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: [email protected]
(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
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
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
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
New York Heart Association
Defibrillators in Non-ischemic Cardiomyopathy
Optimal Therapy in Myocardial infarction with
the Angiotensin II Antagonist Losartan
Digitalis Investigation Group
Perindopril for Elderly People with Chronic
positron emission tomography
extracorporeal membrane oxygenation
polyunsaturated fatty acid
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
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
Suggested wording to use
Evidence and/or general agreement
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.
Weight of evidence/opinion is in
Should be considered
favour of usefulness/efficacy.
Usefulness/efficacy is less well
May be considered
established by evidence/opinion.
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
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
The ESC CPG supervises and coordinates the preparation of
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,
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
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-
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-
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,
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-
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-
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)
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
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
Decompensated HF, anaemia, fever, hyperthyroidism
Clinical assessment Laboratory investigation
Beta-blockade, digoxin, ivabradine, verapamil, diltiazem
Review drug therapy
HypothyroidismSick sinus syndrome
Hyperthyroidism, infection, mitral valve disease
Slow AV conduction, anticoagulation, pharmacological
cardioversion, electrical cardioversion, catheter ablation
Decompensated HF, infarction
Ischaemia, infarction, cardiomyopathy, myocarditis
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
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
(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,
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
Review drug therapy
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
Treat thyroid abnormality
Reconsider amiodarone use
Proteinuria, glycosuria, bacteria
Diagnostic work-up Rule out infection, diabetes
International normalized ratio >3.5
Review anticoagulant dose
Assess liver function
Review drug therapy
CRP >10 mg/L, neutrophilic leukocytosis
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
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
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
Eosinophilic syndromes +
Iron: haemochromatosis +
Endomyocardial fibrosis +
High quality images
Relatively low cost
Image quality limited Limited
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.
eHaemodynamic evaluation (constriction).
fDescribes disease activity by contrast-enhanced CMR.
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
LV global systolic dysfunction
LV fractional shortening
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
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
Grey zone (additional parameters necessary)
Mitral inflow E/A ratiob
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
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
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
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
† 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.
† 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.
† 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
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,
though its findings were generally consistent with the above
† 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
† 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.
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
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
† 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.
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
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
† 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
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
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-
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-
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.
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.
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.
† 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
aClass of recommendation.
bLevel of evidence.
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
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
(or rate–limiting CCB)
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
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
(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.
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
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.
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.
aClass of recommendation.
bLevel of evidence.
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,
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.
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
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
aClass of recommendation.
bLevel of evidence.
† 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
11. Importance and management
11.4 Asthma: see chronic obstructive
of other co-morbidity in heart
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
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.
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
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
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.
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.
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
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.
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 therapy126.96.36.199 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
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)
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.
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
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.
188.8.131.52 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
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
Section 7.2 and Web Table 13). As the dose of MRA used to treat
25–75 µg/kg over 10–20
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
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
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
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
aClass of recommendation.
bLevel of evidence.
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
to consider intubation and ventilation.
Non-invasive ventilationContinuous positive airway pressure (CPAP) and non-invasive
184.108.40.206 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
of loop diuretic1
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
Consider vasodilator (e.g. NTG8)
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
• 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 220.127.116.11) 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).
• Treat symptoms
• 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
• 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
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
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-
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
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).
End-stage heart failure with severe symptoms,
a poor prognosis, and no remaining alternative
Secondary mitral regurgitation
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
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
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
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.
In some patients, LV reverse remodelling and functional
aClass of recommendation.
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
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
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.
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
• 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
• 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
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
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.
CME questions for this article are available at: European Heart Journal and European Society of Cardiology
7. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: patho-
physiology, diagnosis, and treatment. Eur Heart J 2011;32:670–679.
1. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P,
8. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA,
Poole-Wilson PA, Stromberg A, van Veldhuisen DJ, Atar D, Hoes AW,
Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF,
Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K. ESC guidelines for
Borbely A, Edes I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K,
the diagnosis and treatment of acute and chronic heart failure 2008: the Task
Fraser AG, Brutsaert DL. How to diagnose diastolic heart failure: a consensus
Force for the diagnosis and treatment of acute and chronic heart failure 2008
statement on the diagnosis of heart failure with normal left ventricular ejection
of the European Society of Cardiology. Developed in collaboration with
fraction by the Heart Failure and Echocardiography Associations of the Euro-
the Heart Failure Association of the ESC (HFA) and endorsed by the
pean Society of Cardiology. Eur Heart J 2007;28:2539–2550.
European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail 2008;
9. Marwick TH, Raman SV, Carrio I, Bax JJ. Recent developments in heart failure
imaging. JACC Cardiovasc Imaging 2010;3:429–439.
2. Davie AP, Francis CM, Caruana L, Sutherland GR, McMurray JJ. Assessing diag-
10. Paterson DI, O'Meara E, Chow BJ, Ukkonen H, Beanlands RS. Recent advances
nosis in heart failure: which features are any use? QJM 1997;90:335–339.
in cardiac imaging for patients with heart failure. Curr Opin Cardiol 2011;26:
3. Mant J, Doust J, Roalfe A, Barton P, Cowie MR, Glasziou P, Mant D, McManus RJ,
Holder R, Deeks J, Fletcher K, Qume M, Sohanpal S, Sanders S, Hobbs FD. Sys-
11. McMurray JJ, Clinical practice. Systolic heart failure. N Engl J Med 2010;362:
tematic review and individual patient data meta-analysis of diagnosis of heart
failure, with modelling of implications of different diagnostic strategies in
12. Chen J, Normand SL, Wang Y, Krumholz HM. National and regional trends in
primary care. Health Technol Assess 2009;13:1–207, iii.
heart failure hospitalization and mortality rates for Medicare beneficiaries,
4. Oudejans I, Mosterd A, Bloemen JA, Valk MJ, van Velzen E, Wielders JP,
1998–2008. JAMA 2011;306:1669–1678.
Zuithoff NP, Rutten FH, Hoes AW. Clinical evaluation of geriatric outpatients
13. Dunlay SM, Redfield MM, Weston SA, Therneau TM, Hall Long K, Shah ND,
with suspected heart failure: value of symptoms, signs, and additional tests.
Roger VL. Hospitalizations after heart failure diagnosis a community perspective.
Eur J Heart Fail 2011;13:518–527.
J Am Coll Cardiol 2009;54:1695–1702.
5. Fonseca C. Diagnosis of heart failure in primary care. Heart Fail Rev 2006;11:
14. Khot UN, Jia G, Moliterno DJ, Lincoff AM, Khot MB, Harrington RA, Topol EJ.
Prognostic importance of physical examination for heart failure in
6. Kelder JC, Cramer MJ, van Wijngaarden J, van Tooren R, Mosterd A, Moons KG,
non-ST-elevation acute coronary syndromes: the enduring value of Killip classi-
Lammers JW, Cowie MR, Grobbee DE, Hoes AW. The diagnostic value of phys-
fication. JAMA 2003;290:2174–2181.
ical examination and additional testing in primary care patients with suspected
15. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007;93:
heart failure. Circulation 2011;124:2865–2873.
16. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ,
34. Sicari R, Nihoyannopoulos P, Evangelista A, Kasprzak J, Lancellotti P,
Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H,
Poldermans D, Voigt JU, Zamorano JL. Stress echocardiography expert consen-
McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A,
sus statement: European Association of Echocardiography (EAE) (a registered
Wolpert C, Zipes DP. HRS/EHRA expert consensus statement on the state
branch of the ESC). Eur J Echocardiogr 2008;9:415–437.
of genetic testing for the channelopathies and cardiomyopathies: this document
35. Davie AP, Francis CM, Love MP, Caruana L, Starkey IR, Shaw TR, Sutherland GR,
was developed as a partnership between the Heart Rhythm Society (HRS) and
McMurray JJ. Value of the electrocardiogram in identifying heart failure due to
the European Heart Rhythm Association (EHRA). Heart Rhythm 2011;8:
left ventricular systolic dysfunction. BMJ 1996;312:222.
36. Thomas JT, Kelly RF, Thomas SJ, Stamos TD, Albasha K, Parrillo JE, Calvin JE.
17. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular
Utility of history, physical examination, electrocardiogram, and chest radiograph
systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll
for differentiating normal from decreased systolic function in patients with heart
failure. Am J Med 2002;112:437–445.
18. Lam CS, Donal E, Kraigher-Krainer E, Vasan RS. Epidemiology and clinical course
37. Khunti K, Squire I, Abrams KR, Sutton AJ. Accuracy of a 12-lead electrocardio-
of heart failure with preserved ejection fraction. Eur J Heart Fail 2011;13:18–28.
gram in screening patients with suspected heart failure for open access echocar-
19. Meta-analysis Global Group in Chronic Heart Failure (MAGGIC). The survival of
diography: a systematic review and meta-analysis. Eur J Heart Fail 2004;6:
patients with heart failure with preserved or reduced left ventricular ejection
fraction: an individual patient data meta-analysis. Eur Heart J 2012;33:1750–1757.
38. Madias JE. Why recording of an electrocardiogram should be required in every
20. Shah AM, Mann DL. In search of new therapeutic targets and strategies for heart
inpatient and outpatient encounter of patients with heart failure. Pacing Clin Elec-
failure: recent advances in basic science. Lancet 2011;378:704–712.
21. Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJ. More ‘malignant' than
39. Ewald B, Ewald D, Thakkinstian A, Attia J. Meta-analysis of B type natriuretic
cancer? Five-year survival following a first admission for heart failure. Eur J Heart
peptide and N-terminal pro B natriuretic peptide in the diagnosis of clinical
heart failure and population screening for left ventricular systolic dysfunction.
22. Stewart S, Ekman I, Ekman T, Oden A, Rosengren A. Population impact of heart
Intern Med J 2008;38:101–113.
failure and the most common forms of cancer: a study of 1 162 309 hospital
40. Doust JA, Glasziou PP, Pietrzak E, Dobson AJ. A systematic review of the diag-
cases in Sweden (1988 to 2004). Circ Cardiovasc Qual Outcomes 2010;3:573–580.
nostic accuracy of natriuretic peptides for heart failure. Arch Intern Med 2004;
23. Jhund PS, Macintyre K, Simpson CR, Lewsey JD, Stewart S, Redpath A,
Chalmers JW, Capewell S, McMurray JJ. Long-term trends in first hospitalization
41. Zaphiriou A, Robb S, Murray-Thomas T, Mendez G, Fox K, McDonagh T,
for heart failure and subsequent survival between 1986 and 2003: a population
Hardman SM, Dargie HJ, Cowie MR. The diagnostic accuracy of plasma BNP
study of 5.1 million people. Circulation 2009;119:515–523.
and NTproBNP in patients referred from primary care with suspected heart
24. Rutten FH, Moons KG, Cramer MJ, Grobbee DE, Zuithoff NP, Lammers JW,
failure: results of the UK natriuretic peptide study. Eur J Heart Fail 2005;7:
Hoes AW. Recognising heart failure in elderly patients with stable chronic ob-
structive pulmonary disease in primary care: cross sectional diagnostic study.
