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European Journal of Heart Failure 1999 1(2):133-137; doi:10.1016/S1388-9842(99)00025-2
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© 1999 European Society of Cardiology

Treatment of arrhythmias in heart failure

Peter A. O'Callaghan* and A. John Camm

Department of Cardiological Sciences, St George's Hospital Medical School Cranmer Terrace, London SW17 ORE, UK

* Corresponding author. Tel.: +44-181-725-5916; fax: +44-181-767-7141 e-mail: pocallag{at}sghms.ac.uk

Key Words: Arrhythmia • Antiarrhythmia agents • Heart failure • Death, sudden • Defibrillation

Accepted April 7, 1999


   1. Introduction
Top
 1. Introduction
2. Secondary prevention of...
 3. Primary prevention of...
 4. Conclusion
 References
 
The last decade has seen major advances in the treatment of congestive heart failure and left ventricular systolic dysfunction. Nevertheless, despite conventional medical therapy including diuretics, digoxin, and angiotensin converting enzyme (ACE) inhibitors, the mortality rate associated with this condition remains unacceptably high, in the range of 5–15% annually in mild heart failure and increasing to 20–50% annually in patients with severe heart failure [1]. Angiotensin-converting enzyme (ACE) inhibitors reduce total mortality in patients with cardiac failure but in most trials do not reduce the frequency of ventricular arrhythmias or sudden cardiac death [2,3]. Sudden cardiac death is responsible for approximately half of all cardiac deaths in patients with heart failure. Sudden and unexpected death accounts for the majority of deaths in mild heart failure; in contrast death due to progressive pump failure accounts for the majority of deaths in severe heart failure (Table 1) [1]. Interventions that prevent either sudden death or progressive pump failure should have a neutral or beneficial effect on the other mode of death if a reduction in overall mortality is to be realized.


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  		Table 1 Annual mortality and proportion of deaths which are sudden according to New York Heart Association functional classa

 

   2. Secondary prevention of life-threatening ventricular tacyhyarrhythmias
Top
 1. Introduction
 2. Secondary prevention of...
3. Primary prevention of...
 4. Conclusion
 References
 
2.1. The decline of pharmacologic therapy
In the late 1980s guided antiarrhythmic drug therapy (usually Class I agents) using either invasive electrophysiologic drug testing or non-invasive electrocardiographic monitoring was routinely employed in the management of life-threatening ventricular tachyarrhythmias (cardiac arrest survivors, symptomatic sustained ventricular tachycardia). In patients with poor left ventricular ejection fraction (LVEF<30%) or with substrates other than chronic coronary atherosclerosis, guided drug therapy does not accurately predict efficacy [4,5]. The results of the CAST trials revealed that although Class I agents effectively suppress ventricular ectopic activity in patients post-myocardial infarction, overall mortality is increased compared to placebo due to both an increased frequency of life threatening arrhythmias and by converting more ischaemic and heart failure episodes into fatal events [6,7]. As a result it is now generally agreed that Class I agents should be avoided in the management of heart failure patients. In recent years the only drug therapy that has challenged the superiority of implantable defibrillators in the management of life-threatening ventricular tachyarrhythmias has been empiric amiodarone therapy [8].

2.2. The rise of device therapy
In patients with heart failure there was a concern that implantable defibrillators may have little effect on overall survival for several reasons. Firstly, as NYHA functional class deteriorates the proportion of deaths which are sudden and unexpected decreases (Table 1). Secondly, in advanced heart failure the proportion of sudden deaths which are due to bradyarrhythmias and, electromechanical dissociation becomes substantial, accounting for up to half of all sudden deaths in some series [9,10]. These episodes are usually agonal rhythms in patients with severely impaired systolic function and death is not prevented by backup pacing. Finally, successfully terminating an episode of ventricular tachycardia or fibrillation will have little effect on overall survival if the patient dies shortly thereafter of progressive pump failure. Because of these concerns, prospective randomised trials have been conducted in recent years to test the hypothesis that implantable defibrillators significantly improve total mortality.

The results of two large prospective multicentre trials (AVID and CIDS) comparing implantable defibrillators and amiodarone therapy in patients with life-threatening ventricular tachyarrhythmias have reported that the implantable defibrillator is superior to amiodarone for increasing overall survival (Dr S. Connolly, personal communication, CIDS) [11]. In the AVID trial, implantable defibrillators resulted in a 31% reduction in total mortality at 3 years compared to patients treated with amiodarone. Of note, subgroup analysis suggests that patients with a left ventricular ejection fraction ≤30% derive a greater survival benefit from defibrillator therapy than patients with an ejection fraction >35%. As a result the implantable defibrillator is now regarded as the treatment of choice in heart failure patients with life-threatening ventricular tachyarrhythmias.

