Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000676516p
Ethics application status
Submitted, not yet approved
Date submitted
1/05/2024
Date registered
28/05/2024
Date last updated
28/05/2024
Date data sharing statement initially provided
28/05/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparison of two different surgical techniques for the treatment of recurrent atrial fibrillation after initial catheter ablation.
Scientific title
Efficacy of Left Atrial Posterior Wall Isolation VS Left Atrial Posterior Wall isolation and Superior Vena Cava Isolation and Cavo-tricuspid isthmus Isolation and Mitral Isthmus Isolation for Recurrent Atrial Fibrillation Post Pulmonary Vein Isolation – A Randomised Control Trial
Secondary ID [1] 312069 0
None
Universal Trial Number (UTN)
Trial acronym
ENDURE-AF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Atrial Fibrillation
 333689 0
Condition category
Condition code
Cardiovascular 330368 330368 0 0
Other cardiovascular diseases
Surgery 330429 330429 0 0
Surgical techniques

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will be a prospective randomised control trial of patients with recurrent AF post durable pulmonary vein isolation (PVI) which investigates the utility of of empiric left atrial posterior wall, mitral isthmus, cavo-tricuspid isthmus (CTI), and superior vena cava (SVC) isolation as compared to standard of care which in this case is assumed to be left atrial posterior wall. Note that if study participants do not have durable PVI at index study procedure, the PV will be re-isolated and the participants excluded from the study. The two comparison groups will be:

1) Left Atrial Posterior Wall - Control Group.
2) Combined ablation targets: Left atrial posterior wall, mitral isthmus, CTI, and SVC - Comparison group. This procedure will take approximately 2 hours, and involve ablation lines which isolate each anatomical area described. This procedure will be performed once, except in cases where recurrent AF is documented and the patient may require another procedure. The procedure will be performed under General Anaesthesia. The procedure will be completed by at least one, and usually two qualified cardiologists. Detailed procedural notes will be made which will form part of the data collection strategies for the studt.
Intervention code [1] 328509 0
Treatment: Surgery
Comparator / control treatment
In the ENDURE-AF trial, the comparator or control treatment involves isolating just the back wall of the left atrium, also known as left atrial posterior wall isolation. This method focuses on a specific area between the left and right pulmonary veins, which is often involved in the recurrence of atrial fibrillation (AF) after the initial pulmonary vein isolation (PVI) surgery. This procedure is completed under general anaesthesia, and usually take about 90 minutes. This procedure will be completed once unless the patient has a recurrence of AF and requires a further procedure. Detailed operation notes will be taken to ensure compliance with the study protocols and the procedure will be performed by at least one and usually two cardiologists.
Control group
Active

