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A Prospective, Multicentre Randomised Controlled Trial Comparing Catheter Ablation Versus Antiarrhythmic Drugs in Patients With Structural Heart Disease Related Ventricular Tachycardia: The CAAD-VT Trial Protocol
Corresponding author at: Associate Professor Saurabh Kumar, Cardiology Department, Westmead Hospital, Corner Hawkesbury and Darcy Roads, Westmead, New South Wales 2145, Australia
Randomised trials have shown that catheter ablation (CA) is superior to medical therapy for ventricular tachycardia (VT) largely in patients with ischaemic heart disease. Whether this translates to patients with all forms and stages of structural heart disease (SHD—e.g., non-ischaemic heart disease) is unclear. This trial will help clarify whether catheter ablation offers superior outcomes compared to medical therapy for VT in all patients with SHD.
Objective
To determine in patients with SHD and spontaneous or inducible VT, if catheter ablation is more efficacious than medical therapy in control of VT during follow-up.
Design
Randomised controlled trial including 162 patients, with an allocation ratio of 1:1, stratified by left ventricular ejection fraction (LVEF) and geographical region of site, with a median follow-up of 18-months and a minimum follow-up of 1 year.
Setting
Multicentre study performed in centres across Australia.
Participants
Structural heart disease patients with sustained VT or inducible VT (n=162).
Intervention
Early treatment, within 30 days of randomisation, with catheter ablation (intervention) or initial treatment with antiarrhythmic drugs only (control).
Main outcomes, measures, and results
Primary endpoint will be a composite of recurrent VT, VT storm (≥3 VT episodes in 24 hrs or incessant VT), or death. Secondary outcomes will include each of the individual primary endpoints, VT burden (number of VT episodes in the 6 months preceding intervention compared to the 6 months after intervention), cardiovascular hospitalisation, mortality (including all-cause mortality, cardiac death, and non-cardiac death) and LVEF (assessed by transthoracic echocardiography from baseline to 6-, 12-, 24- and 36-months post intervention).
Conclusions and Relevance
The Catheter Ablation versus Anti-arrhythmic Drugs for Ventricular Tachycardia (CAAD-VT) trial will help determine whether catheter ablation is superior to antiarrhythmic drug therapy alone, in patients with SHD-related VT.
Trial Registry
Australian New Zealand Clinical Trials Registry (ANZCTR)
]. The evidence for the efficacy of CA as an adjunct to antiarrhythmic drugs (AADs), was largely based on four major randomised trials, which demonstrated that CA significantly reduces VT recurrence [
Catheter ablation for ventricular tachycardia (VT) in patients with ischemic heart disease: a systematic review and a meta-analysis of randomized controlled trials.
Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial.
Impact of Substrate Modification by Catheter Ablation on Implantable Cardioverter-Defibrillator Interventions in Patients With Unstable Ventricular Arrhythmias and Coronary Artery Disease: Results From the Multicenter Randomized Controlled SMS (Substrate Modification Study).
], compared to medical therapy in patients with ischaemic cardiomyopathy (ICM) and recurrent VT. More recently, two randomised trials have demonstrated efficacy of VT ablation in patients with both ischaemic and non-ischaemic cardiomyopathy (NICM) [
Does timing of ventricular tachycardia ablation affect prognosis in patients with an implantable cardioverter defibrillator? Results from the multicenter randomized PARTITA Trial.
First-line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy concurrent with defibrillator implantation: the PAUSE-SCD randomized trial.
]. However, there remains limited data on the efficacy of CA in all forms of SHD related VT including early or advanced ICM, and all aetiologies of NICM.
Important differences exist between ischaemic and non-ischaemic substrate, which influence VT patterns and response to CA [
]. Ischaemic scar is located in specific vascular territories, with ischaemia progressing from subendocardial to transmural myocardium, depending on the degree of infarction. In contrast, the heterogeneity of NICM dictates the differing anatomical distribution and progression of non-ischaemic scar, with patchy, intramural and epicardial substrate more commonly present [
Contrast-enhanced MRI-derived scar patterns and associated ventricular tachycardias in nonischemic cardiomyopathy: implications for the ablation strategy.
Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars.
]. Whilst there is a preponderance of identifiable ablation targets in ischaemic substrate (e.g., local abnormal ventricular activities [LAVAs], late potentials and conducting channels) these are often absent or not identifiable in non-ischaemic substrate. The latter often have deep septal substrate that may be beyond the reach of contemporary radiofrequency (RF) ablation [
], and/or have substrate that is located in close proximity to the His bundle, phrenic nerve, or coronary arteries. Indeed, comparative studies have shown worse outcomes of CA in patients with non-ischaemic, compared to ischaemic cardiomyopathy who have drug refractory VT [
]. Furthermore, there is uncertainty if CA is more effective than standard AADs across all patients with structural heart disease (SHD) and recurrent VT.
This multicentre randomised controlled trial will seek to clarify the optimal management of patients in real-world settings by comparing CA to AAD therapy alone for the treatment of all forms of SHD-related VT.
