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European Heart Journal (2012) 33, 1787–1847 ESC Guidelines for the diagnosis and treatmentof acute and chronic heart failure 2012The Task Force for the Diagnosis and Treatment of Acute andChronic Heart Failure 2012 of the European Society of Cardiology.
Developed in collaboration with the Heart Failure Association (HFA)of the ESC Authors/Task Force Members: John J.V. McMurray (Chairperson) (UK)*,Stamatis Adamopoulos (Greece), Stefan D. Anker (Germany), Angelo Auricchio(Switzerland), Michael Bo¨hm (Germany), Kenneth Dickstein (Norway),Volkmar Falk (Switzerland), Gerasimos Filippatos (Greece), Caˆndida Fonseca(Portugal), Miguel Angel Gomez-Sanchez (Spain), Tiny Jaarsma (Sweden),Lars Køber (Denmark), Gregory Y.H. Lip (UK), Aldo Pietro Maggioni (Italy),Alexander Parkhomenko (Ukraine), Burkert M. Pieske (Austria), Bogdan A. Popescu(Romania), Per K. Rønnevik (Norway), Frans H. Rutten (The Netherlands),Juerg Schwitter (Switzerland), Petar Seferovic (Serbia), Janina Stepinska (Poland),Pedro T. Trindade (Switzerland), Adriaan A. Voors (The Netherlands), Faiez Zannad(France), Andreas Zeiher (Germany).
ESC Committee for Practice Guidelines (CPG): Jeroen J. Bax (CPG Chairperson) (The Netherlands),Helmut Baumgartner (Germany), Claudio Ceconi (Italy), Veronica Dean (France), Christi Deaton (UK),Robert Fagard (Belgium), Christian Funck-Brentano (France), David Hasdai (Israel), Arno Hoes (The Netherlands),Paulus Kirchhof (Germany/UK), Juhani Knuuti (Finland), Philippe Kolh (Belgium), Theresa McDonagh (UK),Cyril Moulin (France), Bogdan A. Popescu (Romania), Zˇeljko Reiner (Croatia), Udo Sechtem (Germany),Per Anton Sirnes (Norway), Michal Tendera (Poland), Adam Torbicki (Poland), Alec Vahanian (France),Stephan Windecker (Switzerland).
Document Reviewers: Theresa McDonagh (CPG Co-Review Coordinator) (UK), Udo Sechtem (CPG Co-ReviewCoordinator) (Germany), Luis Almenar Bonet (Spain), Panayiotis Avraamides (Cyprus), Hisham A. Ben Lamin(Libya), Michele Brignole (Italy), Antonio Coca (Spain), Peter Cowburn (UK), Henry Dargie (UK), Perry Elliott(UK), Frank Arnold Flachskampf (Sweden), Guido Francesco Guida (Italy), Suzanna Hardman (UK), Bernard Iung * Corresponding author. Chairperson: Professor John J.V. McMurray, University of Glasgow G12 8QQ, UK. Tel: +44 141 330 3479, Fax: +44 141 330 6955, Email: Other ESC entities having participated in the development of this document:Associations: European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Association of Echocardiography (EAE), European Heart Rhythm Association(EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI)Working Groups: Acute Cardiac Care, Cardiovascular Pharmacology and Drug Therapy, Cardiovascular Surgery, Grown-up Congenital Heart Disease, Hypertension and the Heart,Myocardial and Pericardial Diseases, Pulmonary Circulation and Right Ventricular Function, Thrombosis, Valvular Heart DiseaseCouncils: Cardiovascular Imaging, Cardiovascular Nursing and Allied Professions, Cardiology Practice, Cardiovascular Primary CareThe content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of theESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to OxfordUniversity Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC.
Disclaimer. The ESC Guidelines represent the views of the ESC and were arrived at after careful consideration of the available evidence at the time they were written. Healthprofessionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, override the individual responsibility of healthprofessionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient'sguardian or carer. It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.
& The European Society of Cardiology 2012. All rights reserved. For permissions please email: journals.permissions@oup.com (France), Bela Merkely (Hungary), Christian Mueller (Switzerland), John N. Nanas (Greece),Olav Wendelboe Nielsen (Denmark), Stein Ørn (Norway), John T. Parissis (Greece), Piotr Ponikowski (Poland).
The disclosure forms of the authors and reviewers are available on the ESC website Online publish-ahead-of-print 19 May 2012 Heart failure † Natriuretic peptides † Ejection fraction † Renin–angiotensin system † Beta-blockers †Digitalis † Transplantation Table of ContentsAbbreviations and acronyms . . . . . . . . . . . . 1789 7.2 Treatments recommended in potentially all patients with systolic heart failure . . . . . . . . . . . . . .1804 7.2.1 Angiotensin-converting enzyme inhibitors and 3. Definition and diagnosis . . . . . . . . . . . . .1792 3.1 Definition of heart failure . . . . . . . . . . 1792 7.2.2 Mineralocorticoid/aldosterone receptor 3.2 Terminology related to left ventricular ejection fraction .1792 3.3 Terminology related to the time-course of heart failure 1793 7.2.3 Other treatments recommended in selected patients 3.4 Terminology related to the symptomatic severity of heart with systolic heart failure . . . . . . . . . . . 1809 7.2.4 Angiotensin receptor blockers . . . . . . . 1809 3.5 Epidemiology, aetiology, pathophysiology, and natural history of heart failure . . . . . . . . . . . . .1794 7.2.6 Digoxin and other digitalis glycosides . . . . . 1810 3.6 Diagnosis of heart failure . . . . . . . . . . .1794 7.2.7 Combination of hydralazine and isosorbide 3.6.1 Symptoms and signs . . . . . . . . . . .1794 3.6.2 General diagnostic tests in patients with suspected 7.2.8 Omega-3 polyunsaturated fatty acids . . . . . 1810 7.3 Treatments not recommended (unproven benefit) . . 1811 3.6.3 Essential initial investigations: echocardiogram, 7.3.1 3-Hydroxy-3-methylglutaryl-coenzyme A reductase electrocardiogram, and laboratory tests . . . . . . 1795 inhibitors (‘statins') . . . . . . . . . . . . . 1811 3.6.4 Natriuretic peptides . . . . . . . . . . .1795 7.3.2 Renin inhibitors . . . . . . . . . . . . 1811 7.3.3 Oral anticoagulants . . . . . . . . . . . 1811 3.6.6 Routine laboratory tests . . . . . . . . . 1797 7.4 Treatments not recommended (believed to cause harm) 1811 3.6.7 Algorithm for the diagnosis of heart failure . . . 1799 4. The role of cardiac imaging in the evaluation of patients with 8. Pharmacological treatment of heart failure with ‘preserved' suspected or confirmed heart failure . . . . . . . . . 1800 ejection fraction (diastolic heart failure) . . . . . . . . .1812 4.1 Echocardiography . . . . . . . . . . . . . 1800 9. Non-surgical device treatment of heart failure with reduced 4.1.1 Assessment of left ventricular systolic dysfunction .1800 ejection fraction (systolic heart failure) . . . . . . . . .1813 4.1.2 Assessment of left ventricular diastolic dysfunction .1800 9.1 Implantable cardioverter-defibrillator . . . . . . .1813 4.2 Transoesophageal echocardiography . . . . . . .1800 9.1.1 Secondary prevention of sudden cardiac death . . 1813 4.3 Stress echocardiography . . . . . . . . . . .1802 9.1.2 Primary prevention of sudden cardiac death . . .1813 4.4 Cardiac magnetic resonance . . . . . . . . . .1802 9.2 Cardiac resynchronization therapy . . . . . . . .1814 4.5 Single-photon emission computed tomography and 9.2.1 Recommendations for cardiac resynchronization radionuclide ventriculography . . . . . . . . . . .1803 therapy where the evidence is certain . . . . . . .1815 4.6 Positron emission tomography imaging . . . . . . 1803 9.2.2 Recommendations for cardiac resynchronization 4.7 Coronary angiography . . . . . . . . . . . .1803 therapy where the evidence is uncertain . . . . . . 1815 4.8 Cardiac computed tomography . . . . . . . . .1803 10. Arrhythmias, bradycardia, and atrioventricular block in patients with heart failure with reduced ejection fraction and 5.1 Cardiac catheterization and endomyocardial biopsy . .1803 heart failure with preserved ejection fraction . . . . . . .1816 10.1 Atrial fibrillation . . . . . . . . . . . . . 1816 5.4 Ambulatory electrocardiographic monitoring . . . . 1804 10.1.2 Rhythm control . . . . . . . . . . . .1817 10.1.3 Thrombo-embolism prophylaxis . . . . . . 1818 7. Pharmacological treatment of heart failure with reduced 10.2 Ventricular arrhythmias . . . . . . . . . . .1818 ejection fraction (systolic heart failure) . . . . . . . . .1804 10.3 Symptomatic bradycardia and atrioventricular block . 1819 7.1 Objectives in the management of heart failure . . . .1804 11. Importance and management of other co-morbidity in heart failure with reduced ejection fraction and heart failure with 14.2 Organization of care and multidisciplinary management preserved ejection fraction . . . . . . . . . . . . .1821 11.1 Heart failure and co-morbidities . . . . . . . .1821 14.3 Serial natriuretic peptide measurement . . . . . .1838 14.4 Remote monitoring (using an implanted device) . . .1838 14.5 Remote monitoring (no implanted device) . . . . 1838 11.4 Asthma: see chronic obstructive pulmonary disease . 1821 14.6 Structured telephone support . . . . . . . . .1838 14.7 Palliative/supportive/end-of-life care . . . . . . .1838 11.7 Chronic obstructive pulmonary disease . . . . . .1821 15.3 Non-pharmacological, non-interventional therapy . . 1839 11.10 Erectile dysfunction . . . . . . . . . . . .1823 15.4 Pharmacological therapy . . . . . . . . . . 1839 11.13 Hyperlipidaemia . . . . . . . . . . . . .1823 11.15 Kidney dysfunction and cardiorenal syndrome . . .182411.16 Obesity . . . . . . . . . . . . . . . .182411.17 Prostatic obstruction . . . . . . . . . . . 1824 Appendix: six tables (,,) are available on the 11.18 Renal dysfunction . . . . . . . . . . . . 1824 ESC Website only at 11.19 Sleep disturbance and sleep-disordered breathing . .1824 ‘Web Tables' throughout the document.
12.1 Initial assessment and monitoring of patients . . . .182512.2 Treatment of acute heart failure . . . . . . . .1825 12.2.1 Pharmacological therapy . . . . . . . . . 182512.2.2 Non-pharmacological/non-device therapy . . . 1827 Abbreviations and acronyms 12.3 Invasive monitoring . . . . . . . . . . . . 1831 12.3.1 Intra-arterial line . . . . . . . . . . . .183112.3.2 Pulmonary artery catheterization . . . . . . 1831 12.4 Monitoring after stabilization . . . . . . . . . 1831 adult congenital heart disease 12.5 Other in-patient assessments . . . . . . . . .1831 atrial fibrillation 12.6 Readiness for discharge . . . . . . . . . . .1831 Atrial Fibrillation and Congestive Heart Failure 12.7 Special patient populations . . . . . . . . . .1831 acute heart failure 12.7.1 Patients with a concomitant acute coronary Acute Infarction Ramipril Efficacy angiotensin receptor blocker 12.7.2 Isolated right ventricular failure . . . . . . .1832 absolute risk reduction 12.7.3 Acute heart failure with ‘cardiorenal syndrome' . 1832 Assessment of Treatment with Lisinopril And 12.7.4 Perioperative acute heart failure . . . . . . 1832 12.7.5 Peripartum cardiomyopathy . . . . . . . .1832 12.7.6 Adult congenital heart disease . . . . . . . 1832 arginine vasopressin 13. Coronary revascularization and surgery, including valve MorBidity-mortality EvAlUaTion of the If inhibi- surgery, ventricular assist devices, and transplantation . . . .1832 tor ivabradine in patients with coronary disease 13.1 Coronary revascularization . . . . . . . . . .1832 and left ventricULar dysfunction 13.2 Ventricular reconstruction . . . . . . . . . .1833 Beta-Blocker Evaluation of Survival Trial bi-ventricular assist device 13.3.1 Aortic stenosis . . . . . . . . . . . . 1833 B-type natriuretic peptide 13.3.2 Aortic regurgitation . . . . . . . . . . .1833 13.3.3 Mitral regurgitation . . . . . . . . . . .1833 bridge to candidacy 13.4 Heart transplantation . . . . . . . . . . . 1834 bridge to decision 13.5 Mechanical circulatory support . . . . . . . . 1834 bridge to recovery 13.5.1 End-stage heart failure . . . . . . . . . .1835 bridge to transplantation 13.5.2 Acute heart failure . . . . . . . . . . .1835 coronary artery bypass graft 14. Holistic management, including exercise training and coronary artery disease multidisciplinary management programmes, patient monitoring, Cardiac Resynchronization in Heart Failure Study calcium-channel blocker CHA2DS2-VASc Cardiac failure, Hypertension, Age (Doubled), Diabetes, Stroke (Doubled)-Vascular intra-aortic balloon pump disease, Age 65–74 and Sex category (Female) Candesartan in Heart Failure: Assessment of Re- duction in Mortality and Morbidity left bundle branch block Cardiac Insufficiency Bisoprolol Study II cardiac magnetic resonance left ventricular assist device Carvedilol or Metoprolol European Trial left ventricular ejection fraction COMPANION Comparison of Medical Therapy, Pacing, and De- Multicenter Automatic Defibrillator Implantation fibrillation in Heart Failure Cooperative North Scandinavian Enalapril Sur- mechanical circulatory support multi-detector computed tomography chronic obstructive pulmonary disease Metoprolol CR/XL Randomised Intervention Carvedilol Prospective Randomized Cumulative Trial in Congestive Heart Failure mineralocorticoid receptor antagonist Controlled Rosuvastatin Multinational Trial in mid-regional atrial (or A-type) natriuretic continuous positive airway pressure Multisite Stimulation in Cardiomyopathies cardiac resynchronization therapy non-invasive positive pressure ventilation cardiac resynchronization therapy-defibrillator number needed to treat cardiac resynchronization therapy-pacemaker non-steroidal anti-inflammatory drug computed tomography New York Heart Association Defibrillators in Non-ischemic Cardiomyopathy Optimal Therapy in Myocardial infarction with Treatment Evaluation the Angiotensin II Antagonist Losartan Digitalis Investigation Group Perindopril for Elderly People with Chronic destination therapy positron emission tomography extracorporeal membrane oxygenation polyunsaturated fatty acid ejection fraction Resynchronization/Defibrillation for Ambulatory estimated glomerular filtration rate Heart Failure Trial Second Evaluation of Losartan in the Elderly Trial Randomised Aldactone Evaluation Study Eplerenone in Mild Patients Hospitalization and randomized controlled trial Survival Study in Heart Failure relative risk reduction glomerular filtration rate Survival and Ventricular Enlargement Gruppo Italiano per lo Studio della Sopravvi- Sudden Cardiac Death in Heart Failure Trial venza nell'Infarto miocardico-heart failure Study of Effects of Nebivolol Intervention on hydralazine and isosorbide dinitrate Outcomes and Rehospitalization in Seniors Hypertension, Abnormal renal/liver function (1 With Heart Failure point each), Stroke, Bleeding history or predis- Systolic Heart failure treatment with the If inhibi- position, Labile INR, Elderly (.65), Drugs/ tor ivabradine Trial alcohol concomitantly (1 point each) Studies of Left Ventricular Dysfunction Heart failure Endpoint evaluation of Angiotensin single-photon emission computed tomography II Antagonist Losartan Surgical Treatment for Ischemic Heart Failure tricuspid annular plane systolic excursion Heart Failure: A Controlled Trial Investigating tissue Doppler imaging Outcomes of Exercise Training heart failure with ‘preserved' ejection fraction TRAndolapril Cardiac Evaluation heart failure with reduced ejection fraction Valsartan Heart Failure Trial Irbesartan in heart failure with preserved systolic Valsartan In Acute myocardial infarction maximal oxygen consumption ). ESC Guidelines repre- Guidelines summarize and evaluate all available evidence at the sent the official position of the ESC on a given topic and are regu- time of the writing process, on a particular issue with the aim of larly updated.
assisting physicians in selecting the best management strategies Members of this Task Force were selected by the ESC to rep- for an individual patient, with a given condition, taking into resent professionals involved with the medical care of patients account the impact on outcome, as well as the risk–benefit ratio with this pathology. Selected experts in the field undertook a of particular diagnostic or therapeutic means. Guidelines are no comprehensive review of the published evidence for diagnosis, substitutes, but are complements, for textbooks and cover the management, and/or prevention of a given condition according European Society of Cardiology (ESC) Core Curriculum topics.
to ESC Committee for Practice Guidelines (CPG) policy. A crit- Guidelines and recommendations should help physicians to make ical evaluation of diagnostic and therapeutic procedures was per- decisions in their daily practice. However, the final decisions con- formed including assessment of the risk–benefit ratio. Estimates cerning an individual patient must be made by the responsible of expected health outcomes for larger populations were included, where data exist. The level of evidence and the strength A large number of Guidelines have been issued in recent years of recommendation of particular treatment options were weighed by the ESC as well as by other societies and organizations. Because and graded according to pre-defined scales, as outlined in Tables A of the impact on clinical practice, quality criteria for the develop- ment of guidelines have been established in order to make all deci- The experts of the writing and reviewing panels filled in declara- sions transparent to the user. The recommendations for tions of interest forms of all relationships which might be perceived formulating and issuing ESC Guidelines can be found on the as real or potential sources of conflicts of interest. These forms Table A Classes of recommendations Classes of
Suggested wording to use
Evidence and/or general agreement
Is recommended/is
that a given treatment or procedure
is beneficial, useful, effective.
Conflicting evidence and/or a
divergence of opinion about the
usefulness/efficacy of the given
treatment or procedure.

Class IIa
Weight of evidence/opinion is in
Should be considered
favour of usefulness/efficacy.
Class IIb
Usefulness/efficacy is less well
May be considered
established by evidence/opinion.
Class III
Evidence or general agreement that
Is not recommended
the given treatment or procedure
is not useful/effective, and in some
cases may be harmful.

were compiled into one file and can be found on the ESC Table B Levels of evidence website (Any changes indeclarations of interest that arise during the writing period must Data derived from multiple randomized
be notified to the ESC and updated. The Task Force received its evidence A
clinical trials or meta-analyses.
entire financial support from the ESC without any involvement Data derived from a single randomized
from the healthcare industry.
clinical trial or large non-randomized
evidence B
The ESC CPG supervises and coordinates the preparation of studies.
new Guidelines produced by Task Forces, expert groups, or con- Consensus of opinion of the experts and/
sensus panels. The Committee is also responsible for the endorse- or small studies, retrospective studies,
evidence C
ment process of these Guidelines. The ESC Guidelines undergo extensive review by the CPG and external experts. After appropri-ate revisions, it is approved by all the experts involved in the Task Force. The finalized document is approved by the CPG for publi- 3. Definition and diagnosis cation in the European Heart Journal.
The task of developing ESC Guidelines covers not only the inte- 3.1 Definition of heart failure gration of the most recent research, but also the creation of edu- Heart failure can be defined as an abnormality of cardiac struc- cational tools and implementation programmes for the ture or function leading to failure of the heart to deliver recommendations. To implement the guidelines, condensed oxygen at a rate commensurate with the requirements of the pocket guidelines versions, summary slides, booklets with essential metabolizing tissues, despite normal filling pressures (or only messages, and an electronic version for digital applications (smart- at the expense of increased filling pressures).For the pur- phones, etc.) are produced. These versions are abridged and, thus, poses of these guidelines, HF is defined, clinically, as a syn- if needed, one should always refer to the full text version which is drome in which patients have typical symptoms (e.g.
freely available on the ESC website. The National Societies of the breathlessness, ankle swelling, and fatigue) and signs (e.g. ele- ESC are encouraged to endorse, translate, and implement the ESC vated jugular venous pressure, pulmonary crackles, and dis- Guidelines. Implementation programmes are needed because it has placed apex beat) resulting from an abnormality of cardiac been shown that the outcome of disease may be favourably influ- structure or function. The diagnosis of HF can be difficult enced by the thorough application of clinical recommendations.
(see Section 3.6). Many of the symptoms of HF are non- Surveys and registries are needed to verify that real-life daily discriminating and, therefore, of limited diagnostic value.– practice is in keeping with what is recommended in the guidelines, Many of the signs of HF result from sodium and water reten- thus completing the loop between clinical research, writing of tion and resolve quickly with diuretic therapy, i.e. may be guidelines, and implementing them into clinical practice.
absent in patients receiving such treatment. Demonstration of The guidelines do not, however, override the individual respon- an underlying cardiac cause is therefore central to the diagno- sibility of health professionals to make appropriate decisions in the sis of HF (see Section 3.6). This is usually myocardial disease circumstances of the individual patients, in consultation with that causing systolic ventricular dysfunction. However, abnormalities patient, and, where appropriate and necessary, the patient's guard- of ventricular diastolic function or of the valves, pericardium, ian or carer. It is also the health professional's responsibility to endocardium, heart rhythm, and conduction can also cause verify the rules and regulations applicable to drugs and devices at HF (and more than one abnormality can be present) (see the time of prescription.
Section 3.5). Identification of the underlying cardiac problemis also crucial for therapeutic reasons, as the precise pathologydetermines the specific treatment used (e.g. valve surgery for valvular disease, specific pharmacological therapy for LV systol-ic dysfunction, etc.).
The aim of this document is to provide practical, evidence-basedguidelines for the diagnosis and treatment of heart failure (HF).
3.2 Terminology related to left The principal changes from the 2008 guidelinesrelate to: ventricular ejection fraction (i) an expansion of the indication for mineralocorticoid The main terminology used to describe HF is historical and is (aldosterone) receptor antagonists (MRAs); based on measurement of LV ejection fraction (EF). Mathematical- (ii) a new indication for the sinus node inhibitor ivabradine; ly, EF is the stroke volume (which is the end-diastolic volume minus (iii) an expanded indication for cardiac resynchronization therapy the end-systolic volume) divided by the end-diastolic volume. In patients with reduced contraction and emptying of the left ven- (iv) new information on the role of coronary revascularization in tricle (i.e. systolic dysfunction), stroke volume is maintained by an increase in end-diastolic volume (because the left ventricle (v) recognition of the growing use of ventricular assist devices; dilates), i.e. the heart ejects a smaller fraction of a larger volume.
The more severe the systolic dysfunction, the more the EF is (vi) the emergence of transcatheter valve interventions.
reduced from normal and, generally, the greater the end-diastolic There are also changes to the structure and format of the guide- and end-systolic volumes.
lines. Therapeutic recommendations now state the treatment The EF is considered important in HF, not only because of its effect supported by the class and level of recommendation in prognostic importance (the lower the EF the poorer the survival) tabular format; in the case of chronic heart failure due to left but also because most clinical trials selected patients based upon ventricular (LV) systolic dysfunction, the recommendations EF (usually measured using a radionuclide technique or echocardi- focus on mortality and morbidity outcomes. Detailed summaries ography). The major trials in patients with HF and a reduced EF of the key evidence supporting generally recommended treat- (HF-REF), or ‘systolic HF', mainly enrolled patients with an EF ments have been provided. Practical guidance is provided for ≤35%, and it is only in these patients that effective therapies the use of the more important disease-modifying drugs and have been demonstrated to date.
diuretics. When possible, other relevant guidelines, consensus Other, more recent, trials enrolled patients with HF and an EF statements, and position papers have been cited to avoid .40 – 45% and no other causal cardiac abnormality (such as unduly lengthy text. All tables should be read in conjunction valvular or pericardial disease). Some of these patients did not with their accompanying text and not read in isolation.
have an entirely normal EF (generally considered to be .50%) some time are often said to have ‘chronic HF'. A treated patient Table 1 Diagnosis of heart failure with symptoms and signs, which have remained generally un-changed for at least a month, is said to be ‘stable'. If chronic The diagnosis of HF-REF requires three conditions to be satisfied: stable HF deteriorates, the patient may be described as ‘decom- 1. Symptoms typical of HF pensated' and this may happen suddenly, i.e. ‘acutely', usuallyleading to hospital admission, an event of considerable prognostic 2. Signs typical of HFa importance. New (‘de novo') HF may present acutely, for example as a consequence of acute myocardial infarction or in a subacute(gradual) fashion, for example in a patient who has had asymptom- The diagnosis of HF-PEF requires four conditions to be satisfied: atic cardiac dysfunction, often for an indeterminate period, and 1. Symptoms typical of HF may persist or resolve (patients may become ‘compensated'). Al- 2. Signs typical of HFa though symptoms and signs may resolve in the latter patients,their underlying cardiac dysfunction may not, and they remain at 3. Normal or only mildly reduced LVEF and LV not dilated risk of recurrent ‘decompensation'. Occasionally, however, a 4. Relevant structural heart disease (LV hypertrophy/LA patient may have HF due to a problem that resolves completely enlargement) and/or diastolic dysfunction (see Section 4.1.2) (e.g. acute viral myopericarditis). Some other patients, particularlythose with ‘idiopathic' dilated cardiomyopathy, may also show sub- HF ¼ heart failure; HF-PEF ¼ heart failure with ‘preserved' ejection fraction; stantial or even complete recovery of LV systolic function with HF-REF ¼ heart failure and a reduced ejection fraction; LA ¼ left atrial; LV ¼ left ventricular; LVEF modern disease-modifying therapy [including an angiotensin- ¼ left ventricular ejection fraction.
aSigns may not be present in the early stages of HF (especially in HF-PEF) and in converting enzyme (ACE) inhibitor, beta-blocker, and mineralocor- patients treated with diuretics (see Section 3.6).
ticoid receptor antagonist (MRA)]. ‘Congestive HF' is a term that issometimes still used, particularly in the USA, and may describe acuteor chronic HF with evidence of congestion (i.e. sodium and water but also did not have a major reduction in systolic function either.
retention). Congestion, though not other symptoms of HF (e.g.
