Author + information
- Received July 20, 2016
- Revision received November 7, 2016
- Accepted November 17, 2016
- Published online May 15, 2017.
- Jackson J. Liang, DOa,
- Wei Yang, PhDb,
- Pasquale Santangeli, MDa,
- Robert D. Schaller, DOa,
- Gregory E. Supple, MDa,
- Mathew D. Hutchinson, MDa,
- Fermin Garcia, MDa,
- David Lin, MDa,
- Sanjay Dixit, MDa,
- Andrew E. Epstein, MDa,
- David J. Callans, MDa,
- Francis E. Marchlinski, MDa and
- David S. Frankel, MDa,∗ ()
- aElectrophysiology Section, Cardiovascular Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- bCenter for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- ↵∗Address for correspondence:
Dr. David S. Frankel, Hospital of the University of Pennsylvania, 9 Founders Pavilion, 3400 Spruce Street, Philadelphia, Pennsylvania 19104.
Objectives This study sought to examine long-term outcomes in patients with structural heart disease in whom amiodarone was reduced/discontinued after ventricular tachycardia (VT) ablation.
Background VT in patients with structural heart disease increases morbidity and mortality. Amiodarone can decrease VT burden, but long-term use may result in organ toxicities and possibly increased mortality. Catheter ablation can also decrease VT burden. Whether amiodarone can be safely reduced/discontinued following ablation remains unknown.
Methods We studied consecutive patients undergoing VT ablation from 2008 to 2011, typically followed by noninvasive programmed stimulation several days later. Patients were divided into 3 groups by amiodarone use: group A—amiodarone reduced/discontinued following ablation; group B—amiodarone not reduced; group C—not on amiodarone at time of ablation. Baseline characteristics and outcomes were compared between groups.
Results Overall, 231 patients (90% male; mean age: 63.4 ± 12.9 years; 53.7% ischemic cardiomyopathy) were included (group A: 99 patients; group B: 29 patients; group C: 103 patients). Group B patients were older with more advanced heart failure. Group A patients less frequently had inducible VT at the end of ablation or noninvasive programmed stimulation. In follow-up, 1-year VT-free survival was similar between groups (p = 0.10). Mortality was highest in group B (p < 0.001). Higher amiodarone dose after ablation (hazard ratio: 1.23; 95% confidence interval: 1.03 to 1.47; p = 0.02) was independently associated with shorter time to death.
Conclusions After successful VT ablation, as confirmed by noninducibility at the end of ablation and noninvasive programmed stimulation, amiodarone may be safely reduced/discontinued without an unacceptable increase in VT recurrence. Reduction/discontinuation of amiodarone should be considered an important goal of VT ablation.
Ventricular tachycardia (VT) frequently occurs in patients with ischemic and nonischemic cardiomyopathies. Whereas implantable cardioverter-defibrillators (ICD) prolong life in appropriately selected patients, ICD shocks themselves may be associated with increased morbidity and mortality (1,2). Antiarrhythmic drugs (AAD) are frequently prescribed to suppress VT in patients with structural heart disease. Amiodarone is the most effective AAD (3), but it can cause several organ toxicities with long-term use, which is particularly concerning in younger patients (4–7). Catheter ablation is a potentially curative treatment option for VT.
Management of AAD following VT ablation has not been well studied. Whereas the 2009 Consensus Statement on Catheter Ablation of Ventricular Arrhythmias states that amiodarone dose reduction or discontinuation may be considered following apparently successful ablation, this recommendation is based on expert consensus rather than clinical evidence (8). To our knowledge, outcomes following amiodarone reduction or discontinuation after VT ablation in patients with structural heart disease have not been previously reported.
We hypothesized that amiodarone could be reduced or discontinued following apparently successful VT ablation without an unacceptable increase in risk of VT recurrence. We tested this hypothesis retrospectively in our large, single center experience.
