Ablation of frequent PVC in patients meeting criteria for primary prevention ICD implant: Safety of withholding the implant

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Ablation of Frequent PVC in Patients Meeting Criteria for Primary Prevention ICD Implant. Safety of withholding the Implant Diego Penela MD, Juan Acosta MD, Luis Aguinaga MD, Luis Tercedor MD, PhD, Augusto Ordoñez MD, Juan Fernández-Armenta MD, PhD, David Andreu MSc, PhD, Pablo Sánchez MD, Nuno Cabanelas MD, Jose Maria Tolosana MD, PhD, Francesca Vassanelli MD, Mario Cabrera MD, Viatcheslav Korshunov MD, Marta Sitges MD, PhD, Josep Brugada MD, PhD, Lluis Mont MD, PhD, Antonio Berruezo MD, PhD

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Cite this article as: Diego Penela MD, Juan Acosta MD, Luis Aguinaga MD, Luis Tercedor MD, PhD, Augusto Ordoñez MD, Juan Fernández-Armenta MD, PhD, David Andreu MSc, PhD, Pablo Sánchez MD, Nuno Cabanelas MD, Jose Maria Tolosana MD, PhD, Francesca Vassanelli MD, Mario Cabrera MD, Viatcheslav Korshunov MD, Marta Sitges MD, PhD, Josep Brugada MD, PhD, Lluis Mont MD, PhD, Antonio Berruezo MD, PhD, Ablation of Frequent PVC in Patients Meeting Criteria for Primary Prevention ICD Implant. Safety of withholding the Implant, Heart Rhythm, http://dx.doi.org/ 10.1016/j.hrthm.2015.09.011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Ablation of frequent PVC in patients meeting criteria for primary prevention ICD implant. Safety of withholding the implant Short title: PVC ablation avoids unnecessary ICD implantations

Diego Penela, MD1; Juan Acosta, MD1; Luis Aguinaga, MD2; Luis Tercedor, MD, PhD3; Augusto Ordoñez, MD4; Juan Fernández-Armenta MD, PhD1; David Andreu MSc, PhD1; Pablo Sánchez, MD3; Nuno Cabanelas, MD1; Jose Maria Tolosana, MD, PhD1; Francesca Vassanelli, MD1; Mario Cabrera, MD1; Viatcheslav Korshunov, MD1; Marta Sitges, MD, PhD1; Josep Brugada, MD, PhD1; Lluis Mont, MD, PhD1; Antonio Berruezo, MD, PhD1

1 Cardiology Department, Thorax Institute, Hospital Clínic and IDIBAPS (Institut d’Investigació Agustí Pi i Sunyer), Barcelona, Catalonia, Spain 2 Private Cardiology Center, Tucuman, Argentina 3 Cardiology Department, Hospital Virgen de las Nieves, Granada, Spain. 4 Cardiology Department, Hospital Sant Pau i Santa Tecla, Tarragona, Catalonia, Spain

Address for Correspondence: Antonio Berruezo, MD, PhD Arrhythmia Section, Cardiology Department. Thorax Institute, Hospital Clinic C/ Villarroel 170, 08036 Barcelona Phone: 0034 93 2275551 Fax: 0034 93 4513045 Email: [email protected]

No conflicts of interest

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ABSTRACT Background: Premature ventricular complex (PVC) ablation has been shown to improve left ventricular ejection fraction (LVEF) and functional class in patients with LV dysfunction. Both are considered key variables in predicting risk of sudden cardiac death. Objective: The objective was to assess whether ablation might remove primary prevention (PP) implantable cardioverter-defibrillator (ICD) indication in patients with frequent PVC. Methods: Sixty-six consecutive patients with PP-ICD indication and frequent PVC (50% men, aged 53±13 years, 17% ischemic heart disease) underwent PVC ablation. ICD was withheld and indication was re-evaluated at 6 and 12 months. Results: LVEF progressively improved from 28±4% at baseline to 42±12% at 12 months (p<0.001). NYHA class improved from 2 (3%) patients with NYHA-1 at baseline to 35 (53%) at 12 months (p<0.001). BNP decreased from 246±187 pg/mL to 176±380 (p=0.004). The PP-ICD indication was removed from 42 (64%) patients during follow-up, 38 (92%) of them at 6 months, showing an independent association with baseline PVC burden and successful sustained ablation (SSA). In patients with SSA, a cut-off value of 13% PVC burden had 100% sensitivity and 93% specificity (AUC 99%) for removing ICD indication post-ablation. No sudden cardiac deaths or malignant ventricular arrhythmias were observed. Conclusion: In patients with frequent PVC and PP-ICD indication, ablation improves LVEF and in most cases allows removal of the indication. Withholding the ICD and reevaluating within 6 months post-ablation seems to be a safe and appropriate strategy.