Because of this, the term HF with ‘preserved' EF (HF-PEF) was fatigue), may resolve with diuretic treatment. Many or all of these created to describe these patients. Patients with an EF in the terms may be accurately applied to the same patient at different range 35–50% therefore represent a ‘grey area' and most prob- times, depending upon their stage of illness.
ably have primarily mild systolic dysfunction. The diagnosis ofHF-PEF is more difficult than the diagnosis of HF-REF because it 3.4 Terminology related to the is largely one of exclusion, i.e. potential non-cardiac causes of symptomatic severity of heart failure the patient's symptoms (such as anaemia or chronic lungdisease) must first be discounted (Table Usually these The NYHA functional classification (Table ) has been used to patients do not have a dilated heart and many have an increase select patients in almost all randomized treatment trials in HF in LV wall thickness and increased left atrial (LA) size. Most and, therefore, to describe which patients benefit from effective have evidence of diastolic dysfunction (see Section 4.1.2), which therapies. Patients in NYHA class I have no symptoms attribut- is generally accepted as the likely cause of HF in these patients able to heart disease; those in NYHA classes II, III or IV are (hence the term ‘diastolic HF').
sometimes said to have mild, moderate or severe symptoms, It is important to note that EF values and normal ranges are de- pendent on the imaging technique employed, method of analysis, It is important to note, however, that symptom severity corre- and operator. Other, more sensitive measures of systolic function lates poorly with ventricular function, and that although there is a may show abnormalities in patients with a preserved or even clear relationship between severity of symptoms and survival, normal EF (see Section 4.1.1), hence the preference for stating pre- patients with mild symptoms may still have a relatively high abso- served or reduced EF over preserved or reduced ‘systolic lute risk of hospitalization and death.–Symptoms can also change rapidly; for example, a stable patient with mild symptomscan become suddenly breathless at rest with the onset of an ar- 3.3 Terminology related to the rhythmia, and an acutely unwell patient with pulmonary oedemaand NYHA class IV symptoms may improve rapidly with the ad- time-course of heart failure ministration of a diuretic. Deterioration in symptoms indicates The terms used to describe different types of HF can be confusing.
heightened risk of hospitalization and death, and is an indication As described above, in these guidelines the term HF is used to de- to seek prompt medical attention and treatment. Obviously, im- scribe the symptomatic syndrome, graded according to the provement in symptoms (preferably to the point of the patient be- New York Heart Association (NYHA) functional classification coming asymptomatic) is one of the two major goals of treatment (see Section 3.4 and Table ), although a patient can be rendered of HF (the other being to reduce morbidity, including hospital asymptomatic by treatment. In these guidelines, a patient who has admissions, and mortality).
never exhibited the typical signs or symptoms of HF is described as The Killip classification may be used to describe the severity of having asymptomatic LV systolic dysfunction (or whatever the the patient's condition in the acute setting after myocardial underlying cardiac abnormality is). Patients who have had HF for Two key neurohumoral systems activated in HF are the renin– Table 2 New York Heart Association functional classification based on severity of symptoms and system. In addition to causing further myocardial injury, these sys- physical activity temic responses have detrimental effects on the blood vessels,kidneys, muscles, bone marrow, lungs, and liver, and create a No limitation of physical activity. Ordinary physical pathophysiological ‘vicious cycle', accounting for many of the clin- activity does not cause undue breathlessness, fatigue, ical features of the HF syndrome, including myocardial electrical in- or palpitations.
stability. Interruption of these two key processes is the basis of Slight limitation of physical activity. Comfortable at much of the effective treatment of HF.
rest, but ordinary physical activity results in undue Clinically, the aforementioned changes are associated with the breathlessness, fatigue, or palpitations.
development of symptoms and worsening of these over time, Marked limitation of physical activity. Comfortable at leading to diminished quality of life, declining functional capacity, Class III
rest, but less than ordinary physical activity results in undue breathlessness, fatigue, or palpitations.
episodes of frank decompensation leading to hospital admission(which is often recurrent and costly to health services), and prema- Unable to carry on any physical activity without ture death, usually due to pump failure or a ventricular arrhythmia.
discomfort. Symptoms at rest can be present. If any physical activity is undertaken, discomfort is increased.
The limited cardiac reserve of such patients is also dependent onatrial contraction, synchronized contraction of the left ventricle,and a normal interaction between the right and left ventricles.
Intercurrent events affecting any of these [e.g. the development 3.5 Epidemiology, aetiology, of AF or conduction abnormalities, such as left bundle branch pathophysiology, and natural history of block (LBBB)] or imposing an additional haemodynamic load onthe failing heart (e.g. anaemia) can lead to acute decompensation.
Before 1990, the modern era of treatment, 60–70% of patients Approximately 1–2% of the adult population in developed coun- died within 5 years of diagnosis, and admission to hospital with tries has HF, with the prevalence rising to ≥10% among persons worsening symptoms was frequent and recurrent, leading to an 70 years of age or older.There are many causes of HF, and epidemic of hospitalization for HF in many –Effective these vary in different parts of the world (Web Table 3). At least treatment has improved both of these outcomes, with a relative half of patients with HF have a low EF (i.e. HF-REF). HF-REF is reduction in hospitalization in recent years of 30–50% and the best understood type of HF in terms of pathophysiology and smaller but significant decreases in mortality.– treatment, and is the focus of these guidelines. Coronary arterydisease (CAD) is the cause of approximately two-thirds of cases 3.6 Diagnosis of heart failure of systolic HF, although hypertension and diabetes are probable 3.6.1 Symptoms and signs contributing factors in many cases. There are many other causes The diagnosis of HF can be difficult, especially in the early stages.
of systolic HF (Web Table 3), which include previous viral infection Although symptoms bring patients to medical attention, many of (recognized or unrecognized), alcohol abuse, chemotherapy (e.g.
the symptoms of HF (Table are non-specific and do not, there- doxorubicin or trastuzumab), and ‘idiopathic' dilated cardiomyop- fore, help discriminate between HF and other problems. Symp- athy (although the cause is thought to be unknown, some of these toms that are more specific (i.e. orthopnoea and paroxysmal cases may have a genetic nocturnal dyspnoea) are less common, especially in patients with HF-PEF seems to have a different epidemiological and aetiological milder symptoms, and are, therefore, insensitive.– profile from HF-REFPatients with HF-PEF are older and Many of the signs of HF result from sodium and water retention, more often female and obese than those with HF-REF. They are and are, therefore, also not specific. Peripheral oedema has other less likely to have coronary heart disease and more likely to have causes as well, and is particularly non-specific. Signs resulting from hypertension and atrial fibrillation (AF). Patients with HF-PEF have sodium and water retention (e.g. peripheral oedema) resolve a better prognosis than those with HF-REF (see below).
quickly with diuretic therapy (i.e. may be absent in patients receiv- In patients with LV systolic dysfunction, the maladaptive changes ing such treatment, making it more difficult to assess patients occurring in surviving myocytes and extracellular matrix after myo- already treated in this way). More specific signs, such as elevated cardial injury (e.g. myocardial infarction) lead to pathological ‘re- jugular venous pressure and displacement of the apical impulse, modelling' of the ventricle with dilatation and impaired are harder to detect and, therefore, less reproducible (i.e. agree- contractility, one measure of which is a reduced EFWhat ment between different doctors examining the same patient may characterizes untreated systolic dysfunction is progressive worsen- ing of these changes over time, with increasing enlargement of the Symptoms and signs may be particularly difficult to identify and left ventricle and decline in EF, even though the patient may be interpret in obese individuals, in the elderly, and in patients with symptomless initially. Two mechanisms are thought to account chronic lung disease.– for this progression. The first is occurrence of further events The patient's medical history is also important. HF is unusual in an leading to additional myocyte death (e.g. recurrent myocardial in- individual with no relevant medical history (e.g. a potential cause of farction). The other is the systemic responses induced by the cardiac damage), whereas certain features, particularly previous decline in systolic function, particularly neurohumoral activation.
myocardial infarction, greatly increase the likelihood of HF in a 3.6.3 Essential initial investigations: echocardiogram, Table 4 Symptoms and signs typical of heart failure electrocardiogram, and laboratory testsThe echocardiogram and electrocardiogram (ECG) are the most useful tests in patients with suspected HF. The echocardiogramprovides immediate information on chamber volumes, ventricular systolic and diastolic function, wall thickness, and valve func- Elevated jugular venous pressure tion.––This information is crucial in determining appropri- Hepatojugular reflux ate treatment (e.g. an ACE inhibitor and beta-blocker for systolicdysfunction or surgery for aortic stenosis). Echocardiography is Paroxysmal nocturnal dyspnoea Third heart sound (gal op rhythm) discussed in detail later (see Section 4). The ECG shows the Reduced exercise tolerance Lateral y displaced apical impulse heart rhythm and electrical conduction, i.e. whether there is sino- Fatigue, tiredness, increased time atrial disease, atrioventricular (AV) block, or abnormal intraventri- to recover after exercise cular conduction (see Table ). These findings are also importantfor decisions about treatment (e.g. rate control and anticoagulation for AF, pacing for bradycardia, or CRT if the patient has LBBB) (see Section 9.2 on treatment). The ECG may also show evidence of LV Peripheral oedema (ankle, sacral, hypertrophy or Q waves (indicating loss of viable myocardium), giving a possible clue to the aetiology of HF. HF is very unlikely(likelihood ,2%) in patients presenting acutely and with a com- Pulmonary crepitations pletely normal –In patients with a non-acute presenta- Reduced air entry and dul ness to tion, a normal ECG has a somewhat lower negative predictive Weight gain (>2 kg/week) percussion at lung bases (pleural effusion) value (likelihood ,10–14%).
The information provided by these two tests will permit an initial working diagnosis and treatment plan in the majority of (in advanced heart failure) patients. Routine biochemical and haematological investigations are also important, partly to determine whether renin–angioten- Tachypnoea (>16 breaths/min) sin–aldosterone blockade can be initiated safely (renal functionand potassium) and to exclude anaemia (which can mimic or aggra- vate HF) and because they provide other, useful information (see (especial y in the elderly) Section 3.6.6).
Other tests are generally only required if the diagnosis remains Tissue wasting (cachexia) unclear (e.g. if echocardiographic images are suboptimal or if anunusual cardiac cause, or a non-cardiac cause, of the patient's con- dition is suspected) or if further evaluation of the underlying causeof the patient's cardiac problem is indicated (e.g. perfusion imagingor angiography in suspected CAD or endomyocardial biopsyin certain infiltrating diseases of the myocardium). Special tests patient with appropriate symptoms and –These points high- are discussed in more detail in Sections 4 and 5.
light the need to obtain objective evidence of a structural or func-tional cardiac abnormality that is thought to account for the 3.6.4 Natriuretic peptides patient's symptoms and signs, to secure the diagnosis of HF (see Because the signs and symptoms of HF are so non-specific, many patients with suspected HF referred for echocardiography are Once the diagnosis of HF has been made, it is important to not found to have an important cardiac abnormality. Where the establish the cause, particularly specific correctable causes (Web availability of echocardiography is limited, an alternative approach Table 3). Symptoms and signs are important in monitoring a to diagnosis is to measure the blood concentration of a natriuretic patient's response to treatment and stability over time. Persistence peptide, a family of hormones secreted in increased amounts when of symptoms despite treatment usually indicates the need for add- the heart is diseased or the load on any chamber is increased (e.g.
itional therapy, and worsening of symptoms is a serious develop- by AF, pulmonary embolism, and some non-cardiovascular condi- ment (placing the patient at risk of urgent hospital admission and tions, including renal failur–Natriuretic peptide levels also death) and merits prompt medical attention.
increase with age, but may be reduced in obese Anormal natriuretic peptide level in an untreated patient virtuallyexcludes significant cardiac disease, making an echocardiogram un- 3.6.2 General diagnostic tests in patients with suspected necessary (investigation for a non-cardiac cause of the patient's problems is likely to be more productive in such patients).
In view of the difficulty in grading the evidence for diagnostic tests, The use of natriuretic peptides as a ‘rule-out' test in the diagnosis all diagnostic recommendations have been given an arbitrary of HF is discussed in detail elsewhere.–Multiple studies have evidence level of C.
examined the threshold concentration that excludes HF for the Recommendations for the diagnostic investigations in ambulatory patients suspected of having heart failurec Investigations to consider in all patients
Transthoracic echocardiography is recommended to evaluate cardiac structure and function, including diastolic function (Section 4.1.2), and to measure LVEF to make the diagnosis of HF, assist in planning and monitoring of treatment, and to obtain prognostic information.
A 12-lead ECG is recommended to determine heart rhythm, heart rate, QRS morphology, and QRS duration, and to detect other relevant abnormalities (Table 5). This information also assists in planning treatment and is of prognostic importance. A completely normal ECG makes systolic HF unlikely.
Measurement of blood chemistry (including sodium, potassium, calcium, urea/blood urea nitrogen, creatinine/estimated glomerular filtration rate, liver enzymes and bilirubin, ferritin/TIBC) and thyroid function is recommended to: (i) Evaluate patient suitability for diuretic, renin–angiotensin–aldosterone antagonist, and anticoagulant therapy (and monitor treatment) (ii) Detect reversible/treatable causes of HF (e.g. hypocalcaemia, thyroid dysfunction) and co-morbidities (e.g. iron deficiency) (iii) Obtain prognostic information.
A complete blood count is recommended to: (i) Detect anaemia, which may be an alternative cause of the patient's symptoms and signs and may cause worsening of HF (ii) Obtain prognostic information.
Measurement of natriuretic peptide (BNP, NT-proBNP, or MR-proANP) should be considered to: (i) Exclude alternative causes of dyspnoea (if the level is below the exclusion cut-point–see Figure 1–HF is very (ii) Obtain prognostic information.
A chest radiograph (X-ray) should be considered to detect/exclude certain types of lung disease, e.g. cancer (does not exclude asthma/ COPD). It may also identify pulmonary congestion/oedema and is more useful in patients with suspected HF in the acute setting.
Investigations to consider in selected patients
CMR imaging is recommended to evaluate cardiac structure and function, to measure LVEF, and to characterize cardiac tissue, especially in subjects with inadequate echocardiographic images or where the echocardiographic findings are inconclusive or incomplete (but taking account of cautions/contraindications to CMR).
Coronary angiography is recommended in patients with angina pectoris, who are considered suitable for coronary revascularization, to evaluate the coronary anatomy.
Myocardial perfusion/ischaemia imaging (echocardiography, CMR, SPECT, or PET) should be considered in patients thought to have CAD, and who are considered suitable for coronary revascularization, to determine whether there is reversible myocardial ischaemia and viable myocardium.
Left and right heart catheterization is recommended in patients being evaluated for heart transplantation or mechanical circulatory support, to evaluate right and left heart function and pulmonary arterial resistance.
Exercise testing should be considered: (i) To detect reversible myocardial ischaemia (ii) As part of the evaluation of patients for heart transplantation and mechanical circulatory support (iii) To aid in the prescription of exercise training (iv) To obtain prognostic information.
BNP ¼ B-type natriuretic peptide; CAD ¼ coronary artery disease; CMR ¼ cardiac magnetic resonance; COPD ¼ chronic obstructive pulmonary disease; ECG ¼ electrocardiogram; HF ¼ heart failure; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; MR-proANP ¼ mid-regional pro atrial natriuretic peptide; NT-proBNP ¼ N-terminal pro B-type natriuretic peptide; PET ¼ positron emission tomography; SPECT ¼ single photon emission computed tomography; TIBC ¼ total iron-binding capacity.
aClass of recommendation.
bLevel of evidence.
cThis list is not exhaustive and other investigations are discussed in the text. Additional investigations may be indicated in patients with suspected acute HF in the emergency department/hospital, including troponins and D-dimer measurement and right heart catheterization.
two most commonly used natriuretic peptides, B-type natriuretic hospital emergency department) and those presenting with a peptide (BNP) and N-terminal pro B-type natriuretic peptide more gradual onset of symptoms.
(NT-proBNP).–The exclusion threshold differs for patients For patients presenting with acute onset or worsening of presenting with acute onset or worsening of symptoms (e.g. to a symptoms, the optimal exclusion cut-off point is 300 pg/mL Table 5 Most common abnormalities on the electrocardiogram in heart failure Sinus tachycardia Decompensated HF, anaemia, fever, hyperthyroidism Clinical assessment Laboratory investigation Sinus bradycardia Beta-blockade, digoxin, ivabradine, verapamil, diltiazem Review drug therapy Laboratory investigation HypothyroidismSick sinus syndrome Hyperthyroidism, infection, mitral valve disease Slow AV conduction, anticoagulation, pharmacological cardioversion, electrical cardioversion, catheter ablation Decompensated HF, infarction Ventricular arrhythmias Ischaemia, infarction, cardiomyopathy, myocarditis Laboratory investigation hypokalaemia, hypomagnesaemiaDigitalis overdose Exercise test, perfusion/viability studies, coronary angiography, electrophysiology testing, ICD Myocardial ischaemia/infarction Coronary artery disease Echocardiography, troponins, perfusion/viability studies, coronary angiography, revascularization Infarction, hypertrophic cardiomyopathy Echocardiography, perfusion/viability studies, coronary angiography LBBB, pre-excitation Hypertension, aortic valve disease, hypertrophic Infarction, drug toxicity, myocarditis, sarcoidosis, genetic Review drug therapy, evaluate for systemic disease; family history/ cardiomyopathy (laminopathy, desminopathy), Lyme disease genetic testing indicated. Pacemaker or ICD may be indicated.
Obesity, emphysema, pericardial effusion, amyloidosis Echocardiography/CMR, chest X-ray; for amyloidosis consider further imaging (CMR, 99mTc-DPD scan) and endomyocardial biopsy QRS duration ≥120 ms and Electrical and mechanical dyssynchrony AV ¼ atrioventricular; CMR ¼ cardiac magnetic resonance; CRT-P ¼ cardiac resynchronization therapy pacemaker; CRT-D ¼ cardiac resynchronization therapy defibrillator; ECG ¼ electrocardiogram; HF ¼ heart failure; ICD ¼ implantable cardioverter-defibrillator; LBBB ¼ left bundle branch block; LV ¼ left ventricular. 99mTc-DPD ¼ for NT-proBNP and 100 pg/mL for BNP. In one other study, 3.6.6 Routine laboratory tests mid-regional atrial (or A-type) natriuretic peptide (MR-proANP), In addition to standard biochemical [sodium, potassium, creatin- at a cut-off point of 120 pmol/L, was shown to be non-inferior ine/estimated glomerular filtration rate (eGFR)] and haemato- to these thresholds for BNP and NT-proBNP in the acute logical tests (haemoglobin, haematocrit, ferritin, leucocytes, and platelets), it is useful to measure thyroid-stimulating hormone For patients presenting in a non-acute way, the optimum exclu- (thyrotropin) as thyroid disease can mimic or aggravate HF sion cut-off point is 125 pg/mL for NT-proBNP and 35 pg/mL for (Table ). Blood glucose is also worth measuring as undiagnosed BNP. The sensitivity and specificity of BNP and NT-proBNP for the diabetes is common in patients with HF. Liver enzymes may also diagnosis of HF are lower in non-acute patients.– be abnormal in HF (important if considering amiodarone orwarfarin).
As well as a pre-treatment check, biochemical monitoring is 3.6.5 Chest X-ray important after the initiation of renin–angiotensin system block- A chest X-ray is of limited use in the diagnostic work-up of patients ers, while the dose is being up-titrated (see Section 7.2) and with suspected HF. It is probably most useful in identifying an alterna- during longer term follow-up, especially if an intercurrent illness tive, pulmonary explanation for a patient's symptoms and signs. It may, leading to sodium and water loss occurs (e.g. diarrhoea and however, show pulmonary venous congestion or oedema in a patient vomiting) or another drug that affects sodium and water homeo- with HF. It is important to note that significant LV systolic dysfunction stasis or renal function is started or the dose altered [e.g. non- may be present without cardiomegaly on the chest X-ray.
steroidal anti-inflammatory drugs (NSAIDs) or diuretics]. Many Table 6 Common laboratory test abnormalities in heart failure Renal/kidney impairment (creatinine >150 µmol/L/1.7 mg/dL, Consider reducing ACE inhibitor/ARB or MRA eGFR <60 mL/mim/1.73 m2) dose (or postpone dose up-titration) ACE inhibitor/ARB, MRA Check potassium and BUNConsider reducing diuretic dose if dehydrated but if renal congestion, more diuresis may help NSAIDs and other nephrotoxic drugs Review drug therapy Anaemia (<13 g/dL/8.0 mmol/L in men, Chronic HF, haemodilution, iron loss or poor Diagnostic work-up <12 g/dL/7.4 mmol/L in women) utilization, renal failure, chronic disease, Consider treatment Hyponatraemia (<135 mmol/L) Chronic HF, haemodilution, AVP release, Consider water restriction, adjusting diuretic dosage diuretics (especially thiazides) and other drugs Ultrafiltration, vasopressin antagonist Review drug therapy Hypernatraemia (>150 mmol/L) Water loss/inadequate water intake Assess water intake Diagnostic work-up Hypokalaemia (<3.5 mmol/L) Diuretics, secondary hyperaldosteronism Risk of arrhythmia Consider ACE inhibitor/ARB, MRA, potassium supplements Hyperkalaemia (>5.5 mmol/L) Renal failure, potassium supplement, renin– Stop potassium supplements/potassium sparing diuretic angiotensin–aldosterone system blockers Reduce dose of/stop ACE inhibitor/ARB, MRAAssess renal function and urine pH Risk of bradycardia and serious arrhythmias Hyperglycaemia (>6.5 mmol/L/117 mg/dL) Diabetes, insulin resistance Evaluate hydration, treat glucose intolerance Hyperuricaemia (>500 µmol/L/8.4 mg/dL) Diuretic treatment, gout, malignancy Reduce diuretic dose Albumin high (>45 g/L) Albumin low (<30 g/L) Poor nutrition, renal loss Diagnostic work-up Transaminase increase Liver dysfunction Diagnostic work-up Review drug therapy Elevated troponins Evaluate pattern of increase (mild increases common in severe HF) Prolonged ischaemia, severe HF, myocarditis, sepsis, renal failure Coronary angiographyEvaluation for revascularization Elevated creatine kinase Inherited and acquired myopathies (including Consider genetic cardiomyopathy (laminopathy, desminopathy, myositis) dystrophinopathy), muscular dystrophies Statin use Abnormal thyroid tests Hyper-/hypothyroidism Treat thyroid abnormality Reconsider amiodarone use Proteinuria, glycosuria, bacteria Diagnostic work-up Rule out infection, diabetes International normalized ratio >3.5 Anticoagulant overdose Review anticoagulant dose Liver congestion/disease Assess liver function Drug interactions Review drug therapy CRP >10 mg/L, neutrophilic leukocytosis Infection, inflammation Diagnostic work-up ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; AVP ¼ arginine vasopressin; BNP ¼ B-type natriuretic peptide; BUN ¼ blood urea nitrogen; CRP ¼ C-reactive protein; eGFR ¼ estimated glomerular filtration rate; HF ¼ heart failure; MRA ¼ mineralocorticoid receptor antagonist; NSAID ¼ non-steroidal routine laboratory tests provide valuable prognostic information In patients presenting to hospital as an emergency with sus- (see Section 6).
pected HF and acute onset of symptoms, early echocardiog-raphy is recommended (and immediate echocardiography inshocked or severely haemodynamically compromised patients).
3.6.7 Algorithm for the diagnosis of heart failure If a natriuretic peptide is measured, a high exclusion cut-off An algorithm for the diagnosis of HF or LV dysfunction is shown in non-emergently in primary care, or to a hospital outpatient Suspected heart failure
Possibly chest x-ray NT-proBNP <300 pg/mL NT-proBNP 300 pg/mLb NT-proBNP 125 pg/mLa NT-proBNP <125 pg/mL BNP <100 pg/mL Heart failure unlikelyc Heart failure unlikelyc If heart failure confirmed, determine aetiologyd and start appropriate treatment *In the acute setting, MR-proANP may also be used (cut-off point 120 pmol/L, i.e. <120 pmol/L = heart failure unlikely). BNP = B-type natriuretic peptide; ECG = electrocardiogram; HF = heart failure; MR-proANP = mid-regional pro atrial natriuretic peptide; NT-proBNP = N-terminal pro B-type natriuretic peptide.
a Exclusion cut-off points for natriuretic peptides are chosen to minimize the false-negative rate while reducing unnecessary referrals for echocardiography.
b Other causes of elevated natriuretic peptide levels in the acute setting are an acute coronary syndrome, atrial or ventricular arrhythmias, pulmonary embolism, and severe chronic obstructive pulmonary disease with elevated right heart pressures, renal failure, and sepsis. Other causes of an elevated natriuretic level in the non-acute setting are: old age (>75 years), atrial arrhythmias, left ventricular hypertrophy, chronic obstructive pulmonary disease, and chronic kidney disease.
c Treatment may reduce natriuretic peptide concentration, and natriuretic peptide concentrations may not be markedly elevated in patients with HF-PEF.
dSee Section 3.5 and Web Table 3.
Figure 1 Diagnostic flowchart for patients with suspected heart failure—showing alternative ‘echocardiography first' (blue) or ‘natriureticpeptide first' (red) approaches.
clinic, with slow onset of symptoms (and signs) suggestive of HF, LV dysfunction; the same is true for another technique for asses- an ECG and natriuretic peptide measurement may be used as a sing LV systolic function—fractional shortening. These and visual means of identifying patients who most need echocardiography assessment of EF (‘eye-balling') are not recThree- (an echocardiogram is indicated if the natriuretic peptide level is dimensional echocardiography of adequate quality further above the exclusion threshold/ECG is abnormal). In these improves the quantification of ventricular volumes and EF calcu- patients, a lower exclusion natriuretic peptide cut-off point The LV wall motion score index may be an acceptable should be used to prevent a ‘false-negative' diagnosis of alternative to EF but is not widely used. Other indices of LV sys- HF.–Patients with a high pre-test likelihood of HF, such tolic function include AV plane systolic excursion, systolic tissue as those with a history of myocardial infarction, may be referred Doppler velocities, and measurements of deformation (strain directly for echocardiography.
and strain rate). Deformation imaging is more sensitive than EFin detecting minor changes in LV systolic function. However, 4. The role of cardiac imaging in issues of reproducibility and standardization currently limit theroutine clinical use of deformation imaging. Stroke volume and the evaluation of patients with cardiac output can also be calculated by measuring the velocity suspected or confirmed heart time integral at the LV outflow tract area.
The most common echocardiographic abnormalities seen in patients with HF and their clinical significance are presented inTable .