The study cohort consisted of consecutive patients with sustained VT and structural heart disease who were referred to the Hospital of the University of Pennsylvania for VT ablation between January 1, 2008 and June 30, 2011. Patients with idiopathic VT were excluded. Whenever possible, AAD were discontinued at least 5 half-lives prior to the procedure; amiodarone was discontinued 2 weeks prior to ablation when possible. Per institutional guidelines, all patients provided written informed consent both for the ablation procedure and for their anonymized medical information to be included in research studies.
Conscious sedation was used whenever possible. General anesthesia was used when necessary for ventilation, oxygenation, or patient comfort. In addition, general anesthesia was routinely initiated prior to obtaining epicardial access.
Electroanatomic mapping (CARTO, Biosense Webster, Inc., Diamond Bar, California) was performed during sinus or paced rhythm to define areas of low voltage and abnormal electrograms, consistent with scar (9,10). Programmed stimulation was performed, and induced VT were compared to those occurring spontaneously. Clinical VT was identified by matching the QRS morphology with either a 12-lead electrocardiogram (when available) or the stored ICD cycle length, as well as near-field and far-field electrogram morphology. All spontaneously occurring VT was considered clinical; thus, a single patient could have multiple clinical VTs. Special attention was paid to elimination of clinical VT. Additionally, all mappable VT and all VTs with cycle length >250 ms were considered relevant and targeted for ablation whenever possible.
When hemodynamically tolerated, entrainment mapping was used to define critical components of the VT circuit. If VT was not mappable, substrate modification was performed with linear and/or cluster lesions targeting sites identified by pace mapping and late potentials. Ablation was typically performed using an irrigated ablation catheter (Thermocool, Biosense Webster, Inc.) using powers up to 50 W with a goal of 12- to 15-Ω impedance drop. Epicardial mapping and ablation were performed when 12-lead electrocardiogram of VT suggested an epicardial exit and/or endocardial ablation failed to eliminate targeted VT (11). At the end of the ablation procedure, programmed stimulation was repeated in patients who were medically stable, with up to 3 ventricular extrastimuli delivered to refractoriness from up to 2 sites at 2 pacing cycle lengths.
Noninvasive programmed stimulation
In the absence of clinical VT being inducible at the end of ablation or spontaneous VT recurrence, noninvasive programmed stimulation (NIPS) was typically performed within several days of ablation, before hospital discharge, as previously described (12). AAD were not restarted following ablation until after NIPS, if at all. In the fasting state, with intermittent boluses of propofol titrated to deep sedation, single, double, and then triple ventricular extrastimuli were delivered to refractoriness at drive trains of 600 and 400 ms, via the right ventricular ICD lead. In patients without ICDs, programmed stimulation was performed via a quadripolar catheter advanced through the femoral vein to the right ventricle. Response to NIPS was categorized as “clinical VT inducible” if any sustained, monomorphic VT was induced matching any spontaneous VT. Response was categorized as “nonclinical VT inducible” if only sustained monomorphic VT not matching any of the clinical VT was induced. Finally, if no sustained monomorphic VT could be induced, the response was categorized as “no VT inducible.”
Patients with inducible nonsustained monomorphic VT, polymorphic VT, or ventricular fibrillation only were included in the “no VT inducible” group. The NIPS results were used for prognostic purposes, to guide AAD prescription, and to optimize ICD programming. The detection rate was programmed lower than the rate of the slowest VT induced during ablation or NIPS. Antitachycardia pacing was programmed for all patients with pace-terminable VT. For the small number of patients who underwent NIPS more than once during the index hospitalization, the results from the last NIPS are reported.
Patients were routinely evaluated in the Penn Arrhythmia Center 6 weeks following ablation and then at 3- to 6-month intervals. For patients not followed at our institution, referring cardiologists were contacted at 6- to 12-month intervals, and ICD interrogations were reviewed to determine arrhythmia recurrence. Vital status was determined by querying the Social Security Death Index.
