systematic review and meta-analysis of catheter ablation ... · catheter ablation (n 5 54) no...

Systematic review and meta-analysis of catheterablation of ventricular tachycardia in ischemic heartdisease

Brandon K. Martinez, PharmD,1,2 William L. Baker, PharmD,1,2 Anna Konopka, PharmD,1

Devon Giannelli, PharmD,1 Craig I. Coleman, PharmD,1,2 Jeffrey Kluger, MD,3,4

Edmond M. Cronin, MB, BCh, BAO, FHRS, CCDS, CEPS-A3,4

Document Reviewers: Samuel J. Asirvatham, MD, FHRS; Sabine Ernst, MD, PhD.

From the 1University of Connecticut School of Pharmacy, Storrs, Connecticut, 2Hartford Hospital Evidence-Based
Practice Center, Hartford, Connecticut, 3Hartford HealthCare Heart and Vascular Institute, HartfordHospital, Hartford, Connecticut, and 4University of Connecticut School of Medicine, Farmington,Connecticut.
Appendix 1 Author Disclosure Table .................. e13Appendix 2 Reviewer Disclosure Table ............... e14

BACKGROUND Patients with ischemic heart disease (IHD) are atrisk for ventricular tachycardia (VT). Catheter ablation (CA) mayreduce this risk.

OBJECTIVE To perform a systematic review and meta-analysis ofrandomized controlled trials (RCTs) of CA of VT in patients with IHD.

METHODS Literature searches of MEDLINE, the Cochrane Central Reg-ister of Controlled Trials (CENTRAL), and the CochraneDatabaseof Sys-tematic Reviews (CDSR) were performed from January 2000 throughApril 2018 to identify RCTs comparing a strategy of CA vs no ablationin patients with IHD and an implantable cardioverter defibrillator(ICD). Outcomes of interest included appropriate ICD therapies,appropriate ICD shocks, VT storm, recurrent VT/ventricular fibrillation(VF), cardiac hospitalizations, and all-cause mortality. Using an in-verse variance random-effects model, odds ratios (ORs) and 95% con-fidence intervals (CIs) were calculated for each endpoint.

RESULTS A total of 5 RCTs (N5 635 patients) were included, with aduration of follow-up ranging from 6 months to 27.9 months. Patientswho underwent CA experienced decreased odds of appropriate ICD ther-apies (OR 0.49; 95% CI 0.28–0.87), appropriate ICD shocks (OR 0.52;95% CI 0.28–0.96), VT storm (OR 0.64; 95% CI 0.43–0.95), and cardiachospitalization (OR 0.67; 95% CI 0.46–0.97) vs those who did not un-dergo ablation. There was no evidence of a benefit for recurrent VT/VF(OR 0.87; 95% CI 0.41–1.85), although this endpoint was not reportedin all trials, or for all-cause mortality (OR 0.89; 95% CI 0.60–1.34).

KEYWORDS Catheter ablation; Implantable cardioverter defibrillator;Ischemic heart disease; Meta-analysis; Systematic review; VentriculartachycardiaABBREVIATIONS AAD5 antiarrhythmic drug; ATP5 antitachycardiapacing; CA5 catheter ablation; CI5 confidence interval;ERC5 Evidence Review Committee; ICD5 implantable cardioverterdefibrillator; IHD5 ischemic heart disease; MI5myocardial infarc-tion;OR5 odds ratio;RCT5 randomized controlled trial;VF5 ventric-ular fibrillation; VT5 ventricular tachycardia (Heart Rhythm 2019;-:e1–e14)

DcpsaqHE

1547-5271/$-see front matter © 2019 Published by Elsevier Inc. on behalf of Hea

PGL 5.5.0 DTD � HRTHM7988_proo

CONCLUSION In this systematic review and meta-analysis of RCTs,CA was associated with a significant reduction in the odds of appro-priate ICD therapies, appropriate ICD shocks, VT storm, and cardiachospitalizations in patients with IHD.

TABLE OF CONTENTS

Forepartmation, aermittetructionbout/ouuests aeart a-mail a

rt Rhyth

f � 27

Background ....................................................
e2 Methods ......................................................... e2
copentlterd ws for-bndndddr

m

A

Data Sources and Search Strategy ...........
e2 Study Selection ......................................... e2 Data Extraction ......................................... e2 Statistical Analysis .................................... e3
Results ............................................................
e3 Post Hoc Sensitivity Analysis and Meta-Regression ................................................. e6 Adverse Events ......................................... e7
Discussion ......................................................
e7 Conclusion ..................................................... e11
ies of this document, please contact the Elsevier Inc. Reprint([email protected]). Permissions: Multiple copies, modifi-ation, enhancement, and/or distribution of this document are notithout the express permission of the Heart Rhythm Society. In-r obtaining permission are located at https://www.elsevier.com/usiness/policies/copyright/permissions. Address reprint re-correspondence: Dr. Edmond M. Cronin, Hartford HealthCareVascular Institute, 80 Seymour Street, Harford, CT 06102.ess: [email protected].

