Optimal Ablation Strategy for Non-Paroxysmal Atrial Fibrillation During the Index Procedure

Because the pulmonary veins (PVs) and the antra are the major triggers and substrate of atrial fibrillation (AF), PV isolation (PVI) remains the cornerstone of AF ablation. However, it has been well recognized that catheter ablation is less effective in patients with non-paroxysmal AF as compared with paroxysmal AF due to the presence of a more complex substrate. The mechanisms of AF change over time with the transition of AF from paroxysmal to non-paroxysmal. Triggers from the PVs are the predominant mechanism in the early stage of AF, but the change in the underlying atrial substrate with remodeling becomes a more important mechanism in the later stage of AF. Though a variety of empirical adjunctive ablation strategies has been applied in patients with non-paroxysmal AF, few studies have proven consistent beneficial effect beyond PVI-alone, presumably because non-paroxysmal AF includes the wide spectrum of AF progression. Such results confirm the necessity to explore tailor-made adjunctive strategies rather than an empirical strategy following PVI for non-paroxysmal AF.

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The EARNEST-PVI trial was a prospective, multicenter (8 Japanese centers), randomized, open-label trial in which 512 non-paroxysmal AF (128 longstanding persistent AF) patients were randomly assigned in a 1 : 1 ratio to either PVI-alone or PVI-plus any adjunctive ablation (linear ablation or complex fractionated electrogram [CFAE] ablation).^1,2 At the beginning of the procedure, AF triggers were explored using isoproterenol infusion and/or electrical cardioversion. An AF trigger was defined as an arrhythmogenic focus causing the initiation of AF at least twice with the same intracardiac activation sequence. Additional ablation as recommended by the guidelines, such as targeting non-PV triggers, was accepted.¹ The results of the study did not establish the non-inferiority of PVI-alone to PVI-plus at the 12-month follow-up (freedom from atrial arrhythmias was 71.3% vs. 78.3% [P=0.306]) in the main study;² however, just recently, the reported extended 3-year follow-up data showed significantly lower arrhythmia freedom in the PVI-plus group than in the PVI-alone group (P=0.037).³ Interestingly, in the on-treatment analysis, arrhythmia freedom was significantly lower in the PVI+Line group than in the PVI-alone group, but was similar in the PVI+CFAE group and PVI-alone group.³

In this issue of the Journal, Matsunaga-Lee and colleagues⁴ demonstrate that intraprocedural assessment, which is the baseline rhythm at the beginning of the procedure, and exploration of AF triggers before PVI aided in choosing the optimal ablation strategy for non-paroxysmal AF, determined by post hoc analysis of the EARNEST-PVI trial. In their study, patients with PV-specific AF triggers were defined as those whose AF triggers consistently and exclusively originated from the PVs only, and patients with no PV-specific AF triggers were defined as those with no apparent AF triggers from the PVs or those with non-PV triggers as well as PV triggers.⁴ Among the 492 patients for whom data were available during 2.8 years of follow-up, the baseline rhythm was sinus rhythm in 116 patients (24%) and AF in 376 (76%). PV-specific AF triggers were confirmed in 233 patients (47%) and non-PV triggers in 24 (5%). Based on these results, the patients were divided into 4 groups; 22 patients (in sinus rhythm at baseline and PV-specific AF triggers), 211 (in AF at baseline and PV-specific AF triggers), 94 (in sinus rhythm at baseline and no PV-specific AF triggers), and 165 (in AF at baseline and no PV-specific AF triggers). The patients of each group were almost equally allocated to the PVI-alone and PVI-plus groups. The main findings of this post hoc analysis are: (1) arrhythmia freedom was similar between the PVI-alone and PVI-plus arms in patients who were in sinus rhythm at baseline or who had PV-specific AF triggers, and (2) adjunctive ablation improved the arrhythmia freedom in patients who were in AF at baseline and had no PV-specific AF triggers.

