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In depth: Heart failure - chronic
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Age from 16 years onwards
This Topic Review covers the diagnosis and management of people with chronic heart failure.
This Topic Review is based on guidelines published by the National Institute for Health and Clinical Excellence
(NICE) [National Collaborating Centre for Chronic Conditions, 2003; NHS Improvement, 2008], and informed by
guidelines developed by the European Society of Cardiology [European Society of Cardiology, 2008].
This Topic Review does not cover the management of underlying causes of heart failure (such as coronary artery
disease or hypertension), or the management of heart failure due to lung disease (cor pulmonale) or tricuspid
valve disease. It does not cover the management of heart failure in children or the management of acute heart
failure (for example pulmonary oedema and heart failure during the course of a myocardial infarction).
There are separate CKS topics on Atrial fibrillation, Angina, CVD risk assessment and management, Diabetes Type
2, Hypertension, Lipid modification - CVD prevention, and MI - secondary prevention.
The target audience for this Topic Review is healthcare professionals working within the NHS in England, and
providing first contact or primary health care. Patient information from NHS Direct is intended to be printed and
given to people with this condition or their carers.
Changes
Version 1.0, revision planned in 2011.
January 2009 — converted from PRODIGY guidance to CKS Topic Review structure. The evidence-base has been
reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting
evidence.
This update has added a scenario for the management of end-stage heart failure, and a scenario for the
management of heart failure with preserved left systolic ejection fraction, and there is more detailed information
on the management of comorbidities. The only substantive change to previous treatment recommendations is for
people with heart failure and left ventricular dysfunction who are still symptomatic despite optimal treatment with
diuretics, an angiotensin-converting enzyme inhibitor, and a beta-blocker. In this situation CKS recommends
seeking specialist advice regarding the addition of an aldosterone antagonist, an angiotensin-II receptor
antagonist, or digoxin.
In depth
Goals and outcome measures
Goals
The goals when treating chronic heart failure are to:
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Reduce mortality
Relieve symptoms including breathlessness and fatigue
Improve the quality of life
Increase exercise capacity
Provide for end of life care
Minimize adverse effects from treatments
Background information
What is it?
Heart failure is a complex syndrome in which the ability of the heart to maintain the circulation of blood is
impaired. This results in breathlessness and fatigue, and signs of fluid retention such as raised jugular venous
pressure, pulmonary crepitations, and peripheral oedema [National Collaborating Centre for Chronic Conditions,
2003; European Society of Cardiology, 2008].
Terms used to describe heart failure
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Acute and chronic heart failure
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The terms 'acute' and 'chronic' are used to describe the rate of onset of symptoms (acute = rapid) and
duration of symptoms (chronic = prolonged).
o
'Acute' should not be used to indicate severity of symptoms, although typically acute heart failure
presents dramatically with sudden severe breathlessness and tachycardia, and signs of pulmonary
oedema, peripheral oedema, and systemic underperfusion.
New onset, transient, and chronic heart failure
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In depth: Heart failure - chronic
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Because the classification of heart failure as acute or chronic confuses rate of onset and duration of
symptoms, the European Society of Cardiology (ESC) has suggested that it would be a more accurate to
describe heart failure as new onset, transient, or chronic [European Society of Cardiology, 2008].
Heart failure with left systolic dysfunction versus heart failure with preserved ejection fraction
o
Most people with heart failure have evidence of left ventricular systolic dysfunction, with reduced left
ventricular ejection fraction (LVEF) on echocardiography.
o
A significant proportion of people with heart failure have a normal LVEF on echocardiocardiography, and
this is called heart failure with preserved ejection fraction (HFPEF). However, there is no agreement on
what level should be used to separate normal from abnormal LVEF: the usual cut-off is about 40–50%,
although many clinical trials have used a cut-off of 35%.
o
In most cases, HFPEF is probably caused by diastolic dysfunction (due to decreased left ventricular
filling, with abnormal left ventricular relaxation or distensibility during diastole) [Sanderson, 2007;
European Society of Cardiology, 2008; Sanderson and Yip, 2009].
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Most people with reduced LVEF also have diastolic dysfunction.
Right versus left heart failure
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The terms right heart failure and left heart failure are used to contrast situations where the
predominant symptoms and signs reflect congestion of the systemic (right) or pulmonary (left) veins.
With right heart failure there is dependent oedema, the liver is engorged, and the jugular veins are
distended. With left heart failure there are features of pulmonary oedema: symptoms of breathlessness
and signs on chest X-ray of excess fluid in the lungs.
o
The term right heart failure seems to imply that the primary problem has to do with the right side of
the heart, and left heart failure seems to imply that the primary problem has to do with the left side of
the heart. However, this is often not the case. For example, the most common cause of right heart
failure is failure of the left ventricle to pump sufficient blood through the kidneys — salt and water are
retained, fluid accumulates in the systemic circulation, and the pulmonary artery pressure rises to the
point where the right ventricle fails.
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Because the terms 'right heart failure' and 'left heart failure' can be misleading, they are not further
used in this Topic Review.
Asymptomatic heart failure
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There are no symptoms of heart failure, but there is objective evidence of left ventricular systolic
dysfunction (for example, echocardiography shows a reduced ejection fraction).
Cardiac impairment
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Because the term 'heart failure' is imprecise and because it may lead patients to lose hope, 'cardiac
impairment' has been suggested as a replacement term [Lehman et al, 2005].
How common is it?
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The prevalence of heart failure rises with age — very slowly until about the age of 65 years, and then
rapidly. For example, in the UK, the prevalence of heart failure is estimated to be about [British Heart
Foundation, 2008]:
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1% for people aged 45–64.
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3% for people aged 65–74.
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7% for people aged 75–84.
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20% for people over the age of 85.
Men are more likely than than women to have heart failure, but because there are more older women than
older men there are more women with heart failure than men.
Heart failure accounts for about [National Collaborating Centre for Chronic Conditions, 2003]:
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2% of all inpatient bed-days.
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5% of all medical emergency admissions.
On average, a GP will look after 30 people with heart failure, and will suspect a new diagnosis of heart failure
in perhaps 10 people annually [National Collaborating Centre for Chronic Conditions, 2003].
Nearly half the people with heart failure have preserved left ventricular ejection fraction (HFPEF)
[Sanderson, 2007]. The proportions reported in epidemiological studies vary from 40–70%, but are difficult
to interpret because they used various definitions of heart failure and different thresholds for classifying
ejection fraction as reduced or normal.
What causes it?
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About 70% of cases of heart failure are caused by coronary artery disease, and about 10% due to valve
disease and a further 10% due to cardiomyopathies [European Society of Cardiology, 2008].
A large number of conditions can lead to chronic heart failure, and include:
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Conditions that damage heart muscle or limit its ability to function normally:
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Coronary artery disease (most common).
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Hypertension (about one third of cases).
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Cardiomyopathies.
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Drugs (such as beta-blockers, calcium channel antagonists antiarrhythmics, cytotoxic agents).
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Toxins (alcohol, drugs, cocaine, mercury, cobalt, arsenic).
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Endocrine (diabetes mellitus, hypothyroidism, hyperthyroidism, Cushing syndrome, adrenal
insufficiency, excessive growth hormone, phaeochromocytoma).
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In depth: Heart failure - chronic
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Nutritional conditions (thiamine deficiency).
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Infiltrative conditions (sarcoidosis, amyloidosis, haemochromotosis, connective tissue disease.
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Other conditions (Chaga's disease, HIV infection, endstage renal failure).
Conditions that reduce cardiac output:
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Increased vascular resistance with hypertension.
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Abnormal heart rhythm (for example atrial fibrillation and other tachyarrhythmias).
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Pericardial disease.
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Obstructive sleep apnoea.
Conditions that result in a high cardiac output:
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Anaemia.
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Thyrotoxicosis.
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Septicaemia.
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Liver failure.
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Arterio-venous shunts.
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Paget's disease.
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Thiamine (vitamin B1) deficiency.
How do I know my patient has it?
It can be difficult to confidently diagnose chronic heart failure because the symptoms and signs are often difficult
to elicit, and are often found in other common conditions. Accurate diagnosis requires taking a history, making an
examination, excluding other conditions with similar presentations, and confirming the diagnosis and type of
heart failure with tests.
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Suspect heart failure in a person who has typical symptoms and signs, and a suggestive medical
history:
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Symptoms
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Breathlessness — on exertion (or at rest if the person has severe heart failure), on lying flat
(orthopnea), waking the person from sleep (paroxysmal nocturnal dyspnoea).
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Fatigue (tiredness, exhaustion, decreased exercise tolerance).
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Ankle swelling.
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Signs
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Laterally displaced apex beat.
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Raised jugular venous pressure.
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Enlarged liver (due to engorgement).
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Third heart sound (gallop rhythm).
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Tachycardia.
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Lung crackles (crepitations).
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Dependent oedema (legs, sacrum).
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Medical history
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Myocardial infarction, or coronary artery disease, or angina.
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Atrial fibrillation.
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Diabetes mellitus.
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Hypertension.
Exclude conditions that can have similar clinical presentations — see Differential diagnosis.
Consider the following tests (they may support a diagnosis of heart failure, or suggest alternative
diagnoses):
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Chest X-ray.
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Blood tests: urea and electrolytes, creatinine, full blood count, thyroid function tests, liver function
tests, glucose, lipids.
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Urinalysis.
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Lung function (peak flow or spirometry).
Do tests that can help exclude heart failure:
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12-lead electrocardiogram (ECG).
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Natriuretic peptide (if available) — either B-type natriuretic peptide (BNP), or N-terminal pro-BNP
(NTproBNP).
If either the ECG or the natriuretic peptide test is abnormal, arrange echocardiography in order to:
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Confirm or exclude chronic heart failure with left ventricular dysfunction.
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Document the size and shape of the heart, its pumping capacity, and pathological changes to the heart
valves, walls, vessels, or other structures.
For a graphical overview of the process of diagnosis see the Flowchart of diagnostic process.
Clarification / Additional information
ECG
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Heart failure is unlikely if the ECG is normal. However, up to 1 in 10 people with heart failure may have a
normal ECG.
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In depth: Heart failure - chronic
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ECG can help to identify possible causes of heart failure or aggravating factors (for example, atrial
fibrillation, ventricular arrhythmias).
Natriuretic peptide tests
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B-type natriuretic peptide (BNP) is a cardiac neurohormone. N-terminal (NT-proBNP) is the inactive
prohormone of BNP and is secreted from the ventricles in response to volume expansion and pressure
overload. BNP increases renal excretion of sodium (natriuresis) and water (diuresis), and relaxes vascular
smooth muscle which leads to vasodilation.
Heart failure is unlikely if levels of BNP or NT-proBNP are low or normal in an untreated person.
Raised levels of BNP or NT-proBNP are not helpful in diagnosing heart failure because the levels rise not only
with heart failure, but also with age and severity of renal failure. Levels may differ between men and
women, and alter with comorbidities and drug treatments.
Echocardiography
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Echocardiography can exclude important valvular disease, assess systolic (and diastolic) function, and detect
intracardiac shunts.
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The most important measurement of ventricular function provided by echocardiography is the left ventricular
ejection fraction (LVEF).
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Cutoff levels vary between laboratories, but a LVEF greater than or equal to 45–50% is usually considered to
be normal.
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In most people with heart failure, left ventricular systolic function will be impaired and the LVEF will be
reduced.
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In people with typical symptoms or signs of heart failure who have normal or only mildly abnormal left
ventricular systolic function, further specialist assessment should be considered, as there is still uncertainty
over what the best management is — see Normal ejection fraction on echocardiography.
Basis for recommendation
These recommendations reflect recommendations made by the National Institute for Health and Clinical Evidence
(NICE) [National Collaborating Centre for Chronic Conditions, 2003], as well as Scottish guidelines [SIGN, 2007]
and European specialist society guidelines [European Society of Cardiology, 2008]. No symptom, clinical sign,
item in the medical history, or clinical test is individually sufficiently accurate to make a reliable diagnosis of heart
failure — in other words, the individual findings are not sufficiently sensitive and specific. Diagnosis thus needs to
be based on all the findings from the history, examination, and a series of tests.
Symptoms, signs, and medical history for diagnosing heart failure
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There is evidence that diagnostically useful information is provided by: overall clinical impression,
breathlessness, dependent oedema, third or fourth heart sounds, abdominojugular reflux, jugular venous
distension, pulmonary crackles, and past history of myocardial infarction, coronary artery disease,
hypertension, diabetes mellitus, and dyslipidaemia. The findings that are most specific for heart failure are
third heart sound (gallop rhythm) and elevated jugular venous pressure. There is great variability in the
precision of clinical findings associated with heart failure, but no studies have directly investigated the
variability between different observers or the variability between different observations made by one
observer.
Chest X-ray
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There is evidence from systematic reviews that diagnostically useful information is provided by X-ray
features of pulmonary venous congestion, interstitial oedema, alveolar oedema, cardiomegaly, and pleural
effusion, but most of the studies included in the systematic reviews were conducted in hospital where the
patients were likely to be more severely ill than people managed in primary care.
ECG
There is evidence that diagnostically useful information is provided ECG features of atrial fibrillation, new T-wave
changes, and ST segment elevation or depression. In particular, a normal ECG has reasonable negative predictive
value for heart failure.
B-type natriuretic peptides
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There is good evidence to support the use of B-type natriuretic peptide (BNP) tests and N-terminal-proBNP
(NT-proBNP) in excluding heart failure. A Scottish health technology assessment found that costs could be
saved if BNP tests were used to rule out the need for echocardiography, but that the tests are too inaccurate
to help confirm a diagnosis of heart failure. Six subsequent systematic reviews and meta-analyses provide
further support for the conclusions of the Scottish health technology assessment. There is no evidence that
the accuracy of BNP differs from that of NT-proBNP. However, as BNP has been studied more, there is more
data on its use in people with concomitant disease and in the elderly.
Diagnostic strategy
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CKS found no evidence on how best to sequence diagnostic tests. CKS recommendations reflect the
guidelines published by NICE and other organizations [National Collaborating Centre for Chronic Conditions,
2003; SIGN, 2007; European Society of Cardiology, 2008], and which are based on expert opinion.
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In depth: Heart failure - chronic
Flowchart of the diagnosis of chronic heart failure
Figure 1. Approach to the diagnosis of chronic heart failure.
What else might it be?
A number of conditions can present with symptoms and signs similar to those of heart failure. These conditions
can be grouped according to whether their most prominent feature is shortness of breath or peripheral oedema:
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Conditions causing shortness of breath
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Chest disease (lung, diaphragm, or chest wall), for example:
▪
Pulmonary embolic disease
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In depth: Heart failure - chronic
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Chronic obstructive pulmonary disease
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Asthma
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Pneumonia
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Obesity
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Volume overload from renal failure or nephrotic syndrome
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Angina
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Anxiety
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Anaemia
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Being unfit
Conditions causing peripheral oedema
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Dependent oedema that is not pathological, for example from prolonged inactivity.
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Nephrotic syndrome.
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Drugs (for example, dihydropyridine calcium-channel blockers, nonsteroidal anti-inflammatory drugs)
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Hypoalbuminaemia (from renal or hepatic disease)
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Venous insufficiency
New York Heart Association classification of severity of heart failure symptoms
The New York Heart Association (NYHA) classification grades the severity of heart failure symptoms into one of
four functional classes. The NYHA classification is widely used in clinical practice and in research because it
provides a standard description of severity that can be used to assess response to treatment and to guide
management. It is less useful for prognosis because symptoms can fluctuate and the severity of symptoms does
not always reflect the severity of the underlying heart problem — people with severe heart disease can have mild
symptoms, and vice versa.
NYHA classification of heart failure symptoms [American Heart Association, 1994]
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NYHA class I
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No limitations. Ordinary physical activity does not cause fatigue, breathlessness or palpitation.
(Asymptomatic left ventricular dysfunction is included in this category.)
NYHA class II
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Slight limitation of physical activity. Such patients are comfortable at rest. Ordinary physical activity
results in fatigue, palpitation, breathlessness or angina pectoris.
(Symptomatically 'mild' heart failure.)
NYHA class III
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Marked limitation of physical activity. Although patients are comfortable at rest, less than ordinary
physical activity will lead to symptoms.
(Symptomatically 'moderate' heart failure.)
NYHA class IV
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Inability to carry on any physical activity without discomfort. Symptoms of cardiac failure are present
even at rest.
(Symptomatically 'severe' heart failure).
How do I recognize end-stage heart failure?
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People can be regarded as being in end-stage heart failure if they are at high risk of dying within about 6
months. However, predicting the illness trajectory is difficult: it is much harder in severe heart failure than in
cancer [Stewart and McMurray, 2002].
People are likely to be in end-stage heart failure if [Heart Failure Society of America, 2006b]:
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They respond poorly to treatment and are severely breathless (and if measured, the left ventricular
systolic ejection fraction is less than 20%).
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A minor decompensation or an additional illness (such as a respiratory infection) results in acute
deterioration and increasingly frequent hospital admissions.
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Renal impairment and low blood pressure limit the use of drug treatments.
What are the complications?
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Cachexia (wasting)
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Wasting is a serious complication of chronic heart failure. It usually occurs together with severe
dyspnoea and weakness. Life expectancy for heart failure with cachexia is worse than that for most
cancers [European Society of Cardiology, 2008].
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The pathophysiology of cachexia in heart failure is poorly understood, and it not known if it can be
improved by treatment [European Society of Cardiology, 2008].
Depression
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Up to a third of people with heart failure develop severe and prolonged depression [DH, 2000; Thombs
et al, 2008].
Sexual dysfunction
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Sexual dysfunction is common in people with heart failure. This may be related to cardiovascular
disease, fatigue, weakness, the use of drugs such as beta-blockers, or depression and anxiety
[European Society of Cardiology, 2008].
Arrhythmias
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In depth: Heart failure - chronic
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Arrhythmias occur commonly in people with heart failure at any stage [DH, 2000].
The prevalence of atrial fibrillation increases with the severity of heart failure, rising from about 10% in
people with mild to moderate heart failure (NHYA classes II and III) to 50% in people with severe heart
failure (NHYA class IV) [Maisel and Stevenson, 2003].
It is unclear if atrial fibrillation is an independent predictor of mortality in people with heart failure
[Neuberger et al, 2007].
What is the prognosis?
Prognosis and left ventricular ejection fraction
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The prognosis for people with heart failure and preserved left ventricular ejection fraction is a little better
than the prognosis for people with heart failure and reduced ejection fraction [Owan et al, 2006].
Prognosis in general
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The prognosis can be difficult to estimate for an individual because [European Society of Cardiology, 2008]:
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Heart failure usually does not evolve gradually, but has stable periods interrupted by episodes of acute
destabilization.
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The prognosis depends on the cause of the heart failure, the person's age, comorbidities (such as
ischaemic heart disease, hypertension, diabetes, renal dysfunction, chronic obstructive pulmonary
disease, and depression), and adherence to treatment.
About 50% of people with heart failure die within 4 years of diagnosis, and about 40% of people admitted to
hospital with heart failure die or are readmitted within 1 year [European Society of Cardiology, 2008].
Management issues
Overview of management
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Before starting treatment, and when monitoring progress, assess:
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Functional capacity, for example with the New York Heart Association (NHYA) classification.
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Fluid status
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Cardiac rhythm
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Biochemistry
Adjust the frequency and detail of monitoring to the severity and stability of the condition.
Ensure optimal management of comorbidities such as other cardiovascular disease, diabetes, renal
impairment, chronic obstructive pulmonary disease, obstructive sleep apnoea, anaemia, and depression.
Arrange for annual influenza immunization, and for one immunization against pneumococcus.
Advise about self-care, including monitoring symptoms and weight, knowing when and how to seek medical
advice or adjust drug doses, keeping physically active, stopping smoking, losing excess weight, using
alcohol prudently, restricting consumption of salt, and when to restrict fluid intake.
Provide information about online resources, sexual activity, travel, and driving.
For heart failure with left ventricular systolic dysfunction:
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Treat with a diuretic to relieve symptoms of fluid retention.
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Treat with an angiotensin-converting enzyme inhibitor (or, if this is not tolerated or contra-indicated,
an angiotensin-II receptor antagonist).
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When stable, add a beta-blocker.
o
If still symptomatic, seek specialist advice regarding the addition of an aldosterone antagonist, an
angiotensin-II receptor antagonist, or digoxin.
For heart failure with preserved left ventricular systolic ejection fraction:
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Review the differential diagnosis to ensure that the diagnosis is accurate.
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Seek expert opinion on the diagnosis and advice on drug treatment.
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Treat with a diuretic to relieve symptoms of fluid retention.
For someone with end-stage chronic heart failure:
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Plan ahead together with the patient and carers.
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Ensure that all symptoms (including anxiety, breathlessness, nausea, constipation, and pain) are
treated.
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Stop all unnecessary drugs, and continue other drugs by the most appropriate route.
Suspected chronic heart failure
How should I manage a person with suspected heart failure while they are waiting for echocardiography?
For someone who is suspected of having heart failure and is awaiting echocardiography for a definitive diagnosis:
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Assess for and manage any possible underlying causes.
Assess the severity of symptoms, for example by using the New York Heart Association classification.
If symptoms are sufficiently severe to warrant treatment while waiting for echocardiography, start a loop
diuretic and titrate the dose to control the symptoms — for details see Diuretics in Prescribing information.
If treatment with a diuretic fails to relieve symptoms adequately, review the differential diagnosis.
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In depth: Heart failure - chronic
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Consider obtaining specialist advice in the following situations:
o
Severe symptoms — refer urgently if diuretic treatment is ineffective.
▪
The person may have an underlying condition such as valve disease, and this may require urgent
investigation.
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Specialists may advise starting an angiotensin-converting enzyme inhibitor whilst waiting for the
results of the echocardiograph.
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The diagnosis is uncertain.
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Angina, atrial fibrillation, or other symptomatic arrhythmia.
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Women who are pregnant.
Basis for recommendation
The question on how to manage someone with presumed heart failure while they are waiting for
echocardiography has not been addressed in national guidelines and CKS found no direct evidence from clinical
trials to provide guidance on this. Therefore, these recommendations are pragmatic.
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Prescribing a diuretic is recommended because diuretics rapidly relieve the symptoms of fluid retention (such
as peripheral oedema and breathlessness), are easy to initiate, and require simple monitoring.
Angiotensin converting enzyme (ACE) inhibitors (and other drugs) are not generally recommended for use
while waiting for echocardiography because the potential benefits do not outweigh the disadvantages when a
diagnosis of heart failure has not been confirmed: their effects are slow to become apparent, and they are
complex to initiate and monitor.
Chronic heart failure due to left ventricular systolic dysfunction
What self-care advice should I give someone with chronic heart failure?
