Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF

• Medtronic PulseSelect Pulsed Field Ablation (PFA) System (Device): Adult subjects with a history of drug refractory recurrent symptomatic atrial fibrillation (AF) will undergo ablation of pulmonary veins and confirmation of entrance block and, where assessable, exit block with the PulseSelect PFA System.

Primary outcomes

• Safety: Number of Participants With at Least One Primary Safety Event [up to 6 months]: Primary safety events are: Within 6 months post-ablation: * Pulmonary vein stenosis (≥70% diameter reduction) * Phrenic nerve injury/diaphragmatic paralysis (ongoing at 6 months) * Atrioesophageal fistula Within 30 days of ablation procedure: * Cardiac tamponade/perforation * Cerebrovascular accident * Major bleeding requiring transfusion * Myocardial infarction * Pericarditis requiring intervention * Transient ischemic attack * Vagal nerve injury resulting in esophageal dysmotility or gastroparesis * Vascular access complications requiring intervention * Systemic/pulmonary embolism requiring intervention * Pulmonary edema * Death * Any PulseSelect PFA System-related or PFA procedure-related cardiovascular and/or pulmonary adverse event that prolongs or requires hospitalization for more than 48 hours (excluding recurrent AF/AFL/AT)
• Effectiveness: Number of Participants With Treatment Success. [up to 12 months]: Treatment success is defined as freedom from treatment failure. The study requires 24-hour Holter monitoring at 6 and 12 months in addition to weekly and symptomatic patient activated ambulatory monitoring transmissions through 12 months, and 12-lead ECGs at all follow up visits. Treatment failure is defined as any of the following components: * Acute procedural failure * Documented AF/AT/AFL on Holter/patient activated ambulatory monitoring/12-lead ECG after the 90-day post-ablation blanking period. * Any subsequent AF surgery or ablation in the left atrium, except for one repeat PVI ablation using PFA within the 90-day blanking period. * Direct current cardioversion for atrial tachyarrhythmia recurrences after the 90-day blanking period. * Class I or III antiarrhythmic drug (AAD) dose increase from the historic maximum ineffective dose (prior to the ablation procedure) or initiation of a new Class I or III AAD after the 90-day blanking period.

Secondary outcomes

• Quality of Life - Change in EQ-5D Score [Baseline to 12 months post-ablation]: Change in EQ-5D score (12-month score - baseline score). The Euroqol EQ-5D questionnaire (5L version) is a standardized instrument for measuring general health status. The Euroqol EQ-5D questionnaire (which consists of a 5-question survey and a visual analog scale) has a composite score based on the 5-question survey that ranges from 0 (least healthy) to 1 (most healthy).
• Quality of Life - Change in AFEQT Score [Baseline to 12 months post-ablation]: Change in AFEQT score (12-month score - baseline score). The AFEQT questionnaire is an atrial fibrillation (AF) specific health-related quality of life questionnaire to assess the impact of AF on a subject's life. The overall score ranges from 0 - 100, with 0 corresponding to complete disability and 100 corresponding to no disability

Other outcomes

• Pilot Phase Safety: Number of Participants With a PFA System-related and PFA Procedure-related Serious Adverse Event (SAE) Within 30 Days Post-ablation. [30 days]: Serious adverse events that count toward the endpoint are: Pulmonary vein stenosis (>70% diameter reduction) Atrioesophageal fistula Cardiac tamponade/perforation Cerebrovascular accident Major bleeding requiring transfusion Myocardial infarction Pericarditis requiring intervention Transient ischemic attack Vagal nerve injury resulting in esophageal dysmotility or gastroparesis Vascular access complications requiring intervention Systemic/pulmonary embolism requiring intervention Pulmonary edema Death
• Pilot Phase Effectiveness: Number of Participants With Acute Procedural Success of PVI Ablation With the PFA System. [Acute (day of procedure)]: Acute procedural failure is defined as the occurrence of any of the following: 1. Inability to isolate all accessible targeted pulmonary veins (assessed for entrance block and, where assessable, exit block) during the index ablation procedure. 2. Ablation using a non-study device in the left atrium. Acute procedural success is the opposite of acute procedural failure.

