers

For patients with left ventricular systolic dysfunction:

. Angiotensin II receptor blockers (ARBs) can be used asan alternative to ACE inhibition in symptomaticpatients intolerant to ACE-inhibitors to improve mor-bidity and mortality (Class of recommendation I, levelof evidence B).6467

. ARBs and ACE-inhibitors seem to have similar efficacy inCHF on mortality and morbidity (Class of recommen-dation IIa, level of evidence B). In acute myocardialinfarction with signs of heart failure or left ventricular

dysfunction ARBs and ACE-inhibitors have similar orequivalent effects on mortality (Class of recommen-dation I, level of evidence B).68

. ARBs can be considered in combination with ACE-inhibi-tors in patients who remain symptomatic, to reduce mor-tality (Class of recommendation IIa, level of evidence B)and hospital admissions for heart failure (Class ofrecommendation I, level of evidence A).65,6971,170

In NYHA class III patients remaining symptomatic despitetherapy with diuretics, ACE-inhibitors, and beta-block-ers, there is no definite evidence for the recommen-

dation of next addition; an ARB or an aldosteroneantagonist to reduce further heart failure hospitaliz-ations or mortality.

Concerns raised by initial studies about a potentialnegative interaction between ARBs and beta-blockershave not been confirmed by recent studies in post-myocardial infarction or CHF (Class of recommendationI, level of evidence A).65,68

Dosing

Initiation and monitoring of ARBs, which are outlined inTable 10, are similar to procedures for ACE-inhibitors.Available ARBs and the recommended dose levels are

shown in Table 16.

Cardiac glycosides

. Cardiac glycosides are indicated in atrial fibrillationand any degree of symptomatic heart failure,whether or not left ventricular dysfunction is thecause. Cardiac glycosides slow the ventricular rate,which improves ventricular function and symptoms(Class of recommendation I, level of evidence B).72

. A combination of digoxin and beta-blockadeappears superior to either agent alone in patients

Table 12 Diuretics (oral): dosages and side effects

Initialdose (mg)

Maximum recommendeddaily dose (mg)

Major side effects

Loop diureticsFurosemide 2040 250500 Hypokalaemia, hypomagnesaemia,

hyponatraemiaBumetanide 0.51.0 510 Hyperuricaemia, glucose intoleranceTorasemide 5

10 100

200 Acid

base disturbance

ThiazidesBendroflumethiazide 2.5 10Hydrochlorothiazide 25 5075 Hypokalaemia, hypomagnesaemia,

hyponatraemiaMetolazone 2.5 10 Hyperuricaemia, glucose intoleranceIndapamide 2.5 2.5 Acidbase disturbance

Potassium-sparing diuretic ACEI 2ACEI ACEI 2ACEIAmiloride 2.5 5 20 40 Hyperkalaemia, rashTriamterene 25 50 100 200 HyperkalaemiaSpironolactone 12.525 50 50 100200 Hyperkalaemia, gynaecomastia

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with atrial fibrillation (Class of recommendationIIa, level of evidence B).73

Digoxin has no effect on mortality but mayreduce hospitalizations and, particularly, wor-sening heart failure hospitalizations, in thepatients with heart failure caused by left ventri-cular systolic dysfunction and sinus rhythmtreated with ACE-inhibitors, beta-blockers,diuretics and in severe heart failure, spironolac-tone (Class of recommendation IIa, level of evi-dence A).

. Contraindications to the use of cardiac glycosidesinclude bradycardia, second- and third-degreeAV block, sick sinus syndrome, carotid sinussyndrome, WolffParkinsonWhite syndrome,hypertrophic obstructive cardiomyopathy, hypo-kalaemia, and hyperkalaemia.

Digoxin

The usual daily dose of oral digoxin is 0.1250.25 mg ifserum creatinine is in the normal range (in the elderly0.06250.125 mg, occasionally 0.25 mg).

Vasodilator agents in chronic heart failure

. There is no specific role for direct-acting vasodilatoragents in the treatment of CHF (Class of recommen-dation III, level of evidence A) though they may beused as adjunctive therapy for angina or concomitanthypertension (Class of recommendation I, level of evi-dence A).

