Clinical trial NCT04208997
Conditions: Tachycardia, Ventricular Catheter Ablation
Keywords: Ventricular Tachycardia Catheter Ablation Antiarrhythmic drugs
Sponsor: Vanderbilt University Medical Center
Start date: 2019-12-19; Completion date: 2021-06-30
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators aim to study if patients that undergo catheter ablation for ventricular tachycardia benefit from continuation of Vaughan-Williams class III antiarrhythmic drugs for 3 months after their ablation.

Detailed description:
Catheter ablation is a valuable option to control recurrent Ventricular Tachycardia (VT) in patients with structural heart disease. A recent trial proved that catheter ablation is superior to escalation of anti arrhythmic drugs (AADs) in prevention of VT recurrence and death (Sapp et al. N Engl J Med 2016; 375:111-121). However, even with ablation, approximately 20-50% of patients will have an episode of VT within one year. This is probably explained in part by the substrate (myocardial scar from cardiomyopathy) persists after VT ablation and that ablation lesions heal and evolve over days, weeks and even months. Most patients (if not all) of patients who undergo ablation are on AADs and usually have failed at least one of them. Furthermore, most AADs, and Vaughan Williams class III AADs in particular (the most frequently used to treat VT) carry significant and life-threatening side effects from pulmonary, hepatic and hematologic toxicities up to significant ventricular arrhythmias and death. Since these patients have already failed AADs, and the significant adverse profile of AADs, there is no evidence that the benefits of continuation of these drugs will surpass the risks after ablation. Therefore the investigators decided to ask the question:

Among patients with structural heart disease who undergo VT ablation, does continuation of class III AADs for 3 months, increases VT-free survival compared to discontinuation of antiarrhythmic drug therapy?

Based on expert consensus about clinical equipoise in regards of AAD continuation after VT ablation, the investigators decided to select patients with lowest risk of VT recurrence after ablation as our study population. The investigators aim to include in our study only those patients who have an Implantable Cardioverter-Defibrillator (ICD), who have NO inducible VT at the end of the ablation procedure and also who have NO inducible VT prior to discharge on a procedure called non-invasive programmed stimulation (NIPS). It has been shown that patients with inducible VT at the end of ablation and during NIPS have significantly higher risk of VT recurrence compared to those in whom VT was not induced. In NIPS, one uses the previously Implanted ICD to pace the ventricle fast enough to try to induce VT. Both procedures will be performed as usual practice in patients who undergo VT ablation in the arrhythmia service.

The specific aim of this pilot study is to evaluate whether the strategy of continuation of class III AADs following initial catheter ablation for VT, improves VT-free survival and reduces readmissions.

Arms: arm 1: Patients will continue the class III antiarrhythmic drug they were receiving prior the VT catheter ablation for 3 months after the ablation. arm 2: Patients will stop class III antiarrhythmic drug they were receiving prior to the VT catheter ablation.
Interventions: intervention 1: Antiarrhythmic drug
Intervention descriptions: intervention 1: Continuation of amiodarone or sotalol.

Protocol documents:
Prot_SAP_001.pdf: 
Continuation of Antiarrhythmics continuation Following 
caThEteR ablation for Ventricular Tachycardia (AFTER-VT) 
trial: Study protocol for a pilot randomized clinical trial.  
 
 
Investigators: Giovanni Davogustto, M.D.1, William G. Stevenson M.D.1, Travis 
Richardson, M.D. 1, Gregory Michaud, M.D.1, Arvindh Kanagasundram M.D.1 
 
 
 
 
 
 
Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, 
TN, USA 
 
 
 
 
 
 
 
 
 
Document date: 09/29/2020  
 
Address Correspondence to 
Arvindh Kanagasundram, M.D. 
Division of Cardiology 
Department of Medicine 
Vanderbilt University Medical Center 
1215 21st Avenue South, 5th Floor  
Nashville, TN 37232, USA.  
E-mail: arvindh.n.kanagasundram@vanderbilt.edu 
 
 
 
 
 


Table of Contents: 
 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Hypothesis 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Outcome measures 
7.0 
Study Procedures 
8.0 
Risks of Investigational Agents/Devices (side effects) 
9.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
10.0 Study Withdrawal/Discontinuation 
11.0 Statistical Considerations and analysis plan 
12.0 Privacy/Confidentiality Issues 
13.0 Follow-up and Record Retention 
14.0 References 
 