42. Maisel A, Mueller C, Adams K Jr, Anker SD, Aspromonte N, Cleland JG,
Cohen-Solal A, Dahlstrom U, DeMaria A, Di Somma S, Filippatos GS,
Fonarow GC, Jourdain P, Komajda M, Liu PP, McDonagh T, McDonald K,
25. Hawkins NM, Petrie MC, Jhund PS, Chalmers GW, Dunn FG, McMurray JJ. Heart
Mebazaa A, Nieminen MS, Peacock WF, Tubaro M, Valle R, Vanderhyden M,
failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epi-
Yancy CW, Zannad F, Braunwald E. State of the art: using natriuretic peptide
demiology. Eur J Heart Fail 2009;11:130–139.
levels in clinical practice. Eur J Heart Fail 2008;10:824–839.
26. Daniels LB, Clopton P, Bhalla V, Krishnaswamy P, Nowak RM, McCord J,
43. Fuat A, Murphy JJ, Hungin AP, Curry J, Mehrzad AA, Hetherington A, Johnston JI,
Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AH,
Smellie WS, Duffy V, Cawley P. The diagnostic accuracy and utility of a B-type
Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC,
natriuretic peptide test in a community population of patients with suspected
McCullough PA, Maisel AS. How obesity affects the cut-points for B-type natri-
heart failure. Br J Gen Pract 2006;56:327–333.
uretic peptide in the diagnosis of acute heart failure. Results from the Breathing
44. Yamamoto K, Burnett JC Jr, Bermudez EA, Jougasaki M, Bailey KR, Redfield MM.
Not Properly Multinational Study. Am Heart J 2006;151:999–1005.
Clinical criteria and biochemical markers for the detection of systolic dysfunc-
27. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K,
tion. J Card Fail 2000;6:194–200.
Solomon SD, Louie EK, Schiller NB. Guidelines for the echocardiographic as-
45. Cowie MR, Struthers AD, Wood DA, Coats AJ, Thompson SG,
sessment of the right heart in adults: a report from the American Society of
Poole-Wilson PA, Sutton GC. Value of natriuretic peptides in assessment of
Echocardiography endorsed by the European Association of Echocardiography,
patients with possible new heart failure in primary care. Lancet 1997;350:
a registered branch of the European Society of Cardiology, and the Canadian
Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685–713; quiz
46. Krishnaswamy P, Lubien E, Clopton P, Koon J, Kazanegra R, Wanner E,
Gardetto N, Garcia A, DeMaria A, Maisel AS. Utility of B-natriuretic peptide
28. Dokainish H, Nguyen JS, Bobek J, Goswami R, Lakkis NM. Assessment of the
levels in identifying patients with left ventricular systolic or diastolic dysfunction.
American Society of Echocardiography-European Association of Echocardiog-
Am J Med 2001;111:274–279.
raphy guidelines for diastolic function in patients with depressed ejection frac-
47. Kelder JC, Cowie MR, McDonagh TA, Hardman SM, Grobbee DE, Cost B,
tion: an echocardiographic and invasive haemodynamic study. Eur J
Hoes AW. Quantifying the added value of BNP in suspected heart failure in
general practice: an individual patient data meta-analysis. Heart 2011;97:
29. Kirkpatrick JN, Vannan MA, Narula J, Lang RM. Echocardiography in heart failure:
applications, utility, and new horizons. J Am Coll Cardiol 2007;50:381–396.
48. Kelder JC, Cramer MJ, Verweij WM, Grobbee DE, Hoes AW. Clinical utility of
30. Lancellotti P, Moura L, Pierard LA, Agricola E, Popescu BA, Tribouilloy C,
three B-type natriuretic peptide assays for the initial diagnostic assessment of
Hagendorff A, Monin JL, Badano L, Zamorano JL. European Association of
new slow-onset heart failure. J Card Fail 2011;17:729–734.
Echocardiography recommendations for the assessment of valvular regurgita-
49. Gustafsson F, Steensgaard-Hansen F, Badskjaer J, Poulsen AH, Corell P,
tion. Part 2: mitral and tricuspid regurgitation (native valve disease). Eur J Echo-
Hildebrandt P. Diagnostic and prognostic performance of N-terminal proBNP
in primary care patients with suspected heart failure. J Card Fail 2005;11:
31. Lancellotti P, Tribouilloy C, Hagendorff A, Moura L, Popescu BA, Agricola E,
Monin JL, Pierard LA, Badano L, Zamorano JL. European Association of Echocar-
50. Nielsen OW, Rasmussen V, Christensen NJ, Hansen JF. Neuroendocrine testing
diography recommendations for the assessment of valvular regurgitation. Part 1:
in community patients with heart disease: plasma N-terminal proatrial natriuretic
aortic and pulmonary regurgitation (native valve disease). Eur J Echocardiogr 2010;
peptide predicts morbidity and mortality stronger than catecholamines and
heart rate variability. Scand J Clin Lab Invest 2004;64:619–628.
32. Popescu BA, Andrade MJ, Badano LP, Fox KF, Flachskampf FA, Lancellotti P,
51. Maisel A, Mueller C, Nowak R, Peacock WF, Landsberg JW, Ponikowski P,
Varga A, Sicari R, Evangelista A, Nihoyannopoulos P, Zamorano JL,
Mockel M, Hogan C, Wu AH, Richards M, Clopton P, Filippatos GS,
Derumeaux G, Kasprzak JD, Roelandt JR. European Association of Echocardiog-
Di Somma S, Anand I, Ng L, Daniels LB, Neath SX, Christenson R, Potocki M,
raphy recommendations for training, competence, and quality improvement in
McCord J, Terracciano G, Kremastinos D, Hartmann O, von Haehling S,
echocardiography. Eur J Echocardiogr 2009;10:893–905.
Bergmann A, Morgenthaler NG, Anker SD. Mid-region pro-hormone markers
33. Nagueh SF, Bhatt R, Vivo RP, Krim SR, Sarvari SI, Russell K, Edvardsen T,
for diagnosis and prognosis in acute dyspnea: results from the BACH (Biomar-
Smiseth OA, Estep JD. Echocardiographic evaluation of hemodynamics in
kers in Acute Heart Failure) trial. J Am Coll Cardiol 2010;55:2062–2076.
patients with decompensated systolic heart failure. Circ Cardiovasc Imaging
52. Schwitter J. Extending the frontiers of cardiac magnetic resonance. Circulation
53. Gebker R, Schwitter J, Fleck E, Nagel E. How we perform myocardial perfusion
73. Arena R, Myers J, Guazzi M. Cardiopulmonary exercise testing is a core assess-
with cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2007;9:
ment for patients with heart failure. Congest Heart Fail 2011;17:115–119.
74. Wedel H, McMurray JJ, Lindberg M, Wikstrand J, Cleland JG, Cornel JH,
54. Beller GA, Heede RC. SPECT imaging for detecting coronary artery disease and
Dunselman P, Hjalmarson A, Kjekshus J, Komajda M, Kuusi T, Vanhaecke J,
determining prognosis by noninvasive assessment of myocardial perfusion and
Waagstein F. Predictors of fatal and non-fatal outcomes in the Controlled Rosu-
myocardial viability. J Cardiovasc Transl Res 2011;4:416–424.
vastatin Multinational Trial in Heart Failure (CORONA): incremental value of
55. Leong DP, De Pasquale CG, Selvanayagam JB. Heart failure with normal ejection
apolipoprotein A-1, high-sensitivity C-reactive peptide and N-terminal pro
fraction: the complementary roles of echocardiography and CMR imaging. JACC
B-type natriuretic peptide. Eur J Heart Fail 2009;11:281–291.
Cardiovasc Imaging 2010;3:409–420.
75. Allen LA, Felker GM, Pocock S, McMurray JJ, Pfeffer MA, Swedberg K, Wang D,
56. Myerson SG. Valvular and hemodynamic assessment with CMR. Heart Fail Clin
Yusuf S, Michelson EL, Granger CB. Liver function abnormalities and outcome in
patients with chronic heart failure: data from the Candesartan in Heart Failure:
57. Raman SV, Simonetti OP. The CMR examination in heart failure. Heart Fail Clin
Assessment of Reduction in Mortality and Morbidity (CHARM) program. Eur J
Heart Fail 2009;11:170–177.
58. Sheikine Y, Di Carli MF. Integrated PET/CT in the assessment of etiology and
76. Jackson CE, Solomon SD, Gerstein HC, Zetterstrand S, Olofsson B,
viability in ischemic heart failure. Curr Heart Fail Rep 2008;5:136–142.
Michelson EL, Granger CB, Swedberg K, Pfeffer MA, Yusuf S, McMurray JJ. Albu-
59. Miller JM, Rochitte CE, Dewey M, Arbab-Zadeh A, Niinuma H, Gottlieb I,
minuria in chronic heart failure: prevalence and prognostic importance. Lancet
Paul N, Clouse ME, Shapiro EP, Hoe J, Lardo AC, Bush DE, de Roos A,
Cox C, Brinker J, Lima JA. Diagnostic performance of coronary angiography
77. Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJ, Pfeffer MA, Swedberg K,
by 64-row CT. N Engl J Med 2008;359:2324–2336.
Wang D, Yusuf S, Michelson EL, Granger CB. Red cell distribution width as a
60. Beanlands RS, Nichol G, Huszti E, Humen D, Racine N, Freeman M,
novel prognostic marker in heart failure: data from the CHARM Program and
Gulenchyn KY, Garrard L, deKemp R, Guo A, Ruddy TD, Benard F, Lamy A,
the Duke Databank. J Am Coll Cardiol 2007;50:40–47.
Iwanochko RM. F-18-fluorodeoxyglucose positron emission tomography
78. Pocock SJ, Wang D, Pfeffer MA, Yusuf S, McMurray JJ, Swedberg KB, Ostergren J,
imaging-assisted management of patients with severe left ventricular dysfunction
Michelson EL, Pieper KS, Granger CB. Predictors of mortality and morbidity in
and suspected coronary disease: a randomized, controlled trial (PARR-2). J Am
patients with chronic heart failure. Eur Heart J 2006;27:65–75.
Coll Cardiol 2007;50:2002–2012.
79. Komajda M, Carson PE, Hetzel S, McKelvie R, McMurray J, Ptaszynska A,
61. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA,
Zile MR, Demets D, Massie BM. Factors associated with outcome in heart
Picard MH, Roman MJ, Seward J, Shanewise J, Solomon S, Spencer KT,
failure with preserved ejection fraction: findings from the Irbesartan in Heart
St John Sutton M, Stewart W. Recommendations for chamber quantification.