Hydralazine-isosorbide dinitrate

. In case of intolerance for ACE-inhibitors and ARBs, thecombination hydralazine/nitrates can be tried to

Table 13 The recommended procedure for starting a beta-blocker

I Patients should be on a background therapy with ACE inhibition, if not contraindicatedII The patient should be in a relatively stable condition, without the need of intravenous inotropic therapy and without signs of

marked fluid retentionIII Start with a very low dose and titrate up to maintenance dosages shown to be effective in large trials. The dose may be doubled

every 12 weeks if the preceding dose was well tolerated. Most patients can be managed as out-patientsIV Transient worsening failure, hypotension, or bradycardia may occur during the titration period or thereafter

a. Monitor the patient for evidence of heart failure symptoms, fluid retention, hypotension, and symptomatic bradycardiab. If worsening of symptoms, first increase the dose of diuretics, or ACE-inhibitor; temporarily reduce the dose of

beta-blockers if necessaryc. If hypotension, first reduce the dose of vasodilators; reduce the dose of the beta-blocker if necessaryd. Reduce or discontinue drugs that may lower heart rate in presence of bradycardia; reduce dose of beta-blockers if

necessary, but discontinue only if clearly necessarye. Always consider the reintroduction and/or uptitration of the beta-blocker when the patient becomes stable

If inotropic support is needed to treat a decompensated patient on beta-blockade, phosphodiesterase inhibitors should be preferredbecause their haemodynamic effects are not antagonized by beta-blocker agents

The following patients should be referred for specialist care:

a. Severe heart failure Class III/IVb. Unknown aetiologyc. Relative contraindications: asymptomatic bradycardia, and/or low blood pressured. Intolerance to low dosese. Previous use of beta-blocker and discontinuation because of symptomsf. Suspicion of bronchial asthma or severe pulmonary disease

Contraindications to beta-blockers in patients with heart failure

g. Asthma bronchialeh. Severe bronchial diseasei. Symptomatic bradycardia or hypotension

Table 14 Initiating dose, target dose, and titration scheme of beta-blocking agents as used in recent large, controlled trials

Beta-blocker First dose (mg) Increments (mg/day) Target dose (mg/day) Titration period

Bisoprolol164 1.25 2.5, 3.75, 5, 7.5, 10 10 WeeksmonthMetoprolol succinate CR165 12.5/25 25, 50, 100, 200 200 WeeksmonthCarvedilol54 3.125 6.25, 12.5, 25, 50 50 WeeksmonthNebivolol58 1.25 2.5, 5, 10 10 Weeksmonth

Daily frequency of administration as in the trials referenced here.

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reduce mortality and morbidity and improved qualityof life (Class of recommendation IIa, level ofevidence B).74

Nitrates

. Nitrates may be used for the treatment of concomitantangina or relief of dyspnoea. (Class of recommendationIIa, level of evidence C). Evidence that oral nitratesimprove symptoms of heart failure chronically orduring an acute exacerbation is lacking.

Alpha-adrenergic blocking drugs

. There is no evidence to support the use of alpha-adrenergic blocking drugs in heart failure (Class of rec-ommendation III, level of evidence B).75

Calcium antagonists

. Calcium antagonists are not recommended for thetreatment of heart failure caused by systolic dysfunc-tion. Diltiazem- and verapamil-type calcium antagon-ists, in particular, are not recommended in heartfailure because of systolic dysfunction; they are

contraindicated in addition to beta-blockade (Class ofrecommendation III, level of evidence C).76,77

. Addition of newer calcium antagonists (felodipine andamlodipine) to standard treatment for heart failuredoes not improve symptoms and does not impact onsurvival (Class of recommendation III, level ofevidence A).76,77

As long-term safety data with felodipine and amlodipineindicate a neutral effect on survival, they may offer asafe alternative for the treatment of concomitant arter-ial hypertension or angina not controlled by nitrates andbeta-blockers.

Nesiritide

Nesiritide, a recombinant human brain or B-typenatriuretic peptide (BNP), has been shown to be effica-cious in improving subjective dyspnoea score as well asinducing significant vasodilation when administeredintravenous to patients with acute heart failure.Clinical experience with nesiritide is still limited.Nesiritide may cause hypotension and some patients arenon-responders.

Positive inotropic therapy

. Repeated or prolonged treatment with oral inotropicagents increases mortality and is not recommended inCHF (Class of recommendation III, level of evidence A).

