Arrhythmia-associated risk: from cardiac arrest to stroke and dementia

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on arrhythmias opens with a Fast Track clinical research article entitled ‘Catheter ablation vs. thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: CASA-AF randomized controlled trial’ by Shouvik Haldar from the Royal Brompton & Harefield NHS Foundation Trust in London, UK, and colleagues. Recent prevalence estimates suggest that at least 33 million persons are affected by atrial fibrillation (AF).1 Catheter ablation is increasingly offered to relieve AF-related symptoms, based on evidence illustrating its efficacy compared with antiarrhythmic drug therapy. There is less evidence supporting AF ablation in persistent AF, although small studies suggest better maintenance of sinus rhythm.2 The authors of the current study note that thoracoscopic surgical ablation has shown promising efficacy in AF.3 This multicentre randomized controlled trial tested whether surgical ablation was superior to catheter ablation as the first interventional strategy in de novo long-standing persistent atrial fibrillation. The authors randomized 120 patients to surgical or catheter ablation. All patients underwent implantable loop recorder insertion. Primary outcome was freedom from AF/atrial tachycardia ≥30 s without antiarrhythmic drugs at 12 months. The rate of the primary outcome was similar (26% in patients treated by surgical ablation vs. 28% in those treated by catheter ablation). The rates of procedure-related serious adverse events within 30 days of intervention were also similar in the two groups (15% vs. 10%, respectively). Surgical ablation was more expensive and provided fewer quality-adjusted life years (QALYs) compared with catheter ablation (Figure 1).3 Left panel: schematic representation of lesions’ placement in catheter and surgical ablation. Most lesions were performed by radiofrequency ablation (thin red or blue lines) but the left atrial appendage (LAA) was occluded with a clip (thick red line) and the ligament of Marshall (LoM) was dissected (dashed green line). Middle panel: Kaplan–Meier survival plots illustrating freedom from AF/AT (left) and clinical success (right) of both treatments. Right panel: Graphical representation of symptom improvement (EHRA score reduction), QALYs gained, and the total costs associated with both treatments at 12 months. (from Haldar S, Khan HR, Boyalla V, Kralj-Hans I, Jones S, Lord J, Onyimadu O, Satishkumar A, Bahrami T, De Souza A, Clague JR, Francis DP, Hussain W, Jarman JW, Jones DH, Chen Z, Mediratta N, Hyde J, Lewis M, Mohiaddin R, Salukhe TV, Murphy C, Kelly J, Khattar RS, Toff WD, Markides V, McCready J, Gupta D, Wong T; on behalf of the CASA-AF Investigators. Catheter ablation vs. thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: CASA-AF randomized controlled trial. See pages 4471--4480.) Left panel: schematic representation of lesions’ placement in catheter and surgical ablation. Most lesions were performed by radiofrequency ablation (thin red or blue lines) but the left atrial appendage (LAA) was occluded with a clip (thick red line) and the ligament of Marshall (LoM) was dissected (dashed green line). Middle panel: Kaplan–Meier survival plots illustrating freedom from AF/AT (left) and clinical success (right) of both treatments. Right panel: Graphical representation of symptom improvement (EHRA score reduction), QALYs gained, and the total costs associated with both treatments at 12 months. (from Haldar S, Khan HR, Boyalla V, Kralj-Hans I, Jones S, Lord J, Onyimadu O, Satishkumar A, Bahrami T, De Souza A, Clague JR, Francis DP, Hussain W, Jarman JW, Jones DH, Chen Z, Mediratta N, Hyde J, Lewis M, Mohiaddin R, Salukhe TV, Murphy C, Kelly J, Khattar RS, Toff WD, Markides V, McCready J, Gupta D, Wong T; on behalf of the CASA-AF Investigators. Catheter ablation vs. thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: CASA-AF randomized controlled trial. See pages 4471--4480.) The authors conclude that thoracoscopic surgical ablation is not superior to catheter ablation in treating long-standing persistent AF. The manuscript is accompanied by an Editorial by Lucas Boersma from the St Antonius Hospital in Nieuwegein, the Netherlands.4 Boersma notes that from the current study it would appear that surgical ablation in its present form is not ready to become first-line therapy, given the fact that catheter ablation is easier and readily available, just as efficacious, safe, less invasive, and cheaper. Nevertheless, he believes that with novel tools, stronger energy sources, and enhanced imaging of individual AF pathophysiology, many different combinations will have to be tested in sufficiently large trials to come up with a strategy that always wins. Accumulating evidence shows that AF is associated with increased risk of dementia.5–7 Catheter ablation for AF prolongs the duration of sinus rhythm, thereby