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

1. Failure of at least one AAD (class I or III) for AF as evidenced by recurrent symptomatic AF, or intolerable side effects due to AAD.
2. A diagnosis of recurrent symptomatic paroxysmal or persistent AF:

   1. Symptomatic paroxysmal AF, which is defined as AF that terminates spontaneously or with intervention within 7 days of onset, documented by the following:

      1. physician's note indicating at least 2 symptomatic paroxysmal AF episodes occurring within 6 months prior to enrollment; and
      2. at least 1 ECG documented AF episode from any form of rhythm monitoring within 12 months prior to enrollment OR
   2. Symptomatic persistent AF, which is defined as continuous AF sustained beyond 7 days and less than 1 year, documented by the following:

      1. physician's note indicating at least 1 symptomatic persistent AF episode occurring within 6 months prior to enrollment; and
      2. any 24-hour continuous ECG recording documenting continuous AF within 6 months prior to enrollment; OR 2 ECGs from any form of rhythm monitoring taken at least 7 days apart, both showing continuous AF within 6 months prior to enrollment
3. Age 18 through 80 years old (or older than 18 if required by local law)

Exclusion Criteria:

1. Long-standing persistent AF (continuous AF that is sustained >12 months)
2. Left atrial diameter > 5.0 cm (anteroposterior)
3. Prior left atrial ablation or surgical procedure (including left atrial appendage closures)
4. Planned LAA closure procedure or implant of a permanent pacemaker, biventricular pacemaker, loop recorder/insertable cardiac monitor (ICM), or any type of implantable cardiac defibrillator (with or without biventricular pacing function) for any time during the follow-up period
5. Patient who is not on oral anticoagulation therapy for at least 3 weeks prior to the ablation procedure
6. Presence of a permanent pacemaker, biventricular pacemaker, loop recorder/insertable cardiac monitor (ICM), or any type of implantable cardiac defibrillator (with or without biventricular pacing function)
7. Presence of any pulmonary vein stents
8. Presence of any pre-existing pulmonary vein stenosis
9. Pre-existing hemidiaphragmatic paralysis
10. Presence of any cardiac valve prosthesis
11. Moderate to severe mitral valve stenosis
12. More than moderate mitral regurgitation (i.e., 3+ or 4+ MR)
13. Any cardiac surgery, myocardial infarction, PCI / PTCA or coronary artery stenting which occurred during the 3-month interval preceding the consent date
14. Unstable angina
15. NYHA Class III or IV congestive heart failure or documented left ventricular ejection fraction (LVEF) less than or equal to 35% measure by acceptable cardiac testing (e.g. TTE)
16. Primary pulmonary hypertension
17. Rheumatic heart disease
18. Thrombocytosis, thrombocytopenia
19. Any condition contraindicating chronic anticoagulation
20. Active systemic infection
21. Hypertrophic cardiomyopathy
22. Known reversible causes of AF, including but not limited to uncontrolled hyperthyroidism, severe untreated obstructive sleep apnea, and acute alcohol toxicity
23. Any cerebral ischemic event (strokes or TIAs) which occurred during the 6-month interval preceding the consent date
24. History of thromboembolic event within the past 6 months or evidence of intracardiac thrombus at the time of the procedure
25. Any woman known to be pregnant or breastfeeding, or any woman of childbearing potential who is not on a reliable form of birth regulation method or abstinence
26. Patient with life expectancy that makes it unlikely 12 months of follow-up will be completed
27. Current or anticipated participation in any other clinical trial of a drug, device or biologic during the duration of the study not pre-approved by Medtronic
28. Known allergies or hypersensitivities to adhesives
29. Unwilling or unable to comply fully with study procedures and follow-up
30. Unable to provide own informed consent