Patients were categorized into 3 groups based on amiodarone dose at the time of admission for VT ablation and discharge following ablation. Group A included patients on amiodarone prior to ablation, whose dose was decreased or discontinued following ablation. Group B included patients on amiodarone prior to ablation whose dose was continued or increased following ablation. Group C included patients not on amiodarone immediately prior to ablation. Patients in whom amiodarone was remotely prescribed but then stopped due to ineffectiveness or intolerance were included in group C. Continuous variables are expressed as mean ± SD. Differences in continuous variables between the 3 groups were assessed using the analysis of variance test. Categorical variables are expressed as percentages and compared using the Pearson chi-square test. The Fisher exact test was used to compare dichotomous variables with expected cell values <5. We constructed Kaplan-Meier curves to illustrate overall survival and survival free of recurrent VT. Follow-up began at the conclusion of the last ablation during the index hospitalization. Survival was compared among groups A, B, and C using the log-rank test. Three subsidiary analyses were conducted. First, VT-free survival was compared among groups A, B, and C among those without clinical VT inducible at the end of ablation. Second, survival free of appropriate ICD shocks was compared among groups A, B, and C. Lastly, mortality was compared between those discharged on and off amiodarone.
Cox proportional hazards modeling was used to identify predictors of time to VT recurrence and death. Variables showing marginal (p < 0.10) associations with recurrent VT or death on univariate testing were further assessed in multivariable models. Variable selection was also performed using the Lasso procedure. Given the similarity between the resultant multivariable models, only the results using univariate testing for variable selection are presented. We tested the proportional hazards assumption by including an interaction term between the log-transformed time and each predictor in the final model. We considered p < 0.05 to indicate statistical significance. Analyses were performed using SPSS software version 20.0 (IBM, Armonk, New York).
During the study period, 231 patients (90% male; mean age 63.4 ± 12.9 years; 53.7% with ischemic cardiomyopathy) with structural heart disease were treated with catheter ablation for VT, 128 (55.4%) of whom were taking amiodarone at the time of ablation. Of the 103 patients (44.6%) who were not on amiodarone at the time of ablation (group C), 34 (33.0%) were previously on amiodarone but stopped the medication secondary to toxicity or intolerance. Following ablation, amiodarone was decreased or discontinued in 99 patients (42.9%, group A) and increased or continued without change in 29 patients (12.6%, group B). Mean and median doses of amiodarone were 233 and 200 mg/day prior to ablation, respectively, compared with 96 and 0 mg/day following ablation.
Baseline characteristics are compared between amiodarone treatment groups in Table 1. Group B patients were older (70.2 vs. 65.5 and 59.6 years for groups A and C, respectively; p < 0.001 for trend across groups), had lower left ventricular ejection fraction ([LVEF]; 29.1% vs. 30.7% and 34.3%; p = 0.04), were more frequently taking beta-blockers (96.6% vs. 89.9% and 75.7%; p = 0.003) and diuretics (89.7% vs. 60.6% and 50.5%; p = 0.001), and were more likely to already have an ICD (100.0% vs. 96.0% and 88.3%; p = 0.003) and biventricular ICD (62.1% vs. 36.4% and 31.1%; p = 0.009) at the time of ablation than patients in group A or C.
VT ablation characteristics
VT ablation characteristics, acute procedural results, NIPS results, and post-ablation AAD use are compared among the 3 groups in Table 2. Group C patients had fewer spontaneous or inducible VTs than patients in groups A and B (2.7 ± 1.8 vs. 3.1 ± 2.2 and 3.2 ± 1.6, respectively; p = 0.003). Group B patients were more likely to have inducible VT at the end of ablation than group A or C patients (63.6% vs. 33.7% and 33.7%, respectively; p = 0.02).