improving quality of life, and might theoretically reduce the risk of dementia. In a clinical research manuscript entitled ‘The risk of dementia after catheter ablation for atrial fibrillation: a nationwide cohort study’, Daehoon Kim from the Yonsei University College of Medicine in Seoul, Republic of Korea and colleagues investigated the association of catheter ablation for AF with the occurrence of dementia.8 Using the Korean National Health Insurance Service database, about 200000 adults with AF treated with ablation or medical therapy (antiarrhythmic or rate control drugs) between 1 January 2005 and 31 December 2015, the authors studied ∼9000 patients undergoing ablation and ∼18 000 patients managed with medical therapy. The time-at-risk was counted from the first medical therapy, and ablation was analysed as a time-varying exposure. Propensity score matching was used to correct for differences between the groups. During a median follow-up of 52 months, compared with patients with medical therapy, ablated patients showed significantly lower incidence and risk of overall dementia [8.1 and 5.6 per 1000 person-years, respectively; hazard ratio (HR) 0.73]. The associations between ablation and dementia risk were consistently observed after additionally censoring for incident stroke (HR 0.76) (Figure 2).8 Ablation was associated with lower risks of dementia subtypes including Alzheimer’s disease and vascular dementia. Association between catheter ablation and dementia in AF. (from Kim D, Yang P-S, Sung J-H, Jang E, Yu HT, Kim T-H, Uhm J-S, Kim J-Y, Pak H-N, Lee M-H, Lip GYH, Joung B. Less dementia after catheter ablation for atrial fibrillation: a nationwide cohort study. See pages 4483--4493.) Association between catheter ablation and dementia in AF. (from Kim D, Yang P-S, Sung J-H, Jang E, Yu HT, Kim T-H, Uhm J-S, Kim J-Y, Pak H-N, Lee M-H, Lip GYH, Joung B. Less dementia after catheter ablation for atrial fibrillation: a nationwide cohort study. See pages 4483--4493.) The authors conclude that in this nationwide cohort of AF patients treated with catheter ablation or medical therapy, ablation was associated with decreased dementia risk. This relationship was evident after censoring for stroke and adjusting for clinical confounders. The manuscript is accompanied by an Editorial by A. John Camm from the University of Oxford in the UK.9 The author notes that the study does provide more evidence leading us a step closer to discovering whether AF provokes dementia, and that it is not a chance association. However, it provides only limited circumstantial evidence that the rhythm itself is responsible for the cognitive impairment and that eliminating the arrhythmia by left atrial ablation will delay or reduce the likelihood of dementia. The author concludes that we may be closer to the answer, but we are not at the finishing post yet. Anticoagulation is an established approach to prevent intravascular clot formation. Unfortunately, whenever we inhibit platelets and/or the coagulation cascade, we not only reduce the risk of thrombosis formation, but also increase the risk of bleeding. Although compared with vitamin K antagonists (VKAs), novel oral anticoagulants or NOACs are an important step forward, this is still no free lunch, in particular in patients with AF undergoing coronary stent implantation.10,11 In a clinical research article entitled ‘Edoxaban in atrial fibrillation patients with percutaneous coronary intervention by acute or chronic coronary syndrome presentation: a pre-specified analysis of the ENTRUST-AF PCI trial’, Pascal Vranckx from Hasselt University in Belgium, and colleagues present a pre-specified subanalysis of the ENTRUST-AF PCI trial in which patients with AF were randomly assigned 1:1 to an edoxaban- or VKA-based strategy following percutaneous coronary intervention (PCI). Participants received edoxaban 60 mg once daily plus a P2Y12 inhibitor for 12 months, or a VKA combined with a P2Y12 inhibitor and aspirin 100 mg (for 1–12 months). In this study, randomization was stratified by acute coronary syndrome (ACS; n = 777) vs. chronic coronary syndrome (CCS; n = 729).12 The primary bleeding endpoint at 12 months occurred in 15% vs. 20% among ACS patients (HR 0.73, P = 0.063), and in 19.0% vs. 20% among CCS patients (HR 0.94, P = 0.708) with edoxaban- and VKA-based therapy, respectively (P for interaction = 0.27). The main secondary endpoint (composite of cardiovascular death, myocardial infarction, stroke, systemic embolic events, or definite stent thrombosis) among ACS patients was 8.5% vs. 7.2% (HR 1.16), compared with 4.4% vs. 4.9% (HR 0.91) among CCS patients with edoxaban- and VKA-based therapy, respectively (P for interaction = 0.5573). Vranckx et al. conclude that in patients with AF who underwent PCI, the edoxaban-based regimen, as compared with the VKA-based regimen, provides consistent safety and similar efficacy for ischaemic events in patients with