ABC of heart failure: Management: digoxin and other inotropes, ß blockers, and antiarrhythmic and antithrombotic treatment
C R Gibbs, M K Davies, G Y H Lip
Digoxin
Use of digoxin for heart failure
varies between countries across Europe, with high rates in Germany and
low rates in the United Kingdom. It is potentially invaluable in
patients with atrial fibrillation and coexistent heart failure,
improving control of the ventricular rate and allowing more effective
filling of the ventricle. Digoxin is also used in patients with chronic
heart failure secondary to left ventricular systolic impairment, in
sinus rhythm, who remain symptomatic despite optimal doses of diuretics
and angiotensin converting enzyme inhibitors, where it acts as an
inotrope.
Digoxin should be considered in patients with sinus rhythm plus
(a) continued symptoms of heart failure despite optimal
doses of diuretics and angiotensin converting enzyme inhibitors;
(b) severe left ventricular systolic dysfunction with
cardiac dilatation; or (c) recurrent hospital admissions
for heart failure
Evidence of symptomatic benefit from digoxin in patients with
chronic heart failure in sinus rhythm has been reported in several
randomised placebo controlled trials and several smaller trials. The
RADIANCE and PROVED trials, for example, reported that the withdrawal
of digoxin from patients with congestive heart failure who had already
been treated with the drug was associated with worsening heart failure
and increased hospital readmission rates. The Digitalis Investigation
Group's large study found that digoxin was associated with improvement
in the symptoms of patients with congestive heart failure, when added
to treatment with diuretics and angiotensin converting enzyme
inhibitors. Importantly, there were greater absolute and relative
benefits in the patients who had resistant symptoms and more severe
impairment of left ventricular systolic function. However, although
there was a reduction in the combined end points of admission and
mortality resulting from heart failure, there was no significant
improvement in overall survival. ² Blockers were used rarely in the
Digitalis Investigation Group's study, and as a result it is not clear
whether digoxin is additive to both the ² blockers and angiotensin
converting enzyme inhibitors in congestive heart
failure.
Incidence of death or admission to hospital due to worsening
heart failure in two groups of patients: those receiving digoxin and
those receiving placebo (Digitalis Investigation Group's study-see
key references box at end of article)
Digoxin: practical aspects
Ensure a maintenance dose of
125-375 ¼g (0.125-0.375 mg) daily Give a reduced maintenance
dose in elderly people, when renal impairment is present,
and when used with drugs that increase digoxin
concentrations (amiodarone, verapamil) Concentrations should
be monitored, especially in cases of uncertainty about
whether therapeutic levels have been achieved (range 6 hours
after dose: 1.2-1.9 ng/ml) Monitor potassium concentrations
(avoid hypokalaemia) and renal function Digoxin toxicity may be associated with:
(a) adverse symptoms (for example, nausea, vomiting,
headache, confusion, visual symptoms); and (b) arrhythmias (for example,
atrioventricular junctional rhythms, atrial tachycardia,
atrioventricular block, ventricular tachycardia) Serious
toxicity should be treated by correcting potassium
concentrations and with drugs such as ² blockers and
glycoside binding agents (cholestyramine), and in severe
cases specific digoxin antibodies (Digibind)
Sources of information: Uretsky et al (J Am Coll Cardiol 1993;22:955) and Packer et al (N Engl J Med 1993;329:1)
Other inotropes
The potential role of inotropic agents
other than digoxin in chronic heart failure has been addressed in
several studies. Although these drugs seem to improve symptoms in some
patients, most have been associated with an increase in mortality.
| Inotropic drugs associated with increased mortality in chronic heart failure |
| Drug |
Class |
Inotropic activity |
| Xamoterol |
² Receptor
antagonist |
Mild |
| Dobutamine |
Dopamine, ±, and ²
receptor antagonist |
Strong |
| Ibopamine |
Dopamine, ±, and ²
receptor antagonist |
Weak |
| Amrinone |
Phosphodiesterase
inhibitor |
Strong |
| Enoximone |
Phosphodiesterase
inhibitor |
Strong |
| Flosequinan |
Attenuates inositol
triphosphate |
Weak |
| Milrinone |
Phosphodiesterase
inhibitor |
Strong |
| Vesnarinone |
Phosphodiesterase
inhibitor |
Mild |
For example, the PRIME II trial (a prospective
randomised study) examined ibopamine, a weak inotrope, in patients with
chronic heart failure who were already receiving standard treatment. An
excess mortality was shown, however, particularly in those with severe
symptoms; this was possibly related to an excess of arrhythmias. In
addition, a previous trial evaluating intermittent dobutamine infusions
in patients with chronic heart failure was stopped prematurely because
of excess mortality in the group taking dobutamine. Xamoterol, a ²
receptor antagonist with mild agonist inotropic effects, also failed to
show any positive benefits in patients with heart failure.