Society. https://doi.org/10.1016/j.hrthm.2019.04.024

pril 2019 � 5:09 pm � ce

Delta:1_given name

Delta:1_surname

Delta:1_given name

Delta:1_surname

Delta:1_given name

Delta:1_surname

Delta:1_given name

mailto:[email protected]

https://www.elsevier.com/about/our-business/policies/copyright/permissions

https://www.elsevier.com/about/our-business/policies/copyright/permissions

mailto:[email protected]

https://doi.org/10.1016/j.hrthm.2019.04.024

e2 Heart Rhythm, Vol -, No -, - 2019

BackgroundPatients with ischemic heart disease (IHD) are at increasedrisk of incident or recurrent ventricular tachycardia (VT),ventricular fibrillation (VF), and sudden cardiac death.Implantable cardioverter defibrillators (ICDs) are themainstay of treatment to reduce the incidence of suddencardiac death by terminating ventricular arrhythmias eitherby antitachycardia pacing (ATP) or by delivering a shock.1–3

However, ICD shocks, whether appropriate or inappropriate,can have negative effects on patients’ quality of life4–7 andare associated with an increased risk of subsequentmortality.8,9 Thus, therapies that can effectively reduce therisk of ICD shocks are of great importance. Catheterablation (CA) of VT has become established as a means totreat VT and prevent recurrence.10 Several randomizedcontrolled trials (RCTs) have been conducted comparingCA with other strategies, such as antiarrhythmic drug(AAD) therapy or control, in patients with IHD.

The Heart Rhythm Society (HRS), the European HeartRhythm Association (EHRA), the Asia Pacific HeartRhythm Society (APHRS), and the Latin American HeartRhythm Society (LAHRS), in collaboration with theAmerican Heart Association (AHA), the American Collegeof Cardiology (ACC), the Japanese Heart Rhythm Society(JHRS), the Brazilian Society of Cardiac Arrhythmias(Sociedade Brasileira de Arritmias Cardíacas [SOBRAC]),and the Pediatric and Congenital Electrophysiology Soci-ety (PACES), appointed a writing committee to draft anexpert consensus statement to update the 2009 EHRA/HRS Expert Consensus on Catheter Ablation of Ventricu-lar Arrhythmias.10 The Scientific and Clinical DocumentsCommittee of HRS recognized the need for a high-quality systematic review and meta-analysis of the pub-lished literature by an Evidence Review Committee(ERC) to inform recommendations. Such an effort mustbe directed toward areas where key clinical questionscan be formed and where published data exist. Here, wereport the findings of this effort, with the purpose of eval-uating the use of CA in preventing VT events in patientswith IHD through a systematic review and meta-analysis.For transparency, ERC members’ comprehensive disclo-sure information is available in Appendix 1, as is compre-hensive disclosure information for the peer reviewers inAppendix 2.

MethodsThis meta-analysis conforms to standard guidelines and iswritten in accordance with the Preferred Reporting Itemsfor Systematic Reviews andMeta-Analyses (PRISMA) state-ment.11 The PICOT format (P 5 population, I 5 interven-tion, C 5 comparator, O 5 outcome, T 5 timing, S 5setting)12 was used to derive the key clinical question. Thisquestion was, “In adults with a history of sustained ventricu-lar tachycardia and ischemic cardiomyopathy, what are theeffectiveness and harms of catheter ablation compared toother interventions?”


Data Sources and Search StrategyWe systematically searched MEDLINE, the CochraneCentral Register of Controlled Trials (CENTRAL), and theCochrane Database of Systematic Reviews (CDSR) fromJanuary 2000 through April 2018 to identify RCTscomparing a strategy of CA vs no ablation in patients withIHD, an ICD, and a history of VT. The following MedicalSubject Headings (MeSH) and keywords were used: ventric-ular tachycardia, ventricular arrhythmia, ventricular fibrilla-tion, catheter ablation, antiarrhythmic agents, andantiarrhythmic drug. All searches were limited to full-text ar-ticles published in English. A manual search of referencesfrom included studies was also performed.

Study SelectionFor the title, abstract, and full-text article review, two inves-tigators independently examined all potentially relevant cita-tions and articles in a parallel manner, using predefinedinclusion and exclusion criteria. Studies were included inthis systematic review and meta-analysis if they 1) wereRCTs; 2) enrolled adults (.18 years of age); 3) enrolled pa-tients with IHD implanted with an ICD and a history of spon-taneous VT or syncope with inducible VT; 4) had at least oneCA treatment group; and 5) had outcomes of interest datasuitable for pooling. Studies were excluded if they werecase reports, reviews, editorials, or non-English languagepublications. The outcomes of interest included appropriateICD therapies (ICD shock or ATP), appropriate ICD shocks,VT storm (defined as �3 shocks within 24 hours), recurrentVT/VF, cardiac hospitalizations, and all-cause mortality.

Data ExtractionFor each study, two investigators used a standardized dataabstraction tool to extract all the relevant and specific informa-tion. Disagreements were resolved by consensus. Informationcollected from each study included author, year of publication,interventions, sample size, key inclusion criteria, months offollow-up, class I or III AADs, other cardiovascular drugs,time to lastmyocardial infarction (MI), prior revascularization,and pertinent patient characteristics. Study authors were con-tacted for clarification of information not covered in the pub-lication. All included studies are multicenter prospectiveRCTs. The risk of bias for each study was independently as-sessed by two investigators using the Cochrane Risk of BiasTool.13 This tool includes 7 items covering the following do-mains: selection bias due to inadequate generation of a ran-domized sequence, or inadequate concealment of allocationsprior to assignment; performance bias due to knowledge ofthe allocated interventions by participants and personnel dur-ing the study; detection bias due to knowledge of the allocatedinterventions by outcome assessors; attrition bias due toamount, nature, or handling of incomplete outcome data; re-porting bias due to selective outcome reporting; and otherbias due to problems not previously covered.13

f � 27 April 2019 � 5:09 pm � ce

Figure 1 PRISMA flow diagram.