Methods
Study Design and Randomisation
Study design
This will be a multicentre, parallel group, un-blinded randomised clinical trial. One hundred and sixty-two (162) patients with SHD and spontaneous or inducible VT during electrophysiology study will be recruited and followed for a median of 18 months, after intervention with CA or AAD therapy.
Assignment of interventions and randomisation
Randomisation will be in the ratio 1:1. Randomisation will be by a computer-generated randomisation list using randomly varying block sizes of two, four, or six. Randomisation will be performed using a secure, password-protected web portal and the allocation sequence will be blinded to investigators and participants until the participants have been deemed eligible and enrolled in the study. It will not be possible to maintain blinding after study enrolment because the intervention is invasive. Randomisation will incorporate stratification according to:
1.
Left ventricular ejection fraction (LVEF) ≤35% or >35%.
2.
Geographical region of recruitment site (Metropolitan Sydney, Greater NSW, Australian Capital Territory, Queensland, Victoria, South Australia).
Participants, Interventions, and Outcomes
Study setting and recruitment
Patients will be identified from a home-monitoring/device clinic database at the treating hospitals, screening medical records of patients with VT who are presenting or have presented in the prior 6 months to cardiology clinics, device clinics and hospital wards at the treating hospital.
Eligibility Criteria
Inclusion criteria
Patients will be eligible if they have:
1.
≥1 prior episode of sustained VT in the prior 6 months;
a.
Spontaneous VT: ≥1 episode of monomorphic VT treated by anti-tachycardia pacing (ATP) and/or internal shock by an implantable cardioverter defibrillator (ICD); lasting ≥30 seconds in the absence of intra-cardiac device therapy (e.g., documented on Holter, electrocardiogram [ECG], loop recorder or other cardiac monitoring device) that could either be self-terminating or requiring reversion by pharmacological therapy or external cardioversion.
b.
Inducible VT: Inducible VT defined as sustained monomorphic VT of cycle length ≥200 ms lasting for ≥10 seconds during a cardiac electrophysiology study in the prior 6 months.
2.
Already a recipient of an implanted cardiac device such as a pacemaker, defibrillator, or a cardiac resynchronisation therapy device and/or is indicated to receive one given a new diagnosis of SHD (SHD included ischaemic and non-ischaemic cardiomyopathies, with the latter comprising idiopathic dilated cardiomyopathy, genetic cardiomyopathies, infiltrative cardiomyopathies, chemotherapy induced cardiomyopathy, congenital heart disease and valvular heart disease), based on current guideline recommendations [
2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary: a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
Patients will be excluded if they meet any of the following criteria:
1.
Unable or unwilling to provide informed consent;
2.
Women who are pregnant or breast feeding;
3.
Suffering from a medical illness with an anticipated life expectancy <3 months;
4.
Unable to complete study procedures or unwilling to be followed up;
5.
Suffering from a concomitant illness, physical impairment or mental condition which in the opinion of the study team/primary care physician could interfere with the conduct of the study including outcome assessments;
6.
Known to have a channelopathy such as long QT, short QT, Brugada syndrome, catecholaminergic polymorphic VT;
7.
Known to have a prior diagnosis of a structurally normal heart [
Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
] (SHD included ischaemic and non-ischaemic cardiomyopathies, with the latter comprising idiopathic dilated cardiomyopathy, genetic cardiomyopathies, infiltrative cardiomyopathies, chemotherapy induced cardiomyopathy, congenital heart disease and valvular heart disease), or known idiopathic VA.
Interventions
Study treatment
Patients in both arms will be managed with appropriate, clinically indicated standard medical therapy by their usual medical practitioners. Standard medical therapy may include:
1.
Optimisation of heart failure status to achieve a euvolemic state with initiation or escalation of diuretics.
2.
Standard medical therapy known to improve outcomes in cardiomyopathy including initiation and titration of beta blockers, angiotensin converting enzyme inhibitors or angiotensin receptor blockers or angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, sodium glucose co-transporter 2 inhibitors and ivabradine.
Control arm
Patients randomised to the control arm will be managed with AAD therapy alone by their usual medical practitioners. A protocol aligned with current clinical guidelines will be provided for guidance (Figure 1). The objective being that the control arm replicates what would constitute standard of care for patients with VT managed with a non-interventional approach [
]. This guidance was based on the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock (VANISH) trial, though we intentionally did not want to be prescriptive, in an attempt to replicate clinical practice.
Figure 1Example guideline approach to medical management.
1. Amiodarone naive – 400 mg twice daily for 2 weeks, 400 mg once daily for 4 weeks, then 200 mg once daily thereafter.
2. Failed <300 mg/day of amiodarone – 400 mg twice daily for 2 weeks, 400 mg once daily for 1 week, then 300 mg once daily thereafter.
∗∗ Specific beta blocker used left to the discretion of the treating cardiologist.∗∗∗Sotalol to be commenced at 160 mg/day, with an increase up to a maximum tolerated/clinically appropriate dose (maximum dose 640 mg/day).
Standard clinical care would usually encompass patients who are AAD naive being commenced on sotalol using a total dose of 160 mg/day, up to a maximum tolerable or recommended does (maximum dose 640 mg/day). A lower dose may be initiated by the treating physician, as clinically indicated. If there is contraindication to sotalol, an alternative beta blocker may be initiated using standard doses. Clinicians may consider an alternative AAD if there is a contraindication to a beta blocker, with dosing up titrated to the maximal tolerated doses.