In overall terms, no evidence exists at present to support the
use of oral catecholamine receptor (or postreceptor pathway) stimulants
in the treatment of chronic heart failure. Digoxin remains the only
(albeit weak) positive inotrope that is valuable in the management of
chronic heart failure.
² Blockers
² Adrenoceptor blockers have
traditionally been avoided in patients with heart failure due to their
negative inotropic effects. However, there is now considerable clinical
evidence to support the use of ² blockers in patients with chronic
stable heart failure resulting from left ventricular systolic
dysfunction. Recent randomised controlled trials in patients with
chronic heart failure have reported that combining ² blockers with
conventional treatment with diuretics and angiotensin converting enzyme
inhibitors results in improvements in left ventricular function,
symptoms, and survival, as well as a reduction in admissions to
hospital.
Potential
mechanisms and benefits of ² blockers: improved left ventricular
function; reduced sympathetic tone; improved autonomic nervous system
balance; up regulation of ² adrenergic receptors; reduction in
arrhythmias, ischaemia, further infarction, myocardial fibrosis, and
apoptosis
| Meta-analysis of
effects of ² blockers on mortality and admissions to hospital
in chronic heart failure |
| No of trials (total
No of patients) |
%
receiving placebo |
% receiving active
treatment |
Risk reduction (%)
|
P value
|
| 18 (3023) |
24.6 |
15.8 |
38 |
<0.001 |
Recently, two randomised controlled trials have studied the
effects of carvedilol, a ² blocker with ± blocking and vasodilator
properties, in patients with symptomatic heart failure. The US
multicentre carvedilol study programme was stopped early because of a
highly significant (65%) mortality benefit in patients receiving
carvedilol, when compared to placebo, and the Australia/New Zealand
heart failure study reported a 41% reduction in the combined primary
end point of all cause hospital admission and mortality. Bisoprolol has
also been studied, and, although the first cardiac insufficiency
bisoprolol study (CIBIS I) reported a trend towards a reduction in
mortality and need for cardiac transplantation, there was no conclusive
survival benefit. The recent CIBIS II study, however, was stopped
prematurely because of the beneficial effects of active treatment on
both morbidity and mortality. Metoprolol has also shown similar
prognostic advantages in the metoprolol
randomised intervention trial in heart failure (MERIT-HF), which was
also stopped early. In summary, evidence is now available to support
the use of ² blockers in chronic heart failure, as the benefits
supplement those already obtained from angiotensin converting enzyme
inhibitors.
| Randomised, placebo controlled ² blocker
trials in congestive heart failure |
| Study |
Treatment |
NYHA class* |
Outcome |
| MDC |
Metoprolol |
II, III |
Improved clinical
state without effect on survival. Reduction in need for
transplantation in patients with dilated cardiomyopathy
|
| CIBIS I |
Bisoprolol |
II, III |
Trend
(non-significant) towards improved survival |
| ANZ trial |
Carvedilol |
I, II |
Carvedilol superior
to placebo for morbidity and mortality |
| Carvedilol (US)
|
Carvedilol |
II, III |
Carvedilol superior
to placebo for morbidity and mortality |
| CIBIS II |
Bisoprolol |
III, IV |
Bisoprolol superior
to placebo for morbidity and mortality |
| MERIT-HF |
Metoprolol |
II, III |
Metoprolol superior
to placebo for morbidity and mortality
|
| Placebo groups in all trials received appropriate
conventional treatment (diuretics alone; diuretics
plus either digoxin or angiotensin converting enzyme inhibitors; or
diuretics plus digoxin and angiotensin converting enzyme inhibitors).
Trials still in progress: COMET (carvedilol v metoprolol) and COPERNICUS
(carvedilol in severe chronic heart failure). *Classification
of the New York Heart Association (I=no symptoms, II=
mild, III= moderate, IV= severe).< /FONT> |
Carvedilol is now licensed in the United Kingdom for use in
mild to moderate chronic stable heart failure, although at present its
use is still not recommended in patients with severe symptoms (New York
Heart Association class IV). This latter group has been
underrepresented in the trials to date.
