Clinical trial NCT02301390
Conditions: Ventricular Tachycardia
Keywords: INTERVENE Ventricular tachycardia India
Sponsor: Icahn School of Medicine at Mount Sinai
Start date: 2009-10-01; Completion date: 2016-09-01
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study to is being conducted in India to determine the role of catheter-based ablation for ventricular tachycardia (VT) in post- heart attack patients who meet established guidelines for implantable cardiodefibrillator (ICD) implantation, but cannot afford it. These patients would be started on chronic Amiodarone therapy, which has been shown to be effective but can often lead to multiple side effects.

Patients will therefore be randomized in an even proportion to either a) the control group, receiving chronic Amiodarone therapy, or the study group, undergoing catheter ablation of VT in addition to chronic Amiodarone therapy.

This trial will serve as a representative model for the developing world.

Detailed description:
Sudden cardiac death (SCD) accounts for approximately 50% of all cardiac death, representing an estimated annual incidence ranging from 250,000 to 350,000 cases in the United States. The pathophysiologic mechanism for sudden death in the majority of these patients is thought to be ventricular tachycardia (VT) related to coronary artery disease (CAD), which can then degenerate to ventricular fibrillation (VF). Patients who survive an initial episode of VT/VF are prone to an extremely high incidence of recurrent life-threatening events (\~25% at one year). Even in patients without a history of VT/VF, the presence of CAD and left ventricular (LV) dysfunction confers a two-year mortality rate of 22%. If VT is inducible at electrophysiological testing, the two-year mortality is \~30%.

The pathogenesis of VT in the setting of CAD is reentry in the area of the scarred myocardium. After an MI, the tissue can be broadly divided into three zones: the dense scar, the surrounding live myocardial tissue, and the intervening border zone. After a myocardial infarction (MI), the "border zone" between dense scar and live tissue contains electrically-active live myocardial fibrils interspersed in areas of infarcted, fibrotic tissue-setting the stage for local reentrant circuits that result in VT.

The use of antiarrhythmic medications (AADs) to suppress the occurrence/recurrence of VT/VF in these high-risk patients has been mostly disappointing. In large clinical trials, most AADs have not only proved to be inefficacious, but to actually increase mortality. The one potential exception appears to be Amiodarone: one study suggests some mortality benefit (GESICA), while others suggest that Amiodarone provides significant antiarrhythmic benefits without a change in mortality (EMIAT, CAMIAT, SCD-HeFT). However, even the use of Amiodarone is plagued with multiple organ toxicities, ranging from pulmonary fibrosis to hepatitis, and thyroid dysfunction.

An important alternative to such questionably efficacious antiarrhythmics is the implantable cardio-defibrillator (ICD), which can accurately and effectively detect and terminate VT/VF, resulting in a significant mortality benefit in both the primary and secondary prevention of sudden cardiac death. Yet, despite these beneficial results, ICD implantation cannot be considered a cure for VT. In addition, it is common for patients to experience painful high-voltage shocks secondary to recurrent ventricular arrhythmias, or to lose consciousness prior to the delivery of therapy. Moreover, the considerable cost of ICDs severely limits their availability in the developing world-where public and/or private health insurance systems are rudimentary at best, and where the incidence of coronary artery disease is four times higher than that of the developed world-highlighting the urgency of establishing an alternative therapy for post-MI patients with ventricular arrhythmias that is both accessibly and effective.

One such option may be catheter ablation of ventricular arrhythmias. It has been well described that for hemodynamically-stable VT circuits, careful ventricular mapping to identify sites critical to the maintenance of a given circuit, followed by discrete applications of catheter-based radiofrequency (RF) energy, can effectively eliminate VT.

This strategy mocks surgical approaches that have been used extensively since the late 1970s for modification of the arrhythmogenic substrate in patients with chronic myocardial infarction. Since the location of the reentrant circuit is most often located at the junction of the normal and scarred myocardium, two effective general strategies were developed over time: a) subendocardial resection-involving surgical removal of the subendocardial layer containing the arrhythmogenic substrate in this border zone, and b) encircling endocardial ventriculotomy-consisting of the placement of a circumferential surgical lesion through the border zone and, presumably, interrupting potential VT circuits. When performed at experienced centers, the long-term freedom from malignant VT/VF after surgery is \>90%. However, the significant mortality (3-14%) and morbidity associated with this invasive procedure has curtailed its use in general practice.

The less invasive, catheter approach to substrate modification relies on electroanatomical mapping systems that create a high fidelity representation of the endocardium, allowing for the reconstruction and electronic manipulation of an endocardial cast of the ventricular chamber that carefully delineates the normal and abnormal tissues. This is based on the observation that during normal sinus rhythm, there are distinguishing characteristics of the endocardial electrogram (EGM) of normal and abnormal tissue: abnormal tissue manifests lower voltage amplitude, prolonged EGM duration, and the presence of late and fractionated potentials. Marchlinski and colleagues reported in a seminal study that by using a substrate-mapping strategy, catheter-based RF ablation lesions directed in a linear fashion were effective in controlling scar-related drug-refractory unstable VT. Furthermore, using this high-density electroanatomical mapping 1) this strategy can be utilized to localize the arrhythmogenic substrate in the majority of patients with a history of myocardial infarction and sustained ventricular tachyarrhythmia's, and 2) RF ablation using an irrigated-tip ablation catheter can be effectively and safely used to modify the arrhythmogenic substrate to render VT non-inducible even in the presence of multiple VT morphologies.

The favorable results in these non-randomized reports prompted the initiation of SMASH-VT (Substrate Mapping \& Ablation in Sinus Rhythm to Halt Ventricular Tachycardia Trial); a prospective randomized clinical trial to objectively assess the clinical utility of substrate ablation of scar-related VT. This trial was a randomized-controlled trial examining the role of substrate mapping and RF ablation in the primary prevention of ICD shocks in patients presenting with clinically life-threatening VT/VF. That is, patients with a history of MI, and who survive an episode of VT/VF are at high-risk for recurrent VT and thus treated with ICDs (in essence, these patients meet AVID/CIDS/CASH criteria). In normal clinical practice, these patients are not routinely treated with adjuvant medications because of their proarrhythmic potential and side effects. In addition to an ICD and routine clinical care, these patients were additionally randomized in SMASH-VT to substrate-based catheter ablation. This catheter ablation group underwent electroanatomic mapping to delineate the endocardial infarct margins (CARTO, Biosense-Webster, Inc.). Substrate modification was then performed targeting the exit sites of induced VTs and/or late potentials within the scar using standard or irrigated radiofrequency ablation catheters.

As published in late 2007 (Reddy et al, NEJM, 357:2657), the 30-day post-ablation mortality was zero, and there was no significant change in ventricular function or functional class during follow up. During an average follow-up of 22.5±5.5 months, appropriate defibrillator therapy (anti-tachycardia pacing and shocks) occurred in 21 control (33%) and 8 ablation (12%) patients (p=0.007 by the log rank test). Of these, appropriate defibrillator shocks alone occurred in 20 control (31%) and 6 ablation (9%) patients (p=0.003). Mortality was not increased in the ablation arm (control 17%, ablation 9%; p=0.29); indeed, there was a trend to decreased mortality in the ablation arm. Thus, the SMASH-VT study revealed several important points: 1) adjuvant substrate based catheter ablation is feasible in this patient population, 2) use of a saline-irrigated RF ablation catheter for this ablation strategy is safe, and 3) this strategy decreases subsequent ICD therapies in post-myocardial infarction patients receiving defibrillators for the secondary prevention of sudden death.

The favorable results of SMASH-VT, combined with considerable technical and scientific improvements in catheter ablation of scar-related VT, also raise the possibility that the therapeutic benefit of ablation may be extrapolated to similar patients in the developing world, who have had an MI and have survived a ventricular arrhythmic event, but are unable to afford an ICD. This is of particular importance because such patients are typically treated with chronic Amiodarone therapy-a strategy with an unestablished mortality benefit and significant side effects.

The investigators therefore propose a randomized clinical trial, in which India-a nation with a population of 1.2 billion-will serve as a representative model for the developing world. The study will evaluate the safety and efficacy of adjunctive catheter ablation in post-myocardial infarction patients who have additionally survived a ventricular arrhythmic event, and would be initiated on chronic Amiodarone therapy because of an inability to afford ICD therapy. Patients will therefore be randomized in an even proportion to either a) the control group, receiving chronic Amiodarone therapy, or the study group, undergoing catheter ablation of VT in addition to chronic Amiodarone therapy.

Arms: arm 1: The control group will receive amiodarone only. arm 2: The experimental group will receive amiodarone plus catheter VT ablation.
Interventions: intervention 1: Amiodarone intervention 2: Catheter Ablation
Intervention descriptions: intervention 1: Amiodarone is a Class III antiarrhythmic agent. intervention 2: The ablation procedure uses radiofrequency energy to destroy cardiac tissue at the origin of the arrhythmia.

