Accumulating evidence for epicardial ablation in malignant forms of Brugada syndrome: summary of two randomized clinical trials

Editorial comment to: Epicardial ablation in high-risk Brugada syndrome to prevent ventricular fibrillation: results from a randomized clinical trial. Europace. 2025 May 7;27(5):euaf097. https://doi.org/10.1093/europace/euaf097. Brugada syndrome (BrS) has been recognized as a distinct disease entity since its first description in the 1990s based upon its ECG presentation.1–3 Importantly, early reports indicated that it was a highly malignant disease due to (recurrent) episodes of ventricular fibrillation (VF). It later became apparent that most patients with the typical BrS-ECG pattern (i.e. the type-1 BrS-ECG, either spontaneously present or provoked with sodium channel blocking drugs) were actually asymptomatic and would never experience malignant arrhythmia.4,5 So in most patients, lifestyle measures, including the avoidance of sodium channel blocking drugs, and long-term follow-up for reassessment, is adequate.6–9 Still, highly symptomatic patients may present to our clinics, either after aborted cardiac arrest or with shocks from their implanted cardioverter defibrillator (ICD). In these patients, isoproterenol in case of VF-storm, or quinidine for long-term treatment, can be extremely useful.8–11 However, quinidine is not widely available and can be hampered by gastrointestinal side effects.12 In 2010, the first series of patients with such malignant forms of BrS, who underwent epicardial ablation at the sites of abnormal and delayed electrograms, was presented by Nademanee et al.13 from Thailand, and published the year thereafter.13 Unsurprisingly, these abnormal electrograms (i.e. late, fractionated and of long duration), were located at the right ventricular outflow tract (RVOT) and the antero-superior part of the right ventricle (RV), which perfectly corresponds to the abnormalities on the body surface ECG. Importantly, ablation of these abnormal electrograms at the RV epicardium (typically after additional provocation with ajmaline) appeared a very successful endeavour. Histopathological study of biopsies from these patients and deceased individuals with BrS and sudden death identified an underlying substrate of subtle fibrosis in the subepicardial RVOT, leading to a proposal of a subepicardial cardiomyopathy as the aetiology.14,15 In the following years, more examples of its value were published.16–18 And now, 15 years later, we even have the results of two contemporaneous, randomized controlled trials, one of which is published in Europace.19,20 In the recent May issue of Europace, Pappone et al.20 from Milan, Italy, present their randomized trial. In their prospective, single-centre, open-label study, they randomized patients with previous cardiac arrest or appropriate ICD therapy to either epicardial ablation or to no epicardial ablation in a 2:1 fashion. The primary outcome measure was freedom of VF-recurrence. Secondary outcome measures included procedure and ICD-related complications and quality-of-life assessment by SF-36 and EQ-5D questionnaires. Before premature termination of the trial by the study team for superiority, they randomized 40 patients (83% males, 44 years old), 26 in the ablation group and 14 in the no-ablation group. After a median follow-up of 4 ± 1.7 years freedom from VF was 96% in the ablation group and 50% in the control group. The one patient with VF recurrence in the ablation group had a subsequent VF-triggering extrasystole ablation from the endocardial RV outflow tract. No unexplained or arrhythmic deaths occurred during the trial, two patients had pericarditis with pericardial effusion after ablation, of which one underwent pericardiocentesis. Although ICD-related complications were not putatively considered to be affected by the study (and the reason for including this as a secondary outcome measure questionable), ICD-related complications including inappropriate shocks and lead extractions were unexpectedly high (33%) in both groups. In addition, quality of life measures were superior in the ablation group compared with the no-ablation group. Surprisingly, the study did not have a formal or independent Data Safety Monitoring Board as ‘safety and protocol adherence were overseen by the Ethics Committee, which included a bioinformatics expert in clinical trials, and the study principal investigator’ as the trial was considered to be ‘exploratory’. Trial governance was therefore not traditional.21 In addition, the open label design unavoidably may influence outcome parameters, like, e.g. quality of life. During the trial, a panel was convened for advice regarding premature termination and indeed led the study team ‘to terminate the trial prematurely to minimize the risks to participants associated with randomisation’. The trial by Pappone et al.20 shows similar results to the recently presented trial by Nademanee et al.19 In the latter multi-centre, open-label trial [please note that two authors (P.G.P. and A.A.M.W.) were part of their ECG core lab], 50 patients with previous cardiac arrest or appropriate ICD therapy were randomized 1:1: 25 to ablation, 25 to no-ablation. Freedom of VF after 1 ablation was 80% vs. 48% in the no-ablation group after 3 years of follow-up. Several patients declined randomisation and opted for ablation or no-ablation, while there were crossovers to ablation and redo-ablations were performed. In 65 patients overall, the freedom from VF was 83% after a single ablation and 90% after a repeat ablation. This slightly lower success rate was potentially due to the inclusion of patients with greater complexity of substrate as indicated by the often present concomitant early repolarisation (ER) pattern on the ECG. Also in this trial, one pericardiocentesis was performed. A summary of the two trials can be found in Table 1. Summary of randomized trials on epicardial ablation in symptomatic BrS Summary of randomized trials on epicardial ablation in symptomatic BrS It can thus be appreciated that these two randomized trials show the same trend: after randomising 90 patients, 51 to ablation and 39 to no-ablation, there was a clear indication that ablation of abnormal electrograms at the epicardial RVOT and RV diminishes the risk of VF recurrence. Moreover, in most patients with recurrences despite ablation, a second ablation could abolish the VF substrate. In addition, in these experienced centres, the complication rate of the ablation strategy was low. So how to continue from here? First, it needs to be repeated,22,23 that epicardial ablation in BrS should be recommended for severely symptomatic patients, noting that the untreated VF-recurrence rate in the trial populations was very high: 50% recurrence over several years. In previous series including resuscitated BrS-patients the recurrence rates were often lower,4,24 indicating that the patients included in these trials were indeed severely affected, as also indicated by the considerable number of VF-episodes before randomisation (Nademanee: 44% with ≥5 previous VF-episodes, Pappone: median 3 previous VF-episodes). In our own tertiary referral centres with many hundreds of BrS-patients, the number of severely symptomatic BrS-patients is very low (<<1%). While ablation thus seems a good option in selected patients, there is still little justification in ablating patients with much lower risk of VF, especially when quinidine therapy is available. This notwithstanding, it is also reassuring that none of the patients in both trials had fatal events with back-up ICD-therapy. Furthermore, concomitant ER syndrome patterns can be an indicator of higher risk, probably due to more extensive substrates, as Nademanee and co-workers have demonstrated.19 Whether there is a different outcome of ablation in BrS-patients with pathogenic SCN5A-variants is uncertain from these data, but it should be noted that such patients may have mixed phenotypes, of which the majority will not be as amenable to ablation therapy. Also, ablation should in our view not be used as an alternative to ICD-implantation or in patients who do not have sufficient risk to justify an ICD according to current guidelines.8 Whether ablation could be regarded as an alternative to ICD-implantation in other high-risk (but not as high as in these trials) BrS-patients is uncertain but also seems worth investigating. We would therefore recommend clinical trials in these patient groups, that adhere to traditional trial design.21 Hartstichting grant 03-003-2021-T061 to P.G.P.