What are the clinical implications of these findings? The message is clear and reasonable. A PVI-alone strategy is recommended for patients who are in sinus rhythm at baseline or who have PV-specific AF triggers (≈70% of the population in this study) because of the lack of any benefit from adjunctive ablation after PVI. A PVI-plus strategy, presumably linear ablation rather than CFAE ablation, is recommended for patients who are in AF at baseline and who do not have any PV-specific AF triggers (≈30% of the population in this study) (Figure). Even though most physicians perform PVI empirically without any provocation test in the current era, the authors draw attention to the importance of evaluating AF triggers prior to ablation. The optimal adjunctive ablation strategy needs to be further discussed in future studies. The current study is not without limitations, notably (1) being a post hoc analysis with a limited number of patients in each group, (2) heterogeneous and operator-dependent choice of adjunctive ablation, and (3) baseline rhythm status can be modified by medication or cardioversion prior to admission. With that said, the authors should be congratulated for their proposal of a reasonable ablation strategy for non-paroxysmal AF.

Figure.

Proposed ablation strategy based on the study results. A PVI-alone strategy is recommended for patients who are in sinus rhythm at baseline or who have PV-specific AF triggers. The PVI-plus strategy is recommended for patients who are in AF at baseline and who do not have any PV-specific AF triggers. The red stars indicate the triggers of AF. AF, atrial fibrillation; CS, coronary sinus; ISP, isoproterenol; I(S)VC, inferior (superior) vena cava; LI(S)PV, left inferior (superior) PV; PV(I), pulmonary vein (isolation); RI(S)PV, right inferior (superior) PV; SR, sinus rhythm.

The effectiveness of AF ablation is well recognized, but safety is also important. When lesions extend outside the PVs, the incidence of complications generally increases. Extensive atrial tissue injury during ablation can potentially reduce atrial function, as well as potentially increasing the risk of clot formation at the ablation site, thus increasing the possibility of embolic stroke or cardiac tamponade. In other words, “the more you burn, the more complications there are” in radiofrequency ablation. A higher rate of complications has been generally observed in ablation requiring longer procedural times, regardless of the strategy used.^5,6 Indeed, strokes, cardiac tamponade, and death were observed only in the PVI-plus arm within 1 week after the procedure in the present study.⁴ An increasing risk of iatrogenic atrial tachycardia is also a concern of adjunctive linear ablation, as shown in the extended EARNEST-PVI trial.³ So far, we have no universally effective ablation strategy beyond PVI for that patient population to improve their clinical outcomes. Even in the PVI-plus group, the arrhythmia freedom was not a fully satisfactory outcome. Moreover, the mechanism of the perpetuation of AF is not completely understood. Hopefully, this study will catalyze more research and the development of an ablation strategy that will improve clinical outcomes.

Conflict of Interest

The author belongs or has belonged to endowed departments of Medtronic, Boston Scientific, Japan Lifeline, APEX, WIN INTERNATIONAL; received lecture fees from Boehringer Ingelheim, Medtronic, Boston Scientific, Bristol Myers Squibb, and Daiichi Sankyo; and received research funding from Johnson & Johnson and Boston Scientific for the past 3 years.

References

• 1.   Dohi T, Nakatani D, Inoue K, Hikoso S, Oka T, Hayashi K. Effect of extensive ablation on recurrence in patients with persistent atrial fibrillation treated with pulmonary vein isolation (EARNEST-PVI) trial: Design and rationale. J Cardiol 2019; 74: 164–168.
• 2.   Inoue K, Hikoso S, Masuda M, Furukawa Y, Hirata A, Egami Y, et al. Pulmonary vein isolation alone vs. more extensive ablation with defragmentation and linear ablation of persistent atrial fibrillation: The EARNEST-PVI trial. Europace 2021; 23: 565–574.
• 3.   Masuda M, Inoue K, Tanaka N, Watanabe T, Makino N, Egami Y, et al. Long-term impact of additional ablation after pulmonary vein isolation: Results from EARNEST-PVI trial. J Am Heart Assoc 2023; 12: e029651.
• 4.   Matsunaga-Lee Y, Inoue K, Tanaka N, Masuda M, Watanabe T, Makino N, et al. Appropriate selection of substrate ablation for persistent atrial fibrillation using intraprocedural assessment. Circ J 2024, doi:10.1253/circj.CJ-23-0936.
• 5.   Verma A, Jiang CY, Betts TR, Chen J, Deisenhofer I, Mantovan R, et al. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015; 372: 1812–1822.
• 6.   Marrouche NF, Wazni O, McGann C, Greene T, Dean JM, Dagher L, et al. Effect of MRI-guided fibrosis ablation vs conventional catheter ablation on atrial arrhythmia recurrence in patients with persistent atrial fibrillation: The DECAAF II randomized clinical trial. JAMA 2022; 327: 2296–2305.