Summary of the cardiac insufficiency bisoprolol study II (CIBIS II)*
Randomised, double blind, parallel
group study 2647 participants (class III-IV (moderate to
severe) according to classification of the New York Heart
Association) Bisoprolol, increased in dose to a maximum of
10 mg a day Trial stopped because of significant mortality
benefit in patients treated with bisoprolol:
(a) 32% reduction in all cause
mortality
(b) 32% reduction in admissions to hospital
for worsening heart failure
(c) 42% reduction in sudden death
*CIBIS II Investigators and Committee (Lancet 1999;353:9-13)
In general, ² blockers should be started at very low doses,
with the dose being slowly increased, under expert supervision, to the
target dose if tolerated. In the short term there may be a
deterioration in symptoms, which may improve with alterations in other
treatment, particularly diuretics.
| Dose and titration of ² blockers in large, placebo controlled heart failure trials |
| |
Weekly
titration schedule: total daily dose (mg) |
|
| ² Blocker |
Initial dose (mg)
|
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8-11 |
12-15 |
Target total daily
dose (mg) |
| Metoprolol (MDC
trial) |
5 |
10 |
15 |
20 |
50 |
75 |
100 |
150 |
NI |
NI |
100-150
|
| Carvedilol (US
trials) |
3.125 |
6.25 |
NI |
12.5 |
NI |
25 |
NI |
50 |
NI |
NI |
50 |
| Bisoprolol (CIBIS
II) |
1.25 |
1.25 |
2.5 |
3.75 |
5 |
5 |
5 |
5 |
7.5 |
10 |
10 |
References: Waagstein F et al (Lancet 1993;342:1442-6), Packer M et al (N Engl J Med 1996;334:1349-55), and CIBIS II Investigators and Committee (Lancet 1999;353:9-13).
NI=no increase in dose.
|
Study of effect of digoxin on mortality and morbidity in patients with heart failure*
Number of participants: 6800
Design: prospective, randomised, double blind, placebo controlled
Participants: left ventricular
ejection fraction <45%
Intervention: randomised to digoxin (0.125-0.500 mg) or placebo; follow up at 37 months
Results:
* Reduced admissions to hospital owing to heart failure
(greater absolute and relative benefits in the patients with resistant
symptoms and more severe impairment of left ventricular systolic
function)
* No effect on overall survival
*The Digitalis Investigation Group's study (see key references box)
Antithrombotic treatment
In patients with chronic heart failure the incidence of stroke
and thromboembolism is significantly higher in the presence of atrial
and left ventricular dilatation, particularly in severe left
ventricular dysfunction. Nevertheless, there is conflicting evidence of
benefit from routine treatment of patients with heart failure who are
in sinus rhythm with antithrombotic treatment, although anticoagulation
should be considered in the presence of mobile ventricular thrombus,
atrial fibrillation, and severe cardiac impairment. Large scale,
prospective randomised controlled trials of antithrombotic treatment in
heart failure are in progress, such as the WATCH study (a trial of
warfarin and antiplatelet therapy); the full results are awaited with
interest.
Echocardiogram showing thrombus at left ventricular apex in
patient with dilated cardiomyopathy (A=thrombus, B=left ventricle,
C=left atrium)
The combination of atrial fibrillation and heart failure (or
evidence of left ventricular systolic dysfunction on echocardiography)
is associated with a particularly high risk of thromboembolism, which
is reduced by long term treatment with warfarin. Aspirin seems to have
little effect on the risk of thromboembolism and overall mortality in
such patients.
Antiarrhythmic treatment
Chronic heart failure and atrial fibrillation
Restoration and long term maintenance
of sinus rhythm is less successful in the presence of severe structural
heart disease, particularly when the atrial fibrillation is
longstanding. In patients with a deterioration in symptoms that is
associated with recent onset of atrial fibrillation, treatment with
amiodarone increases the long term success rate of cardioversion.
Digoxin is otherwise appropriate for controlling ventricular rate in
most patients with heart failure and chronic atrial fibrillation, with
the addition of amiodarone in resistant cases.
The
use of class I antiarrhythmic agents in patients with atrial
fibrillation and chronic heart failure substantially increases the risk
of mortality
Chronic heart failure and ventricular arrhythmias
Ventricular arrhythmias are a common cause of death in severe
heart failure. Precipitating or aggravating factors should thus be
addressed, including electrolyte disturbance (for example,
hypokalaemia, hypomagnesaemia), digoxin toxicity, drugs causing
electrical instability (for example, antiarrhythmic drugs,
antidepressants), and continued or recurrent myocardial ischaemia.