If the patient was already on an AAD other than amiodarone at the time of recruitment, a clinician may choose to commence amiodarone. They will receive a loading dose of 400 mg twice daily for 2 weeks, followed by 400 mg/day for 4 weeks and 200 mg/day thereafter [
]. Patients who have “failed” amiodarone of dose <300 mg/day will receive a repeat loading dose of 400 mg twice a day for 2 weeks, followed by 400 mg/day for 1 week, and 300 mg/day thereafter [
]. Alternatively, a clinician may decide that increasing the dose of the original failed AAD is more appropriate, rather than initiating amiodarone. The trial has specifically been designed to accommodate this, replicating usual clinical care.
The use of additional AADs or changes to drug treatment may be performed by the treating physician. If VT recurs, the AAD dose can be increased at investigator discretion, or an additional AAD such as mexiletine, be added at the discretion of the treating physician. However, long-term administration of >400 mg amiodarone per day is not advised. For patients who do not tolerate the recommended dosing outlined above, the dose can be reduced to a tolerated dose at the discretion of the treating physician. If the patient cannot tolerate any of the above drugs or has a contraindication to their use, then the treating physician will opt for the drug of choice for the treatment of VT.
If the treating physician during the time-course of the trial decides to perform VT ablation, the occurrence and time point of this cross-over will be recorded. Cross-over is estimated to be <2% as per the VANISH trial [
], as patients are usually referred for ablation if medical therapy has failed (i.e., recurrent VT), in which case the primary endpoint would have been met, before cross-over occurs. In the rare instance where a primary endpoint has not been met but cross-over has occurred, analysis will be performed using the ‘intention to treat’ principle.
Intervention arm
Patients randomised to the intervention arm will be expected to receive CA within 30 days after randomisation. AADs can be used as a temporising measure before CA, as is standard of care [
]. If there is breakthrough VT during the period before the clinical procedure, standard practice will be followed in stabilising the VT including intravenous short acting AADs, admission to hospital, internal or external cardioversion [
]. Once CA has been performed, any escalation of AAD therapy that occurred between the time of randomisation and CA will be discontinued. If a patient was on an AAD at the time of randomisation, this AAD can be continued at the same dose or discontinued after CA. This decision will be at the discretion of the operator and treating cardiologist.
Catheter ablation procedures will be performed as accepted by international guidelines [
]. Procedures will be performed under conscious sedation or general anaesthesia, as per the operator preference. This will include venous and/or arterial femoral vascular access, advancement of electrode catheters to the right ventricle (RV) followed by induction of VT with programmed ventricular stimulation from the RV apex [
]. A drive train of 400 ms will be used with each extra-stimulus introduced at 300 ms and decremented by 10 ms until ventricular refractoriness. An additional extra-stimulus will then be added until up to all four extra-stimuli are refractory. If VT is non-inducible, a second RV or left ventricular site may be used for repeat stimulation. The endpoint for stimulation will be sustained monomorphic VT lasting >10 seconds or polymorphic VT or VF lasting ≥10 seconds [
]. An endocardial and/or epicardial approach will be used, based on the operator’s discretion, based on 12-lead ECG of the clinical or induced VT, scar location seen on advanced imaging techniques such as cardiac CT or cardiac magnetic resonance imaging (cMRI). A three-dimensional substrate map will be used to identify the scar using bipolar and unipolar voltage criteria. Low voltage scar will be defined as voltage <1.5 mV [
Endocardial unipolar voltage mapping to detect epicardial ventricular tachycardia substrate in patients with nonischemic left ventricular cardiomyopathy.
] for unipolar mapping. If VT is haemodynamically tolerated, activation and entrainment mapping may be used to guide ablation to terminate VT. If it is not haemodynamically tolerated, ablation targets will be identified using well accepted substrate mapping techniques as deemed necessary by individual operators (e.g. pace mapping, mapping of late, isolated or fractionated potentials, delineation of conduction channels, LAVAs, isochronal late activation mapping, decremental evoked potential mapping) as described previously [
]. Irrigated RF ablation will be performed at standard power settings 30–50 Watts for 30–90 seconds, aiming for an impedance fall of 10–20 ohms. The endpoint will be non-inducibility of any sustained VT using up to four extra-stimuli.
Intravenous heparin will be given at the beginning (bolus) and during the procedure, especially if endocardial left ventricular access is planned to prevent risk of systemic and/or venous thromboembolism, as per published guidelines [
]. Further heparin boluses are given to maintain an ACT >300 seconds, as per published guidelines. The procedure may be performed on uninterrupted warfarin and/or dabigatran, or bridging therapy with intravenous heparin or subcutaneous enoxaparin, as per the operator discretion. Post procedural anticoagulation is recommended, and in follow-up. Repeat ablation procedures, if necessary, are permitted during the 30-day treatment blanking period. This allows for mapping of the epicardial surface (if the initial attempt focussed on endocardial mapping alone) or use of advanced ablation techniques to target deep intramural substrates (e.g., simultaneous unipolar or bipolar ablation, transcoronary or transvenous ethanol ablation, surgical ablation).