Protocol documents:
Prot_SAP_000.pdf: 
INTERVENE
INDIAN TRIAL OF ENDOCARDIAL VENTRICULAR SUBSTRATE ABLATION 
TO PREVENT RECURRENT VT EVENTS
PI: Dr. Vivek Reddy
NCT02301390
Document Date: April 22, 2014


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INTERVENE 
INDIAN TRIAL OF ENDOCARDIAL 
VENTRICULAR SUBSTRATE ABLATION TO 
PREVENT RECURRENT VT EVENTS  
A prospective, multi-center, unblinded, 
randomized trial 


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PROTOCOL SIGNATURE PAGE 
Indian Trial of Endocardial Ventricular Substrate Ablation to PrEvent RecurreNt VT 
Events (INTERVENE) 
A prospective, multi-center, unblinded, randomized study to evaluate the safety and effectiveness 
of adjuvant catheter ablation in post-MI patients who have survived a VT/VF arrest, but cannot 
afford ICD implantation. 
I have read this protocol and agree to adhere to the requirements. I will provide copies of this 
protocol and all pertinent information to the study personnel under my supervision. I will discuss 
this material with them and ensure they are fully informed regarding the investigational device and 
the conduct of the study according to 21 CFR parts 50, 54, 56 and 812, to GCP as described in ICH 
guideline E6 and to hospital IRB/ethics committee requirements. 
CARE Hospital, Road No.1, Banjara Hills, Hyderabad, India 
Pin code: 500 034 
__________________________ 
Clinical Site 
 
_________________________  
_____________________ 
Principal Investigator Signature 
Date 
Dr.C.Narasimhan MD DM 
Principal Investigator  
Printed Name 


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TABLE OF CONTENTS 
PROTOCOL SUMMARY .......................................................................................................................... 4 
1.
TABLE 1. SCHEDULE OF TREATMENTS AND TESTS .............................................................. 6
2.
INTRODUCTION ................................................................................................................................ 7
2.1 
BACKGROUND................................................................................................................................... 7 
2.2 
DESCRIPTION OF DEVICE ................................................................................................................ 10 
3.
STUDY OBJECTIVE, ENDPOINTS, AND DESIGN ..................................................................... 12
3.1 
OBJECTIVE ...................................................................................................................................... 12 
3.2 
ENDPOINTS ..................................................................................................................................... 12 
3.3 
STUDY DESIGN ............................................................................................................................... 13 
3.4 
ANALYSIS POPULATION .................................................................................................................. 14 
4.0 
PROTOCOL...................................................................................................................................... 14 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 14 
4.3 
PATIENT ENROLLMENT ................................................................................................................... 14 
4.4 
STUDY PROCEDURES ....................................................................................................................... 15 
4.4.1. 
PRE-RANDOMIZATION PROCEDURES ........................................................................................... 15 
4.5 
FOLLOW-UP .................................................................................................................................... 21 
6.0 
ADVERSE EVENT HANDLING .................................................................................................... 24 
6.1 
ADVERSE EVENTS ........................................................................................................................... 24 
6.2 
SERIOUS ADVERSE EVENTS AND DEATH......................................................................................... 24 
6.3 
UNANTICIPATED ADVERSE DEVICE EFFECTS .................................................................................. 24 
6.4 
ANTICIPATED ADVERSE EVENTS .................................................................................................... 25 
7.0 
RISK ANALYSIS ............................................................................................................................. 26 
7.1 
RISKS .............................................................................................................................................. 26 
7.2 
BENEFITS ........................................................................................................................................ 27 
8.0 
STUDY COMMITTEES .................................................................................................................. 27 
8.1 
PRINCIPAL INVESTIGATORS............................................................................................................. 27 
8.2 
EXECUTIVE COMMITTEE ................................................................................................................. 27 
8.3 
DATA AND SAFETY MONITORING BOARD ....................................................................................... 28 
8.4 
CLINICAL EVENTS COMMITTEE ...................................................................................................... 28 
9.0 
ETHICAL AND REGULATORY CONSIDERATIONS .............................................................. 29 
9.1. 
 ROLE OF THE COORDINATING CENTER .......................................................................................... 29 
9.2. 
MAINTAINING RECORDS ................................................................................................................ 29 
9.3. 
SITE RECORD RETENTION POLICY ................................................................................................. 29 
9.4. 
INFORMED CONSENT AND INSTITUTIONAL REVIEW BOARD (IRB) / ETHICS COMMITTEE (EC) ...... 29 
9.5. 
 PATIENT CONFIDENTIALITY .......................................................................................................... 29 
10.0 
STUDY MANAGEMENT .............................................................................................................. 29 
10.1. 
STUDY DATA COLLECTION AND PROCESSING .............................................................................. 30 
10.2 
INSTITUTIONAL REVIEW BOARD (IRB) / ETHICS COMMITTEE (EC) INFORMATION ....................... 30 
10.3 
DEVIATIONS FROM PROTOCOL ...................................................................................................... 30 
APPENDIX A: 
REFERENCES ............................................................................................................. 31 


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PROTOCOL SUMMARY 
Title: 
Indian Trial of Endocardial Ventricular Substrate Ablation to 
Prevent Recurrent VT Events (INTERVENE) 
Objective: 
The objective of the INTERVENE trial is to determine the role of 
catheter-based VT ablation in the prevention of recurrent VT in 
post-MI patients who survive a life-threatening VT/VF event (that 
is, AVID / CASH / CIDS criteria) but cannot afford an 
implantable defibrillator.  Patients will be randomized to either 
Amiodarone (usual therapy) or Amiodarone plus catheter ablation. 
Design: 
This study is a prospective, multi-center, unblinded, randomized 
(1:1) clinical trial that will compare two treatment strategies. 
Subjects will be randomized to either an Amiodarone control 
group or an Amiodarone + catheter ablation study group.  Subjects 
will only be eligible for this study if they: i) have had a prior 
ventricular arrhythmic event (VT/VF), ii) have a history of a 
myocardial infarction, and iii) cannot afford the cost of an ICD. 
Once randomized, the ablation group will undergo a strategy of 
catheter-based VT substrate modification.  Follow-up will be 
conducted in regular intervals over a 24 month period.   
Enrollment: 
136 subjects (68 control group, 68 study group).  
Clinical Sites: 
5-12 sites in India 
Time Course: 
Initial enrollment: Q4 2008 
Last enrollment: Q2 2015 
Last 24-month follow-up: Q2 2017 
Subject Description: 
Study Group: 
Eligible subjects include those who have sustained a previous MI 
(at least 1 month prior) and have survived a VT/VF event that 
would mandate the placement of an ICD.  However, eligible 
patients cannot afford an ICD, and would instead be treated solely 
with chronic Amiodarone therapy. 
The subjects in this group will receive treatment with oral 
Amiodarone treatment as per usual medical therapy.  Additionally, 
this group will undergo electroanatomic mapping to delineate the 
endocardial infarct margins (CARTO, Biosense Webster, Inc). 
Substrate modification will be performed using one or more of a 


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Control Group: 
number of acceptable substrate mapping strategies (e.g., targeting 
the exit sites of induced VTs, targeting late potentials within the 
scar, etc.) using a saline-irrigated radiofrequency mapping/ablation 
catheter (NaviStar ThermoCool catheter, Biosense Webster, 
Inc).   
Subjects in the control group will receive treatment with oral 
Amiodarone treatment as per usual medical therapy (outlined in 
the protocol). 
Primary Endpoint: 
All-cause mortality + Cardiac Arrest + Sustained VT 
Secondary Endpoints: 
1. Proportion of subjects that die within a) 30 days, or b) by the 
end of the study (~24 months). 
2.
Total number of ventricular arrhythmic events, compared
between the 2 treatment arms. 
3.
Differences in LV ejection fraction between paired
measurements recorded at baseline and 3 months for each 
patient will be used to test for significant differences between 
the two treatment arms. 
Primary Analytical 
Analysis: 
Intent to treat analysis 
Secondary Analytical 
Analysis: 
Per protocol analysis 
Principal Investigators: 
Vivek Y. Reddy, M.D. 
Icahn School of Medicine at Mount Sinai 
One Gustave Levy Place, Box 1030 
New York, NY  10029 
Calambur Narasimhan, MD  
CARE Hospital  
Hyderabad, India 
Site, Monitoring, and Data 
Management Center: 
Icahn School of Medicine at Mount Sinai 
One Gustave Levy Place, Box 1030 
New York, NY  10029 
Data Safety and Monitoring 
Board Coordination: 
Jonathan Halperin MD, Mount Sinai (Chair) 
Jacob Koruth MD, Mount Sinai 
K.K. Narayanan Namboodri MD, SCT Trivandrum 
Michael K. Parides (Statistician) 
O. Sai Satish MD, Nizam’s Institute of Medical Sciences 
Study Sponsor:     
Vivek Reddy, MD, Icahn School of Medicine at Mount Sinai 
Study Funding Agency: 
Biosense Webster Inc. 


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TABLE 1. SCHEDULE OF TREATMENTS AND TESTS 
Baseline 
Ablation 
Procedure* 
Discharge 
3, 6, 9, 12, 18, 24Months 
Type of visit 
Office 
Hospital 
Office 
Informed Consent 
X 
Brief History & Physical 
X 
X 
X 
12-lead ECG 
X 
X 
X 
Randomization 
X 
Hospital Admission 
X 
EP Mapping & Ablation 
X* 
Warfarin 
X 
4-6 weeks 
Transthoracic echocardiogram 
X 
X 
 3, 24 month visit 
Medications 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
* The ablation procedure must be performed during the 2-month “blanking” period of Amiodarone loading. Multiple
ablations may be performed within the initial hospitalization, without constituting treatment failure. 
Ablation procedures will be done only at principal investigators and not in satellite sites. 


