Arrhythmias, Cardiac, Atrial Fibrillation
Conditions
Keywords
Atrial fibrillation, Coronary sinus-left atrium connection, Ablation
Brief summary
Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting millions of people in the US and around the world. Over the last 20 years, catheter based AF ablation has been widely adopted offering improved symptom control for many patients worldwide. However, long-term success rates remain suboptimal. Prior work indicates that distal connections between coronary sinus musculature and the left atrium exist and provide a substrate for single or multiple reentry beats as a trigger for atrial fibrillation. In this trial, the investigators will examine the efficacy of elimination of distal connection(s) between coronary sinus and left atrial musculature for suppression of recurrent atrial arrhythmias.
Detailed description
Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting millions of people in the US and around the world. Over the last 20 years, catheter based AF ablation has been widely adopted. However, long-term success rates fhave been reported to be as low as 50% and 20% for paroxysmal and persistent AF, respectively. To achieve permanent arrhythmia suppression, repeated ablation procedures are often needed. Prior work indicates that distal connections between coronary sinus musculature and the left atrium provide a substrate for single or multiple reentry beats as a trigger for atrial fibrillation. In this prospective randomized trial the investigators will define the efficacy of elimination of distal connections between coronary sinus and left atrial musculature for suppression of recurrent atrial arrhythmias. Patients will be randomly assigned to standard of care ablation (pulmonary vein isolation and non pulmonary vein trigger ablations) alone, or standard of care ablation augmented by distal coronary sinus to left atrial connection elimination.
Interventions
The AF ablation procedures should follow the sequence below: Diagnostic catheter placement Electrophysiology study; Transseptal puncture; Left atrial electro-anatomical mapping is required prior to an ablation procedure. Post ablation pacing procedure(s) and/or infusion of cardiac medications to localize triggers/ assess and localize pulmonary vein reconnections (e.g., Adenosine, Isoproterenol 2-20 mcg/min). Study procedure requirements are outlined below: Isolation of all pulmonary veins and Non-pulmonary vein trigger ablation for all patients. Linear ablation lines are only required to treat documented macro-reentry atrial tachycardias and limited to the following targets only: LA roof line, mitral valve isthmus line, LA floor line, right atrial carvotricuspid isthmus linear ablation.
PROCEDURECoronary sinus to left atrium connection elimination
Distal coronary sinus pacing will be utilized to localize distal connections between the main coronary sinus body and the left atrium. Focal lesions will be applied to early left atrial activation sites, until no distal coronary sinus to left atrial connections are electrically manifest. If vein of marshall connections to the left atrium are present, differential pacing will be utilized to prove the lack of distal coronary sinus to left atrium connections.
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Once patients are enrolled in the study, they will be randomized to arm A: PVI + triggers ablation, or arm B: PVI + triggers ablation + coronary sinus-left atrium connection ablation. Patients will be blinded to the randomization scheme.
Intervention model description
The PRECAF study is designed as a randomized, single-blind, small scale pilot study. Enrolled subjects who satisfy all eligibility criteria will then undergo the ablation procedure. Study randomization will be performed in a 1:1 fashion using the Urn Randomization program (https://health.uconn.edu/community-medicine/programs/health-services-research-unit/project-match/urn-randomization/) while balancing sex and AF type (paroxysmal and non-paroxysmal). The master list of study assignments will be kept by the study coordinator in a password protected and encrypted computer. After the ablation procedure, participants will remain in the study for 6 months. A 30-day event monitor will be used for the first month after ablation. Then, regular clinic visits at 6 weeks and 6 months will be arranged after ablation with 12 lead electrocardiogram check-up. In the last month, a 30-day event monitor will again be utilized to detect atrial arrhythmia recurrence.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with paroxysmal or persistent atrial fibrillation; AND Undergoing first AF ablation; AND Age ≥ 18 years.
Exclusion criteria
* Previous left atrial ablation; Women currently pregnant; Mental or physical inability to take part in the study; Known terminally ill patients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence Rate of Atrial Arrhythmias | Time to atrial arrhythmia recurrence will be recorded as time to the first ECG or monitor that shows atrial arrhythmia recurrence between the end of the blanking period (90 days post ablation) and the end of the study (180±45 days post ablation). | The primary endpoint of the study is recurrence rate of atrial arrhythmia following ablation. The primary endpoint will be assessed using survival statistical models measuring time to failure among the two study arms. Failure is defined as a non-self-terminating bout of atrial fibrillation, atrial flutter, or atrial tachycardia \>30 seconds in duration following the 90-day post-ablation blanking period. If no AF occurs during the study period, censoring will occur at 180±45 days post-ablation. |
Countries
United States
Participant flow
Recruitment details
The study is a single-center, randomized, controlled trial, enrolling drug-refractory symptomatic patients who presented for first-time atrial fibrillatoin ablation at the Hospital of the University of Pennsylvania between August 2018 and August 2019 (PRECAF \[Prospective Elimination of Distal Coronary Sinus to Left Atrial Connection for Atrial Fibrillation Ablation\])
Participants by arm
| Arm | Count |
|---|---|
| PVI, Non-PV Triggers Interventions: Atrial fibrillation ablation, including conventional pulmonary vein isolation (PVI) and non-PV triggers ablation.
