An ounce of prevention is worth a pound of cure: drugs and devices to prevent sudden cardiac death in heart failure

This editorial refers to ‘Sinergy between drugs and devices in the fight against sudden cardiac death and heart failure’ by G. Boriani et al., pp. 110–123. Sudden cardiac death (SCD) is an important contributor to mortality in patients with heart failure (HF), despite advances in pharmacological and device management. Sudden cardiac death is responsible for ∼35% of all-cause mortality in HF with reduced ejection fraction (HFrEF), and the proportion of deaths due to SCD exceeds mortality due to pump failure (21%).1 The relative risk of SCD is higher among patients with less impaired functional status compared to those with more advanced HFrEF.2 However, patients with less severe HF are often perceived as clinically stable, and novel pharmacological therapies with an incremental benefit in risk reduction for SCD may be underutilized. In patients with HF with preserved ejection fraction (HFpEF), data are less consistent, but SCD accounts for ∼25% of mortality.3 The underlying mechanisms of SCD in HFpEF are incompletely understood, and current knowledge is limited about the risk factors, precipitating causes, and effective prevention.4 Given the significant impact on mortality due to SCD in HF, deeper understanding of the causes and triggering factors,5 as well as a critical appraisal of risk stratification and prevention strategies are of utmost importance for the management of HF. In the present issue of the journal, Boriani et al. provide a comprehensive and up-to-date review of these important matters6. The review firstly deals with the burden and the underlying mechanisms of SCD in HF. The authors underline that SCD occurs in HF at a rate 6–9 times greater than the general population (1–2 per 1000 per years), and accounts for a substantial proportion of potentially preventable deaths. This is particularly significant for patients with less advanced HF, in whom the competing risk of dying due to pump failure or comorbidities is low. In those patients, the mechanism of SCD is largely attributed to ventricular tachyarrhythmias (i.e. ventricular tachycardia and/or fibrillation), whereas the triggering events might be acute ischaemia, neurohormonal activation (e.g. a surge in sympathetic nervous system activity), electrolyte disturbances or other, less well-defined factors. Indeed, those are the patients who derive the greatest benefit from ICD implantation, irrespective of whether HF aetiology is ischaemic or non-ischaemic.7 However, as HF progresses to a more advanced stage, the proportion of SCD non-responsive to ICD therapy increases substantially. Sudden cardiac death in those patients is often caused by asystole, electromechanical dissociation, or non-shockable ventricular tachycardia, and presumably results from severe ventricular remodelling and extensive myocardial fibrosis. In those patients, SCD tends to occur without an identifiable precipitating cause and is frequently not amenable to resuscitative measures. Furthermore, Boriani et al. discuss an integrative approach to SCD prevention in HF, including the role of traditional and novel pharmacological agents, and implantable devices. It is emphasized that membrane-active antiarrhythmic medications have no role in the prevention of SCD in HF, and that in some instances, these medications may be even harmful. Although the amiodaron treatment had an overall neutral effect on all-cause mortality in the SCD-HeFT trial, its use was associated with an excess in the risk of death among patients with the more severe HFrEF.7 Among the drugs used for the treatment of HF, only three classes of medications have been decisively associated with risk reduction for SCD, including beta-blockers, mineralocorticoid receptor antagonists (MRAs) and, off recent, an angiotensin receptor neprilysin inhibitor, sacubitril/valsartan. As indicated by meta-analyses of clinical trials with beta-blockers and MRAs in HFrEF, both classes of medications reduce the risk of SCD, by 25–30%.8,9 It is likely that a common mechanism of risk reduction includes a favourable impact on reverse ventricular remodelling, but also reflects prevention of sympathetic overactivity with beta-blockers,10 and antifibrotic effects with MRAs. Interestingly, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, although associated with an improvement in ventricular remodelling and outcomes in HFrEF, have not been associated with risk reduction for SCD, apart from the 20% lower risk observed with ACE inhibitors in patients with left ventricular dysfunction following myocardial infarction.11 The incremental value of pharmacological treatment in risk reduction for SCD in HFrEF has been recently outlined by the PARADIGM-HF trial. This trial has shown an overall 20% lower risk of SCD with sacubitril/valsartan compared with enalapril, with a similar magnitude of treatment effect in patients with and those without an implantable cardioverter defibrillator (ICD).1 The effectiveness of sacubitril/valsartan in patients with an ICD suggests that the underlying mechanism probably relates to the more pronounced reverse ventricular remodelling with sacubitril/valsartan compared with enalapril and prevention of SCD non-responsive to ICD therapy. The advantageous effect of sacubitril/valsartan on arrhythmic events has been described in observational studies as well, reporting a decreased burden of ventricular arrhythmia and appropriate ICD shocks in HFrEF patients receiving this medication.12–14 Whether the emerging therapies for HFrEF, including sodium-glucose cotransporter type 2 inhibitors15 and vericiguat,16 confer a benefit in risk reduction of SCD remains to be defined. Discussing the role of devices in the prevention of SCD, Boriani et al. outline several important issues. Firstly, the assumption that prevention of SCD translates into a reduction in all-cause mortality is not always true as demonstrated for patients with a significant competing risk of non-arrhythmic and/or non-cardiovascular mortality. This includes high-risk individuals early after an acute myocardial infarction, as well as the elderly and multi-comorbid patients in whom a reduction in SCD may be offset by an increase in non-arrhythmic mortality. Indeed, a prespecified analysis of the DANISH trial in non-ischaemic HFrEF has shown an inverse association between ICD and mortality with advancing age, with a cut-off at the age ≤70 years for all-cause mortality benefit with an ICD.17 This has led to an expert consensus recommendation that ICD may be deterred in patients with non-ischaemic HFrEF, aged >70 years, with advanced symptoms, or impaired life expectancy due to severe comorbidity.18 Furthermore, in the setting of new-onset HF, device implantation should be considered after a usual 3-month period of optimal pharmacological management that would allow a window of opportunity for reverse ventricular remodelling. If substantial enough, improvement in ventricular function may obviate the indication for device therapy in some cases. Arguably, there may be a requirement to prolong this period to achieve a favourable impact on ventricular remodelling with pharmacological therapy.19 Although this approach may decrease the risk of SCD, pharmacological treatment of HFrEF does not terminate arrhythmia when it happens, and therefore some patients may be exposed to an unwarranted risk of fatal arrhythmias. This points to the currently unmet need for an improvement in risk assessment for SCD in HF, that would enable identification and a timely intervention in individuals with an excess early arrhythmic risk. A limitation of the present review is that it had not delved further into risk assessment for SCD in specific types and aetiologies of HF, including HFpEF and particular forms of cardiomyopathies.20,21 Also, prevention of SCD in the setting of reversible causes of HF (e.g. myocarditis, takotsubo syndrome, tachycardiomyopathy) deserves more attention. Nevertheless, the review provides an in-depth recapitulation of the aspects most relevant for understanding the pathophysiology, risk stratification, and the role of synergy between drugs and devices in preventing SCD in HF. Conflict of interest: Dr Seferović received honorarium for lectures for Medtronic, Abbott, Servier, Astra Zeneca, Respicardia; Boehringer Ingelheim consultancy agreement and honorarium for lecture, Novartis consultancy agreement and honorarium for lecture, Vifor Pharma consultancy agreement. Dr Polovina received honorarium for lectures for Boehringer Ingelheim and Novartis. The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Preventive Cardiology or of the European Society of Cardiology.