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Key Words: premature ventricular complex, ablation, implantable cardioverterdefibrillator, primary prevention, sudden cardiac death.

Abbreviations ASA: acute successful ablation CRT: cardiac resynchronization therapy device ICD: implantable cardiac defibrillator IHD: ischemic heart disease LVEF: left ventricular ejection fraction MI: myocardial infarction NICM: non-ischemic cardiomyopathy OTVA: outflow tract ventricular arrhythmias PP: primary prevention PVC: premature ventricular complex SCD: sudden cardiac death SSA: successful sustained ablation SOO: site of origin

INTRODUCTION Ablation of frequent PVC improves LVEF in patients with left ventricular (LV) dysfunction (1-7). Recently, it has been shown that this benefit occurs not only in patients with “PVC-induced” cardiomyopathy but also in those with “PVC-worsened” cardiomyopathy (8-9). On the other hand, primary prevention (PP) of sudden cardiac death (SCD) with an implantable cardiac defibrillator (ICD) improves survival in heart failure patients with severely depressed LVEF due to either ischemic heart disease (IHD) or non-ischemic cardiomyopathy (NICM) (10-12). As the decision to implant an

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ICD depends on the established cut-off value for LVEF, heart failure treatment must first be optimized with appropriate drugs (angiotensin-converting enzyme inhibitors and beta-blockers) before LVEF is assessed. In fact, current guidelines (13) recommend withholding the implant in some circumstances, as for instance after surgical myocardial revascularization, with the assumption that LVEF could improve. However, there are no specific timing recommendations on re-evaluation of LVEF and the subsequent decision to proceed with the ICD after ablation of frequent PVC in PP patients meeting ICD criteria. The aim of the present study was to assess whether the indication for PP-ICD might be removed by PVC ablation, as well as to evaluate the safety of withholding the implant. METHODS This was a multicentre, prospective study. The three participating centres included patients with frequent PVC who met at least one of the following criteria for PP-ICD implantation under current guidelines (13): 1) LV dysfunction due to prior myocardial infarction (MI), at least 40 days post-MI with LVEF £30%, and NYHA Functional Class I; 2) LVEF £35% due to prior MI, at least 40 days post-MI, and NYHA II-III; 3) NICM, LVEF £35%, and NYHA II-III. Patients meeting at least one of the following criteria were excluded: survivors of SCD, previous spontaneous sustained ventricular arrhythmia or syncope, previous ICD, or diagnosis of arrhythmogenic right ventricular dysplasia. Frequent PVC was defined as a burden of more than 4% at baseline 24-hour Holter monitoring, which is the lowest PVC burden associated with tachycardiomyopathy in the literature (14). No patient was excluded because of the number of PVC morphologies or the presumed site of origin (SOO) based on electrocardiography (ECG)

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criteria. The entire population had received optimal medical therapy for heart failure at maximum tolerated dose for at least 3 months at the time of study inclusion. The ICD was withheld and implant indication was re-evaluated at 6 and 12 months. In one centre, an early re-evaluation at 1 month was performed. The local Ethics Committee approved the study and all participants signed the written informed consent. Baseline evaluation A detailed medical history including drug therapies, a clinical evaluation, and a basal blood test including brain natriuretic peptide (BNP) levels were obtained for all participants. Before the ablation procedure, 12-lead surface ECG and 24-hour Holter monitoring were done in all patients to evaluate the presence of multiple morphologies and to calculate the PVC burden. Baseline echocardiography was performed within the 3 months preceding the procedure. Echocardiographic studies were blinded to ablation time and success. LVEF was calculated by the Simpson formula, computing 3 consecutive averaged beats to minimize distortion generated by PVC. The echocardiographic evaluation did not include ectopic or post-ectopic cycles. Ablation procedure Before the ablation, anti-arrhythmic drugs except amiodarone were withdrawn for 5 half-lives. Ablation was guided by the CARTO navigation system (Biosense-Webster, Waterloo, Belgium), using a 3.5-mm irrigated-tip catheter (Navi-Star, Biosense Webster) for mapping and ablation. Acute successful ablation (ASA) was considered when targeted PVC was eliminated. Patients were monitored for 30 minutes after the procedure to ensure complete PVC abolition. As the entire population of the study had LV dysfunction, therapy with beta-blockers was maintained, independent of ablation success.

