Sudden cardiac death: addressing unresolved issues

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Sudden death is a devastating event for patients and their families. Although the event is common among certain cardiac conditions and patient groups such as those with acute ischaemia, genetic cardiomyopathies,1 Tako Tsubo syndrome,2 channelopathies,3 and sarcoidosis,4 among others, prediction of such events remains challenging. The introduction of implantable cardioverter defibrillators (ICDs5) has provided an effective preventive measure, but their use is not free of complications such as inappropriate shocks and infection.6 In many patients, however, sudden cardiac death occurs out of the blue. Under such circumstances, bystander cardiopulmonary resuscitation (CPR) is essential,7 but out-of-hospital cardiac arrest without return of spontaneous circulation despite conventional resuscitation is common and has poor outcomes, particularly among women.8 Thus, adding extracorporeal membrane oxygenation (ECMO) to cardiopulmonary resuscitation (extracorporeal-CPR) has been suggested as a possible adjunctive measure in such patients, as has been successfully used in high-risk pulmonary embolism.9 Wulfran Bougouin from the European Georges Pompidou Hospital in Paris, France and colleagues from the Sudden Death Expertise Center Investigators report the results of such a measure in their article ‘Extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest: a registry study’.10 In their prospective registry of 13 191 out-of-hospital cardiac arrests in the Paris region, they compared survival at hospital discharge with and without extracorporeal-CPR. Survival was similarly low in both groups, with 8% with extracorporeal-CPR and 9% with conventional CPR. Even after adjusted multivariate analysis, extracorporeal-CPR was not associated with hospital survival. By conditional logistic regression with matching on a propensity score (including age, sex, occurrence at home, bystander CPR, initial rhythm, collapse to CPR time, duration of resuscitation, and return of spontaneous circulation), similar results were found. In the extracorporeal-CPR group, factors associated with hospital survival were initial shockable rhythm, with a hazard ratio (HR) of 3.9, unsustained return of spontaneous circulation before ECMO, with a HR of 2.3, and pre-hospital ECMO implantation, with a HR of 2.9. Thus, in the Paris population-based registry, 4% of out-of-hospital cardiac arrests were treated with extracorporeal-CPR, which overall did not improve survival, while early ECMO implantation may improve outcomes. The initial rhythm and return of spontaneous circulation may help select patients for extracorporeal-CPR. These important findings are further discussed in a thought-provoking Editorial by Anthony Gershlick from the Glenfield Hospital in Leicester, UK.11 While data from randomized trials testing neurohumoral blockers suggest a declining incidence of sudden cardiac death among heart failure patients,12 the extent to which such a trend is present among patients who have received cardiac resynchronization therapy (CRT) is uncertain. As very long-term survival with CRT has recently been reported,13 this issue is of interest and is addressed in the article entitled ‘Time trends in sudden cardiac death risk in heart failure patients with cardiac resynchronization therapy: a systematic review’, by Eloi Marijon and colleagues from the Hopital Europeen Georges Pompidou in Paris, France.14 They analysed 53 observational and randomized studies with 22 996 CRT patients. There was a gradual decrease in sudden cardiac death rates since the early 2000s in both randomized and observational studies, with rates falling more than four-fold. The rate of decline was steeper than that of all-cause mortality, and accordingly the proportion of deaths which were due to sudden cardiac death declined over the years. The magnitude of absolute decline in sudden cardiac death was more prominent among patients who had received a pacing-only CRT (CRT-P) compared with those receiving CRT-ICD, with the difference in sudden cardiac death rates between CRT-P and CRT-ICD decreasing considerably over time. There was a progressive increase in age, use of beta-blockers, and left ventricular ejection fraction, and, conversely, a decrease in QRS duration and antiarrhythmic drug use. Thus, sudden cardiac death progressively declined in the CRT heart failure population over time, with the difference between CRT-ICD and CRT-P recipients narrowing considerably. These findings are obviously relevant for the selection of CRT-P vs. CRT-ICD in the future. Whether the recently published SEMMELWEIS Score15 will be helpful in this regard as well as many other issues are outlined further in an insightful Editorial by Lars Kober from the University Hospital of Copenhagen in Denmark.16 The prediction of sudden cardiac death is obviously essential for the identification and proper management of patients at risk. Although an ejection fraction below 35% or 30% is commonly used as a major risk factor, its predictive value is far from satisfactory. Therefore, several risk scores for patients with atherosclerotic vascular disease17 or cardiomyopathies18 have been developed. Easily available information comes from the ECG. Thus, in their article ‘Simple electrocardiographic measures improve sudden arrhythmic death prediction in coronary disease’ Neal Chatterjee from the University of Washington in Seattle, Washington (USA) and colleagues report on behalf of the PREDETERMINE Investigators whether the combination of standard ECG markers reflecting domains of arrhythmic risk (Figure 1) improves sudden and/or arrhythmic death risk stratification in patients with coronary artery disease.19 In the derivation cohort, the 5-year cumulative incidence of sudden cardiac death was 1.5% and 6.2% in those with a low- and high-risk ECG score, respectively. A high-risk ECG score was more strongly associated with sudden cardiac death than non-arrhythmic mortality, with an adjusted HR of 2.87 vs. 1.38, respectively. The proportion of sudden arrhythmic deaths was greater in the high- vs. low-risk group, with 24.9% vs. 16.5%, and this was confirmed in the validation cohort. The addition of ECG markers to a clinical risk factor model including left ventricular ejection fraction (LVEF) proved indices of discrimination and reclassification in both the derivation and validation cohorts, including correct