AF regardless of their clinical presentation. This manuscript is accompanied by an Editorial by Renato Lopes from the Duke University School of Medicine in Durham, North Carolina, USA, and Alexander Fanaroff from the University of Pennsylvania in Philadelphia, USA.13 The authors note that for now, in the 12 months after PCI, the current evidence is clear that patients with AF should be treated with an NOAC plus a P2Y12 inhibitor, regardless of indication for PCI. Cardiac death is the most common cause of death in Europe. Approximately half of those deaths occur because of sudden out-of-hospital cardiac arrest (OOHCA). Recent articles have shown that outcomes of witnessed cardiac arrest have improved due to greater emphasis on resuscitation training, increased density of automatic external defibrillators, better organization of emergency medical systems, and improved post-resuscitation care. There has also been reassuring information about the quality of life and functional outcomes after successful resuscitation from OOHCA. However, it is still unusual to see >10% of the victims leaving the hospital alive.14,15 In a clinical research article entitled ‘A practical risk score for early prediction of neurological outcome after out-of-hospital cardiac arrest: MIRACLE2’, Nilesh Pareek from King’s College Hospital NHS Foundation Trust in London, UK, and colleagues sought to develop a practical risk score to predict poor neurological outcome after OOHCA.16 From May 2012 to December 2017, a total of 1055 patients had OOHCA in their region, of whom 373 patients were included in the King’s Out of Hospital Cardiac Arrest Registry (KOCAR). The authors performed prediction modelling with multivariable logistic regression to identify predictors of the primary outcome to derive a risk score. This was externally validated in two independent cohorts comprising 473 patients. The primary outcome was poor neurological function at 6-month follow-up (Cerebral Performance Category 3–5). Seven independent predictors of outcome were identified: Missed (unwitnessed) arrest, Initial non-shockable rhythm, non-Reactivity of pupils, Age (60–80 years, 1 point; >80 years, 3 points), Changing intra-arrest rhythms, Low pH <7.20, and Epinephrine administration (2 points).The MIRACLE2 score had an area under the receiver operating characteristic curve (AUC) of 0.90 in the development cohort and 0.84/0.91 in the validation cohort. The MIRACLE2 score had significantly superior discrimination to the OHCA and CAHP models and equivalent performance to the TTM score. The authors conclude that the MIRACLE2 is a practical risk score for early accurate prediction of poor neurological outcome after OOHCA, which has been developed for simplicity of use on hospital admission. The manuscript is accompanied by an Editorial by Christopher Granger from the Duke University Medical Center in Durham, North Carolina, USA and Carolina Malta Hansen from the University of Copenhagen, Denmark.17 The authors note that for now, the MIRACLE2 score is an effective tool for assessing longer term outcome for patients with cardiac arrest presenting to hospitals which provide primary PCI for acute myocardial infarction. However, they propose that it should not be used as the sole factor to decide who should have aggressive care withheld. It can be included as one of several parameters to identify the unusual patient who may have such a low chance of good recovery at presentation that limiting care may be appropriate. The greatest need now is to develop tools to predict futile care for those with persistent coma several days after arrest. The issue is accompanied by Discussion Forum contributions. In a contribution entitled ‘Biomarkers in inherited arrhythmias: opportunities for validation and collaboration’, Robert Hamilton from the Hospital for Sick Children in Toronto, Canada, and colleagues comment on the recent publication ‘A highly specific biomarker for Brugada syndrome. Also too good to be true?’ by Arthur Wilde and Elisabeth Lodder from the Academic University Medical Center in Amsterdam, the Netherlands.18,19 Wilde et al. respond in a separate comment.20 In another Discussion Forum contribution entitled ‘Is the clinical benefit of primary prevention implantable cardioverter-defibrillator overestimated? The role of sudden cardiac death to total mortality ratio’, Marcello Disertori from the Santa Chiara Hospital in Trento, Italy, and colleagues comment on the recent publication ‘Clinical effectiveness of primary prevention implantable cardioverter-defibrillators: results of the EU-CERT-ICD controlled multicentre cohort study’ by Markus Zabel from the German Center for Cardiovascular Research in Göttingen, Germany, and colleagues.21,22 Zabel and colleagues respond in a separate comment.23 The editors hope that this issue of the European Heart Journal will be of interest of its readers. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.