Martinez et al Systematic Review and Meta-analysis of Catheter Ablation of VT in IHD e3

Statistical AnalysisAll outcome data were pooled using an inverse variancerandom-effects model producing odds ratios (ORs) andaccompanying 95% confidence intervals (CIs) for eachendpoint, with between-study heterogeneity (t2) calculatedusing the Paule-Mandel estimator. The I2 statistic wascalculated to estimate the percentage of variability in thetreatment estimate attributable to statistical heterogeneitybetween studies, with a value .50% considered substan-tial.14 Small study effects, including publication bias,were not examined, given fewer than 10 eligible studieswere identified. All analyses were performed using the‘meta’ package in R (version 3.4.3; the R Project for Sta-tistical Computing).

In order to better quantify the effects of CA on our out-comes of interest, we conducted a random-effects meta-regression via iterative maximum likelihood.15 An analysisevaluating the impact of baseline amiodarone therapy oneach of the outcomes of interest was performed. The percent-age of patients administered baseline amiodarone was used to


conduct meta-regression to examine whether baseline amio-darone therapy altered the effectiveness of CA.

ResultsThe inclusion and exclusion of citations and articles identi-fied through our systematic literature search is illustrated inFigure 1. A total of 5 studies evaluating the use of CA in pa-tients with IHD and an ICD published between 2007 and2017 were included in the analysis (Table 1).16–20 Allincluded studies were multicenter RCTs. Individual studysample sizes ranged from 27 patients to 259 patients. Themean patient age ranged from 64 years to 68 years, and theduration of follow-up was 6–27.9 months. The time to lastMI ranged from,1 year to 15.7 years. The use of AADs var-ied between studies. The Substrate Mapping and Ablation inSinus Rhythm to Halt Ventricular Tachycardia (SMASH-VT) study excluded patients treated with class I or III antiar-rhythmics20; 3 studies included between 32% and 37% ofpatients treated with amiodarone and sotalol16,18,19; and the

f � 27 April 2019 � 5:09 pm � ce

Table 1 Baseline characteristics of included studies

StudyYearN

Interventions(N) Key inclusion criteria

Actual FU(months) LVEF NYHA class

Age, years(range ofmeans) Other CV drugs

Class I orIII AADs

Time to last MI,years

Priorrevascularization

SMS2017N 5 111

Catheterablation(N 5 54)

No ablation(N 5 57)

CAD, LVEF �40%, andclinically unstablespontaneous VT; orcardiac arrest orsyncope with unstableVT inducible atelectrophysiologicalstudy

27.6 6 13.2 �30 5 45%.30 5 NR

I–III 5 100%IV 5 0%

66–68 ACEI/ARB 5 95%BB 5 91%Digoxin 5 NRDiuretic 5 NRStatin 5 NRASA 5 NRAC 5 NR

32%(amiodarone)

9.8 6 7.3 PCI 5 46%Surgical 5 42%

VANISH2016N 5 259

Catheterablation 1backgroundof AAD(N 5 132)

No ablation 1escalation ofAAD(N 5 127)

Previous MI; undergoneplacement of an ICD;had an episode of VTduring treatment withamiodarone oranother class I or IIIAAD within theprevious 6 months

27.9 6 17.1 31 (mean) I 5 24%II 5 53%III 5 24%IV 5 0%

67–70 ACEI/ARB 5 88%BB 5 95%Digoxin 5 20%Diuretic 5 69%Statin 5 NRASA 5 71%AC 5 43%

100% 15.7 PCI 5 43%CABG 5 46%

CALYPSO2015N 5 27

Catheterablation 1no AAD(N 5 13)

No ablation 1AAD (N 5 14)

ICD implanted forprimary or secondarypreventionindication; IHD; �1documented ICDshock or � 3 ATPtherapies within 6months formonomorphic VT

92% completed3 months;71%completed6 months

23%–25%(range ofmedians)

I 5 19%II 5 30%III 5 15%IV 5 0%

64–65 ACEI/ARB 5 93%BB 5 93%Digoxin 5 NRDiuretic 5 NRStatin 5 85%ASA 5 NRAC 5 NR

37%(amiodaroneand sotalol)

,1 year 5 7%1–2 years 5 0%.2 years 5 41%Unknown 5 48%

PCI 5 52%CABG 5 59%

VTACH2010N 5 110


No ablation(N 5 56)

Indication for ICD assecondary preventionafter documentedstable clinical VTwithout a reversiblecause; CAD; previousMI; and LVEF �50%

22.5 6 9 �30 5 40%.30 5 60%

NR 64–68 ACEI/ARB 5 NRBB 5 75%Digoxin 5 NRDiuretic 5 NRStatin 5 NRASA 5 NRAC 5 NR

35%(amiodarone)

12.9 6 8.2 PTCA 5 47%Surgical 5 45%

SMASH-VT2007N 5 128


No ablation(N 5 64)

MI �1 month;undergone a plannedor recent (within 6months) implantationof a defibrillator forVF, hemodynamicallyunstable VT, orsyncope withinducible VT; class I orclass III AAD-naïve

22.5 6 5.5 �30 5 52%.30 5 48%

I/II 5 80%III/IV 5 20%

66–67 ACEI/ARB 5 92%BB 5 96%Digoxin 5 NRDiuretic 5 NRStatin 5 59%ASA 5 71%AC 5 NR

0% 7.9–8.8 (rangeof means)