A total of 149 patients (64.5%) underwent NIPS a mean of 2.1 ± 3.1 days following ablation. Again, patients in group B were more likely to have clinical VT induced at NIPS (41.2% vs. 25.4% and 4.7%; p < 0.001) and any VT induced at NIPS (64.7% vs. 71.6% and 34.6%, respectively, p < 0.001). In 50.5% of patients in group A, amiodarone was discontinued following ablation, whereas amiodarone dose was reduced in the remaining 49.5%. Only 4 patients in group A were discharged on amiodarone >200 mg/day. Meanwhile, 13 patients (12.6%) in group C were newly started on amiodarone following ablation.
One-year VT recurrence
The majority of patients (68.8%) were followed in the Penn Arrhythmia Center after ablation. Seventy-eight patients (33.8%) had recurrent VT after 1.3 ± 0.7 ablation procedures, including 41 patients (17.7%) with at least 1 ICD shock. There was no significant difference in 1-year VT-free survival among groups (p = 0.10) (Figure 1). In a subsidiary analysis restricted to those without clinical VT inducible at the end of ablation, again there was no significant difference in 1-year VT-free survival among groups (p = 0.20). Lastly, there was no significant difference in 1-year survival free of appropriate ICD shocks (p = 0.10). In univariate Cox regression, lower LVEF, more advanced New York Heart Association (NYHA) heart failure class, higher creatinine, diuretic use, increased number of spontaneous/inducible VTs, not performing programmed stimulation at end of ablation, inducibility of clinical VT during NIPS, and higher amiodarone dose prior to ablation were all associated with shorter time to VT recurrence (p values all <0.05) (Table 3). However, in multivariate testing, only inducibility of clinical VT at NIPS remained an independent, significant predictor of shorter time to VT recurrence (hazard ratio: 3.33; 95% confidence interval: 1.74 to 6.37; p < 0.001). Among the 17 patients in whom clinical VT was induced at NIPS and amiodarone subsequently reduced or discontinued, 13 (76.5%) had recurrent VT over the following year.
Over a mean follow-up of 1.8 ± 1.6 years, survival in group B was lower than in groups A and C (20% vs. 58% and 61%, respectively; log-rank p < 0.001) (Figure 2). In a subsidiary analysis, survival was lower among those discharged on amiodarone than off amiodarone (p < 0.001). In univariate Cox regression, older age, ischemic cardiomyopathy, lower LVEF, higher NYHA heart failure class, history of heart surgery, higher creatinine, diuretic use, absence of beta-blocker use, presence of biventricular ICD, not performing programmed stimulation at end of ablation, not performing NIPS, inducibility of clinical VT at NIPS, and higher amiodarone dose at discharge were all associated with shorter time to death (all p values < 0.05) (Table 4). In multivariate modeling, older age, not performing programmed stimulation at the end of ablation, not performing NIPS, inducibility of clinical VT at NIPS, and higher amiodarone dose at discharge remained independently associated with shorter time to death (all p values <0.05). Eleven patients developed amiodarone toxicity during follow-up. Survival among those developing amiodarone toxicity did not significantly differ from those not developing amiodarone toxicity (p = 0.90).
In our series of consecutive patients with VT and structural heart disease, reduction or discontinuation of amiodarone in patients after apparently successful VT ablation was not associated with a significantly higher rate of VT recurrence at 1 year. Furthermore, higher discharge amiodarone dose was associated with increased mortality in long-term follow-up, highlighting the importance of dose reduction/discontinuation when possible. Given the observational nature of our study, causality cannot be established.
Clinical profile of patients treated with amiodarone presenting for VT ablation
The rate of amiodarone use in patients presenting for VT ablation (55.4%) in this study was remarkably similar to 2 international, multicenter cohorts assembled by Tung et al. (13) and Yokokawa et al. (14) (55.3% and 55.0%, respectively). Patients on amiodarone (groups A and B) at the time of ablation in our study were older than those not treated with amiodarone. Additionally, these patients tended to have more advanced heart failure, with lower LVEF and higher rates of diuretic use, ICD, and biventricular ICD. We have previously shown that patients who present for ablation later in their arrhythmia course tend to be on higher doses of amiodarone compared with those referred early for VT ablation (15). However, despite the fact that patients treated with amiodarone in our study were “sicker” at baseline, likely with more advanced arrhythmia substrate, amiodarone reduction was still achieved in group A patients, without an unacceptable increase in VT recurrence, compared with group C patients.