Imaging plays a central role in the diagnosis of HF and in guidingtreatment. Of the several imaging modalities available, echocardi-ography is the method of choice in patients with suspected HF 4.1.2 Assessment of left ventricular diastolic dysfunction for reasons of accuracy, availability (including portability), safety, LV diastolic dysfunction is thought to be the underlying patho- and –It may be complemented by other modalities, physiological abnormality in patients with HF-PEF, and thus its chosen according to their ability to answer specific clinical ques- identification is fundamental to the diagnosis of this type of HF tions and taking account of contraindications to, and risks of, spe- (Table –The Doppler echocardiographic diastolic cific tests (see Table –All imaging examinations, indices commonly measured in patients with HF are shown in regardless of type, should be performed only by individuals compe- Table Of note, normal values for functional echocardiographic tent and experienced in the specific technique.
indices of LV diastolic dysfunction may also depend on age, heartrate, and body Importantly, no single echocardiographic 4.1 Echocardiography parameter is sufficiently accurate and reproducible to be used inisolation to make a diagnosis of LV diastolic dysfunction. There- Echocardiography is a term used here to refer to all cardiac ultra- fore, a comprehensive echocardiographic examination incorporat- sound imaging techniques, including two-dimensional/three- ing all relevant two-dimensional and Doppler data is dimensional echocardiography, pulsed and continuous wave recommended.This should include the evaluation of both Doppler, colour flow Doppler, and tissue Doppler imaging structural (LV hypertrophy, LA dilation) and functional abnormal- (TDI).––Echocardiography provides information about ities (Table ). Tissue Doppler imaging-derived early diastolic cardiac anatomy (e.g. volumes, geometry, mass) and function myocardial velocities (e'), measured at the mitral annulus, allow (e.g. LV function and wall motion, valvular function, right ventricu- the assessment of myocardial relaxation. A normal e' (.8 cm/s lar function, pulmonary artery pressure, pericardium).
septal, .10 cm/s lateral, or .9 cm/s average, measured usingreal-time pulsed TDI) is very unusual in a patient with HF. The 4.1.1 Assessment of left ventricular systolic dysfunction E/e' ratio correlates with LV filling pr(Table LVEF is not an index of contractility as it depends on volumes, Thus, echocardiographic evidence of LV diastolic dysfunction preload, afterload, heart rate, and valvular function, and is not may consist of a reduced e' (e' average ,9 cm/s) or an increased the same as stroke volume. Stroke volume may be maintained by E/e' ratio (.15), or a combination of these parameters (Table LV dilation in a patient with HF-REF, whereas it may be reduced The presence of at least two abnormal measurements and/or AF in patients with HF-PEF and concentric LV hypertrophy. EF may increases the likelihood of the diagnosis.
also be preserved (and stroke volume reduced) in patients withsignificant mitral regurgitation. Thus EF must be interpreted in itsclinical context.
4.2 Transoesophageal echocardiography The recommended echocardiographic method for measure- Transoesophageal echocardiography (TOE) is not needed in ment of EF is the apical biplane method of discs (the modified routine diagnostic assessment unless the transthoracic ultrasound Simpson's –However, because this method relies window is inadequate (e.g. because of obesity, chronic lung on accurate tracing of the endocardial border, use of a contrast disease, ventilated patients) and an alternative modality agent to better delineate the endocardial border is recom- [e.g. cardiac magnetic resonance (CMR) imaging] is not available mended when image quality is suboptimal (i.e. where ,80% of or applicable.
the endocardial border is adequately The Teichholz TOE is, however, valuable in patients with complex valvular and Quinones methods of calculating EF from linear dimensions disease (especially mitral disease and prosthetic valves), suspected may result in inaccuracies, particularly in patients with regional endocarditis, and in selected patients with congenital heart disease.
Table 7 Possible applications of various imaging techniques in the diagnosis of HF LV diastolic dysfunction Hypertrophic CMP: Eosinophilic syndromes + Iron: haemochromatosis + Iron: thalassaemia Endomyocardial fibrosis + Wide availability High quality images Relatively low cost Limited availability Image quality limited Limited Functional analysis limited if arrhythmia Selection of a test in daily practice should consider availability, local expertise, advantages/disadvantages, and, in the case of several questions to address, which test could bestanswer several of them.
ARVC ¼ arrhythmogenic right ventricular cardiomyopathy; CAD ¼ coronary artery disease; Cath ¼ cardiac catheterization; CMP ¼ cardiomyopathy; CMR ¼ cardiac magnetic resonance; EDV ¼ end-diastolic volume; EF ¼ ejection fraction; ESV ¼ end-systolic volume; HCM ¼ hypertrophic cardiomyopathy; LV ¼ left ventricular; MDCT ¼ multidetector computed tomography; PET ¼ positron emission tomography; RV ¼ right ventricular; SPECT ¼ single photon emission computed tomography.
aStress (dobutamine) imaging.
bFractional flow reserve or ‘Doppler' flow reserve measurements.
cIncluding measurements of aortic annulus for transcatheter aortic valve implantation.
dEndomyocardial biopsy.
eHaemodynamic evaluation (constriction).
fDescribes disease activity by contrast-enhanced CMR.
gCalcifications.
hGood quality irrespective of patient habitus.
iExcellent attenuation correction.
kForeign metallic bodies in specific locations (e.g. in the eye) and electronic devices (some pacemakers are MR-compatible); relative contraindication: claustrophobia.
Table 8 Common echocardiographic abnormalities in patients with heart failure Parameters related to systolic function
LV ejection fraction Reduced (<50%) LV global systolic dysfunction LV fractional shortening Reduced (<25%) LV radial systolic dysfunction LV regional function Hypokinesis, akinesis, dyskinesis Myocardial infarction/ischaemia Cardiomyopathy, myocarditis LV end-diastolic size Increased (diameter ≥60 mm, >32 mm/m2, Volume overload HF likely volume >97 mL/m2) LV end-systolic size Increased (diameter >45 mm/>25 mm/m2, Volume overload HF likely volume >43 mL/m2) LV outflow tract velocity time integral Reduced (<15 cm) Reduced LV stroke volume Parameters related to diastolic function
LV diastolic dysfunction parameters Abnormalities of the mitral inflow pattern, Indicate LV diastolic dysfunction degree and suggest level of filling tissue velocities (e ) or the E/e ratio Left atrial volume index Increased (volume >34 mL/m2) Increased LV filling pressure (past or present)Mitral valve disease Increased: >95 g/m2 in women and Hypertension, aortic stenosis, hypertrophic cardiomyopathy >115 g/m2 in men Parameters related to valvular function
Valvular structure and function Valvular stenosis or regurgitation (especially May be the cause of HF or a complicating factor or the result of aortic stenosis and mitral regurgitation) HF (secondary mitral regurgitation) Assess dysfunction severity and haemodynamic consequencesConsider surgery Other parameters
RV function (e.g. TAPSE) Reduced (TAPSE <16 mm) RV systolic dysfunction Tricuspid regurgitation peak velocity Increased (>3.4 m/s) Increased RV systolic pressure Systolic pulmonary artery pressure Increased (>50 mmHg) Pulmonary hypertension likely Inferior vena cava Dilated, with no respiratory collapse Increased right atrial pressureRV dysfunction, volume overloadPulmonary hypertension possible Effusion, haemopericardium, calcification Consider tamponade, malignancy, systemic diseases, acute or chronic pericarditis, constrictive pericarditis E/e' ¼ ratio of the mitral inflow E wave to the tissue Doppler e' wave; HF¼ heart failure; LV ¼ left ventricular; RV ¼ right ventricular; TAPSE ¼ tricuspid annular plane systolic TOE is also used to check for thrombus in the left atrial appendage standard with respect to accuracy and reproducibility of of patients with AF.
volumes, mass, and wall motion. Because CMR yields good imagequality in most patients, it is the best alternative imaging modality 4.3 Stress echocardiography in patients with non-diagnostic echocardiographic studies.
Exercise or pharmacological stress echocardiography may be used CMR is particularly valuable in identifying inflammatory and infil- to identify the presence and extent of inducible ischaemia and to trative conditions, and in predicting prognosis in patients with determine whether non-contracting myocardium is viable (see these (Table CMR is also useful in the work-up of patients Section 13).This technique may also be useful in evaluating with suspected cardiomyopathy, arrhythmias, suspected cardiac patients with suspected severe aortic stenosis, reduced EF, and a tumours (or cardiac involvement by tumour), or pericardial dis- low transvalvular gradient (see Section 13.3.1). Diastolic stress eases, and is the imaging method of choice in patients with testing is an emerging procedure to identify HF-PEF in patients complex congenital heart disease.
with HF symptoms during physical activity, normal EF, and incon- Limitations include lack of availability, inability to image clusive diastolic function parameters at res patients with certain metallic implants (including many, but notall, cardiac devices), and cost. Also, the accuracy of functional 4.4 Cardiac magnetic resonance analysis is limited in patients with atrial arrhythmias. Some CMR is a non-invasive technique that provides most of the ana- patients cannot tolerate the procedure, often because of claus- tomical and functional information available from echocardiog- trophobia. Linear gadolinium chelates are contraindicated in raphy, including evaluation of ischaemia and viability, as well as individuals with a GFR ,30 mL/min/m2 because they cause additional CMR is regarded as the gold the rare condition known as nephrogenic systemic fibrosis Table 9 Common echocardiographic measures of left ventricular diastolic dysfunction in patients with heart failure Decreased (<8 cm/s septal, <10 cm/s lateral, Delayed LV relaxation or <9 cm/s average) High LV filling pressure Normal LV filling pressure Intermediate (8–15) Grey zone (additional parameters necessary) Mitral inflow E/A ratiob ‘Restrictive' (>2) High LV filling pressure ‘Impaired relaxation' (<1) Delayed LV relaxation Normal LV filling pressure Inconclusive (may be ‘pseudonormal') Mitral inflow during Valsalva manoeuvre Change of the ‘pseudonormal' to the ‘impaired High LV filling pressure (unmasked through Valsalva)relaxation' pattern (with a decrease in E/A ratio ≥0.5) (A pulm–A mitral) duration High LV filling pressure A pulm–A mitral ¼ time difference between pulmonary vein flow A-wave duration and mitral flow A-wave duration; E/A ¼ ratio of early to late diastolic mitral inflow waves; e' ¼ early diastolic velocity of mitral annulus; E/e' ¼ ratio of the mitral inflow E wave to the tissue Doppler e' wave; HF ¼ heart failure; LV ¼ left ventricular.
aDifferent cut-off points exist in different consensus document,for the cut-off points mentioned in this table both septal and average e' may be used.
bHighly variable and unsuitable for diagnosis on its own; largely depending on loading conditions; age-corrected normal values (this may be less of a concern with newer macrocyclic gadolin- also be carried out before angiography as some observational ium chelates).
data show that coronary angiography may be of little, if any,benefit and may confer considerable risk, in the absence of signifi- 4.5 Single-photon emission computed cant viability. In cases where ischaemia information is lacking, frac- tomography and radionuclide tional flow reserve gives information about the haemodynamic relevance of lesions.
Coronary angiography may be required, urgently, in selected Single-photon emission computed tomography (SPECT) may be patients with acute HF (AHF) (shock or acute pulmonary useful in assessing ischaemia and viability if CAD is suspected, oedema), particularly those with an associated acute coronary syn- and provides prognostic as well as diagnostic information drome (see Section 12.7.1 and revascularization ). Cor- (Table Gated SPECT can also yield information on ventricular onary angiography may also be indicated in patients with valve volumes and function, but exposes the patient to ionizing radiation.
disease when surgical correction is planned.
4.6 Positron emission tomography 4.8 Cardiac computed tomography The main use of CT in patients with HF is a non-invasive means to Positron emission tomography (PET) [alone or with computed visualize the coronary anatomyThe risk vs. benefit of this pro- tomography (CT)] may be used to assess ischaemia and viability, cedure should be considered as discussed above, under coronary but the flow tracers (N-13 ammonia or O-15 water) require an angiography (Section 4.7).
on-site cyclotrRubidium is an alternative tracer for is-chaemia testing with PET, which can be produced locally at rela-tively low cost (Table Lack of availability, radiation exposure, 5. Other investigations and cost are the main limitations.
5.1 Cardiac catheterization and 4.7 Coronary angiography endomyocardial biopsy Coronary angiography should be considered in patients with angina In patients with suspected constrictive or restrictive cardiomyop- pectoris or a history of cardiac arrest if the patient is otherwise athy, cardiac catheterization used in combination with other non- suitable for coronary revascularization. Angiography should also invasive imaging techniques may help to establish the correct diag- be considered in patients with evidence of reversible myocardial nosis (see Table ). In patients with suspected myocarditis and infil- ischaemia on non-invasive testing, especially if the EF is reduced trative diseases (e.g. amyloidosis, see Table endomyocardial (because coronary artery bypass surgery may be beneficial) biopsy may be needed to confirm the diagnosis. The use of this (Section 13). Non-invasive assessment of myocardial viability may procedure is described in detail in other 5.2 Exercise testing hospitalization is important for patients and healthcare systems.
Exercise testing allows objective evaluation of exercise capacity Reductions in mortality and hospital admission rates both reflect and exertional symptoms, such as dyspnoea and fatigue.The the ability of effective treatments to slow or prevent progressive 6-min walk test and a variety of treadmill and bicycle protocols worsening of HF. This is often accompanied by reverse LV remod- are available. Gas exchange analysis helps differentiate between elling and a reduction in circulating natriuretic peptide cardiac and respiratory causes of dyspnoea, shows whether the an- aerobic threshold has been reached, and provides prognostic infor- The relief of symptoms, improvement in quality of life, and in- mation (peak oxygen consumption is often measured as part of the crease in functional capacity are also of the utmost importance assessment of candidates for heart transplantation). A normal ex- to patients, but they have not been the primary outcome in ercise capacity in a patient not receiving treatment effectively most This is in part because they are difficult to measure excludes the diagnosis of symptomatic HF, although it must be and partly because some treatments previously shown to remembered that there is a poor correlation between exercise improve these outcomes also decreased However, capacity and resting haemodynamic measures, including EF.
effective pharmacological therapies and CRT improve theseoutcomes, as well as mortality and hospitalization.
5.3 Genetic testing Figure shows a treatment strategy for the use of drugs (and devices) in patients with HF-REF; the recommendations for each The emerging role of genetic testing in ‘idiopathic' dilated and treatment are summarized below. Three neurohumoral antago- hypertrophic cardiomyopathy is described in detail elsewhere.
nists—an ACE inhibitor [or angiotensin receptor blocker (ARB)], Currently this is recommended in patients with dilated cardiomy- a beta-blocker, and an MRA—are fundamentally important in opathy and AV block or a family history of premature unexpected modifying the course of systolic HF and should at least be consid- sudden death, as a prophylactic implantable cardioverter- ered in every patient. They are commonly used in conjunction with defibrillator (ICD) may be indicated.
a diuretic given to relieve the symptoms and signs of congestion.
5.4 Ambulatory electrocardiographic The following text summarizes the evidence supporting therecommendations in this section, in Web Tables 11–13 and in Figure The recommended doses of these disease-modifying med- Ambulatory ECG monitoring is valuable in the assessment of ications are given in Table The recommendations given in patients with symptoms suggestive of an arrhythmia or bradycardia Section 7.4 summarize drugs that should be avoided in patients (e.g. palpitations or syncope) and in monitoring ventricular rate with HF-REF.
control in patients with AF. It is useful for identifying the type, fre-quency, and duration of atrial and ventricular arrhythmias, silentepisodes of ischaemia and bradycardia, and conduction distur- 7.2 Treatments recommended in bances, which may cause or exacerbate HF.
potentially all patients with systolic heart 7.2.1 Angiotensin-converting enzyme inhibitors andbeta-blockers Many variables provide prognostic information (Web Table 10), al- The pivotal trials with beta-blockers were conducted in patients though most of this can be obtained from readily available data with continuing symptoms and a persistently low EF, despite treat- such as age, aetiology, NYHA class, EF, key co-morbidities (renal ment with an ACE inhibitor and, in most cases, a diuretic. Despite dysfunction, diabetes, anaemia, hyperuricaemia), and plasma natri- this, there is consensus that these treatments are complementary uretic peptide concentrat–Clearly these variables change and that a beta-blocker and an ACE inhibitor should both be over time, as does prognosis. Assessment of prognosis is particu- started as soon as possible after diagnosis of HF-REF. This is in larly important when counselling patients about devices and part because ACE inhibitors have a modest effect on LV remodel- surgery (including transplantation) and in planning end-of-life care ling whereas beta-blockers often lead to a substantial improvement with patients, their family, and caregivers.
in EF. Furthermore, beta-blockers are anti-ischaemic, are probablymore effective in reducing the risk of sudden cardiac death, and 7. Pharmacological treatment of lead to a striking and early reduction in overall mortality.
heart failure with reduced ejection Key evidence supporting the use of angiotensing-converting enzyme fraction (systolic heart failure) 7.1 Objectives in the management of † Two key randomized controlled trials [Cooperative North Scandinavian Enalapril Survival Study (COand Studies of Left Ventricular Dysfunction (SOLVD)-Treatment] The goals of treatment in patients with established HF are to assigned #2800 patients with mild to severely symptomatic relieve symptoms and signs (e.g. oedema), prevent hospital admis- HF to placebo or enalapril. Most were also treated with a diur- sion, and improve survival. Although the focus of clinical trials was etic and digoxin, but ,10% of patients in each trial were treated previously mortality, it is now recognized that preventing HF with a beta-blocker. In CONSENSUS, which enrolled patients Diuretics to relieve symptoms/signs of congestiona
ACE inhibitor (or ARB if not tolerated)b
ADD a beta-blockerb
Still NYHA class II–IV? ADD a MR antagonist b,d
Still NYHA class II–IV? Sinus rhythm and HR 70 beats/min? Still NYHA class II–IV and LVEF 35%? QRS duration 120 ms? Still NYHA class II–IV? No further specific treatmentc Continue in disease-management programme Consider digoxinh and/or H-ISDN i If end stage, consider LVAD and/or transplantation ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CRT-D = cardiac resynchronization therapy defibrillator; CRT-P = cardiac resynchronization therapy pacemaker; H-ISDN = hydralazine and isosorbide dinitrate; HR = heart rate; ICD = implantable cardioverter-defibrillator; LBBB = left bundle branch block; LVAD = left ventricular assist device; LVEF = left ventricular ejection fraction; MR antagonist = mineralocorticoid receptor antagonist; NYHA = New York Heart Association. a Diuretics may be used as needed to relieve the signs and symptoms of congestion (see Section 7.5) but they have not been shown to reduce hospitalization or death.
b Should be titrated to evidence-based dose or maximum tolerated dose below the evidence-based dose.
c Asymptomatic patients with an LVEF ≤35% and a history of myocardial infarction should be considered for an ICD.
d If mineralocorticoid receptor antagonist not tolerated, an ARB may be added to an ACE inhibitor as an alternative.
e European Medicines Agency has approved ivabradine for use in patients with a heart rate ≥75 b.p.m. May also be considered in patients with a contraindication to a beta-blocker or beta-blocker intolerance.
f See Section 9.2 for details—indication differs according to heart rhythm, NYHA class, QRS duration, QRS morphology and LVEF.
g Not indicated in NYHA class IV.
h Digoxin may be used earlier to control the ventricular rate in patients with atrial fibrillation—usually in conjunction with a beta-blocker.
i The combination of hydralazine and isosorbide dinitrate may also be considered earlier in patients unable to tolerate an ACE inhibitor or an ARB. Figure 2 Treatment options for patients with chronic symptomatic systolic heart failure (NYHA functional class II–IV).
HF were randomized to low- or high-dose lisinopril. There Pharmacological treatments indicated in potentially all was an RRR of 15% in the risk of death or HF hospitalization patients with symptomatic (NYHA functional class II– in the high-dose lisinopril group compared with the low-dose IV) systolic heart failure lisinopril group.
† Additional support for the use of ACE inhibitors comes from an RCT in patients with a low EF but no symptoms of HF (‘asymp- An ACE inhibitor is tomatic LV systolic dysfunction') and three large (5966 patients recommended, in addition to in total) placebo-controlled, randomized, outcome trials in a beta-blocker, for all patients patients with HF, LV systolic dysfunction, or both after acute with an EF ≤40% to reduce the myocardial infarctionIn the SOLVD-Prevention trial (which risk of HF hospitalization and the risk of premature death.
randomized 4228 patients with asymptomatic LV systolic dys-function), there was a 20% RRR in death or HF hospitalization.
A beta-blocker is recommended, in addition to In the myocardial infarction trials, which used captopril [Survival an ACE inhibitor (or ARB if and Ventricular Enlargement (SAVE)], ramipril [Acute Infarction ACE inhibitor not tolerated), Ramipril Efficacy (AIRE)], and trandolapril [TRAndolapril for all patients with an EF Cardiac Evaluation (TRACE)], there was a 26% RRR in death ≤40% to reduce the risk of HF hospitalization and the risk of and a 27% RRR in death or HF hospitalization.
premature death.
† ACE inhibitors occasionally cause worsening of renal function, hyperkalaemia, symptomatic hypotension, cough, and, rarely, An MRA is recommended for all patients with persisting angioedema. An ACE inhibitor should only be used in patients symptoms (NYHA class with adequate renal function (creatinine ≤221 mmol/L or II–IV) and an EF ≤35%, despite treatment with an ACE ≤2.5 mg/dL or eGFR ≥30 mL/min/1.73 mand a normal inhibitor (or an ARB if an ACE serum potassium level (see Web Table 11).
inhibitor is not tolerated) and a beta-blocker, to reduce the Practical guidance on how to use ACE inhibitors is given in Web risk of HF hospitalization and the risk of premature death.
Key evidence supporting the use of beta-blockers ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; EF ¼ ejection fraction; HF ¼ heart failure; MRA ¼ mineralocorticoid receptor † More RCTs have been undertaken with beta-blockers than with antagonist; NYHA ¼ New York Heart Association.
ACE inhibitors in patients with HF.
aClass of recommendation.
b † Three key trials [Cardiac Insufficiency Bisoprolol Study II (CIBIS Level of evidence.
II), Carvedilol Prospective Randomized Cumulative Survival(COPERNICUS), and Metoprolol CR/XL Randomised Interven-tion Trial in Congestive Heart Failure (MERIT-HF)] randomized with severe HF, 53% of patients were treated with nearly 9000 patients with mild to severely symptomatic HF to placebo or a beta-blocker (bisoprolol, carvedilol, or metoprolol † Both of these two RCTs showed that ACE inhibitor treatment succinate CR/XL).–More than 90% of the patients were on reduced mortality [relative risk reduction (RRR) 27% in CON- an ACE inhibitor or ARB.
SENSUS and 16% in SOLVD-Treatment]. In SOLVD- † Each of these three trials showed that beta-blocker treatment Treatment there was also an RRR of 26% in HF hospitaliza- reduced mortality (RRR #34% in each trial) and HF hospitaliza- tion. These benefits were additional to those gained with con- tion (RRR 28–36%) within #1 year of starting treatment. There ventional treatment at that time (i.e. a diuretic, digoxin, and was also an also an improvement in self-reported patient well- being in COPERNICUS and MERIT-HF. These benefits were † The absolute risk reduction (ARR) in mortality in patients with additional to those gained with conventional treatment, includ- mild or moderate HF (SOLVD-Treatment) was 4.5%, equating ing an ACE inhibitor.
to a number needed to treat (NNT) of 22 to postpone one † The ARR in mortality (after 1 year of treatment) in patients with death (over an average of 41 months). The equivalent figures mild to moderate HF (CIBIS II and MERIT-HF combined) was for severe HF (CONSENSUS) were 14.6% for ARR and 7 for 4.3%, equating to an NNT (for 1 year to postpone NNT (over an average of 6 months).
one death) of 23. The equivalent figures for severe HF † These findings are supported by a meta-analysis of smaller, (COPERNICUS) were ARR 7.1% and NNT 14.
short-term, placebo-controlled randomized controlled trials † These findings are supported by another placebo-controlled (RCTs), which showed a clear reduction in mortality within RCT [Study of Effects of Nebivolol Intervention on Outcomes only 3 These RCTs also showed that ACE inhibitors and Rehospitalization in Seniors With Heart Failure improve symptoms, exercise tolerance, quality of life, and exer- (SENIORS)] in 2128 elderly (≥70 years) patients, 36% of cise performance.
whom had an LVEF .35%. Treatment with nebivolol resulted † In the Assessment of Treatment with Lisinopril And Survival in an RRR of 14% in the primary composite endpoint of death (ATLAS) 3164 patients with mainly moderate to severe or cardiovascular hospitalization, but did not reduce mortality.
† The findings of these trials were also supported by an earlier programme of studies with carvedilol (US carvedilol studies), a Table 14 Evidence-based doses of disease-modifying meta-analysis of other small beta-blocker trials, and a placebo- drugs used in key randomized trials in heart failure controlled RCT in 1959 patients with an LVEF (or after myocardial infarction) acute myocardial infarction in which the RRR in mortality withcarvedilol was 23% during a mean follow-up of 1.3 Starting dose (mg) † One large RCT [Beta-Blocker Evaluation of Survival Trial (BEST)] with bucindolol, a beta-blocker with partial agonist properties, did not show a significant reduction in mortality, 10–20 b.i.d.
though its findings were generally consistent with the above 2.5–5.0 o.d.
20–35 o.d.
† Another RCT [Carvedilol or Metoprolol European Trial (COMET)] showed that carvedilol increased survival compared with short-acting metoprolol tartrate (different from the long- acting succinate formulation used in 3.125 b.i.d.
25–50 b.i.d.
† Beta-blockers should usually be initiated in stable patients, and Metoprolol succinate (CR/XL) 12.5/25 o.d.
used only with caution in recently decompensated patients (and only initiated in hospital in these patients). Recently de- compensated patients were, however, safely initiated on beta- blocker treatment in COPERNICUS.
† Continuation of beta-blocker treatment during an episode of decompensation has been shown in an RCT to be safe, although dose reduction may be necessary.Temporary discontinu- ation is advised in shocked or severely hypoperfused patients.
25–50 o.d.
Re-institution of treatment should be attempted beforedischarge.