Outcomes
Primary outcome [1] 338136 0
primary endpoints of this study will be time to AF recurrence defined as any atrial tachyarrhythmia lasting greater than 1 hour after a 4-week blanking period as a time to event analysis.
Timepoint [1] 338136 0
Baseline, 3, 6, 9, 12 months post procedure for both groups.
Primary outcome [2] 338137 0
Atrial Fibrillation burden at 12 months.
Timepoint [2] 338137 0
12 months in all participants
Secondary outcome [1] 434635 0
Major adverse Cardiovascular events
Timepoint [1] 434635 0
12 months for all participants
Secondary outcome [2] 434636 0
Major adverse cerebrovascular events
Timepoint [2] 434636 0
12 months in all participants
Secondary outcome [3] 434637 0
Procedural duration
Timepoint [3] 434637 0
Upon completion of procedure
Secondary outcome [4] 434638 0
Fluoroscopy time
Timepoint [4] 434638 0
Upon completion of procedure
Secondary outcome [5] 434639 0
Freedom from documented any atrial arrhythmia episodes > 1 hour at 12 months after one or two ablation procedures with / without anti arrhythmic medications. This will be assessed as a composite outcome.
Timepoint [5] 434639 0
12 months post procedure
Secondary outcome [6] 434640 0
Freedom from documented atrial flutter or atrial tachycardia episodes >1 hour at 12 months after one or two ablation procedures with / without anti arrhythmic medications. This is a composite outcome
Timepoint [6] 434640 0
12 months post procedure
Secondary outcome [7] 434641 0
Freedom from symptomatic AF episodes >1 hour at 12 months after one or two ablation procedures with / without anti arrhythmic medications.
Timepoint [7] 434641 0
12 months post procedure
Secondary outcome [8] 434642 0
Freedom from symptomatic atrial arrhythmia episodes >1 hour at 12 months after one or two ablation procedures with / without anti arrhythmic medications. This will be assessed as a composite outcome.
Timepoint [8] 434642 0
12 months post procedure
Secondary outcome [9] 434643 0
Incidence of peri-procedural complications, including femoral vascular access injury, stroke, PV stenosis, cardiac perforation, oesophageal injury, phrenic nerve injury, gastroparesis and death. This is a composite outcome
Timepoint [9] 434643 0
12 months post procedure
Secondary outcome [10] 434644 0
Number of repeat procedures
Timepoint [10] 434644 0
12 months post procedure
Secondary outcome [11] 434645 0
Percentage achievement of complete linear block in roof line
Timepoint [11] 434645 0
During procedure
Secondary outcome [12] 434646 0
Percentage achievement of complete posterior wall isolation at completion of roof and inferior line.
Timepoint [12] 434646 0
During procedure
Secondary outcome [13] 434647 0
Percentage achievement of complete posterior wall isolation
Timepoint [13] 434647 0
During procedure
Secondary outcome [14] 434649 0
Quality of life
Timepoint [14] 434649 0
Baseline before procedure, also at 3 months, 6 months, 9 months, and 12 months.
Secondary outcome [15] 434650 0
Evaluation of change in anxiety and depression using the HADS score during follow up. This is a composite outcome.
Timepoint [15] 434650 0
12 months post procedure
Secondary outcome [16] 434651 0
Difference in AF burden (>20% relative difference) between study groups, with or without anti-arrhythmic therapy, at 12 months after 1 ablation procedure. This will be assessed as a composite outcome.
Timepoint [16] 434651 0
12 months post procedure
Secondary outcome [17] 434652 0
Change in AF burden post ablation.
Timepoint [17] 434652 0
12 months post procedure
Secondary outcome [18] 434654 0
percentage of low voltage area (<0.5mV) / scar (<0.05mV) over the posterior wall
Timepoint [18] 434654 0
Baseline post procedure
Secondary outcome [19] 434655 0
Echocardiographic dimensions (LA dimensions and volume, left ventricular end-systolic and end-diastolic dimensions)
Timepoint [19] 434655 0
12 months post procedure
Secondary outcome [20] 434656 0
Healthcare utilisation
Timepoint [20] 434656 0
12 months post procedure
Secondary outcome [21] 434657 0
Quality of Life
Timepoint [21] 434657 0
Baseline, 3 months, 6 months, 9 months, and 12 months post procedure
Secondary outcome [22] 434825 0
Quality of life
Timepoint [22] 434825 0
Baseline, 3 months, 6 months, 9 months, and 12 months post procedure

Eligibility
Key inclusion criteria
1. Patients aged greater than 18 years old
2. Patients undergoing a second-time ablation procedure for AF
3. Durable PVI found on second procedure.
4. Persistent or paroxysmal AF - defined as a sustained episode lasting at least 7 days and less than three years (including or required chemical or electrical direct current cardioversion greater than 7 days post procedure)
5. At least one episode of recurrent AF must have been documented by electrocardiogram (ECG), holter, loop recorder, telemetry, trans telephonic monitoring (TTM), or implantable device within last 6 months of enrolment in this investigation
6. Patients must be able and willing to provide written informed consent to participate in this investigation; and
7. Patients must be willing and able to comply with all peri-ablation and follow- up requirements.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients with long-standing persistent AF - defined as a sustained episode lasting more than 3 years
2. Patients for whom cardioversion or sinus rhythm will never be attempted/pursued
3. Patients with AF felt to be secondary to an obvious reversible cause
4. Patients with contraindications to systemic anticoagulation with heparin or coumadin or a direct thrombin inhibitor
5. Pregnancy - will be assessed by patients informing the physicians
6. End stage renal or hepatic failure.
7. Severe valvular heart disease or cyanotic congenital heart disease.
8. Diagnosis of hypertrophic cardiomyopathy.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Concealed by central randomization by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
computerized sequence generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Overview. All data analysis will occur offline and be completed by a qualified statistician. Baseline patient characteristics will be presented in mean ± SD or median [IQR]. A significance level of 0.05 will be considered significant. Appropriate adjustments for multiple comparisons will be made. Differences in variables between groups will be analysed with the chi squared or fisher exact test for categorical data and the T test or Mann-Whitney U test for continuous data depending on distribution.

