Use of implantable cardioverter defibrillator in nonischaemic cardiomyopathy

According to the WHO, sudden cardiac death (SCD) is defined as a natural, nontraumatic, unexpected death characterized by a sudden loss of consciousness and subsequent decease within 1 h of symptoms onset.1 This temporal limit is conventionally extended to 24 h when death occurs unwitnessed. It has been estimated that 30–50% of SCDs occur in patients with known severe left ventricular systolic dysfunction (LVSD) independently from underlying cause (ischaemic vs. nonischaemic).2,3 Among patients with heart failure and severe LVSD, the percentage of deaths attributable to SCD is higher in patients with less severe degree of symptoms [64% in New York Heart Association (NYHA) functional class II patients enrolled in the MERIT-HF trial] and decreases with the worsening of heart failure (33% in NYHA functional class IV patients enrolled in the MERIT-HF trial).4 Ventricular fibrillation or sustained ventricular tachycardia degenerating in ventricular fibrillation are the commonest malignant arrhythmias causing SCD in patients with heart failure or dilated cardiomyopathy and severe LVSD. However, the occurrence of pathological bradyarrhythmias and of pulseless electrical activity can determine SCD in a significant proportion of patients with advanced heart failure.5 From a pathophysiological stand point, the occurrence of SCD in patients with heart failure and severe LVSD can be explained by the three determinants of arrhythmogenesis proposed by Philippe Coumel at the end of the last century.6 The presence of remodelled, often hypertrophied myocardial tissue, mixed with fibrotic area of varying extension may act as substrate for the onset of arrhythmic events under the effect of proarrhythmic triggers such as premature ventricular contractions (isolated or repetitive), electrolyte abnormalities and haemodynamic and/or ischaemic disorders which are extremely frequent in this category of patients. Moreover, the imbalance between the sympathetic and parasympathetic nervous systems (with the hyperactivation of the first and the suppression of the latter) may negatively modulate these interactions further facilitating the onset of malignant and life-threatening arrhythmic events (Fig. 1).Fig. 1: The arrhythmogenesis triangle proposed by Coumel is useful to describe the main pathophysiological mechanisms involved in sudden cardiac death among patients with heart failure. LV, left ventricle; PVC, premature ventricular contraction; SCD, sudden cardiac death; VT, ventricular tachycardia.The use of antiarrhythmic drugs for SCD prevention in patients with heart failure and severe LVSD is of limited utility. Several studies have demonstrated that class I antiarrhythmic drugs can increase mortality, whereas class III antiarrhythmic drugs, although safe, are not effective in reducing the risk of death. Therefore, the implantable cardioverter defibrillator (ICD), which was developed in the seventies by Mirowski and Mower and tested in human for the first time in February 1980, has progressively become established for SCD prevention among patients with heart failure and LVSD. The small size of modern ICDs makes the subcutaneous, subclavicular implant of such devices, including one or more transvenous leads, feasible and relatively safe. In addition to antibradycardia pacing, the ICD can detect and treat malignant tachyarrhythmias by means of overdrive pacing, electrical cardioversion and defibrillation. Initially, the impact of ICD on mortality has been shown in randomized controlled clinical trials enrolling SCD survivors (secondary prevention trials) and comparing the clinical efficacy of ICD with antiarrhythmic drugs (e.g. Antiarrhythmics Versus Implantable Defibrillators, Cardiac Arrest Survivor Hamburg and the Canadian Implantable Defibrillator Study).7 The vast majority of patients enrolled in these studies had an underlying ischaemic cardiomyopathy. More recently, randomized controlled clinical trials enrolled patients without prior ventricular arrhythmias deemed at risk for SCD because of severe LVSD and symptoms of heart failure (primary prevention trials). Several studies like the Multicenter Automatic Defibrillator Implantation Trial (MADIT-I), the Multicenter Unsustained Tachycardia Trial and the MADIT-II have shown the efficacy of ICD in reducing all-cause mortality among patients with previous myocardial infarction and severe LVSD demonstrating a relative risk (RR) reduction ranging from 28 to 59%.8 Although patients with nonischaemic cardiomyopathy carry an annual SCD risk of 