Prophylactic Catheter Ablation of Ventricular Tachycardia in Ischemic Cardiomyopathy: a systematic review and meta-analysis of randomized controlled trials Electrophysiology Collaborative Consortium for Metaanalysis – ELECTRAM Investigators

Kuldeep Shah1, Mohit Turagam2, Brijesh Patel1, Andrea Natale3, Dhanunjaya Lakkireddy4#, Jalaj Garg5#

1Division of Cardiology, West Virginia University, Morgantown, WV.2Helmsley Electrophysiology Center, Icahn School of Medicine at Mount Sinai, New York, NY.3Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, TX.4Kansas City Heart Rhythm Institute and Research Foundation, Kansas City, KS.5Division of Cardiology, Cardiac Arrhythmia Service, Medical College of Wisconsin, Milwaukee, WI.#D.L and J.G are co-senior authors.

Abstract

Aims

Catheter ablation is an effective strategy for drug-refractory ventricular tachycardia (VT) in ischemic cardiomyopathy. We aimed to perform a systematic review and meta-analysis of outcomes of prophylactic catheter ablation (PCA) of Ventricular Tachycardia (VT) in ischemic cardiomyopathy patients

Methods

We performed a comprehensive literature search through February 10, 2020, for all eligible randomized controlled trials that compared “PCA” versus “No PCA” for VT. Primary efficacy outcomes included - appropriate ICD therapy (composite of anti-tachycardia pacing and ICD shock), appropriate ICD shocks, electrical storm, cardiac mortality, and all-cause mortality. The primary safety outcome was any adverse events.

Results

Four randomized controlled trials (N = 505) met inclusion criteria. Prophylactic catheter ablation was associated significant reduction in appropriate ICD therapies (RR 0.70; 95% CI 0.55 - 0.89, p = 0.004), appropriate ICD shocks (RR 0.57 95% CI 0.40 - 0.80, p = 0.001) with a trend towards reduced risk of electrical storm (RR 0.64; CI 0.39 - 1.05; p = 0.075) compared to “No PCA”. There was no significant difference in cardiac mortality (RR 0.66, 95% CI 0.31 – 1.43, p = 0.29) and all-cause mortality (RR 0.98, 95% CI 0.52 – 1.82, p = 0.94) with similar adverse events (RR 1.46, 95% CI 0.73 – 2.95, p = 0.29) between two groups.

Conclusions

Prophylactic catheter ablation in ischemic cardiomyopathy patients was associated with a lower risk of ICD therapies, including ICD shocks and VT storm with no difference in cardiac and all-cause mortality.

Key Words : Ventricular tachycardia, Prophylactic catheter ablation, Ischemic cardiomyopathy.

Jalaj Garg MD FACC FESC Division of Cardiology, Cardiac Arrhythmia Service Medical College of Wisconsin 10000 Innovation Drive Milwaukee, WI 53226

Introduction

Patients with ischemic cardiomyopathy who survive a spontaneous episode of ventricular arrhythmias are at an increased risk for recurrent ventricular tachycardia (VT) or ventricular fibrillation (VF). Implantable cardioverter-defibrillators (ICDs) reduce the risk of sudden cardiac death (SCD) in these patients and have, therefore, become the standard of care in the management of ventricular arrhythmias 1. However, patients who experience ICD shocks have a decreased quality of life and increased mortality compared to patients who do not receive shocks, even if the shocks are considered inappropriate 2,3. Additionally, ICDs do not provide absolute protection from SCD in about 3-7 % of patients 4. Thus, modalities that can effectively reduce recurrent ventricular arrhythmias and ICD therapies (both shocks and anti-tachycardia pacing) are of great importance. Drug treatment, especially amiodarone in combination with beta-blockers reduces ICD interventions, but are associated with serious adverse events on long-term treatment 5. Catheter ablation for VT in the past was infrequently used because VT episodes were often hemodynamically unstable, rendering the mapping of clinical VT difficult 6. Recent advances in mapping and ablation strategies have enabled electrophysiologists to perform both activation mapping/ablation during VT and substrate mapping/ablation during sinus rhythm targeting late/fractionated potentials, thereby resulting in higher acute procedure success and long-term clinical outcomes. Several trials have also demonstrated that catheter ablation of scar related VT significantly reduces ICD therapies, including shocks and overall VT burden 7-10. Despite encouraging data from randomized controlled trials, the optimal timing of catheter ablation for VT remains unclear. The current guidelines recommend referral for catheter ablation in patients who failed antiarrhythmic treatment 11. Prophylactic catheter ablation (“PCA”) has also been evaluated as an adjunct treatment option in patients eligible for ICD implantation (with documented life threatening ventricular arrhythmias), with conflicting results 12-15. Given the lack of data, we aimed to perform a systematic review and meta-analysis of outcomes of preventive catheter ablation for VT in ischemic cardiomyopathy patients.