 
 


1. Background 
 
Ventricular tachycardia (VT) is an important cause of morbidity and mortality in 
almost all forms of heart disease[1, 2]. Most of the patients with structural heart 
disease will have implantable cardioverter defibrillators (ICDs), which reduce the 
risk of sudden cardiac death[3]. Although ICDs are effective in terminating VT 
and preventing sudden cardiac death, shocks from ICDs reduce quality of life, 
and multiple shocks are associated with post-traumatic stress disorder[4, 5]. 
Most importantly, ventricular arrhythmia episodes and ICD shocks are also 
associated with increased overall-mortality and progression of heart failure, 
although the extent to which arrhythmia recurrences actually contribute to 
adverse outcomes or are simply markers for deteriorating cardiac status remains 
unclear[6]. Anti-arrhythmic drugs (AADs) are usually the first line therapy for VT. 
Of all AAD classes, the most commonly used for long-term prevention of VT 
recurrence are the Vaughan Williams class III AADs (sotalol, amiodarone and 
dofetilide). Unfortunately,  AADs are often insufficient in suppressing VT and they 
carry a significant adverse effect profile. In cases of recurrent VT, catheter 
ablation (CA) has been shown to be a safe and effective treatment modality [7]. 
However, patients with structural heart disease who undergo CA still have 
substrate that predisposes them to VT recurrences. In addition, catheter ablation 
lesions heal and evolve over days to weeks, resulting in VT recurrences that are 
particularly associated with poor outcomes[8-10].   
 
Although most patients undergoing VT ablation are on AADs, it is currently 
unknown the best management strategy of AADs following VT ablation, i.e., it is 
unclear if these patients should continue AADs or not. 
 
2. Rationale and Specific Aims 
 
Catheter ablation is a valuable option to control recurrent VT in patients with 
structural heart disease [3, 7]. However, after VT ablation the VT substrate 
remains and ablation lesions heal and evolve over days to weeks, such that 
some patients will suffer recurrent VT that is associated with worse mortality than 
patients who remain free of VT. Currently, it is not known if continuation of AADs 
following VT ablation can prevent these recurrent VT episodes. Of the currently 
available AADs, class III have the strongest antiarrhythmic profile, however, their 
significant adverse effect profile limits their use. Therefore, there is equipoise in 
clinical practice that benefits of class III AADs preventing recurrent VT outweighs 
the risks of their toxicities.  
 
The specific aim of this pilot study is to obtain preliminary data to evaluate 
whether the strategy of continuation of class III AADs following CA for VT, 
improves VT-free survival and reduces readmissions. The goal of this study will 
be to answer the following question: 
 


Among patients with structural heart disease who undergo VT 
ablation, does continuation of class III AADs 3 months after 
ablation, increases VT-free survival compared to discontinuation of 
antiarrhythmic drug therapy?  
 
3. Hypothesis 
 
We hypothesize that VT-free survival after catheter ablation is greater with 
continuation of class III AADs.  
 
4. Inclusion/Exclusion Criteria 
 
1. Age >18 years.  
2. Able to give written, informed consent 
3. Structural heart disease.  
4. Implanted and normally functioning ICD or undergoing ICD implant 
at index admission. 
5. Undergoing radiofrequency ablation procedure for sustained 
monomorphic VT. 
6. Primarily on class III AADs for VT.  
7. No clinically relevant VT inducible at the end of VT ablation 
8. No clinically relevant VT inducible on non-invasive programmed 
stimulation following VT ablation.  
 
       Exclusion Criteria: 
1. LV assist device in place 
2. Decompensated heart failure and/or requiring continuous inotropic 
therapy and/or awaiting cardiac transplantation 
3. Ongoing acute coronary syndrome. 
4. Mechanical prosthetic aortic and mitral valves.  
5. Pedunculated or mobile left ventricular thrombus.  
6. Persistency of clinically relevant VT at the end of catheter ablation.  
7. Absolute contraindications for amiodarone.  
8. Participation in other trial.  
9. Clinical VT induced on NIPS after VT ablation. 
10. Another reason for continuation of class III AADs (i.e., atrial fibrillation).   
 