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Figure 1  Instead of a single bundle of myocardium 
forming the tachycardia circuit (A), there is an 
extensive sheet of surviving myocardial fibers 
linked in the subendocardium through multiple 
entrance and exit points (B & C).26 This accounts 
for multiple reentrant paths (that is, different VT 
morphologies) at different times all originating 
from the same mass of infarcted tissue. [Figure 
adapted from REF # 26.] 
INTRODUCTION 
2.1 
Background 
Sudden cardiac death (SCD) accounts for approximately 50% of all cardiac death, representing 
an estimated annual incidence ranging from 250,000 to 350,000 cases in the United States.i  The 
pathophysiologic mechanism for sudden death in the majority of these patients is thought to be 
ventricular tachycardia (VT) related to coronary artery disease (CAD), which can then 
degenerate to ventricular fibrillation (VF).  Patients who survive an initial episode of VT/VF are 
prone to an extremely high incidence of recurrent life-threatening events (~25% at one year).ii  
Even in patients without a history of VT/VF, the presence of CAD and left ventricular (LV) 
dysfunction confers a two-year mortality rate of 22%.iii  If VT is inducible at 
electrophysiological testing, the two-year mortality is ~30%.iv, v   
The pathogenesis of VT in the setting of CAD is reentry in the area of the scarred 
myocardium.vi, vii  After an MI, the tissue can be broadly divided into three zones: the dense scar, 
the surrounding live myocardial tissue, and the intervening border zone.  After a myocardial 
infarction (MI), the “border zone” between dense scar and live tissue contains electrically-active 
live myocardial fibrils interspersed in areas of infarcted, fibrotic tissue—setting the stage for 
local reentrant circuits that result in VT (Figure 1).  
The use of antiarrhythmic medications 
(AADs) 
to 
suppress 
the 
occurrence/recurrence of VT/VF in   these 
high-risk 
patients 
has 
been 
mostly 
disappointing.  In large clinical trials, most 
AADs 
have 
not 
only 
proved 
to 
be 
inefficacious, 
but 
to 
actually 
increase 
mortality. 
viii,ix,x,xi,xii,xiii,xiv,xv 
 
The 
one 
potential 
exception 
appears 
to 
be 
Amiodarone: one study suggests some 
mortality benefit (GESICA), while others 
suggest that Amiodarone provides significant 
antiarrhythmic benefits without a change in 
mortality (EMIAT, CAMIAT, SCD-HeFT).  
However, even the use of Amiodarone is 
plagued with multiple organ toxicities, 
ranging from pulmonary fibrosis to hepatitis, 
and thyroid dysfunction.xvi   


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An important alternative to such questionably efficacious antiarrhythmics is the implantable 
cardio-defibrillator (ICD), which can accurately and effectively detect and terminate VT/VF, 
resulting in a significant mortality benefit in both the primaryiii,iv,v and secondaryii,xvii prevention 
of sudden cardiac death.  Yet, despite these beneficial results, ICD implantation cannot be 
considered a cure for VT.  In addition, it is common for patients to experience painful high-
voltage shocks secondary to recurrent ventricular arrhythmias, or to lose consciousness prior to 
the delivery of therapy.  Moreover, the considerable cost of ICDs severely limits their 
availability in the developing world—where public and/or private health insurance systems are 
rudimentary at best, and where the incidence of coronary artery disease is four times higher than 
that of the developed world—highlighting the urgency of establishing an alternative therapy for 
post-MI patients with ventricular arrhythmias that is both accessibly and effective. 
One such option may be catheter ablation of ventricular arrhythmias.  It has been well described 
that for hemodynamically-stable VT circuits, careful ventricular mapping to identify sites critical 
to the maintenance of a given circuit, followed by discrete applications of catheter-based 
radiofrequency (RF) energy, can effectively eliminate VT.  
This strategy mocks surgical approaches 
that have been used extensively since the 
late 
1970s 
for 
modification 
of 
the          
arrhythmogenic substrate in        patients 
with chronic myocardial infarction.  Since 
the location of          the reentrant circuit is 
most often  located at the junction of the         
normal and scarred myocardium,       two 
effective general strategies   
  were 
developed over time: a) subendocardial 
resection—involving surgical removal of 
the subendocardial layer containing the 
arrhythmogenic substrate in this border 
zone,xviii, 
xix, 
xx and b)    encircling 
endocardial ventriculotomy—consisting of 
the placement of a circumferential surgical 
lesion through the border zone and, 
presumably, 
interrupting 
potential 
VT 
circuits (Figure 2).xxi, xxii  When performed 
at experienced centers, the long-term 
freedom from malignant VT/VF after surgery is >90%.  However, the significant mortality (3-
14%) and morbidity associated with this invasive procedure has curtailed its use in general 
practice. 
The less invasive, catheter approach to substrate modification relies on electroanatomical 
mapping systems that create a high fidelity representation of the endocardium, allowing  
Figure 2.  The border between the normal and infarcted/ 
aneurysmal wall contains a stylized VT circuit—
predominantly endocardial, and partially intramural.  The 
surgical 
procedures, 
encircling 
ventriculotomy 
& 
subendocardial resection, either remove or transect critical 
portions of the VT circuit, respectively.  Alternately, 
catheter-based lesions (in red) can be empirically placed to 
interrupt the circuit. [Figure adapted from REF # 31.] 


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for the reconstruction and electronic manipulation of an endocardial cast of the ventricular 
chamber that carefully delineates the normal and abnormal tissues.  This is based on the 
observation that during normal sinus rhythm, there are distinguishing characteristics of the 
endocardial electrogram (EGM) of normal and abnormal tissue: abnormal tissue manifests a 
lower voltage amplitude, prolonged EGM duration, and the presence of late and fractionated 
potentials.xxiii
xxvii
,xxiv,xxv  Marchlinski and colleagues reported in a seminal study that by using a 
substrate-mapping strategy, catheter-based RF ablation lesions directed in a linear fashion were 
effective in controlling scar-related drug-refractory unstable VT.xxvi  Furthermore, using this 
high-density electroanatomical mapping 1) this strategy can be utilized to localize the 
arrhythmogenic substrate in the majority of patients with a history of myocardial infarction and 
sustained ventricular tachyarrhythmias, and 2) RF ablation using an irrigated-tip ablation catheter 
can be effectively and safely used to modify the arrhythmogenic substrate to render VT non-
inducible even in the presence of multiple VT morphologies.
 
The favorable results in these non-randomized reports prompted the initiation of SMASH-VT 
(Substrate Mapping & Ablation in Sinus Rhythm to Halt Ventricular Tachycardia Trial), a 
prospective randomized clinical trial to objectively assess the clinical utility of substrate ablation 
of scar-related VT.  This trial was a randomized-controlled trial examining the role of substrate 
mapping and RF ablation in the primary prevention of ICD shocks in patients presenting with 
clinically life-threatening VT/VF.  That is, patients with a history of MI, and who survive an 
episode of VT/VF are at high-risk for recurrent VT and thus treated with ICDs (in essence, these 
patients meet AVID/CIDS/CASH criteria). In normal clinical practice, these patients are not 
routinely treated with adjuvant medications because of their proarrhythmic potential and side 
effects.  In addition to an ICD and routine clinical care, these patients were additionally 
randomized in SMASH-VT to substrate-based catheter ablation.  This catheter ablation group 
underwent electroanatomic mapping to delineate the endocardial infarct margins (CARTO, 
Biosense-Webster, Inc).  Substrate modification was then performed targeting the exit sites of 
induced VTs and/or late potentials within the scar using standard or irrigated radiofrequency 
ablation catheters.   
As published in late 2007,xxxvi the 30-day post-ablation mortality was zero, and there was no 
significant change in ventricular function or functional class during follow up.  During an 
average follow-up of 22.5±5.5 months, appropriate defibrillator therapy (anti-tachycardia pacing 
and shocks) occurred in 21 control (33%) and 8 ablation (12%) patients (p=0.007 by the log rank 
test).  Of these, appropriate defibrillator shocks alone occurred in 20 control (31%) and 6 
ablation (9%) patients (p=0.003).  Mortality was not increased in the ablation arm (control 17%, 
ablation 9%; p=0.29); indeed, there was a trend to decreased mortality in the ablation arm.  Thus, 
the SMASH-VT study revealed several important points: 1) adjuvant substrate based catheter 
ablation is feasible in this patient population, 2) use of a saline-irrigated RF ablation catheter for 
this ablation strategy is safe, and 3) this strategy decreases subsequent ICD therapies in post-
myocardial infarction patients receiving defibrillators for the secondary prevention of sudden 
death.   
The favorable results of SMASH-VT, combined with considerable technical and scientific 
improvements in catheter ablation of scar-related VT, also raise the possibility that the 