Survival curves from GESICA trial (see key references box),
showing difference between patients taking amiodarone and controls
Amiodarone
is effective for the symptomatic control of ventricular arrhythmias in
chronic heart failure, although most studies have reported that long
term antiarrhythmic treatment with amiodarone has a neutral effect on
survival. An Argentinian trial (the GESICA study) of empirical
amiodarone in patients with chronic heart failure reported, however,
that active treatment was associated with a 28% reduction in total
mortality, although this trial included a high incidence of patients
with non-ischaemic heart failure. In contrast, in the survival trial of
antiarrhythmic therapy in congestive heart failure (CHF-STAT),
amiodarone did not improve overall survival, although there was a
significant (46%) reduction in cardiac death and admission to hospital
in the patients with non-ischaemic chronic heart failure.
| Summary of drug management in chronic heart failure |
| Drug class |
Potential
therapeutic role |
| Diuretics |
Symptomatic
improvement of congestion. Spironolactone improves survival in
severe (NYHA class IV) heart failure |
| Angiotensin
converting enzyme (ACE) inhibitors |
Improved symptoms,
exercise capacity, and survival in patients with asymptomatic
and symptomatic systolic dysfunction |
| Digoxin |
Improved symptoms,
exercise capacity, and fewer admissions to hospital
|
| Angiotensin II
receptor antagonists |
Treatment of
symptomatic heart failure in patients intolerant to ACE
inhibitors* |
| Nitrates and
hydralazine |
Improved survival in
symptomatic patients intolerant to ACE inhibitors or
angiotensin II receptor antagonists* |
| ² Blockers |
Improved symptoms
and survival in stable patients who are already receiving ACE
inhibitors |
| Amiodarone |
Prevention of
arrhythmias in patients with symptomatic ventricular
arrhythmias |
| *Recommendations of when these agents might be
considered (the use of these agents has not been addressed in
randomised trials of patients intolerant to ACE inhibitors).
|
In general, amiodarone should probably be reserved for
patients with chronic heart failure who also have symptomatic
ventricular arrhythmias. Interest has also developed in implantable
cardioverter defibrillators, which reduce the risk of sudden death in
high risk patients with ventricular arrhythmias (MADIT and AVID
studies), although the role of these devices in patients with chronic
heart failure still remains to be
established.
Key references
- Australia/New Zealand Heart Failure Research
Collaborative Group. Randomized, placebo-controlled trial of carvedilol
in patients with congestive heart failure due to ischaemic heart
disease. Lancet 1997;349:375-80.
- Lip GYH. Intracardiac thrombus formation in cardiac
impairment: investigation and the role of anticoagulant therapy.
Postgrad Med J 1996;72:731-8.
- Massie BM, Fisher SG, Radford M, Deedwania PC, Singh
BN, Fletcher RD, et al for the CHF-STAT Investigators. Effect of
amiodarone on clinical status and left ventricular function in patients
with congestive heart failure. Circulation
1996;93:2128-34.
- MERIT-HF Study Group. Effect of metoprolol CR/XL in
chronic heart failure: metoprolol CR/XL randomised intervention trial
in congestive heart failure (MERIT-HF). Lancet
1999;353:2001-7.
- Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman
GR, Curiel R, et al. Randomised trial of low-dose amiodarone in severe
congestive heart failure [GESICA trial]. Lancet
1994;344:493-8.
- Packer M, Bristow MR, Cohn JN,
Colucci WS, Fowler MB, Gilbert EM, et al. Effect of carvedilol on
morbidity and mortality in patients with chronic heart failure.
N Engl J Med 1996;334:1349-55.
- Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med
1997;336:525-33.
The survival graph is adapted with permission from Doval et al (Lancet 1994;344:493-8).
The table of inotropic drugs is adapted with permission from Niebauer et al (Lancet 1997;349:966).
The table of results of a meta-analysis of effects of ² blockers is adapted with permission from Lechat P et al (Circulation 1998;98:1184-91).
The table on doses and titration of ² blockers is adapted with permission from Remme WJ (Eur Heart J 1997;18:736-53).
The ABC of heart failure is edited by C R Gibbs, M K Davies, and G Y H Lip.
CRG is research fellow and GYHL is consultant cardiologist and reader in medicine in the university department of medicine and the department of cardiology, City Hospital, Birmingham; MKD is consultant cardiologist in the department of cardiology, Selly Oak Hospital, Birmingham. The series will be published as a book in the spring. BMJ 2000;320:495-8
studentBMJ 2000;08:217-258 July ISSN 0966-6494