If the treating physician, during the time-course of the trial, decides to escalate or commence new AAD therapy, the occurrence and time point of this cross-over will be recorded. Cross-over is estimated to be <2% as per the VANISH trial [
], as patients are most likely to have AAD therapy commenced or escalated if ablation has failed (i.e., recurrent VT), in which case the primary endpoint would have been met, before cross-over occurs. In the rare instance where a primary endpoint has not been met but cross-over has occurred, analysis will be performed using the ‘intention to treat’ principle.
ICD implantation and programming
The majority of patients will already be a recipient of an ICD at the time of recruitment. As per guidelines, patients with a new diagnosis of SHD and VT will have an ICD implanted [
2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary: a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
]. In this setting, ICD implantation will occur after randomisation and initiation of therapy according to group assignment. This will mean than an ICD will be implanted after CA in the intervention arm, and after initiation of medical therapy in the control arm.
Uniform ICD programming across various devices will be based upon expert consensus guidelines and resembles the recent VANISH trial [
There will be a 30-day treatment blanking period after commencement of treatment (after initiation of medical therapy in the control arm and after catheter ablation in the intervention arm) until assessment of study outcomes, except for fatal outcomes which will be included in this period [
]. The 30-day treatment period is imposed to exclude non-fatal outcomes that might occur before adequate medical therapy is established or actual performance of CA. The 30-day treatment period also allows for a repeat procedure if the treating physician feels that the substrate for the clinical and inducible VTs was not sufficiently targeted on the index procedure and required mapping on the opposite chamber, epicardial surface or was located intramurally. This also allows for the use of advanced ablation techniques to target deep intramural substrates (e.g., simultaneous unipolar or bipolar ablation, transcoronary or transvenous ethanol ablation, surgical ablation).
Primary Outcome
The primary outcome (assessed after the 30-day treatment blanking period, except for mortality which will be assessed from randomisation) will be a composite of recurrent VT (detected by cardiac device as lasting ≥30 seconds or shorter in duration if treated by the ICD, or documented on ECG or cardiac monitoring as lasting ≥30 seconds or shorter in duration if treated by external cardioversion when the rate is below the monitoring zone on the ICD); VT storm (≥3 documented episodes of VT within 24 hrs or incessant VT), or death (at any time) due to any cause.
Secondary Outcomes
Secondary outcomes will include (all will be assessed after the 30-day treatment blanking period, except for mortality which will be assessed from randomisation):
1.
Recurrent sustained VT detected by ICD (VT identified and treated by the ICD with ATP and/or internal ICD delivered shock or ≥30 seconds of VT if untreated by ICD);
2.
VT storm (≥3 documented episodes of VT within 24 hours or incessant VT);
3.
Change in VT burden (number of episodes of VT in the preceding 6-months compared to the 6 months after initiation of intervention);
4.
Cardiovascular hospitalisation
a.
All cardiovascular hospitalisation
b.
Heart failure
c.
Hospitalisation for arrhythmia
5.
Mortality
a.
All-cause mortality
b.
Cardiovascular mortality
c.
Non-cardiac death
6.
LVEF as assessed by transthoracic echocardiography from baseline to 6-, 12-, 24- and 36-months post intervention.
Follow-up
Patients will be followed until the end of the trial (36 months) or death, with a median follow-up of 18 months and a minimum follow-up of 1 year. Patients will be evaluated at baseline, then at 3- and 6-monthly thereafter until the study end date, by the treating physician and/or device clinic. The primary endpoint is assessed by a combination of patient interview, ICD transmission by remote monitoring and 6-monthly ICD interrogation at follow-up. All events will be adjudicated by the event committee blinded to the treatment allocation. ICD interrogation will provide the main component of the primary endpoint. Electrograms from device downloads will be saved to disk and downloaded for analysis by the endpoint committee. Only documented (by ECG or cardiac monitor) sustained VT will be included. VT with a cycle length below the detection zone, will be included if it is documented on ECG.
Potential effects of either intervention on ventricular function will be assessed by routine echocardiography, using standard techniques at 6- and 12-months, then yearly at 24- and 36-months after commencing treatment.
Participant Timeline
All eligible participants will be randomised and followed up for a period of 3 years with a minimum follow up of 1 year and a median follow-up of 18 months (Figure 2). Randomised participants who deviate from the protocol will still be followed up to 3 years, as their data will be analysed on the ‘intention to treat’ principle, as outlined in Table 1.
Once every 6-months, or as clinically indicated. Echo/cMRI are not mandated as study procedures. Data is collected if performed as standard of care.
x
x
x
x
Follow-up laboratory tests
Strongly recommended but not mandated by study.
x
x
x
x
x
x
Follow-up of outcomes
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
∗ Only if a patient does not have remote monitoring will they have 6, 12, 18, 24, 30, 36 months ICD checks.
∗∗ Strongly recommended but not mandated by study.
∗∗∗ Once every 6-months, or as clinically indicated. Echo/cMRI are not mandated as study procedures. Data is collected if performed as standard of care.