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therapeutic benefit of ablation may be extrapolated to similar patients in the developing world, 
who have had an MI and have survived a ventricular arrhythmic event, but are unable to afford 
an ICD.  This is of particular importance because such patients are typically treated with chronic 
Amiodarone therapy—a strategy with an unestablished mortality benefit and significant side 
effects.  
We therefore propose a randomized clinical trial, in which India—a nation with a population of 
1.2 billion—will serve as a representative model for the developing world.  The study will 
evaluate the safety and efficacy of adjunctive catheter ablation in post-myocardial infarction 
patients who have additionally survived a ventricular arrhythmic event, and would be initiated on 
chronic Amiodarone therapy because of an inability to afford ICD therapy. Patients will 
therefore be randomized in an even proportion to either a) the control group, receiving chronic 
Amiodarone therapy, or the study group, undergoing catheter ablation of VT in addition to 
chronic Amiodarone therapy.  
2.2 
Description of Device 
The NAVISTAR® THERMOCOOL® Catheter 
The NAVISTAR® THERMOCOOL® catheter is a luminal, electrophysiology electrode catheter with 
a 3.5-mm tip electrode, three ring electrodes, a location sensor and a temperature sensor 
incorporated into the 7.5 F deflectable tip (see Figure 3).  The 3.5-mm tip electrode serves to 
deliver RF current from the RF generator to the desired ablation site, and incorporates several 
small holes through which normal saline is passed for irrigation and cooling.  A temperature 
sensor is embedded in the tip electrode and is mainly used to verify that the irrigation flow rate is 
adequate. 
The tip electrode and ring electrodes are made from platinum-iridium; the spacing of the ring 
electrodes is 2-5-2.  The deflectable tip is extruded from biocompatible polyurethane and is 
comprised of three lumens:  one lumen (.022”) contains a coil spring and a puller-wire; the 
second lumen (expanded to .033”) is used for irrigation; and the third lumen (.036”) contains the 
location sensor and lead wires.  
The catheter body is single lumen high-torque 7.5 F shaft extruded from biocompatible PEBAX 
with handpiece at the proximal end.  A pullwire is anchored in the tip electrode and runs through 
Irrigation Port 
Handpiece 
Thumbknob 
Triple Lumen Deflectable Tip 
PEBAX Shaft 
Platinum/Irridium Tip 
and Rings 


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the catheter shaft to a piston in the handpiece.  A saline tube also extends from the tip, through 
the shaft to an irrigation port on the handpiece.  The irrigation port terminates in a standard Luer-
lock fitting to permit the injection of normal saline to irrigate the tip electrode. 
The irrigation is typically performed using the COOLFLOW™ Irrigation Pump.  This is a 
peristaltic pump designed for the delivery of sterile saline irrigation solution.  The pump has a 
dual rate feature for one-touch irrigation rate change between a low flow rate (1-5 ml/min) and a 
high flow rate (5-60 ml/min).  A large LED display indicates the flow rate selected.  An optional 
foot pedal can be used to initiate high flow irrigation. 
The catheter tip is deflected via the pullwire.  The piston in the handpiece is    
attached to   the pullwire   and is operated by a thumbknob.  When the thumbknob is pushed 
forward, the tip is deflected (curved).  When the thumbknob is pulled back, the tip   straightens. 
The shape of the curve depends on the deflectable tip length (2”-3”).  The high-torque shaft 
allows the plane of the curved tip to be rotated to facilitate accurate positioning of the catheter tip 
at the desired site, while the deflectable tip feature allows physicians to maneuver the catheter to 
perform both the prerequisite mapping and placement of the electrode tip for ablation.  A 
compression coil translates the force of deflection onto the piston without buckling the catheter 
shaft. 
The usable length of the NAVISTAR® THERMOCOOL® catheter is 115 cm.  The catheter is 
provided sterile. 
The NAVISTAR® THERMOCOOL® catheter is designed to work with the CARTO™ Cardiac 
Electrophysiological Mapping System (CARTO™ system) to provide the user with real-time 
anatomical and electrophysiological information.  The CARTO™ system consists of a location 
positioning sensor embedded in the tip of the NAVISTAR® THERMOCOOL® catheter, an external 
reference device (REFSTAR™), an external magnetic field generator located underneath the 
subject (locator pad), a post-processing graphical display unit (CARTO™), and a junction box 
which serves to connect the catheters to the processing unit and to the RF generator. 
The locator pad is placed beneath the operating table and includes three coils that generate 
ultralow magnetic fields.  When the catheter is moved within this magnetic field, the currents 
generated within the positioning sensor represent movement in three dimensions.  The spatial 
and temporal characteristics of the sensed magnetic fields contain the information necessary to 
determine the location (x, y, and z) and orientation (roll, yaw, and pitch) of the catheter.  The 
resolution of the location capabilities of the system has been shown to be < 1mm in both in vitro 
and in vivo studies. 
This information enables tracking of the tip of the mapping catheter within the heart, enabling 
navigation of the catheter independent of the use of fluoroscopy.  Signals generated within the 
location sensor are transmitted through a printed circuit board (PCB) in the catheter handpiece to 
the main processing unit, via the junction box.  The 3D geometry of the chamber is reconstructed 
in real time and the color-coded electrophysiological information obtained by the sensing 
electrode can be superimposed on the anatomical map. 


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3. STUDY OBJECTIVE, ENDPOINTS, AND DESIGN
3.1 
Objective 
The objective of this study is to compare Amiodarone plus substrate-based VT ablation to 
Amiodarone (usual therapy) for all-cause mortality, including cardiac arrest and sustained VT, in 
patients with recurrent VT post-MI who have survived a life-threatening VT/VF event (that is, 
AVID / CASH / CIDS criteria) but cannot afford an implantable defibrillator. 
3.2 
Endpoints 
3.2.1 Primary Endpoint 
The primary endpoint of this study is freedom from all-cause mortality, sustained VT and cardiac 
arrest, at 24 months. 
3.2.2 Secondary Endpoints 
The secondary endpoints in this study are: 
1. Proportion of subjects that die within 30 days or die by 24 months.
2. Total number of ventricular arrhythmic events, compared between the 2 treatment arms.
3. Differences in LV ejection fraction between paired measurements recorded at baseline
and 24 months, for each patient will be used to test for significant differences between the
two treatment arms.


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3.3 
Study Design 
This is a prospective, multi-center, unblinded, randomized, trial which will randomize (1:1) 136 
post-MI subjects who have survived a recent VT/VF episode, thereby mandating ICD 
implantation. However, these patients are unable to afford an ICD and thus would receive 
medical therapy with chronic Amiodarone therapy.  This study will take place at 5-15 Indian 
sites, and will compare chronic Amiodarone therapy alone (control group) and catheter ablation 
+ chronic Amiodarone therapy (study group).  Additionally, the study group will undergo a 
strategy of substrate modification or VT ablation with a saline-irrigated radiofrequency ablation 
catheter.  Follow-up will be conducted in regular intervals over a 24 month period.  All 
physicians participating in this study are expected to have previous experience using NaviStar 
ThermoCool catheter. 
Randomization
CONTROL ARM 
BBLs,ACE-I,statins,Asprin, 
Amiodarone Loading X 2months 
ABLATION ARM 
BBLs,ACE-I,Statins,Asprin, 
Amiodarone Loading X 2 months* 
catheter Ablation 
*During this 2-month period, any events that occur will be censored and not
counted to the primary endpoint. 
Ablation will be performed during the 2-months “blanking” period 
Remote MI 
Recent VT/VF Event 
Meets Inclusion Exclusion/Criteria 
Baseline evaluation: ECG, Echo 
Follow –Up 
Clinic Visits with EKG @ 3,6,9,12,18 and 24 months 
Echo @ 3 and 24 months 


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3.4 
Analysis Population 
The primary and all secondary endpoints will be analyzed on an intent-to-treat basis for all 
enrolled patients.  Patients who qualify for the study by medical history and who provide consent 
will be included in the primary analysis population, regardless of the actual sequence of 
treatments. 
4.0 PROTOCOL 
4.1 
Inclusion Criteria 
Candidates will be included in the study if all of the following conditions apply. 
1.
≥ 18 and ≤ 85 years of age
2.
History of a remote MI  (≥1 month)
3.
Survival of a ventricular arrhythmic event (VT/VF) that would mandate
placement of an implantable cardioverter-defibrillator (ICD)

[Clarification] Patients who experience a ventricular arrhythmic event
(VT/VF) while already being treated with Amiodarone (100-200 mg/day) are 
not excluded from the study.  This is permitted provided that the patient had 
been treated with Amiodarone for at least 2 months prior to experiencing the 
index VT/VF event.  These patients are randomized to either a higher dose of 
Amiodarone (e.g., 100mg/day  200mg/day or 200mg/day  400mg/day) or 
a higher dose of Amiodarone plus catheter ablation.   
4.
Patient cannot afford an ICD and thus has been planned for treatment with
Amiodarone (or an increased dose of Amiodarone) 
5.
Ability to understand the requirements of the study
6.
Willingness to adhere to study restrictions and comply with all post-
procedural follow-up requirements
4.2 
Exclusion Criteria  
Candidates will be excluded from the study if any of the following conditions apply. 
1.
Patients with NYHA class IV congestive heart failure
2.
Prior ablation for a ventricular arrhythmia
3.
Presence of an LV thrombus
4.
Contraindication to anticoagulation
5.
Inability to access the endocardium because of mechanical mitral and aortic valve
6.
Life expectance <1 year for any medical condition
4.3 
Patient Enrollment 
4.3.1 Screening Procedure 
The investigator or designated member of the research team will approach the patient to obtain 
written informed consent.  The background of the proposed study and the potential benefits and 
risks of the study will be explained to the patient.  The patient must sign the consent form prior 
to enrollment.  This form must have prior approval of the study site's Investigational Review 


