Clinical review

Management: digoxin and other inotropes,  blockers, and antiarrhythmic and antithrombotic treatment

C R Gibbs,  M K Davies,  G Y H Lip. 

	Digoxin

Top Digoxin Other inotropes Blockers Antithrombotic treatment Antiarrhythmic treatment

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.

View larger version (23K): [in this window] [in a new window]   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 studysee key references box at end of article)

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 a symptomatic improvement in 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.  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  blockers and angiotensin converting enzyme inhibitors in congestive heart failure.

	Other inotropes

Top Digoxin Other inotropes Blockers Antithrombotic treatment Antiarrhythmic treatment

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.

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  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.

	Blockers

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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  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  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.

Randomised, placebo controlled  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).

Recently, two randomised controlled trials have studied the effects of carvedilol, a  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  blockers in chronic heart failure, as the benefits supplement those already obtained from angiotensin converting enzyme inhibitors.

Meta-analysis of effects of  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

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.

In general,  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  blockers in large, placebo controlled heart failure trials Blocker Initial dose (mg) Weekly titration schedule: total daily dose (mg) Target total daily dose (mg) 1 2 3 4 5 6 7 8-11 12-15 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.

	Antithrombotic treatment

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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.

View larger version (120K): [in this window] [in a new window]   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

Top Digoxin Other inotropes Blockers Antithrombotic treatment 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 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.

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.

View larger version (22K): [in this window] [in a new window]   Survival curves from GESICA trial (see key references box), showing difference between patients taking amiodarone and controls

	Acknowledgments

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  blockers is adapted with permission from Lechat P et al (Circulation 1998;98:1184-91). The table on doses and titration of  blockers is adapted with permission from Remme WJ (Eur Heart J 1997;18:736-53).

	Footnotes

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.