PTCA/CABG 5 67%

AAD5 antiarrhythmic drug; AC5 anticoagulant; ACEI5 angiotensin converting enzyme inhibitor; ARB5 angiotensin II receptor blocker; ASA5 aspirin; ATP5 antitachycardia pacing; BB5 beta blocker; CABG5coronary artery bypass grafting; CAD 5 coronary artery disease; CV 5 cardiovascular; FU 5 follow-up; ICD 5 implantable cardioverter defibrillator; IHD 5 ischemic heart disease; LVEF 5 left ventricular ejectionfraction; MI 5 myocardial infarction; N 5 number; NR 5 not reported; NYHA 5 New York Heart Association; PCI 5 percutaneous coronary intervention; PTCA 5 percutaneous transluminal coronary angioplasty;SMASH-VT 5 Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia; VF 5 ventricular fibrillation; VT 5 ventricular tachycardia.

e4Heart

Rhythm,Vol

-,No

-,-

2019

PGL5.5.0

DTD

�HRTHM7988_proof�

27April

2019�

5:09pm

�ce

Figure 2 Cochrane risk of bias assessment.

Figure 3 Pooled odds of appropriate ICD therapies (A), appropriate ICD shocksICD 5 implantable cardioverter defibrillator; OR 5 odds ratio.



Ventricular Tachycardia Ablation versus EscalatedAntiarrhythmic Drug Therapy in Ischemic Heart Disease(VANISH) trial required patients to have receivedbackground amiodarone or another class I or class III AADwithin the previous 6 months.17 ICD programming was stan-dardized in each study; however, recommendations variedbetween studies. Three studies reported the incidence ofICD therapies,16,19,20 4 studies reported ICD shocks andVT storm,15,16,18,19 all studies reported all-cause mortal-ity,16–20 4 studies reported hospitalizations for cardiaccause,15–18 and 3 studies reported recurrent VT/VF.16,18,19

Trial investigators provided additional outcome results:appropriate ATP or appropriate shocks in VANISH; andappropriate ATP or appropriate shocks, VT storm, andcardiac hospitalizations in Catheter Ablation for VentricularTachycardia in Patients with an Implantable CardioverterDefibrillator (CALYPSO). The majority of studies were atlow risk for selection bias, attrition bias, and reporting bias.All studies were at high risk of performance bias due to alack of blinding of participants and personnel, given the

(B), and all-cause mortality (C). ABL5 ablation; CI5 confidence interval;

f � 27 April 2019 � 5:09 pm � ce

Figure 4 Pooled odds of VT storm (A), recurrent VT/VF (B), and cardiac hospitalizations (C). ABL5 ablation; CI5 confidence interval; OR5 odds ratio; VF5 ventricular fibrillation; VT 5 ventricular tachycardia.


nature of patients being randomized to receiving a procedureor no procedure. Two studies were determined to be at highrisk of other biases due to their study design comparingpatients who received an ablation with those who receivedchanges in AAD therapy.17,18 Additionally, 2 studies weredetermined to possess a high risk of other biases due tosubstantial crossover between randomized groupsthroughout the study (Figure 2).18,19

Upon meta-analysis, patients who were randomized to CAhad decreased odds of appropriate ICD therapies (OR 0.49;95% CI 0.28–0.87), appropriate ICD shocks (OR 0.52;95% CI 0.28–0.96), VT storm (OR 0.64; 95% CI 0.43–0.95), and cardiac hospitalizations (OR 0.67; 95% CI 0.46–0.97) vs those who did not undergo CA. There was no evi-dence of a significant difference in the odds of recurrentVT/VF (OR 0.87; 95% CI 0.41–1.85) or all-cause mortality(OR 0.89; 95% CI 0.60–1.34) between the ablation and noablation groups (Figures 3 and 4).

Post Hoc Sensitivity Analysis and Meta-RegressionThe VANISH and CALYPSO trials differed from the otherstudies included in this meta-analysis in that they compared


CA with AAD therapy. Patients in the VANISH trial wererandomly assigned to receive either CA (ablation group)with continuation of baseline AADs or escalated AAD ther-apy (escalated-therapy group).17 The CALYPSO trial was acomparison of AADs with CA.18 Due to the differences intrial design, we ran a sensitivity analysis with the removalof these two trials. Upon analysis, the removal of theVANISH and CALYPSO trials decreased the between-study heterogeneity (I2 5 0% vs 65%) and showed a greatereffect of ablation on appropriate ICD shocks (OR 0.38; 95%CI 0.22–0.64). The removal of these two studies resulted inlower odds of VT storm (OR 0.55; 95% CI 0.30–1.01), car-diac hospitalizations (OR 0.58; 95% CI 0.29–1.15), recurrentVT/VF (OR 0.71; 95% CI 0.34–1.50), and all-cause mortal-ity (OR 0.77; 95% CI 0.41–1.46); however, statistical signif-icance was lost for some outcomes, likely due to type 2 error(Figure 5). A random-effects meta-regression showed no sig-nificant association between baseline amiodarone therapyand appropriate ICD therapies (P 5 .27), VT storm (P 5.35), cardiac hospitalizations (P5 .65), or all-cause mortality(P 5 .43). There was, however, a significant association be-tween baseline amiodarone therapy and appropriate ICD

f � 27 April 2019 � 5:09 pm � ce

Figure 5 Sensitivity analysis of appropriate ICD shocks (A), VT storm (B), cardiac hospitalizations (C), recurrent VT/VF (D), and all-cause mortality (E). ABL5 ablation; CI5 confidence interval; ICD5 implantable cardioverter defibrillator; OR5 odds ratio; VF5 ventricular fibrillation; VT5 ventricular tachycardia.


shocks (P,.01). A negative association was seen: as the per-centage of patients on concomitant AAD therapy increased,the effectiveness of CA in preventing appropriate ICD shocksdecreased (Figure 6).