5. Enrollment/Randomization 
 
A patient will be identified as a candidate for participation in this study while 
receiving care at Vanderbilt University Medical Center. The clinical team will 
contact the patient in-person while being evaluated for VT ablation. The clinical 
team will ask the patient if they are interested to discuss participation in the 
clinical trial. If yes, information about participation will be provided by approved 
research staff. The patient may sign the consent document, decline, or defer until 
the day prior to ablation. At that time, research staff will again be available to 


provide further information and/or obtain consent.  Patients who decline 
participation will continue to receive usual care and the decision to not participate 
will not interfere with their medical care. Each candidate will receive a copy of the 
signed consent form. The consent form is presented in Appendix 1.  
 
Patients will have VT ablation. Those with no evidence of clinical VT inducibility 
after ablation will then undergo Non-Invasive Programmed Stimulation (NIPS) 
prior to discharge. NIPS will be performed as there is evidence that patients with 
inducible clinical VT on NIPS after VT ablation have greater risk of VT recurrence 
[11] and might not be appropriate to withhold anti-arrhythmic therapy for those 
with inducible VT in NIPS.  
 
Patients that meet inclusion criteria and agree to participate will be randomized 
and allocated to continue class III AADs or discontinuation using block 
randomization, stratified by type of AADs used until goal enrollment is achieved. 
The randomization sequence will be created using STATA 14.2 (StataCorp, 
College Station, TX, USA) statistical software. 
 
Adherence to study-assigned group will be achieved by clinician education and 
reminders in routine daily meetings performed by the electrophysiology service. 
 
Before enrollment begins, approval from the Institutional Review Board of 
Vanderbilt University Medical Center will be obtained, and the trial will be 
registered in ClinicalTrials.gov. 
 
6. Outcome measures 
 
The primary outcome will be VT-free survival, a composite of all-cause mortality 
and VT recurrence one year after VT ablation. Secondary outcomes will be all-
cause mortality, VT recurrence, incidence of VT storm, and readmission for heart 
failure for one year after VT ablation. Both self-terminating sustained VTs (>30 
seconds or hemodynamic instability) and VT requiring device therapies for 
termination will be considered as recurrences when considering VT recurrence.  
 
Subgroup analysis. 
 
The primary and secondary outcomes will also be investigated according to type 
of cardiomyopathy (ischemic vs dilated) and according to type of AADs.  
 
7. Study Procedures 
 
Enrollment:  
At the time of enrollment, baseline information pertaining to symptoms and 
details clinical presentation, imaging, and heart catheterization procedures will be 
obtained from examination of their medical record and recorded in a Redcap 
database 


 
VT ablation procedure 
Ablation will be performed according to our usual practice. When feasible, prior to 
ablation class III AADs will be held for 72 hours prior to ablation per usual 
practice in our institution. 
 
Ablation will be standardized and performed in all participants per usual care and 
without any differences in protocol. Briefly, in fasting state patients are taken to 
the electrophysiology laboratory and are continuously monitored during the 
ablation with external surface EKG leads.  
 
The procedure will be performed with the usual sterile preparation under 
moderate sedation or general anesthesia. The left ventricular endocardial cavity 
will be accessed via either retrograde aortic or trans-septal access. A hexapolar 
catheter will be positioned in the right ventricular apex. A mapping catheter or a 
multi-polar mapping catheter will be used to collect voltage and activation data 
from the left ventricle during sinus rhythm or RV apical pacing. Areas of slow 
conduction with crowding of isochrones will be outlined.  
 
 
Programmed stimulation for initiation of VT will be performed at the start of the 
procedure after catheter are placed and use 1, 2, and then 3 extrastimuli during 2 
paced cycle lengths from 2 RV sites. Systemic anticoagulation with heparin will 
be required for LV mapping and dosed per usual protocol. After induction of VT 
the specific extra-stimulus protocol (site, drive cycle length and extra-stimuli) will 
be recorded. A comprehensive endocardial substrate map will then be created 
during sinus rhythm or RV apical pacing to capture both voltage and activation to 
the offset of the local electrogram. Areas of interest on the basis of pace-
mapping or electrogram characteristics will be tagged. If at any point during this 
procedure, the origin of VT is located in the epicardial surface, pericardial access 
will be obtained and an epicardial substrate map will be generated. After 
completion of the substrate map repeat programmed stimulation for initiation of 
VT will be performed using the same protocol as the start of the case.  
 