Provide the following self-care advice for people being treated for chronic heart failure. Whenever appropriate,
include family members or carers.
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How to recognize the symptoms of heart failure, and what to do if symptoms deteriorate
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When symptoms suggest deteriorating heart failure they should promptly seek medical attention, or
adjust the doses of their drugs (as pre-agreed), or both.
When and how to monitor body weight, and what to do if there is a gain in weight
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Because a rapid gain in weight in people with heart failure is often the result of fluid retention,
worsening of heart failure may be detected early if weight is measured daily.
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Home monitoring of weight is not practical for all people, for example those who are unable to stand
unaided on a scale.
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If body weight is to be monitored at home, normal fluctuations in body weight should be minimized:
weighing should be at the same time each day (for example, after waking and voiding, but before
dressing or eating).
o
If there is a sudden and sustained gain in weight (for example more than 2 kg in 3 days), they should
(as pre-agreed) either seek medical advice, or increase the dose of their diuretic, or both.
o
Patients and their carers should understand that deterioration can occur without weight gain.
How to keep active and practice physical exercise
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Explain that keeping as fit as possible is safe and beneficial if exercise does not exceed the person's
capacity.
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Encourage regular aerobic exercise (such as walking) and/or resistive exercise (e.g. weight training).
This may be more effective when part of a supervised exercise or rehabilitation programme, and may
be available as 'an exercise referral scheme'.
How to stop smoking
o
Advise smokers to quit, and offer referral to a smoking-cessation service.
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For detailed information on the harmful effects of smoking and for advice on smoking cessation, see the
CKS topic on Smoking cessation.
How to use alcohol prudently
o
People with alcohol-related heart failure should never drink alcohol.
o
People with heart failure not due to alcohol should keep their alcohol intake within recommended levels.
o
For detailed information on sensible drinking limits and how to help people reduce their drinking, see
the CKS topic on Alcohol - problem drinking.
How to lose excess weight and then maintain weight within recommended limits
o
For advice on the management of obesity, see the CKS topic on Obesity.
How to restrict salt consumption
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Excessive intake of salt is to be avoided, but there are no specific guidelines on salt intake.
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Patients should be informed about the salt content of common foods.
o
Websites that have useful information about salt in the diet are listed in Online resources.
When to restrict fluid intake
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People with severe symptoms of heart failure should restrict fluid intake to between 1.5 and 2.0 litres a
day.
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People with mild or moderate symptoms are unlikely to benefit from fluid restriction.
What immunizations to have
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In depth: Heart failure - chronic
o
Annual immunization against influenza and immunization once against pneumococcus are
recommended.
Basis for recommendation
These recommendations reflect recommendations in the National Institute for Health and Clinical Effectiveness
(NICE) guidelines on Chronic heart failure [National Collaborating Centre for Chronic Conditions, 2003], as well as
Scottish national guidelines and European professional association guidelines [SIGN, 2007; European Society of
Cardiology, 2008].
Recognizing the symptoms of heart failure
•
The recommendation to teach people how to recognize the symptoms of heart failure is largely based on
expert opinion [European Society of Cardiology, 2008].
How to monitor body weight
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The recommendation to teach people monitor their weight is largely based on expert opinion [SIGN, 2007;
European Society of Cardiology, 2008].
There is evidence from one study that increases in body weight are not always associated with a
deterioration of symptoms of heart failure and fluid retention [Lewin et al, 2005].
Keeping active and fit
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Keeping active and fit is generally recommended — see CKS topic CVD risk assessment and management.
But, this may be even more important for people with heart failure.
Systematic reviews found small studies providing evidence that exercise reduces mortality and
hospitalization, and improves exercise tolerance and health-related quality of life [Piepoli et al, 2004; Rees
et al, 2004; Smart and Marwick, 2004].
More recent randomized controlled trials (RCTs) in people with chronic heart failure suggest that intensive
aerobic exercise is more effective than less intensive exercise and weight training [Feiereisen et al, 2007;
Wisloff et al, 2007].
A small RCT found that 6 years after participation in a residential rehabilitation programme, people with
chronic heart failure had slightly better outcomes than control subjects, maintained exercise capacity, and
engaged in activities that exceed the minimal amount recommended by guidelines for cardiovascular health
[Mueller et al, 2007].
Stopping smoking
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Stopping smoking is recommended for everyone — see CKS topic on Smoking cessation. But, it may be even
more important for people with heart failure to stop smoking.
o
The effect of smoking cessation in people with heart failure has not been studied in clinical trials.
However, current smoking was an independent predictor of readmissions for heart failure in two
observational studies [Evangelista et al, 2000; Suskin et al, 2001].
Prudent use of alcohol
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Prudent use of alcohol is generally recommended — see CKS topic Alcohol - problem drinking. But, it may be
even more important for people with heart failure to use alcohol prudently.
A recent review [Djousse and Gaziano, 2008] found:
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Good evidence that heavy alcohol use is associated with cardiomyopathy, and that abstinence leads to
improved survival.
o
Limited evidence that moderate alcohol use reduces the risk of heart failure compared with abstainers.
o
No evidence on the type of beverage and heart failure, or on drinking patterns (binge drinking versus
frequent light-to-moderate drinking) and heart failure.
Losing excess weight and maintaining weight loss
•
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Losing excess weight and maintaining weight loss is generally recommended — see CKS topic Obesity.
Losing excess weight is thought to be important for people with heart failure, although there is little evidence
to support this assumption [Kenchaiah et al, 2007; Abdulla et al, 2008; Shirley et al, 2008].
How to restrict salt consumption
•
•
The recommendation to restrict salt consumption is largely based on expert opinion and extrapolation from
evidence of the effects of salt consumption on hypertension [National Collaborating Centre for Chronic
Conditions, 2003SIGN, 2007; European Society of Cardiology, 2008].
Two RCTs of low salt diets in people with heart failure found weak evidence for modest benefits in terms of
weight loss, oedema, fatigue, quality of life, and NYHA class [Alvelos et al, 2004; Colin Ramirez et al, 2004].
Restricting fluid intake
•
•
The recommendation to restrict fluid intake in people with severe symptoms of heart failure is largely based
on expert opinion [National Collaborating Centre for Chronic Conditions, 2003SIGN, 2007; European Society
of Cardiology, 2008].
One open RCT in people hospitalized for severe heart failure symptoms failed to find evidence of benefit from
fluid restriction [Travers et al, 2007]. Nevertheless, there is no concern that fluid restriction to 1.5–2.0 litres
per day could be harmful.
Immunizations
•
The recommendation for influenza and pneumococcal immunization is largely based on expert opinion and
extrapolation from the benefits of these immunizations in other populations at risk — see separate CKS
topics on Immunization - influenza and Immunizations - pneumococcal.
9
In depth: Heart failure - chronic
•
A large epidemiological study in the elderly, found that immunization against influenza was associated with
reductions in the risk of hospitalization for heart disease, cerebrovascular disease, and pneumonia or
influenza as well as the risk of death from all causes during influenza seasons [Nichol et al, 2003].
Information about online resources, driving regulations, and travel
For someone with chronic heart failure, provide the information about online resources, driving, sexual activity,
and travel. When appropriate, include family members or carers.
What information about online resources is available for people with chronic heart failure?
Online information resources that may be useful for people with heart failure (and their families) include:
•
Living with heart failure
o
www.bhf.org.uk — the British Heart Foundation
o
www.heartfailurematters.org — the European Society of Cardiology
•
Salt in the diet
o
www.bhf.org.uk — the British Heart Foundation
o
www.salt.gov.uk — the British Food Standards Agency
o
www.bda.uk.com — the British Dietetics Association
•
Coronary heart disease (a common cause of heart failure)
o
www.heartforum.org.uk — the National Heart Forum
•
Planning ahead, and end of life issues
o
www.endoflifecareforadults.nhs.uk — the NHS National End of Life Care Programme supports the
implementation of the UK Department of Health's End of Life Care Strategy by sharing good practice in
collaboration with local and national stakeholders.
o
www.endoflifecareforadults.nhs.uk — Preferred Priorities for Care — this document is a combined
information leaflet and form that can be used as by patients and carers to plan, and document their
preferred priorities for care.
o
www.westonhospicecare.org.uk — Planning Ahead — this document, developed by Weston Hospice with
patients and palliative care professionals, is a set of leaflets that can be used to facilitate discussions
and to document decisions about end of life life issues.
Basis for recommendation
This information is in line with recommendations in the guidelines published by the National Institute of Health
and Clinical Excellence (NICE) on Chronic heart failure [National Collaborating Centre for Chronic Conditions,
2003], as well as Scottish national guidelines and European professional association guidelines [SIGN, 2007;
European Society of Cardiology, 2008]. These guidelines strongly emphasize the importance of providing
information to affected individuals, their family and carers.
What information should I provide about driving and chronic heart failure?
•
The latest information from the Driver and Vehicle Licensing Agency (DVLA) regarding medical fitness to
drive can be obtained at www.dvla.gov.uk.
•
It is the responsibility of the patient to inform the DVLA of any condition that may impact on the ability to
drive.
•
The DVLA's medical rules regarding heart failure are:
o
For group-1 entitlement (cars, motorcycles):
▪
Driving may continue, provided there are no symptoms that may distract the driver's attention.
▪
The DVLA need not be notified.
o
For group-2 entitlement (lorries, buses):
▪
Disqualified from driving if symptomatic.
▪
Re-licensing may be permitted, provided that the left ventricular ejection fraction is at least 40%,
and there is no other disqualifying condition.
Basis for recommendation
This information on medical rules is from the Driver and Vehicle Licensing Authority (DVLA) [DVLA, 2009].
What information should I provide about sexual activity?
•
Sexual problems may be related to cardiovascular disease, medical treatments (such as beta-blockers),
fatigue, or depression.
•
People who can tolerate moderate exertion without cardiovascular symptoms such as dyspnoea, palpitations,
or angina, should be able to engage in sexual activity without provoking these symptoms.
•
People with New York Heart Association (NHYA) class III or IV symptoms may have a slightly increased risk
of worsening heart failure triggered by sexual activity.
•
Phosphodiesterase type-5 inhibitors (such as sildenafil) are not recommended for use in people with
advanced heart failure, and should never be used in combination with nitrates.
Basis for recommendation
These recommendations and the information are in line with recommendations in the guidelines published by the
National Institute of Health and Clinical Excellence (NICE) on Chronic heart failure [National Collaborating Centre
10
In depth: Heart failure - chronic
for Chronic Conditions, 2003], as well as European professional association guidelines [European Society of
Cardiology, 2008].
Risk of sexual activity
•
The recommendation to counsel people about sexual activity and the advice on the safety of sexual activity
is largely based on expert opinion [National Collaborating Centre for Chronic Conditions, 2003; European
Society of Cardiology, 2008] and a consensus development panel [Jackson et al, 2006].
Sildenafil contraindicated when nitrates are used
•
Sildenafil should not be used together with nitrates (including amyl nitrite) because sildenafil potentiates the
hypotensive effects of nitrates.
o
Nitrates act as a source of nitric oxide. Nitric oxide activates the enzyme guanylate cyclase, which
results in increased levels of cyclic guanosine monophosphate (cGMP), which relaxes smooth muscle in
blood vessels. Sildenafil selectively inhibits cGMP specific phosphodiesterase type 5 (PDE5) in the
corpus cavernosum, which results in increased levels of cGMP. The combination of increased levels of
nitric oxide (from nitrates) and increased cGMP from sildenafil can cause blood pressure to fall to
dangerous levels. [ABPI Medicines Compendium, 2008a].
What information should I provide about travel?
•
•
•
Air travel is usually preferable to other means of travel for long journeys.
Air travel is not suitable for people who require oxygen.
People with symptoms of heart failure should try to avoid travelling to high altitudes (for example, above
1500 m) and to hot and humid destinations.
•
For many people with heart failure the most difficult part of air travel will be the long walk within the airport,
and they may require assistance.
Basis for recommendation
This information is in line with recommendations in the guidelines published by the National Institute of Health
and Clinical Excellence (NICE) on Chronic heart failure [National Collaborating Centre for Chronic Conditions,
2003], as well as European professional association guidelines [European Society of Cardiology, 2008]. The
information is largely based on expert opinion.
What drug treatments should I consider in a person with heart failure and left ventricular systolic
dysfunction?
•
To relieve symptoms of fluid retention, prescribe a diuretic.
o
Titrate the dose (up and down) according to symptoms; review the dose and adjust as necessary after
introducing other drug treatments for heart failure.
•
To improve morbidity and mortality:
o
Prescribe an angiotensin-converting enzyme (ACE) inhibitor unless contraindicated or not tolerated. If
ACE inhibitors cause troublesome cough, use an angiotensin-II receptor antagonist (AIIRA).
▪
Do not start a diuretic and an ACE inhibitor at the same time because of the risk of hypotension.
▪
If the person is already using high doses of a loop diuretic (equivalent to 80 mg furosemide or
more), consider seeking specialist advice before starting an ACE inhibitor or AIIRA.
▪
Titrate the dose of ACE inhibitor or AIIRA upwards until the target dose or the highest tolerated
dose is reached.
▪
Monitor renal function and serum electrolytes before starting an ACE inhibitor or an AIIRA and
after each dose increase.
o
Once stable, add a beta-blocker unless contraindicated (for example, asthma, heart block, or
symptomatic hypotension) or not tolerated.
▪
Start at a low dose and titrate slowly upwards until the target dose or the highest tolerated dose is
reached.
•
If still symptomatic, seek specialist advice regarding the addition of an aldosterone antagonist or
digoxin to current treatment, or the combination of an AIIRA with existing ACE inhibitor treatment.
•
In all people, consider whether an antiplatelet and a statin is indicated.
o
An antiplatelet drug is indicated if the person has atherosclerotic arterial disease (such as coronary
heart disease, stroke/transient ischaemic attack, or peripheral vascular disease). See the CKS topic on
Antiplatelet treatment.
o
A statin is indicated if the person has atherosclerotic arterial disease or has a 10-year risk of a
cardiovascular event which is 20% or more. See the CKS topics on CVD risk assessment and
management and Lipid modification - CVD prevention for more information.
•
Consider morbidities which may influence the treatment of heart failure.
▪
Angina
▪
Asthma or COPD
▪
Diabetes
▪
Gout
▪
Renal impairment
Basis for recommendation
Diuretics
11
In depth: Heart failure - chronic
•
The recommendation to give diuretics to relieve symptoms of heart failure is consistent with guidelines from
the National Institute of Health and Clinical Excellence (NICE), the Scottish Intercollegiate Guidelines
Network (SIGN), and the European Society of Cardiology (ESC) [NICE, 2003; SIGN, 2007; European Society
of Cardiology, 2008].
o
The use of diuretics to improve congestive symptoms of heart failure is well established. Although there
is no direct evidence from randomized controlled trials (RCTs), it is widely accepted that they are
effective at improving symptoms and exercise performance in people with heart failure.
o
There is limited evidence from several small RCTs that diuretics may also reduce the risk of death and
worsening heart failure compared with placebo.
ACE inhibitors
•
•
The recommendation to give an ACE inhibitor to all people with heart failure and left ventricular systolic
dysfunction is consistent with guidelines from NICE, SIGN, and the ESC [NICE, 2003; SIGN, 2007; European
Society of Cardiology, 2008].
There is good evidence that ACE inhibitors reduce the mortality and morbidity associated with heart failure.
o
A systematic review of large randomized controlled trials (RCTs) has confirmed that ACE inhibitors
reduce the risk of death from any cause, readmission because of heart failure, and reinfarction after a
myocardial infarction (MI). The benefits of ACE inhibitors occur soon after the start of treatment and
persist long-term. The benefits appear to be independent of age, sex, and baseline use of diuretics,
aspirin, and beta-blockers, and occur over a full range of ventricular dysfunction.
o
There is some evidence from one large RCT that higher doses of an ACE inhibitor may improve
morbidity more than lower doses, with no increase in adverse events.
AIIRAs
•
•
The recommendation to give an AIIRA to people who are intolerant of and ACE inhibitor is consistent with
guidelines from NICE, SIGN, and the ESC [NICE, 2003; SIGN, 2007; European Society of Cardiology, 2008].
There is good evidence that angiotensin-II receptor antagonists are effective at reducing mortality and
morbidity associated with heart failure.
o
Data from one large placebo-controlled study shows that AIIRAs are beneficial in people with chronic
heart failure and are a suitable alternative in people who intolerant of an ACE inhibitor. This is backed
up by a subgroup analysis of another large placebo-controlled trial.
o
Evidence from several large RCTs suggests that there is no difference in efficacy between AIIRAs and
ACE inhibitors. However, unless they are not tolerated, ACE inhibitors are preferred to AIIRAs because
there is more evidence and clinical experience to support their use.
Beta-blockers
•
•
The recommendation to give a beta-blocker to all people with heart failure and left ventricular systolic
dysfunction is consistent with guidelines from NICE, SIGN, and the ESC [NICE, 2003; SIGN, 2007; European
Society of Cardiology, 2008].
There is good evidence from large RCTs that certain beta-blockers reduce the mortality and morbidity
associated with heart failure. This improvement appears to be independent of the cause or severity of heart
failure.
Referral for specialist advice
•
CKS recommends seeking specialist advice regarding the most suitable treatment option for people who
remain symptomatic despite optimal treatment with diuretics, and ACE inhibitor and a beta-blocker because:
o
There is no clear evidence regarding the most appropriate drug to use next in most people with heart
failure.
o
The addition of another drug at this stage greatly increases the risk of adverse effects with less
evidence of benefit.
o
People at this stage usually have severe heart failure and would probably benefit from specialist
opinion.
ACE inhibitor in combination with an AIIRA
•
•
The recommendation to consider an AIIRA for people with chronic heart failure who remain symptomatic
despite optimal treatment with a diuretic, an ACE inhibitor, and a beta-blocker is consistent with guidelines
from SIGN and the ESC [SIGN, 2007; European Society of Cardiology, 2008]. When the NICE guideline on
heart failure was published, there was insufficient evidence to make a recommendation regarding this
combination, and no AIIRA was licensed for this indication [NICE, 2003].
There is some evidence to support the addition of an angiotensin-II receptor antagonist to existing treatment
with an ACE inhibitor, however, the combination increases the risk of adverse effects.
o
One large RCT found that adding valsartan to current treatment significantly reduced the risk of
hospitalization due to heart failure, but not the risk of all cause mortality. A second RCT found that
adding candesartan to an ACE inhibitor significantly reduced the risk of cardiovascular death and the
risk of hospitalization due to heart failure, but not the risk of all-cause mortality.
o
There is evidence from meta-analyses including more than 17,000 people of a significant increase in
adverse effects with the combination of an ACE inhibitor plus an AIIRA, including hypotension,
worsening renal function, and hyperkalaemia.
Aldosterone antagonists
•
The recommendation to consider an aldosterone antagonist for people with chronic heart failure who remain
moderate to severely symptomatic despite optimal treatment with a diuretic, an ACE inhibitor and a beta-
12
In depth: Heart failure - chronic
•
blocker is consistent with guidelines from NICE, SIGN, and the ESC [NICE, 2003; SIGN, 2007; European
Society of Cardiology, 2008].
There is good evidence from large RCTs to support the use of aldosterone antagonists in addition to optimal
treatment in people with moderate to severe heart failure. It is not know whether aldosterone blockade is
advantageous in people with milder heart failure.
o
There is good evidence from one large RCT that, when added to optimal therapy, spironolactone
improves symptoms, reduces mortality, and reduces hospitalizations in people with moderate to severe
heart failure (NYHA class III–IV).
o
Evidence from another large RCT supports the use of eplerenone, in addition to optimal treatment, to
reduce mortality and hospitalizations in people with heart failure after an acute myocardial infarction
(MI).
o
CKS found no studies directly comparing spironolactone with eplerenone.
Digoxin
•
The recommendation to consider digoxin for people with chronic heart failure who remain moderate to
severely symptomatic despite optimal treatment with a diuretic, an ACE inhibitor and a beta-blocker is
consistent with guidelines from NICE, SIGN, and the ESC [NICE, 2003; SIGN, 2007; European Society of
Cardiology, 2008].
o
Evidence from a Cochrane systematic review including one large randomized trial suggests that, in
people with normal sinus rhythm, digoxin improves symptoms and reduces the number of
hospitalizations due to worsening heart failure when added to treatment with diuretic and angiotensinconverting enzyme (ACE) inhibitors, but it does not appear to reduce mortality.
Aspirin
•
•
•
•
There remains some uncertainty surrounding the use of aspirin in people with chronic heart failure.
o
There is no good RCT evidence on the efficacy of aspirin in the management of heart failure. However,
there is good evidence that aspirin reduces the risk of cardiovascular events in people with established
cardiovascular disease or those who are at high risk of developing cardiovascular disease
[Antithrombotic Trialists' Collaboration, 2002], and aspirin is currently recommended for people with
cardiovascular disease [Joint British Societies, 2005National Collaborating Centre for Primary Care,
2008].
o
There are concerns from post-hoc analyses of some of the studies of angiotensin-converting enzyme
inhibitors in heart failure that aspirin may reduce the beneficial effect of ACE inhibitors, although this
has not been confirmed by further analysis.
NICE recommends that, in the absence of conclusive evidence, and general consensus as to the benefits of
aspirin in patients with atherosclerotic arterial disease, aspirin (75–150 mg once daily) should be prescribed
for people with heart failure and atherosclerotic arterial disease (including coronary heart disease) [National
Collaborating Centre for Chronic Conditions, 2003].
SIGN concludes that there is no firm evidence to support the use or the withdrawal of aspirin in people with
chronic heart failure [SIGN, 2007].
The ESC guidelines conclude that there is no evidence that antiplatelet drugs reduce atherosclerotic risk in
people with heart failure [European Society of Cardiology, 2008].
Statins
•
Evidence from one large RCT suggests that statins are no more effective than placebo at reducing mortality
in people with chronic heart failure. However, there is good evidence that statins reduce the risk of
cardiovascular events in people with established cardiovascular disease or those who are at high risk of
developing cardiovascular disease, and they are currently recommended for people with cardiovascular
disease.
13
In depth: Heart failure - chronic
Algorithm illustrating the approach to drug treatment of chronic heart failure with left ventricular systolic dysfunction
Figure 2. Algorithm illustrating the approach to treatment of chronic heart failure with left ventricular
systolic dysfunction. (Adapted from guidelines published by the National Institute for Health and Clinical
Excellence [NICE, 2003] and the National Prescribing Centre [MeReC, 2008]).
14
In depth: Heart failure - chronic
How should I follow up someone with heart failure?
