Randomized clinical trials (RCTs) of interventions sometimes use a post-procedure blanking period in which outcome events are not measured. This is common in trials of atrial fibrillation (AF) ablation. Within 90 days after an AF ablation procedure, a substantial proportion of patients develop atrial arrhythmias, which may be caused by inflammation from the procedure itself. The current expert consensus, therefore, recommends a 90-day blanking period, during which, recurrent atrial arrhythmias are not classified as treatment failure. This recommendation has been adopted in numerous trials comparing AF ablation to medical therapy.
In a sub-analysis of the CABANA trial [1]; AF burden, after the 90-day blanking period, was 6.3 % in the ablation group versus 14.4 % in the drug therapy group (rate or rhythm control) at one year, and 14.7 % in the ablation group versus 20.8 % in the drug therapy group at five years. A 90-day blanking period was also used in the EARLY-AF trial [2] which randomized patients with AF to catheter ablation or anti-arrhythmic drugs. Recurrence of atrial tachyarrhythmias, lasting 30 s or longer, at 12 months was 42.9 % in the ablation arm and 67.8 % in the anti-arrhythmic arm. Symptomatic events occurred in 11.0 % and 26.2 % in the ablation and anti-arrhythmic arms, respectively. The SHAM-PVI study randomized AF patients to catheter ablation or a sham procedure with phrenic nerve pacing. The primary outcome is AF burden at six months excluding the 90-days blanking period. Study results are expected in 2024.
In trials that primarily focus on hard outcomes, such as mortality, excluding non-lethal arrhythmic events does not significantly influence the overall results. However, when the specific interest of a trial is the burden of arrhythmias, excluding such events may influences study results. Patients have no blanking period as every arrhythmic event holds significance to them.
Atrial tachyarrhythmia events during the first 90-days following an AF ablation procedure are common. Liang et al. and Willems et al. showed that approximately half of patients undergoing AF ablation experience atrial tachyarrhythmias within this timeframe [3,4], and about half of them experience recurrent episodes [3]. Nearly half (44.6 %) of these patients develop symptoms [4]. Both studies defined recurrences as episodes lasting >30 s, similar to the definition used in the EARLY-AF trial. Furthermore, in a study by Baman et al., 18.2 % of patients required cardioversion for persistent atrial tachyarrhythmia, defined as lasting >24 h, within 90 days following AF ablation [5]. These findings highlight that atrial tachyarrhythmias during the 90-day blanking period are common, frequently symptomatic and often necessitates interventions. We propose not ignoring these episodes.
One reason that counting blanking period events is important is that it may alter the interpretation of AF ablation trials. In the sub-analysis of CABANA trial [1], the absolute difference in AF burden at five years was 6.1 % favoring the ablation arm. In the EARLY-AF trial [2], the absolute difference in recurrent symptomatic or asymptomatic atrial tachyarrhythmia was 24.9 %. Although these are large absolute differences, the effect size could be attenuated when adjusting for events in the 90-days blanking period considering the prevalence of atrial tachyarrhythmias in this period is about 50 % of patients when using the same definition of recurrence used in the EARLY-AF trial [3,4]. Whether the inclusion of the blanking period changes the interpretation of AF ablation trials results is unclear and should be explored in future studies.
Another reason to count blanking period events is that other trials of cardiovascular interventions have included procedural-related events. For example, the ISCHEMIA trial randomized patients with stable coronary artery disease to either an initial early invasive strategy (including angiography and revascularization) or a delayed strategy of intervention only if recurrent symptoms on medical therapy. In this trial, all causes of myocardial infarction (MI) were counted, regardless of whether they were directly related to the revascularization procedure or not. Had revascularization-related infarctions not been counted, the revascularization arm would have demonstrated a significant reduction in myocardial infarction (HR 0.67, 95 % CI 0.53–0.83). Since all MIs were included in the analysis, there was no significant difference between the two treatment arms. These findings highlight the substantial impact excluding procedural-related events has on the outcomes estimate of the study.
The inclusion of a blanking period in an RCT of AF ablation introduces complexities in interpreting the results and poses challenges for shared decision-making because patients are concerned about all symptomatic events. Since these periods exclude a large number of events from being counted, they bias trial results in favor of AF ablation. In trials of AF ablation, understanding the burden of arrhythmias requires acknowledgment of all arrhythmic events following randomization. We propose reporting the following in each group after randomization: the number of symptomatic events, events that require intervention or AF burden.
CRediT authorship contribution statement
Mohammed Ruzieh: Conceptualization, Writing – original draft. John M Mandrola: Conceptualization, Writing – review & editing. Andrew J Foy: Conceptualization, Writing – review & editing.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
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