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Follow-up Patients were followed up at the outpatient clinic at 6 and 12 months. Echocardiography was repeated and results were available for the scheduled outpatient visits, which included evaluation of functional class, 24-hour Holter ECG, measurement of BNP level, and re-evaluation of the ICD indication. One of the participating centres also conducted these evaluations at 1 month post-ablation. All patients completed the oneyear follow-up, irrespective of the initial findings at 6 months post-ablation. Successful sustained ablation (SSA) was defined as the persistent elimination of at least 80% of PVC after the ablation procedure with no recurrences during the follow-up. Statistical analysis Continuous variables are presented as the mean value ± standard deviation. Categorical variables are presented as total number and percentages. To compare means of two variables, Student t test was used (or Wilcoxon when necessary). Proportions were compared using Chi-square or Fisher exact test, as appropriate. Friedman analysis of variance by ranks was used for repeated measures. Logistic regression analysis was used to study the effects of baseline characteristics in predicting the SSA as well the probability of removal of ICD indication during follow-up. A P-value <0.10 was used to screen covariates for inclusion in the multivariate analysis. A backward-stepwise selection algorithm was applied to select covariates for inclusion in the multivariate regression model. At each step, the least significant variable was discarded and odds ratio and 95% confidence interval were calculated. Receiver operating curve analysis was used to evaluate the optimal cut-off value for predicting the removal of ICD indication during follow-up. To measure the association between the reduction in PVC burden and the change in LVEF, a Pearson correlation coefficient was computed. A P-

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value <0.05 was considered statistically significant. Statistical analysis was performed using R software for Windows, version 2.15.0 (R project for statistical computing, Vienna, Austria). RESULTS From February 2010 to December 2013, the 3 participating centres accepted 122 consecutive patients with LV systolic dysfunction for PVC ablation; 74 patients (61%) met PP-ICD criteria. Eight patients were excluded: 6 were previously implanted with a PP-ICD, 1 had AV block during the ablation procedure and was implanted with a cardiac resynchronization therapy device (CRT) with defibrillation capability, and 1 was diagnosed with arrhythmogenic right ventricular dysplasia. Therefore, 66 patients were included in the study [33 (50%) male, aged 53±13 years]. Mean LVEF was 28±4%, with a mean PVC burden of 21±12% in pre-ablation 24-hour Holter monitoring (Table 1). Fifteen patients (23%) had a previously diagnosed structural heart disease (SHD): 11 had ischemic heart disease, 3 had non-compaction cardiomyopathy, and 1 patient had valvular heart disease. In all patients without previously diagnosed SHD, IHD was ruled out by coronary angiography or non-invasive stress test before the ablation procedure. With regard to ICD indication, 11 (17%) patients met the criteria associated with prior MI and 55 (83%) met the NICM criteria. Table 1 shows baseline characteristics and differences between patients with and without prior MI. Patients with prior MI were more frequently male (91% vs. 42%, p=0.003) and had a higher baseline PVC burden (28% vs. 19%, p=0.03). A total of 71 PVCs were ablated (site of origin of the PVC are described in Supplemental Material) and 57 (86%) patients had monomorphic PVC. Nine (14%) patients had 2 or more PVC morphologies. At least 2 different PVC morphologies were targeted in 5 patients and only the dominant morphology in the remaining 4. ASA was