. Intravenous administration of inotropic agents is com-monly used in patients with severe heart failure withsigns of both pulmonary congestion and peripheralhypoperfusion. However, treatment-related compli-cations may occur and their effect on prognosis is

uncertain. Depending on agent level of evidence andstrength of recommendation varies.13

. Preliminary data suggests that some calcium sensitizers(e.g. levosimendan) may have beneficial effects onsymptoms and end-organ function and are safe.78

Anti-thrombotic agents

. In CHF associated with atrial fibrillation, a previousthromboembolic event or a mobile left ventricularthrombus, anti-coagulation is firmly indicated (Classof recommendation I, level of evidence A).79

. There is little evidence to show that anti-thrombotictherapy modifies the risk of death or vascular eventsin patients with heart failure.

. After a prior myocardial infarction, either aspirin ororal anti-coagulants are recommended as secondaryprophylaxis (Class of recommendation IIa, level of evi-dence C).80

. Aspirin should be avoided in patients with recurrenthospitalization with worsening heart failure (Class ofrecommendation IIb, level of evidence B). Because ofthe potential for increased bleeding complications,anti-coagulant therapy should be administered underthe most controlled conditions, planning monitoringin properly managed anti-coagulation clinics.

Table 16 Currently available angiotensin II receptorantagonists

Drug Daily dose (mg)

Documented effects on mortality/morbidityCandesartan cilexetil65 432Valsartan67 80320

Also availableEprosartan165 400800Losartan166,167 50100Irbesartan168 150300Telmisartan169 4080

Table 15 Administration and dosing considerations withaldosterone antagonists (spironolactone, eplerenone)

. Consider whether a patient is in severe heart failure (NYHAIIIIV) despite ACE-inhibition/diuretics

. Check serum potassium (,5.0 mmol/L) and creatinine(,250 mmol/L)

. Add a low dose (spironolactone 12.525 mg, eplerenone

25 mg) daily. Check serum potassium and creatinine after 46 days. If at any time serum potassium 55.5 mmol/L, reduce dose

by 50%. Stop if serum potassium .5.5 mmol/L. If after 1 month symptoms persist and normokalaemia

exists, increase to 50 mg daily. Check serum potassium/creatinine after 1 week

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Patients with CHF are at high risk of thromboembolicevents. Factors predisposing to thromboembolism arelow cardiac output with relative stasis of blood indilated cardiac chambers, poor contractility, regionalwall motion abnormalities, and atrial fibrillation.There is little evidence to support the concomitanttreatment with an ACE-inhibitor and aspirin in heartfailure.8183

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

Anti-arrhythmics

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

Class I anti-arrhythmics

. Class I anti-arrhythmics should be avoided as theymay provoke fatal ventricular arrhythmias, have anadverse haemodynamic effect and reduce survivalin heart failure (Class of recommendation III, level ofevidence B).84

Class II anti-arrhythmics

. Beta-blockers reduce sudden death in heart failure(Class of recommendation I, level of evidence A) (see

also page 1127).

85

Beta-blockers may also be indicatedalone or in combination with amiodarone or non-pharmacological therapy in the management of sus-tained or non-sustained ventricular tachy-arrhythmias(Class of recommendation IIa, level of evidence C).86

Class III anti-arrhythmics

. Amiodarone is effective against most supraventricularand ventricular arrhythmias (Class of recommendationI, level of evidence A). It may restore and maintainsinus rhythm in patients with heart failure and atrialfibrillation even in the presence of enlarged leftatria, or improve the success of electrical cardioversionand amiodarone is the preferred treatment in thiscondition.87,88 Amiodarone is the only anti-arrhythmicdrug without clinically relevant negative inotropiceffects.

Routine administration of amiodarone in patients withheart failure is not justified (Class of recommendationIII, level of evidence A).89,90

Oxygen therapy

. Oxygen is used for the treatment of AHF, but in generalhas no application in CHF (Class of recommendation III,level of evidence C).

Surgery and devices

Revascularization procedures, mitral valvesurgery, and ventricular restoration

. If clinical symptoms of heart failure are present,surgically correctable pathologies must always beconsidered (Class of recommendation I, level of evi-

dence C).