Bocker et al. assessed the potential benefit from implantable defibrillator therapy in patients with and without heart failure [12]. They defined the hyopthetical death rate as total deaths plus the occurrence of fast (>240/min) ventricular tachyarrhythmia (which presumably would have been fatal had the device not been implanted) and estimated the benefit of the device as the difference between overall mortality and the hypothetical death rate. The estimated survival benefit from the implantable defibrillator after 5 years follow-up was 36%, 22% and 23% in patients with NYHA Class I, II and III, respectively [12].

Although these results support the use of implantable defibrillators in patients with NYHA Class I, II and III heart failure, in NYHA Class IV failure defibrillator therapy is contrindicated. This is because only a small proportion of deaths are due to ventricular tachyarrhythmias; progressive pump failure, bradyarrhythmic deaths and non-cardiac deaths combined, account for the majority of deaths in these patients. Also patients with very poor ventricular function can experience very frequent episodes of ventricular tachyarrhythmias resulting in frequent shock delivery. If this persists despite device reprogramming, antiarrhythmic therapy and possibly ablative therapy, one needs to consider, in consultation with the patient and family, deactivating the device.

Patients on the waiting list for heart transplantation deserve special mention. A substantial proportion of these patients die while on the waiting list, many of them suddenly [13]. As a result the ICD has been proposed to avoid sudden death in patients who could otherwise expect prolonged survival following transplantation. A recent study has shown benefit in implanting defibrillators in patients with life-threatening ventricular tachyarrhythmias awaiting transplantation [14]. However, the hypothesis that prophylactic ICD implantation in all patients as a ‘bridge’ to transplantation will result in significant survival benefit remains to be proven in a prospective trial.


   3. Primary prevention of sudden cardiac death
Top
 1. Introduction
 2. Secondary prevention of...
 3. Primary prevention of...
4. Conclusion
 References
 
The majority of patients with heart failure who die suddenly have not previously experienced a sustained ventricular tachyarrhythmia. Therefore primary prevention will have the greatest impact on reducing mortality from sudden cardiac death. A multidimensional approach to arrhythmia prevention, such as the prevention of scar tissue (e.g. thrombolysis or revascularisation) or the suppression of trigger factors (e.g. anti-ischaemic agents or platelet inhibitors) will probably impact most on the risk of sudden cardiac death.

Newer pharmacological agents employed in the management of heart failure not only decrease the death rate from progressive pump failure but also reduce the number of sudden cardiac deaths. Carvedilol is a non-selective β1 and β2 receptor blocker, and an {alpha}1 blocker (hence a vasodilator). In contrast to metoprolol, carvedilol selectively lowers coronary sinus norepinephrine levels and does not increase the density of cardiac β receptors [15]. The US Cardvedilol Heart Failure Study Group reported that in mild to moderate heart failure, carvedilol was associated with a large reduction in the risk of dying of both progressive heart failure and sudden cardiac death [16]. These results are supported by a recent meta-analysis of the effect of beta-blockers on mortality in patients with heart failure [17]. In the ELITE (Evaluation of Losartan in the Elderly) trial, the angiotensin II antagonist, losartan, reduced total mortality by 46% compared to captopril, primarily due to a reduction in sudden cardiac death [18]. If these results are confirmed it is possible that in the future losartan and carvediolol will replace ACE inhibitors in the management of mild to moderate heart failure, resulting in a reduction in sudden cardiac death.

Much attention has focused in recent years on the primary prevention of sudden cardiac death in patients with heart failure using amiodarone therapy. The results of prospective randomised trials in patients with heart failure (GESICA and CHF-STAT) [19,20] and post-myocardial infarction (EMIAT and CAMIAT) [21,22] as well as a meta-analysis of amiodarone trials are published [23]. Based on these trials a number of conclusions can be drawn. Firstly, unlike other antiarrhythmic drugs, amiodarone appears reasonably safe with little or no associated increase in mortality, and a low risk of proarrhythmia when administered to patients with heart failure. Secondly apart from the GESICA trial in which the majority of patients had non-ischaemic cardiomyopaythy, amiodarone therapy does not significantly reduce total mortality. Therefore, in patients with heart failure, amiodarone is the preferred antiarrhythmic drug to treat symptomatic tachyarrhythmias. In addition, subgroup analysis suggests that the combination of amiodarone and beta-blocker therapy has synergistic effects with respect to its ability to suppress arrhythmias and prevent sudden cardiac death [24].