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; Practical guidance on how to use beta-blockers is given in Web b.i.d. ¼ bis in die (twice daily); MRA ¼ mineralocorticoid receptor antagonist; o.d. ¼ omni die (once every day); t.i.d. ¼ ter in die (three times daily).
aIndicates an ACE inhibitor where the dosing target is derived frompost-myocardial infarction trials.
bIndicates drugs where a higher dose has been shown to reduce morbidity– 7.2.2 Mineralocorticoid/aldosterone receptor antagonists mortality compared with a lower dose of the same drug, but there is no Spironolactone and eplerenone block receptors that bind aldoster- substantive placebo-controlled randomized controlled trial and the optimum dose one and other corticosteroids, and are best characterized as is uncertain.
cIndicates a treatment not shown to reduce cardiovascular or all-cause mortality in MRAs. Although patients in the Eplerenone in Mild Patients Hospi- patients with heart failure or after acute mycocardial infarction (or shown to be talization and Survival Study in Heart Failure (EMPHASIS-HF) non-inferior to a treatment that does).
were required to have additional features elevating risk (recentcardiovascular hospitalization or elevated natriuretic peptide con-centration), the benefits of MRAs probably extend to all patientswith systolic HF, particularly as the two RCTs in chronic HF are to those gained with conventional treatment, including an supported by an additional RCT in patients with acute myocardial ACE inhibitor.
† The ARR in mortality (after a mean of 2 years of treatment) in patients with severe HF was 11.4%, equating to an NNT (for 2 Key evidence supporting the use of mineralocorticoid receptor years to postpone one death) of 9.
† More recently the EMPHASIS-HF trialwas undertaken in † The Randomized Aldactone Evaluation Study (RALES) trial patients with systolic HF and mild symptoms.
was undertaken with the MRA spironolactone in patients with † In EMPHASIS-HF, 2737 patients aged ≥55 years with NYHA functional class II symptoms and an EF ≤30% (≤35% if the † In RALES, 1663 patients with an EF ≤35% and in NYHA func- QRS duration was .130 ms) were enrolled. Patients had to tional class III (having been in class IV within the past 6 have either experienced a cardiovascular hospitalization within months) were randomized to placebo or spironolactone 25– the previous 6 months or have an elevated plasma natriuretic 50 mg once daily added to conventional treatment. At the peptide concentration and be treated with an ACE inhibitor, time this trial was conducted, beta-blockers were not widely ARB, or both, and a beta-blocker.
used to treat HF, and only 11% were treated with a † Treatment with eplerenone (up to 50 mg once daily) led to an RRR of 37% in cardiovascular death or HF hospitalization.
† Treatment with spironolactone led to an RRR in death of 30% Reductions were also seen in rates of death from any cause and an RRR in HF hospitalization of 35% within an average of (24%), cardiovascular death (24%), hospitalization for any 2 years of starting treatment. These benefits were additional reason (23%), and HF hospitalization (42%). These benefits were obtained within an average of 21 months of starting treat- HF or diabetes.Patients were randomized to placebo or ment and were additional to those gained with conventional eplerenone 25–50 mg once daily added to conventional treat- treatment, including an ACE inhibitor and beta-blocker.
ment including an ACE inhibitor/ARB (87%) and a beta-blocker † The ARR in the primary composite mortality–morbidity end- (75%). Treatment with eplerenone led to an RRR in death of point in patients with mild symptoms was 7.7%, equating to an NNT (for an average of 21 months to postpone one † Spironolactone and eplerenone can cause hyperkalaemia and event) of 13. The ARR in mortality was 3%, equating to an worsening renal function, which were uncommon in the RCTs, but may occur more frequently in ordinary clinical prac- † These findings are supported by another RCT [Eplerenone tice, especially in the elderly. Both should only be used in Post-Acute Myocardial Infarction Heart Failure Efficacy and Sur- patients with adequate renal function and a normal serum po- vival Study (EPHESUS)], which enrolled 6632 patients 3–14 tassium concentration; if either is used, serial monitoring of days after acute myocardial infarction with an EF ≤40% and serum electrolytes and renal function is mandatory.
Other treatments with less-certain benefits in patients with symptomatic (NYHA class II–IV) systolic heart failure Recommended to reduce the risk of HF hospitalization and the risk of premature death in patients with an EF ≤40% and unable to tolerate an ACE inhibitor because of cough (patients should also receive a beta-blocker and an MRA).
Recommended to reduce the risk of HF hospitalization in patients with an EF ≤40% and persisting symptoms (NYHA class II–IV) despite treatment with an ACE inhibitor and a beta-blocker who are unable to tolerate an MRA.d Should be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤35%, a heart rate remaining ≥70 b.p.m., and persisting symptoms (NYHA class II–IV) despite treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose below that), ACE inhibitor (or ARB), and an MRA (or ARB).e May be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤35% and a heart rate ≥70 b.p.m. who are unable to tolerate a beta-blocker. Patients should also receive an ACE inhibitor (or ARB) and an MRA (or ARB).e May be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤45% who are unable to tolerate a beta-blocker (ivabradine is an alternative in patients with a heart rate ≥70 b.p.m.). Patients should also receive an ACE inhibitor (or ARB) and an MRA (or ARB).
May be considered to reduce the risk of HF hospitalization in patients with an EF ≤45% and persisting symptoms (NYHA class II–IV) despite treatment with a beta-blocker, ACE inhibitor (or ARB), and an MRA (or ARB).
May be considered as an alternative to an ACE inhibitor or ARB, if neither is tolerated, to reduce the risk of HF hospitalization and risk of premature death in patients with an EF ≤45% and dilated LV (or EF ≤35%). Patients should also receive a beta-blocker and an MRA.
May be considered to reduce the risk of HF hospitalization and risk of premature death in patients in patients with an EF ≤45% and dilated LV (or EF ≤35%) and persisting symptoms (NYHA class II–IV) despite treatment with a beta-blocker, ACE inhibitor (or ARB), and an MRA (or ARB).
An n-3 PUFAf preparation may be considered to reduce the risk of death and the risk of
cardiovascular hospitalization in patients treated with an ACE inhibitor (or ARB),

beta-blocker, and an MRA (or ARB).
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; CHARM-Added ¼ Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity-Added; EF ¼ ejection fraction; HF ¼ heart failure; H-ISDN ¼ hydralazine and isosorbide dinitrate; MRA ¼ mineralocorticoid receptor antagonist; NYHA ¼ New York Heart Association; PUFA ¼ polyunsaturated fatty acid.
aClass of recommendation.
bLevel of evidence.
cReferences.
dIn the CHARM-Added trial, candesartan also reduced cardiovascular mortality.
eEuropean Medecines Agency has approved ivabradine for use in patients with a heart rate ≥75 b.p.m.
fPreparation studied in cited trial; the GISSI-HF trial had no EF limit.
† Spironolactone can also cause breast discomfort and enlargement of cardiovascular or HF hospitalization of 23% (ARR 7%, NNT in men (10% compared with 1% on placebo, in RALE); this 14, over 34 months of follow-up).Valsartan was also benefi- side effect is infrequent with eplerenone.
cial in the subset of patients in Val-HeFT not treated with anACE Practical guidance on how to use MRAs is given in Web † Another trial [Evaluation of Losartan In The Elderly (ELITE) II] failed to show that losartan 50 mg daily was as effectiveas captopril 50 mg three times daily. However, a subsequent 7.2.3 Other treatments recommended in selected patientswith systolic heart failure RCT [Heart failure Endpoint evaluation of Angiotensin II Antag-onist Losartan showed that 150 mg daily of losar- This section describes other treatments that are valuable in tan was superior to 50 mg daily, supporting the similar findings patients with systolic HF. They have not, however, been shown of the Assessment of Treatment with Lisinopril And Survival clearly to reduce all-cause mortality [or in the case of hydralazine (ATLAS) trial with the ACE inhibitor lisinopril—see above. In and isosorbide dinitrate (H-ISDN), this has only been clearly HEAAL there was an RRR of 10% in death or HF hospitalization shown in African-Americans]. Most of these drugs have shown in the high-dose losartan group (P convincing benefits in terms of symptom reduction, HF hospitaliza- ¼ 0.027) over a median follow-up of 4.7 years. The results from these two trials, tion, or both, and are useful alternative or additional treatments in Aand HEAAL,indicate that more benefit is obtained patients with HF.
from using higher doses of renin–angiotensin system blockersand underscore the importance of attaining, if possible, the 7.2.4 Angiotensin receptor blockers target doses proven to be of benefit in the key RCTs.
ARBs remain recommended as an alternative in patients intolerantof an ACE However, ARBs are no longer the first- † Additional support for the use of ARBs comes from the Valsartan In Acute myocardial infarction trial (VALIANT),an RCT in choice recommendation in patients with HF and an EF ≤40% who which 14 703 patients with HF, LV systolic dysfunction, or both remain symptomatic despite optimal treatment with an ACE inhibi- after acute myocardial infarction were assigned to treatment tor and beta-blocker. This is because in EMPHASIS-HF, eplerenone with captopril, valsartan, or the combination. Valsartan was led to a larger reduction in morbidity–mortality than seen in the found to be non-inferior to captopril. In a similar trial [Optimal ARB ‘add-on' trials discussed below, and because in both the Ran- Therapy in Myocardial infarction with the Angiotensin II Antagon- domized Aldactone Evaluation Study (RALES) and EMPHASIS-HF, ist Losartan (OPTIMAAL)], losartan 50 mg once daily did not MRA treatment reduced all-cause mortality, whereas ARB ‘add-on' demonstrate non-inferiority when compared with captopril.
treatment did not.
Practical guidance on how to use an ARB is given in Web † Two key placebo-controlled RCTs [Valsartan Heart Failure Trial (Val-HeFT) and CHARM-Added] randomized #7600 patients with mild to severely symptomatic HF to placebo or an ARB (val- Ivabradine is a drug that inhibits the If channel in the sinus node. Its sartan and candesartan), added to an ACE inhibitor (in 93% of only known pharmacological effect is to slow the heart rate in patients in Val-HeFT and all patients in CHARM-Added) patients in sinus rhythm (it does not slow the ventricular rate in AF).
In addition, 35% of patients in Val-HeFT and 55% inCHARM-Added were treated with a beta-blocker.
† Each of these two trials showed that ARB treatment reduced the risk of HF hospitalization (RRR 24% in Val-HeFT and 17% in † The Systolic Heart failure treatment with the If inhibitor ivabra- CHARM-Added) but not all-cause hospitalization. There was a dine Trial (SHIFT) enrolled 6588 patients in NYHA functional 16% RRR in the risk of cardiovascular death with candesartan in class II–IV, sinus rhythm with a rate of ≥70 b.p.m., and an EF CHARM-Added. These benefits were additional to those gained ≤35%.Patients were also required to have had a HF hospi- with conventional treatment, including a diuretic, digoxin, an ACE talization in the previous 12 months. They were randomized inhibitor, and a beta-blocker (but few patients were taking an MRA).
to ivabradine (up-titrated to a maximal dosage of 7.5 mg twice † The ARR in the primary composite mortality–morbidity end- daily) or placebo, added to a diuretic (in 84%), digoxin (22%), point in patients with mild to moderate HF was 4.4%, equating an ACE inhibitor (79%), an ARB (14%), a beta-blocker (90%), to an NNT (for an average of 41 months to postpone one and an MRA (60%). Only 26% of patients were, however, on event) of 23 in CHARM-Added. The equivalent figures for full-dose beta-blocker. The median follow-up was 23 months.
Val-HeFT were ARR 3.3% and NNT 30 (over an average of The RRR in the primary composite outcome of cardiovascular death or HF hospitalization was 18% (P , 0.0001); the reduc- † The CHARM trials and Val-HeFT also showed that ARBs tion in cardiovascular death (or all-cause death) was not signifi- improve symptoms and quality of life. Other trials showed cant, but the RRR in HF hospitalization was 26%. The ARR in the that these agents improve exercise capacity.
primary composite mortality–morbidity endpoint was 4.2%, † CHARM-Alternative was a placebo-controlled RCT with cande- equating to an NNT (for an average of 23 months to postpone sartan in 2028 patients with an LVEF ≤40%, intolerant of an one event) of 24. Ivabradine also improved LV function and ACE inhibitor. Treatment with candesartan resulted in an RRR quality of life.
† Five per cent of patients on ivabradine had symptomatic brady- early termination (for mortality benefit) have left uncertainty cardia compared with 1% of the placebo group (P , 0.0001).
about the real value of this combination therapy, especially in non- Visual side effects (phosphenes) were reported by 3% of black patients.
patients on ivabradine and 1% on placebo (P , 0.0001).
† Additional safety evidence for ivabradine comes from the MorBidity-mortality EvAlUaTion of the If inhibitor ivabradinein patients with coronary disease and left ventricULar dysfunc- † There are two placebo-controlled (V-HeFT-I and A-HeFT) tion (BEAUTIFUL) trial, an RCT in which 10 917 patients with RCTs and one active-controlled (V-HeFT-II) RCT with coronary heart disease and an EF ,40% were assigned to treat- ment with ivabradine 7.5 mg twice daily or placebo and followed † In V-HeFT-I, 642 men were randomized to placebo, prazosin, or for a median of 19 months. Although ivabradine did not reduce H-ISDN added to a diuretic and digoxin.No patients were the primary outcome of cardiovascular death, myocardial infarc- treated with a beta-blocker or an ACE inhibitor (and the use tion, or HF hospitalization, it was well tolera of MRAs was not documented). Mortality rates were not differ-ent in the placebo and prazosin groups. With H-ISDN, therewas a trend to a reduction in all-cause mortality during the 7.2.6 Digoxin and other digitalis glycosides overall period of follow-up (mean 2.3 years): RRR 22%; ARR In patients with symptomatic HF and AF, digoxin may be used to 5.3%; NNT 19. H-ISDN increased exercise capacity and LVEF slow a rapid ventricular rate, although other treatments are pre- compared with placebo.
ferred (see Section 10.1).
† In A-HeFT, 1050 African-American men and women in NYHA Digoxin may also be used in patients in sinus rhythm with symp- class III or IV were randomized to placebo or H-ISDN, added tomatic HF and an LVEF ≤40% as recommended below, based on to a diuretic (in 90%), digoxin (60%), an ACE inhibitor (70%), the evidence summarized below.
an ARB (17%), a beta-blocker (74%), and spironolactoneThe initial dose of treatment was 20 mg ISDN/ 37.5 mg hydralazine thrice daily, increasing to a target of40 mg/75 mg thrice daily. The trial was discontinued premature- † A single large morbidity–mortality RCT [Digitalis Investigation ly, after a median follow-up of 10 months, because of a signifi- Group (DIG)] has been undertaken with digoxin in patients cant reduction in mortality (RRR 43%; ARR 4.0%; NNT 25).
with symptomatic HF and a low EF H-ISDN also reduced the risk of HF hospitalization (RRR † In the DIG trial, 6800 patients with an EF ≤45% and in NYHA 33%) and improved quality of life.
functional class II–IV were randomized to placebo or digoxin † In V-HeFT-II, 804 men, mainly in NYHA class II or III, were ran- (0.25 mg once daily), added to a diuretic and an ACE inhibitor.
domized to enalapril or H-ISDN, added to a diuretic and This trial was performed before beta-blockers were widely used No patients were treated with a beta-blocker.
There was a trend in the H-ISDN group to an increase in all- † Treatment with digoxin did not alter all-cause mortality but did cause mortality during the overall period of follow-up (mean lead to an RRR for hospital admission for worsening HF of 28% 2.5 years): relative increase in risk was 28%.
within an average of 3 years of starting treatment. The absolute † The most common adverse effects with H-ISDN in these trials ARR was 7.9%, equating to an NNT (for 3 years to postpone were headache, dizziness/hypotension, and nausea. Arthralgia one patient admission) of 13.
leading to discontinuation or reduction in dose of H-ISDN oc- † These findings are supported by a meta-analysis of smaller trials curred in 5–10% of patients in V-HeFT I and II and a sustained suggesting that digoxin can improve symptoms and prevent increase in antinuclear antibody in 2–3% of patients (but lupus- like syndrome was rare).
† Digoxin can cause atrial and ventricular arrhythmias, particularly in the context of hypokalaemia, and serial monitoring of serumelectrolytes and renal function is mandatory.
7.2.8 Omega-3 polyunsaturated fatty acids † The efficacy and safety of other digitalis glycosides such as digi- The small treatment effect of n-3 polyunsaturated fatty acids toxin have not been studied properly in heart failure.
(PUFAs) in the Gruppo Italiano per lo Studio della Sopravvivenzanell'Infarto miocardico-heart failure (GISSI-HF) trial was onlydetected after covariate adjustment in the statistical analysis and 7.2.7 Combination of hydralazine and isosorbide dinitrate there was no effect on HF hospitalization.The effect of n-3 In one relatively small RCT conducted exclusively in men (and PUFAs after myocardial infarction is uncertain.
before ACE inhibitor or beta-blockers were used to treat HF),this vasodilator combination led to a borderline reduction in mor- tality when compared with placebo.–In a subsequent RCT,the addition of H-ISDN to conventional therapy (ACE inhibitor, † In the GISSI-HF PUFA trial, 6975 patients with NYHA class II–IV beta-blocker, and MRA) reduced morbidity and mortality (and symptoms and an EF ≤40% (or if .40%, HF hospitalization in improved symptoms) in African-Americans with HFThe the previous year) were randomized to placebo or 1 g daily of selected patient population studied, relatively small RCT size, and an n-3 PUFA preparation in addition to standard therapy includ- ing an ACE inhibitor/ARB in 94%, beta-blocker in 65%, and spir- ACE inhibitor/ARB in 94%, beta-blocker in 63% and spironolac- onolactone in The median follow-up was 3.9 years. n-3 tone in 40%. The median follow-up was 3.9 years. The PUFA treatment led to an RRR of 8% in the co-primary com- co-primary endpoints of all-cause mortality and the composite posite outcome of death or cardiovascular hospitalization in of all-cause death or cardiovascular hospitalization were not an adjusted analysis (adjusted P ¼ 0.009). There was no reduc- reduced by rosuvastatin.
tion in HF hospitalization, but there was a 10% RRR in cardio-vascular mortality (adjusted P ¼ 0.045) and 7% RRR incardiovascular hospitalization (adjusted P ¼ 0.026).
7.3.2 Renin inhibitors † These findings are supported by one post-myocardial infarction One direct renin inhibitor (aliskiren) is currently being evaluated in RCT (GISSI-Prev) but not by another (OMEGA two morbidity–mortality RCTs. It is not presently recommended In GISSI-Prevenzione, involving 11 324 patients enrolled after as an alternative to an ACE inhibitor or ARB.
a recent (≤3 months) myocardial infarction, patients receivedplacebo or 1 g daily of n-3 PUFA. n-3 PUFA treatment led to 7.3.3 Oral anticoagulants an RRR of 10% in the primary composite outcome of death, Other than in patients with AF (both HF-REF and HF-PEF), there is myocardial infarction, or stroke (largely driven by a reduction no evidence that an oral anticoagulant reduces mortality–morbid- in cardiovascular death).
ity compared with placebo or aspirin (see Section 10.1).
† OMEGA randomized 3851 patients 3–14 days after acute myo- cardial infarction to placebo or 1 g n-3 PUFA daily for 1 year.
7.4 Treatments not recommended Outcomes did not differ between treatment groups.
(believed to cause harm) † n-3 PUFA preparations differ in composition and the dose may be important.
† The main adverse effects of n-3 PUFAs reported in these trials were nausea and other minor gastrointestinal disturbances.
Treatments (or combinations of treatments) that may 7.3 Treatments not recommended cause harm in patients with symptomatic (NYHA class (unproven benefit) II–IV) systolic heart failure 7.3.1 3-Hydroxy-3-methylglutaryl-coenzyme A reductaseinhibitors (‘statins') Classa Levelb Ref C
Although there is a wealth of robust evidence supporting the value of statins in patients with atherosclerotic (arterial) disease, most should not be used as they cause worsening HF and increase trials excluded patients with HF (because it was uncertain that the risk of HF hospitalization. they would benefitTwo recent trials studied statin treatment Most CCBs (with the exception specifically in patients with chronic HF and did not demonstrate of amlodipine and felodipine) convincing evidence of benefit (although there was little evidence should not be used as they have of harm).Despite the evidence in other areas of cardiovas- a negative inotropic effect and can cause worsening HF. cular medicine, the evidence does not therefore support the initi-ation of statins in most patients with chronic HF.
NSAIDs and COX-2 inhibitors should be avoided if possible as they may cause sodium and water retention, worsening renal function and worsening HF. † The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) and GISSI-HF compared rosuvastatin with placebo The addition of an ARB (or renin inhibitor) to the in patients with symptomatic HF combination of an ACE inhibitor AND † CORONA enrolled 5011 older patients (≥60 years) with symp- a mineralocorticoid antagonist is tomatic HF (NYHA class II–IV) of ischaemic aetiology with an because of the risk of renal EF ≤40%, felt by the investigator not to require cholesterol- dysfunction and hyperkalaemia. lowering therapy. Rosuvastatin did not reduce the primary end-point (cardiovascular death, myocardial infarction, or stroke) or ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; CCB ¼ calcium-channel blocker; COX ¼ cyclo-oxygenase; EF ¼ ejection † The GISSI-HF statin trial enrolled 4574 patients with symptom- fraction; HF ¼ heart failure; NSAID ¼ non-steroidal anti-inflammatory drug; atic HF (NYHA class II–IV) of ischaemic and non-ischaemic aeti- NYHA ¼ New York Heart Association.
aClass of recommendation.
ology. Patients had an EF ≤40% (or if .40%, HF hospitalization bLevel of evidence.
in the previous year) and were randomized to placebo or rosu- vastatin 10 mg daily, in addition to standard therapy including an can be trained to self-adjust their diuretic dose, based on The effects of diuretics on mortality and morbidity have not monitoring of symptoms/signs of congestion and daily weight been studied in patients with HF, unlike ACE inhibitors, beta- blockers, and MRAs (and other treatments). However, diuretics Practical guidance on the use of diuretics is given in Web relieve dyspnoea and oedema and are recommended for this Table 15 and the doses of commonly used diuretics are shown reason in patients with signs and symptoms of congestion, irre- spective of EF.
Loop diuretics produce a more intense and shorter diuresis than thiazides, which cause a more gentle and prolonged diur- Use of potassium-sparing diuretics and potassium supplements esis. Thiazides may be less effective in patients with reducedkidney function. Loop diuretics are usually preferred to thiazides † If a potassium-losing diuretic is used with the combination of an in HF-REF although they act synergistically and the combination ACE inhibitor and an MRA (or ARB), potassium replacement is may be used (usually on a temporary basis) to treat resistant usually not required.
† Serious hyperkalaemia may occur if potassium-sparing diuretics The aim of using diuretics is to achieve and maintain euvolae- or supplements are taken in addition to the combination of an mia (the patient's ‘dry weight') with the lowest achievable dose.
ACE inhibitor (or ARB) and MRA.
This means that the dose must be adjusted, particularly after † The use of all three of an ACE inhibitor, MRA and ARB is not restoration of dry body weight, to avoid the risk of dehydration leading to hypotension and renal dysfunction. This may reducecardiac output in patients with HF-PEF and often needlesslyprevents the use of (or achievement of the target dose of) 8. Pharmacological treatment of other disease-modifying therapies such as ACE inhibitors(or ARBs) and MRAs in patients with HF-REF. Many patients heart failure with ‘preserved' ejection fraction (diastolic heart Table 16 Doses of diuretics commonly used to treat No treatment has yet been shown, convincingly, to reduce morbid- heart failure (with and without a preserved ejection ity and mortality in patients with HF-PEF. Diuretics are used to fraction, chronic and acute) control sodium and water retention and relieve breathlessnessand oedema as in HF-REF. Adequate treatment of hypertension Initial dose (mg) Usual daily dose (mg) and myocardial ischaemia is also considered to be important, as is control of the ventricular rate in patients with AF (see Section 11). Two very small studies (,30 patients each) have shown that the heart rate-limiting calcium-channel blocker (CCB) verap- amil may improve exercise capacity and symptoms in these patients.Rate-limiting CCBs may also be useful for ventricu- lar rate control in patients with AF and in the treatment of hyper- tension and myocardial ischaemia (which is not the case in patients with HF-REF where their negative inotropic action can be danger- ous). Beta-blockers may also be used to control the ventricular rate in patients with HF-PEF and AF.
The drugs that should be avoided in HF-REF (see Section 7.4) should also be avoided in HF-PEF, with the exception of CCBs.
The key mortality–morbidity trials to date are: † The 3023-patient Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Preservedtrial, which showed no reduction in the primary composite end- ACEi ¼ angiontensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor point (cardiovascular death or HF † The 850-patient Perindopril for Elderly People with Chronic Oral or intravenous; dose might need to be adjusted according to volume status/ Heart failure trial (PEP-CHF), which showed no reduction in weight; excessive doses may cause renal impairment and ototoxicity.
bDo not use thiazides if estimated glomerular filtration rate ,30 mL/min, except when prescribed synergistically with loop diuretics.
cIndapamide is a non-thiazide sulfonamide.
dA mineralocorticoid antagonist (MRA) i.e. spironolactone/eplerenone is always † The 4128 patient Irbesartan in heart failure with preserved sys- preferred. Amiloride and triamterene should not be combined with an MRA.
tolic function trial (I-Preserve) which showed no reduction inthe primary composite outcome of death or cardiovascular hospitalization (specifically, HF, myocardial infarction, unstableangina, arrhythmia, or str Recommendations for the use of implantedcardioverter defibrillators in patients with heart failure 9. Non-surgical device treatment of heart failure with reduced ejection fraction (systolic heart An ICD is recommended in a patient with a ventricular arrhythmia causing haemodynamic instability, who This section discusses the use of ICDs and CRT. While no new is expected to survive for >1 year with good functional ICD RCT has completed since publication of the 2008 guidelines, status, to reduce the risk of there have been several important RCTs using CRT that have sudden death.
changed the recommendations (see below). Other technologies including a wearable defibrillator vesand implantable monitors An ICD is recommended in (either ‘stand-alone' or incorporated into other devices) are of re- a patient with symptomatic search interest, but do not yet have enough evidence behind them HF (NYHA class II–III) and an EF ≤35% despite ≥3 months to support guideline recommendations.
of treatment with optimal pharmacological therapy, who is expected to survive for >1 year with good functional status, to reduce the risk of Approximately half of the deaths in patients with HF, especially in those with milder symptoms, occur suddenly and unexpectedly, (i) Ischaemic aetiology and >40 days after acute and many, if not most, of these are related to ventricular arrhyth- myocardial infarction mias (whereas others may be related to bradycardia and asystole).