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achieved in 64 patients (97%). The PVC SOO was the right ventricle in 39 (59%) and the LV in 27 (41%) patients. Patients with LV origin had a higher baseline PVC burden (28±11 vs. 16±9, p=0.001) and more frequently had a previously diagnosed SHD (14 [52%] vs. 1 [3%], p<0.001). Complications occurred in 4 (6%) patients: 1 femoral pseudoaneurysm, 1 pericarditis episode, 1 periprocedural tamponade that was resolved without further complications, and 1 AV block (this patient was implanted with a CRT device and was excluded from the analysis, as noted above). Follow-up PVC recurred in 14 (22%) of 64 patients with ASA, in 12 (86%) of them within the first 6 months. Therefore, SSA was achieved in 50 (76%) patients. Table 2 shows the univariate and multivariate analysis for SSA. Age and monomorphic PVC at baseline were independently associated with SSA. In the whole population, LVEF improved progressively during follow-up, from 28±4% at baseline to 40±11% and 42±12% at 6 and 12 months, respectively (p<0.001). Accordingly, LV end-diastolic diameter decreased from 61±6 mm to 57±6mm at 12 months (p<0.01) and LV end-systolic diameter from 48±6 mm to 42±9mm at 12 months (p<0.01). NYHA class progressively improved during follow-up, from 2 (3%) patients with NYHA I at baseline to 35 (53%) at 12 months, from 43 (65%) patients with NYHA II to 23 (35%) at 12 months, and from 21 (32%) with NYHA III to 4 (6%) at 12 months (p<0.001). Finally, there was a significant reduction in BNP level, from 246±187 pg/mL at baseline to 176±380 at 12 months (p=0.004). In patients with SSA, LVEF improved from 28±4 at baseline to 44±11 at 12 months (p<0.001); NYHA class improved from 2 (4%) patients in NYHA I at baseline to 30 (60%) at 12 months (p<0.001); BNP levels decreased from 118±208 to 55±55 (p=0.006). Seventeen patients with SSA had normalized (>50%) LVEF after PVC

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abolition (Figure 1). As expected, patients without SSA showed less improvement in these parameters during follow-up (Figure 2): LVEF improved from 28±4 at baseline to 33±9 at 12 months (p=0.03); NYHA class improved from 0 patients in NYHA 1 at baseline to 5 (31%) at 12 months (p=0.007); BNP levels did not change significantly, from 313±288 baseline to 322±555 at 12 months (p=0.8). ICD indication In the whole sample, the PP-ICD indication was removed for 42 (64%) patients during the follow-up, 38 (92%) of them in the first 6 months (Figure 3). At 6 months postablation, the indication was removed from all but one patient with a previously diagnosed SHD; this included 10 of the 11 patients with IHD, all 3 patients with noncompaction cardiomyopathy, and the patient with valvular heart disease. With respect to the patients with SSA, the PP-ICD indication was removed in 35 (70%) of them during follow-up, compared to 7 (43%) patients without SSA (p=0.06) (Figure 4); these 7 patients had recurrence during follow-up, even though the PVC burden at the time of recurrence was inferior to the burden at baseline. This reduction in PVC burden, although less than the 80% cut-off to consider SSA, was enough to remove the PP-ICD indication. Figure 5 shows the increasing linear association between the absolute reduction in baseline PVC burden in the whole sample and the change in LVEF during follow-up (r=0.59, p<0.001). On average, LVEF increased by 0.68% points for each (1) absolute point of PVC burden abolished. There was also a close relationship between the percentage of PVC at baseline and the outcome. The PP-ICD indication was removed during follow-up in 42 (89%) of the 47 patients with a PVC burden ≥13%. Remarkably, the indication was not removed for any patient with <13% PVC burden. Moreover, in patients with SSA, a baseline PVC burden ≥13% had a sensitivity of 100%