4%,9 the efficacy of ICD for SCD primary prevention seems inferior in these patients as compared with those with an underlying ischaemic cardiomyopathy.10 Five prospective randomized controlled clinical trials have tested the use of ICD in primary prevention of SCD among patients with nonischaemic cardiomyopathy so far (main features of these studies are summarized in Table 1). The first studies which included approximately 200 patients with nonischaemic cardiomyopathy [i.e. the Cardiomyopathy Trial and the Amiodarone Versus Implantable Cardioverter Defibrillator Trial (AMIOVIRT)] did not show significant benefit for ICD therapy on the primary endpoint of all-cause mortality.11,12 Until 2016, the larger prospective randomized study exclusively enrolling patients with nonischaemic cardiomyopathy was the Defibrillator in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Trial which randomized 458 patients with severe LVSD [i.e. left ventricular (LV) ejection fraction ≤35%] and prior nonsustained ventricular tachycardia to ICD implantation and medical therapy vs. optimized medical therapy (approximately 85% of patients were taking an angiotensin converting enzyme (ACE)-inhibitor and a beta-blocker).13 Over a mean follow-up of 2.5 years, there was a trend toward reduction in the primary endpoint of all-cause mortality in patients treated with ICD (2 years all-cause mortality 8 vs. 14% in ICD recipients and patients treated with optimal medical therapy respectively, P = 0.08).Table 1: Randomized controlled clinical trials testing implantable cardioverter defibrillator therapy for sudden cardiac death primary prevention among patients with nonischaemic cardiomyopathyOther data in support of the use of ICD for primary prevention of SCD among patients with nonischaemic cardiomyopathy derive from the Sudden Cardiac Death in Heart Failure Trial which enrolled patients with both ischaemic (52%) and nonischaemic (48%) cardiomyopathy and severe LVSD.14 The design feature of this trial envisaged three-arms randomization: placebo group vs. amiodarone group vs. ICD group. During a median follow-up of 45.5 months, amiodarone therapy showed no survival benefit over placebo [hazard ratio = 1.06; 97.5% confidence interval (CI) 0.86–1.30; P = 0.53], whereas a significant reduction was observed in patients receiving an ICD (hazard ratio = 0.77; 97.5% CI 0.62–0.96; P = 0.007) with a significant absolute risk reduction of 7.2% as compared with control. As a prespecified subgroup analysis, the benefit of ICD was tested in patients with nonischaemic cardiomyopathy separately: all-cause mortality reduction was similar to that observed in the overall study although not reaching statistical significance (hazard ratio = 0.73; 97.5% CI 0.50–1.07; P = 0.06). On the basis of these data, the recent guidelines on diagnosis and treatment of patients with heart failure issued by the European Society of Cardiology suggest ICD therapy for primary prevention of SCD in symptomatic (functional class NYHA II–III) patients with nonischaemic cardiomyopathy, severe LVSD (i.e. LV ejection fraction ≤35%) despite at least 3 months of optimal medical therapy with a class I recommendation, level of evidence B (whereas for patients with ischaemic cardiomyopathy the level of evidence is A).15 However, these recommendations should be revisited in light of the new findings from the Danish Study to Assess the Efficacy of ICDs in Patients with Non-Ischemic Systolic Heart Failure on Mortality (DANISH) which were presented at the Congress of the European Society of Cardiology in August 2016.16 This study enrolled 1116 patients with symptomatic heart failure and severe LVSD (i.e. LV ejection fraction ≤35%) not caused by ischaemic heart disease (which was ruled out in the vast majority of patients by means of coronary angiography, coronary computer tomography (CT) or single-photon emission CT). Demonstration of ventricular premature contractions at the time of enrolment or history of nonsustained ventricular tachycardia, which have an uncertain and inconstant prognostic impact (Fig. 2), were not amongst the inclusion criteria in contrast to prior studies (i.e. AMIOVIRT and DEFINITE). Patients were randomized 1 : 1 to ICD with guideline-directed optimal medical therapy or medical therapy alone. There were no significant differences between the two study arms at the time of randomization and both groups were optimally treated from a pharmacological (97% of patients were on an ACE-inhibitor or an angiotensin receptor blocker, 92% on a beta-blocker and 58% on a mineralocorticoid receptor antagonist) and