Prevention of sudden death is therefore an important goal in HF.
(ii) Non-ischaemic aetiology While the key disease-modifying neurohumoral antagonists men-tioned earlier reduce the risk of sudden death, they do not HF ¼ heart failure; ICD ¼ implantable cardioverter defibrillator; abort it. Specific antiarrhythmic drugs do not decrease this risk NYHA ¼ New York Heart Association.
aClass of recommendation.
(and may even increase it).For this reason, ICDs have an im- bLevel of evidence.
portant role to play in reducing the risk of death from ventricular 9.1.1 Secondary prevention of sudden cardiac deathKey evidence † The ARR in mortality with an ICD was 6.9%, equating to an ICDs reduce mortality in survivors of cardiac arrest and in patients NNT (for 45.5 months to postpone one death) of 14.
with sustained symptomatic ventricular arrhythmias. Consequently, † Additional support for the use of ICDs comes from the Multi- an ICD is recommended in such patients, irrespective of EF, with good functional status, a life expectancy of .1 year, and where (MADIT-II),an RCT in which patients with a prior myocar- the intent is to increase dial infarction and an EF ≤30% (59% of which were in NYHAclass II or III) were assigned to receive either conventional 9.1.2 Primary prevention of sudden cardiac death treatment or conventional treatment plus an ICD. Use of an ICD led to a 31% RRR in mortality. Two other RCTs † The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) showed no benefit in patients treated with an ICD early enrolled 2521 patients with non-ischaemic dilated cardiomyop- (≤40 days) after myocardial infarction.This is why athy or ischaemic HF, no prior symptomatic ventricular arrhyth- ICD use in patients with coronary heart disease receives mia, and an EF ≤35% who were in NYHA functional class II or level of evidence A, but only in patients .40 days after III. These patients were randomized to placebo, amiodarone, or acute myocardial infarction.
an ICD, in addition to conventional treatment including an ACE † There is less evidence in patients with non-ischaemic HF, with inhibitor or ARB (96%) and a beta-blocker (69%); MRA use was one moderate sized trial [Defibrillators in Non-ischemic Car- not reported.
diomyopathy Treatment Evaluation (DEFINITE), n ¼ 458] † ICD treatment led to an RRR in death of 23% (P ¼ 0.007) over a showing only a non-significant trend to a reduction in mortality; median follow-up of 45.5 months. This benefit was additional to hence the evidence level of that gained with conventional treatment, including an ACE in- † ICD implantation should be considered only after a sufficient hibitor and a beta-blocker. Amiodarone did not reduce period of optimization of medical therapy (at least 3 months) and only if the EF remains persistently low.
† ICD therapy is not indicated in patients in NYHA class IV with who are more severely symThere is little doubt severe, drug-refractory, symptoms who are not candidates for that patients expected to survive with good functional status CRT, a ventricular assist device, or cardiac transplantation for .1 year should receive CRT if they are in sinus rhythm, (because such patients have a very limited life expectancy and their LVEF is low (≤30%), QRS duration is markedly prolonged are more likely to die from pump failure).
(≥150 ms), and an ECG shows a left bundle branch morphology, † Patients should be counselled as to the purpose of an ICD and irrespective of symptom severity. There is less consensus about the complications related to its use (predominantly inappropri- patients with right bundle branch block or interventricular con- duction delay (based on subgroup analyses) and those in AF † If HF deteriorates, deactivation of a patient's ICD may be con- (because most trials excluded these patients and because a high sidered after appropriate discussion with the patient and ventricular rate will prevent resychronization). Another area of debate is what to do in an HF-REF patient without an indicationfor CRT who needs a conventional pacemakThe possibilitythat patients with a QRS duration of ,120 ms may have ‘mech- 9.2 Cardiac resynchronization therapy anical dyssynchrony' (detectable by imaging) and might benefit Two large RCTs have shown that CRT is of benefit in patients from CRT is another area of research interest but remains to with mild (NYHA class II) symptomsas well as in those Recommendations for the use of CRT where the evidence is strong—patients in sinus rhythm with NYHA functional classIII and ambulatory class IV heart failure and a persistently reduced ejection fraction, despite optimal pharmacologicaltherapy LBBB QRS morphology
CRT-P/CRT-D is recommended in patients in sinus rhythm with a QRS duration of ≥120 ms, LBBB QRS morphology,
and an EF ≤35%, who are expected to survive with good functional status for >1 year, to reduce the risk of HF hospitalization and the risk of premature death.
Non-LBBB QRS morphology
CRT-P/CRT-D should be considered in patients in sinus rhythm with a QRS duration of ≥150 ms, irrespective of QRS
morphology, and an EF ≤35%, who are expected to survive with good functional status for >1 year, to reduce the risk of HF hospitalization and the risk of premature death.
CRT-D ¼ cardiac resynchronization therapy defibrillator; CRT-P ¼ cardiac resynchronization therapy pacemaker; EF ¼ ejection fraction; HF ¼ heart failure; LBBB ¼ left bundle branch block; NYHA ¼ New York Heart Association.
aClass of recommendation.
bLevel of evidence.
cReferences.
Recommendations for the use of CRT where the evidence is strong—patients in sinus rhythm with NYHA functional classII heart failure and a persistently reduced ejection fraction, despite optimal pharmacological therapy LBBB QRS morphology
CRT, preferably CRT-D is recommended in patients in sinus rhythm with a QRS duration of ≥130 ms, LBBB QRS
morphology, and an EF ≤30%, who are expected to survive for >1 year with good functional status, to reduce the risk of HF hospitalization and the risk of premature death.
Non-LBBB QRS morphology
CRT, preferably CRT-D should be considered in patients in sinus rhythm with a QRS duration of ≥150 ms, irrespective
of QRS morphology, and an EF ≤30%, who are expected to survive for >1 year with good functional status, to reduce the risk of HF hospitalization and the risk of premature death.
CRT-D ¼ cardiac resynchronization therapy defibrillator; EF ¼ ejection fraction; HF ¼ heart failure; LBBB ¼ left bundle branch block; NYHA ¼ New York Heart Association.
aClass of recommendation.
bLevel of evidence.
cReferences.
9.2.1 Recommendations for cardiac resynchronization † Each of these two trials showed that CRT reduced the risk of therapy where the evidence is certain the primary composite endpoint of death or HF hospitalization Key evidence supporting the use of cardiac resynchronization therapy (HF event in MADIT-CRT) (RRR of 34% in MADIT-CRT and Moderate to severely symptomatic heart failure 25% in RAFT). There was a 25% reduction in all-cause mortalityin RAFT (P ¼ 0.003), but mortality was not reduced in † Two key placebo-controlled RCTs [Comparison of Medical MADIT-CRT. These benefits were additional to those gained Therapy, Pacing, and Defibrillation in Heart Failure (COMPAN- with conventional treatment, including a diuretic, digoxin, an ION) and Cardiac Resynchronization in Heart Failure Study ACE inhibitor, a beta-blocker, an MRA, and an ICD.
(CARE-HF)] randomized 2333 patients with moderate to se- † The ARR in the primary composite mortality–morbidity end- verely symptomatic HF (NYHA class III or IV) to either point in MADIT-CRT was 8.1%, equating to an NNT (for an optimal medical therapy or optimal medical therapy plus average of 2.4 years to postpone one event) of 12. The equiva- CRTPatients in COMPANION were required to be in lent figures for RAFT were ARR 7.1% and NNT 14 (over an sinus rhythm, to have an EF ≤35% and a QRS duration of average of 40 months).
at least 120 ms, and a HF hospitalization or equivalent in the † These trials also showed that CRT improves symptoms, quality preceding year. Patients in CARE-HF were required to be in of life, and ventricular function. Other trials showed that these sinus rhythm and to have an EF ≤35%, a QRS duration agents improve exercise capacity.
≥120 ms (if the QRS duration was 120–149 ms other echo- † Both MADIT-CRT and RAFT showed a significant treatment-by- cardiographic criteria for dyssynchrony had to be met), and subgroup interaction whereby QRS duration modified the treat- an LV end-diastolic dimension of at least 30 mm (indexed to ment effect (CRT appeared more effective in patients with a QRS ≥150 ms) and patients with LBBB also seemed to obtain more † Each of these two trials showed that CRT reduced the risk of benefit than those with right bundle branch block or an interven- death from any cause and hospital admission for worsening tricular conduction defect (these groups overlap considerably, as HF [RRR in death of 24% with a CRT-pacemaker (CRT-P) patients with LBBB are more likely to have a QRS duration and of 36% with CRT-defibrillator (CRT-D) in COMPANION ≥150 ms). These findings are supported by echocardiographic and of 36% with CRT-P in CARE-HF]. In CARE-HF, the RRR analyseFor these reasons, in patients with milder symptoms, in HF hospitalization with CRT-P was 52%. These benefits CRT is recommended only in those with either a QRS duration were additional to those gained with conventional treatment, in- ≥150 ms or ≥130 ms plus an LBBB pattern.
cluding a diuretic, digoxin, an ACE inhibitor, a beta-blocker, andan MRA.
9.2.2 Recommendations for cardiac resynchronization † The ARR with CRT-D in the composite outcome of cardiovas- therapy where the evidence is uncertain cular death or cardiovascular hospitalization in COMPANION Two commonly encountered clinical situations where there is little was 8.6%, equating to an NNT (over a median duration of robust evidence for (or against) CRT are AF and when a patient follow-up of #16 months) to postpone one event of 12. The with a reduced EF has an indication for conventional pacing and corresponding figures for CRT-P in CARE-HF (over a mean no other indication for CRT.
follow-up of 29 months) were an ARR of 16.6% and an NNTof 6.
Atrial fibrillation † These trials also showed that CRT improves symptoms, quality One small, single-blind study [Multisite Stimulation in Cardiomyop- of life, and ventricular function. Other trials showed that these athies (MUSTIC)] included 59 HF-REF patients with persistent/per- agents improve exercise capacity.
manent AF, a slow ventricular rate necessitating permanent † Because these severely symptomatic patients have much to gain ventricular pacing, and a paced QRS duration ≥200 ms.The and because there was no subgroup of patients that clearly did study had a crossover design (3 months conventional pacing vs.
not benefit from CRT, individuals in NYHA functional class III 3 months CRT). There was a high drop-out rate (42%) and and IV have been given the broadest indication for CRT.
there was no difference in the primary endpoint of 6-min walk dis-tance. The key large RCTs of CRT all excluded patients in AF, with Mild to moderately symptomatic HF the exception of RAFTRAFT included 229 patients with per-manent AF or flutter either with a controlled ventricular rate † Two key placebo-controlled RCTs randomized 3618 patients (≤60 b.p.m. at rest and ≤90 b.p.m. during a 6-min walk test) or with mild (MADIT-CRT, 15% NYHA class I and 85% NYHA with planned AV junction ablation. Further analysis did not show class II) to moderately [Resynchronization/Defibrillation for Am- a significant interaction between baseline rhythm and treatment bulatory Heart Failure Trial (RAFT), 80% NYHA class II and 20% effect, but this subgroup represented only a small proportion of NYHA class III] symptomatic HF to either optimal medical the overall population. Other data suggesting that patients with therapy plus an ICD or optimal medical therapy plus a AF (without AV nodal ablation) may benefit from CRT are Patients in MADIT-CRT were required to have limited by being observational in natur an EF ≤30%, a QRS duration ≥130 ms, and to be in sinusrhythm. Patients in RAFT were required to have an EF ≤30% Patients with an indication for conventional pacing and a QRS duration ≥120 ms (13% of enrolled patients had All the major RCTs of CRT, with the exception of RAFT, excluded AF with a well-controlled ventricular rate).
patients with a conventional indication for pacing. RAFT included Recommendations for the use of CRT where the evidence is uncertain—patients with symptomatic HF (NYHAfunctional class II–IV) and a persistently reduced EF despite optimal pharmacological therapy and in AF or with aconventional pacing indication Patients in permanent AF
CRT-P/CRT-D may be considered in patients in NYHA functional class III or ambulatory class IV with a QRS duration ≥120 ms and an EF ≤35%, who are expected to survive with good functional status for >1 year, to reduce the risk of HF worsening if: • The patient requires pacing because of an intrinsically slow ventricular rate • The patient is pacemaker dependent as a result of AV nodal ablation • The patient's ventricular rate is ≤60 b.p.m. at rest and ≤90 b.p.m. on exercise.
Patients with an indication for conventional pacing and no other indication for CRT
In patients who are expected to survive with good functional status for >1 year: • CRT should be considered in those in NYHA functional class III or IV with an EF ≤35%, irrespective of QRS duration, to reduce the risk of worsening of HF • CRT may be considered in those in NYHA functional class II with an EF ≤35%, irrespective of QRS duration, to reduce the risk of worsening of HF.
CRT-D ¼ cardiac resynchronization therapy defibrillator; CRT-P ¼ cardiac resynchronization therapy pacemaker; EF ¼ ejection fraction; HF ¼ heart failure; NYHA ¼ New York Heart Association.
aClass of recommendation.
bLevel of evidence.
cReferences.
135 patients with a paced QRS duration ≥200 ms, a subgroup too standing persistent, or permanent), recognizing the uncertainty small for meaningful analysis.Conventional right ventricular about the actual duration of the episode and about previous un- pacing, however, alters the normal sequence of cardiac activation detected episodes.
in a similar way to LBBB, and experimental and observational The following issues need to be considered in patients with HF data suggest that this may lead to deterioration in LV systolic func- and AF, especially a first episode of AF or paroxysmal AF: tion.It is on this basis that CRT is recommended as an alter-native to conventional right ventricular pacing in patients with † Identification of correctable causes (e.g. hyperthyroidism, elec- HF-REF who have a standard indication for pacing or who trolyte disorders, uncontrolled hypertension, mitral valve require a generator change or revision of a conventional † Identification of potential precipitating factors (e.g. recent surgery, chest infection or exacerbation of chronic pulmonary 10. Arrhythmias, bradycardia, and disease/asthma, acute myocardial ischaemia, alcohol binge) asthis may determine whether a rhythm-control strategy is pre- atrioventricular block in patients ferred to a rate-control strategy.
with heart failure with reduced † Assessment for thromboembolism prophylaxis.
ejection fraction and heart failure 10.1.1 Rate control with preserved ejection fraction An approach to controlling the ventricular rate in patients with HFand AF is shown in Figure . Recommendations for stepwise use of The management of arrhythmias is discussed in other ESC guide- individual treatments in patients with HF-REF are given below.
lines,and this section focuses only on aspects that are par- For rate control in patients with HF-REF, a beta-blocker is pre- ticularly relevant to patients with HF.
ferred over digoxin as the latter does not provide rate controlduring exercise.Furthermore, beta-blockers have favourable 10.1 Atrial fibrillation effects on mortality and morbidity in systolic HF per se (see AF is the most common arrhythmia in HF; it increases the risk of above). The combination of digoxin and a beta-blocker is more ef- thrombo-embolic complications (particularly stroke) and may lead fective than a beta-blocker alone in controlling the ventricular rate to worsening of symptoms. Whether AF is an independent pre- dictor of mortality is less certain, as is whether it can cause systolic In patients with HF-PEF, rate-limiting CCBs (verapamil and diltia- zem) are an effective alternative to a beta-blocker (but their use is AF should be classified and managed according to the current not recommended in patients with HF-REF as their negative ino- AF guidelines (i.e. first episode, paroxysmal, persistent, long- tropic action may further depresses LV systolic Rate–limiting CCBo (or Beta-blocker) Substitute amiodarone (or rate–limiting CCB) Maintenance therapy advice, including advice, including consideration of AV consideration of AV *Thrombo-embolism prophylaxis should also be considered in parallel. †Beta-blocker treatment can cause worsening in acutely decompensated patients with HF-REF (see section on acute heart failure). °Rate-limiting CCBs should be avoided in HF-REF. AV = atrioventricular; CCB = calcium-channel blocker; HF-PEF = heart failure with preserved ejection fraction; HF-REF = heart failure with reduced ejection fraction.
Figure 3 Recommendations for controlling the ventricular rate in patients with heart failure and persistent/permanent atrial fibrillation andno evidence of acute decompensation*.
The combination of digoxin and a rate-limiting CCB is more effect- rate was ,80 b.p.m. at rest and ,110 b.p.m. during a 6-min ive than a CCB alone in controlling the ventricular rate at rest.
Assessment of control of the ventricular rate on exertion In extreme cases, AV node ablation and pacing may be required; requires either ambulatory ECG monitoring or measurement of in this situation in patients with systolic HF, CRT may be consid- the rate during moderate exercise. The optimum ventricular rate ered instead of conventional pacing (see Section 9.2).
in patients with HF and AF is uncertain because the one RCT com-paring strict with lenient rate control included very few patients 10.1.2 Rhythm control with HF.In the Atrial Fibrillation and Congestive Heart Failure In patients with chronic HF, a rhythm-control strategy (including (AF-CHF) study (which showed similar outcomes for a rate- pharmacological or electrical cardioversion) has not been demon- control compared with a rhythm-control strategy) the target strated to be superior to a rate-control strategy in reducing Recommendations for controlling the ventricular rate in patients with symptomatic HF (NYHA functional class II–IV),LV systolic dysfunction, persistent/permanent AF and no evidence of acute decompensation Step 1: A beta-blocker
A beta-blocker is recommended as the preferred first-line treatment to control the ventricular rate because of the associated benefits of this treatment (reducing the risk of hospitalization for worsening HF and reducing the risk of premature death).
Alternative Step 1 treatment
(i) Digoxin is recommended in patients unable to tolerate a beta-blocker (ii) Amiodarone may be considered in patients unable to tolerate a beta-blocker or digoxin.
(iii) AV node ablation and pacing (possibly CRT) may be considered in patients unable to tolerate any of a beta-blocker, digoxin, or amiodarone.
Step 2: Digoxin
Digoxin is recommended as the preferred second drug, in addition to a beta-blocker, to control the ventricular rate in patients with an inadequate response to a beta-blocker.
Alternative Step 2 treatment
(i) Amiodarone may be considered in addition to either a beta-blocker or digoxin (but not both) to control the ventricular rate in patients with an inadequate response and unable to tolerate the combination of both a beta-blocker and digoxin.
(ii) AV node ablation and pacing (possibly CRT) may be considered in patients with an inadequate response to two of three of a beta-blocker, digoxin and amiodarone.
No more than two of three of a beta-blocker, digoxin, and amiodarone (or any other drug suppressing cardiac conduction) should be considered because of the risk of severe bradycardia, third-degree AV block, and asystole.
AF ¼ atrial fibrillation; AV ¼ atrioventricular; EF ¼ ejection fraction; HF ¼ heart failure; LV ¼ left ventricular; NYHA ¼ New York Heart Association.
aClass of recommendation.
bLevel of evidence.
cReferences.
mortality or morbidity.This strategy is probably best reserved (.65), Drugs/alcohol concomitantly (1 point each) (HAS-BLED for patients with a reversible secondary cause of AF (e.g. hyperthy- score) (Table ) is recommended to assess bleeding risk, in roidism) or an obvious precipitant (e.g. recent pneumonia) and in keeping with the 2010 ESC AF A substantial pro- patients who cannot tolerate AF after optimization of rate control portion of patients with HF will have a score ≥3, indicating that and HF therapy. Amiodarone is the only antiarrhythmic that should careful consideration should be given before prescribing an oral be used in patients with systolic HFThe role of catheter ab- anticoagulant and that regular review is needed (and correctable lation as a rhythm control strategy in HF is at present risk factors addressed) if an oral anticoagulant is given.
Some new anticoagulant drugs such as the oral direct thrombin In patients with AHF, emergency cardioversion may be required inhibitors and oral factor Xa inhibitors are contraindicated in to correct profound haemodynamic instability (see Section 12.2).
severe renal impairment (creatinine clearance ,30 mL/min).–This is clearly a concern in many patients with HF and, if 10.1.3 Thrombo-embolism prophylaxis these drugs are used, serial monitoring of renal function is Thrombo-embolism prophylaxis in patients with HF and AF should required. There is no known way to reverse the anticoagulant be based on the Cardiac failure, Hypertension, Age ≥75 action of these new drugs.
(Doubled), Diabetes, Stroke (Doubled)-Vascular disease, Age65–74 and Sex category (Female) (CHA 10.2 Ventricular arrhythmias 2DS2-VASc) score (see Table ), in keeping with the 2010 ESC AF Ventricular arrhythmias are frequent in HF patients, particularly in Most patients with systolic HF will have a risk score consistent those with a dilated left ventricle and reduced EF. Ambulatory with a firm indication for (score ≥2), or preference for, an oral ECG recording detects premature ventricular complexes in virtu- anticoagulant (score ¼ 1), although bleeding risk must also be con- ally all HF patients, and episodes of asymptomatic, non-sustained sidered (see below).
ventricular tachycardia are common.Historical studies have The Hypertension, Abnormal renal/liver function (1 point each), suggested that ‘complex ventricular arrhythmias' (frequent pre- Stroke, Bleeding history or predisposition, Labile INR, Elderly mature ventricular complexes and non-sustained ventricular Recommendations for a rhythm control-management Table 17 Assessment of stroke risk in patients with strategy in patients with AF, symptomatic HF (NYHA atrial fibrillation functional class II–IV), and LV systolic dysfunction andno evidence of acute decompensation CHA DS -VASc
Congestive HF or LVEF ≤40% Electrical cardioversion or pharmacological cardioversion with amiodarone may be considered in patients with Diabetes mel itus persisting symptoms and/or Stroke, transient ischaemic attack, or thrombo-embolism signs of HF, despite optimum pharmacological treatment Vascular disease (previous myocardial infarction, peripheral and adequate control of the artery disease, or aortic plaque) ventricular rate, to improve clinical/symptomatic status.
Age 65–74 years Amiodarone may be Sex category (i.e. female sex) considered prior to (and following) successful electrical cardioversion to maintain CHA DS -VASc score = 0: recommend no antithrombotic therapy.
sinus rhythm.
CHA DS -VASc score = 1: recommend antithrombotic therapy with oral Dronedarone is not anticoagulation or antiplatelet therapy, but preferably oral anticoagulation.
recommended because of an increased risk of hospital CHA DS -VASc score = 2: recommend oral anticoagulation. admissions for cardiovascular causes and an increased risk of premature death.
CHA2DS2-VASc ¼ Cardiac failure, Hypertension, Age ≥75 (Doubled), Diabetes, Stroke (Doubled), Vascular disease, Age 65–74, and Sex category (Female); HF ¼ Class I antiarrhythmic agents heart failure; LVEF ¼ left ventricular ejection fraction.
are not recommended because of an increased risk of premature death.
Table 18 Assessment of bleeding risk in patients with AF ¼ atrial fibrillation; EF ¼ ejection fraction; HF ¼ heart failure; LV ¼ left ventricular; NYHA ¼ New York Heart Association.
atrial fibrillation aClass of recommendation.
bLevel of evidence.
cReferences.
Hypertension (systolic blood pressure >160 mmHg) Abnormal renal and liver function (1 point each) tachycardia) are associated with a poor outcome in HF. Certainrecommendations from the American College of Cardiology/ Bleeding tendency or predisposition American Heart Association/ESC guidelines on the management Labile international normalized ratio (if on warfarin) of ventricular arrhythmias and sudden death, which may be par- Elderly (e.g. age > 65 years) ticularly relevant to patients with HF, are summarized below. Therole of catheter ablation in patients with HF other than as an Drugs (e.g. concomitant aspirin, NSAID) or alcohol adjunct in the treatment of refractory ventricular arrhythmias is The reader is also referred to the section on ICDs (Section 9.1).
A HAS-BLED score ≥3 suggests that caution is warranted when prescribing oral anticoagulation and regular review is recommended.
10.3 Symptomatic bradycardia and HAS-BLED ¼ Hypertension, Abnormal renal/liver function (1 point each), Stroke, atrioventricular block Bleeding history or predisposition, Labile international normalized ratio, Elderly(.65), Drugs/alcohol concomitantly (1 point each); NSAID Although the indications for pacing in patients with HF are similar to those in other patients, as described in the ESC guidelines onpacthere are issues specific to HF, including: † Before implanting a conventional pacemaker in a patient with † Because right ventricular pacing may induce dyssynchrony and HF-REF, consider whether there is an indication for an ICD, worsen symptoms, CRT should be considered instead of con- CRT-P, or CRT-D (see Sections 9.1 and 9.2).
ventional pacing in patients with HF-REF (see Section 9.2).
Recommendations for the prevention of thromboembolism in patients with symptomatic HF (NYHA functional class II–IV) and paroxysmal or persistent/permanent AF The CHA DS -VASc and HAS-BLED scores (Tables 17 and 18) are recommended to determine the likely risk–benefit (thrombo-embolism prevention vs. risk of bleeding) of oral anticoagulation.
An oral anticoagulant is recommended for all patients with paroxysmal or persistent/permanent AF and a CHA DS -VASc score ≥1, without contraindications, and irrespective of whether a rate- or rhythm-management strategy is used (including after successful cardioversion).
In patients with AF of ≥48 h duration, or when the known duration of AF is unknown, an oral anticoagulant is recommended at a therapeutic dose for ≥3 weeks prior to electrical or pharmacological cardioversion.
Intravenous heparin or LMWH is recommended for patients who have not been treated with an anticoagulant and require urgent electrical or pharmacological cardioversion.
Alternative to i.v. heparin or LMWH A TOE-guided strategy may be considered for patients who have not been treated with an anticoagulant and require urgent electrical or pharmacological cardioversion.
Combination of an oral anticoagulant and an antiplatelet agent is not recommended in patients with chronic (>12 months after an acute event) coronary or other arterial disease, because of a high risk of serious bleeding. Single therapy with an oral anticoagulant is preferred after 12 months.
AF ¼ atrial fibrillation; CHA2DS2-VASc ¼ Cardiac failure, Hypertension, Age ≥75 (Doubled), Diabetes, Stroke (Doubled), Vascular disease, Age 65–74 and Sex category (Female); EF ¼ ejection fraction; HAS-BLED ¼ Hypertension, Abnormal renal/liver function (1 point each), Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (.65), Drugs/alcohol concomitantly (1 point each); HF ¼ heart failure; i.v. ¼ intravenous; LMWH ¼ low molecular weight heparin; LV ¼ left ventricular; NYHA ¼ New York Heart Association; TOE ¼ transoesophageal echocardiography.
aClass of recommendation.
bLevel of evidence.
cReferences.