Adverse EventsAdverse events were variably defined, and some protocolsmandated ICD implantation at or soon after randomization,making attribution of adverse events to the ablationprocedure or the ICD implantation procedure difficult. How-ever, adverse events related to the ablation procedure


occurred in 30 of 315 (9.5%) patients in the ablation armsof the included trials. Adverse events in the control armswere not reported uniformly due to variations in control stra-tegies. In the two trials that directly compared ablation versusAAD therapy, adverse events were more common in theAAD arm than in the ablation arm.17,18

DiscussionIn this systematic review of the literature and a meta-analysisof 5 RCTs, we found that CA reduced the likelihood ofappropriate ICD therapies, appropriate ICD shocks, VT

f � 27 April 2019 � 5:09 pm � ce

Figure 6 Random-effects meta-regression evaluating relationship between percentage of concomitant AAD and effectiveness of catheter ablation on reductionof appropriate ICD shocks. The circles represent individual studies, with the size of the circle proportional to the weight of each study. The line represents the bestfit line describing the relationship between the percent AAD use in each study (x-axis) and the effect on appropriate ICD shocks (y-axis). As the percentage ofAAD users in the studies increased, the beneficial effect of catheter ablation on reducing appropriate ICD shocks decreased. AAD5 antiarrhythmic drug; ICD5implantable cardioverter defibrillator.


storm, and cardiac hospitalization vs controls. In a sensitivityanalysis, excluding the 2 studies that specifically randomizedpatients to CA versus AAD, the magnitude of such reductionswas increased, although CIs also widened. This result mightsuggest an effect of AAD in reducing the risk of VT recur-rence and ICD therapies, as found in earlier pharmacotherapytrials.21,22

Although at first it might appear contradictory that abla-tion reduced the risk of several VT-related endpoints, butnot recurrent VT/VF, this contradiction is likely explainedby the different endpoints reported by the trials, meaningsome trials did not contribute data to each endpoint in ouranalysis. For example, only 3 trials, including fewer thanhalf of the total of 635 patients, contributed to the recurrentVT/VF endpoint. In contrast, 4 of 5 trials, including .95%of the total number of patients, contributed to the appropriateICD shocks and VT storm endpoints; and all trials contrib-uted to the all-cause mortality endpoint, leading to a higherdegree of confidence for these findings. Overlap of eventswas possible; for example, slow VT underdetection of anICD could count toward recurrent VT/VF but not towardappropriate ICD therapies.

The finding that baseline amiodarone therapy was asso-ciated with appropriate ICD shocks could indicate that pa-tients receiving amiodarone had more advanced heartdisease, as reported in a subgroup analysis of VANISH,23

and therefore were at higher risk of receiving ICD shocks.It is also possible that amiodarone was stopped after anacutely successful ablation procedure in some patients,with subsequent recurrence of VT that had been suppressed


by amiodarone therapy. However, these interpretations arehypotheses that require confirmation. Of note, onlyVANISH included a 30-day “blanking” period to allowfor full loading of amiodarone17; in the other trials, theduration of amiodarone therapy prior to an endpoint wasnot reported.

Our results are largely consistent with several other inves-tigations in this field. Three previous meta-analyses did notinclude the most recently published trials,24–26 or includedstudies available only in abstract form.24 One systematic re-view and meta-analysis has focused on prophylactic CA only(excluding trials in which patients were randomized toAAD).27 However, one of these trials enrolled patients whohad received their first ICD shock from a primary preventionICD after a protocol amendment,20 whereas the other twoenrolled patients after a qualifying VT event, and permittedAAD therapy in both arms.16,19 In practice, the choicebetween starting or changing AAD therapy on the onehand, vs CA on the other, is often the most relevantdecision to be made. This question was addressed by twoof the included trials.17,18 Due to the small size of one ofthese trials, a separate meta-analysis of these two was not per-formed. A recent systematic review and meta-analysis of theeffect of AAD and CA in patients with an ICD (includingsubstrates other than IHD) is also available.28 The currentstudy is the only one to use an expert ERC to systematicallyreview the literature on CA in IHD and perform ameta-analysis.

Our study has several limitations. The trials included inthis analysis mandated the presence of an ICD, or

f � 27 April 2019 � 5:09 pm � ce

Table 2 Ablation strategy characteristics

StudyYearN Ablation strategy description

Mapping strategiesN (%)

VT induction(Yes/No) Endpoint

Epicardialapproach %

Totalradiofrequencytime (min)

Fluoroscopytime (min)

SMS2017N 5 111

Catheter ablation was to beperformed before ICDimplantation. Mapping criteriafor ablation in stable VT andthe lesion design for substratemodification in cases ofnoninducible or unstable VTfollowed standard criteria.Inducibility of the targeted VTwas assessed by programmedstimulation using the sameprotocol as before ablation,stimulation at 2 sites in theright ventricle, with �3extrastimuli at 2 drive cyclelengths.