Patients with a diagnosis of SHD and sustained monomorphic VT will be eligible for inclusion in the trial. All patients screened will be recorded by the study team. Initial screening activities will include a verbal assessment of the potential participant’s medical history, their willingness to participate, and current medications. If a patient is potentially suitable for inclusion in the study, an invitation package including a copy of the Participant Information sheet will be provided to the potential participant. If the patient is not eligible the main reason as to why a participant is excluded will be recorded on a screening log form.
Informed Consent
Written informed consent will be obtained from all participants before conducting any study-specific procedures including screening assessments.
Baseline Visit
For baseline assessment, the information listed in Table 1 and Supplemental Materials (Trial Protocol, Appendix 2) will be collected from each participant. This will include details of medical history, physical exam, concomitant medications, and if clinically available, results of blood tests and baseline imaging. The ICD log will be downloaded and details regarding VT recorded from the device (duration, therapies received, frequency of events).
Premature withdrawal and early study termination
If a participant wishes to withdraw or the study team/responsible physician decides it is in the best interest of the participant to withdraw from the study, every effort should be made to conduct all assessments until the date of the last follow-up.
Statistical Considerations
A comprehensive statistical analysis plan is provided in Supplemental Materials (Statistical Analysis Plan).
Sample size calculations
At 12 months, published data suggests spontaneous VT recurs in an estimated 62% of patients on AADs with NICM [
Programmed ventricular stimulation in patients with idiopathic dilated cardiomyopathy and syncope receiving implantable cardioverter-defibrillators: a case series and a systematic review of the literature.
Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial.
]. At the lead site, Westmead Hospital, non-randomised pilot data has demonstrated a 45% rate of combined VT recurrence and death in patients with SHD related VT following CA [
]. To detect a relative risk reduction of 35% with CA, power 80%, two-sided significance of p<0.05 and allowing for a 2% drop-out rate, 162 patients (81 in each arm) will be randomised.
Recruitment rate
Approximately 1,100 patients undergo follow-up at the lead site ICD clinic. Of these approximately 30–40% would experience recurrent VT (pool of ∼400 patients). In addition, there are on average, ∼40–50 new referrals for SHD related VT each year. We estimated that there will be at least 120 patients eligible each year for randomisation across all study sites. Patients will be recruited from Westmead Hospital (NSW, Australia), Blacktown Hospital (NSW, Australia), John Hunter Hospital (NSW, Australia), Nepean Hospital (NSW, Australia), Royal Prince Alfred Hospital (NSW, Australia), Royal North Shore Hospital (NSW, Australia), The Prince Charles Hospital (Qld, Australia), Gold Coast University Hospital (Qld, Australia), The Canberra Hospital (ACT, Australia), The Alfred Hospital (Vic, Australia), The Royal Melbourne Hospital (Vic, Australia), and Royal Adelaide Hospital (SA, Australia).
Cross-over rates
Since the primary endpoints of the trial comprise most clinically reasonable indications for cross-over, we anticipate a low rate of cross-over (<2%) before a trial endpoint has been reached. Sample size impact should therefore be minimal.
Loss to follow-up
We anticipate that <2% of patients will be lost to follow-up. Patients with ICDs are followed routinely at tertiary care centres to monitor device function. This patient group is closely engaged with care providers. Prior and ongoing trials of ICD therapy have had <1% loss to follow-up [
Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial.
Clinical demographic information collected is described in the Supplemental Materials (Trial Protocol, Appendix 2). These will be summarised by means of frequency distributions (for categorical variables) and descriptive statistics of mean, standard deviation, median and range for continuous variables, based on intention-to-treat populations.
Primary Analysis
The primary analysis approach will be ‘intention to treat’ and will compare the time to the primary outcome (composite of recurrent VT, VT storm and death) in ablation versus medical therapy groups, using survival analysis techniques. The time-to-event will be summarised using Kaplan-Meier product limit estimates and the non-parametric log rank test procedure will be used for comparing the survival curves. The null hypothesis is that the time-to-event of the primary outcome is not different between the ablation and medical therapy groups. The alternative hypothesis is that the time-to-event of the primary outcome is different between these therapy groups.
Secondary Analyses
Individual secondary analyses comparing the occurrence of recurrent sustained VT, VT storm, hospitalisation for cardiac causes, all-cause mortality, cardiac mortality, and non-cardiac mortality will compare time to each outcome using the Kaplan-Meier product limit estimates and the nonparametric log rank test procedure. The change in VT burden, defined as number of episodes of VT in the preceding 6 months compared to the 6 months after randomisation and therapy, will be compared using linear regression models, adjusting for baseline clinical variables. Frequency of adverse events will be compared using Chi-square tests. Data on LVEF will be compared using paired sampled t-tests.
Adverse Events
Any adverse event occurring as a result of standard medical therapy or CA will be recorded. A comprehensive list of potential adverse events is provided in Supplemental Materials (Trial Protocol, Appendix 3). An adverse event is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product at any dose or a medical procedure that does not necessarily have to have a causal relationship with this treatment.