Methods

Search strategy

The reporting of this systematic review and meta-analysis complies with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines 16 [Supplement Table 1].

Table 1. PRISMA checklist
Section/topic # Checklist item
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both.
ABSTRACT
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known.
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means).
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis.
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15).
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).
DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.
FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal. pmed1000097

The initial search strategy was developed by two authors (K.S. and M.T). We performed a systematic search, without language restriction, using PubMed, EMBASE, SCOPUS, Google Scholar, and ClinicalTrials.gov from inception to February 10th, 2020, for studies comparing clinical outcomes between “PCA” versus “No PCA”—only in eligible patients with VT and ischemic cardiomyopathy. We used the following keywords and medical subject heading: “ventricular tachycardia,” “ventricular fibrillation,” “catheter ablation,” “implantable cardioverter-defibrillator.”

Study selection and data extraction

Only randomized controlled trials that compared “PCA” versus “No PCA” were included in the analysis. The data from included studies were extracted using a standardized protocol and a data extraction form. Any discrepancies between the two investigators were resolved with a consultation with the senior investigators (D.L and J.G). Studies comparing prophylactic catheter ablation versus antiarrhythmic drugs, review articles, editorials were excluded from our analysis. The following data were extracted: title, study date, sample size, comorbid conditions, ejection fraction, mapping and ablation technique, antiarrhythmic drugs, ICD type (single, dual, or cardiac resynchronization therapy), medications, clinical outcomes, and complications. The Cochrane – Risk bias assessment tool was used to appraise the quality of included studies [Supplement Table 2].

Table 2. Appraisal of the clinical trials for bias
Bias Type SMASH VT VTACH SMS BERLIN VT
Selection Bias
Random Sequence generation Low risk Low risk High risk Low risk
Allocation concealment Low risk Low risk High risk Low risk
Performance Bias
Blinding of participant and personnel High risk High risk High risk High risk
Detection Bias
Blinding of outcome assessment High risk High risk High risk High risk
Attrition bias
Incomplete outcome data Intermediate risk Intermediate risk Intermediate risk Intermediate risk
Reporting data
Selective reporting Low risk Low risk Low risk Intermediate risk



Clinical outcomes

The primary efficacy outcome of our study was – (1) appropriate ICD therapy (composite of anti-tachycardia pacing and ICD shock); (2) appropriate ICD shocks; (3) electrical storm, (4) cardiac mortality and (5) all-cause mortality. The definition of the electrical storm was similar across all included trials except BERLIN VT15 (was not enlisted as clinical outcome). The electrical storm was defined as three or more VT episodes in 24 hours. Deaths secondary to cardiac causes were included under cardiac mortality. The primary safety outcome of our study was any adverse events [acute procedural related adverse events – composite of vascular complications, pericardial effusion (with and without tamponade), heart failure exacerbation secondary to catheter ablation, complete heart block, device and lead dysfunction (requiring replacement), lead dislodgement, stroke/transient ischemic attack, deep vein thrombosis, transient ST-segment elevation, or pneumothorax].

Statistical analyses

The meta-analysis was performed using a meta-package for R version 4.0 and Rstudio version 1.2. Mantel-Haenszel risk ratio (RR) random-effects model (DerSimonian and Laird method) was used to summarize data across the groups 17. The heterogeneity of effects among the included studies was assessed by Higgins I-squared (I2) statistic18. A value of I2 of 0–25% represented insignificant heterogeneity, 26–50% represented low heterogeneity, 51–75% represented moderate heterogeneity, and more than 75% represented high heterogeneity, as set forth by the Cochrane Collaboration. Publication bias was visually assessed using funnel plots and Egger’s linear regression test of funnel plot asymmetry. A two-tailed p < 0.05 was considered statistically significant for all analyses.