Participant flow

Outcome results

• Safety: Number of Participants With at Least One Primary Safety Event (Primary), Count of participants, Participants: Pivotal - Paroxysmal AF 1; Pivotal - Persistent AF 1
• Effectiveness: Number of Participants With Treatment Success. (Primary), Count of participants, Participants: Pivotal - Paroxysmal AF 100; Pivotal - Persistent AF 83
• Quality of Life - Change in EQ-5D Score (Secondary), Mean, units on a scale: Pivotal - Paroxysmal AF 0.05 (0.02 to 0.08); Pivotal - Persistent AF 0.06 (0.04 to 0.09)
• Quality of Life - Change in AFEQT Score (Secondary), Mean, units on a scale: Pivotal - Paroxysmal AF 29.4 (25.8 to 33.1); Pivotal - Persistent AF 29.0 (25.5 to 32.5)
• Pilot Phase Safety: Number of Participants With a PFA System-related and PFA Procedure-related Serious Adverse Event (SAE) Within 30 Days Post-ablation. (Other pre specified), Count of participants, Participants: Pilot 0
• Pilot Phase Effectiveness: Number of Participants With Acute Procedural Success of PVI Ablation With the PFA System. (Other pre specified), Count of participants, Participants: Pilot 38

Adverse events

Time frame: Study enrollment to 12 months post-ablation

Serious adverse events by term

27 more terms not shown.

Other adverse events by term

• Results publication: Verma A, Haines DE, Boersma LV, Sood N, Natale A, Marchlinski FE, Calkins H, Sanders P, Packer DL, Kuck KH, Hindricks G, Onal B, Cerkvenik J, Tada H, DeLurgio DB; PULSED AF Investigators. Pulsed Field Ablation for the Treatment of Atrial Fibrillation: PULSED AF Pivotal Trial. Circulation. 2023 May 9;147(19):1422-1432. doi: 10.1161/CIRCULATIONAHA.123.063988. Epub 2023 Mar 6. PMID 36877118
• Results publication: Verma A, Boersma L, Haines DE, Natale A, Marchlinski FE, Sanders P, Calkins H, Packer DL, Hummel J, Onal B, Rosen S, Kuck KH, Hindricks G, Wilsmore B. First-in-Human Experience and Acute Procedural Outcomes Using a Novel Pulsed Field Ablation System: The PULSED AF Pilot Trial. Circ Arrhythm Electrophysiol. 2022 Jan;15(1):e010168. doi: 10.1161/CIRCEP.121.010168. Epub 2021 Dec 29. PMID 34964367
• Results publication: Yamane T, Sasano T, Tomita H, Aoyama D, Miyazaki S, Takigawa M, Kimura M, Itoh T, Yamashita S, Selma JM, Cerkvenik J, Verma A, Tada H; PULSED AF Investigators. Safety, efficacy, and quality of life outcomes of pulsed field ablation in Japanese patients with atrial fibrillation: results from the PULSED AF trial. J Interv Card Electrophysiol. 2025 Jan;68(1):149-157. doi: 10.1007/s10840-024-01912-w. Epub 2024 Sep 7. PMID 39243306
• Results publication: Verma A, Haines DE, Boersma LV, Sood N, Natale A, Marchlinski FE, Calkins H, Sanders P, Packer DL, Kuck KH, Hindricks G, Tada H, Hoyt RH, Irwin JM, Andrade J, Cerkvenik J, Selma J, DeLurgio DB; PULSED AF Investigators. Influence of monitoring and atrial arrhythmia burden on quality of life and health care utilization in patients undergoing pulsed field ablation: A secondary analysis of the PULSED AF trial. Heart Rhythm. 2023 Sep;20(9):1238-1245. doi: 10.1016/j.hrthm.2023.05.018. Epub 2023 May 19. PMID 37211146

• Study Protocol and Statistical Analysis Plan: version 7 (PDF, 2020-12-03)
• Study Protocol and Statistical Analysis Plan: version 6 (PDF, 2020-10-02)
• Study Protocol and Statistical Analysis Plan: version 3 (PDF, 2020-01-19)
• Study Protocol and Statistical Analysis Plan: version 2 (PDF, 2019-10-24)

• Atul Verma, MD, Principal investigator, McGill University Health Centre/Research Institute of the McGill University Health Centre