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and a specificity of 93% (AUC 99%) for removing the PP-ICD indication during follow-up. The univariate and multivariate analysis for predicting removal of the PP-ICD indication is shown in Table 3. Baseline PVC burden and SSA were independently associated with removing the indication during follow-up; however, only PVC burden can be considered as a predictor of response, since SSA is evaluated during follow-up. At the time of the ablation procedure, only ASA can be evaluated. The PP-ICD indication was removed in 41 (91%) of the 45 patients with ASA and a PVC burden ≥13% (Supplemental Material shows the accuracy of using PVC burden ≥13% to predict the removal of ICD indication in the whole population, in patients with ASA, and in patients with SSA). The other variables analysed in the univariate and multivariate analysis were sex, age, SOO (right vs left), QRS width of the PVC, and presence of IHD. Even though there was a trend to a high rate of response in patients with IHD (Figure 3), this association was not confirmed in the multivariate analysis. A greater baseline PVC burden in patients with IHD could explain the high rate of removing the ICD indication in this subgroup. There were 2 deaths during the follow-up. One ischemic patient with the ICD indication removed at 6 months died from a non-cardiac death (malignancy) at 10 months. One patient without previously diagnosed SHD died of heart failure; in this patient, ablation was unsuccessful and PVC burden was not reduced during follow-up. The patient was implanted with an ICD at 6 months re-evaluation and died because of pump failure at 12 months. There was no SCD or malignant ventricular arrhythmia during the follow-up in the whole population.

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Early re-evaluation One of the participating centres re-evaluated patients at 1 month post-ablation. In these 17 (26%) patients (14 male, aged 66±13 years, 4 IHD), LVEF significantly improved from 28±5% at baseline to 38±12% at 1 month (p=0.002), NYHA class improved from 2.3±0.6 at baseline to 1.8±0.7 at 1 month (p=0.002), and BNP level improved from 267±257 at baseline to 169±160 at 1 month (p=0.03). The temporal recovery pattern of LVEF, NYHA class and BNP level in this subgroup are described in detail in Supplemental Material. The PP-ICD indication was removed for 13 (76%) patients in this population during the 12-month follow-up, for 10 (77%) of them at 1 month and 2 (15%) at 6 months; at 6-month follow-up, only 1 of the first group was reclassified as indicated for PP-ICD, due to PVC recurrence. DISCUSSION The present study describes the echocardiographic, clinical, and neurohormonal benefits of frequent PVC ablation in the specific subgroup of patients with severe LV dysfunction meeting PP-ICD criteria. In these patients, PVC ablation achieved significant improvement in LVEF and in NYHA class, which resulted in 64% of patients no longer meeting PP-ICD criteria at the end of follow-up. In patients with a high baseline PVC burden and ASA, the rate of removing the indication significantly improves (up to 91%), and reaches 97% in patients with SSA. The results of the present study support the strategy of withholding the indicated ICD after PVC ablation and show that re-evaluation within 6 months of the ablation is appropriate and safe. Finally, baseline PVC burden and SSA were independently associated with removing the PPICD indication during follow-up.

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Benefit of PVC ablation A recent meta-analysis (15) estimates a mean improvement of 12% in LVEF after PVC ablation, observed in the whole population of patients with frequent PVC and LV dysfunction. There was a similar LVEF improvement in patients with PP-ICD indication (a mean of 13.6±13.1% in the present study), despite the greater baseline LV dysfunction in this population. This significant improvement in echocardiographic parameters is clinically relevant because it is superior to that achieved by other heart failure treatments. Solomon et al described a mean LVEF improvement of 2.7±7.2 after 20 months of treatment with angiotensin-converting enzyme inhibitors in patients with previous MI (16). De Groote at al showed an improvement in LVEF of 10 absolute points after treatment with beta-blockers in patients with chronic heart failure (17). Finally, LVEF improved 3.6% absolute points after 6 months of CRT in the MIRACLE trial (18). Moreover, a strategy of serial LVEF evaluation shows an early improvement in echocardiography parameters after PVC ablation; in the subgroup of patients with an early re-evaluation, LVEF increased a mean of 9.5±10.8 points in the first month. These results contrast with CRT, for example, in which LV reverse remodelling occurs later, within the first 3-9 months (19). As the incidence of frequent PVC in patients with heart failure is unknown, epidemiologic studies are needed to estimate the percentage of patients that could benefit from ablation. PVC-worsened vs. PVC-induced cardiomyopathy Although improvement in LVEF after PVC ablation was initially described in patients with suspected PVC-induced cardiomyopathy, a recent study showed a comparable benefit in patients with previously diagnosed cardiomyopathy and therefore considered to have a “PVC-worsened” cardiomyopathy (9). However, in patients without a