Failure with Preserved Ejection Fraction Study (I-PRESERVE). Circ Heart Fail
Eur J Echocardiogr 2006;7:79–108.
80. Ketchum ES, Levy WC. Establishing prognosis in heart failure: a multimarker
62. Lang RM, Badano LP, Tsang W, Adams DH, Agricola E, Buck T, Faletra FF,
approach. Prog Cardiovasc Dis 2011;54:86–96.
Franke A, Hung J, de Isla LP, Kamp O, Kasprzak JD, Lancellotti P,
81. Stewart S, Jenkins A, Buchan S, McGuire A, Capewell S, McMurray JJ. The
Marwick TH, McCulloch ML, Monaghan MJ, Nihoyannopoulos P, Pandian NG,
current cost of heart failure to the National Health Service in the UK. Eur J
Pellikka PA, Pepi M, Roberson DA, Shernan SK, Shirali GS, Sugeng L, Ten
Heart Fail 2002;4:361–371.
Cate FJ, Vannan MA, Zamorano JL, Zoghbi WA. EAE/ASE Recommendations
82. Masson S, Latini R, Anand IS, Barlera S, Angelici L, Vago T, Tognoni G, Cohn JN.
for Image Acquisition and Display Using Three-Dimensional Echocardiography.
Prognostic value of changes in N-terminal pro-brain natriuretic peptide in
Eur Heart J Cardiovasc Imaging 2012; 13:1–46.
Val-HeFT (Valsartan Heart Failure Trial). J Am Coll Cardiol 2008;52:997–1003.
63. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA,
83. Wong M, Staszewsky L, Latini R, Barlera S, Volpi A, Chiang YT, Benza RL,
Waggoner AD, Flachskampf FA, Pellikka PA, Evangelisa A. Recommendations
Gottlieb SO, Kleemann TD, Rosconi F, Vandervoort PM, Cohn JN. Valsartan
for the evaluation of left ventricular diastolic function by echocardiography.
benefits left ventricular structure and function in heart failure: Val-HeFT echo-
Eur J Echocardiogr 2009;10:165–193.
cardiographic study. J Am Coll Cardiol 2002;40:970–975.
64. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quinones MA. Doppler
84. Ekman I, Cleland JG, Andersson B, Swedberg K. Exploring symptoms in chronic
tissue imaging: a noninvasive technique for evaluation of left ventricular relax-
heart failure. Eur J Heart Fail 2005;7:699–703.
ation and estimation of filling pressures. J Am Coll Cardiol 1997;30:1527–1533.
85. Packer M, Narahara KA, Elkayam U, Sullivan JM, Pearle DL, Massie BM,
65. Schwitter J, Arai AE. Assessment of cardiac ischaemia and viability: role of car-
Creager MA. Double-blind, placebo-controlled study of the efficacy of flosequi-
diovascular magnetic resonance. Eur Heart J 2011;32:799–809.
nan in patients with chronic heart failure. Principal Investigators of the REFLECT
66. Kilner PJ, Geva T, Kaemmerer H, Trindade PT, Schwitter J, Webb GD. Recom-
Study. J Am Coll Cardiol 1993;22:65–72.
mendations for cardiovascular magnetic resonance in adults with congenital
86. Cowley AJ, Stainer K, Wynne RD, Rowley JM, Hampton JR. Comparison of the
heart disease from the respective working groups of the European Society of
effects of captopril and enoximone in patients with severe heart failure: a
Cardiology. Eur Heart J 2010;31:794–805.
placebo controlled double-blind study. Int J Cardiol 1989;24:311–316.
67. Luchinger R, Schwitter J, Bruder O. Safety of CMR. In: Schwitter J, ed. CMR
87. Effects of enalapril on mortality in severe congestive heart failure. Results of the
Update 2012. 2nd ed. Lausanne; p. 31–51. ISBN: 978-3-033-01674-3.
Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The
68. Bruder O, Schneider S, Nothnagel D, Pilz G, Lombardi M, Sinha A, Wagner A,
CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429–1435.
Dill T, Frank H, van Rossum A, Schwitter J, Nagel E, Senges J, Sabin G,
88. Effect of enalapril on survival in patients with reduced left ventricular ejection
Sechtem U, Mahrholdt H. Acute adverse reactions to gadolinium-based contrast
fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med
agents in CMR: multicenter experience with 17,767 patients. from the EuroCMR
Registry. J Am Coll Cardiol-Cardiovasc Imaging 2011;4:1171–1176.
89. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting
69. Sheikine Y, Di Carli MF. Integrated PET/CT in the assessment of etiology and
enzyme inhibitors on mortality and morbidity in patients with heart failure. Col-
viability in ischemic heart failure. Curr Heart Fail Rep 2008;5:136–142.
laborative Group on ACE Inhibitor Trials. JAMA 1995;273:1450–1456.
70. Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, Klauss V,
90. Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD,
Manoharan G, Engstrom T, Oldroyd KG, Ver Lee PN, MacCarthy PA,
Massie BM, Ryden L, Thygesen K, Uretsky BF. Comparative effects of low and
Fearon WF. Fractional flow reserve versus angiography for guiding percutaneous
high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbid-
coronary intervention. N Engl J Med 2009;360:213–224.
ity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999;
71. Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, Garg S, Huber K,
James S, Knuuti J, Lopez-Sendon J, Marco J, Menicanti L, Ostojic M, Piepoli MF,
91. The SOLVD Investigators. Effect of enalapril on mortality and the development
Pirlet C, Pomar JL, Reifart N, Ribichini FL, Schalij MJ, Sergeant P, Serruys PW,
of heart failure in asymptomatic patients with reduced left ventricular ejection
Silber S, Sousa Uva M, Taggart D. Guidelines on myocardial revascularization.
fractions. N Engl J Med 1992;327:685–691.
Eur Heart J 2010;31:2501–2555.
92. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet
72. Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U,
Levine GN, Narula J, Starling RC, Towbin J, Virmani R. The role of endomyocar-
93. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Rando-
dial biopsy in the management of cardiovascular disease: a scientific statement
mised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;
from the American Heart Association, the American College of Cardiology,
and the European Society of Cardiology Endorsed by the Heart Failure
94. Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J,
Society of America and the Heart Failure Association of the European Society
Wikstrand J, El Allaf D, Vitovec J, Aldershvile J, Halinen M, Dietz R,
of Cardiology. Eur Heart J 2007;28:3076–3093.
Neuhaus KL, Janosi A, Thorgeirsson G, Dunselman PH, Gullestad L, Kuch J,
Herlitz J, Rickenbacher P, Ball S, Gottlieb S, Deedwania P. Effects of
angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet
controlled-release metoprolol on total mortality, hospitalizations, and well-being
in patients with heart failure: the Metoprolol CR/XL Randomized Intervention
112. Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A,
Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA
Lerebours G, Tavazzi L. Ivabradine and outcomes in chronic heart failure
(SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–885.
95. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL,
113. The effect of digoxin on mortality and morbidity in patients with heart failure.
Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL. Effect of carve-
The Digitalis Investigation Group. N Engl J Med 1997;336:525–533.
dilol on survival in severe chronic heart failure. N Engl J Med 2001;344:
114. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE,
Dunkman WB, Jacobs W, Francis GS, Flohr KH, for the Veterans Administration
96. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, Mohacsi P,
Cooperative Study Group. Effect of vasodilator therapy on mortality in chronic
Rouleau JL, Tendera M, Staiger C, Holcslaw TL, Amann-Zalan I, DeMets DL.
congestive heart failure. Results of a Veterans Administration Cooperative Study.
Effect of carvedilol on the morbidity of patients with severe chronic heart
N Engl J Med 1986;314:1547–1552.
failure: results of the carvedilol prospective randomized cumulative survival
115. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R,
(COPERNICUS) study. Circulation 2002;106:2194–2199.
Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD,
97. Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A,
Doherty J, Hughes CV, Carson P, Cintron G, Shabetai R, Haakenson C. A com-
Borbola J, Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, Soler-Soler J,
parison of enalapril with hydralazine–isosorbide dinitrate in the treatment of
Tavazzi L, Spinarova L, Toman J, Bohm M, Anker SD, Thompson SG,
chronic congestive heart failure. N Engl J Med 1991;325:303–310.
Poole-Wilson PA. Randomized trial to determine the effect of nebivolol on mor-
116. Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R Jr, Ferdinand K,
tality and cardiovascular hospital admission in elderly patients with heart failure
Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN. Combination of isosor-
(SENIORS). Eur Heart J 2005;26:215–225.
bide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:
98. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM,
Shusterman NH. The effect of carvedilol on morbidity and mortality in patients
117. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D,
with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J
Nicolosi GL, Porcu M, Tognoni G. Effect of n-3 polyunsaturated fatty acids in
patients with chronic heart failure (the GISSI-HF trial): a randomised, double-
99. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J.
blind, placebo-controlled trial. Lancet 2008;372:1223–1230.
The effect of spironolactone on morbidity and mortality in patients with severe
118. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ,
heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med
Konstam MA, Riegger G, Klinger GH, Neaton J, Sharma D, Thiyagarajan B.
Effect of losartan compared with captopril on mortality in patients with symp-
100. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H,
tomatic heart failure: randomised trial—the Losartan Heart Failure Survival
Vincent J, Pocock SJ, Pitt B. Eplerenone in patients with systolic heart failure
Study ELITE II. Lancet 2000;355:1582–1587.
and mild symptoms. N Engl J Med 2011;364:11–21.
119. Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M, Martinez FA,
101. Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, Torp-Pedersen C,
Riegger GA, Malbecq W, Smith RD, Guptha S, Poole-Wilson PA. Effects of high-
Ball S, Pogue J, Moye L, Braunwald E. Long-term ACE-inhibitor therapy in
dose versus low-dose losartan on clinical outcomes in patients with heart failure
patients with heart failure or left-ventricular dysfunction: a systematic overview
(HEAAL study): a randomised, double-blind trial. Lancet 2009;374:1840–1848.
of data from individual patients. ACE-Inhibitor Myocardial Infarction Collabora-
120. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP,
tive Group. Lancet 2000;355:1575–1581.
Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M,
102. McMurray J, Cohen-Solal A, Dietz R, Eichhorn E, Erhardt L, Hobbs FD, Krum H,
Edwards S, Zelenkofske S, Sellers MA, Califf RM. Valsartan, captopril, or both
Maggioni A, McKelvie RS, Pina IL, Soler-Soler J, Swedberg K. Practical recom-
in myocardial infarction complicated by heart failure, left ventricular dysfunction,
mendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists
or both. N Engl J Med 2003;349:1893–1906.
and angiotensin receptor blockers in heart failure: putting guidelines into prac-
121. Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and mor-
tice. Eur J Heart Fail 2005;7:710–721.
bidity in high-risk patients after acute myocardial infarction: the OPTIMAAL ran-
103. Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker
domised trial. Optimal Trial in Myocardial Infarction with Angiotensin II
bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;
Antagonist Losartan. Lancet 2002;360:752–760.
122. Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable
104. Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P,
coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a
Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C,
randomised, double-blind, placebo-controlled trial. Lancet 2008;372:807–816.
Scherhag A, Skene A. Comparison of carvedilol and metoprolol on clinical out-
123. Hood WB Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treat-
comes in patients with chronic heart failure in the Carvedilol Or Metoprolol
ment of congestive heart failure in patients in sinus rhythm: a systematic review
European Trial (COMET): randomised controlled trial. Lancet 2003;362:7–13.
and meta-analysis. J Card Fail 2004;10:155–164.
105. Krum H, Roecker EB, Mohacsi P, Rouleau JL, Tendera M, Coats AJ, Katus HA,
124. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after
Fowler MB, Packer M. Effects of initiating carvedilol in patients with severe
myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per
chronic heart failure: results from the COPERNICUS Study. JAMA 2003;289:
lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 1999;354:447–455.
125. Rauch B, Schiele R, Schneider S, Diller F, Victor N, Gohlke H, Gottwik M,
106. Jondeau G, Neuder Y, Eicher JC, Jourdain P, Fauveau E, Galinier M, Jegou A,
Steinbeck G, Del Castillo U, Sack R, Worth H, Katus H, Spitzer W, Sabin G,
Bauer F, Trochu JN, Bouzamondo A, Tanguy ML, Lechat P. B-CONVINCED:
Senges J. OMEGA, a randomized, placebo-controlled trial to test the effect of
Beta-blocker CONtinuation Vs. INterruption in patients with Congestive
highly purified omega-3 fatty acids on top of modern guideline-adjusted
heart failure hospitalizED for a decompensation episode. Eur Heart J 2009;30:
therapy after myocardial infarction. Circulation 2010;122:2152–2159.
126. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O,
107. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R,
Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R,
Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in
Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D, Bax J, Vahanian A,
patients with left ventricular dysfunction after myocardial infarction. N Engl J
Auricchio A, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R,
Filippatos G, Funck-Brentano C, Hasdai D, Hoes A, Kearney P, Knuuti J,
108. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B,
Kolh P, McDonagh T, Moulin C, Poldermans D, Popescu BA, Sechtem U,
Ostergren J, Pfeffer MA, Swedberg K. Effects of candesartan in patients with
Sirnes PA, Tendera M, Torbicki A, Vardas P, Widimsky P, Windecker S,
chronic heart failure and reduced left-ventricular systolic function intolerant
Berkenboom G, De Graaf J, Descamps O, Gotcheva N, Griffith K, Guida GF,
to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial.
Gulec S, Henkin Y, Huber K, Kesaniemi YA, Lekakis J, Manolis AJ,
Marques-Vidal P, Masana L, McMurray J, Mendes M, Pagava Z, Pedersen T,
109. Maggioni AP, Anand I, Gottlieb SO, Latini R, Tognoni G, Cohn JN. Effects of val-
Prescott E, Rato Q, Rosano G, Sans S, Stalenhoef A, Tokgozoglu L,
sartan on morbidity and mortality in patients with heart failure not receiving
Viigimaa M, Wittekoek ME, Zamorano JL. ESC/EAS Guidelines for the manage-
angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2002;40:1414–1421.
ment of dyslipidaemias: the Task Force for the management of dyslipidaemias of
110. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker
the European Society of Cardiology (ESC) and the European Atherosclerosis
valsartan in chronic heart failure. N Engl J Med 2001;345:1667–1675.
Society (EAS). Eur Heart J 2011;32:1769–1818.
111. McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL,
127. Kjekshus J, Apetrei E, Barrios V, Bohm M, Cleland JG, Cornel JH, Dunselman P,
Olofsson B, Yusuf S, Pfeffer MA. Effects of candesartan in patients with
Fonseca C, Goudev A, Grande P, Gullestad L, Hjalmarson A, Hradec J, Janosi A,
chronic heart failure and reduced left-ventricular systolic function taking
Kamensky G, Komajda M, Korewicki J, Kuusi T, Mach F, Mareev V, McMurray JJ,
Ranjith N, Schaufelberger M, Vanhaecke J, van Veldhuisen DJ, Waagstein F,
Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP,
Wedel H, Wikstrand J. Rosuvastatin in older patients with systolic heart
Page RL, Riegel B. ACC/AHA/ESC 2006 guidelines for management of patients
failure. N Engl J Med 2007;357:2248–2261.
with ventricular arrhythmias and the prevention of sudden cardiac death—ex-
128. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D,
ecutive summary: a report of the American College of Cardiology/American
Nicolosi GL, Porcu M, Tognoni G. Effect of rosuvastatin in patients with
Heart Association Task Force and the European Society of Cardiology Commit-
chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-
tee for Practice Guidelines (Writing Committee to Develop Guidelines for Man-
controlled trial. Lancet 2008;372:1231–1239.
agement of Patients with Ventricular Arrhythmias and the Prevention of Sudden
129. Krum H, Massie B, Abraham WT, Dickstein K, Kober L, McMurray JJ, Desai A,
Cardiac Death) Developed in collaboration with the European Heart Rhythm
Gimpelewicz C, Kandra A, Reimund B, Rattunde H, Armbrecht J. Direct renin
Association and the Heart Rhythm Society. Eur Heart J 2006;27:2099–2140.
inhibition in addition to or as an alternative to angiotensin converting enzyme
144. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in
inhibition in patients with chronic systolic heart failure: rationale and design of
patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhyth-
the Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (AT-
mics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med
MOSPHERE) study. Eur J Heart Fail 2011;13:107–114.
130. Gheorghiade M, Albaghdadi M, Zannad F, Fonarow GC, Bohm M,
145. Kuck KH, Cappato R, Siebels J, Ruppel R. Randomized comparison of antiar-
Gimpelewicz C, Botha J, Moores S, Lewis EF, Rattunde H, Maggioni A. Rationale
rhythmic drug therapy with implantable defibrillators in patients resuscitated
and design of the multicentre, randomized, double-blind, placebo-controlled
from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation
Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT). Eur J Heart
146. Connolly SJ, Gent M, Roberts RS, Dorian P, Roy D, Sheldon RS, Mitchell LB,
130a. Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR,
Green MS, Klein GJ, O'Brien B. Canadian implantable defibrillator study
Ammon SE, Graham S, Sacco RL, Mann DL, Mohr JP, Massie BM, Labovitz AJ,
(CIDS): a randomized trial of the implantable cardioverter defibrillator against
Anker SD, Lok DJ, Ponikowski P, Estol CJ, Lip GY, Di Tullio MR, Sanford AR,
Mejia V, Gabriel AP, Del Valle ML, Buchsbaum R; the WARCEF Investigators.
147. Oseroff O, Retyk E, Bochoeyer A. Subanalyses of secondary prevention implan-
Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J
table cardioverter-defibrillator trials: antiarrhythmics versus implantable defibril-
Med 2012; Published online ahead of print 2 May 2012. PubMed PMID:
lators (AVID), Canadian Implantable Defibrillator Study (CIDS), and Cardiac
Arrest Study Hamburg (CASH). Curr Opin Cardiol 2004;19:26–30.
131. Komajda M, McMurray JJ, Beck-Nielsen H, Gomis R, Hanefeld M, Pocock SJ,
148. Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine JH,
Curtis PS, Jones NP, Home PD. Heart failure events with rosiglitazone in type2 diabetes: data from the RECORD clinical trial. Eur Heart J 2010;31:824–831.
Saksena S, Waldo AL, Wilber D, Brown MW, Heo M. Improved survival with
132. Hernandez AV, Usmani A, Rajamanickam A, Moheet A. Thiazolidinediones and
an implanted defibrillator in patients with coronary disease at high risk for ven-
risk of heart failure in patients with or at high risk of type 2 diabetes mellitus:
tricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Inves-
a meta-analysis and meta-regression analysis of placebo-controlled randomized
tigators. N Engl J Med 1996;335:1933–1940.
clinical trials. Am J Cardiovasc Drugs 2011;11:115–128.
149. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M,
133. Erdmann E, Charbonnel B, Wilcox RG, Skene AM, Massi-Benedetti M, Yates J,
Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N,
Tan M, Spanheimer R, Standl E, Dormandy JA. Pioglitazone use and heart
Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH. Amiodarone or
failure in patients with type 2 diabetes and preexisting cardiovascular disease:
an implantable cardioverter-defibrillator for congestive heart failure. N Engl J
data from the PROactive study (PROactive 08). Diabetes Care 2007;30:
150. Hohnloser SH, Kuck KH, Dorian P, Roberts RS, Hampton JR, Hatala R, Fain E,
134. Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S. Diltiazem increases late-onset
Gent M, Connolly SJ. Prophylactic use of an implantable cardioverter-
congestive heart failure in postinfarction patients with early reduction in ejection
defibrillator after acute myocardial infarction. N Engl J Med 2004;351:
fraction. The Adverse Experience Committee; and the Multicenter Diltiazem
Postinfarction Research Group. Circulation 1991;83:52–60.
151. Steinbeck G, Andresen D, Seidl K, Brachmann J, Hoffmann E, Wojciechowski D,
135. Mamdani M, Juurlink DN, Lee DS, Rochon PA, Kopp A, Naglie G, Austin PC,
Kornacewicz-Jach Z, Sredniawa B, Lupkovics G, Hofgartner F, Lubinski A,
Laupacis A, Stukel TA. Cyclo-oxygenase-2 inhibitors versus non-selective non-
Rosenqvist M, Habets A, Wegscheider K, Senges J. Defibrillator implantation
steroidal anti-inflammatory drugs and congestive heart failure outcomes in
early after myocardial infarction. N Engl J Med 2009;361:1427–1436.
elderly patients: a population-based cohort study. Lancet 2004;363:1751–1756.
152. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP, Calkins H,
136. Huerta C, Varas-Lorenzo C, Castellsague J, Garcia Rodriguez LA. Non-steroidal
Hoch D, Goldberger J, Shalaby A, Sanders WE, Schaechter A, Levine JH. Prophy-
anti-inflammatory drugs and risk of first hospital admission for heart failure in
lactic defibrillator implantation in patients with nonischemic dilated cardiomyop-
the general population. Heart 2006;92:1610–1615.
athy. N Engl J Med 2004;350:2151–2158.
137. Setaro JF, Zaret BL, Schulman DS, Black HR, Soufer R. Usefulness of verapamil
153. Stewart GC, Weintraub JR, Pratibhu PP, Semigran MJ, Camuso JM, Brooks K,
for congestive heart failure associated with abnormal left ventricular diastolic
Tsang SW, Anello MS, Nguyen VT, Lewis EF, Nohria A, Desai AS,
filling and normal left ventricular systolic performance. Am J Cardiol 1990;66:
Givertz MM, Stevenson LW. Patient expectations from implantable defibrillators
to prevent death in heart failure. J Card Fail 2010;16:106–113.