reclassification of 28% of patients in the validation cohort. Thus, for patients with coronary artery disease, the current externally validated ECG score improved risk stratification compared with standard clinical risk factors including LVEF. These results are put into context in an informative Editorial by Brian Olshansky from the University of Iowa in Iowa City, USA.20 Simple electrocardiographic markers predict actionable sudden death risk in patients with coronary heart disease. Our study demonstrates that simple electrocardiographic markers, reflecting distinct domains of risk, can specifically identify sudden arrhythmic death risk in patients with coronary heart disease. In combination, these electrocardiographic markers identify clinically actionable sudden death at 5 years in derivation and validation cohorts. The electrocardiographic risk score enriches for sudden death risk across the spectrum of risk defined by clinical risk factors. The highest risk subgroups in our study were estimated to derive significant survival benefit from implantable cardioverter-defibrillator (ICD) therapy. We show that randomized controlled trials (RCT) needed to identify this survival benefit are feasible (from Chatterjee NA, Tikkanen JT, Panicker GK, Narula D, Lee DC, Kentta T, Junttila JM, Cook NR, Kadish A, Goldberger JJ, Huikuri HV, Albert CM, for the PREDETERMINE Investigators. Simple electrocardiographic measures improve sudden arrhythmic death prediction in coronary disease. See pages 1988–1999). ICDs have markedly improved the outcome of patients at risk for sudden arrhythmic death. Indeed, multiple randomized clinical trials have established the role of ICDs as the mainstay in the treatment of ventricular tachyarrhythmias and sudden cardiac death prevention,21,22 and have become an important part of guideline recommendations.23 However, patients and device selection are still an issue, as outlined in the review ‘The role of implantable cardioverter-defibrillators and sudden cardiac death prevention: indications, device selection, and outcome’ by Jens Cosedis Nielsen and colleagues from the University of Rochester Medical Center in Rochester, USA.24 ICD trials have mainly focused on patients with heart failure and advanced left ventricular dysfunction and were mostly conducted two decades ago, whereas a more recent trial has provided conflicting results. Therefore, much remains to be determined on how best to balance identifying patients at high risk and those who would benefit most from an ICD. Indeed, ICDs have multiple features such as defibrillation-only devices to more advanced technologies of multichamber devices, with physiological bradycardic pacing, including CRT, atrial and ventricular therapeutic pacing algorithms, as well as subcutaneous ICDs suitable for specific patient populations. These options necessitate an individualized approach to device selection and programming, as discussed in detail in this comprehensive review (Figure 2). Suggested algorithm for patients and device selection among candidates for implantable cardioverter-defibrillator therapy. aAn implantable cardioverter-defibrillator with VDD pacing may be a cost-effective alternative in selected patients with intact sinus node function and AV block (acquired, congenital or postoperative) with near-normal structure of the heart. bThe level of recommendation is based on QRS duration, morphology, and on NYHA functional class (see Table 2 for a more detailed description). CAVB, complete AV block; CRT-D, cardiac resynchronization therapy with a defibrillator; GDMT, guideline recommended medical therapy; ICD, implantable cardioverter-defibrillator; S-ICD, subcutaneous implantable cardioverter-defibrillator; TV, transvenous (fromGoldenberg I, Huang DT, Nielsen JC. The role of implantable cardioverter-defibrillators and sudden cardiac death prevention: indications, device selection, and outcome. See pages 2003–2011). Although effective in preventing and treating brady- and tachyarrhythmias, pacemakers, ICDs, and CRT devices are not without risk. One such risk are infections associated with significant morbidity, increased hospitalizations, reduced survival, and increased healthcare costs,6 as comprehensively discussed in the Current Opinion ‘EHRA international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections’ by Carina Blomstrom-Lundqvist from the University Hospital in Uppsala, Sweden and colleagues from the ESC Scientific Document Group.25 They note that recommended preventive strategies such as administration of intravenous antibiotics before implantation are effective and well recognized. Uncertainties have remained about the role of various preventive, diagnostic, and treatment measures such as skin antiseptics, pocket antibiotic solutions, antibacterial envelopes, and prolonged antibiotics post-implantation, among others. The present document gives guidance on the use of novel device alternatives, novel oral anticoagulants, antibacterial envelopes, prolonged antibiotics post-implantation, as well as definitions on minimum quality requirements for centres, operators, and volumes. This document provides recommendations in optimally managing device infections. This issue is complemented by various Discussion Forum contributions. In their contribution entitled ‘The role of implantable cardioverter-defibrillators in New York Heart Class I heart failure patients: do not abandon the asymptomatic just yet’ Cornelis Allaart and colleagues from the Vrije Universiteit medical centre in the Netherlands comment on the recent publication ‘The role of implantable cardioverter-defibrillators and sudden cardiac death prevention: indications, device selection, and outcome’ by Ilan Goldenberg and colleagues from the University of Rochester Medical Center in Rochester, USA. 24,26 Goldenberg et al. respond in a separate comment.27 In the contribution entitled ‘Animals in cardiovascular research: important role of rabbit models in cardiac electrophysiology’, Katja Odening and colleagues from the Heart Center University of Freiburg in Germany comment on the recent CardioPulse contribution ‘Animals in cardiovascular research: clinical relevance and translational limitations of animal models in cardiovascular research’ by Maximilian Emmert and colleagues from the University of Zurich, Switzerland.28,29 Emmert et al. respond in a separate comment.30 The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet for help with compilation of this article.