Effect of amiodarone on inducibility and role of NIPS
Multiple studies have shown that complete noninducibility with programmed stimulation after ablation is associated with lower rates of subsequent VT recurrence and mortality, in both ischemic and nonischemic cardiomyopathies (14,16–18). In patients on chronic oral amiodarone, drug levels remain therapeutic for weeks following discontinuation, given the medication’s extremely long half-life (5). When discontinued only days prior to ablation, as is often the case in patients presenting for emergent ablation due to VT storm, the persistence of amiodarone may inhibit inducibility of some potential VT circuits with programmed stimulation. Unfortunately, as amiodarone levels decrease in follow-up and the electrophysiologic milieu changes, new VTs not observed during ablation may emerge. Therefore, we try to hold amiodarone for as many days as possible prior to ablation. Additionally, we perform NIPS several days following ablation, when amiodarone levels may be slightly lower, though certainly still present. Occasionally we repeat NIPS weeks or months following ablation.
Amiodarone, organ toxicity, and mortality
In the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), randomization to treatment with amiodarone was associated with 44% increased mortality compared with placebo, among those with NYHA functional class III (19). This was subsequently demonstrated to be secondary to increased noncardiac mortality (20). No increase in mortality was observed among those with NYHA functional class II heart failure. In our multivariate model, higher amiodarone dose at hospital discharge was similarly associated with increased mortality. The dose response relationship we observed adds to the biologic plausibility. One recent study demonstrated increased mortality with amiodarone compared to sotalol when used for atrial fibrillation in patients with coronary artery disease (21). Furthermore, other retrospective studies of patients undergoing VT ablation have demonstrated an association between amiodarone use at baseline and increased mortality. For example, Tung et al. (13) reported higher rates of amiodarone use among patients who either died or required transplant within 1 year of VT ablation (71.1% vs. 52.9%; p < 0.001). Whether amiodarone is the cause of this excess mortality or a marker of patients with greater comorbidities cannot be definitively concluded from our data. However, despite similar baseline characteristics, it is notable that patients in group A had better survival than those in group B, after amiodarone was reduced or discontinued.
In contrast to our findings, a randomized trial of patients with ischemic cardiomyopathy and LVEF ≤40%, found a reduction in arrhythmic death (risk ratio: 0.65) and a neutral effect on all-cause mortality (risk ratio: 0.99) among those treated with amiodarone (22). Importantly, these patients had not undergone ablation, and thus the reduction in arrhythmic death seemed to be counterbalanced by an increase in nonarrhythmic death. However, in a post-ablation population such as ours, in whom the arrhythmogenic substrate (and thereby risk of arrhythmic death) is ideally reduced or eliminated, the increase in nonarrhythmic death may predominate. To confirm this hypothesis, a prospective trial would need to be performed in which patients who are noninducible at the end of ablation and at NIPS are randomized to continuing versus stopping amiodarone. Long-term arrhythmia- free and overall survival could then be compared.
Risk stratification for VT recurrence after ablation to guide amiodarone therapy
In patients with no inducible VT at the end of ablation and during NIPS, we often discontinue amiodarone prior to hospital discharge, or at least decrease the dose to 200 mg/day. We have previously found these endpoints to be reliable in risk stratifying patients for VT recurrence (12). When only nonclinical VT can be induced, amiodarone is often continued or the dose reduced and ICD programming optimized to treat the induced VT. When clinical VT remains inducible at the end of ablation, repeat ablation is typically performed. It has since become our practice to do the same when clinical VT is induced during NIPS. This strategy allows us to identify a group of patients in whom amiodarone can generally be discontinued or reduced without an unacceptable increase in risk of recurrence.