CARTO electroanatomical system*36 (75%)

EnSite NavX system10 (21%)Conventional mapping2 (4%)

Yes Success: Noninducibility of theclinical tachycardia

Failure: Lack of adequateendocardial target sites orineffective lesions despiteadequate target sites

No NR NR

VANISH2016N 5 259

Procedures followed astandardized approach thatspecifically targeted allinducible VTs. VT induction waswith programmed ventricularstimulation from twoventricular sites at two drivecycle lengths with �3extrastimuli, coupled notcloser than 180 msec. Ifclinical VT was not induced,isoproterenol could beadministered 0.5–10 mcg/minin a dose adjusted to achieve a30% increase in baseline heartrate. Hemodynamicallytolerated VT was approachedwith activation andentrainment mapping.Nontolerated VT was mappedwith pace mapping and bipolarvoltage mapping and linearablation performed parallel tothe scar margin. Very fast ornoninducible clinical VTablated with a puresubstrate-based approach was

Activation mapping92 (41.1%)Entrainment mapping80 (35.7%)Substrate mapping197 (87.9%)Pace mapping168 (75.0%)

Yes Noninducibility; very fast VT(cycle length ,300 msec) andpolymorphic VTs were notspecifically targeted

NR CatheterAblationGroup:38.7 6 21.9

AntiarrhythmicGroup:36.8 6 20.6

CatheterAblationGroup:31.5 6 20.8

AntiarrhythmicGroup:29.4 6 35.1

(Continued )

Martinez

etal

Systematic

Reviewand

Meta-analysis

ofCatheter

Ablationof

VTin

IHD

e9

PGL5.5.0

DTD


27April

2019�

5:09pm

�ce

Table 2 (Continued )

StudyYearN Ablation strategy description

Mapping strategiesN (%)

VT induction(Yes/No) Endpoint

Epicardialapproach %

Totalradiofrequencytime (min)

Fluoroscopytime (min)

used, targeting late potentialsand sites with a long stimulus-QRS.

CALYPSO2015N 5 27

Although endocardial ablationwas the preferred ablationstrategy in this trial, epicardialablation was allowed only if theclinical VT could not be ablatedvia an endocardial approach.The only ablation catheter thatwas allowed in this study wasthe Biosense Webster NaviStarThermoCool externallyirrigated 3.5-mm electrodecatheter.‡

The selection of the mappingsystem and details of methodsfor identifying reentry circuitsites were left to the discretionof the treating physician withinguidelines based on whetherthe VTs were hemodynamicallystable or not.

Yes Success: Achieve noninducibilityof clinical or presumptiveclinical VT if the clinical orpresumptive clinical VT wasknown and was inducible at thebeginning of the procedure

Other acute proceduralendpoints: 1) modification ofinduced VT cycle length(elimination of all VTs withcycle lengths equal to or longerthan the spontaneouslydocumented or targeted VT); 2)noninducibility of any VT

NRx NR NR

VTACH2010N 5 110

Mapping criteria for ablation instable VT and the lesion designfor substrate modification incase of noninducible orunstable VT followed standardcriteria.

CARTO electroanatomical system*32 (71.1%)EnSite noncontact system†11 (24.4%)Conventional mapping2 (4.4%)

Yes Success: Noninducibility of any VTat the end of the procedure

For patients with noninducibleVT, the ablation endpoint wassubstrate modification, definedas absence of all channelsinside the area of interest orablation with linear lesionsbased on pace mapping alongthe infarct scar target sites

No NR NR

SMASH-VT2007N 5 128

The ablation procedure wasperformed in sinus rhythm. Theprocedure was divided into 3steps: 1) induction of VT; 2)localization of the myocardialinfarct; and 3) targeting the“arrhythmogenic portions” ofthe infarct for catheterablation. Programmedstimulation was performedusing up to triple extrastimuliand rapid pacing from the rightventricular apex, rightventricular outflow tract, orleft ventricle. If only VF orpolymorphic VT was inducible,stimulation was repeated after

CARTO electroanatomical system*was used in all procedures

Yes VT was repeatedly induced untileither the same VT morphologywas induced, or the patientrequired multiple shocks toterminate induced rhythmsduring the procedure

NR NR NR

e10Heart

Rhythm,Vol

-,No

-,-

2019

PGL5.5.0

DTD


27April

2019�

5:09pm

�ce

firstinfusing

aclassI

antiarrhythm

icdrug

intravenou

sly(procainam

ideor

ajmaline).C

athetermapping

andradiofrequency

ablation

wereperformed

usingeither

theNa

viStar

4-mmtip*

standard

ortheThermocoo

l3.5-mm

tipsalin

e-irrigated

catheter.*

ICD5

implantablecardioverterdefibrillator;m

m5

millimeter;m

sec5

millisecon

d;N5

number;NR

5no

treported;

SMAS

H-VT5

SubstrateMapping

andAb

lation

inSinu

sRh

ythm

toHaltV

entricularTachycardia;

VF5

ventricular

fibrillation;

VT5

ventricular

tachycardia.

*BiosenseWebster,D

iamon

dBa

r,CA

.†Ab

bottLabo

ratorie

s,Ab

bottPark,IL.

‡Diam

ondBa

r,CA

.x Epicardialapproachallowed,n

opercentagesreported.



implantation of one soon after randomization. Althoughthis requirement likely improved the sensitivity and unifor-mity of arrhythmia detection, it limits applicability of ourresults to patients with an ICD and cannot be extrapolatedto those without. Different ablation techniques, technolo-gies, and endpoints were used during the timeframe inwhich these studies were conducted (Table 2). Causes ofdeath were not uniformly reported across all trials. The ab-solute number of deaths was small, therefore a separateanalysis by cause of death (arrhythmic, cardiac, noncar-diac) was not performed. We limited our analysis to trialspublished as a full peer-reviewed article. The authors areaware of at least 3 other prospective trials that were pre-sented in abstract form, and other studies that were closeddue to low enrollment and remain unpublished. How inclu-sion of these trials would have affected our results isunknown.