Sample Size. We wish to prove superiority of empirical SVC, mitral isthmus, CTI, and left atrial posterior wall isolation when compared to current standard of care post durable PVI. A number of studies have described the proportion of patients with sustained arrythmia free survival. Kistler et al (1) describe freedom from atrial arrythmia in patients with persistent AF undergoing first AF ablation with PVI + posterior left atrial wall isolation vs just PVI. The rate of arrythmia free survival in the PVI + left atrial posterior wall isolation was 52%, and in the PVI group was 54%. A further study (2) looked at freedom from arrythmia after > 1 ablation procedure, the freedom from arrythmia proportion was 52%. Importantly this observation study pooled the various ablation techniques together when reporting this outcome.

The PARTY-PVI (3) retrospective study remains most similar to our anticipated study design. It investigated the rates of AF recurrence after a second ablation procedure (the first necessarily being a durable PVI). Unfortunately, the study grouped a number of different ablation techniques into the one group but the numbers are still of interest. When looking at the group which included posterior left atrial wall isolation. Despite this, the recurrence rate of AF was approximately 43% of patients presented with recurrent AF and the specific ablation technique used was not a predictor. Furthermore, recurrence rates for linear based techniques were 34%, EGM based were 40%, and trigger based were 32%. Interestingly Kim et al (4) describe a recurrence rate of 16% in a group of AF patients that had index PVI and left atrial posterior wall isolation. Regarding empirical SVC isolation, a small study (5) demonstrated no significant difference in AF recurrence rates in patients with repeat AF ablation and empirical SVC isolation vs no SVC isolation (recurrence rate 27%). A further study (6) also found that empirical SVC isolation did not alter the recurrence rate of AF was also 27%. Importantly, in this study, the SVC was only isolated if < 2 of the pulmonary veins had reconnected.
Considering this data, assuming a baseline arrythmia free survival of 52% for the left atrial posterior wall group, and 35% for the intervention group (combination), a power of 80%, type 1 error rate of 0.05, enrolment ratio 1:1, 132 patients are required in each arm.

Randomisation process. Patients will be randomly assigned in a 1:1 ratio to group 1 or 2. Randomisation will be computer generated. The participants will be blinded to the randomisation group, but the procedural cardiologists cannot be.

Crossover. Crossover will be allowed if repeat atrial arrythmias are detected more than 3 months post ablation provided there was durable isolation of whatever structure was isolated at the original procedure.

Prespecified analysis. All arrythmia outcome analysis will be performed on patients who had undergone an ablation procedure and were followed up for longer that the initial 3 month blanking period. Analysis of safety outcomes will also be done at regular timepoints. The primary outcome, time to primary outcomes, secondary outcome, and time to secondary outcome will be assessed with Kaplan Meir curves. Treatment groups will be compared with the log rank test. Hazard ratios and confidence intervals for time to event outcomes will be calculated with univariable Cox proportional hazards models. Patients lost to follow-up after 3 months will be censored from date of last known contact.