Revascularization

. There are no data from multicenter trials to supportthe use of revascularization procedures for the reliefof heart failure symptoms. Single centre, observationalstudies on heart failure of ischaemic origin, suggestthat revascularization might lead to symptomaticimprovement (Class of recommendation IIb, level ofevidence C).

. Until the results of randomized trials are reported,revascularization (surgical or percutaneous) is not rec-

ommended as routine management of patients withheart failure and coronary disease (Class of recommen-dation III, level of evidence C).

Mitral valve surgery

. Mitral valve surgery in patients with severe left ventri-cular systolic dysfunction and severe mitral valve insuf-ficiency due to ventricular insuffiency may lead tosymptomatic improvement in selected heart failurepatients (Class of recommendation IIb, level of evi-dence C). This is also true for secondary mitral insuffi-ciency due to left ventricular dilatation.

Left ventricular restoration

LV aneurysmectomy

. LV aneurysmectomy is indicated in patients with large,discrete left ventricular aneurysms who developheart failure (Class of recommendation I, level of evi-dence C).

Cardiomyoplasty

. Currently, cardiomyoplasty cannot be recommendedfor the treatment of heart failure (Class of recommen-

dation III, level of evidence C).. Cardiomyoplasty cannot be considered a viable

alternative to heart transplantation (Class of rec-ommendation III, level of evidence C).

Partial left ventriculectomy (Batista operation)

. Partial left ventriculectomy cannot be recommendedfor the treatment of heart failure (Class of recommen-dation I, level of evidence C). Furthermore, the Batistaoperation should not be considered an alternative toheart transplantation (Class of recommendation III,level of evidence C).

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External ventricular restoration

. Currently, external ventricular restoration cannot berecommended for the treatment of heart failure.Preliminary data suggest an improvement in LV dimen-sions and NYHA class with some devices (Class of rec-ommendation IIb, level of evidence C).

Pacemakers

. Pacemakers have been used in patients with heartfailure to treat bradycardia when conventional indi-cations exist. Pacing only of the right ventricle inpatients with systolic dysfunction will induce ventricu-lar dyssynchrony and may increase symptoms (Class ofrecommendation III, level of evidence A).

. Resynchronization therapy using bi-ventricular pacingcan be considered in patients with reduced ejectionfraction and ventricular dyssynchrony (QRS width!120 ms) and who remain symptomatic (NYHA IIIIV)despite optimal medical therapy to improve symptoms(Class of recommendation I, level of evidence A), hos-

pitalizations (Class of recommendation I, level of evi-dence A) and mortality (Class of recommendation I,level of evidence B).

Bi-ventricular pacing improves symptoms, exercisecapacity, and reduces hospitalizations.9194 A beneficialeffect 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

. Implantation of an implantable cardioverter defibrilla-

tors (ICD) in combination with bi-ventricular pacing canbe considered in patients who remain symptomaticwith severe heart failure NYHA class IIIIV withLVEF 35% and QRS duration ! 120 ms to improve mor-tality or morbidity (Class of recommendation IIa, levelof evidence B).93

. ICD therapy is recommended to improve survival inpatients who have survived cardiac arrest or who havesustained ventricular tachycardia, which is eitherpoorly tolerated or associated with reduced systolicleft ventricular function (Class of recommendation I,level of evidence A).95

. ICD implantation is reasonable in selected patients withLVEF, 3035%, not within 40 days of a myocardial

infarction, on optimal background therapy includingACE-inhibitor, ARB, beta-blocker, and an aldosteroneantagonist, where appropriate, to reduce suddendeath (Class of recommendation I, level of evidenceA).90,96,97

In patients with documented sustained ventricular tachy-cardia or ventricular fibrillation, the ICD is highly effec-tive in treating recurrences of these arrhythmias, eitherby anti-tachycardia pacing or cardioversion/defibrilla-tion, thereby reducing morbidity and the need forrehospitalization. The selection criteria, the limitedfollow-up and increased morbidity associated with ICD-

implantation and the low cost-effectiveness make itinappropariate to extend the findings into a generalpopulation with CHF. The COMPANION trial includedpatients with left ventricular systolic dysfunction, wideQRS complex suggesting dyssynchrony and heart failureand showed that implantation of an ICD in combinationwith resynchronization in patients with severe heartfailure reduced mortality and morbidity (See under