Results

Search results

A total of 974 citations were identified [Figure 1] during the initial search. Nine hundred sixty-three records were excluded. After a detailed evaluation of these studies, four randomized clinical trial studies ultimately met the inclusion criteria (N=505 patients) 12-15. The follow-up duration for the studies ranged from 396 days to 40 months. [Table 1] summarizes the study characteristics of the included trials.

Figure 1. Flow Diagram illustrating the systematic search of studies



Study characteristics

This meta-analysis of 4 randomized trials includes a total of 505 patients comparing “PCA” (N = 246) versus “No PCA” approach (N = 259). The mean age of the patients included in the trials ranged from 64.4 (±8.2) – 68.4 (±7.7) years. The mean (SD) follow-up duration ranged from 22.5 (5.5) to 27.6 (13.2) months. The mean (%) left ventricular ejection fraction (LVEF) ranged from 30.4±7.3 to 41±6%.

Mapping and ablation techniques varied between the trials – most commonly done using the CARTO electroanatomic system (Biosense Webster, Inc, Diamond Bar, CA). Bipolar electrogram voltage amplitude >1.5 mV was considered as normal myocardium, while <1.5 mV was considered border zone/scarred myocardium. Fractionated and late potentials were identified and tagged along the scar border zone (characterized by multiple high frequency continuous delayed components separated from higher amplitude local ventricular electrograms and recorded within or at the end of QRS complex, respectively. Substrate-based approach ± entrainment mapping ± pace mapping was performed in SMASH-VT12, VTACH13, and SMS14 study, while only substrate-based approach was performed in BERLIN-VT trial15. Non-inducibility of VT with programmed stimulation was the endpoint in all studies.

Ablation was performed before ICD implantation in all patients in BERLIN-VT, 92% in VTACH, 88.9% in SMS, and 13% in the SMASH-VT trial. None of the patients in SMASH-VT received antiarrhythmic medications (until any ICD event). This is in contrast to the VTACH trial, where 35% of patients were on amiodarone, 32% in SMS trial, and 33% in the BERLIN VT study.

Clinical outcomes

Efficacy outcomes

Appropriate ICD therapy (anti-tachycardia pacing plus shock) and ICD shock

The data for any ICD therapy or ICD shock was available in all four studies. There was a significant reduction in appropriate ICD therapy (32.1% vs. 47.1% respectively; RR 0.70; 95% CI 0.55 – 0.89, p = 0.004) in “PCA” versus “No PCA” approach. No heterogeneity was observed (I2 =18%) ([Figure 2a] and [Figure 2b]). The number needed to prevent any appropriate ICD therapy was 7.

Figure 2a and 2b. Efficacy Outcomes: Appropriate ICD therapy (anti-tachycardia pacing plus shock).The Forest plot shows the outcomes of the individual trials as well as the aggregate. Point estimates to the left favor prophylactic catheter ablation. The Funnel plot demonstrates no publication bias.



Similarly, the “PCA” approach was associated with reduced risk of appropriate ICD shocks (16.66% vs. 30.11% respectively; RR 0.57 95% CI 0.40 – 0.80, p=0.001) as compared to “No PCA” approach. No significant heterogeneity was observed (I2 = 8%). No publication bias was observed for either outcome ([Figure 3a] and [Figure 3b]). The number needed to prevent appropriate ICD shock was 7.

Figure 3a and 3b. Efficacy Outcomes: Appropriate ICD shock.The Forest plot shows the outcomes of the individual trials as well as the aggregate. Point estimates to the left favor prophylactic catheter ablation. The Funnel plot demonstrates no publication bias.