Serious Adverse Event
This will be defined as any untoward medical or procedural occurrence that:
•
results in death;
•
is life threatening in the opinion of the attending clinician (i.e., the patient was at risk of death at the time of the event; it does not refer to an event that might hypothetically have caused death had it been more severe);
•
requires inpatient hospitalisation or prolongation of existing hospitalisation (any hospitalisation that was planned prior to randomisation will not meet the serious adverse event [SAE] criteria. Any hospitalisation that is planned post randomisation will meet the SAE criteria);
•
results in persistent or significant disability or incapacity;
•
is an important medical event in the opinion of the attending clinician, that is not immediately life-threatening and does not result in death or hospitalisation, but which may jeopardise the patient or may require intervention to prevent one of the other outcomes listed above.
The following events are not considered to be SAEs:
•
planned hospitalisations for pre-existing condition;
•
hospital admission for interventions or procedures required by the study protocol, e.g. hospitalisation for initial or repeat ablation(s) within the 30-day blanking period after treatment initiation;
•
hospitalisation for recurrent VT or VT storm within the 30-day blanking period after treatment initiation;
•
expected side effects from of clinically indicated medications, e.g. delirium from lignocaine or thyroid dysfunction from amiodarone;
•
appropriate implanted cardioverter defibrillator (ICD) activation, i.e. VT identified and treated by the ICD with anti-tachycardia pacing (ATP) and/or internal ICD delivered shock.
Discussion
The purpose of the CAAD-VT trial is to determine whether CA of SHD related VT results in better long-term outcomes compared to AAD therapy alone. It will be the first study to prospectively compare CA versus AAD therapy in all forms of SHD related VT.
Previous Studies
The pioneering randomised controlled trials on VT ablation demonstrated that CA is highly effective for control or even cure of VT, in patients with ischaemic heart disease. When compared to AAD or medical therapy alone without AAD, CA results in a 53% reduction in the risk of recurrent VT [
Catheter ablation for ventricular tachycardia (VT) in patients with ischemic heart disease: a systematic review and a meta-analysis of randomized controlled trials.
Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial.
Impact of Substrate Modification by Catheter Ablation on Implantable Cardioverter-Defibrillator Interventions in Patients With Unstable Ventricular Arrhythmias and Coronary Artery Disease: Results From the Multicenter Randomized Controlled SMS (Substrate Modification Study).
]. However, these studies focussed almost entirely on patients with modest ICM related VT, with no inclusion of patients with NICM and a lack of representation of patients with early and advanced ICM related VT.
As alluded to earlier, non-ischaemic VT substrate is distinctly different to that present in ischaemic heart disease. Non-ischaemic scar tends to be heterogeneous with patchy interstitial fibrosis involving the intramural and/or epicardial layers [
Contrast-enhanced MRI-derived scar patterns and associated ventricular tachycardias in nonischemic cardiomyopathy: implications for the ablation strategy.
Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars.
]. Typically, NICM substrates have a basal septal and perivalvular component, especially subtending the aortic and mitral valves, but a predominant inferolateral epicardial subtype, is also well recognised [
Contrast-enhanced MRI-derived scar patterns and associated ventricular tachycardias in nonischemic cardiomyopathy: implications for the ablation strategy.
]. Substrate may be concealed with fewer identifiable ablation targets such as markers of slow conduction and may not be ‘reachable’ with conventional RF if situated in a deep intramural location and/or can often be located adjacent to critical structures such as epicardial coronary arteries and the His-Purkinje system. Furthermore, the location and aetiology of VT substrate strongly dictates the response to catheter ablation, with epicardial inferolateral phenotypes experiencing better VT free survival compared to the typically intramural anteroseptal phenotypes [
]. In contrast, ischaemic substrate tends to have frequently identifiable ablation targets (late potentials, fragmented potentials and LAVAs), located in specific vascular territories and is most commonly endocardial in origin, with ischaemia progressing from subendocardial to transmural myocardium, depending on the degree of infarction. These differences dictate the need for differing CA strategies between the two aetiologies, with NICM patients more likely to require epicardial access, ablation in both ventricles, longer duration of ablation, with potentially higher powers or novel strategies aimed at achieving deeper ablation lesions [
]. Despite these challenges, acute procedural success and acute procedural complications are not significantly different between ICM and NICM patients, but over long-term follow-up (median 6 yrs), VT recurrence is higher in NICM than ICM [
]. In the idiopathic dilated cardiomyopathy population, long-term freedom from VT recurrence was 69% at 60 months follow-up. Amongst 21% of patients with a VT recurrence, CA still resulted in a significant reduction in VT burden with 53% having only isolated (range 1–3) VT episodes in 12-months (range 4–35) after the procedure. At last follow-up, 45% were only on beta blockers or no treatment, 15% were on sotalol or class I AADs and only 22% were on amiodarone [
]. In addition, a recent propensity matched analysis reported that CA compared to medical therapy in NICM related VT resulted in a 47% lower incidence of in hospital mortality [
Catheter ablation of ventricular tachycardia in nonischemic cardiomyopathy: A propensity score-matched analysis of in-hospital outcomes in the United States.
Does timing of ventricular tachycardia ablation affect prognosis in patients with an implantable cardioverter defibrillator? Results from the multicenter randomized PARTITA Trial.
