INTERVENE: Indian Trial of Endocardial Ventricular Substrate Ablation to Prevent Recurrent VT Events
INTERVENE: Indian Trial of Endocardial Ventricular Substrate Ablation to Prevent Recurrent VT Events
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.
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.
Inclusion Criteria:

 -  ≥ 18 and ≤ 85 years of age

 -  History of a remote MI (≥1 month)

 -  Survival of a ventricular arrhythmic event (VT/VF) that would mandate placement of an
 implantable cardioverter-defibrillator (ICD) (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.)

 -  Patient cannot afford an ICD and thus has been planned for treatment with Amiodarone
 (or an increased dose of Amiodarone)

 -  Ability to understand the requirements of the study

 -  Willingness to adhere to study restrictions and comply with all post- procedural
 follow-up requirements

 Exclusion Criteria:

 -  Patients with NYHA class IV congestive heart failure

 -  Prior ablation for a ventricular arrhythmia

 -  Presence of an LV thrombus

 -  Contraindication to anticoagulation

 -  Inability to access the endocardium because of mechanical mitral and aortic valve

 -  Life expectance <1 year for any medical condition