138. Hung MJ, Cherng WJ, Kuo LT, Wang CH. Effect of verapamil in elderly patients
154. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA 3rd,
with left ventricular diastolic dysfunction as a cause of congestive heart failure.
Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D,
Int J Clin Pract 2002;56:57–62.
Zareba W. Cardiac-resynchronization therapy for the prevention of heart-failure
139. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ,
events. N Engl J Med 2009;361:1329–1338.
Michelson EL, Olofsson B, Ostergren J. Effects of candesartan in patients with
155. Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S,
chronic heart failure and preserved left-ventricular ejection fraction: the
Hohnloser SH, Nichol G, Birnie DH, Sapp JL, Yee R, Healey JS, Rouleau JL.
CHARM-Preserved Trial. Lancet 2003;362:777–781.
Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J
140. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. The peri-
ndopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J
156. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P,
DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM.
141. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR,
Cardiac-resynchronization therapy with or without an implantable defibrillator
Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A. Irbesartan in
in advanced chronic heart failure. N Engl J Med 2004;350:2140–2150.
patients with heart failure and preserved ejection fraction. N Engl J Med 2008;
157. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L,
Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality
142. Chung MK, Szymkiewicz SJ, Shao M, Zishiri E, Niebauer MJ, Lindsay BD,
in heart failure. N Engl J Med 2005;352:1539–1549.
Tchou PJ. Aggregate national experience with the wearable cardioverter-
158. Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray J,
defibrillator: event rates, compliance, and survival. J Am Coll Cardiol 2010;56:
Ponikowski P, Priori SG, Sutton R, van Veldhuisen DJ. 2010 focused update of
ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC
143. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M,
Guidelines for the diagnosis and treatment of acute and chronic heart failure
Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA,
and the 2007 ESC Guidelines for cardiac and resynchronization therapy. Devel-
Roden DM, Silka MJ, Tracy C, Blanc JJ, Budaj A, Dean V, Deckers JW,Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J,
oped with the special contribution of the Heart Failure Association and the
Osterspey A, Tamargo JL, Zamorano JL, Smith SC Jr, Jacobs AK, Adams CD,
European Heart Rhythm Association. Eur J Heart Fail 2010;12:1143–1153.
159. Beshai JF, Grimm RA, Nagueh SF, Baker JH 2nd Beau SL, Greenberg SM,
and severe left ventricular systolic dysfunction: a randomised controlled trial.
Pires LA, Tchou PJ. Cardiac-resynchronization therapy in heart failure with
narrow QRS complexes. N Engl J Med 2007;357:2461–2471.
176. Kober L, Torp-Pedersen C, McMurray JJ, Gotzsche O, Levy S, Crijns H, Amlie J,
160. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J,
Carlsen J. Increased mortality after dronedarone therapy for severe heart failure.
Abraham WT, Ghio S, Leclercq C, Bax JJ, Yu CM, Gorcsan J 3rd, St John
N Engl J Med 2008;358:2678–2687.
Sutton M, De Sutter J, Murillo J. Results of the Predictors of Response to
177. Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D,
CRT (PROSPECT) trial. Circulation 2008;117:2608–2616.
Avezum A, Blomstrom P, Borggrefe M, Budaj A, Chen SA, Ching CK,
161. Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C. Rando-
Commerford P, Dans A, Davy JM, Delacretaz E, Di Pasquale G, Diaz R,
mized trial of cardiac resynchronization in mildly symptomatic heart failure
Dorian P, Flaker G, Golitsyn S, Gonzalez-Hermosillo A, Granger CB,
patients and in asymptomatic patients with left ventricular dysfunction and pre-
Heidbuchel H, Kautzner J, Kim JS, Lanas F, Lewis BS, Merino JL, Morillo C,
vious heart failure symptoms. J Am Coll Cardiol 2008;52:1834–1843.
Murin J, Narasimhan C, Paolasso E, Parkhomenko A, Peters NS, Sim KH,
162. Leclercq C, Walker S, Linde C, Clementy J, Marshall AJ, Ritter P, Djiane P,
Stiles MK, Tanomsup S, Toivonen L, Tomcsanyi J, Torp-Pedersen C, Tse HF,
Mabo P, Levy T, Gadler F, Bailleul C, Daubert JC. Comparative effects of per-
Vardas P, Vinereanu D, Xavier D, Zhu J, Zhu JR, Baret-Cormel L, Weinling E,
manent biventricular and right-univentricular pacing in heart failure patients
Staiger C, Yusuf S, Chrolavicius S, Afzal R, Hohnloser SH. Dronedarone in high-
with chronic atrial fibrillation. Eur Heart J 2002;23:1780–1787.
risk permanent atrial fibrillation. N Engl J Med 2011;365:2268–2276.
163. Wilton SB, Leung AA, Ghali WA, Faris P, Exner DV. Outcomes of cardiac resyn-
178. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH,
chronization therapy in patients with versus those without atrial fibrillation: a
Arensberg D, Baker A, Friedman L, Greene HL, Huther ML, Richardson DW,
systematic review and meta-analysis. Heart Rhythm 2011;8:1088–1094.
the CAST Investigators. Mortality and morbidity in patients receiving encainide,
163a. Ganesan AN, Brooks AG, Roberts-Thomson KC, Lau DH, Kalman JM,
flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med
Sanders P. Role of AV nodal ablation in cardiac resynchronization in patients
with coexistent atrial fibrillation and heart failure. A systematic review. J Am
179. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratifi-
Coll Cardiol 2012;59:719–726.
cation for predicting stroke and thromboembolism in atrial fibrillation using a
164. Tops LF, Schalij MJ, Bax JJ. The effects of right ventricular apical pacing on ven-
novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation.
tricular function and dyssynchrony implications for therapy. J Am Coll Cardiol
180. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-
165. Vardas PE, Auricchio A, Blanc JJ, Daubert JC, Drexler H, Ector H, Gasparini M,
friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients
Linde C, Morgado FB, Oto A, Sutton R, Trusz-Gluza M. Guidelines for cardiac
with atrial fibrillation: the Euro Heart Survey. Chest 2010;138:1093–1100.
pacing and cardiac resynchronization therapy: the Task Force for Cardiac
181. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J,
Pacing and Cardiac Resynchronization Therapy of the European Society of Car-
Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R,
diology. Developed in collaboration with the European Heart Rhythm Associ-
Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus war-
ation. Eur Heart J 2007;28:2256–2295.
farin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151.
182. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M,
166. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC,
Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD,
Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A,
Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S,
Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B,
Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS,
Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. Guide-
Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L.
lines for the management of atrial fibrillation: the Task Force for the Manage-
Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;
ment of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur
Heart J 2010;31:2369–2429.
183. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G,
167. Lewis RV, McMurray J, McDevitt DG. Effects of atenolol, verapamil, and xamo-
Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF,
terol on heart rate and exercise tolerance in digitalised patients with chronic
Berkowitz SD, Fox KA, Califf RM. Rivaroxaban versus warfarin in nonvalvular
atrial fibrillation. J Cardiovasc Pharmacol 1989;13:1–6.
atrial fibrillation. N Engl J Med 2011;365:883–891.
168. Khand AU, Rankin AC, Martin W, Taylor J, Gemmell I, Cleland JG. Carvedilol
184. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to
alone or in combination with digoxin for the management of atrial fibrillation
prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern
in patients with heart failure? J Am Coll Cardiol 2003;42:1944–1951.
169. Lewis RV, Laing E, Moreland TA, Service E, McDevitt DG. A comparison of
185. Larson RJ, Fisher ES. Should aspirin be continued in patients started on warfarin?
digoxin, diltiazem and their combination in the treatment of atrial fibrillation.
J Gen Intern Med 2004;19:879–886.
Eur Heart J 1988;9:279–283.
186. Aliot EM, Stevenson WG, Almendral-Garrote JM, Bogun F, Calkins CH,
170. Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM,
Delacretaz E, Bella PD, Hindricks G, Jais P, Josephson ME, Kautzner J,
Hillege HL, Bergsma-Kadijk JA, Cornel JH, Kamp O, Tukkie R, Bosker HA,
Kay GN, Kuck KH, Lerman BB, Marchlinski F, Reddy V, Schalij MJ, Schilling R,
Van Veldhuisen DJ, Van den Berg MP. Lenient versus strict rate control in
Soejima K, Wilber D. EHRA/HRS Expert Consensus on Catheter Ablation of
patients with atrial fibrillation. N Engl J Med 2010;362:1363–1373.
Ventricular Arrhythmias: developed in a partnership with the European Heart
171. Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG,
Rhythm Association (EHRA), a Registered Branch of the European Society of
Arnold JM, Buxton AE, Camm AJ, Connolly SJ, Dubuc M, Ducharme A,
Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with
Guerra PG, Hohnloser SH, Lambert J, Le Heuzey JY, O'Hara G,
the American College of Cardiology (ACC) and the American Heart Association
Pedersen OD, Rouleau JL, Singh BN, Stevenson LW, Stevenson WG,
(AHA). Europace 2009;11:771–817.
Thibault B, Waldo AL. Rhythm control versus rate control for atrial fibrillation
187. McMurray JJ, Anand IS, Diaz R, Maggioni AP, O'Connor C, Pfeffer MA, Polu KR,
and heart failure. N Engl J Med 2008;358:2667–2677.
Solomon SD, Sun Y, Swedberg K, Tendera M, van Veldhuisen DJ,
172. Piepoli M, Villani GQ, Ponikowski P, Wright A, Flather MD, Coats AJ. Overview
Wasserman SM, Young JB. Design of the Reduction of Events with Darbepoetin
and meta-analysis of randomised trials of amiodarone in chronic heart failure. Int
alfa in Heart Failure (RED-HF): a phase III, anaemia correction, morbidity-
J Cardiol 1998;66:1–10.
mortality trial. Eur J Heart Fail 2009;11:795–801.
173. Effect of prophylactic amiodarone on mortality after acute myocardial infarction
188. Packer M, O'Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN,
and in congestive heart failure: meta-analysis of individual data from 6500
Miller AB, Neuberg GW, Frid D, Wertheimer JH, Cropp AB, DeMets DL.
patients in randomised trials. Amiodarone Trials Meta-Analysis Investigators.
Effect of amlodipine on morbidity and mortality in severe chronic heart
failure. Prospective Randomized Amlodipine Survival Evaluation Study Group.
174. Khan MN, Jais P, Cummings J, Di Biase L, Sanders P, Martin DO, Kautzner J,
N Engl J Med 1996;335:1107–1114.