nonpharmacological (58% of patients had a cardiac resynchronization therapy device) standpoint. Over a median follow-up of 5.6 years, there were no significant differences in the primary endpoint of all-cause mortality between ICD recipients and the control group [120 deaths (21.6%) vs. 131 deaths (23.4%) in the ICD and in the control group, respectively, hazard ratio = 0.87; 95% CI 0.68–1.12; P = 0.28, 1.8% absolute risk reduction]. Similarly, taking into account the secondary endpoint of cardiovascular mortality, there were no significant differences between the two arms [77 deaths (13.8%) vs. 95 deaths (17.0%), hazard ratio = 0.77; 95% CI 0.57–1.05; P = 0.10, 3.2% absolute risk reduction], whereas a significant reduction in SCD occurrence was observed among ICD recipients as compared with control group [24 SCDs (4.3%) vs. 46 SCDs (8.2%), hazard ratio = 0.50; 95% CI 0.31–0.82, P = 0.005, 3.9% absolute risk reduction]. Subgroup analysis did not show significant differences in the primary outcome across prespecified subgroups with the exception of age. More in detail, among patients aged 68 years or less receiving an ICD, a significant reduction in all-cause mortality was observed as compared with the control group (hazard ratio = 0.64; 95% CI 0.45–0.90). When interpreting the findings from the DANISH study a few remarks must be made: compared with prior primary prevention ICD trials, observed mortality rates were significantly lower, possibly reflecting the improvements in heart failure medical therapy and the extensive use of cardiac resynchronization therapy which was not available when older primary prevention trials were conducted; in addition, the results from DANISH study suggest that patients with heart failure due to nonischaemic causes receiving optimized therapy have a much better prognosis than commonly perceived; considering that the event rates were lower than expected, it is likely that the DANISH sample size was insufficient to demonstrate an ICD benefit on overall mortality; however, patients enrolled in clinical trials are usually younger and have fewer comorbidities as compared with patients encountered in everyday clinical practice; therefore, the risk of death for cardiovascular vs. noncardiovascular causes (on which the ICD has no effect) is greater in the context of a clinical trial possibly favouring an overestimation of ICD efficacy; whenever an ICD is indicated for primary prevention, the existence of competing causes of death should always be considered, especially among the elderly; in other words, both frailty and the high number of comorbidities typical of such group of patients might increase the risk of death for noncardiovascular causes hampering ICD efficacy. Fig. 2: Nonsustained ventricular arrhythmias can have a different prognostic impact among patients with heart failure. Premature ventricular contractions, especially if isolated and monomorphic, together with slow nonsustained ventricular tachycardia of short duration are usually benign (green light); short coupling nonsustained ventricular tachycardia of longer duration and with shorter cycle length may be potentially dangerous (yellow light); rapid, polymorphic nonsustained ventricular tachycardia are always malignant (red light).The findings of the DANISH trial have been recently included in a meta-analysis that grouped all the studies testing ICD efficacy in SCD primary prevention among patients with heart failure and nonischaemic cause.17 Overall, among the 2970 patients included, ICD was associated with a significant all-cause mortality RR reduction as compared with medical therapy (hazard ratio = 0.76; 95% CI 0.62–0.94). The authors of the same study, by combining the results of the DANISH trial and of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure Study,18 speculated on the hypothesis that ICD may be effective in reducing mortality among candidates to cardiac resynchronization therapy. In conclusion, the recent findings from the DANISH trial underline the importance of accurate selection of ICD candidates in the setting of SCD primary prevention and question current knowledge and beliefs. Selection of patients for ICD therapy should be based on careful weighting of expected advantages and potential risks bearing in mind that, in primary prevention of SCD, elderly and nonischaemic patients may benefit less than other patients. Guideline recommendations should be revised in light of these new pivotal observations. Acknowledgements Conflicts of interest There are no conflicts of interest.

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