Left ventricular (LV) systolic dysfunction, defined by depressed LV ejection fraction (LVEF), has been recognised over the last two decades as the most robust parameter for identifying risk of sudden cardiac death (SCD). Specifically, LVEF has been a major determinant for entry into numerous randomised trials that aimed to investigate the efficacy of implantable cardioverter–defibrillators (ICDs) compared with antiarrhythmic or best medical therapy in the primary prevention of SCD. The goal of this article is to review the clinical utility of ICD implantation in patients with structural heart disease. Several trials have attempted to use additional risk parameters beyond low LVEF in order to magnify the benefit of ICD compared with antiarrhythmic therapy. All of these trials were conducted in patients with ischaemic LV dysfunction. The Multicenter Automatic Defibrillator Implantation Trial (MADIT)1 was the first randomised clinical trial that compared ICD therapy with conventional care in primary prevention, i.e. in patients with no prior history of life-threatening arrhythmias. Patients with ischaemic LV dysfunction (LVEF ≤0.35), non-sustained ventricular tachycardias (VTs) and inducible but non-suppressible sustained ventricular arrhythmias during programmed electrical stimulation were enrolled. MADIT demonstrated a 54% relative mortality reduction (p=0.009) in the ICD arm. The Coronary Artery Bypass Graft Path Trial (CABG Patch)2 compared ICD therapy with usual care in patients undergoing coronary artery bypass grafting and having LV dysfunction (LVEF <0.36) and the presence of late potentials assessed by signal-averaged electrocardiogram (ECG) recording. Although ICD significantly reduced the risk of SCD, no significant reduction in mortality was observed with ICD therapy, probably due to the strong beneficial effect of revascularisation. The Multicentre Unsustained Tachycardia Trial (MUSTT)3 compared antiarrhythmic therapy with best medical therapy in patients with ischaemic LV dysfunction (LVEF ≤0.40), non-sustained VT and inducible sustained ventricular arrhythmias during programmed ventricular stimulation. ICD therapy could be used only in a non-randomised fashion after the failure of serial electrophysiologically guided testing of antiarrhythmic drugs. The survival benefit in the electrophysiologically guided therapy group (significant 27% relative reduction in cardiac arrests/arrhythmic deaths compared with conventional care) was limited to those patients who received an ICD. Drug therapy alone was not associated with the reduction in mortality compared with best medical therapy.
In order to simplify the risk stratification procedure, MADIT II4 was conducted. This was the first trial that included patients primarily based on advanced LV dysfunction (LVEF ≤0.30) late after myocardial infarction (MI) without the need for invasive testing. Prophylactic ICD implantation was associated with a significant reduction (31%; p=0.016) of all-cause mortality compared with the conventional-therapy group. The survival benefit was similar in strata according to age, sex, LVEF, New York Heart Association (NYHA) class and the QRS width. The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT)5 was designed to test whether prophylactic implantation of an ICD would reduce mortality in survivors of a recent MI (six to 40 days after MI) with LV dysfunction (LVEF ≤0.35) and impaired cardiac autonomic function manifested as depressed heart-rate variability or an elevated average 24-hour heart rate on Holter monitoring. No difference was found in overall mortality between the ICD and conventional-therapy arms. ICD therapy was associated with a reduction in the rate of death due to arrhythmia, but this was offset by an increase in the rate of death from non-arrhythmic causes. In contrast to the previous two trials in patients with ischaemic heart disease, the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)6 was designed to evaluate the hypothesis that amiodarone or an ICD would decrease the risk of death from any cause in a broad population of patients with mild to moderate ischaemic or non-ischaemic congestive heart failure (LVEF ≤0.35) with NYHA class II–III. Patients receiving ICD had a significantly lower risk of death (relative reduction of 23%; p=0.007) compared with those in the placebo arm. Surprisingly, there was no difference in mortality between patients treated with amiodarone and those treated with placebo. The results did not vary according to either ischaemic or non-ischaemic causes of congestive heart failure, but they varied according to NYHA class. ICD therapy had a significant benefit in patients in NYHA class II, but not in those in NYHA class III. However, this unanticipated subgroup effect – which was in conflict with the results of other ICD trials – was not assumed to be a sufficient basis for withholding ICD therapy from patients in NYHA class III. Two other trials focused primarily on subjects with non-ischaemic cardiomyopathy. The Amiodarone versus Implantable Defibrillator (AMIOVIRT) trial7 compared amiodarone with ICD in a randomised fashion in patients with idiopathic dilated cardiomyopathy (LVEF ≤0.35), NYHA class I–III and asymptomatic non-sustained VT. Mortality in patients treated with amiodarone or an ICD was not statistically different, probably due to the low number of patients enrolled and the short duration of follow-up.
The Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE)8 trial randomly assigned patients to ICD or standard medical therapy. Inclusion criteria were non-ischaemic LV systolic dysfunction (LVEF <0.36), history of symptomatic heart failure, NYHA class I–III and non-sustained VT and/or frequent ventricular premature beats (>10 per hour). ICD therapy significantly reduced the risk of SCD and was associated with a statistically borderline reduction in the risk of all-cause death (relative risk reduction of 35%; p=0.08). The lower than expected rate of SCD may have resulted in the non-significant reduction in total mortality.
All of the above trials, together with complementary meta-analyses,9–11 provided the basis for evidence-based indication criteria for prophylactic ICD therapy that were summarised in the American College of Cardiology (ACC)/American Heart Association (AHA)/European Society of Cardiology (ESC) 2006 guidelines for the management of patients with ventricular arrhythmias and the prevention of SCD.12 Because of inconsistency between trials in enrolment cut-off values of LVEF, average values of LVEF and subgroup analyses, the Guideline Writing Committee decided to construct recommendations applicable to patients with LVEF less than or equal to a range of values. It is important to realise that, in general, recommendations are pertinent to patients who have a reasonable expectation of survival with a good functional status for more than one year. Based on these guidelines, ICD therapy is recommended for primary prevention to reduce total mortality by a reduction in SCD in patients with LV dysfunction due to prior MI (LVEF ≤30–40%) and NYHA class II–III (recommendation class I, level of evidence A), and is reasonable in patients with LV dysfunction due to prior MI (LVEF ≤30–35%) and NYHA class I (recommendation class IIa, level of evidence B).12 Essentially, evaluation should be deferred until at least three months after revascularisation procedures2 and, more strictly, until at least 40 days after acute MI5,13 to allow adequate time for recovery of ventricular function. ICD therapy is also recommended for primary prevention to reduce total mortality by a reduction in SCD in patients with non-ischaemic heart disease receiving chronic optimal medical therapy with LVEF ≤30–35% and NYHA class II–III (recommendation class I, level of evidence B), and may be considered in patients with non-ischaemic heart disease with LVEF ≤30–35% and NYHA class I (recommendation class IIb, level of evidence B).12 LVEF in risk stratification in the secondary prevention of SCD – i.e. in survivors of cardiac arrest due to VT/ventricular fibrillation (VF), patients with haemodynamically unstable VT, recurrent stable VT or VT with syncope – is generally less useful and less supported by clinical data compared with primary prevention.
Current recommendations are based on the results of three important randomised clinical trials14–16 and their meta-analyses.11,17,18 In summary, ICD is recommended for secondary prevention of SCD in patients with structural heart disease and significant LV dysfunction (LVEF ≤40%) who are receiving chronic optimal medical therapy (recommendation class I, level of evidence A). ICD is reasonable for secondary prevention of SCD in patients with structural heart disease and normal or near-normal LVEF who are receiving chronic optimal medical therapy (recommendation class IIa, level of evidence C).12 Even in a secondary preventative setting, patients with relatively preserved LV function (≥0.35) may not have better survival when treated with the ICD compared with antiarrhythmic drugs.19 Proper evaluation of arrhythmia morphology may occasionally be crucial for further management. The possibility should be considered that patients with structural heart disease may develop sustained VT due to other mechanisms such as bundle-branch re-entry or focal VT.
There are insufficient data on the value of LVEF for ICD therapy to be recommended in valvular heart disease, congenital heart disease and metabolic, endocrine, infiltrative, neuromuscular and inflammatory disorders/cardiomyopathies. Patients with ventricular arrhythmias should be evaluated and treated according to specific recommendations for each disorder. LVEF is for obvious reasons useless in genetic arrhythmia syndromes (long and short QT syndrome, Brugada syndrome, orcatecholaminergic polymorphic VT) and in disorders that are, by definition, not associated with LV dysfunction (hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy). In conclusion, reduced LVEF has been a major determinant for entry into the primary preventative ICD studies. Numerous other risk stratifiers continue to be investigated in order to select high-risk patients and to assess the efficacy of ICD therapy. More specific selection of patients in terms of risk of death, based on more than simply LVEF, is crucial for the future development of cost-effective prophylactic treatment aimed at closing the gap between scientific evidence and the limited resources of healthcare systems.