Hao S, Themistoclakis S, Fanelli R, Potenza D, Massaro R, Wazni O,
189. Wijeysundera HC, Hansen MS, Stanton E, Cropp AS, Hall C, Dhalla NS, Ghali J,
Schweikert R, Saliba W, Wang P, Al-Ahmad A, Beheiry S, Santarelli P,
Rouleau JL. Neurohormones and oxidative stress in nonischemic cardiomyop-
Starling RC, Dello Russo A, Pelargonio G, Brachmann J, Schibgilla V, Bonso A,
athy: relationship to survival and the effect of treatment with amlodipine. Am
Casella M, Raviele A, Haissaguerre M, Natale A. Pulmonary-vein isolation for
Heart J 2003;146:291–297.
atrial fibrillation in patients with heart failure. N Engl J Med 2008;359:
190. Yusuf S, Zucker D, Peduzzi P, Fisher LD, Takaro T, Kennedy JW, Davis K, Killip T,
Passamani E, Norris R, Mathur V, Varnauskas E, Chalmers TC. Effect of coronary
175. MacDonald MR, Connelly DT, Hawkins NM, Steedman T, Payne J, Shaw M,
artery bypass graft surgery on survival: overview of 10-year results from rando-
Denvir M, Bhagra S, Small S, Martin W, McMurray JJ, Petrie MC. Radiofrequency
mised trials by the Coronary Artery Bypass Graft Surgery Trialists Collabor-
ablation for persistent atrial fibrillation in patients with advanced heart failure
ation. Lancet 1994;344:563–570.
191. Velazquez EJ, Lee KL, Deja MA, Jain A, Sopko G, Marchenko A, Ali IS, Pohost G,
Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C,
Gradinac S, Abraham WT, Yii M, Prabhakaran D, Szwed H, Ferrazzi P, Petrie MC,
Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M,
O'Connor CM, Panchavinnin P, She L, Bonow RO, Rankin GR, Jones RH,
Widimsky P, Zamorano JL, Erdine S, Kiowski W, Agabiti-Rosei E,
Rouleau JL. Coronary-artery bypass surgery in patients with left ventricular dys-
Ambrosioni E, Lindholm LH, Manolis A, Nilsson PM, Redon J,
function. N Engl J Med 2011;364:1607–1616.
Struijker-Boudier HA, Viigimaa M, Adamopoulos S, Bertomeu V, Clement D,
192. Akashi YJ, Springer J, Anker SD. Cachexia in chronic heart failure: prognostic
Farsang C, Gaita D, Lip G, Mallion JM, Manolis AJ, O'Brien E, Ponikowski P,
implications and novel therapeutic approaches. Curr Heart Fail Rep 2005;2:
Ruschitzka F, Tamargo J, van Zwieten P, Waeber B, Williams B, Zamorano JL,
The task force for the management of arterial hypertension of the European
193. Eschenhagen T, Force T, Ewer MS, de Keulenaer GW, Suter TM, Anker SD,
Society of Hypertension, The task force for the management of arterial hyper-
Avkiran M, de Azambuja E, Balligand JL, Brutsaert DL, Condorelli G,
tension of the European Society of Cardiology. 2007 Guidelines for the manage-
Hansen A, Heymans S, Hill JA, Hirsch E, Hilfiker-Kleiner D, Janssens S, de
ment of arterial hypertension: The Task Force for the Management of Arterial
Jong S, Neubauer G, Pieske B, Ponikowski P, Pirmohamed M, Rauchhaus M,
Hypertension of the European Society of Hypertension (ESH) and of the Euro-
Sawyer D, Sugden PH, Wojta J, Zannad F, Shah AM. Cardiovascular side
pean Society of Cardiology (ESC). Eur Heart J 2007;28:1462–1536.
effects of cancer therapies: a position statement from the Heart Failure Associ-
206. Dorszewski A, Gohmann E, Dorszewski B, Werner GS, Kreuzer H, Figulla HR.
ation of the European Society of Cardiology. Eur J Heart Fail 2011;13:1–10.
Vasodilation by urapidil in the treatment of chronic congestive heart failure in
194. Jones AL, Barlow M, Barrett-Lee PJ, Canney PA, Gilmour IM, Robb SD,
addition to angiotensin-converting enzyme inhibitors is not beneficial: results
Plummer CJ, Wardley AM, Verrill MW. Management of cardiac health in
of a placebo-controlled, double-blind study. J Card Fail 1997;3:91–96.
trastuzumab-treated patients with breast cancer: updated United Kingdom Na-
207. Bayliss J, Norell MS, Canepa-Anson R, Reid C, Poole-Wilson P, Sutton G. Clinical
tional Cancer Research Institute recommendations for monitoring. Br J Cancer
importance of the renin–angiotensin system in chronic heart failure: double
blind comparison of captopril and prazosin. Br Med J (Clin Res Ed) 1985;290:
195. Dungen HD, Apostolovic S, Inkrot S, Tahirovic E, Topper A, Mehrhof F,
Prettin C, Putnikovic B, Neskovic AN, Krotin M, Sakac D, Lainscak M,
208. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H,
Edelmann F, Wachter R, Rau T, Eschenhagen T, Doehner W, Anker SD,
Luscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart
Waagstein F, Herrmann-Lingen C, Gelbrich G, Dietz R. Titration to target
Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P. Ferric carboxymaltose in
dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the
patients with heart failure and iron deficiency. N Engl J Med 2009;361:
CIBIS-ELD trial. Eur J Heart Fail 2011;13:670–680.
196. O'Connor CM, Jiang W, Kuchibhatla M, Silva SG, Cuffe MS, Callwood DD,
209. Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM,
Zakhary B, Stough WG, Arias RM, Rivelli SK, Krishnan R. Safety and efficacy
Bellomo R, Berl T, Bobek I, Cruz DN, Daliento L, Davenport A, Haapio M,
of sertraline for depression in patients with heart failure: results of theSADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic
Hillege H, House AA, Katz N, Maisel A, Mankad S, Zanco P, Mebazaa A,
Heart Failure) trial. J Am Coll Cardiol 2010;56:692–699.
Palazzuoli A, Ronco F, Shaw A, Sheinfeld G, Soni S, Vescovo G,
197. McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B, Hua TA,
Zamperetti N, Ponikowski P; Acute Dialysis Quality Initiative (ADQI) consensus
Belenkov Y, Boolell M, Buse JB, Buckley BM, Chacra AR, Chiang FT,
group. Cardio-renal syndromes: report from the consensus conference of the
Charbonnel B, Chow CC, Davies MJ, Deedwania P, Diem P, Einhorn D,
acute dialysis quality initiative. Eur Heart J 2010;31:703–11.
Fonseca V, Fulcher GR, Gaciong Z, Gaztambide S, Giles T, Horton E,
210. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, Albus C,
Ilkova H, Jenssen T, Kahn SE, Krum H, Laakso M, Leiter LA, Levitt NS,
Benlian P, Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M, Germano G,
Mareev V, Martinez F, Masson C, Mazzone T, Meaney E, Nesto R, Pan C,
Hobbs R, Hoes A, Karadeniz S, Mezzani A, Prescott E, Ryden L, Scherer M,
Prager R, Raptis SA, Rutten GE, Sandstroem H, Schaper F, Scheen A,
Syva¨nne M, Scholte Op, Reimer WJ, Vrints C, Wood D, Zamorano JL,
Schmitz O, Sinay I, Soska V, Stender S, Tamas G, Tognoni G, Tuomilehto J,
Zannad F. European Guidelines on cardiovascular disease prevention in clinical
Villamil AS, Vozar J, Califf RM. Effect of valsartan on the incidence of diabetes
practice (version 2012): The Fifth Joint Task Force of the European Society of
and cardiovascular events. N Engl J Med 2010;362:1477–1490.
Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinic-
198. Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, Raskin P,
al Practice (constituted by representatives of nine societies and by invited
Wright JT, Oakes R, Lukas MA, Anderson KM, Bell DSH; for the GEMINI Inves-
experts) *Developed with the special contribution of the European Association
tigators. Metabolic Effects of carvedilol vs metoprolol in patients with type4 2
for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2012;33:
diabetes mellitus and hypertension—a randomized contolled trial. JAMA 2004;
211. McKelvie RS, Moe GW, Cheung A, Costigan J, Ducharme A, Estrella-Holder E,
199. MacDonald MR, Eurich DT, Majumdar SR, Lewsey JD, Bhagra S, Jhund PS,
Ezekowitz JA, Floras J, Giannetti N, Grzeslo A, Harkness K, Heckman GA,
Petrie MC, McMurray JJ, Petrie JR, McAlister FA. Treatment of type 2 diabetes
Howlett JG, Kouz S, Leblanc K, Mann E, O'Meara E, Rajda M, Rao V, Simon J,
and outcomes in patients with heart failure: a nested case–control study from
Swiggum E, Zieroth S, Arnold JM, Ashton T, D'Astous M, Dorian P,
the U.K. General Practice Research Database. Diabetes Care 2010;33:
Haddad H, Isaac DL, Leblanc MH, Liu P, Sussex B, Ross HJ. The 2011 Canadian
Cardiovascular Society heart failure management guidelines update: focus on
200. Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil
sleep apnea, renal dysfunction, mechanical circulatory support, and palliative
improves left ventricular diastolic function, cardiac geometry, and clinical
care. Can J Cardiol 2011;27:319–338.
status in patients with stable systolic heart failure: results of a 1-year, prospect-
212. Kasai T, Bradley TD. Obstructive sleep apnea and heart failure: pathophysiologic
ive, randomized, placebo-controlled study. Circ Heart Fail 2011;4:8–17.
and therapeutic implications. J Am Coll Cardiol 2011;57:119–127.
201. Hare JM, Mangal B, Brown J, Fisher C Jr, Freudenberger R, Colucci WS,
213. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR,
Mann DL, Liu P, Givertz MM, Schwarz RP. Impact of oxypurinol in patients
LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF,
with symptomatic heart failure. Results of the OPT-CHF study. J Am Coll
McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ,
Bart BA, Mascette AM, Braunwald E, O'Connor CM. Diuretic strategies in
202. Major cardiovascular events in hypertensive patients randomized to doxazosin
patients with acute decompensated heart failure. N Engl J Med 2011;364:
vs chlorthalidone: the antihypertensive and lipid-lowering treatment to
prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group.