], patients with ICM or NICM who received a first ICD shock for VT (n=47) were randomly assigned to ablation or continuation of standard therapy. Those receiving early ablation benefitted from reduced occurrence of death or hospitalisation for worsening heart failure (p=0.034), and reduced VT with ICD shocks (p=0.039). The Pan-Asia United States Prevention of Sudden Cardiac Death (PAUSE-SCD) trial [
First-line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy concurrent with defibrillator implantation: the PAUSE-SCD randomized trial.
], assessed the efficacy of early, first-line VT ablation (before ICD implantation) compared to conventional medical therapy in patients with ICM (n=42), dilated cardiomyopathy (n=37) and arrhythmogenic right ventricular cardiomyopathy (n=42). The composite primary outcome of VT recurrence, cardiovascular hospitalisation, or death occurred less frequently in the ablation (49.3%) compared to control (65.5%) group (HR 0.58 [95% CI, 0.35–0.96]; p=0.04) and was largely driven by a reduction in ICD shocks in the ablation arm. Both these recent randomised trials support our decision to include patients who are seemingly early in the arrhythmogenic pathway, including those patients with either potentially asymptomatic VT detected via remote monitoring or inducible VT during an electrophysiology study. Firstly, remote ICD monitoring for detection of VT provides an important mortality benefit, compared to standard care of ICD checks with routine clinical visits [
]. Many such patients may be asymptomatic, and develop worsening burden of VT, culminating in multiple shocks, or even VT storm. Indeed, the Optimizing Ponatinib Treatment in CP-CML (OPTIC) trial showed that up to 40% of patients who have had sustained VT treated by a device, will go on to experience recurrent VT [
Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial.
]. Furthermore, patients who experience VT with ATP only (which may be asymptomatic), will also have an increased risk of future adverse events, compared to patients who experience no therapy [
]. The PARTITA trial further supports this observation regarding the prognostic importance of ATP. It demonstrated that appropriate shocks for VT were best predicted by the cumulative number of successful ATP and any additional ATP successfully terminating a VT episode was independently associated with 4% increased risk of subsequent shock [
Does timing of ventricular tachycardia ablation affect prognosis in patients with an implantable cardioverter defibrillator? Results from the multicenter randomized PARTITA Trial.
]. Secondly, the inclusion of patients with inducible VT during an electrophysiology study is justifiable as these are patients with SHD, who have experienced palpitations, syncope or pre-syncope and have not had any documented arrhythmia. The clinical suspicion of VT in such patients is high and they will all have had inducible VT during an electrophysiology study. In principle, such a population is similar to patients who have an ICD and have already experienced a clinical VT detected by their ICD, with the notable exception that this population simply did not have an implanted device to have been able to capture the clinical arrhythmia. The Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia (SMASH-VT) trial, a prior randomised trial comparing ablation to medical therapy for VT in patients with prior MI, also included such patients [
In a recent meta-analysis of published trials on efficacy of AADs for the treatment of VT, 46% of patients who received AADs experienced a VT recurrence over a mean follow-up of 15±6 months [
Comparative effectiveness of antiarrhythmic drugs and catheter ablation for the prevention of recurrent ventricular tachycardia in patients with implantable cardioverter-defibrillators: a systematic review and meta-analysis of randomized controlled trials.
]. The OPTIC trial randomised 412 ICD recipients with inducible or spontaneously occurring VT or fibrillation to 1 year with amiodarone plus beta blocker, sotalol alone, or beta blocker alone. Amiodarone plus beta blocker significantly reduced the risk of shock compared with beta blocker alone (hazard ratio [HR] 0.27; 95% confidence interval [CI] 0.14–0.52; p=0.001) and sotalol (HR 0.43; 95% CI 0.22–0.85; p=0.02). There was a trend for sotalol to reduce shocks compared with beta blocker alone (HR 0.61; 95% CI 0.37–1.01; p=0.055). Concerningly however, the rates of study drug discontinuation at 1 year were 18.2% for amiodarone, 23.5% for sotalol, and 5.3% for beta blocker alone [
Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial.
]. Despite the efficacy of amiodarone in reducing VT recurrence, it has well recognised multi-organ toxicity, including pulmonary, thyroid and skin disorders, that restrict long-term use in many patients [
Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Amiodarone Trials Meta-Analysis Investigators.
]. Indeed, long-term follow up (mean 5.6 yrs) of patients in the Canadian Implantable Defibrillator Study showed that 82% had side effects related to amiodarone and 50% required discontinuation or dose reduction. Most strikingly, by 8 years, 100% of patients had either died, had VT recurrence, or had discontinued amiodarone due to side effects [
Long-term comparison of the implantable cardioverter defibrillator versus amiodarone: eleven-year follow-up of a subset of patients in the Canadian Implantable Defibrillator Study (CIDS).
The growing number of recognised patients with NICM related VT, driven by earlier diagnosis through novel cMRI technologies, and subsequent ICD implants that detect and treat VT earlier [
Catheter ablation of ventricular tachycardia in nonischemic cardiomyopathy: A propensity score-matched analysis of in-hospital outcomes in the United States.