•
All people with heart failure require regular follow-up, monitoring, and review of medications to
assess any need for changes and to detect possible adverse effects.
•
The frequency of follow up and detail of monitoring needs to be individualized according to the
severity of symptoms, stability of clinical status, intensity of treatment, and any comorbidities.
o
More frequent follow up and more detailed monitoring will be required if the person has significant
comorbidity or if their condition has deteriorated since the previous review. The follow-up interval
should be short (days to 2 weeks) if the clinical condition or medication has changed, and at least every
6 months if the person's condition is stable.
o
People who wish to be involved in monitoring their condition should be provided with sufficient
education and support to do this, and with clear advice on what to do if their condition deteriorates (see
Self-care advice).
•
Assess and monitor:
o
Functional capacity (chiefly from the history)
▪
The New York Heart Association (NHYA) classification is a useful tool
o
Fluid status (chiefly from the physical examination)
▪
Change in body weight
▪
Jugular venous distension
▪
Lung crackles (crepitations)
▪
Hepatomegaly
▪
Peripheral oedema (ankles, sacrum)
▪
Change in blood pressure on standing up from a lying position (a postural drop of more than
20 mmHg suggests hypovolaemia).
o
Cardiac rhythm (chiefly from the physical examination)
▪
If an arrhythmia is suspected from the physical examination, consider doing a 12-lead
electrocardiogram (ECG), or arranging 24-hour ECG monitoring.
o
Biochemistry — for information on the monitoring recommended for particular drugs, see the
Prescribing information sections on:
▪
Monitoring (diuretics)
▪
Monitoring (ACE inhibitor/AIIRA)
▪
Monitoring (beta-blocker)
▪
Monitoring (aldosterone antagonist)
▪
Monitoring (digoxin)
Basis for recommendation
These recommendations reflect guidelines published by the National institute for Health and Clinical Excellence
(NICE) [National Collaborating Centre for Chronic Conditions, 2003], and are in line with international guidelines
[ICSI, 2007; SIGN, 2007; European Society of Cardiology, 2008].
Functional capacity
•
•
The NHYA classification of functional capacity has been widely used over decades in research and clinical
practice. The current version is the result of a series of updates to the 1928 classification [American Heart
Association, 1994]. It aims to provide a standard and more objective way of describing severity of
symptoms.
A recent UK survey of 30 cardiologists found that they had no consistent method for assessing NYHA class
[Raphael et al, 2006]. The same report included a study of inter-operator variability in 4 cardiologists
assessing 50 patients. The average concordance between any pair of cardiologists was 54%, and there was
very poor agreement in differentiating between class II and class III. The authors considered the NYHA
classification to be useful despite these limitations, and recommended that the objectivity of the
classification be improved by clarifying how 'ordinary physical activity', 'slight limitation', and 'marked
limitation' are elicited from patients.
Fluid status
•
It is necessary to determine fluid status because this allows response to treatment to be assessed and
guides further management.
Assessing cardiac rhythm
•
•
It important to regularly and routinely assess cardiac rhythm because people with heart failure frequently
have treatable arrhythmias (especially atrial fibrillation), and these can be discovered at any time before, at,
or after the initial presentation with heart failure.
For more information, see Complications.
When should I refer someone with chronic heart heart failure?
Consider obtaining specialist advice in the following situations:
•
•
•
•
Heart failure due to valve disease, diastolic dysfunction, or any cause other than left ventricular systolic
dysfunction.
Angina, atrial fibrillation, or other symptomatic arrhythmia.
Women who are planning a pregnancy or who are pregnant.
Severe heart failure.
15
In depth: Heart failure - chronic
•
•
Heart failure that does not respond to treatment.
Heart failure that can no longer be managed effectively in the home setting.
Specialist advice may be appropriate when managing people with heart failure and a comorbidity such as:
•
Renal dysfunction (for example serum creatinine greater than 200 micromols per litre).
•
Anaemia.
•
Thyroid disease.
•
Severe peripheral vascular disease.
•
Asthma, chronic obstructive pulmonary disease.
•
Gout.
Basis for recommendation
The recommendations for referral reflect guidelines published by the National institute for Health and Clinical
Excellence (NICE) [National Collaborating Centre for Chronic Conditions, 2003], and are based on expert opinion.
How do I manage someone with symptoms of chronic heart failure and preserved left ventricular
ejection fraction on echocardiography?
How should I manage unconfirmed heart failure with preserved left ventricular ejection fraction
For someone who has symptoms of heart failure, and echocardiography shows preserved (normal) left ventricular
ejection fraction:
•
•
Reconsider the diagnosis of heart failure.
If heart failure is still thought to be likely:
o
Continue any current treatment that seems to have helped — this will often be a diuretic.
o
Refer for specialist assessment.
Clarification / Additional information
•
The diagnosis of heart failure with preserved left ventricular ejection fraction can be confirmed if the person
has:
o
Breathlessness, and
o
Left ventricular hypertrophy, and
o
Left atrial enlargement, and
o
Evidence of raised left atrial pressure either by increased levels of B-type natriuretic peptide (which is
especially useful in primary care) or newer echocardiographic indices.
Basis for recommendation
Because there is no direct evidence from clinical trials, these recommendations are pragmatic and based on
expert opinion [Heart Failure Society of America, 2006a; Sanderson, 2007; European Society of Cardiology,
2008].
•
The criteria for diagnosis of heart failure with preserved left ventricular ejection fraction reflect those
proposed by the European Society of Cardiology [Paulus et al, 2007].
How should I manage confirmed heart failure with preserved left ventricular systolic ejection fraction?
For someone who has been diagnosed by a specialist to have heart failure but whose echocardiography shows a
preserved (normal) left ventricular ejection fraction:
•
The
o
o
o
o
non-drug management is similar to that for heart failure with left ventricular systolic dysfunction:
Include family members or carers in education and decision-making when appropriate.
Provide self-care advice.
Provide information about online resources, driving, sexual activity, and travel.
Ensure that any comorbidities and precipitating factors such as hypertension, myocardial ischaemia and
atrial fibrillation are optimally managed.
•
Continue drug treatment as recommended by a specialist.
•
Monitor regularly; tailor the detail and frequency of monitoring to the individual's needs.
Clarification / Additional information
•
Drugs recommended by specialists treatment may include:
o
A diuretic to control symptoms of fluid retention.
o
A rate-limiting calcium channel blocker (such as verapamil) — although verapamil and other nondihydropyridines are not recommended for heart failure with left ventricular dysfunction.
o
An angiotensin converting enzyme inhibitor, or an angiotensin-II receptor antagonist (such as
candesartan).
•
A beta-blocker should be considered if the person has had a myocardial infarction, or has hypertension, or
has atrial fibrillation and the ventricular rate requires controlling.
Basis for recommendation
There is little evidence from clinical trials as most trials of treatments for heart failure have excluded people with
preserved ventricular ejection fraction (HFPEF). These recommendations are therefore largely based on expert
opinion [Heart Failure Society of America, 2006a; Sanderson, 2007; European Society of Cardiology, 2008].
16
In depth: Heart failure - chronic
Considerable uncertainty remains about drug treatments for HFPEF as there have been only a few relatively small
trials.
Diuretics
•
Indirect evidence from two small clinical trials suggests that diuretics may improve symptoms in people with
heart failure and preserved left ventricular ejection fraction (HFPEF).
Angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor antagonists
•
One RCT provides moderate evidence for modest clinical benefits for candesartan as add-on treatment. Four
other randomized controlled trials (RCTs) found no benefit or modest clinical benefits from adding an
angiotensin converting enzyme inhibitor or angiotensin-II receptor blocker to other treatments for heart
failure with preserved left ventricular ejection fraction (HFPEF).
Rate-limiting calcium channel blockers
•
Two small randomized placebo-controlled cross-over trials provide weak evidence that verapamil may
improve exercise capacity and symptoms in people with heart failure and preserved left ventricular ejection
fraction.
Digoxin
•
One RCT provides weak evidence from a secondary analysis that digoxin in people with heart failure with
preserved left ventricular ejection fraction (HFPEF) may decrease the risk of admission for worsening heart
failure, but may not reduce the risk of death.
Beta-blockers
•
•
There is little direct evidence to support the use of beta-blockers to treat HFPEF. A small RCT in older people
with HFPEF and a history of myocardial infarction provides weak evidence that propranolol may reduce the
risk of death or non-fatal myocardial infarction.
However, beta-blockers may be indicated to treat underlying causes and comorbidities of heart failure which
are covered in separate CKS topics: Hypertension, MI - secondary prevention, and Atrial fibrillation.
How do I manage a person with end-stage chronic heart failure?
How should I ensure appropriate advance planning for people with end-stage heart failure?
Care plan
•
•
People with end-stage heart failure and their carers, should have a care plan that takes accounts of their
needs, priorities and preferences for end of life care. The plan should address:
o
Symptom control and comfort measures.
o
Anticipatory prescribing of medication to manage exacerbations.
o
Discontinuing inappropriate interventions.
o
Needs for psychological and spiritual care.
o
Care of the family (before and after death of the patient).
o
When, who, and how to call for help when there is a crisis or acute exacerbation, and what the options
are for management.
▪
The benefits of hospital admission can be difficult to predict, as response to treatment is often
unpredictable and deterioration in symptoms may be due to causes other than heart failure.
o
The person’s preferences regarding:
▪
The setting or location in which they wish to be cared for.
▪
Whether or not resuscitation should be attempted if they were to have a life-threatening
deterioration or arrest. This information should be made available to out of hours and ambulance
services.
o
How to dispose of the person's medicines after their death.
Opportunities to discuss end of life issues and review the advance care plan can arise when there is a clinical
event or deterioration, or when there is a change in social circumstances such as a move into a care home.
Online resources for advance planning
•
Patients and carers may find the following online resources useful when planning the management of end of
life issues:
o
www.endoflifecareforadults.nhs.uk — the NHS National End of Life Care Programme supports the
implementation of the UK Department of Health's End of Life Care Strategy by sharing good practice in
collaboration with local and national stakeholders. The website is aimed at health and social care staff
and provides information on a variety of aspects relating to end of life care. This includes more than
100 case studies that highlight good practice.
o
www.endoflifecareforadults.nhs.uk — Preferred Priorities for Care — this document is a combined
information leaflet and form that can be used as by patients and carers to plan, and document their
preferred priorities for care.
o
www.westonhospicecare.org.uk — Planning Ahead — this document, developed by Weston Hospice with
patients and palliative care professionals, is a set of leaflets that can be used to facilitate discussions
and document decisions about end of life issues. The leaflets are entitled:
▪
Preferred Priorities for Care — your advanced wishes
▪
Putting your affairs in order and making a will
▪
Appointing someone to make decisions for you in the future
▪
Writing an advance decision
17
In depth: Heart failure - chronic
For more information see the CKS topic on Palliative cancer care - general issues.
Clarification / Additional information
•
The Liverpool Care Pathway for the dying patient provides a national framework for caring for people in the
terminal phase of a disease. It aims to improve professional communication and documentation, and to
integrate national guidelines into clinical practice (see www.mcpcil.org.uk/liverpool_care_pathway).
•
The Gold Standard Framework provides multiple tools, tasks and resources, which can be adapted within GP
practices and community nursing teams, to improve end of life care for people with any end-stage illness
(see www.goldstandardsframework.nhs.uk).
Basis for recommendation
These recommendations are in line with guidelines from the National Institute for Health and Clinical Excellence
(NICE) [National Collaborating Centre for Chronic Conditions, 2003; NICE, 2004], and policies published by the
Department of Health [End of Life Care Programme, 2007; DH, 2008].
How should I manage someone with end-stage heart failure?
Because palliative care for people with heart failure is similar to that for people with cancer, this overview
provides links to more detailed CKS topics on the management of specific aspects of palliative care in people with
cancer — their recommendations can usually be easily modified for people with end-stage heart failure.
Coordination of care services
•
People with end-stage heart failure may require co-ordination of a diverse range of health and social care
services to enable them to continue living at home and to die there if that is their wish. These services
include primary care, community nursing, domiciliary care, social care, community pharmacy, occupational
therapy, physiotherapy, dietetics and out of hours services.
Managing symptoms
•
•
•
•
•
Breathlessness
o
If standard treatment with diuretics, fluid restriction (to between 1.5 and 2 litres a day) and avoiding
excessive consumption of salt is ineffective, consider prescribing an opioid, a benzodiazepine, or
oxygen.
o
For information on when and how to prescribe opioids, benzodiazepines, and oxygen see Palliative
cancer care - dyspnoea.
Pain
o
Pain is often due to cardiac ischaemia, and this can be relieved by morphine and nitrates. Other pain
can be relieved by opioids.
o
For prescribing information see the CKS topics on Angina and Palliative cancer care - pain.
Anxiety, insomnia, and depression can be managed with sedatives and hypnotics.
o
For prescribing information see the CKS topics on Depression and Insomnia.
Constipation, nausea and loss of appetite can be managed with dietary changes, and laxatives.
o
For prescribing information see the CKS topics on Palliative cancer care - constipation, and Palliative
cancer care - nausea & vomiting.
Urinary incontinence is often related to weakness and the use of diuretics. It can be managed by careful
timing of diuretic doses, incontinence pads, for males a urisheath or a urethral catheter.
Managing an acute exacerbation
•
•
Ensure that medications commonly required to treat distressing symptoms are available in the house (for
example, cyclizine, diamorphine, and midazolam).
Admission is an option that should (ideally) be preplanned and re-evaluated as the person's condition
develops. Secondary care treatments may be appropriate in the early stage of palliative care, but may be
inappropriate at the later stage when they may not improve the quality or duration of life.
Managing the terminal phase
•
Explore understanding, and provide appropriate explanation of the situation to the patient, family, and other
carers.
•
Set realistic goals.
•
Ensure that religious and spiritual care is offered if wanted.
•
Ensure that the environment and care setting is appropriate. If available and appropriate, consider involving
palliative care services.
•
Stop unnecessary drugs and continue with other drugs by an appropriate route.
•
Ensure that physical symptoms are well controlled.
•
For more information, see the CKS topic on Palliative cancer care - general issues.
Clarification / Additional information
•
•
The most distressing symptoms in end-stage heart failure are pain, breathlessness, low mood, anxiety, and
urinary incontinence.
The most common symptoms experienced by people with heart failure in the last months of life are pain,
breathlessness, and fatigue. Other common symptoms and problems include constipation, nausea, loss of
appetite, oedema, anxiety, depression, sleeplessness, urinary incontinence, and faecal incontinence.
[Heart Failure Society of America, 2006b]
Basis for recommendation
18
In depth: Heart failure - chronic
These recommendations are in line with guidelines from the National Institute for Health and Clinical Excellence
(NICE) [National Collaborating Centre for Chronic Conditions, 2003; NICE, 2004], and policies published by the
Department of Health [End of Life Care Programme, 2007; DH, 2008].
•
NICE found substantial evidence from observational studies that there is considerable unmet palliative needs
of people with heart failure and their informal carers — the main areas of need include symptom control,
psychological and social support, planning for the future, and end of life care [National Collaborating Centre
for Chronic Conditions, 2003].
What comorbidities commonly need particular attention in people with chronic heart failure?
Angina
•
•
Ischaemic heart disease is a common cause of heart failure, and people with heart failure often have angina.
Ensure that angina symptoms are well controlled, with optimum use of medical management.
o
Beta-blockers are recommended for the treatment of both heart failure and angina.
o
Nitrates are safe to use in heart failure.
o
Calcium-channel blockers are effective at controlling angina symptoms, but some may aggravate heart
failure.
▪
Amlodipine is recommended, as there is randomized controlled trial evidence that it can be taken
safely in people with heart failure.
▪
Verapamil, diltiazem, and short-acting dihydropyridines should be avoided.
•
Ensure that fluid retention is well controlled with diuretics.
•
Low-dose aspirin is recommended for people with angina and heart failure.
•
For information on the management of angina, see the CKS topic on Angina.
Basis for recommendation
•
•
These recommendations are based on guidelines from the Scottish Intercollegiate Guidelines Network (SIGN)
[SIGN, 2007].
It is important to control fluid retention, because antianginal medication may produce little benefit unless
fluid retention is controlled with diuretics [ACC and AHA, 2005]. (It is possible that the decrease in
ventricular volume and pressures produced by diuretics may exert independent anti-anginal effects.)
Asthma or chronic obstructive pulmonary disease
•
•
Beta-blockers are contraindicated in people with a history of asthma or bronchospasm.
Beta-blockers can be used in people with stable chronic obstructive pulmonary disease.
o
Treatment should be started at a low dose and slowly titrated up.
o
If symptoms worsen, a reduction in dose or withdrawal may be necessary.
o
A cardioselective beta-blocker (e.g. bisoprolol or nebivolol) may be preferred.
Basis for recommendation
•
•
Current guidelines from NICE and the ESC agree that a history of asthma should be considered a
contraindication to the use of any beta-blocker, because they can precipitate an asthma attack [NICE, 2003;
European Society of Cardiology, 2008]. The Medicines and Healthcare products Regulatory Agency (formerly
the Committee on Safety of Medicines) has advised that beta blockers (including those considered to be
cardioselective) should not be given to people with a history of asthma or bronchospasm [CSM, 1996; BNF
56, 2008].
In people with chronic obstructive pulmonary disease (COPD) and heart failure, there is growing evidence
that the benefits of using a beta-blocker outweigh the risks, and many experts believe that beta-blockers
should not be withheld in people with COPD [Egred et al, 2005; Salpeter et al, 2005; Shelton et al, 2006]
Atrial fibrillation
•
Atrial fibrillation (AF) is the most common arrhythmia in people with heart failure. Its onset may lead to a
worsening of symptoms and poor prognosis.
•
In people with AF and left ventricular dysfunction a beta-blocker and/or digoxin are recommended to control
heart rate at rest.
•
In people with AF and heart failure with preserved left ventricular dysfunction a non-dihydropyridine
calcium-channel antagonist should be considered to control heart rate at rest and during exercise.
•
Antithrombotic treatment is recommended for all people with AF and heart failure, unless contraindicated.
•
For further information see the CKS topic on Atrial fibrillation.
Basis for recommendation
•
•
These recommendations are based on guidelines from the European Society of Cardiology (ESC) [European
Society of Cardiology, 2008].
Two small randomized placebo-controlled cross-over trials provide weak evidence that verapamil may
improve exercise capacity and symptoms in people with heart failure and preserved left ventricular ejection
fraction
Diabetes
•
Diabetes mellitus is a frequent comorbidity in people with heart failure and may increase the progression of
heart failure.
19
In depth: Heart failure - chronic
•
•
Good glycaemic control should be maintained.
If using metformin, renal function should be monitored and the use of metformin reviewed if serum
creatinine is greater than 130 micromol/L or estimated glomerular filtration rate (eGFR) is less than 45
mL/min/1.73 m2.
•
Thiazolidinediones (glitazones) are contraindicated in people with heart failure (NYHA I to IV).
•
Warning signs of hypoglycaemia (e.g. tremor, tachycardia) can be masked by non-selective beta-blockers. A
cardioselective beta-blocker (e.g. bisoprolol or nebivolol) is therefore preferred in people with diabetes.
Beta-blockers should be avoided in someone who experiences frequent hypoglycaemia.
•
See the CKS topic on Diabetes Type 2 for details of managing glucose control people with Type 2 diabetes.
Basis for recommendation
•
•
•
A direct beneficial effect of glucose lowering in reducing the risk of heart failure has not been demonstrated,
however, most experts consider this to be good practice [European Society of Cardiology, 2008].
Lactic acidosis is a rare, but potentially fatal, event which has been associated with metformin use. To
minimize the risk of lactic acidosis, the National Institute for Health and Clinical Excellence (NICE)
recommends that metformin treatment should be reviewed if serum creatinine is greater than
130 micromol/L or estimated glomerular filtration rate (eGFR) is less than 45 mL/min/1.73 m2 and
withdrawn if serum creatinine is greater than 150 micromol/L or eGFR is less than 30 mL/min/1.73 m2, or
when tissue hypoxia is suspected [NICE, 2008].
There is an increased risk of fluid retention with the thiazolidinediones, which can exacerbate or precipitate
heart failure and they are therefore contraindicated in all NYHA stages of heart failure [MeReC, 2007; MHRA,
2007b].
Gout
•
•
Loop diuretics can cause an increase in uric acid levels and may precipitate or aggravate gout.
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in people with heart failure; in acute gout,
colchicine is an alternative treatment to suppress inflammation and pain.
•
If allopurinol is used for the prevention of recurrence of gout, renal function should be monitored.
•
For information on the management of gout, see the CKS topic on Gout.
Basis for recommendation
•
These recommendations are based on guidelines from the National Institute of Health and Clinical Excellence
(NICE), the Scottish Intercollegiate Guidelines Network (SIGN), and the European Society of Cardiology
(ESC) [NICE, 2003; SIGN, 2007; European Society of Cardiology, 2008].
Renal impairment
•
Renal impairment is common in people with heart failure and is strongly associated with increased morbidity
and mortality.
•
Assess the underlying cause and manage potentially reversible causes. Possible causes include:
o
Dehydration — consider a reduction in dose of diuretic, or temporary cessation of diuretic.
o
Deterioration due to an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-II receptor
antagonist (AIIRA) — consider stopping or reducing the dose of the ACE inhibitor or AIIRA.
o
Coincidental renal disease (such as diabetic nephropathy or renovascular disease) — undertake
investigations as appropriate.
•
Use aldosterone antagonists with caution in people with renal impairment because they may cause clinically
significant hyperkalaemia.
•
Renal impairment is associated with impaired clearance of digoxin — to avoid toxicity, consider reducing the
dose of digoxin and monitoring for signs and symptoms of toxicity.
Basis for recommendation
•
These recommendations are based on guidelines from the the Scottish Intercollegiate Guidelines Network
(SIGN) and the European Society of Cardiology (ESC) [SIGN, 2007; European Society of Cardiology, 2008].
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
See ESC for specific details on use of ACE/AIIRAs
Prescribing information
Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically
for the drugs recommended in this Topic Review. For further information on contraindications, cautions, drug
interactions, and adverse effects, see the Medicines Compendium (www.medicines.org.uk), or the British National
Formulary (www.bnf.org).
Diuretics
Which diuretic should I use?
•
Loop diuretics are the preferred diuretics in heart failure, because they have a more powerful diuretic
action than thiazides [SIGN, 2007; European Society of Cardiology, 2008].
o
Loop diuretics available in the UK for the management of oedema due to congestive heart failure are
furosemide, bumetanide, and torasemide.
o
Furosemide is more widely used in UK practice; torasemide is not widely used, experience with it is
limited, and it is more expensive than furosemide or bumetanide.