214. Alikhan R, Cohen AT, Combe S, Samama MM, Desjardins L, Eldor A, Janbon C,
Leizorovicz A, Olsson CG, Turpie AG. Prevention of venous thromboembolism
203. Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, Wiltse C,
in medical patients with enoxaparin: a subgroup analysis of the MEDENOX
Wright TJ. Adverse mortality effect of central sympathetic inhibition with
study. Blood Coagul Fibrinolysis 2003;14:341–346.
sustained-release moxonidine in patients with heart failure (MOXCON). Eur J
215. Kleber FX, Witt C, Vogel G, Koppenhagen K, Schomaker U, Flosbach CW. Ran-
Heart Fail 2003;5:659–667.
domized comparison of enoxaparin with unfractionated heparin for the preven-
204. Cohn JN, Ziesche S, Smith R, Anand I, Dunkman WB, Loeb H, Cintron G,
tion of venous thromboembolism in medical patients with heart failure or severe
Boden W, Baruch L, Rochin P, Loss L. Effect of the calcium antagonist felodipine
respiratory disease. Am Heart J 2003;145:614–621.
as supplementary vasodilator therapy in patients with chronic heart failure
216. Tebbe U, Schellong SM, Haas S, Gerlach HE, Abletshauser C, Sieder C,
treated with enalapril: V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT)
Bramlage P, Riess H. Certoparin versus unfractionated heparin to prevent
Study Group. Circulation 1997;96:856–863.
venous thromboembolic events in patients hospitalized because of heart
205. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G,
failure: a subgroup analysis of the randomized, controlled CERTIFY study. Am
Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L,
Heart J 2011;161:322–328.
Rynkiewicz A, Schmieder RE, Struijker Boudier HA, Zanchetti A, Vahanian A,
217. Gray A, Goodacre S, Newby DE, Masson M, Sampson F, Nicholl J. Noninvasive
236. McDonagh TA, Blue L, Clark AL, Dahlstrom U, Ekman I, Lainscak M,
ventilation in acute cardiogenic pulmonary edema. N Engl J Med 2008;359:
McDonald K, Ryder M, Stromberg A, Jaarsma T. European Society of Cardiology
Heart Failure Association Standards for delivering heart failure care. Eur J Heart
218. Cotter G, Metzkor E, Kaluski E, Faigenberg Z, Miller R, Simovitz A, Shaham O,
Marghitay D, Koren M, Blatt A, Moshkovitz Y, Zaidenstein R, Golik A. Rando-
237. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D,
mised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus
Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva MS, Storey RF,
high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary
Wijns W, Zahger D, Bax JJ, Auricchio A, Baumgartner H, Ceconi C, Dean V,
oedema. Lancet 1998;351:389–393.
Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Knuuti J, Kolh P,
219. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congest-
McDonagh T, Moulin C, Poldermans D, Popescu BA, Reiner Z, Sechtem U,
ive heart failure: a randomized controlled trial. JAMA 2002;287:1531–1540.
Sirnes PA, Torbicki A, Vahanian A, Windecker S, Achenbach S, Badimon L,
220. Cohn JN, Franciosa JA, Francis GS, Archibald D, Tristani F, Fletcher R,
Bertrand M, Botker HE, Collet JP, Crea F, Danchin N, Falk E, Goudevenos J,
Montero A, Cintron G, Clarke J, Hager D, Saunders R, Cobb F, Smith R,
Gulba D, Hambrecht R, Herrmann J, Kastrati A, Kjeldsen K, Kristensen SD,
Loeb H, Settle H. Effect of short-term infusion of sodium nitroprusside on mor-
Lancellotti P, Mehilli J, Merkely B, Montalescot G, Neumann FJ, Neyses L,
tality rate in acute myocardial infarction complicated by left ventricular failure:
Perk J, Roffi M, Romeo F, Ruda M, Swahn E, Valgimigli M, Vrints CJ,
results of a Veterans Administration cooperative study. N Engl J Med 1982;
Widimsky P. ESC Guidelines for the management of acute coronary syndromes
in patients presenting without persistent ST-segment elevation: the Task Force
221. Mehta SR, Cannon CP, Fox KA, Wallentin L, Boden WE, Spacek R, Widimsky P,
for the management of acute coronary syndromes (ACS) in patients presenting
McCullough PA, Hunt D, Braunwald E, Yusuf S. Routine vs selective invasive
without persistent ST-segment elevation of the European Society of Cardiology
strategies in patients with acute coronary syndromes: a collaborative
(ESC). Eur Heart J 2011;32:2999–3054.
meta-analysis of randomized trials. JAMA 2005;293:2908–2917.
238. Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, Crea F, Falk V,
222. Indications for fibrinolytic therapy in suspected acute myocardial infarction: col-
Filippatos G, Fox K, Huber K, Kastrati A, Rosengren A, Steg PG, Tubaro M,
laborative overview of early mortality and major morbidity results from all ran-
Verheugt F, Weidinger F, Weis M; Committee for Practice Guidelines (CPG).
domised trials of more than 1000 patients. Fibrinolytic Therapy Trialists' (FTT)
Management of acute myocardial infarction in patients presenting with persistent
Collaborative Group. Lancet 1994;343:311–322.
ST-segment elevation: the Task Force on the Management of ST-Segment Eleva-
223. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients
tion Acute Myocardial Infarction of the European Society of Cardiology. Eur
with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet
Heart J 2008;29:2909–2945.
239. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galie N, Pruszczyk P, Bengel F,
224. Park JH, Balmain S, Berry C, Morton JJ, McMurray JJ. Potentially detrimental car-
Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M,
diovascular effects of oxygen in patients with chronic left ventricular systolic dys-
Bassand JP. Guidelines on the diagnosis and management of acute pulmonary
function. Heart 2010;96:533–538.
embolism: the Task Force for the Diagnosis and Management of Acute Pulmon-
225. Rosenberg J, Gustafsson F, Galatius S, Hildebrandt PR. Combination therapy
ary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008;29:
with metolazone and loop diuretics in outpatients with refractory heart
failure: an observational study and review of the literature. Cardiovasc Drugs
240. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA,
Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G,
226. Channer KS, McLean KA, Lawson-Matthew P, Richardson M. Combination diur-
Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G. Guide-
etic treatment in severe heart failure: a randomised controlled trial. Br Heart J
lines for the diagnosis and treatment of pulmonary hypertension: the Task Force
for the Diagnosis and Treatment of Pulmonary Hypertension of the European
227. Tan LB, Bryant S, Murray RG. Detrimental haemodynamic effects of cyclizine in
Society of Cardiology (ESC) and the European Respiratory Society (ERS),
heart failure. Lancet 1988;1:560–561.
endorsed by the International Society of Heart and Lung Transplantation
228. O'Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K,
(ISHLT). Eur Heart J 2009;30:2493–2537.
Hasselblad V, Heizer GM, Komajda M, Massie BM, McMurray JJ, Nieminen MS,
241. Mebazaa A, Pitsis AA, Rudiger A, Toller W, Longrois D, Ricksten SE, Bobek I, De
Reist CJ, Rouleau JL, Swedberg K, Adams KF Jr, Anker SD, Atar D, Battler A,
Hert S, Wieselthaler G, Schirmer U, von Segesser LK, Sander M, Poldermans D,
Botero R, Bohidar NR, Butler J, Clausell N, Corbalan R, Costanzo MR,
Ranucci M, Karpati PC, Wouters P, Seeberger M, Schmid ER, Weder W,
Dahlstrom U, Deckelbaum LI, Diaz R, Dunlap ME, Ezekowitz JA, Feldman D,
Follath F. Clinical review: practical recommendations on the management of
Felker GM, Fonarow GC, Gennevois D, Gottlieb SS, Hill JA, Hollander JE,
perioperative heart failure in cardiac surgery. Crit Care 2010;14:201.
Howlett JG, Hudson MP, Kociol RD, Krum H, Laucevicius A, Levy WC,
242. Sliwa K, Hilfiker-Kleiner D, Petrie MC, Mebazaa A, Pieske B, Buchmann E,
Mendez GF, Metra M, Mittal S, Oh BH, Pereira NL, Ponikowski P, Tang WH,
Regitz-Zagrosek V, Schaufelberger M, Tavazzi L, van Veldhuisen DJ,
Tanomsup S, Teerlink JR, Triposkiadis F, Troughton RW, Voors AA,
Watkins H, Shah AJ, Seferovic PM, Elkayam U, Pankuweit S, Papp Z,
Whellan DJ, Zannad F, Califf RM. Effect of nesiritide in patients with acute de-
Mouquet F, McMurray JJ. Current state of knowledge on aetiology, diagnosis,
compensated heart failure. N Engl J Med 2011;365:32–43.
management, and therapy of peripartum cardiomyopathy: a position statement
229. van de Borne P, Oren R, Somers VK. Dopamine depresses minute ventilation in
from the Heart Failure Association of the European Society of Cardiology
patients with heart failure. Circulation 1998;98:126–131.
Working Group on peripartum cardiomyopathy. Eur J Heart Fail 2010;12:
230. Gheorghiade M, Konstam MA, Burnett JC
Jr, Grinfeld L, Maggioni AP,
Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C.
243. European Society of Gynecology; Association for European Paediatric Cardi-
Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients
ology; German Society for Gender Medicine; Authors/Task Force Members,
hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA 2007;297:
Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, Cifkova R, Ferreira R,
Foidart JM, Gibbs JS, Gohlke-Baerwolf C, Gorenek B, Iung B, Kirby M, Maas
231. Sjauw KD, Engstrom AE, Vis MM, van der Schaaf RJ, Baan J Jr, Koch KT, de
AH, Morais J, Nihoyannopoulos P, Pieper PG, Presbitero P, Roos-Hesselink
Winter RJ, Piek JJ, Tijssen JG, Henriques JP. A systematic review and
JW, Schaufelberger M, Seeland U, Torracca L; ESC Committee for Practice
meta-analysis of intra-aortic balloon pump therapy in ST-elevation myocardial
Guidelines, Bax J, Auricchio A, Baumgartner H, Ceconi C, Dean V, Deaton C,
infarction: should we change the guidelines? Eur Heart J 2009;30:459–468.
Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Knuuti J, Kolh P, McDonagh
232. Costanzo MR, Saltzberg MT, Jessup M, Teerlink JR, Sobotka PA. Ultrafiltration is
T, Moulin C, Poldermans D, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tor-
associated with fewer rehospitalizations than continuous diuretic infusion in
bicki A, Vahanian A, Windecker S; Document Reviewers, Baumgartner H,
patients with decompensated heart failure: results from UNLOAD. J Card Fail
Deaton C, Aguiar C, Al-Attar N, Garcia AA, Antoniou A, Coman I, Elkayam
U, Gomez-Sanchez MA, Gotcheva N, Hilfiker-Kleiner D, Kiss RG, Kitsiou A,
233. Shah MR, Hasselblad V, Stevenson LW, Binanay C, O'Connor CM, Sopko G,
Konings KT, Lip GY, Manolis A, Mebaaza A, Mintale I, Morice MC, Mulder BJ,
Califf RM. Impact of the pulmonary artery catheter in critically ill patients:
Pasquet A, Price S, Priori SG, Salvador MJ, Shotan A, Silversides CK, Skouby
meta-analysis of randomized clinical trials. JAMA 2005;294:1664–1670.