Standard Atrial fibrillation ablation: The AF ablation procedures should follow the sequence below: Diagnostic catheter placement Electrophysiology study; Transseptal puncture; Left atrial electro-anatomical mapping is required prior to an ablation procedure. Post ablation pacing procedure(s) and/or infusion of cardiac medications to localize triggers/ assess and localize pulmonary vein reconnections (e.g., Adenosine, Isoproterenol 2-20 mcg/min). Study procedure requirements are outlined below: Isolation of all pulmonary veins and Non-pulmonary vein trigger ablation for all patients. Linear ablation lines are only required to treat documented macro-reentry atrial tachycardias and limited to the following targets only: LA roof line, mitral valve isthmus line, LA floor line, right atrial carvotricuspid isthmus linear ablation. | 17 |
| PVI, Non-PV Triggers & CS-LA Connection Interventions: Atrial fibrillation ablation, including conventional pulmonary vein isolation (PVI) and non-PV triggers ablation in addition to coronary sinus-left atrium connection elimination.
Isolation of all pulmonary veins and non-pulmonary vein trigger ablation for all patients. Linear ablation lines are only required to treat documented macro-reentry atrial tachycardias and limited to the following targets only: LA roof line, mitral valve isthmus line, LA floor line, right atrial carvotricuspid isthmus linear ablation.
In persistent atrial fibrillation patients, cardioversion can be performed if rhythm cannot be restored to sinus rhythm after PVI with/without posterior wall box isolation. Then, distal coronary sinus pacing will be utilized to localize the earliest connection (aside from septal) from the coronary sinus to the left atrial musculature. Once localized, focal radiofrequency lesions will be applied at the discretion of the investigator until distal coronary sinus to left atrial connections are eliminated. If vein of marshall connections to the left atrium are present, differential pacing will be utilized to prove the lack of distal coronary sinus to left atrium connections. | 18 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Not yet achieved 6 months study follow-up at the time of analysis | 2 | 2 |
Baseline characteristics
| Characteristic | PVI, Non-PV Triggers & CS-LA Connection | Total | PVI, Non-PV Triggers |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 17 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 13 Participants | 5 Participants |
| Age, Continuous | 64.6 years STANDARD_DEVIATION 8.3 | 65.6 years STANDARD_DEVIATION 7.2 | 66.7 years STANDARD_DEVIATION 6.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 26 Participants | 13 Participants |
| Region of Enrollment United States | 15 Participants | 30 Participants | 15 Participants |
| Sex: Female, Male Female | 5 Participants | 14 Participants | 9 Participants |
| Sex: Female, Male Male | 10 Participants | 16 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 1 / 15 |
Outcome results
Primary
Recurrence Rate of Atrial Arrhythmias
The primary endpoint of the study is recurrence rate of atrial arrhythmia following ablation. The primary endpoint will be assessed using survival statistical models measuring time to failure among the two study arms. Failure is defined as a non-self-terminating bout of atrial fibrillation, atrial flutter, or atrial tachycardia \>30 seconds in duration following the 90-day post-ablation blanking period. If no AF occurs during the study period, censoring will occur at 180±45 days post-ablation.
Time frame: Time to atrial arrhythmia recurrence will be recorded as time to the first ECG or monitor that shows atrial arrhythmia recurrence between the end of the blanking period (90 days post ablation) and the end of the study (180±45 days post ablation).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PVI, Non-PV Triggers Ablation Isolation and Non-pulmonary Vein Trigger Ablation | Recurrence Rate of Atrial Arrhythmias | No Atrial Arrhythmia Recurrence | 8 participants |
| PVI, Non-PV Triggers Ablation Isolation and Non-pulmonary Vein Trigger Ablation | Recurrence Rate of Atrial Arrhythmias | Atrial Arrhythmia Recurrence | 7 participants |
| PVI, Non-PV Triggers Ablation+Elimination of Distal CS to LA Connections | Recurrence Rate of Atrial Arrhythmias | No Atrial Arrhythmia Recurrence | 14 participants |
| PVI, Non-PV Triggers Ablation+Elimination of Distal CS to LA Connections | Recurrence Rate of Atrial Arrhythmias | Atrial Arrhythmia Recurrence | 1 participants |
Comparison: Power calculation: assuming alpha 0.05, power 0.8, 1:1 randomization, and estimated relative risk of 14.4 for AF susceptibility with rate-dependent CS-LA conduction block, we anticipated a minimum sample size of 6 patients per group would be necessary to detect a difference using the log-rank test. Additional patients were recruited to account for potential losses to follow-up and a smaller detectable difference.p-value: 0.04795% CI: [0.02, 0.97]Log Rank