Recommendations for the management of ventricular arrhythmias in heart failure It is recommended that potential aggravating/precipitating factors (e.g. electrolyte disorders, use of proarrhythmic drugs, myocardial ischaemia) should be sought and corrected in patients with ventricular arrhythmias.
It is recommended that treatment with an ACE inhibitor (or ARB), beta-blocker, and MRA should be optimized in patients with ventricular arrhythmias.
It is recommended that coronary revascularization is considered in patients with ventricular arrhythmias and coronary artery disease (see Section 13.2).
It is recommended that an ICD is implanted in a patient with symptomatic or sustained ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation), reasonable functional status, and in whom a goal of treatment is to improve survival.
Amiodarone is recommended in patients with an ICD, who continue to have symptomatic ventricular arrhythmias or recurrent shocks despite optimal treatment and device re-programming.
Catheter ablation is recommended in patients with an ICD who continue to have ventricular arrhythmias causing recurrent shocks not preventable by optimal treatment device re-programming and amiodarone.
Amiodarone may be considered as a treatment to prevent recurrence of sustained symptomatic ventricular arrhythmias in otherwise optimally treated patients in whom an ICD is not considered appropriate.
Routine use of amiodarone is not recommended in patients with non-sustained ventricular arrhythmias because of lack of benefit and potential drug toxicity. Other antiarrhythmic drugs (particularly class IC agents and dronedarone) should not be used in patients with systolic HF because of safety concerns (worsening HF, proarrhythmia, and death).
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; HF ¼ heart failure; ICD ¼ implantable cardioverter-defibrillator; MRA ¼ mineralocorticoid receptor antagonist.
aClass of recommendation.
bLevel of evidence.
cReferences.
† Physiological pacing to maintain an adequate chronotropic re- nicorandil and ranolazine is uncertain, while other drugs, specific- sponse and maintain atrial–ventricular coordination with a ally dilatiazem and verapamil, are thought to be unsafe in patients DDD system is preferable to VVI pacing in patients with both with HF-REF (although they may be used in HF-PEF).Percutan- HF-REF and HF-PEF.
eous and surgical revascularization are alternative approaches to † Pacing solely in order to permit initiation or titration of beta- the treatment of angina (see Section 13). Coronary artery bypass blocker therapy in the absence of a conventional indication is graft surgery may reduce morbidity and mortality in patients not recommended.
with HF-REF.
11. Importance and management 11.4 Asthma: see chronic obstructive of other co-morbidity in heart pulmonary disease failure with reduced ejection See Section 11.7.
fraction and heart failure with preserved ejection fraction A generalized process, wasting all body compartments [i.e. leantissue (skeletal muscle), fat tissue (energy reserves), and bone 11.1 Heart failure and co-morbidities tissue (osteoporosis)], may occur in 10–15% of patients with Co-morbidities are important in patients with HF for four main HF, especially those with HF-REF. This serious complication is reasons. First, co-morbidities may affect the use of treatments associated with worse symptoms and functional capacity, more fre- for HF (e.g. it may not be possible to use renin–angiotensin quent hospitalization, and decreased survival. Cachexia is specific- system inhibitors is some patients with renal dysfunction) (see ally defined as involuntary non-oedematous weight loss ≥6% of Section 7.2). Secondly, the drugs used to treat co-morbidities total body weight within the previous 6–12 The may cause worsening of HF (e.g. NSAIDs given for arthritis) (see causes are uncertain, but may include poor nutrition, malabsorp- Section 7.4). Thirdly, the drugs used to treat HF and those used tion, impaired calorie and protein balance, hormone resistance, to treat co-morbidities may also interact with one another [e.g.
pro-inflammatory immune activation, neurohormonal derange- beta-blockers and beta-agonists for chronic obstructive pulmonary ments, and reduced anabolic drive. Potential treatments include disease (COPD) and asthma] and reduce patient adherence. Lastly, appetite stimulants, exercise training, and anabolic agents (insulin, most co-morbidities are associated with worse clinical status and anabolic steroids) in combination with the application of nutritional are predictors of poor prognosis in HF (e.g. diabetes). This has supplements, although none is of proven benefit and their safety is led to some co-morbidities themselves becoming targets for treat- Management of co-morbidities is a key component of the holis- tic care of patients with HF (see Section 14).
Certain chemotherapeutic agents can cause (or aggravate) LV sys-tolic dysfunction and HF. The best recognized of these are the anthracyclines (e.g. doxorubicin) and trastuzumab.Dexra- Anaemia (defined as a haemoglobin concentration ,13 g/dL in zoxane may confer some cardioprotection in patients receiving men and ,12 g/dL in women) is common in HF, particularly in anthracyclines. Pre- and post-evaluation of EF is essential in hospitalized patients. It is more frequent in women, the elderly, patients receiving cardiotoxic chemotherapy, as detailed else- and in patients with renal impairment. Anaemia is associated where.Patients developing LV systolic dysfunction should with more symptoms, worse functional status, greater risk of HF not receive further chemotherapy and should receive standard hospitalization, and reduced survival. A standard diagnostic treatment for HF-REF. Mediastinal irradiation can also lead to a work-up should be undertaken in anaemic patients. Correctable variety of long-term cardiac complications, although the less fre- causes should be treated in the usual way, although no definite quent use of high-dose, wide-field radiotherapy has led to a aetiology is identified in many patients. Correction of iron defi- decline in these problems.
ciency using i.v. iron has been specifically studied in patients withHF (see Section 11.14). The value of erythropoietin-stimulating 11.7 Chronic obstructive pulmonary agents as a treatment for anaemia of unknown aetiology is unknown but is currently being tested in a large mortality– COPD and asthma may cause diagnostic difficulties, especially in morbidity RCT.
HF-PEFThese conditions are associated with worse functionalstatus and a worse prognosis. Beta-blockers are contraindicated in asthma but not in COPD, although a selective beta-1 adrenoceptor Beta-blockers are effective agents for angina as well as an essential antagonist (i.e. bisoprolol, metoprolol succinate, or nebivolol) is treatment for systolic HF. Certain other effective antianginal drugs preferrOral corticosteroids cause sodium and water reten- have been studied in large numbers of patients with systolic HF and tion, potentially leading to worsening of HF, but this is not believed shown to be safe (e.g. amlodipine,ivabradine,and to be a problem with inhaled corticosteroids. COPD is an inde- nitrat–The safety of other antianginal agents such as pendent predictor of worse outcomes in HF.
Recommendations for the pharmacological treatment of stable angina pectoris in patients with symptomatic HF (NYHAfunctional class II–IV) and LV systolic dysfunction Step 1: A beta-blocker
A beta-blocker is recommended as the preferred first-line treatment to relieve angina because of the associated benefits of this treatment (reducing the risk of HF hospitalization and the risk of premature death).
Alternatives to a beta-blocker:
(i) Ivabradine should be considered in patients in sinus rhythm who cannot tolerate a beta-blocker, to relieve angina (effective antianginal treatment and safe in HF).
(ii) An oral or transcutaneous nitrate should be considered in patients unable to tolerate a beta-blocker, to relieve angina (effective antianginal treatment and safe in HF).
(iii) Amlodipine should be considered in patients unable to tolerate a beta-blocker, to relieve angina (effective antianginal treatment and safe in HF).
(iv) Nicorandil may be considered in patients unable to tolerate a beta-blocker, to relieve angina (effective antianginal treatment but safety in HF uncertain).
(v) Ranolazine may be considered in patients unable to tolerate a beta-blocker, to relieve angina (effective antianginal treatment but safety in HF uncertain).
Step 2: Add a second anti-anginal drug
The following may be added to a beta-blocker (or alternative)—taking account of the combinations not recommended below.
The addition of ivabradine is recommended when angina persists despite treatment with a beta-blocker (or alternative), to relieve angina (ef ective antianginal treatment and safe in HF).
The addition of an oral or transcutaneous nitrate is recommended when angina persists despite treatment with a beta-blocker (or alternative), to relieve angina (ef ective antianginal treatment and safe in HF).
The addition of amlodipine is recommended when angina persists despite treatment with a beta-blocker (or alternative), to relieve angina (ef ective antianginal treatment and safe in HF).
The addition of nicorandil may be considered when angina persists despite treatment with a beta-blocker (or alternative), to relieve angina (ef ective antianginal treatment but safety in HF uncertain).
The addition of ranolazine may be considered when angina persists despite treatment with a beta-blocker (or alternative), to relieve angina (ef ective antianginal treatment but safety in HF uncertain).
Step 3: Coronary revascularization
Coronary revascularization is recommended when angina persists despite treatment with two antianginal drugs (see Section 13).
Alternatives to coronary revascularization: A third antianginal drug from those listed above may be considered when angina persists despite treatment with two antianginal drugs (excluding the combinations not recommended below).
The following are NOT recommended (i) Combination of any of ivabradine, ranolazine, and nicorandil because of unknown safety.
(ii) Combination of nicorandil and a nitrate (because of lack of additional efficacy).
Diltiazem or verapamil are not recommended because of their negative inotropic action and risk of worsening HF EF ¼ ejection fraction; HF ¼ heart failure; LV, left ventricular; NYHA ¼ New York Heart Association.
aClass of recommendation.
bLevel of evidence.
cReferences.
serotonin reuptake inhibitors are thought to be safe, whereas tri- Depression is common and is associated with worse clinical status cyclic antidepressants are not because they may cause hypoten- and a poor prognosis in HF. It may also contribute to poor adher- sion, worsening HF, and ence and social isolation. A high index of suspicion is needed tomake the diagnosis, especially in the elderly. Routine screening using a validated questionnaire is good practice. Psychosocial inter- Dysglycaemia and diabetes are very common in HF, and diabetes is vention and pharmacological treatment are helpful. Selective associated with poorer functional status and worse prognosis.
Diabetes may be prevented by treatment with ARBs and possibly (allopurinol, oxypurinol) may be used to prevent gout, although ACE Beta-blockers are not contraindicated in dia- their safety in HF-REF is uncertain.Gout attacks are better betes and are as effective in improving outcome in diabetic patients treated by colchicine than with NSAIDs (although colchicine as in non-diabetic individuals, although different beta-blockers may should not be used in patients with very severe renal dysfunction have different effects on glycaemic indices.Thiazolidinediones and may cause diarrhoea). Intra-articular corticosteroids are an (glitazones) cause sodium and water retention and increased risk alternative for monoarticular gout, but systemic corticosteroids of worsening HF and hospitalization, and should be avoided (see cause sodium and water retention.
recommendations, Section –Metformin is not recom-mended in patients with severe renal or hepatic impairment 11.13 Hyperlipidaemia because of the risk of lactic acidosis, but is widely (and apparently Elevated low-density lipoprotein cholesterol is uncommon in safely) used in other patients with HFThe safety of newer anti- HF-REF; patients with advanced HF-REF often have low concentra- diabetic drugs in HF is unknown.
tions of low-density lipoprotein, which is associated with a worseprognosis. Rosuvastatin did not reduce the primary composite 11.10 Erectile dysfunction mortality–morbidity endpoints in two large RCTs in HF Erectile dysfunction should be treated in the usual way; phospho-diesterase V inhibitors are not contraindicated other than in 11.14 Hypertension patients taking nitrates. Indeed short-term studies have shown Hypertension is associated with an increased risk of developing HF; that these agents have favourable haemodynamic and other antihypertensive therapy markedly reduces the incidence of HF effects in patients with HF-REFThere are, however, reports (with an exception of alpha-adrenoceptor blockers, which are of phosphodiesterase V inhibitors causing worsening LV outflow less effective than other antihypertensives in preventing HF).
tract obstruction in patients with hypertrophic cardiomyopathy, Negatively inotropic CCBs (i.e. diltiazem and verapamil) should which may be a concern in some patients with HF-PEF.
not be used to treat hypertension in patients with HF-REF (butare believed to be safe in HF-PEF), and moxonidine should also be avoided in patients with HF-REF as it increased mortality in Hyperuricaemia and gout are common in HF and may be caused or patients in one RCTIf blood pressure is not controlled with aggravated by diuretic treatment. Hyperuricaemia is associated an ACE inhibitor (or ARB), a beta-blocker, MRA, and diuretic, with a worse prognosis in HF-REF.Xanthine oxidase inhibitors hydralazine and amlodipine (or are additional Recommendations for the treatment of hypertension in patients with symptomatic HF (NYHA functional class II–IV)and LV systolic dysfunction One or more of an ACE inhibitor (or ARB), beta-blocker, and MRA is recommended as first-, second-, and third-line therapy, respectively, because of their associated benefits (reducing the risk of HF hospitalization and reducing the risk of premature death).
A thiazide diuretic (or if the patient is treated with a thiazide diuretic, switching to a loop diuretic) is recommended when hypertension persists despite treatment with a combination of as many as possible of an ACE inhibitor (or ARB), beta-blocker, and MRA.
Amlodipine is recommended when hypertension persists despite treatment with a combination of as many as possible of an ACE inhibitor (or ARB), beta-blocker, MRA, and diuretic.
Hydralazine is recommended when hypertension persists despite treatment with a combination of as many as possible of an ACE inhibitor (or ARB), beta-blocker, MRA, and diuretic.
Felodipine should be considered when hypertension persists despite treatment with a combination of as many as possible of an ACE inhibitor (or ARB), beta-blocker, MRA, and diuretic.
Moxonidine is NOT recommended because of safety concerns (increased mortality).
Alpha-adrenoceptor antagonists are NOT recommended because of safety concerns (neurohumoral activation, fluid retention, worsening HF).
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; HF ¼ heart failure; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; MRA ¼ mineralocorticoid receptor antagonist; NYHA ¼ New York Heart Association.
aClass of recommendation.
bLevel of evidence.
cReferences.
blood pressure-lowering agents shown to be safe in systolic HF.
that misdiagnosis may explain at least some of this difference in The blood pressure targets recommended in hypertension guide- prevalence. Obesity should be managed as recommended in linesare applicable to HF.
other guidelines.
In patients with AHF, i.v. nitrates (or sodium nitroprusside) are recommended to lower blood pressure (see Section 12).
11.17 Prostatic obstructionAlpha-adrenoceptor blockers cause hypotension, and sodium and 11.14 Iron deficiency water retention, and may not be safe in systolic HF (see Section Iron deficiency may contribute to muscle dysfunction in HF and 11.13).For these reasons, 5-alpha reductase inhibitors causes anaemia. In a single RCT, 459 patients with NYHA class II are generally preferred. Prostatic obstruction should be ruled or III systolic HF, a haemoglobin concentration between 9.5 and out in men with deteriorating renal function.
13.5 g/dL, and iron deficiency (see below) were randomized 2:1to i.v. ferric carboxymaltose or saline. In this trial, iron deficiency 11.18 Renal dysfunction was diagnosed when serum ferritin was ,100 m/L or when the See Section 11.15.
ferritin concentration was between 100 and 299 mg/L and transfer-rin saturation was ,Over 6 months of treatment, iron 11.19 Sleep disturbance and therapy improved self-reported patient global assessment and NYHA class (as well as 6-min walk distance and health-related Patients with HF frequently have sleep disturbance; the causes are quality of life) and may be considered as a treatment for these many, including pulmonary congestion (leading to orthopnea and patients. The effect of treating iron deficiency in HF-PEF and the paroxysmal nocturnal dyspnoea) and diuretic therapy causing noc- long-term safety of iron therapy in HF is unknown.
turnal diuresis. Anxiety and other psychological problems can also 11.15 Kidney dysfunction and cardiorenal lead to insomnia, and reviewing sleep history is part of the holisticcare of patients with HF (see Section 14). Up to one-third of patients with HF have sleep-disordered brSleep The GFR is reduced in most patients with HF, especially if apnoea is of concern in patients with HF because it leads to inter- advanced, and renal function is a powerful independent predictor mittent hypoxaemia, hypercapnia, and sympathetic excitation. Ob- of prognosis in HF. Renin–angiotensin–aldosterone blockers structive sleep apnoea also causes recurrent episodes of negative (ACE inhibitors, renin inhibitors, ARBs, and MRAs) frequently intrathoracic pressure and increases in LV afterload. It is more cause a fall in GFR, although any reduction is usually small and common in patients who are obese and whose sleeping partners should not lead to treatment discontinuation unless marked (see report that the patient snores or exhibits daytime somnolence Web Table 11). Conversely, an immediate and large fall in GFR (the patient may not be aware of these). However, not all patients should raise the suspicion of renal artery stenosis. Sodium and with obstructive sleep apnoea are obese. The prevalence of central water depletion (due to the excessive diuresis or fluid loss due sleep apnoea (including Cheyne–Stokes respiration) in HF is un- to vomiting or diarrhoea) and hypotension are well recognized certain and may have declined since the widespread use of beta- causes of renal dysfunction, but less well known is that volume blockers and CRT. Screening for and the diagnosis and treatment overload, right heart failure, and renal venous congestion may of sleep apnoea is discussed in detail elsewhere.Diagnosis also cause renal dysfunction. Other causes of kidney dysfunction currently requires overnight polysomnography. Nocturnal oxygen are prostatic obstruction and nephrotoxic drugs such as NSAIDs supplementation, continuous positive airway pressure, bi-level and certain antibiotics (e.g. trimethoprim and gentamicin), all of positive airway pressure, and adaptive servo-ventilation may be which should be considered (and corrected or avoided) in HF used to treat nocturnal hypoxaemia.
patients with worsening renal function. Thiazide diuretics may beless effective in patients with a very low eGFR, and certainrenally excreted drugs (e.g. digoxin, insulin, and low molecular 12. Acute heart failure weight heparin) may accumulate in patients with renal impairment.
Acute heart failure (AHF) is the term used to describe the rapid Sometimes the term ‘cardiorenal syndrome' is used to describe onset of, or change in, symptoms and signs of HF. It is a life- concurrent heart and renal failure (and ‘cardiorenal–anaemia syn- threatening condition that requires immediate medical attention drome' if there is concomitant anaemia).
and usually leads to urgent admission to hospital. In most cases, Chronic or acute renal dysfunction is a particular problem in AHF arises as a result of deterioration in patients with a previ- patients with AHF, and is discussed further in that section (see ous diagnosis of HF (either HF-REF or HF-PEF), and all of the Section 12).
aspects of chronic management described in these guidelinesapply fully to these patients. AHF may also be the first presen- tation of HF (‘de novo' AHF). AHF may be caused by an abnor- Obesity is a risk factor for HF and complicates its diagnosis mality of any aspect of cardiac function (Web Table 3). In because it causes dyspnoea, effort intolerance, and ankle swelling, patients with pre-existing HF there is often a clear precipitant and may result in poor-quality echocardiographic images. Obese or trigger (e.g. an arrhythmia or discontinuation of diuretic individuals also have reduced natriuretic peptide levels. Obesity therapy in a patient with HF-REF and volume overload or is more common in HF-PEF than in HF-REF, although it is possible severe hypertension in patients with HF-PEF) (Table ). The 12.1 Initial assessment and monitoring of Table 19 Precipitants and causes of acute heart Three parallel assessments must be made during the initial evalu- Events usually leading to rapid deterioration ation of the patient, aided by the investigations listed in Figure .
• Rapid arrhythmia or severe bradycardia/conduction disturbance (i) Does the patient have HF or is there an alternative cause for • Acute coronary syndrome their symptoms and signs (e.g. chronic lung disease, anaemia, • Mechanical complication of acute coronary syndrome (e.g. rupture of kidney failure, or pulmonary embolism)? interventricular septum, mitral valve chordal rupture, right ventricular (ii) If the patient does have HF, is there a precipitant and does it require immediate treatment or correction (e.g. an arrhyth- • Acute pulmonary embolism mia or acute coronary syndrome)? • Hypertensive crisis (iii) Is the patient's condition immediately life-threatening because • Cardiac tamponade of hypoxaemia or hypotension leading to underperfusion of • Aortic dissection the vital organs (heart, kidneys, and brain)? • Surgery and perioperative problems • Peripartum cardiomyopathy 12.2 Treatment of acute heart failure Events usually leading to less rapid deterioration Often treatment must be administered in parallel with the diagnos- • Infection (including infective endocarditis) tic work-up (see treatment algorithm, Figure ). Although not ‘evi- • Exacerbation of COPD/asthma dence based' in the same way as treatments for chronic HF, the key drugs are oxygen, diuretics, and vasodilators. Opiates and ino-tropes are used more selectively, and mechanical support of the • Kidney dysfunction circulation is required only rarely. Non-invasive ventilation is • Non-adherence to diet/drug therapy used commonly in many centres, but invasive ventilation is • Iatrogenic causes (e.g. prescription of an NSAID or corticosteroid; required in only a minority of patients.
drug interactions) Systolic blood pressure, heart rhythm and rate, saturation of • Arrhythmias, bradycardia, and conduction disturbances not leading to peripheral oxygen (SpO sudden, severe change in heart rate 2) using a pulse oximeter, and urine output should be monitored on a regular and frequent basis • Uncontrolled hypertension until the patient is stabilized (see also Sections 12.3 and 12.4).
• Hypothyroidism or hyperthyroidism • Alcohol and drug abuse 12.2.1 Pharmacological therapy12.2.1.1 Acute management AHF ¼ acute heart failure; COPD ¼ chronic obstructive pulmonary disease; NSAID ¼ non-steroidal anti-inflammatory drug.
Oxygen may be given to treat hypoxaemia (SpO2 ,90%), which isassociated with an increased risk of short-term mortality.
Oxygen should not be used routinely in non-hypoxaemic ‘acuteness' may vary, with many patients describing a period of patients as it causes vasoconstriction and a reduction in cardiac days or even weeks of deterioration (e.g. increasing breathless- ness or oedema) but others developing HF within hours tominutes (e.g. in association with an acute myocardial infarction).
Patients may present with a spectrum of conditions ranging Most patients with dyspnoea caused by pulmonary oedema obtain from life-threatening pulmonary oedema or cardiogenic shock rapid symptomatic relief from administration of an i.v. diuretic, as a to a condition characterized, predominantly, by worsening per- result of both an immediate venodilator action and subsequent ipheral oedema.
removal of fluid. The optimum dose and route of administration Diagnosis and treatment are usually carried out in parallel, es- (bolus or continuous infusion) are uncertain. A recent, small, pro- pecially in patients who are particularly unwell, and management spective RCT compared 12-hourly bolus injection with continuous must be initiated promptly. Close monitoring of the patient's infusion and low-dose (equal to pre-existing oral dose) with high- vital functions is essential during the initial evaluation and treat- dose (×2.5 times previous oral dose) using a 2 × 2 factorial ment (see Sections 12.3 and 12.4) and some patients are best There was no difference between either of the treat- managed in an intensive or coronary care unit. Although the im- ment comparisons for the co-primary endpoints (patient global as- mediate goals of treatment are to improve symptoms and stabil- sessment of symptoms and change in serum creatinine). Compared ize the patient's haemodynamic condition, longer term with the low-dose strategy, the high-dose strategy was, however, management, including post-discharge care, is also particularly associated with greater improvement in a number of secondary important to prevent recurrences and improve prognosis in outcomes (including dyspnoea) but at the expense of more transi- HF-REF. Pre- and post-discharge care should follow the recom- ent worsening of renal function.
mendations outlined elsewhere in these guidelines, where In patients with resistant peripheral oedema (and ascites), a combination of a loop and a thiazide (e.g. bendroflumethiazide) Suspected acute heart failure
History/examination(including blood pressure and respiratory rate)Chest X-ray Echocardiogram or NP (or both) Oxygen saturation assess for
valvular diseasee • Echocardiography • Antithrombotic if present
ECG = electrocardiogram; ETT = endotracheal tube; IABP = intra-aortic bal oon pump; NIV = non-invasive ventilation; NP = natriuretic peptide.
aFor example, respiratory distress, confusion SpO <90%, or PaO <60 mmHg (8.0 kPa).
bFor example, ventricular tachycardia, third-degree atrioventricular block.
cReduced peripheral and vital organ perfusion—patients often have cold skin and urine output ≤15 ml/h and/or disturbance of consciousness.
dPercutaneous coronary revascularization (or thrombolysis) indicated if ST-segment elevation or new left bundle branch block.
eVasodilators should be used with great caution, and surgery should be considered for certain acute mechanical complications (e.g. inter-ventricular septal rupture, mitral valve papil ary muscle rupture).
Figure 4 Initial assessment of patient with suspected acute heart failure. ECG ¼ electrocardiogram; ETT ¼ endotracheal tube; IABP ¼ intra-aortic balloon pump; NIV ¼ non-invasive ventilation; NP ¼ natriuretic peptide.
or thiazide-like diuretic (metolazone) may be needed to achieve anadequate diuresis (see Web Table 15).This potent combin- Table 20 Intravenous vasodilators used to treat acute ation is usually only needed for a few days and requires careful monitoring to avoid hypokalaemia, renal dysfunction, andhypovolaemia.
Main side
Nitroglycerine Start with10–20 µg/min, Hypotension, Tolerance on Opiates such as morphine may be useful in some patients with acute pulmonary oedema as they reduce anxiety and relievedistress associated with dyspnoea. Opiates are also thought Start with 1 mg/h, Hypotension, Tolerance on increase up to 10 mg/h headache to be venodilators, reducing preload, and may also reduce sym- pathetic drive. Conversely, opiates induce nausea (necessitating Nitroprusside Start with 0.3 µg/kg/min Hypotension, Light the concomitant administration of an antiemetic, one of which, and increase up to cyclizine,has vasoconstrictor activity) and depress respira- tory drive, potentially increasing the need for invasive Bolus 2 µg/kg + infusion 0.01 µg/kg/min aNot available in many European Society of Cardiology countries.
Although vasodilators such as nitroglycerine (Table ) reducepreload and afterload and increase stroke volume, there is norobust evidence that they relieve dyspnoea or improve other clin- blood pressure should also be avoided because hypotension is ical outcomes.Vasodilators are probably most useful in associated with higher mortality in patients with AHF. Vasodilators patients with hypertension and should be avoided in patients should be used with caution in patients with significant mitral or with a systolic blood pressure ,110 mmHg. Excessive falls in aortic stenosis.
Nesiritide—a human BNP that acts mainly as a vasodilator—was In large doses (.5 mg/kg/min) dopamine has inotropic and vaso- recently shown to reduce dyspnoea by a small but statistically sig- constrictor activity. At lower doses (,3 mg/kg/min) dopamine nificant amount when added to conventional treatment (mainly may have a selective renal arterial vasodilator activity and promote natriuresis, although this is uncertain. Dopamine maycause Arterial oxygen saturation should be moni- tored, and supplemental oxygen administrated as required.