Electrical Storm

The data on the electrical storm was not reported in the BERLIN VT study. Prophylactic catheter ablation demonstrated trend towards reduced risk of electrical storm compared to “No PCA” approach (12.35% vs 20.45%; RR 0.64; CI 0.39 – 1.05; p = 0.08). No significant heterogeneity was observed. (I2 =1%). No publication bias was observed ([Figure 4a] and [Figure 4b]).

Figure 4a and 4b. Efficacy Outcomes: Electrical storm.The Forest plot shows the outcomes of the individual trials as well as the aggregate. Point estimates to the left favor prophylactic catheter ablation. The Funnel plot demonstrates no publication bias.



All-cause mortality

The data for all-cause mortality was available in all four trials. Prophylactic catheter ablation was not associated with decreased all-cause mortality (RR 0.98, 95% CI 0.52 – 1.82, p = 0.94). Mild heterogeneity was observed between trials (I2 =27%). No publication bias was observed ([Figure 5a] and [Figure 5b]).

Figure 5a. Efficacy Outcomes: All-cause mortality.The Forest plot shows the outcomes of the individual trials as well as the aggregate. Point estimates to the left favor prophylactic catheter ablation. The Funnel plot demonstrates no publication bias.



Cardiac mortality

The data for cardiac mortality was available in all four trials. Prophylactic catheter ablation was not associated with decreased cardiac mortality (RR 0.66, 95% CI 0.31 – 1.43, p = 0.29). No significant heterogeneity was observed between trials (I2 =0%). No publication bias was observed ([6a] and [Figure 6b]).

Figure 6a and 6b. Efficacy Outcomes: Cardiac mortality.The Forest plot shows the outcomes of the individual trials as well as the aggregate. Point estimates to the left favor prophylactic catheter ablation. The Funnel plot demonstrates no publication bias.



Safety outcome

Adverse events

The adverse event rates were reported in all clinical trials [Table 2]. The overall rate of adverse effects was similar in the “PCA” and “No PCA” group (13.41% versus 8.88%, respectively; RR 1.46, 95% CI 0.73 – 2.95, p=0.29]. Mild heterogeneity was observed (I2 =37%). No publication bias was observed ([Figure 7a] and [Figure 7b]).

Figure 7a and 7b. Adverse events.The Forest plot shows the outcomes of the individual trials as well as the aggregate. Point estimates to the left favor prophylactic catheter ablation. The Funnel plot demonstrates no publication bias.



Discussion

Ventricular arrhythmias account for approximately 5.6% of total mortality in the United States. Slow and anisotropic conduction via the surviving myocardial fibrils in and around the dense scar (from prior myocardial infarction) accounts for reentrant circuits for ventricular arrhythmias19. Also, patients with existing ICD are often referred for VT ablation at later stages (following multiple ICD shocks and antiarrhythmic toxicities), resulting in a worse prognosis. Therefore, early referral for prophylactic VT ablation seemed reasonable. In this systematic review and meta-analysis of 4 randomized controlled trials, we demonstrated that prophylactic VT ablation was associated with reduced likelihood of any ICD events and appropriate ICD shocks, with no significant effect on all-cause and cardiac mortality. Studies like SMASH-VT, VTACH, SMS had their primary outcome focused on arrhythmia recurrence and were not statistically powered to look for the difference in all-cause mortality. BERLIN VT, on the other hand, was the only trial that assessed hard clinical outcomes composite of all-cause mortality, hospitalization, and recurrent arrhythmia as their primary outcome of interest. Although the findings in our study are in line with included RCTs, all four trials differed in several ways. VTACH study included patients with only documented stable VT with de novo ICD implantation; SMS included hemodynamically unstable ventricular arrhythmia or syncope with inducible unstable ventricular arrhythmias during electrophysiological study; SMASH VT included hemodynamically unstable ventricular arrhythmias or syncope with inducible ventricular tachycardia during invasive electrophysiological testing while BERLIN VT included patients with both stable and unstable ventricular arrhythmia. Prior to enrollment, amiodarone was used in VTACH (35% of patients), SMS (32%), and BERLIN VT (33%) but not in SMASH VT. Variation in ablation techniques and operator experience, antiarrhythmic use, and differences in ICD programming could have accounted for mild heterogeneity observed in our study [Table 1].