Outcomes in catheter ablation of ventricular tachycardia in dilated nonischemic cardiomyopathy compared with ischemic cardiomyopathy: results from the Prospective Heart Centre of Leipzig VT (HELP-VT) Study.
Comparison of ventricular tachyarrhythmia characteristics in patients with idiopathic dilated or ischemic cardiomyopathy and defibrillators implanted for primary prevention.
], dictates the critical need for further randomised data regarding the efficacy of CA in all patients with SHD related VT. Furthermore, the advancing capabilities of percutaneous coronary intervention and heart failure therapies may potentially be leading to the survival of more complex patients with ICM and VT, in whom CA may be required. The CAAD-VT trial aims to provide much needed randomised data regarding the optimal therapeutic strategies for these patient subgroups.
Study Limitations
The study is not blinded. It will not be possible to maintain blinding after study enrolment because the intervention is invasive. We chose to initiate a 30-day treatment blanking period to allow for staged CA procedures and up-titration of AADs in the respective groups. Whilst all-cause mortality is included in this blanking period, the exclusion of VT recurrence data within 30 days is a limitation. It is possible this will miss potential differences in how quickly therapeutic efficacy is achieved by each treatment. The relatively small and heterogenous patient population make it plausible that any difference identified between the two interventions may be due to a degree of chance. The multi-centre design of the study means that operator experience may vary, potentially resulting in different CA outcomes compared to prior studies performed largely in specialised tertiary referral VT centres. However, the multi-centre design, combined with a heterogenous patient population, are imperative to allow our study to reflect a real-world scenario and help determine if CA or AADs are best overall therapy for SHD related VT.
Conclusions
Catheter ablation is an established treatment for SHD related VT, either as an adjunct or an alternative to medical therapy. The evidence supporting the efficacy of CA is largely based on data from patients with ICM related VT, with minimal representation of early and advanced stages of ICM. Whilst several recent randomised trials have demonstrated efficacy of CA in patients with NICM related VT, the numbers remain small and specific subtypes of patients has been selective. There is therefore uncertainty about whether CA represents the best treatment modality for all patients with SHD related VT. The CAAD-VT trial will help clarify the optimal management of patients in a real-world scenario by comparing CA versus AAD therapy alone for the treatment of all forms of SHD related VT.
Disclosures
Dr Saurabh Kumar is supported by the NSW early-mid Career Fellowship. Dr Kumar has received research grants from Abbott Medical and Biotronik; he has received honoraria from Biosense Webster, Abbott Medical, Biotronik, and Sanofi Aventis. Timothy Campbell has received speakers’ honoraria for Biosense Webster, Inc. in the last 12 months. Clara K. Chow is supported by a NHMRC Investigator grant, APP1195326.
Funding
This project has been funded by the NSW Health early-mid Career Research Grant for 3 years.
Catheter ablation for ventricular tachycardia (VT) in patients with ischemic heart disease: a systematic review and a meta-analysis of randomized controlled trials.
Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial.
Impact of Substrate Modification by Catheter Ablation on Implantable Cardioverter-Defibrillator Interventions in Patients With Unstable Ventricular Arrhythmias and Coronary Artery Disease: Results From the Multicenter Randomized Controlled SMS (Substrate Modification Study).
Does timing of ventricular tachycardia ablation affect prognosis in patients with an implantable cardioverter defibrillator? Results from the multicenter randomized PARTITA Trial.
First-line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy concurrent with defibrillator implantation: the PAUSE-SCD randomized trial.
Contrast-enhanced MRI-derived scar patterns and associated ventricular tachycardias in nonischemic cardiomyopathy: implications for the ablation strategy.
Endocardial and epicardial radiofrequency ablation of ventricular tachycardia associated with dilated cardiomyopathy: the importance of low-voltage scars.
2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary: a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
Endocardial unipolar voltage mapping to detect epicardial ventricular tachycardia substrate in patients with nonischemic left ventricular cardiomyopathy.
Programmed ventricular stimulation in patients with idiopathic dilated cardiomyopathy and syncope receiving implantable cardioverter-defibrillators: a case series and a systematic review of the literature.
Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial.
Catheter ablation of ventricular tachycardia in nonischemic cardiomyopathy: A propensity score-matched analysis of in-hospital outcomes in the United States.
Comparative effectiveness of antiarrhythmic drugs and catheter ablation for the prevention of recurrent ventricular tachycardia in patients with implantable cardioverter-defibrillators: a systematic review and meta-analysis of randomized controlled trials.
Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Amiodarone Trials Meta-Analysis Investigators.
Long-term comparison of the implantable cardioverter defibrillator versus amiodarone: eleven-year follow-up of a subset of patients in the Canadian Implantable Defibrillator Study (CIDS).
Outcomes in catheter ablation of ventricular tachycardia in dilated nonischemic cardiomyopathy compared with ischemic cardiomyopathy: results from the Prospective Heart Centre of Leipzig VT (HELP-VT) Study.
Comparison of ventricular tachyarrhythmia characteristics in patients with idiopathic dilated or ischemic cardiomyopathy and defibrillators implanted for primary prevention.
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