20
In depth: Heart failure - chronic
•
•
•
A thiazide diuretic may be sufficient for someone with mild symptoms [SIGN, 2007].
o
Thiazide diuretics licensed for the management of oedema due to congestive heart failure are
bendroflumethiazide and chlortalidone.
o
Metolazone is a thiazide-type diuretic licensed for the treatment of cardiac oedema.
In people with resistant oedema, consider adding a thiazide to a loop diuretic [NICE, 2003; SIGN,
2007; European Society of Cardiology, 2008].
o
Metolazone is particularly effective when combined with a loop diuretic.
o
Use caution when combining a thiazide and a loop diuretic, because this combination can cause
dramatic diuresis and dehydration, hypovolaemia, hyponatraemia, and hypokalaemia — consider
seeking specialist advice.
Potassium-sparing diuretics are not generally recommended in the management of heart failure,
because most people with heart failure will be taking an angiotensin-converting enzyme (ACE) inhibitor or
angiotensin-II receptor antagonist (AIIRA) and possibly an aldosterone antagonist, all of which counteract
the potassium-losing effect of diuretics. In addition, there is an increased risk of hyperkalaemia when
potassium-sparing diuretics are given with an ACE inhibitor or an AIIRA.
What dose of diuretic should I prescribe and how should the dose be titrated?
•
•
•
Start with a low dose of diuretic and titrate up (or down) according to symptoms and signs of congestion
[NICE, 2003; SIGN, 2007; European Society of Cardiology, 2008]. A duration of 2 weeks is suggested
between titrations.
o
Suitable starting doses are shown in Table 2.
o
The dose is usually given once a day, in the morning, but they can be given twice a day (morning and
lunchtime) for additional diuresis.
Review the dose and adjust as necessary after restoration of dry body weight (that is after removal of most
or all of the person's excess fluid) and after subsequent treatment for heart failure has been introduced, to
avoid dehydration, renal dysfunction, and electrolyte disturbances [NICE, 2003; European Society of
Cardiology, 2008].
Provide patient education regarding self-adjustment of the dose based on regular weight measurements and
other signs and symptoms of fluid retention [European Society of Cardiology, 2008].
Table 2. Diuretic doses in people with heart failure.
Diuretic
Starting dose (mg/day)
Usual daily dose (mg)
Bumetanide
0.5–1.0
1–5
Furosemide
20–40
40–240
Torasemide
5–10
10–20
Bendroflumethiazide
2.5
2.5–10
Chlortalidone
25
25–50
Metolazone
2.5
2.5–10
Loop diuretics:
Thiazide diuretics:
Data taken from [NICE, 2003; BNF 56, 2008; European Society of Cardiology, 2008]
How should I monitor someone taking a diuretic?
•
•
•
•
Measure renal function and serum electrolytes before starting treatment.
Check renal function and serum electrolytes 1–2 weeks after starting treatment, and after each increase in
dose.
o
Earlier monitoring (after 5–7 days) may be required for people with existing renal impairment, or those
taking a combination of a diuretic plus an angiotensin-converting enzyme inhibitor, an angiotensin-II
receptor antagonist, or an aldosterone antagonist.
For people on a combination of a loop diuretic and a thiazide:
o
Check renal function 5–7 days after starting combination treatment, and recheck every 5–14 days,
depending on the person's stability.
o
Monitor weight and hydration status — if diuresis is extensive, consider earlier testing of renal function.
Once treatment is stable, measure renal function and serum electrolytes every 3–6 months in people at
'higher risk' and once a year in people at 'lower risk'.
[Smellie et al, 2007; London and South East Medicines Information Service et al, 2008]
How should I manage abnormal results?
•
•
If serum creatinine increases by more than 20% of baseline, or eGFR falls by more than 15% baseline,
remeasure renal function within 2 weeks.
If potassium falls below 3 mmol/L (or 4 mmol/L in 'high risk' people) review diuretic treatment.
21
In depth: Heart failure - chronic
[Smellie et al, 2007; London and South East Medicines Information Service et al, 2008]
What are the adverse effects of diuretics and how can they be managed?
•
•
Excessive diuresis may cause orthostatic hypotension, dehydration, renal dysfunction, and electrolyte
imbalances.
o
If there is evidence of symptomatic hypotension (low blood pressure coupled with dizziness, lightheadedness, or confusion), consider steps to counteract this (reduce the dose of diuretic, or reduce the
dose of any concomitant drugs known to reduce blood pressure) or seek expert advice.
o
Titrate the dose of diuretic (up and down) according to the person's symptoms; use the lowest possible
dose to control symptoms.
o
Monitor renal function and serum electrolytes regularly, especially after increasing the dose of diuretic
or adding another drug for heart failure.
Diuretics can cause hyperuricaemia and may precipitate or aggravate gout.
o
Consider prophylaxis with allopurinol to reduce the risk of recurrence of gout.
[NICE, 2003; Smellie et al, 2007; European Society of Cardiology, 2008]
What advice to I give to someone taking diuretics for heart failure?
•
Where appropriate provide education and advice regarding self-adjustment of the diuretic dose based on
regular weight measurements and other symptoms of fluid retention.
o
Ensure that the person or their carer knows how to adjust the dose in response to symptoms, and when
to seek help if their symptoms deteriorate or do not respond to dosage adjustment.
[National Collaborating Centre for Chronic Conditions, 2003; European Society of Cardiology, 2008].
Angiotensin-converting enzyme inhibitors
Which ACE inhibitor is recommended?
•
•
•
CKS recommends enalapril, lisinopril, ramipril, and trandolapril for the treatment of heart failure
in primary care, because these have the best evidence to support their use, and there is generally more
experience using them.
Cilazapril, fosinopril, perindopril, and quinapril are also licensed for the treatment of heart failure but target
doses have not been determined from large-scale randomized controlled trials.
Captopril is licensed for the treatment of heart failure and has been extensively studied. However, it has a
shorter half-life than other ACE inhibitors and needs to be taken three times a day, which may result in poor
compliance. It is rarely used now and is not recommended.
Who should avoid taking ACE inhibitors?
•
Contraindications to angiotensin-converting enzyme (ACE) inhibitors include:
o
History of angioedema associated with previous exposure to an ACE inhibitor.
o
Hereditary or idiopathic angioedema.
o
Renal artery stenosis.
o
Pregnancy.
▪
ACE inhibitors are contraindicated during the second and third trimesters of pregnancy. Exposure
to an ACE inhibitor during the second and third trimester is known to induce human fetal toxicity
(decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity
(renal failure, hypotension, hyperkalaemia) [MHRA, 2007c; Schaefer et al, 2007; ABPI Medicines
Compendium, 2008c; ABPI Medicines Compendium, 2008b; ABPI Medicines Compendium, 2009b;
ABPI Medicines Compendium, 2009c].
▪
ACE inhibitors are not recommended during the first trimester of pregnancy. Evidence regarding
the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of
pregnancy is conflicting, and an increase in the risk of congenital malformation (particularly of the
cardiovascular system and CNS) cannot be excluded [MHRA, 2007c; NTIS, 2007].
▪
Unless continued treatment with an ACE inhibitor is considered essential, women who are planning
a pregnancy should be changed to alternative treatment with an established safety profile for use
in pregnancy. The balance of risks and benefits of continued treatment with an ACE inhibitor
versus the potential risk of congenital anomaly should be discussed with the woman. When
pregnancy is confirmed, treatment with an ACE inhibitor should be stopped as soon as possible
and, if appropriate, alternative treatment should be started [MHRA, 2007c].
o
Breastfeeding.
▪
The use of an ACE inhibitor is not recommended in a woman who is breastfeeding because of a
lack of safety data [ ABPI Medicines Compendium, 2008c; ABPI Medicines Compendium, 2008b;
ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2009c].
What dose of ACE inhibitor should I prescribe and how should the dose be titrated?
•
•
Angiotensin-converting enzyme (ACE) inhibitors can usually be initiated in primary care. However, consider
seeking specialist advice before starting if the person is receiving high-dose loop diuretics (equivalent to 80
mg furosemide or more).
Start with a low dose of ACE inhibitor and titrate upwards by doubling the dose in short intervals (usually 2week intervals are suitable). After each upward titration, monitor the person's renal function and blood
pressure.
22
In depth: Heart failure - chronic
•
•
•
Aim for the target dose, or failing that the highest tolerated dose — a low dose of an ACE inhibitor is better
than no ACE inhibitor at all.
Maintain the ACE inhibitor at the target dose (or highest tolerated dose) indefinitely unless complications
occur.
Details of the starting and target doses are given in Table 3.
Table 3. Doses of ACE inhibitors recommended for heart failure.
ACE inhibitor
Initial dose
Target dose*
Enalapril
2.5 mg twice a day
10–20 mg twice a day
Lisinopril†
2.5 mg once a day
20–35 mg once a day
Ramipril
2.5 mg once a day
5 mg twice a day or 10 mg once a day
Trandolapril
0.5 mg once a day
4 mg once a day
* Use the higher dose if there are still symptoms at the lower target dose.
† Do not increase lisinopril by increments of more than 10 mg per day.
Data from: [National Collaborating Centre for Chronic Conditions, 2003; McMurray et al, 2005; European Society of Cardiology, 2008]
What monitoring is required for someone taking an ACE inhibitor or an AIIRA?
•
•
•
Measure renal function and serum electrolytes before starting treatment.
Check renal function and serum electrolytes 1–2 weeks after starting treatment, and 1–2 weeks after each
increase in dose.
o
Earlier monitoring (after 5–7 days) may be required for people with existing renal impairment, or those
taking a combination of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin-II receptor
antagonist (AIIRA) plus a diuretic or an aldosterone antagonist.
Once treatment is stable, measure renal function and serum electrolytes every 3–6 months in people at
higher risk (this includes people with existing renal dysfunction; age over 60 years; taking a combination of
a diuretic, an ACE inhibitor/AIIRA, or an aldosterone antagonist; or with relevant concomitant disease) and
once a year in people at 'lower risk'.
[Smellie et al, 2007; London and South East Medicines Information Service et al, 2008]
How should I manage abnormal results?
•
•
•
•
•
Some rise in serum creatinine, and potassium is expected after starting an angiotensin-converting enzyme
(ACE) inhibitor or an angiotensin-II receptor antagonist (AIIRA). Acceptable increases are:
o
An increase in serum creatinine up to 50% from baseline or up to 265 micromol/L (whichever is
smaller).
o
An increase in potassium up to 5.5 mmol/L.
If there are significant rises in serum creatinine, or potassium, consider stopping or reducing the dose of the
following drugs (where appropriate) if the person is taking them:
o
Nephrotoxic drugs (e.g. nonsteroidal anti-inflammatory drugs)
o
Vasodilators (e.g. calcium-channel blockers, nitrates)
o
Potassium supplements or potassium-sparing diuretics
o
Diuretics (consider dose reduction if hypovolaemic)
If creatinine persists above 50% of baseline (or > 265 micromol/L), or potassium persists above 5.5
mmol/L, halve the dose of ACE inhibitor/AIIRA and recheck in 5–7 days.
If creatinine increases above 100% of baseline (or > 310 micromol/L), or potassium rises above 5.9 mmol/L,
stop the ACE inhibitor/AIIRA immediately and seek specialist advice.
An increase in serum creatinine of 30% or more with a large fall in blood pressure soon after starting
treatment may suggest renovascular disease that should be investigated.
[McMurray et al, 2005; Smellie et al, 2007; London and South East Medicines Information Service et al, 2008]
What adverse effects are associated with ACE inhibitors and how can they be managed?
The risks of worsening renal function and hyperkalaemia are increased if an angiotensin-converting
enzyme (ACE) inhibitor is combined with an angiotensin-II receptor antagonist (AIIRA) or an
aldosterone antagonist and monitoring is essential.
•
•
Deterioration in renal function.
o
Monitor renal function after starting an ACE inhibitor, after each increase in dose, and regularly
throughout treatment.
Hyperkalaemia.
o
Monitor serum electrolytes after starting an ACE inhibitor, after each increase in dose, and regularly
throughout treatment.
23
In depth: Heart failure - chronic
•
•
Orthostatic hypotension is a common adverse effect of ACE inhibitors and may cause dizziness, lightheadedness, and confusion.
o
If hypotension is asymptomatic, there is no need to change treatment.
o
If hypotension is symptomatic:
▪
If there are no signs or symptoms of congestion, consider reducing the dose of any concomitant
diuretic.
▪
Consider seeking specialist advice.
Cough occurs in 0–15% of people taking an ACE inhibitor, although it rarely necessitates stopping treatment
(less than 5% of people) [Micromedex, 2008].
o
Cough is common in people with heart failure and can be due to smoking-related lung disease or
pulmonary oedema.
o
If the cough is troublesome (for example it prevents the person from sleeping) and other causes have
been ruled out, consider switching to an AIIRA.
[McMurray et al, 2005; European Society of Cardiology, 2008]
What advice should I give to someone taking an ACE inhibitor?
•
•
•
Explain the expected benefits of treatment and the importance of taking the treatment as prescribed.
o
Treatment improves symptoms, prevents worsening of symptoms, and increases survival.
o
Symptoms improve within a few weeks to a few months.
Advise the person that they may experience adverse effects, but that these rarely necessitate stopping
treatment.
o
Advise people to report symptoms of hypotension to their healthcare professional.
Advise the person to avoid nonsteroidal anti-inflammatory drugs (these may be present in over-the-counter
products) and salt substitutes that are high in potassium.
[NICE, 2003; McMurray et al, 2005]
Angiotensin-II receptor antagonists
Which angiotensin-II receptor antagonist is recommended?
•
CKS recommends candesartan, losartan, and valsartan for the treatment of heart failure in
primary care, because these have the best evidence to support their use.
o
Candesartan is licensed for the treatment of people with heart failure and impaired left ventricle systolic
function (left ventricular ejection fraction 40% or less) when angiotensin-converting enzyme (ACE)
inhibitors are not tolerated [ABPI Medicines Compendium, 2008f].
o
Valsartan is licensed to improve survival following myocardial infarction (MI) in people with signs,
symptoms, or radiological evidence of left ventricular failure and/or left ventricular systolic dysfunction
[ABPI Medicines Compendium, 2008g].
o
Losartan is licensed for the treatment of chronic heart failure (in patients aged 60 years or above),
when treatment with an ACE inhibitors is not considered suitable (for example because of cough) [ABPI
Medicines Compendium, 2009a].
o
Candesartan is the only AIIRA licensed for the treatment of people with heart failure and impaired left
ventricle systolic function as add-on therapy to an ACE inhibitor [ABPI Medicines Compendium, 2008f].
Who should avoid taking angiotensin-II receptor antagonists?
Contraindications to angiotensin-II receptor antagonists (AIIRAs) include:
o
o
o
Renal artery stenosis.
Severe hepatic impairment.
Pregnancy.
▪
AIIRAs are contraindicated during the second and third trimesters of pregnancy. Exposure to an
ACE inhibitor during the second and third trimester is known to induce human fetal toxicity
(decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity
(renal failure, hypotension, hyperkalaemia) [MHRA, 2007c; Schaefer et al, 2007; ABPI Medicines
Compendium, 2008c; ABPI Medicines Compendium, 2008b; ABPI Medicines Compendium, 2009b;
ABPI Medicines Compendium, 2009c].
▪
AIIRAs are not recommended during the first trimester of pregnancy. Evidence regarding the risk
of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy is
conflicting, and an increase in the risk of congenital malformation (particularly of the
cardiovascular system and CNS) cannot be excluded [MHRA, 2007c; NTIS, 2007].
▪
There are fewer data for the risks with AIIRAs, although there are case reports of congenital
anomalies after exposure to AIIRAs during the second and third trimesters. There are no data to
exclude a possible risk similar to that noted with ACE inhibitors in the first trimester [MHRA,
2007a].
▪
Unless continued treatment with an AIIRA is considered essential, women who are planning a
pregnancy should be changed to alternative treatment with an established safety profile for use in
pregnancy. The balance of risks and benefits of continued treatment with an AIIRA versus the
potential risk of congenital anomaly should be discussed with the woman. When pregnancy is
confirmed, treatment with an AIIRA should be stopped as soon as possible and, if appropriate,
alternative treatment should be started [MHRA, 2007c].
24
In depth: Heart failure - chronic
o
Breastfeeding.
▪
The use of an AIIRA is not recommended in a woman who is breastfeeding because of a lack of
safety data [ABPI Medicines Compendium, 2008f; ABPI Medicines Compendium, 2008g; ABPI
Medicines Compendium, 2009a].
What dose of AIIRA should I prescribe and how should the dose be titrated?
•
•
•
•
•
Angiotensin-II receptor antagonists (AIIRAs) can usually be initiated in primary care. However, consider
seeking specialist advice before starting if the person is receiving high-dose loop diuretics (equivalent to 80
mg furosemide or more).
Start with a low dose of AIIRA and titrate upwards by doubling the dose in short intervals (usually 2-week
intervals are suitable). After each upward titration, monitor the person's renal function and blood pressure.
Aim for the target dose, or failing that the highest tolerated dose.
Maintain the AIIRA at the target dose (or highest tolerated dose) indefinitely unless complications occur.
Details of the starting and target doses are given in Table 4.
Table 4. Doses of recommended AIIRAs for heart failure.
AIIRA
Initial dose
Target dose
Candesartan
4 mg once a day
32 mg once a day
Losartan
12.5 mg once a day
50 mg once a day
Valsartan
40 mg twice a day
160 mg twice a day
Data from: [National Collaborating Centre for Chronic Conditions, 2003; McMurray et al, 2005; European Society of Cardiology, 2008]
What monitoring is required for someone taking an ACE inhibitor or an AIIRA?
•
•
•
Measure renal function and serum electrolytes before starting treatment.
Check renal function and serum electrolytes 1–2 weeks after starting treatment, and 1–2 weeks after each
increase in dose.
o
Earlier monitoring (after 5–7 days) may be required for people with existing renal impairment, or those
taking a combination of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin-II receptor
antagonist (AIIRA) plus a diuretic or an aldosterone antagonist.
Once treatment is stable, measure renal function and serum electrolytes every 3–6 months in people at
higher risk (this includes people with existing renal dysfunction; age over 60 years; taking a combination of
a diuretic, an ACE inhibitor/AIIRA, or an aldosterone antagonist; or with relevant concomitant disease) and
once a year in people at 'lower risk'.
[Smellie et al, 2007; London and South East Medicines Information Service et al, 2008]
How should I manage abnormal results?
•
•
•
•
•
Some rise in serum creatinine, and potassium is expected after starting an angiotensin-converting enzyme
(ACE) inhibitor or an angiotensin-II receptor antagonist (AIIRA). Acceptable increases are:
o
An increase in serum creatinine up to 50% from baseline or up to 265 micromol/L (whichever is
smaller).
o
An increase in potassium up to 5.5 mmol/L.
If there are significant rises in serum creatinine, or potassium, consider stopping or reducing the dose of the
following drugs (where appropriate) if the person is taking them:
o
Nephrotoxic drugs (e.g. nonsteroidal anti-inflammatory drugs)
o
Vasodilators (e.g. calcium-channel blockers, nitrates)
o
Potassium supplements or potassium-sparing diuretics
o
Diuretics (consider dose reduction if hypovolaemic)
If creatinine persists above 50% of baseline (or > 265 micromol/L), or potassium persists above 5.5
mmol/L, halve the dose of ACE inhibitor/AIIRA and recheck in 5–7 days.
If creatinine increases above 100% of baseline (or > 310 micromol/L), or potassium rises above 5.9 mmol/L,
stop the ACE inhibitor/AIIRA immediately and seek specialist advice.
An increase in serum creatinine of 30% or more with a large fall in blood pressure soon after starting
treatment may suggest renovascular disease that should be investigated.
[McMurray et al, 2005; Smellie et al, 2007; London and South East Medicines Information Service et al, 2008]
What adverse effects are associated with AIIRAs and how can they be managed?
The risks of worsening renal function and hyperkalaemia are increased if an angiotensin-II receptor
antagonist (AIIRA) is combined with an angiotensin-converting enzyme (ACE) inhibitor or an
aldosterone antagonist and monitoring is essential.
•
Adverse effects with AIIRAs are similar to those seen with angiotensin converting enzyme (ACE) inhibitors,
although they tend to be milder. These include:
25
In depth: Heart failure - chronic
•
o
Hypotension
o
Hyperkalemia
o
Renal dysfunction
AIIRAs do not cause cough.
[McMurray et al, 2005; European Society of Cardiology, 2008]
What advice should I give to someone taking an AIIRA?
•
•
•
Explain the expected benefits of treatment and the importance of taking the treatment as prescribed.
o
Treatment improves symptoms, prevents worsening of symptoms, and increases survival.
o
Symptoms improve within a few weeks to a few months.
Advise the person that they may experience adverse effects, but that these rarely necessitate stopping
treatment.
o
Advise people to report symptoms of hypotension to their healthcare professional.
Advise the person to avoid nonsteroidal anti-inflammatory drugs (these may be present in over-the-counter
products) and salt substitutes that are high in potassium.
[NICE, 2003; McMurray et al, 2005]
Beta blockers
Which beta-blocker should I prescribe?
•
•
CKS recommends bisoprolol, carvedilol, and nebivolol for the treatment of heart failure in primary
care, because they have the best evidence to support thier use. The effect of beta-blockers in heart failure is
thought not to be a class effect [NICE, 2003; SIGN, 2007].
o
Bisoprolol (Cardicor®) is licensed for the treatment of stable chronic moderate to severe heart failure
with reduced systolic ventricular function (ejection fraction <35%, based on echocardiography) in
addition to angiotensin-converting enzyme (ACE) inhibitors, and diuretics, and optionally cardiac
glycosides [ABPI Medicines Compendium, 2008d].
o
Carvedilol is licensed for the treatment of stable mild, moderate and severe chronic heart failure as
adjunct to standard therapies e.g. diuretics, digoxin, and ACE inhibitors [ABPI Medicines Compendium,
2008e].
o
Nebivolol is licensed for the treatment of stable mild and moderate chronic heart failure in addition to
standard therapies in elderly patients > 70 years [ABPI Medicines Compendium, 2007b].
People who develop heart failure due to left ventricular systolic dysfunction and who are already on
treatment with a beta-blocker for a concomitant condition (for example, angina or hypertension) should
continue with a beta-blocker — either their current beta-blocker or an alternative licensed for heart failure
treatment [NICE, 2003].
Who should avoid taking beta-blockers?
•
•
Beta-blockers are contraindicated in:
o
People with a history of asthma or bronchospasm.