Although amiodarone is the preferred antiarrhythmic drug to treat symptomatic tachyarrhythmias in patients with heart failure, prophylactic amiodarone therapy in all patients with left ventricular dysfunction is not recommended at present. In these patients, the absolute risk of sudden cardiac death is much less than in cardiac arrest survivors. In this setting, adverse drug side effects may increase the number of non-arrhythmic deaths (e.g. increased deaths from pump failure, bradyarrhythmias, or pulmonary fibrosis) such that the overall mortality is unchanged, as seen in the EMIAT trial (Fig. 1).


Figure 1
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  		Fig. 1 Mortality rates in the EMIAT trial. Amiodarone resulted in a significant reduction in sudden cardiac death (SCD) but did not decrease all cause mortality (ACM). Mediam follow-up was 21 months [21].

 
Ongoing trials such as the sudden cardiac death in heart failure (SCD-HeFT) trial which is randomising 2500 patients with dilated cardiomyopathy, ejection fraction ≤35%, and NYHA Class II or III heart failure to either conventional therapy, amiodarone or implantable defibrillator therapy will determine how these patients will be managed in the future [25].

3.1. Risk stratification and primary prevention
Rather than treating all patients with prophylactic antiarrhythmic therapy, attempts have been made to target subgroups of patients who have not experienced a documented episode of life-threatening ventricular tachyarrhythmia but who are at high risk of sudden cardiac death. One such group is patients with prior myocardial infarction, ejection fraction ≤35%, non-sustained ventricular tachycardia and inducible, non-suppressible ventricular tachyarrhythmia on invasive electrophysiologic testing. In this select high risk group, prophylactic therapy with an implanted defibrillator leads to improved survival compared with conventional medical therapy [26]. Also patients with impaired left ventricular function, syncope of unknown origin and inducible ventricular tachycardia on electrophysiologic testing are a very high risk of sudden cardiac death and implantable defibrillator therapy is indicated [27].

The use of conventional risk factor stratification in patients with heart failure is limited. For example it is well established that non-sustained ventricular tachycardia (NSVT) is an independent risk factor for cardiac mortality. However, in more advanced heart failure NSVT is documented in up to 60% of all patients and is associated more with the overall risk of death than with the risk of sudden cardiac death [28]. Risk stratification either by non-invasive testing (e.g. 24-h Holter, signal averaged ECG, T wave alternans, etc.) or by invasive electrophysiologic testing is only useful in post myocardial infarction patients with mild to moderate heart failure. In advanced heart failure and in patients with non-ischaemic cardiomyopathy, these tests contribute little useful or reliable information. It is possible in the future that other measures such as resting heart rate, heart rate variability, or circulating norepinephrine levels may be useful in selecting high risk patients that would benefit most from prophylactic antiarrhythmic therapy.


   4. Conclusion
Top
 1. Introduction
 2. Secondary prevention of...
 3. Primary prevention of...
 4. Conclusion
References
 
In patients with documented life-threatening ventricular tachyarrhythmias the implantable defibrillator is superior to empiric amidoarone therapy for increasing overall survival. Implantable defibrillators have been shown to improve survival in patients with NYHA Class I–III heart failure but in NYHA Class IV heart failure, defibrillator therapy is contraindicated. In patients with heart failure and symptomatic tachyarrhythmias who require antiarrhythmic drug therapy, amiodarone is the preferred antiarrhythmic agent.

Sudden cardiac death is responsible for approximately half of the cardiac deaths in patients with heart failure. Primary prevention of sudden cardiac death will require a multidimensional approach. New agents are being tested that can favorably affect both sudden death and progressive pump failure. The utility of conventional risk factors is limited in heart failure patients and new non-invasive markers are needed to identify those who would benefit most from antiarrhythmic therapy. Stategies need to be devised to identify high risk subgroups (e.g. MADIT patients). Recommendations regarding prophylactic amiodarone or defibrillator therapy in all patients with left ventricular dysfunction await the results of ongoing clinical trials such as the SCD-HeFT trial.


   References
Top
 1. Introduction
 2. Secondary prevention of...
 3. Primary prevention of...
 4. Conclusion
 References
 

  1. Uretsky B.F., Sheahan R.G. Primary prevention of sudden cardiac death in heart failure: will the solution be shocking? J Am Coll Cardiol (1997) 30:1589–1597.[Abstract]
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  19. Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA). Doval H.C., Nul D.R., Grancielli H.O., Perrone S.V., Bortman G.R., Curiel R. Randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet (1994) 344:493–498.[CrossRef][Web of Science][Medline]
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