Ours is an observational study, and thus the decision to reduce or discontinue amiodarone was not randomized. Patients in whom amiodarone was continued or increased following ablation were older, with more advanced heart failure and more inducible VT at the end of ablation and at NIPS. Even though the association between higher amiodarone dose at discharge and increased mortality persisted after adjustment for these confounders, the possibility of residual confounding remains significant. Thus conclusions regarding the impact of amiodarone on mortality should be considered hypothesis generating. Further, one should not conclude from our study that amiodarone can be reduced or discontinued in all patients without an increase in VT recurrence, but rather, that amiodarone can be reduced or discontinued in selected patients, in whom the operator believes a successful outcome has been achieved based on the results of programmed stimulation at the end of ablation, NIPS, and/or other endpoints. Lastly, those who developed clinically apparent amiodarone toxicity during follow-up did not have increased mortality compared to those who did not develop amiodarone toxicity, leaving the potential mechanisms of increased nonarrhythmic mortality incompletely defined.
In patients undergoing aggressive catheter ablation, in whom VT cannot be induced at the end of ablation or at NIPS, amiodarone can generally be reduced or discontinued without an unacceptable increase in VT recurrence. Reduction or discontinuation of amiodarone should be considered a goal of VT ablation in patients with structural heart disease.
COMPETENCY IN MEDICAL KNOWLEDGE: In a retrospective analysis of consecutive patients with structural heart disease undergoing VT ablation, amiodarone dose was reduced or discontinued in 43% of patients, most commonly when noninducibility was achieved at the end of ablation and confirmed at NIPS several days later, prior to hospital discharge. These patients did not have a significant increase in 1-year VT recurrence. Higher amiodarone dose following ablation was associated with increased long-term mortality.
TRANSLATIONAL OUTLOOK: To confirm our findings, a prospective trial should be conducted in which patients without inducible VT at the end of ablation and NIPS are randomized to continuing versus stopping amiodarone. Long-term arrhythmia-free and overall survival could then be compared.
Dr. Hutchinson has served on the advisory panel of Biosense Webster. Dr. Garcia has received speaking honoraria from Biosense Webster and St. Jude Medical. Dr. Callans has received honoraria from Biosense Webster and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- antiarrhythmic drug(s)
- implantable cardioverter-defibrillator
- left ventricular ejection fraction
- noninvasive programmed stimulation
- New York Heart Association
- ventricular tachycardia
- Received July 20, 2016.
- Revision received November 7, 2016.
- Accepted November 17, 2016.
- 2017 American College of Cardiology Foundation
- Ruwald A.C.,
- Schuger C.,
- Moss A.J.,
- et al.
- Connolly S.J.
- Hohnloser S.H.,
- Dorian P.,
- Roberts R.,
- et al.
- Aliot E.M.,
- Stevenson W.G.,
- Almendral-Garrote J.M.,
- et al.
- Cassidy D.M.,
- Vassallo J.A.,
- Miller J.M.,
- et al.
- Hutchinson M.D.,
- Gerstenfeld E.P.,
- Desjardins B.,
- et al.
- Frankel D.S.,
- Mountantonakis S.E.,
- Zado E.S.,
- et al.
- Tung R.,
- Vaseghi M.,
- Frankel D.S.,
- et al.
- Yokokawa M.,
- Kim H.M.,
- Baser K.,
- et al.
- Ghanbari H.,
- Baser K.,
- Yokokawa M.,
- et al.
- Dinov B.,
- Fiedler L.,
- Schonbauer R.,
- et al.
- Dinov B.,
- Arya A.,
- Schratter A.,
- et al.
- Packer D.L.,
- Prutkin J.M.,
- Hellkamp A.S.,
- et al.
- Piccini J.P.,
- Al-Khatib S.M.,
- Wojdyla D.M.,
- et al.
- Julian D.G.,
- Camm A.J.,
- Frangin G.,
- et al.,
- for the European Myocardial Infarct Amiodarone Trial Investigators