▪
Current guidelines from NICE and the ESC agree that a history of asthma should be considered a
contraindication to the use of any beta-blocker, because they can precipitate an asthma attack
[NICE, 2003; European Society of Cardiology, 2008]. The Medicines and Healthcare products
Regulatory Agency (formerly the Committee on Safety of Medicines) has advised that beta
blockers (including those considered to be cardioselective) should not be given to people with a
history of asthma or bronchospasm [CSM, 1996; BNF 56, 2008].
▪
Beta-blockers can be used in people with chronic obstructive pulmonary disease but caution should
be used if severe.
o
Second- or third-degree heart block (in the absence of a permanent pacemaker)
o
Sick sinus syndrome
o
Sinus bradychardia (less than 50 beats per minute at the start of treatment)
o
Severe hypotension
Seek specialist advice before starting a beta-blocker in someone with a current or recent exacerbation of
heart failure.
[McMurray et al, 2005; European Society of Cardiology, 2008]
What dose of beta-blocker should I prescribe and how should the dose be titrated?
•
•
•
A beta-blocker should only be started once the person is stable (without fluid overload or hypotension).
Beta-blockers should be started at a low dose and titrated up slowly to the target dose or failing that to the
highest tolerated dose (see Table 5).
o
Do not increase the dose if there are signs of worsening heart failure, symptomatic hypotension (e.g.
dizziness), or excessive bradycardia (< 50 beats per minute) [European Society of Cardiology, 2008].
Continue treatment at the target dose (or highest tolerated dose) indefinitely unless complications occur.
26
In depth: Heart failure - chronic
Table 5. Doses of beta-blockers recommended for heart failure.
ACE
inhibitor
Initial
dose
Target
dose
Titration regimen
Bisoprolol
1.25 mg
oncea day
10 mg
once a day
Increase from 1.25 mg to 2.5 mg to 3.75 mg to 5 mg at one
week intervals. Then increase to 7.5 mg and finally to 10 mg,
leaving an interval of 4 weeks between increases.
Carvedilol
3.125 mg
twice a
day
25–50 mg
twice a
day
Titrate the dose by doubling every 2 weeks. If the person has
severe heart failure or weighs less than 85 kg, the target dose
is 25 mg twice a day. If the person has mild to moderate heart
failure and weighs more than 85 kg, the target dose is 50 mg
twice a day.
Nebivolol
1.25 mg
once aday
10 mg
once a day
Increase dose from 1.25 mg, to 2.5 mg, to 5 mg, and finally to
10 mg, leaving an interval of 1–2 weeks, depending on the
person's ability to tolerate the drug.
Data from: [National Collaborating Centre for Chronic Conditions, 2003; McMurray et al, 2005; European Society of Cardiology, 2008]
Basis for recommendation
Basis for the recommendation goes here.
What monitoring is required for someone taking a beta-blocker
Beta-blockers should not be stopped suddenly unless absolutely necessary; there is a risk of rebound myocardial
ischaemia or infarction, or arrhythmias. Ideally, specialist advice should be sought before stopping a betablocker.
•
•
•
Monitor clinical status for symptoms and signs of heart failure, particularly after each dose-increase.
If the condition is worsening (e.g. increasing dyspnoea, fatigue, oedema, or weight gain), consider the
following actions:
o
Increasing congestion: double the dose of diuretic and, if this does not work, consider halving the dose
of beta-blocker.
o
Marked fatigue: halve the dose of beta-blocker (rarely necessary).
o
Serious deterioration: halve the dose or stop the beta-blocker (seek specialist advice).
o
Review the person in 1–2 weeks. If there is no improvement, seek specialist advice.
Check heart rate after each dose-increase; if heart rate drops to 50 beats per minute or less, consider the
following:
o
Halve the dose of beta-blocker, or, if deterioration is severe, stop the beta-blocker (seek specialist
advice).
o
Review the need for other drugs that slow heart rate (e.g. digoxin, amiodarone, diltiazem).
o
Arrange for an electrocardiograph to exclude heart block.
o
Seek specialist advice.
Check serum electrolytes, urea, and creatinine 1–2 weeks after initiation, and 1–2 weeks after reaching
the target dose.
[NICE, 2003; McMurray et al, 2005]
What adverse effects are associated with beta-blockers and how can they be managed?
•
•
•
•
•
•
Adverse effects that should be checked for during monitoring include:
o
Deteriorating symptoms of heart failure (e.g. congestive symptoms and fatigue)
o
Hypotension
o
Abnormally low heart rate (bradycardia)
Cold extremities, paraesthesiae, and numbness can occur, and are more common in people with
peripheral vascular disease [Lopez-Sendon et al, 2004]. If troublesome, beta-blockers might need to be
stopped — this is most likely in people with severe peripheral vascular disease.
Sleep disturbance or nightmares can occur, but are reported to be uncommon with bisoprolol, carvedilol,
and nebivolol [ABPI Medicines Compendium, 2008d; ABPI Medicines Compendium, 2007a; ABPI Medicines
Compendium, 2007b].
Fatigue: an incidence of approximately 18 per 1000 people treated with a beta-blocker has been reported
but in clinical trials only 0.4% of people stopped taking their beta-blocker for this reason [Ko et al, 2002].
Sexual dysfunction (impotence and loss of libido) occurs in approximately 5 per 1000 people on
treatment, leading to discontinuation of treatment in 2 per 1000 person-years [Ko et al, 2002]. People
should be directly questioned about whether they are having sexual problems because this adverse effect is
often not volunteered due to embarrassment.
Depression has been claimed to be an adverse effect of beta-blockers, but a recent meta-analysis found no
significant increased risk of depressive symptoms in people taking beta-blockers [Ko et al, 2002].
27
In depth: Heart failure - chronic
•
Warning signs of hypoglycaemia (e.g. tremor, tachycardia) can be masked by non-selective betablockers. A selective beta-blocker is therefore preferred in people with diabetes [Lopez-Sendon et al, 2004].
Avoid beta-blockers in someone who experiences frequent hypoglycaemia [BNF 56, 2008].
What key drug interactions should I be aware of?
•
•
•
•
•
Verapamil and diltiazem
o
The combination of a beta-blocker and verapamil should not be prescribed because bradycardia,
asystole, severe hypotension, and heart failure can occur.
o
Caution should be used if prescribing diltiazem with a beta-blocker — monitor pulse and blood pressure
carefully, as bradycardia and atrioventricular block can occur. Asystole/sudden death has also been
reported.
Class I anti-arrhythmics (e.g.quinidine, flecainide)
o
The combination of a beta-blocker and a class I anti-arrhythmic is not recommended because
bradycardia and myocardial depression can occur.
Class III anti-arrhythmics (e.g. amiodarone)
o
The combination of a beta-blocker and amiodarone should be prescribed with caution — monitor pulse,
blood pressure, and check for signs of worsening heart failure, as there is an increased risk of
bradycardia, AV block, and myocardial depression.
Digoxin
o
Concomitant administration of a beta-blocker and digoxin can reduce heart rate and prolong AV
conduction time, increasing the risk of AV block and bradycardia — monitor pulse carefully.
o
An increase in plasma digoxin levels has been noted with carvedilol — monitor for signs of digoxin
toxicity (confusion, anorexia, nausea, disturbance of colour vision) when starting, adjusting, or stopping
carvedilol [ABPI Medicines Compendium, 2007a].
Other drugs that reduce blood pressure
o
An additive hypotensive effect may occur — monitor for signs of hypotension (e.g. dizziness, lightheadedness, confusion).
[BNF 56, 2008; ABPI Medicines Compendium, 2007a; ABPI Medicines Compendium, 2007b; ABPI Medicines
Compendium, 2008d]
What advice should I give to someone taking a beta-blocker?
•
•
•
Explain the expected benefits of beta-blockers:
o
Beta-blockers slow down the worsening of the disease (reducing hospital admissions) and prolong lifeexpectancy.
o
Beta-blockers improve symptoms of heart failure.
Explain that there may be an initial deterioration in symptoms before improvement:
o
Temporary deterioration occurs in 20–30% of people during the titration stage.
o
Symptomatic improvement may develop slowly after starting treatment (over the course of 3–6
months).
Advise people to:
o
Seek medical advice if there is a rapid deterioration in symptoms such as tiredness, fatigue, or
breathlessness. Worsening symptoms can usually be controlled by adjusting other medications, and
beta-blockers should never be stopped without consulting a healthcare professional.
o
Weigh themselves regularly and consult their healthcare professional if there is persistent weight gain
(an increase of more than 1.5 kg persisting over more than 2 days).
[McMurray et al, 2005]
Aldosterone antagonists
Which aldosterone antagonist is recommended?
•
•
Spironolactone is the aldosterone antagonist of choice.
o
Its use in people with moderate to severe heart failure is supported by trial evidence, and experience.
Eplerenone may be considered as an alternative to spironolactone in men who develop
gynaecomastia with spironolactone.
o
There is less evidence to support the use of eplerenone, it is more expensive than spironolactone and
there is less experience with its use. Eplerenone is a black triangle drug (it is a newly licensed medicine
that is still under intensive surveillance by the Medicines and Healthcare Regulatory Agency [MHRA].
[SIGN, 2007; European Society of Cardiology, 2008]
Who should avoid taking an aldosterone antagonist?
•
•
Spironolactone (and eplerenone) is contraindicated in people:
o
With addison's disease.
o
Who are already taking a combination of an angiotensin-converting enzyme inhibitor and an
angiotensin-II receptor antagonist.
Use caution or seek specialist advice when starting spironolactone in people with:
o
Anuria, acute renal insufficiency, rapidly deteriorating or severe impairment of renal function (serum
creatinine > 220 micromol/L).
28
In depth: Heart failure - chronic
o
Hyperkalaemia (potassium > 5 mmol/L).
[McMurray et al, 2005]
What dose of aldosterone antagonist should I prescribe and how should the dose be titrated?
•
•
Start with a low dose of aldosterone antagonist and consider titrating up after 4–8 weeks if tolerated.
o
On each upward titration, monitor the person's renal function and blood pressure.
o
Do not increase the dose if there is worsening renal function of hyperkalaemia.
Details of the starting and target doses are given in Table 6.
Table 6. Doses of aldosterone antagonists recommended for heart failure.
Aldosterone antagonist
Initial dose
Target dose
Spironolactone
25 mg once a day†
25–50 mg once a day
Eplerenone
25 mg once a day
50 mg once a day
† This dose can be given on alternate days if poorly tolerated
Data from: [McMurray et al, 2005; SIGN, 2007; European Society of Cardiology, 2008]
What monitoring is required for someone taking an aldosterone antagonist?
•
Check blood chemistry (electrolytes, urea, and creatinine) before starting treatment with spironolactone and
after 1, 4, 8, and 12 weeks. Check again after 6, 9, and 12 months, and every 6 months thereafter:
o
If potassium rises to between 5.5 and 5.9 mmol/L, or creatinine rises above 220 micromol/L, reduce
the dose to 25 mg taken on alternate days, and monitor blood chemistry frequently to ensure that renal
function is not worsening.
o
If potassium rises to 6.0 mmol/L or above, or creatinine rises above 310 micromol/L, stop
spironolactone immediately and seek specialist advice.
[McMurray et al, 2005]
•
Monitoring parameters specifically for eplerenone are not provided in current guidelines, but it is assumed
that eplerenone should be monitored in the same way as spironolactone.
What adverse effects are associated with aldosterone antagonists and how can they be managed?
•
•
•
Spironolactone (and eplerenone) may cause elevated levels of serum potassium (hyperkalaemia):
o
Potassium levels require careful monitoring to ensure that renal function is not deteriorating.
o
Potassium levels at the higher end of the normal range may be desirable in people with heart failure,
particularly if they are taking digoxin.
o
Note: many 'low salt' preparations have a high potassium content.
Spironolactone may cause hormonal disturbances, especially in men, resulting in gynaecomastia and breast
tenderness in about 10% of men receiving low-dose spironolactone [Pitt et al, 1999].
o
Consider eplerenone as an alternative in men who develop gynaecomastia whilst taking spironolactone.
Other adverse effects include fatigue, gastrointestinal disturbances, menstrual disruption, skin complaints,
and blood disorders.
[NICE, 2003; BNF 56, 2008]
What advice should I give to someone taking an aldosterone antagonist?
•
•
•
Explain the potential benefits of spironolactone:
o
Spironolactone slows down the worsening of the disease and prolongs life expectancy.
o
Spironolactone improves symptoms of heart failure.
Explain that symptom improvement may not occur for a few weeks or months after starting treatment.
Advise people to:
o
Temporarily stop spironolactone and seek specialist advice if they develop diarrhoea or vomiting
suspected to be associated with spironolactone use.
o
Avoid using nonsteroidal anti-inflammatory drugs (because of nephrotoxicity), unless specifically
prescribed by a physician.
o
Avoid using salt substitutes that are high in potassium.
[McMurray et al, 2005]
Digoxin
Who should avoid taking digoxin?
•
Digoxin is contraindicated in people with:
o
Some supraventricular arrhythmias, such as Wolff-Parkinson-White syndrome.
o
Heart conduction problems, such as intermittent complete heart block or atrioventricular heart block.
o
Ventricular tachycardia.
29
In depth: Heart failure - chronic
o
Hypertrophic obstructive myopathy.
[ABPI Medicines Compendium, 2007a]
What dose of digoxin should I prescribe and how should the dose be titrated?
•
•
Loading doses of digoxin are not needed in people who are stable with sinus rhythm [European Society of
Cardiology, 2008].
The usual dose of digoxin is 125–250 micrograms in people with normal renal function.
o
Higher doses (above 250 micrograms) are rarely needed to treat heart failure.
o
Lower doses (62.5–125 micrograms) are usually used in the elderly or people with impaired renal
function.
[NICE, 2003; European Society of Cardiology, 2008]
What monitoring is required for someone taking digoxin
•
•
•
•
Routine monitoring of serum digoxin is not recommended.
o
There is no evidence that regular monitoring confers better outcomes.
Consider checking serum digoxin levels:
o
When there are adverse effects suggestive of toxicity (e.g. confusion, nausea, anorexia, disturbance of
colour vision).
o
When other factors may affect the serum digoxin level, such as the use of a concomitant drug that may
affect levels (e.g. amiodarone, diltiazem, verapamil), or deteriorating renal function.
o
When poor compliance is suspected.
The therapeutic range of digoxin for heart failure recommended in the literature varies from between 0.7
and 2.0 nanograms per millilitre [NICE, 2003] and between 0.6 and 1.2 nanograms per millilitre [European
Society of Cardiology, 2008]. The exact range is not important, because a diagnosis of digoxin toxicity
should be based on both clinical signs of toxicity and digoxin level.
o
Blood samples should be taken at least 6 hours after the previous dose, but ideally 8–12 hours
afterwards.
In addition, blood chemistry measurements should be taken (electrolytes, urea, and creatinine), as this can
affect digoxin toxicity (these tests will often be done routinely in this patient group, as they are likely to be
monitored for renal function owing to the use of nephrotoxic drugs such as diuretics or angiotensinconverting enzyme inhibitors).
[NICE, 2003]
What adverse effects are associated with digoxin and how can they be managed?
•
•
•
Digoxin has a narrow therapeutic window — there is only a small range of plasma concentration between the
drug being ineffective through underdosing, and toxic through overdosing. Adverse effects usually occur at
serum concentrations above the upper limit of the therapeutic window, and are dose-dependent. If
significant adverse effects occur, serum levels of digoxin should be measured.
Non-cardiac adverse effects are usually associated with overdosage and include:
o
Nausea, vomiting and, less commonly, diarrhoea. Nausea in particular is indicative of overdosage.
o
Visual abnormalities (blurred or yellow vision).
o
Central nervous system effects such as weakness, dizziness, confusion, apathy, malaise, headache,
depression, and psychosis.
Cardiac adverse effects are usually associated with overdosage, although electrolyte imbalances may
predispose the person to cardiac adverse effects so that they occur even at therapeutic concentrations. They
include various conduction and rhythm disturbances such as:
o
Sinoatrial and AV block.
o
Premature ventricular contractions (resulting in bigeminy or trigeminy).
o
PR prolongation and ST segment depression.
[ABPI Medicines Compendium, 2008e; BNF 56, 2008; European Society of Cardiology, 2008]
What key drug interactions should I be aware of?
•
•
•
•
Beta-blockers:
o
Concomitant administration of a beta-blocker and digoxin can reduce heart rate and prolong AV
conduction time, increasing the risk of AV block and bradycardia — monitor pulse carefully.
o
An increase in plasma digoxin levels has been noted with carvedilol — monitor for signs of digoxin
toxicity (confusion, anorexia, nausea, disturbance of colour vision) when starting, adjusting, or stopping
carvedilol.
Calcium-channel blockers:
o
The plasma concentration of digoxin is increased by diltiazem and verapamil and, possibly by nifedipine
— monitor for signs and symptoms of toxicity.
o
There is an increased risk of AV block and bradycardia with verapamil.
Amiodarone:
o
The plasma concentration of digoxin is increased by amiodarone — halve the dose of digoxin and
monitor for signs and symptoms of toxicity.
Antibiotics:
30
In depth: Heart failure - chronic
o
•
The plasma concentration of digoxin is increased by itraconazole, macrolide antibiotics, tetracycline,
and trimethoprim — monitor for signs and symptoms of toxicity.
St John's wort:
o
The plasma concentration of digoxin may be reduced by St John's wort — advise people taking digoxin
that they should not use St John's wort, and that they should check with their pharmacist before using
any other over-the-counter drugs.
[ABPI Medicines Compendium, 2007a; ABPI Medicines Compendium, 2008e; BNF 56, 2008].
31
In depth: Heart failure - chronic
Appendices
Supporting evidence
The scope of the supporting evidence section
This section reviews the evidence used to support the information, advice and recommendations in this Topic
Review.
This section does not review the evidence on interventions that are not discussed in this Topic Review. These
interventions are not generally used in primary care, either because they require specialist skills and facilities
available in secondary care, or because they are unproven.
Evidence on diagnostic tests (including symptoms and signs) for heart failure
Evidence on symptoms, signs, and medical history for diagnosing heart failure
No symptom, clinical sign, or item in the medical history has been shown has been shown to provide a
reliable diagnosis of heart failure. But, clinically useful information is provided by a number of items,
including: overall clinical impression, breathlessness, dependent oedema, third or fourth heart
sounds, abdominojugular reflux, jugular venous distension, pulmonary crackles, and past history of
myocardial infarct, coronary artery disease, hypertension, diabetes mellitus, and dyslipidaemia. There
is great variability in the precision of clinical findings associated with heart failure, but no studies
have directly investigated the variability between different observers or the variability between
different observations made by one observer.
The evidence on the diagnostic accuracy of symptoms, signs, and past medical history used to diagnose heart
failure is synthesized in two systematic reviews. The most directly relevant review is of diagnostic tests for
diagnosing 'left-sided heart failure' [Badgett et al, 1997]. A more recent review assessed the accuracy of tests for
'congestive heart failure' in dyspnoeic people presenting to the emergency room [Wang et al, 2005]. Although
the two reviews addressed different problems in different populations, they came to qualitatively similar
conclusions for the accuracy of symptoms and signs, which suggest that the results are applicable in UK general
practice. We therefore summarize only the results of the more recent review, which also assessed the
contribution that past medical history can make to the accuracy of the diagnosis.
Table 7 summarizes the diagnostic accuracy of symptoms, signs, and medical history in people with dyspnoea
and suspected heart failure. The table shows the sensitivity, specificity, positive likelihood ratio, and negative
likelihood ratio for individual diagnostic items. The diagnostic accuracy of combinations of tests was not estimated
by the meta-analysis. The table does not show the 95% confidence interval (CI) for sensitivity and specificity as
these were not published. However, the table does show 95% CIs for likelihood ratios. In general the 95% CIs
are wide, and this provides evidence of large variability in the accuracy of the signs, symptoms and past medical
history.
32
In depth: Heart failure - chronic
Appendices
Table 7. Summary of diagnostic accuracy of symptoms, signs, and medical history in people with dyspnoea
and suspected heart failure.
Diagnostic item
No.
studies
Sensitivity*
Specificity†
LR+‡
(95%
CI)
LR–§
(95%
CI)
Initial clinical
judgement
4
0.61
0.86
4.4 (1.810.0)
0.45
(0.280.73)
Paroxysmal nocturnal
dyspnoea
5
0.41
0.84
2.6 (1.54.5)
0.70
(0.540.91)
Orthopnoea
6
0.50
0.77
2.2 (1.23.9)
0.65
(0.450.92)
Oedema
3
0.51
0.76
2.1
(0.925.0)
0.64
(0.391.1)
Dyspnoea on exertion
2
0.84
0.34
1.3 (1.21.4)
0.48
(0.350.67)
Fatigue and weight
gain
1
0.31
0.70
1.0
(0.741.4)
0.99
(0.851.1)
Cough
5
0.36
0.61
0.93
(0.701.2)
1.0
(0.871.3)
Third heart sound
(ventricular gallop)
8
0.13
0.99
11 (4.925.0)
0.88
(0.830.94)
Abdominojugular
reflux
1
0.24
0.96
6.4
(0.8151.0)
0.79
(0.621.0)
Jugular venous
distension
8
0.39
0.92
5.1 (3.27.9)
0.66
(0.570.77)
Crepitations
8
0.60
0.78
2.8 (1.94.1)
0.51
(0.370.70)
Any murmur
4
0.27
0.90
2.6 (1.74.1)
0.81
(0.730.90)
Lower extremity
oedema
6
0.50
0.78
2.3 (1.53.7)
0.64
(0.470.87)
Valsalva manoeuvre
1
0.73
0.65
2.1 (1.04.2)
0.41
(0.171.0)
Systolic blood
pressure <100 mm Hg
1
0.06
0.97
2.0
(0.606.6)
0.97
(0.911.0)
Fourth heart sound
(atrial gallop)
3
0.05
0.97
1.6
(0.475.5)
0.98
(0.931.0)
Symptoms
Signs
33
In depth: Heart failure - chronic
Appendices
Systolic blood
pressure >=150 mm
Hg
1
0.28
0.73
1.0
(0.691.6)
0.99
(0.841.2)
Wheezing
5
0.22
0.58
0.52
(0.380.71)
1.3 (1.11.7)
Ascites
1
0.01
0.97
0.33
(0.042.9)
1.0
(0.991.1)
Myocardial infarction
6
0.40
0.87
3.1 (2.04.9)
0.69
(0.580.82)
Coronary artery
disease
4
0.52
0.70
1.8 (1.12.8)
0.68
(0.480.96)
Dyslipidemia
1
45 0
23 0.87
1.7
(0.436.9)
0.89
(0.691.1)
Diabetes mellitus
5
0.28
0.83
1.7 (1.02.7)
0.86
(0.731.0)
Hypertension
8
0.60
0.56
1.4 (1.11.7)
0.71
(0.550.93)
Smoker
1
0.62
0.27
0.84
(0.581.2)
1.4
(0.583.6)
Chronic obstructive
pulmonary disease
4
0.34
0.57
0.81
(0.601.1)
1.1
(0.951.4)
History
* Sensitivity: the proportion of people with a condition who have a positive test.