ConclusionThis systematic review and meta-analysis of 5 RCTs foundthat patients with IHD who underwent CA for VT experi-enced decreased odds of appropriate ICD therapies, appro-priate ICD shocks, VT storm, and cardiac hospitalizationvs those who did not undergo ablation.

AcknowledgmentsThe authors thank Sana M. Al-Khatib, MD, MHS, FHRS,CCDS (Duke University Medical Center, Durham, NorthCarolina) and John L. Sapp, Jr., MD, FHRS (Queen Eliza-beth II Health Sciences Centre, Halifax, Canada) for theirassistance in providing additional data.

References1. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update

of the 2008 guidelines for device-based therapy of cardiac rhythm abnormal-ities: a report of the American College of Cardiology Foundation/AmericanHeart Association Task Force on Practice Guidelines. Heart Rhythm 2012;9:1737–1753.

2. Pedersen CT, Kay GN, Kalman J, et al. EHRA/HRS/APHRS expert consensus onventricular arrhythmias. Heart Rhythm 2014;11:e166–e196.

3. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRSguideline for management of patients with ventricular arrhythmias and the pre-vention of sudden cardiac death: a report of the American College of Cardiol-ogy/American Heart Association Task Force on Clinical Practice Guidelinesand the Heart Rhythm Society. Heart Rhythm 2018;15:e73–e189.

4. Schron EB, Exner DV, Yao Q, et al. Quality of life in the antiarrhythmics versusimplantable defibrillators trial: impact of therapy and influence of adverse symp-toms and defibrillator shocks. Circulation 2002;105:589–594.

5. Irvine J, Dorian P, Baker B, et al. Quality of life in the Canadian Implantable Defi-brillator Study (CIDS). Am Heart J 2002;144:282–289.

6. Kamphuis HC, de Leeuw JR, Derksen R, Hauer RN, Winnubst JA. Implantablecardioverter defibrillator recipients: quality of life in recipients with and withoutICD shock delivery: a prospective study. Europace 2003;5:381–389.

7. Passman R, Subacius H, Ruo B, et al. Implantable cardioverter defibrillators andquality of life: results from the Defibrillators in Nonischemic CardiomyopathyTreatment Evaluation study. Arch Intern Med 2007;167:2226–2232.

8. Poole JE, Johnson GW, HellkampAS, et al. Prognostic importance of defibrillatorshocks in patients with heart failure. N Engl J Med 2008;359:1009–1017.

9. Moss AJ, Greenberg H, Case RB, et al. Long-term clinical course of patients aftertermination of ventricular tachyarrhythmia by an implanted defibrillator. Circula-tion 2004;110:3760–3765.

10. Aliot EM, Stevenson WG, Almendral-Garrote JM, et al. EHRA/HRS Expertconsensus on catheter ablation of ventricular arrhythmias: developed in a

f � 27 April 2019 � 5:09 pm � ce


partnership with the European Heart Rhythm Association (EHRA), a RegisteredBranch of the European Society of Cardiology (ESC), and the Heart Rhythm So-ciety (HRS); in collaboration with the American College of Cardiology (ACC)and the American Heart Association (AHA). Heart Rhythm 2009;6:886–933.

11. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMAGroup. Preferred reportingitems for systematic reviews and meta-analyses: the PRISMA statement. AnnIntern Med 2009;151:264–269.

12. Institute of Medicine (US). Committee on Standards for Systematic Reviews ofComparative Effectiveness Research. Finding what works in health care: stan-dards for systematic reviews. Washington, DC: National Academies Press; 2011.

13. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s toolfor assessing risk of bias in randomised trials. BMJ 2011;343:d5928.

14. Higgins JP, Thomas SG, Deeks JJ, Altman DG.Measuring inconsistency in meta-analyses. BMJ 2003;327:557–560.

15. Baker WL, White CM, Cappelleri JC, Kluger J, Coleman CI, Health Outcomes,Policy, and Economics (HOPE) Collaborative Group. Understanding heterogene-ity in meta-analysis: the role of meta-regression. Int J Clin Pract 2009;63:1426–1434.

16. Kuck KH, Tilz RR, Deneke T, et al. Impact of substrate modification by catheterablation on implantable cardioverter-defibrillator interventions in patients withunstable ventricular arrhythmias and coronary artery disease: results from themulticenter randomized controlled SMS (Substrate Modification Study). Circ Ar-rhythm Electrophysiol 2017;10:e004422.

17. Sapp JL,Wells GA, Parkash R, et al. Ventricular tachycardia ablation versus esca-lation of antiarrhythmic drugs. N Engl J Med 2016;375:111–121.

18. Al-Khatib SM, Daubert JP, Anstrom KJ, et al. Catheter ablation for ventriculartachycardia in patients with an implantable cardioverter defibrillator (CALYPSO)pilot trial. J Cardiovasc Electrophysiol 2015;26:151–157.

19. Kuck KH, Schaumann A, Eckardt L, et al. Catheter ablation of stable ventriculartachycardia before defibrillator implantation in patients with coronary artery dis-ease (VTACH): a multicentre randomised controlled trial. Lancet 2010;375:31–40.


20. Reddy VY, Reynolds MR, Neuzil P, et al. Prophylactic catheter ablation for theprevention of defibrillator therapy. N Engl J Med 2007;357:2657–2665.

21. Pacifico A, Hohnloser SH, Williams JH, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol ImplantableCardioverter-Defibrillator Study Group. N Engl J Med 1999;340:1855–1862.

22. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodaroneplus beta-blockers, or sotalol for prevention of shocks from implantable cardioverterdefibrillators: the OPTIC Study: a randomized trial. JAMA 2006;295:165–171.

23. Parkash R, Nault I, Rivard L, et al. Effect of baseline antiarrhythmic drug on out-comes with ablation in ischemic ventricular tachycardia: a VANISH substudy(Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Ther-apy in Ischemic Heart Disease). Circ Arrhythm Electrophysiol 2018;11:e005663.

24. Mallidi J, Nadkarni GN, Berger RD, Calkins H, Nazarian S. Meta-analysis of cath-eter ablation as an adjunct tomedical therapy for treatment of ventricular tachycardiain patients with structural heart disease. Heart Rhythm 2011;8:503–510.

25. Patel D, Hasselblad V, Jackson KP, Pokorney SD, Daubert JP, Al-Khatib SM.Catheter ablation for ventricular tachycardia (VT) in patients with ischemic heartdisease: a systematic review and a meta-analysis of randomized controlled trials. JInterv Card Electrophysiol 2016;45:111–117.

26. Maskoun W, Saad M, Abualsuod A, Nairooz R, Miller JM. Outcome of catheterablation for ventricular tachycardia in patients with ischemic cardiomyopathy: asystematic review and meta-analysis of randomized clinical trials. Int J Cardiol2018;267:107–113.

27. Atti V, Vuddanda V, Turagam MK, et al. Prophylactic catheter ablation of ven-tricular tachycardia in ischemic cardiomyopathy: a systematic review and meta-analysis of randomized controlled trials. J Interv Card Electrophysiol 2018;21:207–215.

28. Santangeli P, Muser D, Maeda S, et al. Comparative effectiveness of antiar-rhythmic drugs and catheter ablation for the prevention of recurrent ventriculartachycardia in patients with implantable cardioverter-defibrillators: a systematicreview and meta-analysis of randomized controlled trials. Heart Rhythm 2016;13:1552–1559.

f � 27 April 2019 � 5:09 pm � ce

Appendix 1 Author disclosure table

Committee member Employment

Honoraria/Speaking/Consulting

Speakers’bureau Research*

Fellowshipsupport*

Ownership/Partnership/Principal/Majoritystockholder

Stock orstockoptions

Intellectualproperty/Royalties Other

Brandon K. Martinez,PharmD

University of Connecticut School ofPharmacy, Storrs, Connecticut;Hartford Hospital Evidence-BasedPractice Center, Hartford, Connecticut

None None None None None None None None

William L. Baker,PharmD

University of Connecticut School ofPharmacy, Storrs, Connecticut;Hartford Hospital Evidence-BasedPractice Center, Hartford, Connecticut


Anna Konopka, PharmD University of Connecticut School ofPharmacy, Storrs, Connecticut


Devon Giannelli, PharmD University of Connecticut School ofPharmacy, Storrs, Connecticut


Craig I. Coleman, PharmD University of Connecticut School ofPharmacy, Storrs, Connecticut;Hartford Hospital Evidence-BasedPractice Center, Hartford, Connecticut


Jeffrey Kluger, MD Hartford HealthCare Heart and VascularInstitute, Hartford Hospital, Hartford,Connecticut; University ofConnecticut School of Medicine,Farmington, Connecticut


Edmond M. Cronin, MB, BCh,BAO, FHRS, CCDS, CEPS-A

Hartford HealthCare Heart and VascularInstitute, Hartford Hospital, Hartford,Connecticut; University ofConnecticut School of Medicine,Farmington, Connecticut


Number value: 0 5 $0; 1 5 � $10,000; 2 5 . $10,000 to � $25,000; 3 5 . $25,000 to � $50,000; 4 5 . $50,000 to � $100,000; 5 5 . $100,000.*Research and fellowship support are classed as programmatic support. Sources of programmatic support are disclosed but are not regarded as a relevant relationship with industry for writing group members or re-viewers.

Martinez

etal

Systematic

Reviewand

Meta-analysis

ofCatheter

Ablationof

VTin

IHD

e13

PGL5.5.0

DTD


27April

2019�

5:09pm

�ce

Appendix 2 Reviewer disclosure table

Peer reviewer Employment

Honoraria/Speaking/Consulting

Speakers’bureau Research*

Fellowshipsupport*

Ownership/Partnership/Principal/Majority stockholder

Stock orstockoptions

Intellectualproperty/Royalties Other

Samuel J.Asirvatham, MD,FHRS

Mayo Clinic Collegeof Medicine,Rochester,Minnesota

1: Abbott; 1:BIOTRONIK; 1:Boston Scientific;1: Medtronic

None None None None None 1: AliveCor None

Sabine Ernst, MD,PhD

Royal Brompton andHarefieldHospitals,London, England

2: BiosenseWebster; 2:Stereotaxis

None 3: CatheterPrecision; 4:Baylis; 4: SpectrumDynamics

None None None None None

Number value: 0 5 $0; 1 5 � $10,000; 2 5 . $10,000 to � $25,000; 3 5 . $25,000 to � $50,000; 4 5 . $50,000 to � $100,000; 5 5 . $100,000.*Research and fellowship support are classed as programmatic support. Sources of programmatic support are disclosed but are not regarded as a relevant relationship with industry for writing group members or re-viewers.

e14Heart

Rhythm,Vol

-,No

-,-

2019

PGL5.5.0

DTD


27April

2019�

5:09pm

�ce