SO, Stein JI, Tornos P, Vejlstrup N, Walker F, Warnes C. ESC Guidelines on
234. Shepperd S, McClaran J, Phillips CO, Lannin NA, Clemson LM, McCluskey A,
the management of cardiovascular diseases during pregnancy: the Task Force
Cameron ID, Barras SL. Discharge planning from hospital to home. Cochrane
on the Management of Cardiovascular Diseases during Pregnancy of the Euro-
Database Syst Rev 2010;(1):CD000313.
pean Society of Cardiology (ESC). Eur Heart J 2011;32:3147–3197.
235. Phillips CO, Wright SM, Kern DE, Singa RM, Shepperd S, Rubin HR. Compre-
244. Diller GP, Dimopoulos K, Okonko D, Li W, Babu-Narayan SV, Broberg CS,
hensive discharge planning with postdischarge support for older patients with
Johansson B, Bouzas B, Mullen MJ, Poole-Wilson PA, Francis DP,
congestive heart failure: a meta-analysis. JAMA 2004;291:1358–1367.
Gatzoulis MA. Exercise intolerance in adult congenital heart disease:
comparative severity, correlates, and prognostic implication. Circulation 2005;
257. Khazanie P, Rogers JG. Patient selection for left ventricular assist devices. Congest
Heart Fail 2011;17:227–234.
245. Baumgartner H, Bonhoeffer P, De Groot NM, de Haan F, Deanfield JE, Galie N,
258. Pagani FD, Miller LW, Russell SD, Aaronson KD, John R, Boyle AJ, Conte JV,
Gatzoulis MA, Gohlke-Baerwolf C, Kaemmerer H, Kilner P, Meijboom F,
Bogaev RC, MacGillivray TE, Naka Y, Mancini D, Massey HT, Chen L,
Mulder BJ, Oechslin E, Oliver JM, Serraf A, Szatmari A, Thaulow E, Vouhe PR,
Klodell CT, Aranda JM, Moazami N, Ewald GA, Farrar DJ, Frazier OH. Extended
Walma E. ESC Guidelines for the management of grown-up congenital heart
mechanical circulatory support with a continuous-flow rotary left ventricular
disease (new version 2010). Eur Heart J 2010;31:2915–2957.
assist device. J Am Coll Cardiol 2009;54:312–321.
246. Jones RH, Velazquez EJ, Michler RE, Sopko G, Oh JK, O'Connor CM, Hill JA,
259. Lainscak M, Blue L, Clark AL, Dahlstrom U, Dickstein K, Ekman I, McDonagh T,
Menicanti L, Sadowski Z, Desvigne-Nickens P, Rouleau JL, Lee KL. Coronary
McMurray JJ, Ryder M, Stewart S, Stromberg A, Jaarsma T. Self-care management
bypass surgery with or without surgical ventricular reconstruction. N Engl J
of heart failure: practical recommendations from the Patient Care Committee of
the Heart Failure Association of the European Society of Cardiology. Eur J Heart
247. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baro´n-Esquivias G,
Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V,
260. Paterna S, Gaspare P, Fasullo S, Sarullo FM, Di Pasquale P. Normal-sodium diet
Iung B, Lancellotti P, Pierard L, Price S, Schaefers H-J, Schuler G, Stepinska J,
compared with low-sodium diet in compensated congestive heart failure: is
Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL,
sodium an old enemy or a new friend? Clin Sci (Lond) 2008;114:221–230.
Zembala M. Guidelines on the Management of Valvular Heart Disease
261. Powell LH, Calvin JE Jr, Richardson D, Janssen I, Mendes de Leon CF, Flynn KJ,
(Version 2012). The Joint Task Force on the Management of Valvular Heart
Grady KL, Rucker-Whitaker CS, Eaton C, Avery E. Self-management counseling
Disease of the European Society of Cardiology (ESC) and the EuropeanAssociation for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2012,
in patients with heart failure: the heart failure adherence and retention rando-
doi:10.1093/eurheartj/ehs109, in press.
mized behavioral trial. JAMA 2010;304:1331–1338.
248. Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM,
262. O'Connor CM, Whellan DJ, Lee KL, Keteyian SJ, Cooper LS, Ellis SJ, Leifer ES,
Webb JG, Fontana GP, Makkar RR, Williams M, Dewey T, Kapadia S,
Kraus WE, Kitzman DW, Blumenthal JA, Rendall DS, Miller NH, Fleg JL,
Babaliaros V, Thourani VH, Corso P, Pichard AD, Bavaria JE, Herrmann HC,
Schulman KA, McKelvie RS, Zannad F, Pin˜a IL; HF-ACTION Investigators. Effi-
Akin JJ, Anderson WN, Wang D, Pocock SJ. Transcatheter versus surgical aortic-
cacy and safety of exercise training in patients with chronic heart failure: HF-
valve replacement in high-risk patients. N Engl J Med 2011;364:2187–2198.
ACTION randomized controlled trial. JAMA 2009;301:1439–1450.
249. Smith CR, Leon MB, Mack MJ, Miller C, Moses JW, Svensson LG, Tuzcu M,
263. Piepoli MF, Conraads V, Corra U, Dickstein K, Francis DP, Jaarsma T,
Webb JG, Fontana GP, Makkar RR, WIlliams M, Dewey T, Kapadia S,
McMurray J, Pieske B, Piotrowicz E, Schmid JP, Anker SD, Solal AC,
Babaliaros V, Thourani VH, Corso P, Pichard AD, Bavaria JE, Herrmann HC,
Filippatos GS, Hoes AW, Gielen S, Giannuzzi P, Ponikowski PP. Exercise training
Akin J, Anderson WN, Wang D, Pocock SJ; for the PARTNER Trial Investigators.
in heart failure: from theory to practice. A consensus document of the Heart
Transcatheter versus surgical aortic-valve replacement in high-risk patients. N
Failure Association and the European Association for Cardiovascular Prevention
Eng J Med 2011;364:2187–98.
and Rehabilitation. Eur J Heart Fail 2011;13:347–357.
250. Feldman T, Kar S, Rinaldi M, Fail P, Hermiller J, Smalling R, Whitlow PL, Gray W,
264. Sochalski J, Jaarsma T, Krumholz HM, Laramee A, McMurray JJ, Naylor MD,
Low R, Herrmann HC, Lim S, Foster E, Glower D. Percutaneous mitral repair
Rich MW, Riegel B, Stewart S. What works in chronic care management: the
with the MitraClip system: safety and midterm durability in the initial
case of heart failure. Health Aff 2009;28:179–189.
EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort. J Am Coll
265. Porapakkham P, Zimmet H, Billah B, Krum H. B-type natriuretic peptide-guided
heart failure therapy: a meta-analysis. Arch Intern Med 2010;170:507–514.
251. Banner NR, Bonser RS, Clark AL, Clark S, Cowburn PJ, Gardner RS, Kalra PR,
266. van Veldhuisen DJ, Braunschweig F, Conraads V, Ford I, Cowie MR, Jondeau G,
McDonagh T, Rogers CA, Swan L, Parameshwar J, Thomas HL, Williams SG.
Kautzner J, Aguilera RM, Lunati M, Gerritse B, Borggrefe M. Intrathoracic imped-
UK guidelines for referral and assessment of adults for heart transplantation.
ance monitoring, audible patient alerts, and outcome in patients with heart
failure. Circulation 2011;124:1719–1726.
252. Mehra MR, Kobashigawa J, Starling R, Russell S, Uber PA, Parameshwar J,
267. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR,
Mohacsi P, Augustine S, Aaronson K, Barr M. Listing criteria for heart transplant-
Stevenson LW, Strickland W, Neelagaru S, Raval N, Krueger S, Weiner S,
ation: International Society for Heart and Lung Transplantation guidelines for the
Shavelle D, Jeffries B, Yadav JS. Wireless pulmonary artery haemodynamic mon-
care of cardiac transplant candidates—2006. J Heart Lung Transplant 2006;25:
itoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:
253. Shah KB, Tang DG, Cooke RH, Harton S, Flattery M, Katlaps GJ, Kasirajan V,
268. Anker SD, Koehler F, Abraham WT. Telemedicine and remote management of
Hess ML. Implantable mechanical circulatory support: demystifying patients
patients with heart failure. Lancet 2011;378:731–739.
with ventricular assist devices and artificial hearts. Clin Cardiol 2011;34:147–152.
254. Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W,
269. Inglis SC, Clark RA, McAlister FA, Stewart S, Cleland JG. Which components of
Long JW, Ascheim DD, Tierney AR, Levitan RG, Watson JT, Meier P, Ronan NS,
heart failure programmes are effective? A systematic review and meta-analysis of
Shapiro PA, Lazar RM, Miller LW, Gupta L, Frazier OH, Desvigne-Nickens P,
the outcomes of structured telephone support or telemonitoring as the primary
Oz MC, Poirier VL. Long-term use of a left ventricular assist device for end-stage
component of chronic heart failure management in 8323 patients: Abridged
heart failure. N Engl J Med 2001;345:1435–1443.
Cochrane Review. Eur J Heart Fail 2011;13:1028–1040.
255. Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D, Sun B,
270. Jaarsma T, Beattie JM, Ryder M, Rutten FH, McDonagh T, Mohacsi P, Murray SA,
Tatooles AJ, Delgado RM
3rd, Long JW, Wozniak TC, Ghumman W,
Grodzicki T, Bergh I, Metra M, Ekman I, Angermann C, Leventhal M, Pitsis A,
Farrar DJ, Frazier OH. Advanced heart failure treated with continuous-flow
Anker SD, Gavazzi A, Ponikowski P, Dickstein K, Delacretaz E, Blue L,
left ventricular assist device. N Engl J Med 2009;361:2241–2251.
Strasser F, McMurray J. Palliative care in heart failure: a position statement
256. Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M, Banner NR,
from the palliative care workshop of the Heart Failure Association of the Euro-
Khaghani A, Yacoub MH. Left ventricular assist device and drug therapy for
pean Society of Cardiology. Eur J Heart Fail 2009;11:433–443.
the reversal of heart failure. N Engl J Med 2006;355:1873–1884.
Sale, use and distribution of this product in Nassau and PULL HERE TO OPEN Suffolk Counties in the State of New York is prohibited. GROUP 15 HERBICIDE For weed control in corn; cotton; grasses grown for seed; horseradish; peanuts; beans, peas, and lentils; potatoes; pumpkin; rhubarb; safflowers; sugar beets; sunflowers; sweet, grain or forage sorghum; soybean; soybean, immature seed; and tomatoes
Doing Everything to Conserve Blood Allina Health Hits Benchmarks in a System-wide Effort; Strives for Best in Class Minneapolis Heart Institute AT A GLANCE knew that Pathology could not just mandate new practices Not-for-profit Allina Health serves patients throughout through the system; she needed allies among the providers Minnesota and western Wisconsin at 12 hospitals, 90 clinics