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Board (IRB) or Ethics Committee (EC) prior to obtaining patient consent.  Failure to obtain 
informed consent renders the patient ineligible for the study. 
4.3.2 Informed Consent 
The investigator or designated member of the research team will approach the patient to obtain 
written informed consent.  The background of the proposed study and the potential benefits and 
risks of the study will be explained to the patient.  The patient must sign the consent form prior 
to enrollment.  This form must have prior approval of the study site's Investigational Review 
Board (IRB) or Ethics Committee (EC) prior to obtaining patient consent.  Failure to obtain 
informed consent renders the patient ineligible for the study. 
4.3.3 Randomization Procedure 
Randomization will done using treatment allocation list provided by the sponsor. The sequence 
of allocation is at random. The allocation list will be in possession with a designated person in 
the National central site. 
4.4 
Study Procedures 
4.4.1. Pre-randomization Procedures 
After the patient provides written informed consent, the following data will be collected and 
examinations and tests performed (if required data has not been previously collected within the 
specified window):  
•
Relevant history and medical exam
•
12-lead ECG
•
Baseline Echocardiogram (performed within 3 months prior to randomization)
Once the above information has been obtained and the inclusion and exclusion criteria have 
confirmed the patient’s continued eligibility, randomization will then be performed.  The patient 
will be randomized into one of the two groups: 
1. Control Group:  Amiodarone loading will be initiated in these subjects.  No further
treatment is required as a part of the study.  Further follow-up will be as detailed in this
protocol. Any VT/VF events that occur in the 2-month blanking period designated for
Amiodarone loading will not be included in the analysis.
Patients who experience a ventricular arrhythmic event (VT/VF) while already
being treated with Amiodarone (100-200 mg/day) for at least 2 months will
receive a higher dose of Amiodarone (e.g., 100mg/day  200mg/day or
200mg/day  400mg/day).  Again a 2-month blanking period will be used.
2. Study Group:  Amiodarone loading will also be initiated in these subjects.  In addition,
this group will undergo electrophysiology study with subsequent radiofrequency ablation
of their arrhythmogenic substrate, within 2 months of Amiodarone initiation. Any VT/VF
events that occur in the 2-month blanking period designated for Amiodarone loading will
not be included in the analysis.


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4.4.2. Recruiting sites: Patients for the study would be recruited at principal and satellite 
sites. Principal sites are the sites that have CARTOTM facility. Satellite sites are sites without 
CARTOTM and would refer patients for ablation procedures randomized to ablation arm to 
geographically proximate principal sites for procedures.  All other study related procedures 
including follow up would be done at the respective satellite centers as for patients in control 
arm.  
Sites identified for enrollment of the patients are the following: 
Principal sites 
1. CARE Hospitals, Hyderabad, Nagpur and Bhubaneswar.
2. CARE Institute of Medical Sciences, Ahmedabad, Gujarat
3. KEM hospital, Mumbai, Maharashtra
4. Jawaharlal Institute for Postgraduate Medical Education and Research, Puducherry,
Tamil Nadu
5. Amrita Institute of Medical Sciences, Cochin, Kerala
Satellite Sites 
1. Baroda Heart Institute, Vadodara
2. Poona Hospital and Research Centre, Pune, Maharashtra
3. Avanti Institute of Cardiology Pvt.Ltd., Nagpur, Maharashtra
4. Sri Ramachandra Medial Centre, Porur, Chennai, Tamil Nadu
5. Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh
6. Calicult Medical College, Calicut, Kerala
4.4.3 Ablation Procedure (study group only) 
•
Patient anesthesia will be administered according to standard EP lab protocol.
•
Arterial and venous access will be achieved through cannulation of the right and/or left
femoral arteries and veins as determined by the treating electrophysiologist.
•
Electrophysiology study will be performed using up to triple ventricular extrastimuli
from the right or left ventricle in standard fashion.  Before VT is deemed non-inducible,
the following stimulation attempts must be performed: i) stimulation at ≥ 2 ventricular
sites (e.g. RV apex + RV outflow tract, or RV apex + LV), ii) stimulation at ≥ 2 drive
cycle lengths, and iii) triple extrastimuli.  Of course, if VT is inducible early in the
stimulation protocol, the remaining protocol does not need to be completed if deemed
inappropriate from a safety perspective by the physician.
•
Twelve lead electrocardiograms will be obtained for all inducible ventricular
arrhythmias. An inducible sustained VT is defined as a monomorphic VT lasting >15
seconds or requiring termination with pacing or cardioversion.


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•
In order to minimize the chance of post-procedural pulmonary edema, the fluid status
(I/O, left atrial pressure if a transseptal sheath is employed, etc.) must be carefully
monitored.  Also, a Foley urinary catheter is strongly recommended for patients with an
LVEF < 25% or a clinical history of Class III congestive heart failure.  Hemodynamic
support and type of sedation are at the investigator’s discretion.
a.
Electroanatomic mapping
•
Catheter access to the LV includes retrograde aortic and transseptal approaches.  Either or
both approaches are acceptable.  The RV might also require mapping in certain patients:
e.g., interventricular septal wall involvement.
•
All patients will undergo electroanatomic mapping using CARTO (Biosense Webster,
Inc) and a saline irrigated mapping/ablation catheter (NaviStar ThermoCool catheter,
Biosense Webster, Inc).  Other Navistar catheters may be employed during the mapping
procedures, but only the ThermoCool catheter may be used for ablation.
•
CARTO is a system that uses a low intensity magnetic field to localize the mapping
catheter in space.  The accuracy of the system has been estimated at 0.8 mm and 5
degrees.  Bipolar electrograms are recorded at multiple locations in the LV endocardium
using the mapping/ablation catheter in sinus or paced rhythm.  Using the measured
electrograms, the CARTO system will create a color electroanatomic map of the LV
endocardium based on activation time (in comparison to a designated surface
electrocardiographic lead) or voltage amplitude.  Normal myocardium will be defined as
having a voltage amplitude >1.5 mV.
•
The NaviStar ThermoCool RF catheter has a 3.5mm electrode tip with a saline-
irrigation cooling system.  In addition to measuring bipolar electrograms, the catheter
maintains low electrode-tissue interface temperatures during RF application at high
powers without an impedance rise.  This allows larger, deeper lesions and reduces the
time and the risk of tip charring that can lead to coagulum formation and thromboembolic
events.
•
During electroanatomic mapping, heparin will be given intravenously as a bolus followed
by continuous intravenous infusion.  Activated clotting times (ACT) will be monitored
every 30-60 minutes with a target ACT value >250 seconds.
b.
Ablation
•
After a detailed ventricular endocardial voltage electroanatomic map is created,
radiofrequency ablation will then be performed using the NaviStar ThermoCool
catheter.
•
While a number of ablation strategies have been reported for substrate-based VT
ablation, there is one important fundamental thematic basis to this approach – namely that
a firm understanding of the location/extent of the infarcted tissue facilitates one’s ability