Table 1. Baseline characteristics of studies included in our meta-analysis
Study ID SMASH VT[12] VTACH[13] SMS[14] BERLIN VT[15]
Design Randomized unblinded controlled trial Randomized unblinded controlled trial Randomized unblinded controlled trial Randomized unblinded controlled trial
Study period 2000-2006 2002-2006 2002-2011 2015-2018
Sample size Prophylactic ablation = 64 No Prophylactic ablation = 64 Prophylactic ablation = 52 No Prophylactic ablation = 55 Prophylactic ablation = 54 No Prophylactic ablation = 57 Prophylactic ablation = 76 No Prophylactic ablation = 83
Arrhythmic inclusion criteria Hemodynamically unstable ventricular arrhythmias, or syncope with inducible ventricular tachycardia during invasive electrophysiological testing Stable clinical ventricular tachycardia defined as a ventricular tachycardia not resulting in cardiac arrest or syncope and during which the systolic blood pressure was higher than 90 mm Hg Hemodynamically unstable ventricular arrhythmias, or cardiac arrest or syncope with inducible unstable ventricular arrhythmias during electrophysiological study Sustained stable and unstable ventricular arrhythmia
Follow up 22.5 ± 5.5 months 22.5 ± 9 months 27.6 ± 13.2 months 396 ± 284 days
Patient age mean ± SD (years) Prophylactic ablation: 67±9 No Prophylactic ablation: 66±10 Prophylactic ablation: 67.7±8.3 No Prophylactic ablation: 64.4±8.2 Prophylactic ablation: 68.4±7.7 No Prophylactic ablation: 65.9±8.4 Prophylactic ablation: 66±10 No Prophylactic ablation: 66±9
Ejection fraction (%) Prophylactic ablation: 30.7±9.5 No Prophylactic ablation: 32.9±8.5 Prophylactic ablation: 34±9.6 No Prophylactic ablation: 34.1±8.8 Prophylactic ablation:32±6.9 No Prophylactic ablation: 30.4±7.3 Prophylactic ablation: 41±6 No Prophylactic ablation: 41±6
Interval between last myocardial infarction and enrollment Prophylactic ablation (years): 8.8 ± 8.5 No Prophylactic ablation (years): 7.9 ± 7.8 Prophylactic ablation (years): 12.6 ± 8.0 No Prophylactic ablation(years):13.3 ± 8.6 Prophylactic ablation (years): 11.1 ± 6.6 No Prophylactic ablation (years): 8.6 ± 7.8 Prophylactic ablation (months): 123 ± 144 No Prophylactic ablation (months): 110 ± 109
Ablation technique Substrate modification ± entrainment mapping± pace mapping Endocardial Substrate modification ± entrainment mapping ± pace mapping Endocardial Substrate modification ± non-inducibility of VT Substrate modification ± non-inducibility of VT
Epicardial ablation and Late potential ablation Epicardial ablation not reported but late potentials targeted No epicardial ablation No epicardial ablation Epicardial ablation not reported but late potentials targeted
Ablation endpoints Non-inducible VT on programmed stimulation Inducible VT: non-inducible VT on programmed simulation post ablation Non-inducible VT: substrate modification with no evidence of abnormal electrograms in the scar and scar border zone. Non-inducibility of the clinical tachycardia or lack of adequate endocardial target sites or ineffective lesions despite adequate target sites Non-inducible VT on programmed stimulation and elimination of abnormal potentials
Mapping CARTO CARTO and Non-contact mapping - Ensite CARTO and Ensite -
Antiarrhythmic drugs None Amiodarone Prophylactic ablation: 35% No Prophylactic ablation: 35% Amiodarone Prophylactic ablation: 30% No Prophylactic ablation: 35% Amiodarone Prophylactic ablation: 40.8% No Prophylactic ablation: 26.5%
ICD type
Single chamber Prophylactic ablation: 36% No Prophylactic ablation: 48% Prophylactic ablation: 65% No Prophylactic ablation: 67% Prophylactic ablation:51.8% No Prophylactic ablation: 57.89% Prophylactic ablation: 53.94% No Prophylactic ablation: 75.90%
Dual chamber Prophylactic ablation: 64% No Prophylactic ablation: 52% Prophylactic ablation: 38.8% No Prophylactic ablation: 31.57% Prophylactic ablation: 32.9% No Prophylactic ablation: 20.5%
CRT-D Prophylactic ablation: 9.25% No Prophylactic ablation: 10.52% Prophylactic ablation: 11% No Prophylactic ablation: 3.6%
Unknown Prophylactic ablation: 35% No Prophylactic ablation: 33%
ICD Programming N/A VF zone: 200-220 beats/min VT zone: 60 msec above the slowest documented VT, anti-tachycardia pacing and shock VF zone: 200-220 beats/minute, shock therapy only (detection - 18 out of 24 beats) VT zone: 60 msec above the slowest documented VT, anti-tachycardia pacing and shock (detection - at least 16 consecutive beats) VF zone: 200-222 beats/minute, one anti-tachycardia pacing, shock (detection 18 out of 24 beats) VT zone: 60 msec above the slowest documented VT, three or more anti-tachycardia pacing and shock
Medications (%)
Beta-blockers Prophylactic ablation: 94 % No Prophylactic ablation: 98 % Prophylactic ablation: 75% No Prophylactic ablation: 75 % Prophylactic ablation:91% No Prophylactic ablation: 91 % Prophylactic ablation: 76.3 % No Prophylactic ablation: 71.1 %
ACE inhibitors or angiotensin receptor blockers Prophylactic ablation: 92 % No Prophylactic ablation: 92 % Prophylactic ablation: 61.8 % No Prophylactic ablation: 71.1 %
Statins Prophylactic ablation: 58 % No Prophylactic ablation: 59 %
Aspirin Prophylactic ablation: 81 % No Prophylactic ablation: 61 %