Post hoc subgroup analysis will be pre-specified and include the following variables: Age > 65, Biological sex, subtype of AF, New York Heart Association symptom class, BMI, alcohol use, presence of obstructive sleep apnea. Subgroup analysis will be performed using cox regression modelling, with an interaction term (subgroup x randomisation) to assess significance of subgroup. All subgroup analysis will be corrected for multiple comparisons and address the type 1 error rate. We foresee that the Bonferroni correction will be implemented in this regard.

Missing Data. All attempts to minimise missing data will be made. Missing data will be addressed in consultation with a statistician. Both an intention to treat and per protocol analysis will be reported.

(1) Kistler PM, Chieng D, Kalman JM. Catheter Ablation Using Pulmonary Vein Isolation With vs Without Posterior Left Atrial Wall Isolation in Persistent AF-Reply. Jama. 2023;329(20):1794-5.
(2) Sugumar H, Nanayakkara S, Chieng D, Wong GR, Parameswaran R, Anderson RD, et al. Arrhythmia recurrence is more common in females undergoing multiple catheter ablation procedures for persistent atrial fibrillation: Time to close the gender gap. Heart Rhythm. 2020;17(5 Pt A):692-8.
(3) Benali K, Barré V, Hermida A, Galand V, Milhem A, Philibert S, et al. Recurrences of Atrial Fibrillation Despite Durable Pulmonary Vein Isolation: The PARTY-PVI Study. Circ Arrhythm Electrophysiol. 2023;16(3):e011354
(4) Kim JS, Shin SY, Na JO, Choi CU, Kim SH, Kim JW, et al. Does isolation of the left atrial posterior wall improve clinical outcomes after radiofrequency catheter ablation for persistent atrial fibrillation?: A prospective randomized clinical trial. Int J Cardiol. 2015;181:277-83.
(5) Simu G, Deneke T, Ene E, Nentwich K, Berkovitz A, Sonne K, et al. Empirical superior vena cava isolation in patients undergoing repeat catheter ablation procedure after recurrence of atrial fibrillation. J Interv Card Electrophysiol. 2022;65(2):551-8.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/08/2024
Actual
Date of last participant enrolment
Anticipated
1/05/2027
Actual
Date of last data collection
Anticipated
1/05/2028
Actual
Sample size
Target
264
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 26506 0
The Alfred - Melbourne
Recruitment hospital [2] 26507 0
Cabrini Hospital - Malvern - Malvern
Recruitment hospital [3] 26508 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [4] 26509 0
Melbourne Private Hospital - Parkville
Recruitment postcode(s) [1] 42545 0
3004 - Melbourne
Recruitment postcode(s) [2] 42546 0
3144 - Malvern
Recruitment postcode(s) [3] 42547 0
3050 - Parkville
Recruitment postcode(s) [4] 42548 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 316429 0
Government body
Name [1] 316429 0
NHMRC
Country [1] 316429 0
Australia
Primary sponsor type
Hospital
Name
Alfred Hospital
Address
Country
Australia
Secondary sponsor category [1] 318597 0
None
Name [1] 318597 0
Address [1] 318597 0
Country [1] 318597 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 315222 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 315222 0
Ethics committee country [1] 315222 0
Australia
Date submitted for ethics approval [1] 315222 0
15/04/2024
Approval date [1] 315222 0
Ethics approval number [1] 315222 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 134034 0
Prof Peter Kistler
Address 134034 0
The Alfred Hospital, 55 Commerical Road Melbourne, Victoria 3181
Country 134034 0
Australia
Phone 134034 0
+613 90763263
Fax 134034 0
Email 134034 0
[email protected]
Contact person for public queries
Name 134035 0
Nicholas D'Elia
Address 134035 0
The Alfred Hospital, 55 commercial Road Melbourne, Victoria 3181
Country 134035 0
Australia
Phone 134035 0
+61390762000
Fax 134035 0
Email 134035 0
[email protected]
Contact person for scientific queries
Name 134036 0
Nicholas D'Elia
Address 134036 0
The Alfred Hospital, 55 commercial road Melbourne, Victoria 3181
Country 134036 0
Australia
Phone 134036 0
+61390762000
Fax 134036 0
Email 134036 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.