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to identify critical portions of various VT circuits to target for ablation.  While there is 
considerable overlap, these ablation strategies can be sub-divided into two general 
groups: i) identifying percolations of myocardial activity within the infarcted tissue that 
represent putative physiologic components of the circuit, and ii) identifying and targeting 
putative areas of exit of the VT circuits from the infarcted tissue.  These strategies can be 
further expanded as follows: 
1. Targeting percolations of myocardial activity:
a.
Entrainment mapping:  For VTs that are hemodynamically tolerable for at
least a short period of time (with or without hemodynamic support),
entrainment (or resetting) can be performed during the VT to identify regions
of the scar that participate in the circuit.  RF lesions can be delivered to these
regions.
b. Identification of diastolic potentials:  For VTs that are hemodynamically
tolerable for at least a short period of time (with or without hemodynamic
support), diastolic potentials can be identified in the area of the scar during the
VT and targeted for RF ablation.
c.
Pace-mapping can be performed to identify regions of dense scar based upon
the inability of pacing stimuli to capture any myocardium at a particular site
(using pulses of 2-ms duration, 10-mA amplitude, unipolar stimuli).xxviii
These areas of “electrically unexcitable scar” may delineate isthmuses for VT
circuits that can be transected with ablation lesions connecting these various
dense scar regions to each other and to fixed anatomical barriers (such as the
mitral valve).  Alternatively, it is possible to target channels of high voltage
surrounded by lower voltage in regions of confluent low voltage < 1.0mV.
d. Ablation of late potentials:  Another strategy involves targeting of split/late
potentials based on the observation that the late and long-duration
electrograms, despite a low specificity, were highly sensitive for identifying
VT circuits.xxix This criterion requires recording high-frequency EGMs with
multiple components separated by an isoelectric line. It is certainly true that
targeting these EGMs would invariably result in ablation of bystander sites
that may not be operative in any VTs (e.g. a “dead-end” pathway); but, this
approach has the advantage of placing ablation lesions at regions far from the
normal tissue. Of note, fractionated and late EGMs are infrequently identified
during sinus rhythm. One potential reason is that overlapping of EGMs or a
particular orientation of a line of block with respect to the activation
wavefront may preclude the identification of multiple components during
sinus rhythm. The sensitivity of identifying these components during catheter
mapping may be increased by changing the propagation wavefront during
catheter mapping by RV pacing or LV pacing (for example, from within a
ventricular branch of the coronary sinus).xxx  From a practical perspective, this
can be accomplished by pacing whenever the EGM at the site being mapped is
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e.
Ablation of sites of Latency:  The alternative, “inverse”, strategy to
identification of late potentials is to stimulate directly within the infarcted
tissue at target sites of questionable significance (that is, sites at which it is
difficult to determine if a late potential is present). Because of the limited
myocardial tissue depolarized, activation of the isthmus contributes negligibly
to the surface electrocardiogram until the wavefront of activation exits to the
normal myocardium – thereby producing the observed QRS complex.
Therefore, pace-mapping from a site more proximally-located within the
isthmus should produce a QRS complex similar to the VT QRS morphology,
albeit with a longer stimulus-to-QRS interval.  Accordingly, the duration of
the stimulus-to-QRS interval can serve as a surrogate to late potentials and can
be targeted for catheter ablation to empirically eliminate VT circuits.xxxi
2. Targeting putative VT exit sites:
a.
Pace-mapping: For hemodynamically unstable VTs, pace mapping will be
performed in the area of the scar to identify the exit sites of the VT.  Once the
substrate map is constructed, pace-mapping during sinus or paced rhythm can
be performed to localize the exit site of each inducible monomorphic VT.
When a site is found at which the paced QRS matches the QRS during VT in
12 leads, this exit site will be marked on the CARTO map.  Linear ablation
lesions that bisect this site can be made: one from the center of the substrate
through the exit site, and the second, perpendicular to the first line at the
location of the exit site.  Each line will be made up of multiple sequential
lesions placed 5-10 mm apart.  Of note, while at least one of these lines
(parallel or perpendicular to the scar border) should be placed when
employing this strategy, the physician may elect to omit one or the other line
if deemed unnecessary.  Also, in patients with LVEF < 25% and/or severe
CHF, particular care will be taken to minimize the number of lesions placed at
the borders of the scar in order to minimize any potential adverse effect on left
ventricular function.  Especially in these patients, targets deep within the scar
such as late potentials can be targeted for ablation (these lesions are less likely
to have any significant adverse effect on LV function).
b. Encircling ablation procedure:  The placement of catheter-based ablation
lesions completely around the scar (mimicking the surgical partial encircling
endocardial ventriculotomy procedure) may be employed – particularly in the
setting of a smaller identifiable scar with poor pacemap sites and no late
potentials.
•
Which ablation targets/strategy should be used?  The relative efficacy of these various
criteria to guide identification and targeting of the “arrhythmogenic” portion of the scar is
unknown. However, certain general principles can be stated.  Trying to minimize the
number of ablation lesions placed at the border zone would be advantageous in minimize
adverse effect on left ventricular function. Indeed, a strategy targeting late potentials is
particularly attractive in patients with depressed ventricular function or congestive heart


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failure. Conversely, in patients with preserved ventricular function and small or patchy 
scars it not necessarily possible to identify channels of activity, and ablation lesions based 
in large part on pace-mapping or attempts to make a series of ablation lesions to 
“encircle” the scar (to empirically transect circuits at the scar borders) would be 
appropriate. 
•
In order to minimize adversely affecting LV function, in general ablation lesions should
be confined to areas with abnormal (<1.5 mV or fractionated) electrograms.
•
During ablation, power titration should be performed as per the physician’s usual practice
to avoid thromboembolic complications.  One reasonable strategy includes careful power
titration to achieve an impedance drop not exceeding 10%.
1. Under no circumstances should the tip temperature exceed 45°C, preferably
should stay below 42°C.
•
Standard saline irrigation parameters should be used:
1. During mapping, the flow rate should be 2 ml/min.
2. During ablation, the flow rate should be 17-30 ml/min when using <30 Watts, and
at least 30 ml/min when using ≥ 30 Watts of energy.
•
As previously discussed, in order to minimize the chance of post-procedural pulmonary
edema:
1. The fluid status (I/O, left atrial pressure if a transseptal sheath is employed, etc.)
must be carefully monitored
2. A Foley urinary catheter is strongly recommended for patients with an LVEF <
25% or a clinical history of Class III congestive heart failure.
3. IV diuresis should be considered after the infusion of 1 liter of saline through the
ablation catheter.
4. Additional hemodynamic/inotropic support may be used at the investigator’s
discretion.
•
Regardless of the ablation strategy used, the overall length of the procedure should not
exceed a maximum time limit of 8 hours.
•
Percutaneous pericardial mapping and ablation is not to be employed in this study.
•
During the ablation, an intravenous heparin infusion will be maintained for a target ACT
>250 seconds.  ACTs will be monitored every 30-60 minutes.
•
Following completion of the ablation, the heparin infusion will be discontinued.  The
arterial and venous sheaths will be removed and hemostasis achieved with either (or
both):
1. Manual pressure once ACT <200 sec (protamine may be used to facilitate this).


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2. Percutaneous vascular closure devices may also be employed as per the institution’s
practice.
4.4.4. Post-procedure Hospitalization 
•
Post-ablation patients will be admitted overnight to a telemetry unit for monitoring.  The
following medication regimen will be observed: 
1. Intravenous heparin will be administered overnight.  Weight-adjusted low
molecular weight heparin may be given subcutaneously until the INR ≥2.0. 
2. Warfarin will be initiated within the hospital and continued for at least 4-6
weeks following ablation (target INR 2-3).  Alternatively, if the number of
ablation lesions is minimal, aspirin treatment alone (325 mg QD) may be
prescribed as per the physician’s judgment.
4.5 
Follow-up 
Routine follow-up will be at 3, 6, 9, 12, 18 and 24 months. Each visit will consist of the 
following as detailed in the case report forms (see attached): 
1. Review of hospitalization and ER/OFFICE visits for VF/prolonged VT
2. Documentation of medication changes
3. Documentation of interim adverse events
4. Transthoracic echocardiogram (at 3 and 24 month visits only).
5. ECG at Every Visit
5.0 
STATISTICAL RATIONALE AND ANALYSIS PLAN 
5.1 
General Considerations 
The primary objective of this study is to investigate whether catheter ablation treatment can be 
effective and safe in prolonging survival free from recurrent VT/VF events in post-MI patients 
who have survived a recent VT/VF event, and have been planned for Amiodarone therapy 
because of an inability to afford an ICD. The study is designed as a prospective, multi-center, un-
blinded, randomized (1:1) clinical trial with the goal of comparing two treatment arms: an 
Amiodarone control and Amiodarone + catheter study group.  
The null hypothesis of principal interest is that there will be no difference at 24 months between 
the two treatment arms in patient survival that is free from all-cause mortality, cardiac arrest, and 
sustained VT after a 2-month blanking period. As secondary objectives, the study will compare 
the following additional measures of efficacy between the catheter-ablation treated and the non-
treated groups: I) the proportion of subjects that die within a) 30 days, or b) by the end of the 
study (~24 months); II) the total number of ventricular arrhythmic events; III) differences in LV 


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ejection fraction between paired measurements recorded at baseline, 3 months and 24 months for 
each patient. 
The primary efficacy measure will be analyzed using Kaplan-Meier methods. xxxii  The log-rank 
test will be used to test for difference in event-free survival between the two treatment groups. 
Treatment group differences between survival curves will be further assessed using the stratified 
log-rank test (stratified by primary versus secondary prevention category). Because this study 
involves many centers with relatively small enrollment size per center, data from all centers will 
be pooled for analyses. The Cox proportional hazards model will be used to further explore 
relationships between event-free survival in the two treatment groups and covariates of interest.  
5.2 
Analyses Datasets 
5.2.1 Intent-to-Treat (ITT) Analysis Set.  The ITT population will consist of all enrolled 
patients who have provided consent and have qualified on the basis of inclusion/exclusion 
criteria. All patients in the ITT population will be randomized and included in the analysis of all 
primary and secondary endpoints. A list of major protocol violations will be identified in the 
Statistical Analysis Plan (SAP). Protocol violations will be summarized by treatment and 
clinically-relevant demographic and baseline characteristic groups. 
5.2.2 Safety Analysis Set. The ITT population will also be considered as the safety population. 
All randomized patients will be included in the analysis of safety, demographic, and baseline 
characteristic data. 
5.3 
Sample Size and Statistical Power 
Sample size calculation is based on the primary hypothesis that there will be a difference in 
survival curves between the ICD control and the ICD + catheter ablation groups. Fifty percent of 
patients are expected to meet the primary endpoint in the control arm, and a 50% reduction in the 
primary endpoint is expected in study group patients undergoing adjuvant catheter ablation.  The 
sample size was calculated using the log-rank test with a significance level of α=0.05 and 80% 
statistical power xxxiii (nQuery Advisor Version 6.0). This study is powered (at 80%) to detect at 
least a 30% decrease in the primary endpoint based upon the results of the SMASH-VT study 
xxxvi and another study. xxxix  The required sample size is 68 patients per treatment arm, or a total 
sample size of 136.    
 Plan for Sample Size Re-estimation 
A single interim analysis will be performed after one-half of patients reach a study endpoint. The 
group sequential approach of Lan and Demets will be used, with an O’Brien-Fleming type 
spending function. The critical value will be 2.96 for the interim analysis and 1.97 for the interim 
analysis.  
 As part of the group sequential monitoring plan for this trial, we will consider re-estimating the 
sample size at the proposed interim analysis based on the trial’s conditional power at the interim 