Use of an inotrope such as dobutamine (Table ) should usuallybe reserved for patients with such severe reduction in cardiac Other pharmacological therapy output that vital organ perfusion is compromised. Such patients Thrombo-embolism prophylaxis with heparin or another anti- are almost always hypotensive (‘shocked'). Inotropes cause sinus coagulant should be used, unless contraindicated or unnecessary tachycardia and may induce myocardial ischaemia and arrhythmias.
(because of existing treatment with oral anticoagulants).– There is long-standing concern that they may increase mortality.
Tolvaptan (a vasopressin V2-receptor antagonist) may be used to There is pharmacological rationale to use levosimendan (or a treat patients with resistant hyponatraemia (thirst and dehydration phosphodiesterase III inhibitor such as milrinone) if it is felt neces- are recognized adverse sary to counteract the effect of a beta-blocker.
12.2.1.2 After stabilization Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker Drugs with prominent peripheral arterial vasoconstrictor action In patients with reduced EF not already receiving an ACE inhibitor such as norepinephrine (Table are sometimes given to severely (or ARB), this treatment should be started as soon as possible, ill patients with marked hypotension. These agents are given to blood pressure and renal function permitting (see recommenda- raise blood pressure and redistribute cardiac output from the ex- tions in Section 7.2.1 and Web Table 11). The dose should be tremities to the vital organs. However, this is at the expense of an up-titrated as far as possible before discharge, and a plan made increase in LV afterload, and these agents have adverse effects to complete dose up-titration after discharge.
similar to those of inotropes (and the most commonly used ofthese agents, norepinephrine and epinephrine, have inotropic ac- tivity). Their use should be restricted to patients with persistent In patients with reduced EF not already receiving a beta-blocker, hypoperfusion despite adequate cardiac filling pressures.
this treatment should be started as soon as possible after stabiliza-tion, blood pressure and heart rate permitting (see recommenda-tions in Section 7.1 and Web Table 12). The dose should be Table 21 Drugs used to treat acute heart failure that up-titrated as far as possible before discharge, and a plan made are positive inotropes or vasopressors or both to complete dose up-titration after discharge. It has been shownthat beta-blocker treatment may be continued in many patients during an episode of decompensation and started safely before dis- 2–20 µg/kg/min (β+) charge after an episode of decompensation.
<3 µg/kg/min: renal effect (δ+) Mineralocorticoid (aldosterone) receptor antagonist 3–5 µg/kg/min; In patients with reduced EF not already receiving an MRA, this treatment should be started as soon as possible, renal >5 µg/kg/min: (β+), function and potassium permitting (see recommendations in vasopressor (α+) Section 7.2 and Web Table 13). As the dose of MRA used to treat 25–75 µg/kg over 10–20 0.375–0.75 µg/kg/min HF has a minimal effect on blood pressure, even relatively hypoten-sive patients may be started on this therapy during admission. The 0.5–1.0 mg/kg over 5–10 5–20 µg/kg/min dose should be up-titrated as far as possible before discharge, and a plan made to complete dose up-titration after discharge.
12 µg/kg over 10 min 0.1 µg/kg/min, which can be decreased to 0.05 or increased to 0.2 µg/kg/min In patients with reduced EF, digoxin may be used to control the 0.2–1.0 µg/kg/min ventricular rate in AF, especially if it has not been possible toup-titrate the dose of beta-blocker. Digoxin may also provide Bolus: 1 mg can be given 0.05–0.5 µg/kg/min i.v. during resuscitation, symptom benefit and reduce the risk of HF hospitalization in repeated every 3–5 min patients with severe systolic HF (see recommendations inSection 7.2.6).
aAlso a vasodilator.
bBolus not recommended in hypotensive patients (systolic blood pressure 12.2.2 Non-pharmacological/non-device therapy It is common to restrict sodium intake to ,2 g/day and fluid intake ¼ alpha adrenoceptor; b ¼ beta adrenoceptor; d ¼ dopamine receptor.
to ,1.5–2.0 L/day, especially (the latter in hyponatraemic Recommendations for the treatment of patients with acute heart failure Patients with pulmonary congestion/oedema without shock
An i.v. loop diuretic is recommended to improve breathlessness and relieve congestion. Symptoms, urine output, renal function, and electrolytes should be monitored regularly during use of i.v. diuretic.
High-flow oxygen is recommended in patients with a capillary oxygen saturation <90% or PaO <60 mmHg (8.0 kPa) to correct hypoxaemia. Thrombo-embolism prophylaxis (e.g. with LMWH) is recommended in patients not already anticoagulated and with no contraindication to anticoagulation, to reduce the risk of deep venous thrombosis and pulmonary embolism.
Non-invasive ventilation (e.g. CPAP) should be considered in dyspnoeic patients with pulmonary oedema and a respiratory rate >20 breaths/min to improve breathlessness and reduce hypercapnia and acidosis. Non-invasive ventilation can reduce blood pressure and should not generally be used in patients with a systolic blood pressure<85 mmHg (and blood pressure should be monitored regularly when this treatment is used).
An i.v. opiate (along with an antiemetic) should be considered in particularly anxious, restless, or distressed patients to relieve these symptoms and improve breathlessness. Alertness and ventilatory effort should be monitored frequently after administration because opiates can depress respiration. An i.v. infusion of a nitrate should be considered in patients with pulmonary congestion/oedema and a systolic blood pressure >110 mmHg, who do not have severe mitral or aortic stenosis, to reduce pulmonary capillary wedge pressure and systemic vascular resistance. Nitrates may also relieve dyspnoea and congestion. Symptoms and blood pressure should be monitored frequently during administration of i.v. nitrates.
An i.v. infusion of sodium nitroprusside may be considered in patients with pulmonary congestion/oedema and a systolic blood pressure >110 mmHg, who do not have severe mitral or aortic stenosis, to reduce pulmonary capillary wedge pressure and systemic vascular resistance. Caution is recommended in patients with acute myocardial infarction. Nitroprusside may also relieve dyspnoea and congestion. Symptoms and blood pressure should be monitored frequently during administration of i.v. nitroprusside.
Inotropic agents are NOT recommended unless the patient is hypotensive (systolic blood pressure <85 mmHg), hypoperfused, or shocked because of safety concerns (atrial and ventricular arrhythmias, myocardial ischaemia, and death).
Patients with hypotension, hypoperfusion or shock
Electrical cardioversion is recommended if an atrial or ventricular arrhythmia is thought to be contributing to the patient's haemodynamic compromise in order to restore sinus rhythm and improve the patient's clinical condition.
An i.v. infusion of an inotrope (e.g. dobutamine) should be considered in patients with hypotension (systolic blood pressure <85 mmHg) and/or hypoperfusion to increase cardiac output, increase blood pressure, and improve peripheral perfusion. The ECG should be monitored continuously because inotropic agents can cause arrhythmias and Short-term mechanical circulatory support should be considered (as a ‘bridge to recovery') in patients remaining severely hypoperfused despite inotropic therapy and with a potentially reversible cause (e.g. viral myocarditis) or a potentially surgically correctable cause (e.g. acute interventricular septal rupture).
An i.v. infusion of levosimendan (or a phosphodiesterase inhibitor) may be considered to reverse the effect of beta-blockade if beta-blockade is thought to be contributing to hypoperfusion. The ECG should be monitored continuously because inotropic agents can cause arrhythmias and myocardial ischaemia, and, as these agents are also vasodilators, blood pressure should be monitored carefully.
A vasopressor (e.g. dopamine or norepinephrine) may be considered in patients who have cardiogenic shock, despite treatment with an inotrope, to increase blood pressure and vital organ perfusion. The ECG should be monitored as these agents can cause arrhythmias and/or myocardial ischaemia. Intra-arterial blood pressure measurement shouldbe considered.
Short-term mechanical circulatory support may be considered (as a ‘bridge to decision') in patients deteriorating rapidly before a full diagnostic and clinical evaluation can be made.
Patients with an ACS
Immediate primary PCI (or CABG in selected cases) is recommended if there is an ST elevation or a new LBBB ACS in order to reduce the extent of myocyte necrosis and reduce the risk of premature death.
Alternative to PCI or CABG: Intravenous thrombolytic therapy is recommended, if PCI/CABG cannot be performed, if there is ST-segment elevation or new LBBB, to reduce the extent of myocyte necrosis and reduce the risk of premature death.
Early PCI (or CABG in selected patients) is recommended if there is non-ST elevation ACS in order to reduce the risk of recurrent ACS. Urgent revascularization is recommended if the patient is haemodynamically unstable.
Eplerenone is recommended to reduce the risk of death and subsequent cardiovascular hospitalization in patients with an EF ≤40%.
Recommendations for the treatment of patients with acute heart failure (Cont.) Patients with an ACS
An ACE inhibitor (or ARB) is recommended in patients with an EF ≤40%, after stabilization, to reduce the risk of death, recurrent myocardial infarction, and hospitalization for HF.
A beta-blocker is recommended in patients with an EF ≤40%, after stabilization, to reduce the risk of death and recurrent myocardial infarction. An i.v. opiate (along with an antiemetic) should be considered in patients with ischaemic chest pain to relieve this symptom (and improve breathlessness). Alertness and ventilatory effort should be monitored frequently after administration because opiates can depress respiration.
Patients with AF and a rapid ventricular rate
Patients should be fully anticoagulated (e.g. with i.v. heparin), if not already anticoagulated and with no contraindication to anticoagulation, as soon as AF is detected to reduce the risk of systemic arterial embolism and stroke.
Electrical cardioversion is recommended in patients haemodynamically compromised by AF and in whom urgent restoration of sinus rhythm is required to improve the patient's clinical condition rapidly. Electrical cardioversion or pharmacological cardioversion with amiodarone should be considered in patients when a decision is made to restore sinus rhythm non-urgently (‘rhythm control' strategy). This strategy should only be employed in patients with a first episode of AF of <48 h duration (or in patients with no evidence of left atrial appendage thrombus on TOE). Intravenous administration of a cardiac glycoside should be considered for rapid control of the ventricular rate.
Dronedarone is not recommended because of safety concerns (increased risk of hospital admission for cardiovascular causes and an increased risk of premature death), particularly in patients with an EF ≤40%.
Class I antiarrhythmic agents are not recommended because of safety concerns (increased risk of premature death), particularly in patients with LV systolic dysfunction.
Patients with severe bradycardia or heart block
Pacing is recommended in patients haemodynamically compromised by severe bradycardia or heart block to improve the patient's clinical condition.
ACE ¼ angiotensin-converting enzyme; ACS ¼ acute coronary syndrome; AF ¼ atrial fibrillation; ARB ¼ angiotensin receptor blocker; CABG ¼ coronary artery bypass graft; CPAP ¼ continuous positive airway pressure; ECG ¼ electrocardiogram; EF ¼ ejection fraction; HF ¼ heart failure; i.v. ¼ intravenous; LBBB ¼ left bundle branch block; LMWH ¼ low molecular weight heparin; LV ¼ left ventricular; PaO2 ¼ partial pressure of oxygen; PCI ¼ percutaneous coronary intervention; TOE ¼ transoesophageal echocardiography.
aClass of recommendation.
bLevel of evidence.
cReferences.
patients) during the initial management of an acute episode of HF Endotracheal intubation and invasive ventilation associated with volume overload, although there is no firm evi- The primary indication for endotracheal intubation and invasive dence to support this practice.
ventilation is respiratory failure leading to hypoxaemia, hypercap-nia, and acidosis. Physical exhaustion, diminished consciousness,and inability to maintain or protect the airway are other reasons 12.2.2.1 Ventilation to consider intubation and ventilation.
Non-invasive ventilationContinuous positive airway pressure (CPAP) and non-invasive 12.2.2.2 Mechanical circulatory support positive pressure ventilation (NIPPV) relieve dyspnoea and Intra-aortic balloon pump improve certain physiological measures (e.g. oxygen saturation) The conventional indications for an intra-aortic balloon pump in patients with acute pulmonary oedema. However, a recent (IABP) are to support the circulation before surgical correction large RCT showed that neither type of non-invasive ventilation of specific acute mechanical problems (e.g. interventricular septal reduced mortality or the rate of endotracheal intubation when rupture and acute mitral regurgitation), during severe acute myo- compared with standard therapy, including nitrates (in 90% of carditis and in selected patients with acute myocardial ischaemia patients) and opiates (in 51% of patients)This result is in con- or infarction before, during, and after percutaneous or surgical trast to the findings of meta-analyses of earlier, smaller studies.
revascularization. There is no good evidence that an IABP is of Non-invasive ventilation may be used as adjunctive therapy to benefit in other causes of cardiogenic shock.More recently, relieve symptoms in patients with pulmonary oedema and severe balloon pumps (and other types of short-term, temporary respiratory distress or who fail to improve with pharmacological circulatory support) have been used to bridge patients until im- therapy. Contraindications include hypotension, vomiting, possible plantation of a ventricular assist device or heart transplantation pneumothorax, and depressed consciousness.
(see Section 13.5).
Acute pulmonary oedema/congestion
Intravenous bolus of loop diuretic1 Severe anxiety/distress Consider i.v. opiate4 Measure systolic blood pressure SBP <85 mmHg or shock5 SBP 85–110 mmHg No additional therapy until Add non-vasodilating inotrope6 response assessed7 Consider vasodilator (e.g. NTG8) Adequate response Continue present treatment10 Re-evaluation of patient's clinical status11 Urine output <20 mL/h12 SBP <85 mmHg?5 • Stop vasodilator • Bladder catheterization to confirm • Stop beta-blocker if hypoperfused • Consider NIV15 • Increase dose of diuretic or use • Consider non-vasodilating inotrope • Consider ETT and combination of diuretics17 invasive ventilation16 • Consider low-dose dopamine18 • Consider right-heart catheterization13 • Consider right-heart catheterization13 • Consider mechanical circulatory • Consider ultrafiltration19 CPAP = continuous positive airway pressure; ETT = endotracheal tube; i.v. = intravenous; NIPPV = non-invasive positive pressure ventilation; NIV = non-invasive ventilation;NTG = nitroglycerine; PaO = partial pressure of oxygen; SBP = systolic blood pressure; SpO = saturation of peripheral oxygen.
1In patients' already taking diuretic, 2.5 times existing oral dose recommended. Repeat as needed.
2Pulse oximeter oxygen saturation <90% or PaO <60 mmHg (<8.0 kPa).
3Usually start with 40–60% oxygen, titrating to SpO >90%; caution required in patients at risk of CO retention.
4For example, 4–8 mg of morphine plus 10 mg of metoclopramide; observe for respiratory depression. Repeat as needed.
5Cold skin, low pulse volume, poor urine output, confusion, myocardial ischaemia.
6For example, start an i.v. infusion of dobutamine 2.5 µg/kg/min, doubling dose every 15 min according to response or tolerability (dose titration usually limited by excessive tachycardia, arrhythmias, or ischaemia). A dose >20 µg/kg/min is rarely needed. Even dobutamine may have mild vasodilator activity as a result of beta-2 adrenoceptor stimulation.
7Patient should be kept under regular observation (symptoms, heart rate/rhythm, SpO , SBP, urine output) until stabilized and recovered.
8For example, start i.v. infusion at 10 µg/min and doubled every 10 min according to response and tolerability (usually dose up-titration is limited by hypotension). A dose of >100 µg/min is rarely needed.
9An adequate response includes reduction in dyspnoea and adequate diuresis (>100 mL/h urine production in first 2 h), accompanied by an increase in oxygen saturation(if hypoxaemic) and, usually, reduction in heart and respiratory rate (which should occur in 1–2 h). Peripheral blood flow may also increase as indicated by a reduction in skin vasoconstriction, an increase in skin temperature, and improvement in skin colour. There may also be a decrease in lung crackles.
10Once the patient is comfortable and a stable diuresis has been established, withdrawal of i.v. therapy can be considered (with substitution of oral diuretic treatment).
11Assess for symptoms relevant to HF (dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea), associated co-morbidity (e.g. chest pain due to myocardial ischaemia), and treatment-related adverse effects (e.g. symptomatic hypotension). Assess for signs of peripheral and pulmonary congestion/oedema, heart rate and rhythm, blood pressure, peripheral perfusion, respiratory rate, and respiratory effort. An ECG (rhythm/ischaemia and infarction) and blood chemistry/haematology (anaemia, electrolyte disturbances, kidney failure) should also be examined. Pulse oximetry (or arterial blood gas measurements) should be checked and echocardiography performed (if not already carried out).
12Less than 100 mL/h over 1–2 h is an inadequate initial response to i.v. diuretic (confirm is inadequate by catheterizing bladder).
13In patients with persistently low blood pressure/shock, consider alternative diagnoses (e.g. pulmonary embolism), acute mechanical problems, and severe valve disease (particularly aortic stenosis). Pulmonary artery catheterization may identify patients with an inadequate left ventricular filling pressure (and characterize the patient's haemodynamic pattern, enabling more precise tailoring of vasoactive therapy).
14An intra-aortic balloon pump or other mechanical circulatory support should be considered in patients without contraindications.
15CPAP or NIPPV (see Section 12.2.2.1) should be considered in patients without contraindications.
16Consider endotracheal intubation and invasive ventilation if worsening hypoxaemia, failing respiratory effort, increasing confusion, etc.
17Double dose of loop diuretic up to equivalent of furosemide 500 mg (doses of 250 mg and above should be given by infusion over 4 h).
18If no response to doubling of dose of diuretic despite adequate left ventricular filling pressure (either inferred or measured directly) start i.v. infusion of dopamine 2.5 µg/kg/min. Higher doses are not recommended to enhance diuresis.
19If steps 17 and 18 do not result in an adequate diuresis and the patient remains in pulmonary oedema, venovenous isolated ultrafiltration should be considered.
Figure 5 Algorithm for management of acute pulmonary oedema/congestion.
Ventricular assist devicesVentricular assist devices and other forms of mechanical circula- Table 22 Goals of treatment in acute heart failure tory support (MCS) may be used as a ‘bridge to decision' orlonger term in selected patients (see Section 13.5).
Immediate (ED/ICU/CCU) • Treat symptoms 12.2.2.3 Ultrafiltration • Restore oxygenation Venovenous isolated ultrafiltration is sometimes used to remove • Improve haemodynamics and organ perfusion fluid in patients with HFalthough is usually reserved for • Limit cardiac and renal damage those unresponsive or resistant to diuretics.
• Prevent thrombo-embolism 12.3 Invasive monitoring • Minimize ICU length of stay 12.3.1 Intra-arterial line Intermediate (in hospital) Insertion of an intra-arterial line should only be considered in • Stabilize patient and optimize treatment strategy patients with persistent HF and a low systolic blood pressure • Initiate and up-titrate disease-modifying pharmacological therapy despite treatment.
• Consider device therapy in appropriate patients • Identify aetiology and relevant co-morbidities 12.3.2 Pulmonary artery catheterizationRight heart catheterization does not have a general role in the Pre-discharge and long-term management management of AHF, but may help in the treatment of a minority • Plan follow-up strategy of selected patients with acute (and chronic) HF.Pulmonary • Enrol in disease management programme, educate, and initiate artery catheterization should only be considered in patients: (i) appropriate lifestyle adjustments who are refractory to pharmacological treatment; (ii) who are per- • Plan to up-titrate/optimize dose of disease-modifying drugs sistently hypotensive; (iii) in whom LV filling pressure is uncertain; • Ensure assessed for appropriate device therapy or (iv) who are being considered for cardiac surgery. A primary • Prevent early readmission concern is to ensure that hypotension (and worsening renal func- • Improve symptoms, quality of life, and survival tion) is not due to inadequate LV filling pressure, in which case di-uretic and vasodilator therapy should be reduced (and volume CCU ¼ coronary care unit; ED ¼ emergency department; ICU ¼ intensive care replacement may be required). Conversely, a high LV filling pres- sure and/or systemic vascular resistance may suggest an alternativepharmacological strategy (e.g. inotropic or vasodilator therapy),depending on blood pressure. Measurement of pulmonary vascular stable oral diuretic regimen established for at least 48 h.– resistance (and its reversibility) is a routine part of the surgical Long-term disease-modifying therapy (including a beta-blocker) work-up before cardiac transplantation.
should be optimized as much as possible and appropriate educa- 12.4 Monitoring after stabilization tion provided to the patient and family/caregivers. Pre- and post-discharge management should follow the standards of care laid Heart rate, rhythm, blood pressure, and oxygen saturation should out by the Heart Failure AssociatThe goals of treatment be monitored continuously for at least the first 24 h of admission, during the different stages of management of patients with HF and frequently thereafter. Symptoms relevant to HF (e.g. dys- are summarized in Table pnoea) and related to the adverse effects of treatments used(e.g. dizziness) should be assessed at least daily. Fluid intake andoutput, weight, and the jugular venous pressure and extent of pul-monary and peripheral oedema (and ascites if present) should be 12.7 Special patient populations measured daily to evaluate the correction of volume overload.
12.7.1 Patients with a concomitant acute coronary Blood urea nitrogen, creatinine, potassium, and sodium should be monitored daily during i.v. therapy and when renin–angioten- Patients with a concomitant acute coronary syndrome should be sin–aldosterone system antagonists are being initiated or if the assessed and treated according to the current acute coronary syn- dose of any of these drugs is changed.
drome They should undergo coronary angiog-raphy and revascularization as appropriate. This should be 12.5 Other in-patient assessments undertaken as an urgent procedure in patients with haemodynamic After initial treatment of the acute episode, every patient should be instability and as an emergency procedure in those in cardiogenic assessed for possible causes of HF (if the HF is new) and precipi- shock. If haemodynamic instability persists despite optimal tants of worsening (if the HF has previously been diagnosed). The medical treatment, an IABP should be inserted before coronary focus is detection of reversible or treatable causes (Table ).
angiography and revascularization. Persistent haemodynamic in-stability may also be caused by mechanical complications of infarc- 12.6 Readiness for discharge tion (e.g. mitral valve papillary muscle rupture), which may be Before discharge is contemplated, the acute episode of HF should identified using echocardiography and may require urgent correct- have resolved and, in particular, congestion should be absent and a ive surgery.
12.7.2 Isolated right ventricular failure e.g. those with a Fontan circulation (see ESC guidelines New-onset isolated right ventricular failure may occur secondarily (iii) pulmonary arterial vasodilators may be useful in certain to an acute coronary syndrome (and is managed as described patients with pulmonary hypertension (see ESC guidelines above) and following massive pulmonary embolism (see pulmonary (iv) the role of CRT is unknown; and (v) heart transplantation is embolism guidelinesIn both situations, diuretics and vasodila- an option but may be precluded by factors such as complex cardio- tors should be used cautiously or avoided so as not to reduce right vascular anatomy, and renal and hepatic dysfunction.
Progressive isolated right ventricular failure may occur in patients with pulmonary hypertension. Type V phosphodiesterase inhibitors, 13. Coronary revascularization endothelin antagonists, and prostacyclin analogues may help by de-creasing pulmonary arterial resistance (see guideline and surgery, including valve surgery, ventricular assist devices, 12.7.3 Acute heart failure with ‘cardiorenal syndrome'Acutely worsening HF, or its treatment, or both may cause acute and transplantation worsening of renal function (the so-called ‘type 1 cardiorenal syn-drome') in up to one-third of patients, and is associated with worse 13.1 Coronary revascularization survival and prolonged hospitalization.An acute renocardiac Surgical (and percutaneous) coronary revascularization is indicated syndrome (the so-called ‘type 3 cardiorenal syndrome'), character- for the relief of angina pectoris in patients with either HF-REF or ized by worsening cardiac function secondary to volume overload HF-PEF, and surgical coronary revascularization is indicated for resulting from acute kidney injury, may also occur, but is less ‘prognostic' reasons in other patients with severe CAD, particular- common. The main management issues with these patients are ly those with three-vessel disease or left-main stenosis. The that renal dysfunction may limit the use of renin–angiotensin–al- detailed indications for coronary revascularization are covered dosterone system blockers and that progressive uraemia and volume overload may necessitate renal replacement therapy.
This section focuses on recent developments relevant to HF. The Often these patients are best cared for jointly with a nephrologist.
Surgical Treatment for Ischemic Heart Failure (STICH) trial addressedthe broader role of surgical revascularization in patients with HF-REF 12.7.4 Perioperative acute heart failure and less severe CADPatients with an EF ≤35% and CAD who AHF may occur in patients before (e.g. because of pre-operative in- were suitable for surgery were randomized to coronary artery farction), during (‘failure to wean'), and after (mechanical complica- bypass graft (CABG) plus medical therapy or medical therapy alone.
tions and pericardial tamponade must be excluded) cardiac surgery.
The patients enrolled were young (average age 60 years), predomin- The specialized management of this group of patients is described in antly male (88%), and were in NYHA class I (11%), II (52%), or III detail elsewhereand may involve use of mechanical support, in- (34%). Their Canadian Cardiovascular Society angina class was 0 in cluding extracorporeal membrane oxygenation (ECMO).
36%, I in 16%, II in 43%, III in 4%, and IV in 1%. Most patients had two-vessel (31%) or three-vessel (60%) CAD, and 68% had a severe prox- 12.7.5 Peripartum cardiomyopathy imal left anterior descending stenosis; very few (2%) had a left-main A high index of suspicion is needed to avoid late diagnosis of this stenosis. The primary outcome (all-cause death) was not reduced serious condition, the management of which is described in detail by CABG. CABG did, however, reduce the secondary outcomes of in a Heart Failure Association statement and elsewhere.
cardiovascular death (RRR 19%) and death from any cause or cardio-vascular hospitalization (RRR 26%). This trial may therefore extend 12.7.6 Adult congenital heart disease the indication for CABG to ‘STICH-like' patients with two-vessel Patients with adult congenital heart disease (ACHD) are a very CAD, including a left anterior descending stenosis, who are otherwise heterogeneous patient population. The diagnosis and management suitable for surgery and expected to survive .1 year with good func- of HF in these patients can be very complex, and close collabor- tional status.
ation with a tertiary referral centre is mandatory.