† Specificity: the proportion of people free of a condition who have a negative test.
‡ LR+: the likelihood ratio for a positive test; how much the odds of the condition increase with a postive result.
§ LR–: the likelihood ratio for a negative test; how much the odds of the condition decrease with a negative result.
Data from: [Wang et al, 2005].
Evidence on chest radiography in people with suspected heart failure
No finding on chest X-ray has been shown has been shown to provide a reliable diagnosis of heart
failure. But, clinically useful information is provided by a number of items, including: pulmonary
venous congestion, interstitial oedema, alveolar oedema, cardiomegaly, and pleural effusion. There is
great variability in the precision of clinical findings associated with heart failure, but no studies have
directly investigated the variability between different observers or the variability between different
observations made by one observer. The evidence is mostly based on studies done in hospital, and the
results may not be applicable in primary care with less severely ill people.
The evidence on the diagnostic accuracy of chest radiography used to diagnose heart failure is synthesized in two
systematic reviews. The most directly relevant review is of diagnostic tests for diagnosing 'left-sided heart
failure', although most of the included studies were of people managed in hospital [Badgett et al, 1997]. A more
recent review assessed the accuracy of tests for 'congestive heart failure' in dyspnoeic people presenting to the
emergency room [Wang et al, 2005]. Although the two reviews addressed different problems in different
populations, they came to qualitatively similar conclusions for the accuracy of symptoms and signs. We therefore
summarize only the results of the more recent review.
Table 8 summarizes the diagnostic accuracy of chest radiography in people with dyspnoea and suspected heart
failure. The table shows the sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio for
individual diagnostic items. The diagnostic accuracy of combinations of tests was not estimated by the metaanalysis. The table does not show the 95% confidence interval (CI) for sensitivity and specificity as these were
not published. However, the table does show 95% CIs for likelihood ratios. In general the 95% CIs are wide, and
this provides evidence of large variability in the accuracy of the signs, symptoms and past medical history.
34
In depth: Heart failure - chronic
Appendices
Table 8. Summary of diagnostic accuracy of chest radiography in people with dyspnoea and suspected heart
failure.
Diagnostic item
No.
studies
Sensitivity*
Specificity†
LR+‡
(95% CI)
LR–§
(95% CI)
Pulmonary venous
congestion
4
0.54
0.96
12.0 (6.821.0)
0.48 (0.280.83)
Interstitial oedema
2
0.34
0.97
12.0 (5.227.0)
0.68 (0.540.85)
Alveolar oedema
1
0.06
0.99
6.0 (2.216.0)
0.95 (0.930.97)
Cardiomegaly
6
0.74
0.78
3.3 (2.44.7)
0.33 (0.230.48)
Pleural effusion
2
0.26
0.92
3.2 (2.44.3)
0.81 (0.770.85)
Any oedema
2
0.70
0.77
3.1 (0.6016.0)
0.38 (0.111.3)
Pneumonia
1
0.04
0.92
0.50 (0.290.87)
1.0 (1.01.1)
Hyperinflation
1
0.03
0.92
0.38 (0.200.69)
1.1 (1.01.1)
* Sensitivity: the proportion of people with a condition who have a positive test.
† Specificity: the proportion of people free of a condition who have a negative test.
‡ LR+: the likelihood ratio for a positive test; how much the odds of the condition increase with a postive result.
§ LR–: the likelihood ratio for a negative test; how much the odds of the condition decrease with a negative result.
Data from: [Wang et al, 2005].
Evidence on electrocardiography for diagnosing heart failure
No finding on electrocardiography has been shown has been shown to provide a reliable diagnosis of
heart failure. But, clinically useful information is provided by a number of items, including: atrial
fibrillation, new T-wave changes, and ST segment elevation or depression. There is great variability in
the precision of clinical findings associated with heart failure, but no studies have directly
investigated the variability between different observers or the variability between different
observations made by one observer.
The evidence on the diagnostic accuracy of electrocardiography used to diagnose heart failure is synthesized in
two systematic reviews. The most directly relevant review is of diagnostic tests for diagnosing 'left-sided heart
failure' [Badgett et al, 1997]. A more recent review assessed the accuracy of tests for 'congestive heart failure' in
dyspnoeic people presenting to the emergency room [Wang et al, 2005]. Although the two reviews addressed
different problems in different populations, they came to qualitatively similar conclusions for the accuracy of
symptoms and signs. We therefore summarize only the results of the more recent review.
Table 9 summarizes the diagnostic accuracy of electrocardiography in people with dyspnoea and suspected heart
failure. The table shows the sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio for
individual diagnostic items. The diagnostic accuracy of combinations of tests was not estimated by the metaanalysis. The table does not show the 95% confidence interval (CI) for sensitivity and specificity as these were
not published. However, the table does show 95% CIs for likelihood ratios. In general the 95% CIs are wide, and
this provides evidence of large variability in the accuracy of the signs, symptoms and past medical history.
35
In depth: Heart failure - chronic
Appendices
Table 9. Summary of diagnostic accuracy of electrocardiography in people with dyspnoea and suspected
heart failure.
Diagnostic
item
No.
studies
Sensitivity*
Specificity†
LR+‡
(95% CI)
LR–§
(95% CI)
Atrial fibrillation
5
0.26
0.93
3.8 (1.78.8)
0.79 (0.650.96)
New T-wave
changes
1
0.24
0.92
3.0 (1.75.3)
0.83 (0.740.92)
Any abnormality
2
0.50
0.78
2.2 (1.63.1)
0.64 (0.470.88)
ST elevation
2
0.05
0.97
1.8 (0.804.0)
0.98 (0.941.0)
ST depression
2
0.11
0.94
1.7 (0.972.9)
0.95 (0.901.0)
* Sensitivity: the proportion of people with a condition who have a positive test.
† Specificity: the proportion of people free of a condition who have a negative test.
‡ LR+: the likelihood ratio for a positive test; how much the odds of the condition increase with a postive result.
§ LR–: the likelihood ratio for a negative test; how much the odds of the condition decrease with a negative result.
Data from: [Wang et al, 2005].
Evidence on B-type natriuretic peptides for diagnosing heart failure
A Scottish health technology assessment found that costs could be saved if B-type natriuretic peptide
(BNP) tests were used to rule out the need for echocardiography, but that the tests are too inaccurate
to help confirm a diagnosis of heart failure. Six subsequent systematic reviews and meta-analyses
provide further support for the conclusions of the Scottish health technology assessment on the
diagnostic accuracy of B-type natriuretic peptides for diagnosing heart failure. There is no evidence
that the accuracy of BNP differs from that of N-terminal proBNP (NT-proBNP). However, as BNP has
been studied more, there is more data on its behaviour in concomitant disease and in the elderly.
A Scottish health technology assessment (HTA) investigated whether or not a normal B-type natriuretic peptide
(BNP) result can reliably rule-out heart failure — in the primary care setting to inform the decision on whether or
not to send a patient to a specialist or for echocardiography, and in admission units to inform decisions around
treatment and placement of patients [NHS Quality Improvement Scotland, 2005].
•
•
The HTA found that:
o
Diagnostic accuracy. For diagnosing heart failure, BNP tests have similar sensitivities but higher
specificities than a cardiologist report of an abnormal ECG. An automated report of abnormal ECG has a
similar sensitivity but a much lower specificity than BNP tests.
o
Cost of implementing the use of BNP. It would cost between £200,000 and £550,000 each year to
introduce BNP testing to exclude heart failure when the electrocardiogram (ECG) was normal and there
were symptoms and signs suggestive of heart failure. There would also a one-off cost of about
£300,000 for initial training.
o
Savings arising out of the use of BNP. Reduced use of echocardiography would save between
£600,000 and £1,400,000 each year. Fewer admissions and shorter lengths of stay would save between
£100,000 and £600,000 annually.
Limitations
o
The HTA assumed that all GPs could record and accurately read ECGs.
o
The HTA extrapolated data from a Swiss study of the use of natriuretic peptides in hospital settings.
Six subsequent systematic reviews and meta-analyses provide further support for the conclusions of the Scottish
health technology assessment on the diagnostic accuracy of B-type natriuretic peptides for diagnosing heart
failure [Korenstein et al, 2007; AHRQ, 2006; Worster et al, 2008; Hill et al, 2008; Ewald et al, 2008; Mastandrea,
2008].
•
•
•
The reviews differed considerably with respect to setting (for example primary care, or hospital emergency
service), reference standard for diagnosing heart failure (for example based on clinical criteria, or
echocardiography), and the decision points for BNP and NT-proBNP.
Nevertheless, the reviews were consistent in their conclusions that BNP and NT-proBNP can be used to
exclude heart failure, but are too inaccurate to confirm heart failure. In other words, the tests have
adequate sensitivity to rule out heart failure, but their specificity is too low for the tests to be used to
confirm heart failure.
The reviews provide evidence that:
36
In depth: Heart failure - chronic
Appendices
o
•
•
Natriuretic peptides are raised in a number of situations, including left ventricular hypertrophy,
tachycardia, right ventricular overload, myocardial ischaemia, hypoxaemia, renal dysfunction, advanced
age, cirrhosis of the liver, sepsis, and infection.
o
Natriuretic peptides are decreased in obesity and by drug treatments for heart failure.
The systematic review with the broadest scope compared the performance of the natriuretic peptide tests in
different settings, and concluded that there were no clinically important differences between their use in
primary care, the emergency department, and hospital clinic [AHRQ, 2006].
The same systematic review found indirect evidence that BNP and NT-proBNP provide clinically useful
information independent of the traditional diagnostic measures [AHRQ, 2006].
Graph showing the performance of BNP and NT-proBNP tests
Figure 3. Performance of BNP and NT-proBNP tests for diagnosing heart failure presenting in primary care.
Chart drawn using data in [AHRQ, 2006].
The graph plots the true positive rate (or sensitivity) against the false positive (or 1 minus specificity) for BNP
and NT-proBNP tests used to diagnose heart failure in primary care. The data are taken from a systematic review,
and reflect results from five studies [AHRQ, 2006]. The studies varied in criteria for participation, criteria for
diagnosing heart failure, and cut-off point for considering the BNP or NT-proBNP test normal. Where studies
reported data for multiple cut-off points, the point closest to that in general use was selected. The graph shows
that the performance of the BNP and NT-proBNP tests varied considerably between studies, but all data points lie
well above the line where a test proving no useful diagnostic information would lie. The graph shows that most
studies found a high sensitivity, but that there is considerable variation in the false positive rate and therefore in
the specificity. The ideal test (with 100% sensitivity and 100% specificity) would lie in the top left corner of the
figure.
Evidence on drug treatments for chronic heart failure with left ventricular dysfunction
Evidence on diuretics for chronic heart failure
CKS found no large, long-term randomized controlled trials of loop or thiazide diuretics in heart
failure.
37
In depth: Heart failure - chronic
Appendices
Several small randomized controlled trials (RCTs) found that diuretics appear to reduce the risk of
death and worsening heart failure compared with placebo. Compared with active control, diuretics
appear to improve exercise capacity.
A Cochrane systematic review (updated search date to June 2008) has assessed the efficacy of diuretics for heart
failure [Faris et al, 2006]. The review included 14 randomized controlled trials (n = 525), seven of which were
placebo-controlled and seven compared diuretics against other drugs used to treat chronic heart failure. The
diuretics used in the trials were aldosterone antagonist (two trials), potassium-sparing diuretic (one trial), loop
diuretic (five trials), thiazide (one trial), combination diuretics (two trials), and various or unspecified diuretics
(four trials).
Diuretics compared with placebo
•
•
Mortality: pooled data from three trials (n = 202) found that the mortality rate was significantly lower in
the diuretic group compared with the placebo group (odds ratio [OR] for death 0.24, 95% CI 0.07 to 0.83; p
= 0.02).
Worsening heart failure: pooled data from two trials (n = 169) found that worsening heart failure was
significantly reduced in the diuretic group compared with the placebo group (OR 0.07, 95% CI 0.01 to 0.52;
p = 0.01).
Diuretic compared with active treatment
•
Exercise capacity: pooled data from four trials (n = 91) found that diuretics significantly improved exercise
capacity compared with active control (weighted mean difference 0.72, 95% CI 0.40 to 1.04; p < 0.0001).
Evidence on ACE inhibitors for chronic heart failure
There is good evidence that angiotensin-converting enzyme (ACE) inhibitors are effective at reducing
mortality and morbidity associated with heart failure.
A systematic review of large randomized controlled trials (RCTs) has confirmed that ACE inhibitors
reduce the risk of death from any cause, readmission because of heart failure, and reinfarction after a
myocardial infarction (MI). The benefits of ACE inhibitors occur soon after the start of treatment and
persist long-term. The benefits appear to be independent of age, sex, and baseline use of diuretics,
aspirin, and beta-blockers, and occur over a full range of ventricular dysfunction.
There is some evidence from one large RCT that higher doses of an ACE inhibitor may improve
morbidity more than do lower doses, with no increase in adverse events.
ACE inhibitor compared with placebo
One systematic review of long-term RCTs has reported on the benefits and risks of ACE inhibitors for treating
heart failure [Flather et al, 2000]. The review included large (> 1000 people) long-term (follow-up > 12 months)
randomized trials comparing ACE inhibitors with control in people with left ventricular dysfunction after an MI.
Analysis of the studies pooled data from individual participants. The outcomes analysed were death, death or
readmission for heart failure, death or MI.
•
The review included three randomized placebo-controlled trails (SAVE [Survival and Ventricular
Enlargement], AIRE [Acute Infarction Ramipril Efficacy], and TRACE [trandolapril in patients with reduced
left ventricular function after acute myocardial infarction]), in which participants were enrolled within a week
of an acute MI; plus two SOLVD (Studies on Left Ventricular Dysfunction) trials in which just over half of the
participants had experienced an MI previously. The average follow-up was 35 months.
o
For all five trials (n = 12,763):
▪
ACE inhibitors significantly reduced the number of deaths compared with placebo. Overall, the rate
of death was 23.0% in the ACE inhibitor group and 26.8% in the placebo group (odds ratio [OR]
0.8, 95% CI 0.74 to 0.87; p < 0.0001).
▪
ACE inhibitors significantly reduced the number of readmissions for heart failure compared with
placebo. There were 876 (13.7%) readmissions in the ACE inhibitor group and 1202 (18.9%) in
the placebo group (OR 0.67, 95% CI 0.61 to 0.74; p < 0.0001).
▪
ACE inhibitors significantly reduced reinfarction rate compared with placebo. The rate of
reinfarction was 8.9% in the ACE inhibitor group and 11.0% in the placebo group (OR 0.79, 95%
CI 0.70 to 0.89; p = 0.0001).
o
For the post-infarction trials (n = 5966):
▪
ACE inhibitors significantly reduced the number of deaths compared with placebo. Death rates
were 23.4% in the ACE inhibitor group and 29.1% in the placebo group (OR 0.74, 95% CI 0.66 to
0.83; p < 0.0001).
▪
ACE inhibitors significantly reduced the number of readmissions for heart failure compared with
placebo. There were 355 (11.9%) admissions in the ACE inhibitor group and 460 (15.5%) in the
placebo group (OR 0.73, 95% CI 0.63 to 0.85; p < 0.0001).
▪
ACE inhibitors significantly reduced reinfarction rate compared with placebo. The rate of
reinfarction was 10.8% in the ACE inhibitor group and 13.2% in the placebo group (OR 0.80, 95%
CI 0.69 to 0.94; p = 0.0057).
o
For the SOLVD trials (n = 6797):
▪
ACE inhibitors significantly reduced the number of deaths compared with placebo. Death rates
were 22.5% in the ACE inhibitor group and 24.8% in the placebo group (OR 0.87, 95% CI 0.78 to
0.98; p = 0.021).
38
In depth: Heart failure - chronic
Appendices
▪
o
o
ACE inhibitors significantly reduced the number of readmissions for heart failure compared with
placebo. There were 521 (15.3%) admissions in the ACE inhibitor group and 742 (21.8%) in the
placebo group (OR 0.63, 95% CI 0.56 to 0.72; p < 0.0001).
▪
ACE inhibitors significantly reduced reinfarction rate compared with placebo. The rate of
reinfarction was 7.3% in the ACE inhibitor group and 9.2% in the placebo group (OR 0.78, 95% CI
0.65 to 0.94; p = 0.0043).
The benefits of ACE inhibitors were seen early after the start of treatment and persisted long-term. The
benefits were independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers, and
occurred over a full range of ventricular function.
Data on the adverse effects associated with treatment were available from three of the studies.
▪
Hypotension occurred in 791 (14·7%) of 5387 people randomized to an ACE inhibitor and 466
(8·6%) of 5390 people randomized to placebo.
▪
Renal dysfunction occurred in 281 (5·2%) people randomized to an ACE inhibitor and 194 (3·6%)
people randomized to placebo.
High dose compared with low dose lisinopril
•
The Assessment of Treatment with Lisinopril and Survival (ATLAS) study (n = 3164) compared low-dose
lisinopril (2.5–5 mg daily) with high-dose lisinopril (32.5–35 mg daily) in people with New York Health
Authority class II–IV heart failure [Packer et al, 1999].
o
No significant difference was found in all-cause mortality (hazard ratio [HR] 0.92, 95% CI 0.82 to 1.03,
p = 1.28) or cardiovascular mortality (HR 0.90, 95% CI 0.81 to 1.01, p = 0.07).
o
There was a 12% reduction in the the combined endpoint of death or hospitalization for any reason in
the high-dose compared with the low-dose group (HR 0.88, 95% CI 0.82 to 0.96, p = 0.002).
o
There were 24% fewer hospitalizations due to heart failure in the high-dose group compared with the
low-dose group (p = 0.002).
o
Similar numbers of people stopped medication in both groups (17% in the high-dose group compared
with 18% in the low-dose group).
Evidence on angiotensin-II receptor antagonists for chronic heart failure
There is good evidence that angiotensin-II receptor antagonists are effective at reducing mortality
and morbidity associated with heart failure.
Evidence from one large placebo-controlled study shows that AIIRAs are beneficial in people with
chronic heart failure and are a suitable alternative in people who intolerant of an ACE inhibitor. This is
backed up by a subgroup analysis of another large placebo-controlled trial.
Evidence from several large randomized controlled trials (RCTs) suggests that there is no difference
in efficacy between AIIRAs and ACE inhibitors.
AIIRA compared with placebo
•
•
In the CHARM-alternative study, 2028 people with symptomatic heart failure (NYHA class II-IV) and LVEF
40% or less who were intolerant of an ACE inhibitor (mainly due to cough) were randomized to treatment
with candesartan or placebo [Granger et al, 2003]. The primary outcome was cardiovascular death or
unplanned hospitalization for chronic heart failure. Median follow-up was 33.7 months.
o
The baseline characteristics were generally similar between the treatment groups. The most common
manifestation of ACE-inhibitor intolerance before trial entry was cough (72%), followed by symptomatic
hypotension (13%) and renal dysfunction (12%). At baseline, 55% of people were taking beta-blockers
and 24% spironolactone.
o
The incidence of cardiovascular death or hospital admission for heart failure was significantly lower in
the candesartan group (33%) than in the placebo group (40%) (adjusted hazard ratio [HR] 0.70,
95% CI 0.60 to 0.81; p < 0.0001).
o
All-cause mortality was also significantly lower in the candesartan group (26.2%) than in the
placebo group (26.2% vs. 29.2%; adjusted HR 0.83, 95% CI 0.70 to 0.99; p = 0.033).
o
The drug discontinuation rate was similar in both groups. By the end of the study, 24% of the
candesartan survivors and 22% of the placebo survivors had stopped taking study medication
(p = 0·49).
The Valsartan Heart Failure trial (Val-HeFT) compared valsartan with placebo in people with heart failure,
most of whom were also taking an ACE inhibitor [Cohn and Tognoni, 2001]. Subgroup analysis was
performed in 366 people who were not also taking an ACE inhibitor at baseline (7% of the overall trial
population). Mean follow-up was 23 months [Maggioni et al, 2002].
o
In the subgroup of people who were not also taking an ACE inhibitor, there was a significant reduction
in all-cause mortality in favour of candesartan. There were 32 deaths (17.3%) out of the 185 people in
the valsartan group compared with 49 (27.1%) out of the 181 people in the placebo group (risk ratio
[RR] 0.67, 95% CI 0.42 to 1.06; p = 0.017 — the 95% confidence interval for the RR was calculated
by Cox regression, but the statistical significance is from a log-rank analysis).
o
In the subgroup of people who were not also taking an ACE inhibitor, there was a significant reduction
in the combined endpoint of mortality and morbidity in favour of candesartan. Mortality/morbidity rates
were 24.9% in the valsartan group and 42.5% in the placebo group (risk ratio [RR] 0.56, 95% CI 0.39
to 0.81; p = 0.001).
AIIRA compared with an ACE inhibitor
39
In depth: Heart failure - chronic
Appendices
•
•
•
•
In the ELITE II trial, 3152 people aged 60 years or older with heart failure (NYHA class II–iV) and ejection
fraction of 40% or less were randomly assigned to losartan (titrated to 50 mg once a day) or captopril
(titrated to 50 mg three times a day). The primary end point was all cause mortality (the study was powered
to detect a 25% difference in mortality between treatments). The secondary endpoint was the composite of
sudden cardiac death or resuscitated cardiac arrest. Median follow-up was 1.5 years [Pitt et al, 2000].
o
The difference in all-cause mortality between the two groups was not statistically significant. There
were 280 (17.7%) deaths in the losartan group compared with 250 (15.9%) in the captopril group
(hazard ratio [HR] 1.13, 95.7% CI 0.95 to 1.35; p = 0.16). However, this does not mean that losartan
is as effective as captopril at improving survival, as the study was designed to demonstrate superiority
and not to show equivalence.
o
The rate of sudden death or resuscitated cardiac arrest was not significantly different between the two
groups (9.0% in the losartan group vs. 7.3% in the captopril group, HR 1.25, 95% CI 0.98 to 1.60; p =
0.08).
o
Significantly fewer people in the losartan group (excluding those who died) discontinued treatment
because of adverse effects (p < 0.001),
In the OPTIMAAL trial, 5477 people with heart failure, LVSD or both after an acute MI were randomized to
receive losartan (50 mg once a day) or captopril (50 mg three times a day) [Dickstein and Kjekshus, 2002].