Then, ablation will be performed to target all clinically relevant VTs, which will be 
defined as all sustained monomorphic VTs having a cycle length within 20 ms 
longer than the fastest VT documented prior to ablation. Ablation of VTs of 
shorter cycle lengths will be performed whenever feasible and clinically indicated. 
Anticoagulation following catheter ablation will follow usual practice.  
 
Non-Invasive Programmed Stimulation 
Patients with no evidence of clinical VT being inducible at the end of ablation and 
no spontaneous VT recurrence will undergo NIPS prior to hospital discharge, 
according to our usual practice. Patients will need to provide written informed 
consent on the day of or before of this procedure as done in usual practice. If the 
patient refuses to consent will be excluded from the study. 
 


Briefly, under fasting condition, patients will undergo NIPS via the right ventricle 
ICD per usual protocol, which is the protocol used as usual practice in our 
division when NIPS is performed, under monitored anesthesia care (MAC) and 
continuous external surface EKG lead monitoring.  
 
Response to these stimuli will be categorized as “inducible clinical VT” and “No 
clinical VT inducible”. Patients with inducible clinical VT will be excluded of our 
study.  
 
ICD programming guidelines: 
After catheter ablation, patient’s ICD programming to detect and treat VT will be 
adjusted as per usual practice in our division based on published guidelines[7]. 
VT detection will be programmed depending on clinical VT rate.  
 
- 
If VT is 200 bpm or faster, detection will be set at 165-171 bpm but 
without therapy programmed unless HR is > 200 bpm.  
- 
If VT is slower than 200 bpm, detection programmed at 20 bpm slower 
than the known VT cycle length.  
- 
If the known VT is 140-150 bpm, set detection at 130 bpm.  
- 
If the known VT is slower than 140 bpm, detection should be 
programmed 10 bpm slower than the known VT.   
 
In addition, will allow delay in therapy of 6-12 seconds. Anti-tachycardia pacing is 
recommended in all zones.  
 
Follow-up 
Patients will be evaluated per usual care after VT ablation by their treating 
electrophysiologist. This is at two to four weeks after ablation, and then at three 
months intervals (either in clinic or via remote ICD interrogation) for one year. 
ICD interrogations will be performed in each visit and we will ask to receive 
alarms for episodes of VT/VF and therapies delivered. Changes in medical 
therapy and ICD settings will be at the discretion of the treating 
electrophysiologist. Our consent form will include request of consent to access 
remote as well as in-office ICD interrogations. Most of these patients will likely 
have been already enrolled in a VT registry maintained by the arrhythmia service 
and this will route us the interrogations with no need to have the patient come for 
specific appointments with us for this trial.  
 
8. Risks of Investigational Agents/Devices (side effects) 
 
The added risks of continuation of class III AADs include risk of hyperthyroidism, 
hypothyroidism, hepatotoxicity, pulmonary fibrosis, corneal deposits, optic 
neuropathy, skin deposition, tremors and increased defibrillator thresholds, 
polymorphic ventricular tachycardia, torsades des pointes, bradycardia, fatigue, 
weakness, headache, edema, depression, thrombocytopenia, angioedema, skin 
rash.  


 
However, most of these patients have been already tolerating these medications 
over several months/years. Furthermore, we expect that in the long-term, 
preventing VT will result in reduction of out-of-hospital VT/VF leading to ICD 
shocks which are associated with reduced quality of life and increased mortality.  
 
9. Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
 
Any unanticipated adverse events will be reported by the Principal Investigator 
according to applicable IRB policy. The PI is fully engaged in the performance of 
the study and this ensures that adverse events would be readily known by the PI 
and reported in a timely manner. 
 
10. Study Withdrawal/Discontinuation 
 
If an individual decides to withdraw their consent by informing study staff in 
writing or verbally, we will withdraw the participant. Contact information for the PI 
and study staff will be made available to the participant upon enrollment in the 
consent document.  
 
11.  Statistical Considerations and analysis plan 
 
No studies have previously addressed this question; therefore we have no clear 
expectation on possible effect size and plan to perform this trial as a pilot study 
aimed at including all patients possible in a time frame of 12-24 months to then 
inform power size calculations for a larger and blinded clinical trial. We plan to 
enroll 75 patients per arm. 
 
An intention to treat analysis will be performed. Analysis for the primary outcome 
will be accomplished by using log-rank statistic. Cox proportional-hazards 
regression will be used to estimate relative risks and 95% confidence intervals 
and adjust for differences in baseline outcome predictors.  Differences in 
secondary outcomes will be calculated using log-rank statistic and cox 
proportional-hazards regression for all-cause mortality, VT-free survival, hospital 
readmissions and with unpaired t test for VT storm.   
  