VANISH trial (Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs) demonstrated that the catheter ablation was associated with reduced risk of primary outcome composite of death at any time or VT storm or appropriate ICD shocks as compared to the control group (escalated antiarrhythmic drug with ICD). However, the study failed to demonstrate a significant reduction in mortality as an individual secondary outcome between the two groups 20. The significant difference in the primary outcomes was primarily driven by a reduction in appropriate ICD shocks and VT storms in the ablation arm. Studies have shown that recurrent ICD shocks (both appropriate and inappropriate) have been associated with increased mortality 3,21. Therefore, intuitively prophylactic catheter ablation with an aim to homogenize the myocardial scar (by modifying the channels of slow conduction) may decrease the arrhythmia burden, ICD therapies, and in turn, potentially reduce mortality 7,8. This has been retrospectively demonstrated by Tung and colleague where 2,061 patients who underwent scar-VT ablation (following ICD shocks), VT free survival was associated with reduced all-cause mortality 22.

Inducible VT’s and the number of VT’s induced is a significant predictor of recurrent VT23,24. Studies have shown that extensive substrate-based ablation strategy [targeting fractionated, late, and local abnormal ventricular activation (LAVA) potentials] is superior to ablation targeting only critical isthmus (for clinical VT) in ischemic cardiomyopathy patients25-27. Also, 15% of patients with ischemic cardiomyopathy may have mid myocardial and epicardial substrate requiring adjunct epicardial ablation in addition to the endocardial approach28,29. Therefore, a combined epicardial/endocardial ablation approach might be beneficial in VT free survival and, in turn, reduce ICD therapies and all-cause mortality30,31. Needless to say, the epicardial mapping and ablation approach was not performed in any of the studies. Also, approximately 10-40% of ischemic cardiomyopathy patients experience VT storm and are at increased mortality risk32,33. With the exception of the SMASH-VT trial, no significant difference was observed for VT storm between two groups. One of the possible explanations includes extensive substrate modification of the scar and scar border zone accounting for the reduced burden of ventricular arrhythmias.

As expected with any invasive procedure, the “PCA” group was associated with numerically high complication rates than the “No PCA” group; however, it failed to reach statistical significance [Table 2]. The improvement in the quality of life was not significantly different between the two groups in SMS, which is in contrast to the BERLIN-VT trial, where the quality of life score improved in the “PCA” group. This could be secondary to medication compliance and decline in ventricular arrhythmias and ICD therapies, thereby reducing emergency room/physician visits, and subsequent hospitalizations. This could theoretically translate into an overall reduction in healthcare cost utilizations.

