In the POWDER 1 study, paroxysmal atrial fibrillation (AF) patients undergoing conventional contact force (CF)-guided PVI were investigated. Patients were randomized between continuing previously ineffective antiarrhythmic drug therapy (ADT) or stopping ADT at the end of the blanking period. This trial, showed an added value of ADT after ablation (in support of 'hybrid rhythm control' as an alternative treatment strategy for AF in some patients).

In the POWDER 2 trial, an analogue study in persistent AF patients will be performed. All patients will undergo ablation index (AI)- and IL distance (ILD)-guided PVI (just like in VISTAX trial) and continue previously ineffective ADT during the blanking period. 'PVI only' was chosen as the ablation strategy according to the STAR AF trial findings.

Background: In real-life, ADT is often continued after catheter ablation for persistent AF. No study investigated whether ADT continued beyond the blanking period reduces recurrence after a first ablation for persistent AF.

Purpose: The aim of this trial is to investigate whether continued ADT (ADT ON) reduces recurrence of atrial tachyarrhythmia (ATA) in the first year after contact-force guided PVI for persistent AF.

Hypothesis: Continued use of ADT beyond the blanking period reduces recurrence of ATA in the first year after PVI .

Eligibility: Subjects that are planned for catheter ablation for persistent AF.

Inclusion: Symptomatic persistent AF resistant to ongoing or prior ADT (failed ADT). Persistent AF is defined as the presence of any prior AF episode ≥7 days.

Exclusion: Any prior AF episode ≥12 months, any recurrence of AF <3 days after cardioversion.

Echo criteria: advanced valvular heart disease, left atrium (LA) volume >37ml/m2, left ventricle (LV) ejection fraction <35% (except if suspected tachycardiomyopathy), septal diameter >15mm, Life expectancy <1 year, BMI >35.

Trial design: This is a prospective, multi-center, randomized (1:1), open label, blinded endpoint study (PROBE). Eligible subjects who sign the study informed consent form at the time of procedural planning will be randomized into one of two study arms: In the ADT off arm (ADT OFF), ADT will be stopped at 3 months after the first procedure. In the ADT ON arm, ADT will be continued at 3 months until 1 year follow up (FU).

First ablation and blanking: In both arms, catheter ablation will consist of 'CLOSE'-guided PVI only (abl index and interlesion distance). High-density voltage mapping will be performed during sinus rhythm. After ablation, ADT is continued/restarted during the 3-month blanking period (except for amiodarone). During the blanking period cardioversions are allowed. At the 3-month visit, all patients will be cardioverted if ATA is present.

Repeat ablation strategy: In case of recurrence of ATA's after 3 months, a repeat ablation is recommended. Depending on the reconnection status of the pulmonary veins (PV), repeat ablation will consist of either PVI only or a patient-tailored ablation approach (antral isolation, superior vena cava (SVC) isolation, isolation of low voltage, linear lesions). Patients stay on the ADT ON or ADT OFF arm.

Primary Endpoint: Any documented ATA (atrial fibrillation, AF, atrial tachycardia, AT, atrial flutter, AFL) lasting >30s from 3 months through 12 month follow-up after the first procedure.

Secondary Endpoints:

ATA recurrence in patients with early peristent AF (defined as AF ≤3 months) Incidence of repeat ablation Unscheduled visits and hospitalisation ADT or ablation related adverse events QOL and symptoms Outcome after repeat ablation

Sample size: In the ADT OFF group ATA recurrence after a first PVI is expected to be 50%. ADT are expected to reduce ATA recurrence to 30%. Given power of 80% and α of 0.05 up to 200 subjects need be enrolled in this study (20 per center)

Inclusion Criteria:

1. Patient with symptomatic persistent AF, resistant to ongoing or prior ADT (failed ADT) Patients is considered to have persistent AF if the patient has suffered any prior AF episode ≥7 days (ESC 2016 guidelines).
2. Before PVI, there was at least one episode of persistent AF in the last year.
3. Signed Patient Informed Consent Form.
4. Age 18 years or older.
5. Able and willing to comply with all follow-up testing and requirements.

Exclusion Criteria:

1. Patients not willing or not suited to take any class IC or III ADT.

2. Any prior AF episode ≥12 months, or any recurrence of AF <3 days after cardioversion.

3. Presence of structural heart disease on echo criteria:

   severe valvular heart disease; LA diameter >50mm; LV ejection fraction <35% (except if suspected tachycardiomyopathy); septal diameter >15mm

4. BMI >35

5. Recent (<3 months) coronary artery bypass grafting (CABG), myocardial infarction, cerebral vascular accident (CVA), uncontrolled heart failure or angina

6. Active illness or systemic infection or sepsis

7. AF secondary to electrolyte imbalance, thyroid disease, or reversible or non-cardiac cause

8. Awaiting cardiac transplantation or other cardiac surgery

9. Documented left atrial thrombus or atrial myxoma on imaging

10. History of blood clotting or bleeding abnormalities

11. Enrollment in any other study evaluating another device or drug

12. Women with childbearing potential

13. Life expectancy less than 12 months

14. Contraindication for catheter ablation (intramural thrombus, tumor or other abnormality that precludes catheter introduction, contraindication to anticoagulation therapy)