Elimination of VPB With Ablation Versus Anti-arrhythmic Drug Treatment

Study Overview
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Brief Summary
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The ECTOPIA trial is a randomized, multicenter, clinical trial to assess elimination of ventricular premature beats (VPB) with catheter ablation versus optimal anti-arrhythmic drugs (AAD) treatment with flecainide/verapamil or sotalol.

Detailed Description
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The ECTOPIA trial is a randomized, multicenter, clinical trial to assess elimination of VPB with catheter ablation versus optimal AAD treatment with flecainide/verapamil or sotalol. Due to the use of different AAD (with and without beta-blocking abilities) the investigators will be able to explore the secondary objectives. Finally, this study will assess safety of ablation of non-RVOT VPBs and long-term treatment with two different AAD.

Official Title
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Elimination of Ventricular Premature Beats With CaTheter Ablation Versus OPtImal Anti-arrhythmic Drug Treatment

Conditions
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Ventricular Premature Beats

Intervention / Treatment
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* Drug: Sotalol
* Drug: Flecainide and verapamil
* Procedure: Catheter ablation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients willing and capable to provide written informed consent Patients with frequent symptomatic VPB and/or nonsustained VTs with burden ≥ 5% on 24 hour Holter monitor AND Absence of structural heart disease (excluded by echocardiogram) AND Absence of underlying cardiac ischemia (ruled out by treadmill test, CT coronary arteries, nuclear scintigraphy or coronary angiography) AND Patient is considered an acceptable candidate for catheter ablation treatment with a dominant morphology of VPB/VT origin judged by the treating physician. For those already undergoing treatment, all antiarrhythmic drugs including digitalis must be discontinued during a 2-week washout period before entry to the study Exclusion Criteria: Age >75 years Previous catheter ablation therapy for VPB/VT Patients with sustained ventricular tachycardia or cardiac channelopathies (e.g. Catecholaminergic polymorphic ventricular tachycardia (CPVT), long- or short QT syndrome, Brugada syndrome) Wolff-parkinson-white (WPW) syndrome Use of medication with risk of QTc prolongation (e.g. antidepressant, antiemetic), except for study medication sotalol. Left ventricular dysfunction (LV ejection fraction <55%) Estimated glomerular filtration rate < 50 ml/min/1.73 m2 Hepatic impairment defined by a total bilirubin ≥ 2 times the upper limit (ULN) of normal, or alanine aminotransferase (ALAT) or aspartate aminotransferase (ASAT) ≥ 3 times ULN at screening Untreated hypo- or hyperthyroidism or electrolyte imbalance Untreated obstructive sleep apnea Patients with history of myocardial infarction or bypass surgery More than grade 1/3 valvular regurgitation and/or significant valve stenosis (moderate or severe) Contraindication for any of the antiarrhythmic drugs used in this study Enrolment in another clinical study Woman currently pregnant or breastfeeding or not using reliable contraceptive measures during fertile age Mental or physical inability to participate in the study Life expectancy ≤ 12 months

Ages Eligible for Study
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Minimum Age: 76 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized trial comparing catheter ablation with two different potent AADs with different engagement mechanisms in a 1:1:1 ratio with a crossover design in the AAD arm.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sotalol<br> | Drug: Sotalol<br>* Patients will be titrated to the maximal tolerated dose of sotalol with a targeted dose of 80 thrice daily (TID)<br>|
| Active Comparator: Flecainide and verapamil<br> | Drug: Flecainide and verapamil<br>* Patients will receive maximal tolerated dose of flecainide and verapamil with titration to a maximal dose of 200 mg of flecainide and 240 mg of verapamil per day<br>|
| Active Comparator: Catheter ablation<br> | Procedure: Catheter ablation<br>* Patients will undergo VPB/VT ablation using a percutaneous transfemoral approach according to standard clinical routine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Successful therapy | Number of patients reaching succesfull therapy defined as >80% reduction of of VPB/VT burden after 3 months | After 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VPB/VT burden |  | 3, 6, 12 months after intervention | 
| Change in VPB/VT burden | Measurement in different subgroups e.g.: males, pre and post-menopausal women | Before the intervention (baseline) and 3, 6, 12 months after intervention | 
| The impact in terms of total Quality of Life | Use of the University of Toronto AF severity scale (AFSS) questionnaire to measure Quality of Life. The total score range is 0-35. Seven questions in total with a maximum score of 5 points per question. | 3, 6, 12 months after intervention compared to baseline (before intervention) | 
| Association between number of VPB/hour and heart rate (HR)/hour during 24-hours Holter- monitoring | A scatterplot will be made in order to depict the association between the number of VBP/hour and heart rate (HR)/hour during 24-hour Holter-monitoring | At baseline | 
| Number of pro-arrhythmic effects, (non)-sustained VT or atrial flutter, in AAD arms with frequent visits and use of 24-hour Holter monitoring |  | 3, 6 and 12 months after intervention | 
| QTc prolongation (sotalol) and QRS broadening (flecainide) with requiring frequent checks with standard ECG and/or treadmill test |  | 4-6 weeks after first administration of AAD | 
| Complication rate of catheter ablation | In all patients with special interest to the subgroup of patients with anatomically challenging origin of (non-RVOT) VPB/VTs | Procedure and 3, 6 and 12 months after intervention | 
| Extended evaluation of left ventricular function with transthoracic echo (TTE) (including global longitudinal strain rate measurement) |  | Baseline, 6 and 12 months after intervention | 
| Absolute and relative difference in VPB/VT burden (%) from baseline, during treatment with sotalol versus treatment with flecainide/verapamil |  | 3, 6 and 12 months after intervention | 
| Divide patients in three groups depending on HR dependency of VPB/VT and compare absolute and relative difference in VPB/VT burden (%) from baseline, during treatment with sotalol versus treatment with flecainide/verapamil |  | 3, 6 and 12 months after intervention |