The mean follow-up was 2.7 years.
o
The difference in all-cause mortality between the two groups was not statistically significant. There
were 499 (18.2%) deaths in the losartan group compared with 447 (16.4%) in the captopril group
(relative risk [RR] 1.13, 95% CI 0.99 to 1.28; p = 0.069).
As part of the VALIANT trial, people heart failure, LVSD or both after an acute MI were randomized to
receive valsartan (titrated to 160 mg twice a day; n = 4909) or captopril (titrated to 50 mg three times a
day; n = 4909) [Pfeffer et al, 2003]. The primary end point was mortality from any cause. The median
follow-up was 24.7 months.
o
No significant difference in all-cause mortality was detected between the two groups. There were 979
deaths (19.9%) in the valsartan group compared with 958 (19.5%) in the captopril group (HR 1.0,
95% CI 0.9 to 1.11; p = 0.98).
A meta-analysis of 17 trials (n = 12,469) in which five AIIRAs were studied (losartan, candesartan,
valsartan, irbesartan, and eposartan) concluded that AIIRAs were not superior to ACE inhibitors at improving
clinical outcomes in people with heart failure [Jong et al, 2002]. Overall, there was no difference between
AIIRAs and controls in the pooled rates of death (OR 0.96, 95% CI 0.75 to 1.23) or hospitalization (OR 0.86,
95% CI 0.69 to 1.06).
Evidence on beta-blockers for chronic heart failure
There is good evidence from large randomized controlled trials that certain beta-blockers reduce the
mortality and morbidity associated with heart failure. This improvement appears to be independent of
the cause or severity of heart failure.
There is some evidence from a subgroup analysis of one study to suggest that this benefit may not be
conferred to black people, although this has not been supported or refuted by other studies.
Several large key RCTS have assessed the efficacy of beta-blockers in people with heart failure.
Beta-blocker vs. placebo
•
•
•
In the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), 2647 people with moderate to severe heart failure
(New York Health Authority [NYHA] class III or IV) who were taking diuretics and ACE inhibitors were
randomly assigned to bisoprolol or placebo and followed up over a mean of 1.3 years [CIBIS-II Investigators
and Committees, 1999]. The average age of trial participants was 61 years, which is generally younger than
those seen in primary care settings.
o
The trial was stopped early because of a significant reduction in mortality with bisoprolol (11.8% of the
bisoprolol group died compared with 17.3% of the placebo group, p < 0.001).
o
There were fewer hospitalizations due to heart failure in the bisoprolol group compared with the
placebo group (12% versus 18%, p < 0.001).
o
Treatment effects were independent of the severity or cause of the heart failure.
In the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), 3991 people
with heart failure (NYHA class II–IV) were randomized to treatment with metoprolol CR/XL or placebo
[MERIT-HF Study Group, 1999].
o
The trial was stopped early (after an average follow-up of 1 year) because of a significant reduction in
all-cause mortality in the metoprolol group compared with the placebo group. The death rate in the
metoprolol group was 7.2% per patient-year of follow-up and 11% in the placebo group (RR 0.66,
95% CI 0.53 to 0.81).
o
Cardiovascular deaths were also reduced in the metoprolol group compared with the placebo group
(RR 0.62, 95% CI 0.50 to 0.78, p = 0.00003), as were sudden deaths (RR 0.59, 95% CI 0.45 to 0.78,
p = 0.0002), and death from progressive heart failure (RR 0.51, 95% CI 0.33 to 0.79, p = 0.0023).
In the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial, 2289 people with severe
heart failure (symptoms at rest or on minimal exertion, and an ejection fraction less than 25%) were
randomly assigned to either carvedilol or placebo for a mean follow-up of 10.4 months [Packer et al, 2001].
o
The trial was terminated early because of a significant reduction in annual mortality rate (35% lower
with carvedilol, p < 0.001).
40
In depth: Heart failure - chronic
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o
•
•
Global assessment showed that beta-blockers were more likely to lead to a marked or moderate
improvement in symptoms than a deterioration in symptoms.
o
It was estimated that for every 18 people treated for more than 10 months with a beta-blocker, one life
would be saved.
In the Study of the Effects of Nebivolol Intervention on Outcomes and Re-hospitalization in Seniors
(SENIORS) trial, 2128 patients over 70 years of age with diagnosed chronic heart failure (regardless of
ejection fraction) were randomly assigned to placebo or nebivolol, with an average follow-up of 21 months
[Flather et al, 2005].
o
The primary outcome was a composite of all-cause mortality and first admission to hospital for a
cardiovascular cause, and occurred in 35.3% of people on placebo compared to 31.1% on nebivolol (HR
0.86, 95% CI 0.74 to 0.99; p = 0.039).
o
Death (all causes) occurred in 18.1% of those receiving placebo, compared with 15.8% receiving
nebivolol (HR 0.88, 95% CI 0.71 to 1.08; p = 0.21).
o
The drug was well tolerated and there were few withdrawals.
In the Beta-Blocker Evaluation of Survival Trial (BEST), 2708 people with moderate to severe heart failure
(NYHA class III–IV and ejection fraction less than 35%) were randomized to bucindolol or placebo [BetaBlocker Evaluation of Survival Trial Investigators, 2001]. The mean duration of follow-up was 2.0 years.
o
The trial was stopped early because of the accumulative evidence of the benefits of beta-blockers from
other heart failure trials.
o
There was no evidence of a significant improvement in survival between the two groups. The primary
end point, death from any cause, occurred in 33% of people in the placebo group and 30% of people in
the bucindolol group (HR 0.90, 95% CI 0.78 to 1.02; p = 0.1).
o
There was a significant reduction in death from cardiovascular causes in the bucindolol group. Death
from cardiovascular causes occurred in 29% of people in the placebo group and 25% of people in the
bucindolol group (HR 0.86, 95% CI 0.74 to 0.99; p = 0.04).
o
In a subgroup analysis, there was no evidence of benefit in black people (HR for death 1.17,
95% CI 0.89 to 1.53) but there was a significant reduction in death in non-black people (HR 0.82,
95% CI 0.7 to 0.96). However, only 24% of trial participants were black and there are no other studies
to support or refute this finding.
Comparing beta-blockers
•
In the Carvedilol Or Metoprolol European Trial (COMET), 1511 people with heart failure were randomized to
treatment with carvedilol 25 mg twice-daily or metoprolol tartrate 50 mg twice-daily (a different formulation
and a lower dose from that used in MERIT-HF) [Poole-Wilson et al, 2003]. Follow-up was over 58 months.
o
The carvedilol group had a greater reduction in all-cause mortality than the metoprolol group (34% of
the carvedilol group died compared with 40% of the metoprolol group, hazard ratio 0.83, 95% CI 0.74
to 0.93, p = 0.0017).
o
The composite endpoint of mortality and all-cause hospitalization was no different between the
two groups (74% with carvedilol and 76% with metoprolol, hazard ratio 0.94, 95% CI 0.86 to 1.02;
p = 0.122).
Evidence on aldosterone antagonists for chronic heart failure
There is good evidence from one large RCT that, when added to optimal therapy, spironolactone
improves symptoms, reduces mortality, and reduces hospitalizations in people with moderate to
severe heart failure (NYHA class III–IV).
Evidence from another large RCT supports the use of eplerenone, in addition to optimal treatment, to
reduce mortality and hospitalizations in people with heart failure after an acute myocardial infarction
(MI).
It is not know whether aldosterone blockade is advantageous in people with milder heart failure.
CKS found no studies directly comparing spironolactone with eplerenone.
Spironolactone compared with placebo
•
In the Randomized Aldactone Evaluation Study (RALES), 1663 people with NYHA class III or IV heart failure
were randomized to spironolactone (25 mg once a day) or placebo in addition to their current standard
treatment (diuretic [100%], angiotensin-converting enzyme [ACE] inhibitors if tolerated [95%], digoxin
[74%], beta-blockers [11%] — beta-blockers were not widely used for HF when this study was undertaken)
[Pitt et al, 1999]. The dose of spironolactone could be increased to 50 mg daily if felt to be clinically
indicated. The primary endpoint was death from any cause.
o
The trial was stopped early, after a mean follow-up period of 24 months, owing to evidence of benefit.
o
Mortality was significantly lower in the spironolactone group than in the placebo group. There were 284
deaths (35%) in the spironolactone group and 386 deaths (46%) in the placebo group (relative risk
[RR] 0.70, 95% CI 0.60 to 0.82; p < 0.001). This was largely due to a lower risk of death from
progressive heart failure and sudden death from cardiac causes.
o
Hospitalizations for worsening heart failure were significantly lower in the the spironolactone group
(63% vs. 90%; RR 0.70, 95% CI 0.59 to 0.82; p < 0.001).
o
Symptom improvement (defined as a change to a lower NYHA class) occurred more often in the
spironolactone group than in the placebo group (41% vs. 33%; p < 0.001).
o
Adverse effects:
41
In depth: Heart failure - chronic
Appendices
▪
▪
There were no significant differences between the two groups in serum sodium concentration,
blood pressure, or heart rate during the study.
There were no changes in the median serum creatinine and potassium concentrations in the
placebo group, but there was a small increase in the spironolactone group. The median serum
potassium concentration increased by 0.3 mmol/l, which was statistically significant (p < 0.001)
but not clinically important. Serious hyperkalaemia occurred in 10 people in the placebo group
(1%) and 14 people in the spironolactone group (2%), but this difference was not statistically
significant (p = 0.42).
Eplerenone compared with placebo
•
In the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),
6632 people with heart failure or left ventricular dysfunction after an acute MI were randomized to
eplerenone (25 mg once a day for four weeks then titrated up to 50 mg once a day) or placebo [Pitt et al,
2003]. Study medication was in addition to optimal medical treatment including ACE inhibitors or AIIRAs
(87%), diuretics (60%), and beta-blockers (75%). The primary endpoints were time to death from any
cause and time to death from cardiovascular causes or first hospitalization for a cardiovascular event. Mean
follow-up was 16 months.
o
Mortality was significantly lower in the eplerenone group than in the placebo group. There were 478
deaths (14.4%) in the eplerenone group and 554 deaths (16.7%) in the placebo group (relative risk
[RR] 0.85, 95% CI 0.75 to 0.96; p < 0.008).
o
Cardiovascular death or admission due to a cardiovascular event was significantly reduced in the
eplerenone group compared with the placebo group (26.7% vs. 30.0%; RR 0.87, 95% CI 0.79 to 0.95;
0.002).
o
Adverse effects:
▪
Eplerenone was associated with a smaller mean increase than placebo in blood pressure after
one year (5/3 mmHg vs. 8/4 mmHg).
▪
Eplerenone was associated with a greater mean increase than placebo in serum creatinine after
one year (5.3 micromol/L vs. 1.8 micromol/L; p < 0.001).
▪
The incidence of serious hyperkalaemia (serum potassium ≥ 6.0 mmol/l) was greater with
eplerenone than placebo (5.5% vs. 3.9%; p = 0.002).
▪
The incidence of gynaecomastia, impotence or, in women, breast pain was similar for eplerenone
and placebo.
A recent systematic review on the efficacy of aldosterone antagonists in people with left ventricular dysfunction
confirmed these findings [Ezekowitz and McAlister, 2009].
•
The systematic review identified 19 RCTs (four in acute myocardial infarction and 15 in heart failure; n
= 10,807) comparing spironolactone (14 RCTs), eplerenone (three RCTs), and canrenoate (three RCTs) with
placebo or usual care.
o
Pooled data from 14 RCTs in people with heart failure and left ventricular dysfunction found that
treatment with an aldosterone antagonist significantly reduced all-cause mortality. There were 303
deaths (16.3%) out of 1858 people in the aldosterone antagonist group and 404 deaths (27.0%) out of
1495 people in the control group (relative risk [RR] 0.75, 95% CI 0.67 to 0.84).
o
Adverse effects:
▪
Hyperkalaemia was reported in 3.0% of people in the control group and 5.9% of people in the
aldosterone antagonist group over a median follow-up of 1.25 years.
▪
Renal failure (definitions varied between trials) occurred in 1.6% of people in the control group
and 8.9% of people in the aldosterone antagonist group.
▪
Gynaecomastia was reported in 0.5% of people in the control group and 1.6% of people in the
aldosterone antagonist group. The incidence of gynaecomastia was 0.5% in the trails of
eplerenone and 4.3% in the trials od spironolactone.
Evidence on ACE inhibitors combined with AIIRAs
There is some evidence to support the addition of an angiotensin-II receptor antagonist to an ACE
inhibitor, however, the combination increases the risk of adverse effects. One large randomized
controlled trial (RCT) found that adding valsartan to current treatment significantly reduced the risk
of hospitalization due to heart failure, but not the risk of all cause mortality. A second RCT found that
adding candesartan to an ACE inhibitor significantly reduced the risk of cardiovascular death and the
risk of hospitalization due to heart failure, but not the risk of all-cause mortality. There is evidence
from meta-analyses including more than 17,000 people of a significant increase in adverse effects
with the combination of an ACE inhibitor plus an AIIRA including hypotension, worsening renal
function, and hyperkalaemia.
Two key placebo-controlled RCTs (Val-HeFT and CHARM-Added) have investigated the effects of and AIIRA to and
ACE inhibitor in people with symptomatic left ventricular dysfunction.
•
In the Val-HeFT trial 5010 people with ejection fractions less than 40% and New York Heart Association
(NYHA) class II–IV were randomized to receive valsartan (titrated up to 160 mg twice a day) or placebo in
addition to standard treatment — 93% of people also took an ACE inhibitor and 35% also took a betablocker [Cohn and Tognoni, 2001]. The primary endpoints were all cause mortality, and the combined
endpoint of mortality and morbidity, defined as cardiac arrest with resuscitation, hospitalization for heart
42
In depth: Heart failure - chronic
Appendices
•
failure, or administration of intravenous inotropic or vasodilator drugs for four hours or more without
hospitalization. Mean follow up was 23 months.
o
No difference was found in the primary endpoint of all-cause mortality between the two groups (relative
risk [RR] 1.02, 95% CI 0.88 to 1.18; p = 0.80).
o
The combined endpoint of morbidity and mortality was significantly reduced in the valsartan group
compared with the placebo group (28.8% of people in the valsartan group reached the combined
endpoint compared with 32.1% in the placebo group; RR 0.87, 95% CI 0.77 to 0.97; p = 0.009).
▪
This benefit was predominantly due to a reduction in hospitalizations for worsening heart failure
(13.8% of people in the valsartan group were hospitalized for heart failure compared with 18.2%
in the placebo group; p < 0.001).
o
The beneficial effect of valsartan on the combined endpoint was generally consistent among the
predefined subgroups of patients (young and old, men and women, those with and without diabetes or
coronary artery disease, those with ejection fractions or left ventricular dimensions above and below
the median, and those with NYHA class II and class III or IV symptoms). In the small, heterogeneous
black population, there was a wide confidence interval for relative risk of the combined endpoint with
valsartan that included 1.0 (RR 1.11; 95% CI 0.77 to 1.61).
o
In the sub-group of people who were also treated with an ACE inhibitor and a beta-blocker, the addition
of valsartan had an adverse effect on mortality (p = 0.009) and was associated with a non-significant
trend toward an increase in the combined endpoint of mortality and morbidity.
o
Adverse events leading to the discontinuation occurred in 249 people (9.9%) receiving valsartan and
181 people (7.2%) receiving placebo (p < 0.001). The adverse events leading to discontinuation and
occurring in more than 1% of people in the valsartan group included dizziness (1.6%), hypotension
(1.3%), and renal impairment (1.1%).
In the CHARM-Added trial, 2548 people with ejection fractions less than 40% and NYHA class II–IV who
were already taking an ACE inhibitor were randomized to receive candesartan (titrated up to 32 mg daily) or
placebo [McMurray et al, 2003]. At baseline, 55% of people were also taking a beta-blocker and 17% were
taking spironolactone. The primary endpoint was cardiovascular death or hospitalization for heart failure.
Median follow up was 41 months.
o
The primary endpoint of cardiovascular death or hospitalization for heart failure was significantly
reduced in the candesartan group (38%) compared with the the placebo group (42%) (hazard ratio
[HR] 0.85, 95% CI 0.75 to 0.96; p = 0.011).
o
In addition, people in the candesartan group had significantly reduced cardiovascular mortality
(HR 0.84, 95% CI 0.72 to 0.98; p = 0.029) and fewer hospitalizations for heart failure (HR 0.83,
95% CI 0.71 to 0.96; p = 0.014).
o
Candesartan reduced the risk of cardiovascular death or hospitalization for heart failure in all predefined
subgroups.
o
There was no evidence of a significant difference in all-cause mortality between the two groups, but this
was a secondary outcome and the study may not have been powered to detect such a difference. The
number of deaths in the candesartan group was 337 (30%) compared with 412 (32%) in the placebo
group (HR 0.89, 95% CI 0.77 to 1.02; p = 0.086).
o
Adverse effects: overall 309 (24%) of people in the candesartan group and 233 (18%) in the
placebo group stopped taking their study medication because of an adverse event or an abnormal
laboratory value (p = 0.0003).
▪
Candesartan was discontinued in 4.5% of people because of hypotension, 7.8% because of an
increase in creatinine, and 3.4% because of hyperkalaemia.
One further RCT (VALIANT) has investigated the addition of an AIIRA to an ACE inhibitor in people with heart
failure or left ventricular systolic dysfunction after an acute myocardial infarction.
•
As part of the VALIANT trial 4909 people with post-infarction heart failure were randomized to valsartan
alone (n = 4909), captopril alone (n = 4909), or a combination of valsartan and captopril (n = 4885)
[Pfeffer et al, 2003]. Doses were titrated up to valsartan 160 mg twice a day, captopril 50 mg three times
a day, or valsartan 80 mg twice a day plus captopril 50 mg three times a day. The primary endpoint was allcause mortality. Median follow-up was 24.7 months.
o
Mortality from any cause and cause-specific mortality were similar in the three treatment groups. A
total of 979 people (19.9%) in the valsartan group died, as did 941 (19.3%) in the valsartan plus
captopril group and 958 (19.5%) in the captopril group.
▪
The hazard ratio for death in the valsartan group as compared with the captopril group was 1.00
(97.5% CI 0.90 to 1.11; p = 0.98).
▪
The hazard ratio for death in the valsartan-and-captopril group as compared with the
captopril group was 0.98 (95% CI 0.89 to 1.09, p = 0.73).
o
The combination group had the highest incidence of drug-related adverse effects; 5.8% of people in the
valsartan group stopped taking their medication because of adverse effects, as did 9.0% in the
valsartan plus captopril group and 7.7% in the captopril group. This difference was significant between
the valsartan plus captopril group and the captopril group (p < 0.05), and between the valsartan group
and the captopril group (p < 0.05).
CKS has identified two recent meta-analyses of the safety and tolerability of combining AIIRAs with ACE inhibitors
for left ventricular dysfunction.
43
In depth: Heart failure - chronic
Appendices
•
•
The first meta-analysis included four RCTs, each with 500 or more participants (VALIANT, CHARM-Added,
Val-HeFT, and RESOLVD) [Phillips et al, 2007]. The total number of people in the pooled analysis was
17,337, the mean duration of follow up was 25 months. The combination of valsartan plus an ACE inhibitor
was evaluated in two studies (VALIANT and Val-HeFT) and the combination of candesartan plus enalapril was
evaluated in the other two (CHARM-Added and RESOLVD).
o
Discontinuation of medication: combination treatment was associated with a significant increase in
medication discontinuation because of adverse effects compared with control in people with chronic
heart failure (15.0% vs 11.0%: RR 1.38, 95% CI 1.22 to 1.55; number needed to harm [NNH] = 25)
and also in people with acute MI and symptomatic left ventricular dysfunction (9.0% vs 7.6%; RR 1.17,
95% CI, 1.03-1.34; NNH = 71).
o
Symptomatic hypotension: combination treatment was associated with a significant increase in the
risk of symptomatic hypotension compared with control in people with chronic heart failure (2.4% vs
1.5%; RR 1.50, 95% CI, 1.09 to 2.07; NNH = 111) and also in people with acute MI and symptomatic
left ventricular dysfunction (18.1% vs 11.9%; RR 1.48, 95% CI 1.33 to 3.18; NNH = 16).
o
Worsening renal function: combination treatment was associated with worsening renal function
(defined as an increase in serum creatinine level > 0.5 mg/dL (44.2 micromol/L), up to a doubling over
baseline values) in people with chronic HF (3.3% vs 1.5%; RR 2.17, 95% CI 1.59 to 2.97; NNH = 56),
and also in people with acute MI and symptomatic left ventricular dysfunction (4.8% vs 3.0%; RR 1.61,
95% CI 1.31 to 1.98; NNH = 56).
o
Hyperkalaemia: combination treatment was associated with a significant increase in the risk of
hyperkalemia with serum potassium level of 5.5 mEq/L or greater in people with chronic HF (3.5% vs
0.7%; RR 4.87, 95% CI 2.39 to 9.94; NNH = 36), and with a non-significant increase in people with
symptomatic left ventricular dysfunction (1.2% vs 0.9%; RR 1.33, 95% CI 0.90 to 1.98).
The second meta-analysis included nine RCTs in a total of 18,160 people. AIIRAs included in the metaanalysis were losartan (three RCTs), candesartan (two RCTs), valsartan (three RCTs), irbesartan (one RCT),
eprosartan (one RCT) and telmisartan (one RCT). Follow-up duration varied from 4 weeks to 41 months.
o
Compared with an ACE inhibitor alone, combination treatment was associated with an increased risk of
developing adverse effects leading to discontinuation of therapy. These included increased risks of:
▪
Worsening renal function: 2.1% for ACE inhibitor plus AIIRA vs. 1.1% for ACE inhibitor alone;
RR 2.12 (95% CI 1.30 to 3.46; p = 0.003); number needed to harm [NNH] = 100.
▪
Hypotension: 2.28% vs 1.16%; RR 1.9 (95% CI 1.37 to 2.66; p = 0.0002); NNH = 89).
▪
Hyperkalemia: 0.87% vs 0.20%; RR 4.17 (95% CI 2.3 to 7.5; p = 0.00001); NNH = 149.
▪
Any adverse event: 11.4% vs 9.1%; RR = 1.27 (95% CI 1.2 to 1.4; p = 0.00001); NNH = 42).
▪
There was no evidence of a significant difference in the risk of angioedema or cough.
Evidence on digoxin for chronic heart failure
Evidence from a Cochrane systematic review including one large randomized trial suggests that, in
people with normal sinus rhythm, digoxin improves symptoms and reduces the number of
hospitalizations due to worsening heart failure when added to treatment with diuretic and
angiotensin-converting enzyme (ACE) inhibitors, but it does not appear to reduce mortality.