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analysis. Sample size might be re-estimated if event rates were different from expected or if the 
effect size were different than expected.  Our approach for maintaining the trial’s Type I error 
rate should the sample size be re-estimated will be based on that described by Wassmer, which is 
based on pooling the p-values obtained from each of the trial’s two stages through the inverse 
normal method. This method, which maintains the Type I error of the trial employs weights 
(w1,w2) based on the information fraction at which the single interim analysis will be performed, 
i.e., w1=
n
n /
1
 and w2=
n
n
n
/)
(
1
−
 (where n is the pre-determined total sample size and n1 is 
the number randomized at the time of the first interim analyses (more generally, these weights 
would be based on the information fractions at the time of the one (or more) interim analysis).  
The terminal critical value will be determined by 
)
1(
)
1(
)
,
(
2
1
2
1
1
1
2
1
p
w
p
w
p
p
−
Φ
+
−
Φ
=
−
−
π
 
where p1 and p2 are the p-values associated with the statistical test of the primary endpoint 
performed using data collected during each stage (i.e., prior and subsequent to the interim 
analysis),
1
2
2
2
1
=
+ w
w
, and 
)
(
1 ⋅
Φ −
 represent the inverse-normal cumulative distribution function. 
The analysis informing the sample size re-estimation will be performed by an independent 
statistician. 
5.4 
Randomization 
Study subjects will be randomly assigned to one of the 2 treatment arms. This will be done with 
pre-numbered Treatment Allocation List (random assignment of numbers) which will be in 
possession with the National central site. Each set will contain equal numbers of Control and 
Study group randomization results, in random order. 
5.5 
Treatment Group Comparability at Baseline 
The comparability among treatment groups will be evaluated with respect to all clinically 
relevant demographic and baseline characteristic variables. All randomized patients will be 
included in the analysis of demographic and baseline characteristics.  
5.6 
Safety Analyses 
All randomized patients will be included in the safety analyses. Descriptive statistics and listings 
will be generated for all safety parameters in the study. Adverse events information will be 
collected throughout the study and listed by patient. Summary statistics will be presented for 
treatment-emergent adverse events (AE) under 4 categories (as defined in section 5.0): (i) death, 
(ii) serious adverse event (SAE), and (iii) anticipated adverse event (ADE). Each monitored 
adverse event will be described in detail in the SAP and will include specification of each 
variable with its operational unit of measurement.  
5.7 
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Interim and futility analyses will be performed at one year. The study will be terminated if the 
study demonstrates a significant mortality benefit from ablation, or conversely, significant 
increase in mortality with ablation. 
6.0 ADVERSE EVENT HANDLING 
6.1 
Adverse Events 
An adverse event is any undesirable experience (sign, symptom, illness, abnormal laboratory 
value, or other medical event) occurring in a subject that could be associated with the 
investigational product(s) that appears or worsens during a clinical study.  Significant device 
failure may constitute an adverse event if an undesirable experience occurs. 
Adverse events information will be collected throughout the study.  Adverse events will be 
recorded on the case report forms by the investigator or designee.  Event, date of onset, severity, 
duration, and relationship to device will be recorded on the appropriate case report form. 
Adverse events will be followed until they are adequately resolved, stabilized or explained.  A 
list of adverse events, which may result from this procedure, is located in Section 6.4. 
6.2 
Serious Adverse Events and Death 
The investigator must decide whether each event meets the definition of a “serious” adverse 
event.  The regulatory definition of a serious adverse event is an event that is fatal or life 
threatening, results in persistent or significant disability, requires intervention to prevent 
permanent impairment/damage, or an event that results in congenital anomaly, malignancy, 
hospital admission or prolongation of hospitalization.   
Any serious adverse event or subject death occurring during the follow-up period, regardless of 
cause, must be reported to the Study Principal Investigator and HCRI within one working day 
after the investigator first learns of the event. 
6.3 
Unanticipated Adverse Device Effects 
An Unanticipated Adverse Device Effect (UADE) is defined as any serious adverse effect on 
health or safety or any life-threatening problem or death that is caused by or associated with an 
investigational device.  The effect must have not been previously identified in nature, severity or 
degree of incidence in the investigational plan.  Other serious problems associated with the 
device that effect the rights or welfare of study subjects may also be considered UADEs. 
A list of expected adverse events is provided in Section 6.4.  The occurrence of expected adverse 
events should be reported using the appropriate CRF. 
UADEs must be reported to the Study Principal Investigator, the Institutional Review Board 
(IRB)/Ethics Committee (EC) and the Mount Sinai Coordinating Center within one working day 
after the Investigator first learns of the effect.   


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6.4 
Anticipated Adverse Events 
The following ANTICIPATED EVENTS have been identified as possible complications of the 
electrophysiology study and VT ablation procedure with a saline-irrigated ablation catheter. 
•
Allergic reactions can occur to the local anesthetic, sedatives, x-ray dye, heparin, protamine,
or other agents administered during the procedure.
•
Arterial or venous injury including arterial dissection, thrombosis, occlusion or hemorrhage
at the catheter insertion sites or at other sites along the vessels (risk <1%).   This may result
in hemorrhage, hematoma or ischemic injury to an extremity or major organ.
•
Hemorrhage as a result of anticoagulation (risk <0.5%) that may require transfusion.
•
Infection, either at the catheter insertion site or systemically, including endocarditis and
septic emboli (risk <0.5%).  This risk can be minimized by using standard aseptic technique
and, when indicated, by the use of antibiotic agents.
•
Radiofrequency current may cause occlusion of a coronary artery, either by direct thermal
damage, spasm, or thrombosis (risk <0.5%).  The risk of this complication may be higher
when epicardial ablation is performed.  Coronary arterial occlusion could produce
myocardial infarction, angina or death. Should occlusion of a coronary artery occur for any
reason, the physician will attempt to restore coronary blood flow through pharmacological,
catheter and/or surgical intervention as medically indicated.
•
The application of radiofrequency current close to the AV node or His bundle could damage
or destroy the normal AV conduction system, producing complete heart block.  Patients will
be protected due to the presence of back-up pacing from the ICD.  However, if this
complication does occur, patients may need an addition of an atrial lead (if not already
present) and upgrade of the ICD to a dual chamber device.
•
A thrombus may form on the ablation electrode during the application of radiofrequency
current, usually indicated by an impedance rise. The thrombus might become dislodged and
embolize to produce a stroke, myocardial infarction, or other ischemic injury. The risk of an
embolus is reduced by quickly terminating the application of current after an impedance rise,
which limits the size of the coagulum on the electrode.
•
The placement of linear lines of ablation may require a large number of RF lesions to be
delivered to the left ventricle.  The risk of stroke due to embolization of thrombus is
approximately 1%.  To minimize this risk, patients will be heparinized to an activated
clotting time of greater than 250 seconds during the procedure.
•
Thrombus formation on the endocardium following ablation may produce an arterial or
pulmonary embolus. This risk may be reduced by the use of aspirin or other anticoagulant
therapy, at the discretion of the investigator.
•
Cardiac perforation may result from catheter manipulation or application of radiofrequency
current (risk is <1%).  This may result in cardiac tamponade and may require percutaneous
pericardial drainage or surgical repair.  Significant hemodynamic compromise can result in
neurological injury or death.  An increased risk of cardiac perforation may be associated with
the use of saline-irrigated electrode catheter due to its creation of a larger, deeper RF lesion.
•
Injury to a cardiac valve may result from catheter manipulation or the application of
radiofrequency current (risk <1%). This may produce valvular insufficiency and possibly
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•
Radiation exposure during the fluoroscopic imaging of the catheters may result in an increase
in the lifetime risk of developing a fatal malignancy (0.1%) or a genetic defect in offspring
(0.002%).
•
The risk associated with use of the saline-irrigated electrode catheter rather than the standard
electrode catheter is expected to be small.  The larger RF lesion size produced with this
catheter could theoretically increase pain associated with RF applications and may increase
the risk of cardiac rupture (in practicality, this has not been observed in clinical studies).
Increased pain, however, can be managed with intravenous analgesics.  Additionally, use of
the cooled electrode tip catheter may reduce procedural time, fluoroscopy time and increase
procedural success by increasing lesion depth and by minimizing coagulum formation that
necessitates removal and re-deployment of the catheter.  The risk of cardiac rupture is
minimized by having experienced, thoroughly trained electrophysiologists with experience in
VT ablation perform the procedures.  Pulmonary edema secondary to the volume load from
the saline-irrigated catheter is possible; certainly, some amount of a saline load is expected.
For example, a procedure lasting 5 hours with a total of 30 minutes of RF ablation delivered
would result in the delivery of 1.5 liters of fluid from the ablation catheter irrigation alone.
Diuretics will be given to minimize this possibility.
•
Rales, pulmonary edema, ARDS and asthmatic attack can be sequelae of aspiration
pneumonia and nosocomial pneumonia.  Aspiration of gastric contents can occur when
subjects are intubated, and nosocomial pneumonia is well documented as the second most
common nosocomial infection.  It is now more common in surgical subjects than surgical-site
or wound infection. Although it is not a direct comparison, in various cardiac surgical
procedures, the incidence of aspiration pneumonia and nosocomial pneumonia range from
2% to 6.5%.
•
Phrenic nerve can be a sequela of epicardial radiofrequency ablation.
•
The electromagnetic field required to use the CARTO mapping system is extremely weak
and not known to be associated with any side effects.  It has been safely used with ICDs and
has no known adverse effects.
•
Proarrhythmia, another hypothetical risk, has not been reported with VT ablation.  All
patients involved in the study will be protected against potential life threatening arrhythmias
with ICDs.
•
Ablation could potentially worsen left ventricular function.  However, the tissue being
ablated in these patients will be scar tissue as identified by substrate mapping.  Ablation in
this scar region should cause minimal, if any, impairment of left ventricular function.
Furthermore, as stated above in the Description of Treatments section, every effort will be
made to place lesions within the scar, and to minimize the number of lesions placed in
normal myocardial tissue.
7.0 RISK ANALYSIS 
7.1 
Risks   
7.1.1.   Electrophysiology study and ablation 
•
Electrophysiology study and VT ablation are associated with risks including:


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1. Bleeding
2. Vascular injury
3. Arrhythmia
4. Cardiac perforation
5. Heart block
6. Thromboembolism including stroke.  Ablation in the left ventricle has an
associated 0.5-1% risk of stroke (a risk that is further minimized by use of the
saline irrigated ablation catheter).
•
The electromagnetic field required to use the CARTO mapping system is extremely weak
and not known to be associated with any side effects.
•
The placement of linear lines of ablation may require a large number of RF lesions to be
delivered to the left ventricle--this may increase the risk of stroke to approximately 1%.
To minimize this risk, patients will be heparinized to an activated clotting time of greater
than 250 seconds during the procedure.
•
Proarrhythmia, another hypothetical risk, has not been reported with VT ablation.
•
Ablation could potentially worsen left ventricular function.  However, the tissue being
ablated in these patients will be scar tissue as identified by substrate mapping, and its
exclusion should cause minimal, if any, impairment of left ventricular function.
Furthermore, as stated above in the Description of Treatments section, every effort will
be made to minimize the placement of ablation lesions in normal ventricular tissue.
7.2 
Benefits 
•
The major potential benefit of undergoing substrate modification is the possibility of
providing an alternative to ICD therapy in patient populations unable to afford it. 
•
Data from the preliminary study, SMASH-VT (described in part in the Introduction-
Background section above), revealed a decrease in the overall mortality of patients
enrolled in the ablation+ICD vs. ICD alone arms (8.3% vs. 14.12%, respectively; p =
0.12; unpublished observations: V.Y. Reddy, P. Neuzil & M.E. Josephson).  While these
data are preliminary, are not statistically significant and include patients post-ICD
implantation, they do at least raise the potential for a mortality benefit from adjunctive
substrate modification.
8.0 STUDY ORGANIZATION AND STUDY COMMITTEES 
8.1 
Principal Investigators 
The Principal Investigator for this trial is Vivek Y. Reddy, MD. The National (India) lead 
investigator is Dr. C. Narasimhan, MD, DM. 
8.2 
Executive Committee  
The Executive Committee will approve the final trial design and protocol issued to the Data and 
Safety Monitoring Board (DSMB) and the clinical sites.  This committee by majority vote will 
also be responsible for reviewing the final results, determining the methods of presentation and 
publication, and selection of secondary projects and publications by members of the Steering 


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Committee.  The Executive Committee will also have sole discretion for stopping or otherwise 
modifying the trial based on the recommendations of the DSMB. 
The Executive Committee includes: 
8.3 
Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) is an independent safety oversight board.  They 
are responsible for review of the data for safety and for making recommendations to the 
Operations Committee regarding endpoint analysis and any potential problems.  An initial 
DSMB meeting will occur shortly after beginning the trial to establish a charter and set trial 
guidelines.  Planned meetings will occur during patient enrollment per the committee’s 
discretion, and more often as required by observed events. If the DSMB determines the trial 
should be stopped early either because of efficacy or safety concerns, or otherwise modified, the 
DSMB will prepare formal written recommendations to the Executive Committee to consider 
final action. Moreover, any safety concerns that the DSMB identifies will be verbally 
communicated to both the Executive Committee as soon as possible, prior to written 
documentation.   
The DSMB will consist of at least one Statistician and several Cardiologists with expertise in 
electrophysiology.  Members will not have any affiliation with the manufacturers of the ablation 
catheter used in the study, be participating as a study investigator or be the Study Principal 
Investigator of the trial.   
The tentative members of the DSMB are (note that this may change with circumstances): 
Jonathan Halperin MD, Mount Sinai (Chair) 
Jacob Koruth MD, Mount Sinai 
K.K. Narayanan Namboodri MD, SCT Trivandrum 
Michael K. Parides (Statistician) 
O. Sai Satish MD, Nizam’s Institute of Medical Sciences 
8.4 
Clinical Events Committee 
The Clinical Events Committee (CEC) will be responsible for adjudicating all clinical events 
associated with the primary and secondary endpoints and significant device related 
complications reported during the study.  The CEC membership consists of invasive 
cardiologists and non-invasive cardiologists, some of whom will have a specialty in 
Vivek Y. Reddy, MD 
Principal Investigators 
Andre d’Avila, MD 
Srinivas Dukkipati, MD 
Calambur Narasimhan, MD  
Associate Principal Investigators 


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electrophysiology and arrhythmia management, who are not participating in the study and do not 
sit on other similarly related study committees. 
9.0 ETHICAL AND REGULATORY CONSIDERATIONS 
9.1. 
 Role of the Coordinating Center 
As principal investigator and study sponsor of this clinical study, Vivek Y. Reddy, MD assumes 
the overall responsibility for the conduct of the study, including assurance that the study meets 
national and institutional guidelines for study conduct.  In this study, Vivek Y. Reddy, MD will 
have certain direct responsibilities and will delegate other responsibilities to his staff at the Data 
Coordinating Center at Icahn School of Medicine at Mount Sinai. Together, the coordinating 
center will: 1) ensure adherence to the national and institutional regulations and the sponsor 
general duties; 2) develop and distribute protocols and case report forms; 3) coordinate data 
organization; 4) forward adverse event reporting to the DSMB; 5) perform statistical analyses. 
9.2. 
Maintaining Records 
The Data Coordinating Center will maintain copies of correspondence, data, adverse device 
effects and other records related to the clinical trial.   
9.3. 
Site Record Retention Policy 
All clinical sites will maintain study records for two years after research termination. 
9.4. 
Informed Consent and Institutional Review Board (IRB) / Ethics 
Committee (EC) 
All patients must provide written informed consent in accordance with the local clinical site’s 
IRB/EC.  A copy of the consent form from each center must be forwarded to HCRI for review 
and approval.  The principal investigator at each site must provide HCRI with a copy of the 
clinical site’s IRB/EC approval for the protocol.  Yearly approvals for the continuation of the 
trial at each clinical site must also be forwarded to HCRI. The IRB/EC of the principal sites will 
have the dual responsibility for overseeing the activities of both the principal site and the 
respective satellite site (s) attached to them.  
9.5. 
 Patient Confidentiality 
Patient confidentiality will be maintained throughout the clinical study in a way that assures that 
data can always be tracked back to the source data. For this purpose, a unique subject 
identification code (ID number and patient name code) will be used that allows identification of 
all data reported for each subject.  
Data relating to the study might be made available to third parties (for example in case of an 
audit performed by regulatory authorities) provided the data are treated confidential and that the 
patient’s privacy is guaranteed. 
10.0 STUDY MANAGEMENT 


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Central Site in India: CARE Hospital, Banjara Hills, Hyderabad will be the National Central 
Site. The Central Site will be responsible for the coordination of study activities of the various 
sites in India.   
10.1. Study Data Collection and Processing 
The Case Report Form (CRF) is an integral part of the study and subsequent reports.  The CRF 
must be used to capture all study data recorded in the patient’s medical record.  The CRF must 
be kept current to reflect patient status during the course of the study.  Only a patient 
identification number and patient initials will be used to identify the patient.  The investigator 
must keep a separate log of patient names and medical record numbers (or other personal 
identifiers) for their own reference. 
The PI is responsible for ensuring the following at his/her site: 1) adherence to the protocol; 2) 
verifying adherence to local regulations on the conduct of clinical research; and 3) ensuring 
completeness, accuracy, and consistency of the data entered in the CRF. 
Final CRFs in human readable format must be reviewed and verified for accuracy by the study 
site Principal Investigator and signed-off.  A copy of the final CRF will remain at the 
investigator’s site at the completion of the study.  All completed CRFs will be sent to central site 
where data screening will be done. Data queries will be generated at the central site and 
disseminated to respective sites for query resolution.  Data entry done at the central site will be 
shared with the coordinating center. 
10.2 Institutional Review Board (IRB) / Ethics Committee (EC) Information 
This protocol and the informed consent must be reviewed and approved by the appropriate 
IRB/EC where the trial is to be conducted before enrollment of patients.  Changes to the protocol 
that may increase the risk or present new risks to the patient, or may adversely affect the validity 
of the trial, must be approved in writing by the IRB/EC before the change is made. 
The study site Principal Investigator(s) is responsible for submitting and obtaining initial and 
continuing review (at intervals not greater than once a year) of the trial by their IRB/EC. 
10.3 Deviations from Protocol 
The investigator will not deviate from the protocol except in medical emergencies or in 
unforeseen, isolated instances where minor changes are made that will not increase the patient’s 
risk or affect the validity of the trial.  In medical emergencies, prior approval for protocol 
deviations will not be required, but the IRB/EC must be notified within five days of the incident. 


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