The benefit–risk balance for CABG in patients without angina/ Patients with ACHD may present with HF due to a reduced sys- ischaemia or without viable myocardium remains uncertain.
temic LVEF, reduced systemic right ventricular EF, or isolated sub- Patients with .10% of dysfunctional but viable LV myocardium pulmonary right ventricular failure (see Section 12.7.2). Patients may be more likely to benefit from myocardial revascularization with univentricular hearts, either unoperated or palliated by a (and those with ≤10% less likely to benefit) although this approach Fontan procedure, are particularly difficult to evaluate and treat.
to patient selection for revascularization is unproven. Several non- CMR and cardiopulmonary exercise testing are especially valuable invasive techniques can be used to assess myocardial viability in their assessment, but the acquisition and interpretation of data (Table ). Nuclear imaging has a high sensitivity, whereas techni- require special expertise.
ques evaluating contractile reserve have lower sensitivity but There is a lack of multicentre RCTs to guide the treatment of HF higher specificity. CMR is excellent for assessing the transmural in patients with ACHD. There are, however, a number of general extent of scar, but is not better at detecting viability or predicting empirical principles of management: (i) residual (post-repair) or recovery of wall motion.
new haemodynamic lesions should always be sought first; (ii) the The choice between percutaneous coronary intervention and value of ACE inhibitors, ARBs, and beta-blockers in ACHD is con- CABG should be made by the Heart Team, including a HF special- troversial and these drugs may even be harmful in certain patients, ist, and be based on the extent of CAD, expected completeness of 13.3.1 Aortic stenosis Recommendations for myocardial revascularization in The main concern in patients with LV systolic dysfunction is the patients with chronic HF and systolic LV dysfunction entity of ‘low-flow, low-gradient' aortic stenosis (valve area,1 cm2, EF ,40%, mean gradient ,40 mmHg) because some may have severe aortic stenosis and others ‘pseudo-aortic stenosis' CABG is recommended (i.e. where the low flow across the aortic valve is not caused by a for patients with angina and severe fixed obstruction but by low stroke volume). In such indi- significant left main stenosis, viduals, low-dose dobutamine stress echocardiography may help who are otherwise suitable differentiate between these two types of patient and provide infor- for surgery and expected to survive >1 year with good mation about contractile reserve which is of prognostic import- functional status, to reduce the ance. In patients with severe aortic stenosis and a low EF, risk of premature death.
individuals with contractile reserve have a lower operative mortal- CABG is recommended ity and better long-term prognosis.
for patients with angina and If the mean gradient is .40 mmHg, there is theoretically no two- or three-vessel coronary lower EF limit for aortic valve replacement in symptomatic patients disease, including a left anterior descending stenosis, with severe aortic stenosis. However, substantial recovery of LV who are otherwise suitable function is only likely when the reduced EF is caused by excessive for surgery and expected to afterload and is not due to scar.
survive >1 year with good functional status, to reduce Medical treatment should be optimized, although vasodilators the risk of hospitalization for (ACE inhibitors, ARBs, renin inhibitors, CCBs, hydralazine, and cardiovascular causes and the nitrates) may cause substantial hypotension in patients with risk of premature death from severe aortic stenosis and should only be used with great caution. Optimization of treatment should not delay surgical Alternative to CABG: decision-making. In patients not medically fit for surgery (e.g.
PCI may be considered as because of severe pulmonary disease), transcatheter aortic valve an alternative to CABG replacement should be in the above categories of patients unsuitable for surgery.
13.3.2 Aortic regurgitationAortic valve repair or replacement is recommended in all symp- CABG and PCI are NOT recommended in patients tomatic patients and in asymptomatic patients with severe aortic without angina AND without regurgitation and an EF ,50%, who are otherwise fit for viable myocardium.
surgery. Surgery should also be considered in patients withsevere aortic regurgitation and an LV end-diastolic diameter CABG ¼ coronary artery bypass graft; EF ¼ ejection fraction; HF ¼ heart failure; .70 mm or end-systolic diameter .50 mm (or .25 mm/m2 LV ¼ left ventricular; PCI ¼ percutaneous coronary intervention.
body surface area if small staSurgery is indicated to Class of recommendation.
bLevel of evidence.
reduce the risk of death, and HF and LV function usually improve after aortic valve repair.
It is important not to confuse mild to moderate aortic incompe- tence secondary to LV dilatation with LV dilatation and systolic revascularization, associated valvular disease, and the presence of dysfunction due to primary severe aortic regurgitation.
13.3.3 Mitral regurgitation 13.2 Ventricular reconstruction Assessment of mitral regurgitation is complex, particularly in The value of surgical ventricular reconstruction during which scar patients with systolic dysfunction (and assessment of systolic func- tissue is removed from the LV wall, with the aim of restoring a tion is complicated in the presence of mitral regurgitation—see more physiological LV volume and shape, is uncertain and was Section 4.1). Differentiating between primary and secondary not shown to be of benefit in STICH.This technique is not mitral regurgitation is crucial (see below).
recommended for routine use and is discussed further in the revas- The decision to recommend surgery should take account of cularization guidelines.External containment devices are not symptoms, age, concurrent AF, reduced LV systolic function, pul- monary hypertension, and the suitability of the valve for repair,which are the most important predictors of post-operativeoutcome.
13.3 Valvular surgeryValvular heart disease may cause or aggravate HF. This section Primary (organic) mitral regurgitation briefly addresses problems particularly relevant to HF, and the In primary mitral regurgitation due to flail leaflets, an LV end- reader is referred to the recent ESC/European Association for systolic diameter ≥40 mm is associated with increased mortality Cardio-Thoracic Surgery guidelines on valvular disease for more whether the patient is treated medically or surgically. When the EF is ,30%, a durable surgical repair may improve symptoms, although its effect on survival is unknown. In this situation, the de-cision to operate should take account of response to medical Table 23 Heart transplantation: indications and therapy, co-morbidity, and the likelihood that the valve can be repaired (rather than replaced).
Patients to
End-stage heart failure with severe symptoms, a poor prognosis, and no remaining alternative Secondary mitral regurgitation treatment options This occurs because LV enlargement and remodelling lead to Motivated, wel informed, and emotional y reduced leaflet closing. Effective medical therapy leading to reverse remodelling of the LV may reduce functional mitral regur- Capable of complying with the intensive gitation, and every effort should be made to optimize medical treatment required post-operatively treatment in these patients.
Ischaemic mitral regurgitation is a particular type of secondary Severe peripheral arterial or cerebrovascular mitral regurgitation that may be more suitable for surgical repair.
As it is often a dynamic condition, stress testing is important in Current alcohol or drug abuse its evaluation. An exercise-induced increase of effective regurgitantorifice (≥13 mm2) is associated with a worse prognosis. Com- Treated cancer in previous 5 years bined valve and coronary surgery should be considered in symp- Unhealed peptic ulcer tomatic patients with LV systolic dysfunction, coronary arteries Recent thrombo-embolism suitable for revascularization, and evidence of viability. Predictorsof late failure of valve repair include large interpapillary muscle dis- Significant renal failure (e.g. creatinine clearance <50 mL/min) tance, severe posterior mitral leaflet tethering, and marked LV dila-tation (LV end-diastolic diameter .65 mm). In these patients, Significant liver disease mitral valve replacement, rather than repair, may be advisable. In Systemic disease with multiorgan involvement the presence of AF, atrial ablation and left atrial appendage Other serious co-morbidity with poor closure may be considered at the time of mitral valve surgery.
The role of isolated mitral valve surgery in patients with severe Emotional instability or untreated mental il ness functional mitral regurgitation and severe LV systolic dysfunctionwho cannot be revascularized or have non-ischaemic cardiomyop- High, fixed pulmonary vascular resistance (>4–5 Wood Units and mean transpulmonary athy is questionable, and in most patients conventional medical and gradient >15 mmHg) device therapy are preferred. In selected cases, repair may be con-sidered in order to avoid or postpone transplantation.
HF ¼ heart failure.
In patients with an indication for valve repair but judged inoper- able or at unacceptably high surgical risk, percutaneousedge-to-edge repair may be considered in order to improvesymptoms.
13.4 Heart transplantationHeart transplantation is an accepted treatment for end-stage Table 24 Terms describing various uses of HFAlthough controlled trials have never been conducted, mechanical circulatory support (MCS) there is consensus that transplantation—provided that proper se-lection criteria are applied—significantly increases survival, exer- Use of MCS in patients with drug-refractory acute cise capacity, quality of life, and return to work compared with decision (BTD): circulatory collapse and at immediate risk of death to sustain life until a full clinical evaluation can be completed and additional therapeutic options can Apart from the shortage of donor hearts, the main challenges in be evaluated.
transplantation are the consequences of the limited effectiveness Use of MCS to improve end-organ function in and complications of immunosuppressive therapy in the long candidacy (BTC): order to make an ineligible patient eligible for term (i.e. antibody-mediated rejection, infection, hypertension, renal failure, malignancy, and coronary artery vasculopathy). The Use of MCS to keep a patient at high risk of death indications for and contraindications to heart transplantation are before transplantation alive until a donor organ becomes available.
summarized in Table Use of MCS to keep patient alive until intrinsic 13.5 Mechanical circulatory support recovery (BTR): cardiac function recovers sufficiently to remove MCS.
Long-term use of MCS as an alternative to MCS is an umbrella term describing a number of different tech- transplantation in patients with end-stage heart nologies used to provide both short- and longer term assistance failure ineligible for transplantation.
in patients with either chronic HF or AHF. A variety of termshave been used to describe the use of these technologies MCS ¼ mechanical circulatory support.
(Table ).The most experience is with MCS in end-stage HF, initially as bridge to transplantation (BTT), but more recentlyas destination therapy (DT).
Recommendations for surgical implantation of LVADsin patients with systolic heart failure 13.5.1 End-stage heart failureFor selected patients with end-stage HF, transplantation remains the gold-standard treatment, with good long-term survival.
An LVAD or BiVAD is However, because of the increasing numbers of patients with end- recommended in selected stage HF, limited organ donation, and technological advances, MCS patientsd with end-stage HFdespite optimal pharmacological with an LV assist device (LVAD) or bi-ventricular assist device and device treatment and who (BiVAD) is increasingly seen as an alternative for some of these are otherwise suitable for heart individuals. Initially MCS was used as a short-term BTT treatment transplantation, to improve symptoms and reduce the (Table ), but is now being used long-term, as so-called ‘destin- risk of HF hospitalization for ation therapy (DT)', in patients not eligible for transplantation.
worsening HF and to reduce Ventricular assist devices may ultimately become a more general the risk of premature death alternative to transplantation, as current 2- to 3-year survival while awaiting transplantation.
rates in carefully selected patients receiving the latest continuous An LVAD should be considered in highly selected patientsd who flow devices are much better than with medical therapy have end-stage HF despite only.Patients receiving these devices also have a post- optimal pharmacological and transplant survival rate similar to those not requiring bridging.
device therapy and who are However, despite technological improvements, bleeding, thrombo- not suitable for heart transplantation, but are embolism (both of which can cause stroke), infection, and device expected to survive >1 year failure remain significant problems; these issues, plus the high with good functional status, to cost of devices and implantation, have limited their wider use. It improve symptoms, and reduce the risk of HF hospitalization is recommended that such devices are only implanted and and of premature death.
managed at tertiary heart failure centres with appropriatelytrained, specialist HF physicians and surgeons. Ideally these BiVAD ¼ bi-ventricular assist device; HF ¼ heart failure; LVAD ¼ left ventricular centres should also undertake transplantation.
assist device.
In some patients, LV reverse remodelling and functional aClass of recommendation.
b improvement during MCS permit removal of the ventricular Level of evidence.
dSee text and Table .
may occur in some patients with non-ischaemic cardiomyopathy,but is more likely in patients with an acute fulminant, but reversible,cause of HF such as acute myocarditis.Another concept is usingMCS to permit recovery of end-organ dysfunction, so-called‘bridge to candidacy (BTC)', which may allow ineligible patients Typically, patients with end-stage HF considered for MCS are on to become eligible for transplantation. The difficult decision to continuous inotropic support (Table Evaluation of withdraw MCS may need to be made if the patient does not right ventricular function is crucial as post-operative right ventricular become eligible and DT is not possible.
failure greatly increases perioperative mortality and reduces survivalto, and after, transplantation. Consequently, BiVAD, rather thanLVAD, support should be considered for BTT in patients with biven- Table 25 Patients potentially eligible for implantation tricular failure or at high risk of developing right ventricular failure of a ventricular assist device after LVAD implantation. Referral before right ventricular failuredevelops is preferable. Indeed, earlier ventricular assist device im- Patients with >2 months of severe symptoms despite optimal medical and device therapy and more than one of the following: plantation in less severely ill patients (e.g. with an EF ,25%, peak • LVEF <25% and, if measured, peak VO < 12 mL/kg/min oxygen consumption ,12 mL/kg/min, and only requiring intermit- tent inotropic support), and before right ventricular or multiorgan • ≥3 HF hospitalizations in previous 12 months without an obvious precipitating cause failure develops, leads to better surgical outcomes.
Patients with active infection, severe renal, pulmonary, or • Dependence on i.v. inotropic therapy hepatic dysfunction, or uncertain neurological status after cardiac • Progressive end-organ dysfunction (worsening renal and/or hepatic function) due to reduced perfusion and not to inadequate arrest or due to cardiogenic shock are not usually candidates for ventricular filling pressure (PCWP ≥20 mm Hg and BTT or DT, but may be candidates for BTC.
SBP ≤80–90 mmHg or CI ≤2 L/min/m2) • Deteriorating right ventricular function 13.5.2 Acute heart failureIn addition to ventricular assist devices, other forms of short-term, CI ¼ cardiac index; HF ¼ heart failure; i.v. ¼ intravenous; LVEF ¼ left ventricular temporary MCS may be used in selected patients with AHF, includ- ejection fraction; PCWP ¼ pulmonary capillary wedge pressure; SBP ¼ systolic ing intra-aortic balloon counterpulsation, other percutaneous blood pressure.
cardiac support, and ECMO. In addition to the uses described above, MCS, particularly ECMO, can be used as a ‘bridge to deci- Tables and and detailed practical recommendations on their sion (BTD)' in patients with acute and rapidly deteriorating HF use have been published by the Heart Failure Association.There where full evaluation has not been possible and in whom death is no evidence that most of these improve mortality or morbidity, will occur without MCS. However, the difficult decision to with- and some long-cherished approaches may not be beneficial, e.g.
draw MCS may need to be made if the patient is not eligible for advice to restrict sodium intake and self-management counsel- conventional corrective surgery or longer term MCS.
ling.For this reason, these interventions have not beengiven a recommendation with an evidence level. The exceptionsare implementation of care in a multidisciplinary framework and 14. Holistic management, exercise training, both of which are discussed further below.
including exercise training and 14.1 Exercise training programmes, patient monitoring, Several systematic reviews and meta-analyses of small studies haveshown that physical conditioning by exercise training improves ex- and palliative care ercise tolerance, health-related quality of life, and HF hospitaliza-tion rates in patients with HF. Recently, a single large RCT Non-pharmacological non-device/surgical interventions used in the [Heart Failure: A Controlled Trial Investigating Outcomes of Exer- management of HF (both HF-REF and HF-PEF) are summarized in cise Training (HF-ACTION)] investigated the effects of exercisetraining in 2331 relatively young (mean age 59 years) medically Recommendations for exercise prescription and stable patients with mild to moderately severe symptoms (NYHA class II 63% and class III 35%) and an EF ≤Theintervention comprised 36 supervised sessions in the initial 3 months followed by home-based training. The median follow-upwas 30 months. In an adjusted analysis, exercise training led to It is recommended that regular aerobic exercise is encouraged an 11% reduction in the primary composite outcome of all-cause in patients with heart failure to mortality or all-cause hospitalization (unadjusted P ¼ 0.13; improve functional capacity and adjusted P ¼ 0.03). There was also a 15% RRR in a secondary com- posite outcome of cardiovascular death or HF hospitalization (un- It is recommended that patients adjusted P ¼ 0.06; adjusted P ¼ 0.03). There was no reduction in with heart failure are enrolled in a multidisciplinary-care mortality, and no safety concerns were raised. Adherence to exer- management programme to cise declined substantially after the period of supervised training.
reduce the risk of heart failure Collectively, the evidence suggests that physical training is bene- ficial in HF, although typical elderly patients were not enrolled inmany studies and the optimum exercise ‘prescription' is uncertain.
aClass of recommendation.
b Furthermore, the single large trial showed a borderline treatment Level of evidence.
effect that was only obtained with a very intensive intervention thatmay not be practical to deliver in every centre. Exercise training is Table 26 Characteristics and components of management programmes for patients with heart failure with reducedejection fraction and heart failure with preserved ejection fraction Should employ a multidisciplinary approach (cardiologists, primary care physicians, nurses, pharmacists, etc.) Should target high-risk symptomatic patients Should include competent and professionally educated staff Optimized medical and device management Adequate patient education, with special emphasis on adherence and self-care Patient involvement in symptom monitoring and flexible diuretic use Follow-up after discharge (regular clinic and/or home-based visits; possibly telephone support or remote monitoring) Increased access to healthcare (through in-person follow-up and by telephone contact; possibly through remote monitoring) Facilitated access to care during episodes of decompensation Assessment of (and appropriate intervention in response to) an unexplained increase in weight, nutritional status, functional status, quality of life, and laboratory findings Access to advanced treatment options Provision of psychosocial support to patients and family and/or caregivers Table 27 Essential topics that should be covered during patient education, and the skills and self-care behaviours thatshould be taught in relation to these topics.
Patient skills and self-care behaviours
Definition and aetiology
• Understand the cause of heart failure and why symptoms occur • Understand important prognostic factors and make realistic decisions Symptom monitoring
• Monitor and recognize signs and symptoms • Record daily weight and recognize rapid weight gain • Know how and when to notify healthcare provider • In the case of increasing dyspnoea or oedema or a sudden unexpected weight gain of >2 kg in 3 days, patients may increase their diuretic dose and/or alert their healthcare team • Use flexible diuretic therapy if appropriate and recommended after appropriate education and provision of detailed • Understand indications, dosing, and effects of drugs • Recognize the common side effects of each drug prescribed • Understand the importance of following treatment recommendations and maintaining motivation to follow treatment plan • Sodium restriction may help control the symptoms and signs of congestion in patients with symptomatic heart failure classes III and IV • Avoid excessive fluid intake: fluid restriction of 1.5–2 L/day may be considered in patients with severe heart failure to relieve symptoms and congestion. Restriction of hypotonic fluids may improve hyponatraemia. Routine fluid restriction in all patients with mild to moderate symptoms is probably not of benefit. Weight-based fluid restriction (30 mL/kg body weight, 35 mL/kg if body weight >85 kg) may cause less thirst • Monitor and prevent malnutrition • Eat healthily and keep a healthy weight (see Section 11) • Modest intake of alcohol: abstinence is recommended in patients with alcohol-induced cardiomyopathy. Otherwise, normal alcohol guidelines apply (2 units per day in men or 1 unit per day in women). 1 unit is 10 mL of pure alcohol (e.g. 1 glass of wine, 1/2 pint of beer, 1 measure of spirit) Smoking and drugs
• Stop smoking and/or taking illicit drugs • Understand the benefits of exercise • Perform exercise training regularly • Be reassured and comfortable about physical activity Travel and leisure
• Prepare travel and leisure activities according to physical capacity • When travelling, carry a written report of medical history and current medication regimen and carry extra medication. Monitor and adapt fluid intake particularly during flights and in hot climates. Beware adverse reactions to sun exposure with certain medications (e.g. amiodarone) • Be reassured about engaging in sex and discuss problems with healthcare professionals. Stable patients can undertake normal sexual activity that does not provoke undue symptoms. For treatment of erectile dysfunction, see Section 11.10 • Receive immunization against influenza and pneumococcal disease according to local guidelines and practice Sleep and breathing
• Recognize preventive behaviour such as reducing weight in obese patients, smoking cessation, and abstinence from alcohol • Learn about treatment options if appropriate • Understand that depressive symptoms and cognitive dysfunction are common in patients with heart failure and the importance of social support • Learn about treatment options if appropriate discussed in more detail in a recent Heart Failure Association con- patients with HF should expect have been published by the Heart Failure AssociatioTo achieve this goal, other services, such ascardiac rehabilitation and palliative care, must be integrated into 14.2 Organization of care and the overall provision for patients with HF. Fundamental to the deliv- ery of this complete package of care are multidisciplinary manage-ment programmes designed to improve outcomes through structured follow-up with patient education, optimization of The goal of management of HF is to provide a ‘seamless' system of medical treatment, psychosocial support, and improved access to care, embracing both the community and hospital, to ensure that carKey to the success of these programmes is coordination the management of every patient is optimal, from the beginning to of care along the continuum of HF and throughout the chain-of-care the end of their healthcare journey. The standards of care that delivered by the various services within the healthcare system. This necessitates close collaboration between HF practitioners (cardiol-ogists and HF nurses) and experts in allied health professions, in- Table 28 Patients in whom palliative care should be cluding pharmacists, dieticians, physiotherapists, psychologists, primary care providers, and social workers. Although the contentand structure of HF management programmes may vary in different • Frequent admission to hospital or other serious episodes of decompensation despite optimized treatment countries and healthcare settings, the components shown in • Heart transplantation and mechanical circulatory support ruled out Tables and are recommended.
• Chronic poor quality of life with NYHA class IV symptoms 14.3 Serial natriuretic peptide • Cardiac cachexia/low serum albumin • Dependence in most activities of daily living High natriuretic peptide concentrations are associated with a poor • Clinically judged to be close to the end of life prognosis, and a fall in peptide levels correlates with a better prog-nosis. However, several RCTs that evaluated natriuretic peptide- NYHA ¼ New York Heart Association.
guided treatment (intensifying treatment in order to lowerpeptide levels) have given conflicting results.It is uncertainwhether outcome is better using this approach than by simply op-timizing treatment (combinations and doses of drugs, devices) Table 29 Key components of palliative care service according to guidelines.
• Frequent assessment of patient's physical, psychological, and 14.4 Remote monitoring (using an implanted device) • Focus on complete symptom relief from both HF and other Management adapted in response to monitoring thoracic imped- • Advanced care planning, taking account of preferences for place of ance (as an indirect measure of intrathoracic fluid) has not been death and resuscitation (which may include deactivating ICD) shown to improve outcomes.Treatment adjusted in responseto pulmonary artery pressure measured using an implanted HF ¼ heart failure; ICD ¼ implantable cardioverter-defibrillator.
monitor did reduce hospital admission for HF in one RCT,but the general applicability of this approach is uncertain and aguideline recommendation is not yet possible.
15. Gaps in evidence 14.5 Remote monitoring (no implanted Clinicians responsible for managing patients with HF must fre-quently make treatment decisions without adequate evidence or The optimum approach to non-invasive remote monitoring is un- a consensus of expert opinion. The following is a shortlist of certain, and RCTs performed to date have given inconsistent selected, common issues that deserve to be addressed in future results and do not yet support a guideline recommendation clinical research.
14.6 Structured telephone supportAlthough a meta-analysis of RCTs suggests that structured tele-phone support in addition to conventional care may reduce the risk of hospitalization in patients with HF, few individual RCTs The diagnosis of HF-PEF remains a particular challenge, and the showed this benefit, and the evidence is not robust enough to optimum approach incorporating symptoms, signs, imaging, bio- support a guideline recommendatio markers, and other investigations is uncertain.
14.7 Palliative/supportive/end-of-life care Strain/speckle imaging—value in diagnostic and prognostic as- sessment of both HF-REF and HF-PEF? HF has an unpredictable disease trajectory and it is often difficult Diastolic stress test—value in diagnosis of HF-PEF? to identify a specific time point to consider palliative care. Featuresthat should trigger consideration of palliative care are listed in 15.2 Co-morbidity Tables and At this point in a patient's disease trajectory, The long-term safety and efficacy of many treatments for co- the focus should be on improvement in quality of life, control of morbidities are unknown, but are of great interest and importance.
symptoms, early detection, and treatment of episodes of deterior-ation, and on pursuing a holistic approach to patient care, encom- passing physical, psychological, social, and spiritual well-being.
Depression—selective serotonin reuptake inhibitors, cognitive Liaison between the specialist palliative care service and the HF team and/or the primary care physician, using a shared-care ap- Diabetes—metformin, GLP-1 agonists/analogues, DPP IV inhibi- proach, is required in order to address and coordinate the patients' tors, SGLT-2 inhibitors? care optimally. Palliative care has been discussed in detail in a pos- ition paper from the Heart Failure Association.
† patients with a normal QRS duration but echocardiographic † patients with RBBB and IVCD? Salt restriction—is it effective and safe? † patients in AF? Cardiac cachexia—is there an effective and safe treatment? LVADs—the long-term efficacy and safety of LVADs as an alterna- tive to heart transplantation or medical therapy remains 15.4 Pharmacological therapy Remote monitoring—the long-term efficacy and safety of Digoxin—efficacy and safety in modern era of pharmacological the various remote monitoring strategies available remain and device therapy? Hydralazine and ISDN—efficacy and safety in non-black Renin inhibition—is it an effective and safe alternative to/add- 15.6 Acute heart failure ition to ACE inhibition? The treatment of acute heart failure remains largely opinion-based New oral anticoagulants—efficacy and safety compared with with little good evidence to guide therapy.
aspirin in patients in sinus rhythm? Clopidogrel and other novel antiplatelet agents—efficacy Intravenous nitrates—efficacy and safety still uncertain.
and safety compared with aspirin in patients in sinus rhythm? Levosimendan—efficacy and safety still uncertain.
Dual neprilysin/angiotensin receptor inhibitors—efficacy Omecamtiv mecarbil—is it effective and safe? and safety compared with an ACE inhibitor? Ultrafiltration—efficacy and safety unknown.
15.7 End-of-life care CRT—the efficacy and safety of CRT remains unknown in certain What is the optimum palliative care package? groups of patients.
When should palliative care be started? The CME text ‘European Guidelines on cardiovascular disease prevention in clinical practice (version 2012)' is accredited by the European Board for Accreditation in Cardiology(EBAC). EBAC works according to the quality standards of the European Accreditation Council for Continuing Medical Education (EACCME), which is an institution of the EuropeanUnion of Medical Specialists (UEMS). In compliance with EBAC/EACCME guidelines, all authors participating in this programme have disclosed potential conflicts of interest thatmight cause a bias in the article. The Organizing Committee is responsible for ensuring that all potential conflicts of interest relevant to the programme are declared to the parti-cipants prior to the CME activities.
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