•
•
A Cochrane systematic review (search date 2006) investigated the effectiveness of digitalis (digoxin or
digitoxin) in treating people with heart failure with normal sinus rhythm [Hood et al, 2004]. The review
included 13 RCTs (n = 7896), however, the majority of the effect on mortality and hospitalizations seen was
due to one single trial (the Digitalis Investigation Group (DIG) trial [Digitalis Investigation Group, 1997]).
o
Mortality (eight RCTs; n = 7755):
▪
There was no evidence of a significant difference in mortality between digitalis treatment and
control groups (odds ratio [OR] 0.98, 95% CI 0.89 to 1.09).
o
Hospitalizations (four RCTs; n = 7262):
▪
Digitalis treatment was associated with a (OR 0.68, 95% CI 0.61 to 0.75).
o
Clinical symptoms (12 studies; n = 1234):
▪
Digitalis treatment was associated with a reduction in clinical deterioration (OR 0.31, 95% CI 0.21
to 0.42).
The Digitalis Investigation Group (DIG) trial was a randomized controlled trial (n = 6800) comparing digoxin
with placebo for the treatment of people with heart failure in sinus rhythm [Digitalis Investigation Group,
1997]. Trial participants were allowed to take other heart failure treatments, and most were taking ACE
inhibitors and diuretics. Mean follow-up was 37 months.
o
All-cause mortality was no different between the digoxin and placebo groups (34.8% versus 35.1%,
RR 0.99, 95% CI 0.91 to 1.07).
o
Cardiovascular death rate was no different between the digoxin and placebo groups (29.9% versus
29.5%, RR 1.01, 95% CI 0.93 to 1.10).
o
Hospitalizations due to worsening heart failure were less in the digoxin group than in the placebo group
(26.8% versus 34.7%, RR 0.72, 95% CI 0.66 to 0.79).
o
The benefit of digoxin seemed to be greater among people at highest risk (lower ejection fractions,
enlarged hearts, severe symptoms).
Evidence on aspirin in chronic heart failure
Benefits
44
In depth: Heart failure - chronic
Appendices
There remains some uncertainty surrounding the use of aspirin in people with chronic heart failure.
There is no good RCT evidence on the efficacy of aspirin in the management of heart failure. However, there is
good evidence that aspirin reduces the risk of cardiovascular events in people with established cardiovascular
disease or those who are at high risk of developing cardiovascular disease [Antithrombotic Trialists' Collaboration,
2002], and aspirin is currently recommended for people with cardiovascular disease [Joint British Societies,
2005National Collaborating Centre for Primary Care, 2008].
Harms
There are concerns from post-hoc analyses of some of the studies of angiotensin-converting enzyme inhibitors in
heart failure that aspirin may reduce the beneficial effect of ACE inhibitors, although this has not been confirmed
by further analysis.
NICE recommends that, in the absence of conclusive evidence, and general consensus as to the benefits of aspirin
in patients with atherosclerotic arterial disease, aspirin (75–150 mg once daily) should be prescribed for people
with heart failure and atherosclerotic arterial disease (including coronary heart disease) [National Collaborating
Centre for Chronic Conditions, 2003].
SIGN concludes that there is no firm evidence to support the use or the withdrawal of aspirin in people with
chronic heart failure [SIGN, 2007].
Evidence on statins in chronic heart failure
Evidence from one large RCT suggests that statins are no more effective than placebo at reducing
mortality in people with chronic heart failure.
Most trials with statins have excluded people with heart failure.
•
In the GISSI-HF trial 4574 people with chronic heart failure (NYHA class II-IV, irrespective of cause and
LVEF) were randomized to rosuvastatin (10 mg once a day) or placebo [Gissi-Hf Investigators, 2008]. Study
treatment was given in additional to optimal treatment for chronic heart failure, in accordance with the
ESC guidelines. Primary endpoints were time to death and time to death or admission to hospital for
cardiovascular reasons. Median follow-up was 3.9 years.
o
There were no significant differences between the two groups at baseline.
o
There was no evidence of a significant difference in mortality between the two groups. There were 657
deaths in the rosuvastatin group (29%) and 644 in the placebo group (28%) (adjusted Hazard Ratio
[HR] 1.00 (95.5% CI 0.90 to 1.12; p = 0.94).
o
There was no evidence of a significant difference in death or admission to hospital for cardiovascular
causes between the two groups. There were 1305 occurrences in the rosuvastatin group (57%) and
1283 in the placebo group (56%) (adjusted HR 1.01 (99% CI 0.91 to 1.11; p = 0.66).
o
The risk of death from any cause or admission to hospital for cardiovascular reasons was not affected
by rosuvastatin in and of the predefined subgroups (including ischaemic vs. non-ischaemic cause,
severity of symptoms, and presence or absence of diabetes).
o
No difference was noted in the number of people who discontinued study medication because of an
adverse event (4.6% in the rosuvastatin group vs. 4.0% in the placebo group; p = 0.36).
Evidence on drug treatments for heart failure with preserved ejection fraction
Evidence on angiotensin converting enzyme inhibitors and angiotensin-II receptor blockers for heart failure
with preserved left ventricular ejection fraction
One randomized controlled trial (RCT) provides moderate evidence for modest clinical benefits for
candesartan as add-on treatment. Four RCTs found no benefit or modest clinical benefits from adding
an angiotensin converting enzyme (ACE) inhibitor or angiotensin-II receptor blocker (AIIRB) to other
treatments for heart failure with preserved left ventricular ejection fraction (HFPEF).
Ramipril as add-on treatment
•
Adding an ACE inhibitor, ramipril, to treatment with a diuretic (most commonly frusemide) did not improve
symptoms or measures of cardiac function in one RCT (n=150) [Yip et al, 2008].
o
Changes in symptoms and measures of cardiac function were similar at 12 weeks, 24 weeks, and 52
weeks — the statistical significances of the comparisons was not reported.
Perindopril as add on treatment
•
Adding an ACE inhibitor, perindopril, to treatment with a diuretic reduced the primary outcome of all-cause
mortality and unplanned heart failure related hospitalization, but this was not statistically significant, and the
study was underpowered due to difficulties in recruitment and high transfer rates to open label ACE
inhibitors [Cleland et al, 2006].
o
The trial randomized 850 people to either perinidopril or placebo. After 1 year 28% of people assigned
to perindopril and 26% of people assigned to placebo (26%) were taking open-label ACE-inhibitors.
o
Overall, 107 patients assigned to placebo and 100 assigned to perindopril reached the primary endpoint
(HR 0.919: 95% CI 0.700-1.208; P = 0.545).
o
By 1 year perindopril in comparison with placebo, reduced:
▪
All-cause mortality and unplanned heart failure related hospitalization: hazard ratio (HR) 0.692
(95% CI 0.474 to 1.010; p = 0.055) and hospitalization for heart failure (HR 0.628: 95% CI
0.408-0.966; P = 0.033).
45
In depth: Heart failure - chronic
Appendices
▪
Time to first occurrence of unplanned heart failure: HR 0.63 (95% CI 0.41 to 0.91, p = 0.033);
and relative risk reduction (RRR) 37%.
Irbesartan as add-on treatment
•
•
Adding an angiotensin receptor blocker, irbesartan, to treatment with a diuretic (most commonly frusemide)
did not improve symptoms or measures of cardiac function in one RCT (n=150) [Yip et al, 2008].
o
Changes in symptoms and measures of cardiac function were similar at 12 weeks, 24 weeks, and 52
weeks — the statistical significances of the comparisons was not reported.
Adding irbesartan to treatment with a diuretic (most commonly frusemide) did not improve outcomes in one
RCT (n=4128) [Massie et al, 2008].
o
After a mean follow-up of 49.5 months:
▪
Death from any cause, or hospitalization for a cardiovascular cause (heart failure, myocardial
infarction, unstable angina, arrhythmia, or stroke), the primary outcome measure, occurred at
similar rates in the irbesartan group and placebo groups: 100.4 and 105.4 per 1000 patient-years,
respectively (hazard ratio, 0.95; 95% confidence interval [CI], 0.86 to 1.05; P = 0.35).
▪
Death from any cause occurred at similar rates: 52.6 and 52.3 per 1000 patient-years,
respectively (hazard ratio, 1.00; 95% CI, 0.88 to 1.14; P = 0.98).
▪
Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were
70.6 and 74.3 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% CI, 0.85 to 1.08; p =
0.44).
▪
There were no significant differences in the other prespecified outcomes.
Valsartan as add-on treatment
•
Adding valsartan, an angiotensin receptor blocker, to standard treatments for hypertension was not found to
produce significant benefits in one small randomized controlled trial (RCT, n=384) [Solomon et al, 2007].
o
The study did not measure patient-orientated outcomes.
o
After 38 weeks, systolic and diastolic blood pressures were reduced more in the valsartan group than in
the placebo group, but this was not statistically significant.
o
After 38 weeks, there were small statistically significant changes in 2 of 14 echocardiographic
measures, but the clinical and physiological significance of this is uncertain.
Candesartan as add-on treatment
•
Adding candesartan, an angiotensin receptor blocker, to standard treatments was found to provide modest
benefits in one RCT (n=3023) [Yusuf et al, 2003]. The rate of admission to hospital was modestly reduced,
but no effect on mortality was evident.
o
Participants had symptoms of heart failure classified as New York Heart Association functional class IIIV, and left ventricular ejection fraction greater than 40%.
o
Analysis was done by intention to treat.
o
The median follow-up was 36.6 months.
o
There was no difference between the candesartan and placebo groups with respect to rates of:
▪
Either cardiovascular death or admission to hospital for heart failure (the primary outcome).
▪
Cardiovascular death.
o
Fewer people in the candesartan group than in the placebo group were admitted to hospital for heart
failure: 16% versus 18%, adjusted hazard ratio 0·84 (95% CI 0·70 to 1·00, p=0·047).
Evidence on beta-blockers for heart failure with preserved left ventricular ejection fraction
A small randomized controlled trial (RCT) in older people with a history of myocardial infarction found
that propranolol was associated with 35% reduction in relative risk for death, and 37% reduction in
relative risk for death or non-fatal myocardial infarction.
An RCT (n=158) assessed propanolol for heart failure with preserved left ventricular ejection fraction [Aronow et
al, 1997].
•
•
•
•
•
Participants had heart failure, a myocardial infarction at least 6 months previously, and left ventricular
ejection fraction greater than 40%.
The mean age of participants was 81 years.
Mortality during the 32 months of follow up was 56% in the propranolol group and 76% in the placebo
group, p=0.007, relative risk reduction 35%.
The risk of death or non-fatal myocardial infarction during the 32 months of follow up was 59% in the
propranolol group and 82% in the placebo group, p=0.002, relative risk reduction 37%.
Confidence intervals for the rates were not reported.
Evidence on digoxin for heart failure with preserved left ventricular ejection fraction
One randomized controlled trial (RCT) provides weak evidence from a secondary analysis that digoxin
in people with heart failure with preserved left ventricular ejection fraction (HFPEF) may decrease the
risk of admission for worsening heart failure, but may not reduce the risk of death.
•
The DIG trial was an RCT (n=988) which found that digoxin was associated with no change in mortality and
a non-significant trend toward reduced admission due to worsening heart failure in people with heart failure
and preserved ejection fraction (HFPEF) [Digitalis Investigation Group, 1997].
46
In depth: Heart failure - chronic
Appendices
o
•
Participants had heart failure and left ventricular ejection fraction greater than 45%, and were
randomized to receive either digoxin or placebo in addition to other treatments for heart failure.
o
There was no difference in mortality rates: 23.4% in the digoxin group and 23.4% in the placebo
group.
o
The rate of admission to hospital for heart failure was reduced in the digoxin group, but this was not
statistically significant: risk ratio 0.82 (95% CI 0.63 to 1.07).
The DIG trial included a larger RCT (n=6,800) of digoxin in people with systolic heart failure (left ventricular
ejection fraction less than or equal to 45%). People with systolic heart failure and treated with digoxin had
mortality risk similar to people treated with placebo, but the digoxin group had significantly reduced risk of
hospitalization for worsening heart failure: 26.8% versus 34.7%; risk ratio, 0.72 (95% CI, 0.66 to 0.79;
p=0.001). This prompted further analysis of the data to compare the risk of hospitalization in people with
systolic heart failure and HFPEF when baseline risk factors were matched [Meyer et al, 2008].
o
Each of 916 people with HFPEF was matched with someone with systolic dysfunction and similar
baseline risk factors (using propensity score matching) — an adequate match could not be found for 72
people with HFPEF.
o
At the end of 2 years of follow-up, the hazard ratios (HRs) for digoxin compared with placebo showed
similar decreased risks for the combined end point of hospitalization or death due to heart failure, and
for hospitalization.
o
For the combined end point of hospitalization or death due to heart failure:
▪
In people with systolic heart failure: HR was 0.72 (95% CI 0.55 to 0.95, p 0.022).
▪
In people with HFPEF: HR was 0.69 (95% CI 0.50 to 0.95, p 0.025).
o
For hospitalization due to heart failure:
▪
In people with systolic heart failure: HR was 0.73 (95% CI 0.54 to 0.97, p 0.033).
▪
In people with HFPEF: HR was 0.64 (95% CI 0.45 to 0.90, p 0.010).
Evidence on diuretics for heart failure with preserved left ventricular ejection fraction
Two small clinical trials provide indirect evidence that diuretics may improve symptoms in people with
heart failure and preserved left ventricular ejection fraction (HFPEF).
•
•
•
CKS found no randomized controlled trials (RCTs) of diuretics to treat heart failure with preserved left
ventricular ejection fraction (HFPEF).
One small RCT studied furosemide withdrawal in people with HFPEF [van Kraaij et al, 2003].
o
Heart failure recurred in 2 of 19 patients withdrawn from furosemide, and in 1 of 10 patients continuing
on furosemide. The difference was not statistically significant.
A study of three treatments for HFPEF found that use of diuretics was followed by a reduction in symptoms
but no change in measures of cardiac function [Yip et al, 2008]. The diuretic-only group had 50 participants
who used a variety of diuretics. The main results for this group were:
o
The quality of life score improved (decreased) rapidly and improvements were maintained until the last
followup: 20 at baseline; 12.9 at 12 weeks; 10.9 at 24 weeks; and 10.9 at 52 weeks (p <0.001 for
comparisons with the baseline).
o
Performance on the 6 minute walking test did not change over 24 weeks: at baseline 1011 feet; at 12
weeks 1055 feet; at 24 weeks 1048 (changes were not statistically significant).
o
Most echocardiographic measures of cardiac function did not change.
o
N-terminal pro-B type natriuretic peptide (NT-pro-BNP) levels were raised at baseline (566 pg/ml), and
fell to 390 pg/ml at 12 weeks and 334 pg/ml at 52 weeks (changes were not statistically significant).
Evidence on rate-limiting calcium channel blockers for heart failure with preserved left ventricular ejection
fraction
Two small randomized placebo-controlled cross-over trials found that verapamil improved exercise
capacity and symptoms in people with heart failure and preserved left ventricular ejection fraction
Verapamil compared with placebo
Two small randomized placebo-controlled cross-over trials found that verapamil improved exercise capacity and
symptoms in people with heart failure and preserved left ventricular ejection fraction.
•
•
One double-blind randomized crossover trial assessed the effects of oral verapamil in 20 people with heart
failure and preserved left ventricular systolic ejection fraction (HFPEF) and impaired left ventricular diastolic
filling [Setaro et al, 1990].
o
Participants were randomized to an initial treatment for two weeks with verapamil or placebo.
Treatment was then stopped for 4 days washout, and participants then swapped to the other treatment.
o
Severity score. The median improvement in the severity score after 2 weeks was 3 after taking
verapamil and 1 after taking placebo (p<0.01).
o
Exercise capacity. The mean exercise capacity after 2 weeks was 13.9 minutes after taking verapamil
and 12.3 minutes after taking placebo (p<0.01).
One double-blind randomized crossover trial assessed the effects of oral verapamil in 15 people with HFPEF
and impaired left ventricular diastolic filling [Hung, 2002].
o
Participants were randomized to an initial treatment for three months with verapamil or placebo.
Treatment was then stopped for 7 days washout, and participants then swapped to the other treatment.
47
In depth: Heart failure - chronic
Appendices
o
o
o
Severity score. The median improvement in severity score after 3 months was 2.1 after taking
verapamil and 0.1 after taking placebo.
Exercise capacity. The mean exercise capacity after 3 months was 8.3 minutes after taking verapamil
and 7.4 minutes after taking placebo.
Statistical tests of significance were not reported for differences in changes in outcome measures.
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Search strategy
Scope of search
A literature search was conducted for guidelines on the primary care management of chronic heart failure, with
additional searches for systematic reviews and randomized controlled trials in the following areas:
•
•
Diuretics
Angiotensin-converting enzyme (ACE) inhibitors
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In depth: Heart failure - chronic
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•
Angiotensin II receptor antagonists
•
Beta-blockers
•
Antiplatelet agents
•
Anticoagulants
•
Statins
•
Hydralazine and isosorbide dinitrate
•
Cardiac glycosides
•
Omega-3 fatty acids and fish oils
•
Vitamin E
•
Coenzyme Q10
•
Diet, alcohol, exercise, weight management, smoking cessation
•
Patient monitoring/remote monitoring
•
BNP guided treatment
•
Palliative care of heart failure patients
Search dates
Guidelines, Medline, Embase: Jan 2007 - Jan 2009
Key search terms
Various combinations of searches were carried out. The terms listed below are the core search terms that were
used for Medline and these were adapted for other databases. Further details are available on request via the
Feedback link at the top of this page.
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
heart failure/, heart failure, diastolic/, heart failure, systolic/, exp ventricular dysfunction/, (heart failure.tw
AND (congestive.tw or chronic.tw))
exp diuretics/, diuretic$.tw, bumetanide.tw, furosemide.tw, frusemide.tw, torasemide.tw, exp thiazides/, exp
aldosterone antagonists/, bendroflumethiazide.tw, bendrofluazide.tw, chlorthalidone.tw, chlortalidone.tw,
cyclopehtiazide.tw, indapamide.tw., metolazone.tw, amiloride.tw, spironolactone.tw, eplenerone.tw
exp angiotensin-converting enzyme inhibitors/, ace inhibitor$.tw, angiotensin converting enzyme
inhibitor$.tw, captopril.tw, cilazapril.tw, enalapril.tw, fosinopril.tw, lisinopril.tw, perindopril.tw, quinapril.tw,
ramipril.tw, trandolapril.tw
exp angiotensin II type 1 receptor blockers/, AIIRA$.tw, angiotensin II receptor antagonist$.tw,
candesartan.tw, eprosartan.tw, irbesartan.tw, losartan.tw
exp adrenergic beta-antagonists/, beta-blocker$.tw, bisoprolol.tw, carvedilol, nebivolol.tw
aspirin/, aspirin.tw, platelet aggregation inhibitors/, clopidogrel.tw, antiplatelet$.tw
anticoagulants/ or anticoagulant$.tw, warfarin/, warfarin.tw
hydroxymethyloglutaryl-CoA reductase inhibitors/, statin$.tw, atorvastatin.tw, fluvastatin.tw, pravastatin.tw,
rosuvastatin.tw, simvastatin.tw
hydralazine/, hydralazine.tw, isosorbide dinitrate/, isosorbide dinitrate.tw, bidil.tw
cardiac glycosides/, digoxin/, digitoxin/, digoxin.tw, digitoxin.tw, cardiac glycoside$.tw
exp fatty acids, omega-3/, omega-3.tw, fish oil$.tw
coenzyme q10.tw, coQ10.tw
exp diet, exp diet therapy/, diet.tw, alcohol drinking/, alcohol.tw, exp body weight changes/, weight.tw,
smoking/, smoking cessation/, smoking.tw, exp sodiu, dietary/, salt.tw, sodium.tw, fluid restriction.tw
natriuretic peptide, brain/, brain natriuretic peptide.tw, BNP.tw,
palliative care/, exp terminal care/, palliative.tw, terminal.tw, end of life.tw, terminally ill/
Table 1. Key to search terms.
Search
commands
Explanation
/
indicates a MeSH subject heading with all subheadings selected
.tw
indicates a search for a term in the title or abstract
exp
indicates that the MeSH subject heading was exploded to include the narrower, more
specific terms beneath it in the MeSH tree
$
indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Topic specific literature search sources
•
•
European Society of Cardiology
National Heart Foundation of Australia
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In depth: Heart failure - chronic
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Sources of guidelines
•
National Institute for Health and Clinical Excellence (NICE)
•
Scottish Intercollegiate Guidelines Network (SIGN)
•
National Guidelines Clearinghouse
•
New Zealand Guidelines Group
•
British Columbia Medical Association
•
Dutch College of General Practitioners
•
Canadian Medical Association
•
Institute for Clinical Systems Improvement
•
Guidelines International Network
•
National Library for Health Guideline Finder
•
National Health and Medical Research Council (Australia)
•
Alberta Medical Association
•
University of Michigan Medical School
•
Michigan Quality Improvement Consortium
•
Royal College of Nursing
•
Singapore Ministry of Health
•
Health Protection Agency
•
National Resource for Infection Control
•
CREST
•
World Health Organization
•
NHS Scotland National Patient Pathways
•
Agency for Healthcare Research and Quality
•
TRIP database
•
Patient UK Guideline links
•
UK Ambulance Service Clinical Practice Guidelines
•
RefHELP NHS Lothian Referral Guidelines
•
Medline (with guideline filter)
Sources of systematic reviews and meta-analyses
•
The Cochrane Library:
o
Systematic reviews
o
Protocols
o
Database of Abstracts of Reviews of Effects
•
Medline (with systematic review filter)
•
EMBASE (with systematic review filter)
Sources of health technology assessments and economic appraisals
•
•
National Coordinating Centre for Health Technology Assessment (NCCHTA)
The Cochrane Library:
o
NHS Economic Evaluations
o
Health Technology Assessments
•
Canadian Agency for Drugs and Technologies in Health
•
International Network of Agencies for Health Technology Assessment
Sources of randomized controlled trials
•
The Cochrane Library:
o
Central Register of Controlled Trials
•
Medline (with randomized controlled trial filter)
•
EMBASE (with randomized controlled trial filter)
Sources of evidence based reviews and evidence summaries
•
Bandolier
•
Drug & Therapeutics Bulletin
•
MeReC
•
NPCi
•
BMJ Clinical Evidence
•
DynaMed (access via the CKS website)
•
TRIP database
•
Central Services Agency COMPASS Therapeutic Notes
Sources of national policy
•
Department of Health
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In depth: Heart failure - chronic
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•
Health Management Information Consortium (HMIC)
55