Interim analysis of the primary endpoint and drug adverse events will be planned 
every 6 months from study initiation. An independent statistician blinded to the 
treatment groups will perform the analysis and report findings to the data and 
safety monitoring committee who will decide the continuation of the study.   
 
12. Privacy/Confidentiality Issues 
 
A variety of measures will be utilized to ensure participant privacy: 
 


Data will be stored in REDCap using the participant’s study ID. Their REDCap 
data record may contain some identifying information. Subjects will be tracked 
using their study ID. The identifiable data, excluding date of procedures, will 
reside as a separate form under the data entry sections labeled 
“Registration/PHI” within our REDCap database which will allow us to exclude 
access to the identifiable information, excluding date of procedures, if necessary. 
Minimal paper records will be kept, and they will be kept locked in a cabinet. 
 
Researchers are trained in HIPAA privacy regulations and other applicable 
privacy policies at Vanderbilt University.  No information will be released, nor will 
participation in the research be acknowledged, to any party except where 
compulsory according to law or Vanderbilt policy. There may be unknown or 
unanticipated adverse effects from participation in this trial for which the PI and 
study team will remain observant.   
 
13. Follow-up and Record Retention 
 
Patients will be evaluated per usual care after VT ablation by their treating 
electrophysiologist. This is at two to four weeks after ablation, and then at three 
months intervals (either in clinic or via remote ICD interrogation) for one year.  
ICD interrogations will be performed in each visit and we will receive remote 
alarms for episodes of VT/VF. Changes in medical therapy and ICD settings at 
follow up will be at the discretion of the treating provider.  
 
Data will be retained indefinitely. Electronic data may be destroyed earlier at the 
request of the participant. If so, electronic records will be deleted from the 
REDCap database, paper copies will be deposited into locked containers 
designated for shredding of confidential patient information.  
 
 
14. References 
 
1. 
John, R.M. and W.G. Stevenson, Noninvasive Ablation of Ventricular 
Tachycardia. N Engl J Med, 2017. 377(24): p. 2388-2390. 
2. 
Al-Khatib, S.M., et al., 2017 AHA/ACC/HRS Guideline for Management of 
Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac 
Death: Executive Summary: A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines and the Heart Rhythm Society. Heart Rhythm, 2017. 
3. 
Epstein, A.E., et al., 2012 ACCF/AHA/HRS focused update incorporated into the 
ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm 
abnormalities: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines and 
the Heart Rhythm Society. J Am Coll Cardiol, 2013. 61(3): p. e6-75. 


4. 
Schron, E.B., et al., Quality of life in the antiarrhythmics versus implantable 
defibrillators trial: impact of therapy and influence of adverse symptoms and 
defibrillator shocks. Circulation, 2002. 105(5): p. 589-94. 
5. 
Perini, A.P., et al., Effects of implantable cardioverter/defibrillator shock and 
antitachycardia pacing on anxiety and quality of life: A MADIT-RIT substudy. 
Am Heart J, 2017. 189: p. 75-84. 
6. 
Poole, J.E., et al., Prognostic importance of defibrillator shocks in patients with 
heart failure. N Engl J Med, 2008. 359(10): p. 1009-17. 
7. 
Sapp, J.L., et al., Ventricular Tachycardia Ablation versus Escalation of 
Antiarrhythmic Drugs. New England Journal of Medicine, 2016. 375(2): p. 
111-121. 
8. 
Nagashima, K., et al., Correlates and prognosis of early recurrence after 
catheter ablation for ventricular tachycardia due to structural heart disease. 
Circ Arrhythm Electrophysiol, 2014. 7(5): p. 883-8. 
9. 
Siontis, K.C., et al., Prognostic Impact of the Timing of Recurrence of Infarct-
Related Ventricular Tachycardia After Catheter Ablation. Circ Arrhythm 
Electrophysiol, 2016. 9(12). 
10. 
Santangeli, P., et al., Early Mortality After Catheter Ablation of Ventricular 
Tachycardia in Patients With Structural Heart Disease. J Am Coll Cardiol, 
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11. 
Frankel, D.S., et al., Noninvasive programmed ventricular stimulation early 
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