Table 2. Adverse Events Related to Catheter Ablation and Implanted Device reported in the individual studies
Study Complications Prophylactic ablation versus No Prophylactic ablation Complication type
Prophylactic ablation No Prophylactic ablation
SMASH VT[12] 3 (4.68%) vs 0 Ablation related: 3 1 = pericardial effusion without tamponade 1 = heart failure exacerbation 1 = deep vein thrombosis requiring Anticoagulation None
VTACH[13] 4 (7.69%) vs 8 (14.54%) Ablation related: 2 1 = stroke with aphasia 1 = transient ischemic ST segment Elevation Device related: 2 2 = lead dislodgement Device related: 9 2 = lead dislodgement 2 = dislodged ICD lead requiring repositions 1 = T wave oversensing 1 = lead insulation damage 1 = Twiddler’s syndrome 1 = ICD system infection needing extraction
SMS[14] 14 (25.92%) vs 8 (14.03%) 2 = stroke 2 = complete heart block 2 = pericardial effusion requiring pericardiocentesis 1 = heart transplant 4 = lead dislodgement 2 = lead dysfunction 1 = lead perforation 3 = lead dislodgement or / repositioning 3 = lead dysfunction 1 = pneumothorax 1 = heart transplant
BERLIN VT[15] 12 (15.78%) vs 7 (8.43%) Ablation related: 7 1 = cardiac perforation requiring surgery 1 = Cardiac tamponade 1 = pericardial effusion 2 = major groin bleed 1 = major nasopharyngeal bleed 1 = complete heart block Device related: 6* 3 = right atrial lead dislodgement 3 = right ventricular lead dislodgement * 1 patient had both RA and RV lead dislodgement Deferred ablation: 2 1 = complete heart block 1 = thrombophlebitis Device related: 6* 1 = right atrial lead d dislodgment 4 = right ventricular lead dislodgement 1 = inappropriate retention of ICD therapies for VT * 1 patient had both RA and RV lead dislodgement



There are several important limitations to our study. 1) The small number of studies and small sample size may still be underpowered to assess net clinical benefit; 2) difference in ICD programming and antiarrhythmic drugs exposure might have led to selection bias and thereby influencing the results; 3) Individual patient-level data, data regarding inappropriate therapies and healthcare cost utilization was not available; 4) there was no uniform standardized definition for procedure success that could have impacted clinical outcomes; 5) The BERLIN VT study excluded patients with LVEF ≤ 30%, with a higher mean LVEF of 41% compared to other three trials which could have influenced the outcomes in our analysis (given that these are potentially different patient populations). Finally, there was substantial cross-cover among the trials, which can affect our study results. Further randomized trials on the timing of VT ablation and cost-effectiveness will shed more light on the impact of prophylactic VT ablation versus deferred approach. Despite these limitations, our study provides valuable clinical insights on the role of prophylactic VT ablation without any increased mortality risk.

Despite two decades since the first patient enrollment for prophylactic VT ablation strategy, this has not gained popularity in clinical practice. Current guidelines recommend ablation following the first VT episode regardless of antiarrhythmics 11. This is conceivably primarily driven by increased susceptibility to procedure-related complications (and nature of complications) with the prophylactic ablation approach. Improved procedure techniques (intracardiac echo, mapping systems), and better catheter design (e.g., force sensing catheters, high power short duration ablation) could potentially circumvent these issues. Nevertheless, in our study, the prophylactic VT ablation approach was associated with reduced ICD therapies and ICD shock, without any increased risk of acute procedural complications and all-cause mortality. However, the decision for prophylactic VT ablation should be equipoised with patient comorbidities and hemodynamics.

Conclusions

Prophylactic catheter ablation in eligible patients with ischemic cardiomyopathy was associated with reduced risk of appropriate ICD therapies, including ICD shocks and VT storm with no difference in all-cause mortality compared with “No PCA” approach. Preventive ablation should not be routinely recommended but can be considered in patients with high-risk of VT burden and ICD therapies.

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