Artificial intelligence for individualized treatment of persistent atrial fibrillation: a randomized controlled trial

Abstract

Although pulmonary vein isolation (PVI) has become the cornerstone ablation procedure for atrial fibrillation (AF), the optimal ablation procedure for persistent and long-standing persistent AF remains elusive. Targeting spatio-temporal electrogram dispersion in a tailored procedure has been suggested as a potentially beneficial alternative to a conventional PVI-only procedure. In this multicenter, randomized, controlled, double-blind, superiority trial, patients with drug-refractory persistent AF were randomly assigned to a tailored ablation procedure targeting areas of spatio-temporal dispersion, as detected by an artificial intelligence (AI) algorithm, in addition to PVI (tailored arm, n = 187, 23% women) or to a conventional PVI-only procedure (anatomical arm, n = 183, 19% women). The primary efficacy endpoint was freedom from documented AF with or without antiarrhythmic drugs at 12 months after a single ablation procedure. Secondary endpoints included freedom from any atrial arrhythmic events, and the secondary composite safety endpoint consisted of death, cerebrovascular events, or treatment-related serious adverse events. One year post-procedure, the trial met its primary efficacy endpoint, which was achieved in 88% of patients in the tailored arm compared with 70% of patients in the anatomical arm (log-rank P < 0.0001 for superiority). However, no significant difference between arms was observed for the freedom from any atrial arrhythmia endpoint after one ablation. The safety endpoint did not differ between arms, with procedure and ablation times being twice as long in the tailored arm. These results show that AI-guided ablation of spatio-temporal dispersion areas in addition to PVI is superior to PVI alone in eliminating AF at 1-year follow-up in patients with persistent and long-standing persistent AF. Ablation of subsequent organized atrial tachycardias may be needed to maintain sinus rhythm long term. ClinicalTrials.gov identifier: NCT04702451 .

Fig. 1. Participant flow diagram.

Of the 374 patients randomized to either treatment, 188 were assigned to a tailored cardiac ablation procedure and 186 were assigned to a standard-of-care PVI procedure. Before the ablation procedure, one patient in the tailored arm and three patients in the anatomical arm withdrew their consent. In addition, seven patients in the tailored arm and six patients in the anatomical arm withdrew before the end of the blanking period. The primary analysis in the mITT population consisted of 180 patients and 177 patients in the tailored and anatomical arms, respectively. Of the 357 patients in the mITT population, 43 and 45 were excluded because of important protocol deviations in the tailored and anatomical arms, respectively. A total of 137 and 132 patients were included in the PP population in the tailored and anatomical arms, respectively. BMI, body mass index; LA, left atrium; LVEF, left ventricular ejection fraction; SAE, serious adverse event; incl., inclusion; excl., exclusion.

Fig. 2. Kaplan–Meier analysis of the primary endpoint.

a–d, Kaplan–Meier estimates of freedom from the primary endpoint, which is freedom from documented AF more than 30 s after a single procedure, with or without the use of antiarrhythmic medications after the 3-month blanking period. Comparisons of the tailored arm versus the anatomical arm were performed using the two-sided log-rank test. a, All patients in the mITT population (HR, 0.34; 95% CI, 0.21–0.57). b, All patients in the PP population (HR, 0.29; 95% CI, 0.16–0.51). c, Patients with persistent AF with a duration of AF of 6 months or more in the mITT population (HR, 0.29; 95% CI, 0.15–0.55). d, Patients with persistent AF with a duration of AF greater or equal to 6 months in the PP population (HR, 0.18; 95% CI, 0.08–0.40). In a–d, P < 0.0001 for all comparisons between the tailored and anatomical arms.

Fig. 3. Kaplan–Meier analysis of secondary effectiveness endpoints.

a–d, Kaplan–Meier estimates of freedom from the secondary endpoints, which are freedom from any documented atrial arrhythmia more than 30 s after a single procedure, or up to two procedures, with or without the use of antiarrhythmic medications after a 3-month blanking period. Comparisons of the tailored arm versus anatomical arm were performed using the two-sided log-rank test. a, Outcome after a single procedure for all patients in the PP population (HR, 0.81; 95% CI, 0.56–1.19). b, Outcome after one or two procedures for all patients in the PP population (HR, 0.62; 95% CI, 0.38–1.01). c, Outcome after a single procedure for patients with a duration of AF greater or equal to 6 months in the PP population (HR, 0.60; 95% CI, 0.37–0.97). d, Outcome after one or two procedures for patients with a duration of AF greater or equal to 6 months in the PP population (HR, 0.50; 95% CI, 0.28–0.90).

Extended Data Fig. 1. The Artificial Intelligence-Guided Ablation Strategy vs. the Standard-Of-Care Pulmonary Vein Isolation for Persistent Atrial Fibrillation.

Patients randomly assigned to the Artificial Intelligence-guided Tailored Cardiac Ablation procedure (Tailored arm) had both right and left atria mapped with the Volta system where spatio-temporal dispersion was identified with the artificial intelligence classifier analyzing intra-cardiac electrograms. During a tailored procedure, dispersion areas (white regions) were ablated until atrial fibrillation terminated to sinus rhythm or until all dispersed areas were completely eliminated and/or isolated (red tags). Pulmonary vein isolation was then completed (pink tags). Repeat procedures had to be carried out using that same workflow. For the anatomical arm, antral pulmonary vein isolation only (pink tags) was performed during index procedure until bidirectional block had been achieved. During a repeat procedure, patients were allowed to undergo re-isolation of the pulmonary veins plus up to two additional anatomical lines of ablation (orange tags).

Extended Data Fig. 2. Anatomical PVI arm and AI-guided tailored cardiac ablation arm procedure steps.

AF, atrial fibrillation; AT, atrial tachycardia; DCCV, direct current cardioversion; PVI, pulmonary vein isolation.

Extended Data Fig. 3. Effect of AF termination in the Tailored arm on the effectiveness endpoints.

Kaplan–Meier analysis of the effect of AF termination in the Tailored arm on primary and secondary endpoints. Comparison of patients in the Tailored arm with AF termination by ablation during the index procedure versus patients in the Tailored arm without AF termination was performed using the two-sided log-rank test. a, Freedom from AF after a single procedure, HR 1.37 (0.59 – 3.22). b, Freedom from any atrial arrhythmia after one procedure, HR 2.03 (1.28 – 3.23). c, Freedom from any atrial arrhythmia after one or two procedures, HR 2.75 (1.52 – 4.99).

Extended Data Fig. 4. Examples of electroanatomic maps showing the AI-guided dispersion and final ablation sets in the Tailored arm.

Different maps are presented in antero-posterior (AP) and postero-anterior (PA) views of right and left atria (left and right panels, respectively). Clusters of white and blue dots correspond to AI-detected dispersion regions. Red tags correspond to radiofrequency ablation tags. On the left atrial map presented in the top right panel, the posterior wall region was not completely ablated because of the proximity with the esophagus.