Novel Low-Voltage MultiPulse Therapy to Terminate Atrial Fibrillation

Abstract

Objectives: This first-in-human feasibility study was undertaken to translate the novel low-voltage MultiPulse Therapy (MPT) (Cardialen, Inc., Minneapolis, Minnesota), which was previously been shown to be effective in preclinical studies in terminating atrial fibrillation (AF), into clinical use.

Background: Current treatment options for AF, the most common arrhythmia in clinical practice, have limited success. Previous attempts at treating AF by using implantable devices have been limited by the painful nature of high-voltage shocks.

Methods: Forty-two patients undergoing AF ablation were recruited at 6 investigational centers worldwide. Before ablation, electrode catheters were placed in the coronary sinus, right and/or left atrium, for recording and stimulation. After the induction of AF, MPT, which consists of up to a 3-stage sequence of far- and near-field stimulation pulses of varied amplitude, duration, and interpulse timing, was delivered via temporary intracardiac leads. MPT parameters and delivery methods were iteratively optimized.

Results: In the 14 patients from the efficacy phase, MPT terminated 37 of 52 (71%) of AF episodes, with the lowest median energy of 0.36 J (interquartile range [IQR]: 0.14 to 1.21 J) and voltage of 42.5 V (IQR: 25 to 75 V). Overall, 38% of AF terminations occurred within 2 seconds of MPT delivery (p < 0.0001). Shorter time between AF induction and MPT predicted success of MPT in terminating AF (p < 0.001).

Conclusions: MPT effectively terminated AF at voltages and energies known to be well tolerated or painless in some patients. Our results support further studies of the concept of implanted devices for early AF conversion to reduce AF burden, symptoms, and progression.

Keywords: MultiPulse Therapy; atrial fibrillation; cardioversion; defibrillation.

Figure 1:

MultiPulse Therapy: (A) Study protocol at the start of the atrial fibrillation ablation procedure; (B and C, RA and LA, respectively) Lead positioning for MPT studies. Defibrillation leads were placed in the right atrium and in the coronary sinus and catheters were also placed in the left atria, to allow different vectors for MPT delivery. (D) Schematic of the 3 MultiPulse Therapy stages.

Figure 2:

Patient Disposition Flow Chart: A total of 42 patients were enrolled in the study. and retrospectively divided into two groups. In the first group (n=26), Translational Phase, MPT therapy was not delivered until at least 120 seconds post AF induction. Of the 26 patients 13 patients were excluded due to incomplete waveform data and 1 because AF was not able to be induced and MPT was not delivered resulting in 12 patients in this group. In the second group (n=16), Efficacy Phase, MPT therapy was not delivered until at least 15 seconds post AF induction. Of the 16 consecutive patients in the Efficacy Phase, 2 were excluded from the analysis due to AF refractory to transthoracic cardioversion and because of the lack waveform data.

Figure 3:

Lowest energy and voltage for AF termination: (A) Representative intracardiac electrograms showing termination of AF with MPT (delivered at t=0s). (B & C) The lowest energy and voltage required for AF termination per patient. (D) The median energy and voltage required for successful AF termination. Error bars represent Q1-Q3 (IQR). Data for B, C & D are based on the definition of success as AF termination within 20 seconds of MPT. (E) The % success and median energy and voltage required for cardioversion based on different definitions of success, i.e. termination within 20, 15, 10 and 5 seconds of MPT. Error bars represent Q1-Q3 (IQR).

Figure 4:

Causality analysis for AF terminations after MPT: (A) AF duration plot for all 52 episodes of MPT deliveries (aligned at time of MPT delivery, t=0 seconds), showing the temporal relationship between MPT and AF termination. (B) Distribution of time to AF termination after MPT (time=0 seconds) for all 37 successful terminations. The distribution was skewed towards therapy time (p<0.0001) (Kolmogorov-Smirnov test), with many AF terminations occurring within 2 seconds of MPT, consistent with a causal relationship between MPT and AF termination. (C & D) Kaplan Meier curves comparing AF terminations when assigned to MPT (n=12 patients with 44 episodes) versus a retrospective control untreated arm (n=7 patients with 18 episodes) to an MPT therapy arm. The effect of both a single MPT or multiple MPTs on AF termination are shown.

Figure 5:

Determinants of MPT success: (A & B) The energy and voltage of MPT were not related to time to termination of AF. (C & D) The effects of Time in AF and Cycle Length on probability of AF Termination via multivariate analysis are shown (E) Univariate and multivariate analysis of the predictors of MPT success. For the multivariate analysis, the duration of AF before MPT delivery predicted MPT success. There was a trend towards significance for AF cycle length predicting MPT success.

Central Illustration:

MultiPulse Therapy (MPT) is a sequence of far- and near-field stimulation that terminated AF with average voltage and energy of 50V (25–75) and 0.58J (0.15–1.15) respectively.