Phase I/II Trial of Electrophysiology-Guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia

Abstract

Background: Case studies have suggested the efficacy of catheter-free, electrophysiology-guided noninvasive cardiac radioablation for ventricular tachycardia (VT) using stereotactic body radiation therapy, although prospective data are lacking.

Methods: We conducted a prospective phase I/II trial of noninvasive cardiac radioablation in adults with treatment-refractory episodes of VT or cardiomyopathy related to premature ventricular contractions (PVCs). Arrhythmogenic scar regions were targeted by combining noninvasive anatomic and electric cardiac imaging with a standard stereotactic body radiation therapy workflow followed by delivery of a single fraction of 25 Gy to the target. The primary safety end point was treatment-related serious adverse events in the first 90 days. The primary efficacy end point was any reduction in VT episodes (tracked by indwelling implantable cardioverter defibrillators) or any reduction in PVC burden (as measured by a 24-hour Holter monitor) comparing the 6 months before and after treatment (with a 6-week blanking window after treatment). Health-related quality of life was assessed using the Short Form-36 questionnaire.

Results: Nineteen patients were enrolled (17 for VT, 2 for PVC cardiomyopathy). Median noninvasive ablation time was 15.3 minutes (range, 5.4-32.3). In the first 90 days, 2/19 patients (10.5%) developed a treatment-related serious adverse event. The median number of VT episodes was reduced from 119 (range, 4-292) to 3 (range, 0-31; P<0.001). Reduction was observed for both implantable cardioverter defibrillator shocks and antitachycardia pacing. VT episodes or PVC burden were reduced in 17/18 evaluable patients (94%). The frequency of VT episodes or PVC burden was reduced by 75% in 89% of patients. Overall survival was 89% at 6 months and 72% at 12 months. Use of dual antiarrhythmic medications decreased from 59% to 12% ( P=0.008). Quality of life improved in 5 of 9 Short Form-36 domains at 6 months.

Conclusions: Noninvasive electrophysiology-guided cardiac radioablation is associated with markedly reduced ventricular arrhythmia burden with modest short-term risks, reduction in antiarrhythmic drug use, and improvement in quality of life.

Clinical trial registration: URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT02919618.

Keywords: noninvasive; stereotactic radiotherapy; ventricular tachycardia.

FIGURE 1.. Assessment of Treatment Efficacy.

There were 18 patients who survived to 6 months. Patients with incessant VT or sustained slow VT below the ICD detection rate are noted with a diamond (n=5); these episodes were not included in the total. Patients with PVC-mediated cardiomyopathy are noted with a plus (n=2) and displayed as the PVC burden (percentage) captured on a 24 hour Holter monitor. Each line represents an individual patient; blue lines indicate pre-ablation and red lines post-ablation. Upper boundaries are artificially truncated at 200 episodes. Patients are arranged by recurrences during follow-up, ranging from greatest (bottom) to least (top). Frequency of VT was significantly reduced from a median of 119 episodes in the 6 months pre-ablation to a median of 3 episodes in the post-blanking period through 6 months (p < 0.001). For 2 patients with PVC-related cardiomyopathy, 24-hour PVC burden reduced from 24% to 2% and 26% to 9%. The frequency of VT episodes or PVC burden was reduced by 75% in 89% of patients. VT = Ventricular tachycardia, ICD = Implantable Cardioverter Defibrillator, PVC = Premature ventricular contraction

FIGURE 2.. Summary of Select Secondary Endpoints.

Panel A shows a Kaplan-Meier curve of overall survival for all patients. Actuarial overall survival at 6 months was 89% and 12 months was 72%. Panel B shows a stacked bar graph of anti-arrhythmic medication usage in patients, at baseline and at 6 months after treatment. The y-axis represents the total number of anti-arrhythmic medications used, with the sizes of each color being directly proportional to the number of agents used in that particular class of anti-arrhythmic medication. Amiodarone usage is split into high dose (≥300 mg/day) and low dose (<300 mg/day). Class I agents consisted of mexiletine and flecainide. Class III agents consisted of sotalol. Panel C graphically represents mean scores reported by the 16 patients who were alive at 6 months at baseline, 6 weeks, and 6 months after treatment in 3 selected domains of the Short Form-36 questionnaire – Social Functioning in blue, Health Change in green, General Health in purple. Asterisks denote a significant change (p<0.05) in mean scores over time. VT = Ventricular tachycardia, SBRT = Stereotactic Body Radiotherapy. Figure 2A – Overall Survival for All Patients Underdoing Noninvasive Cardiac Radioablation. Figure 2B - Antiarrhythmic Medication Use. Figure 2C – Select Short Form-36 Quality of Life Measures

FIGURE 2.. Summary of Select Secondary Endpoints.

Panel A shows a Kaplan-Meier curve of overall survival for all patients. Actuarial overall survival at 6 months was 89% and 12 months was 72%. Panel B shows a stacked bar graph of anti-arrhythmic medication usage in patients, at baseline and at 6 months after treatment. The y-axis represents the total number of anti-arrhythmic medications used, with the sizes of each color being directly proportional to the number of agents used in that particular class of anti-arrhythmic medication. Amiodarone usage is split into high dose (≥300 mg/day) and low dose (<300 mg/day). Class I agents consisted of mexiletine and flecainide. Class III agents consisted of sotalol. Panel C graphically represents mean scores reported by the 16 patients who were alive at 6 months at baseline, 6 weeks, and 6 months after treatment in 3 selected domains of the Short Form-36 questionnaire – Social Functioning in blue, Health Change in green, General Health in purple. Asterisks denote a significant change (p<0.05) in mean scores over time. VT = Ventricular tachycardia, SBRT = Stereotactic Body Radiotherapy. Figure 2A – Overall Survival for All Patients Underdoing Noninvasive Cardiac Radioablation. Figure 2B - Antiarrhythmic Medication Use. Figure 2C – Select Short Form-36 Quality of Life Measures

FIGURE 2.. Summary of Select Secondary Endpoints.

Panel A shows a Kaplan-Meier curve of overall survival for all patients. Actuarial overall survival at 6 months was 89% and 12 months was 72%. Panel B shows a stacked bar graph of anti-arrhythmic medication usage in patients, at baseline and at 6 months after treatment. The y-axis represents the total number of anti-arrhythmic medications used, with the sizes of each color being directly proportional to the number of agents used in that particular class of anti-arrhythmic medication. Amiodarone usage is split into high dose (≥300 mg/day) and low dose (<300 mg/day). Class I agents consisted of mexiletine and flecainide. Class III agents consisted of sotalol. Panel C graphically represents mean scores reported by the 16 patients who were alive at 6 months at baseline, 6 weeks, and 6 months after treatment in 3 selected domains of the Short Form-36 questionnaire – Social Functioning in blue, Health Change in green, General Health in purple. Asterisks denote a significant change (p<0.05) in mean scores over time. VT = Ventricular tachycardia, SBRT = Stereotactic Body Radiotherapy. Figure 2A – Overall Survival for All Patients Underdoing Noninvasive Cardiac Radioablation. Figure 2B - Antiarrhythmic Medication Use. Figure 2C – Select Short Form-36 Quality of Life Measures