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previously diagnosed structural heart disease (SHD), the differentiation between NICM having a “PVC-worsened” vs. “PVC-induced” cardiomyopathy can be challenging. The final diagnosis should probably be established only according to whether or not the LVEF is normalized after PVC abolition (see Figure 1). In the present study, 15 (23%) patients had a previously diagnosed SHD; in the remaining 51 patients, 3 groups could be differentiated, but only after completion of the one-year follow-up: 1) 17 (26%) patients with normalized (>50%) LVEF after PVC abolition, in which diagnosis of “PVC-induced” cardiomyopathy can be established; 2) 19 (28%) patients in whom LVEF improved but did not reach normal values after PVC abolition, who should be considered as having NICM; and 3) 15 (23%) patients without a complete PVC abolition (without SSA). In this third patient group, the differentiation between NICM and “PVC-induced” cardiomyopathy cannot be established. With regard to the PVC SOO, outflow tract ventricular arrhythmias (OTVA) are commonly referred to as “idiopathic” ventricular arrhythmias in patients with structurally normal hearts. However, several reports in the literature describe the outflow tract as a frequent SOO in patients with SHD and LV dysfunction (9, 20, 21). Therefore,

the

dichotomization

into

“PVC-worsened”

and

“PVC-induced”

cardiomyopathy in NICM patients cannot be based solely on the PVC’s SOO, but only according to whether or not there is LVEF normalization after PVC abolition. On the other hand, although it has been shown that the scar identified by cardiac magnetic resonance could be a possible PVC SOO in NICM patients (22), imaging shows no scar in up to 80% of NICM patients with ICD indication (23). ICD indication Depressed LVEF and functional class are considered the key variables in predicting SCD risk. Accordingly, current guidelines recommend evaluation of LVEF and NYHA

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class and indicate PP-ICD implantation only after ensuring correct medical therapy, as optimizing heart failure treatment with appropriate drugs like angiotensin-converting enzyme inhibitors and beta blockers can significantly improve both parameters. Moreover, decisions based on the earliest results are problematic because of the potential for substantial remodelling and LVEF improvement in ischemic patients during the initial weeks after MI, compared to the first ejection fraction obtained in the early phase (24). Therefore, the current recommendation is to evaluate the PP-ICD indication at 40 days after the ischemic event. In view of the great benefit obtained with ablation in patients with high PCV burden, LVEF should not be considered “stable low” until PVC abolition. The present study showed that attempting PVC ablation allowed removal of the PP-ICD indication in about two thirds of patients and that withholding the ICD until re-evaluation within the first 6 months post-ablation is a safe strategy. Moreover, the percentage of removal of this indication increased to 91% in patients with high PVC burden and ablation success and up to 97% if the ablation success was sustained. With regard to the re-evaluation timing, this study showed that re-evaluation at 6 months is an appropriate strategy. However, earlier re-evaluation also could be considered, as both LVEF and functional class improvement can occur in the first month post-ablation. Along this line, Yokokawa et al have shown that PVC-induced cardiomyopathy can be resolved within 4 months of successful ablation in most patients (25). In the present study, the improvement observed in the first month was enough to remove the ICD indication in 60% of patients. In the subgroup of patients with a 1month evaluation, only 1 additional patient was removed at 6 months. As no ventricular arrhythmia or SCD were observed in the present study, the safety of re-evaluation at 1 month vs. 6 months cannot be compared. However, a re-evaluation at 1 month could be

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a more conservative early strategy without a significant reduction in the number of implants potentially avoided. Predictors of response In the present study, baseline PVC burden and SSA were independently associated with removing the PP-ICD indication after PVC abolition. The PVC burden necessary to induce or worsen LV dysfunction is not yet clearly defined. The present study suggests an optimal cut-off value of at least 13% PVC at baseline to identify candidates for removal of the PP-ICD indication during follow-up. In patients with persistent PVC abolition, a baseline PVC burden ≥13% had 100% sensitivity and 93% specificity for removing this indication. However, only PVC burden can be considered as a predictor of response, since SSA can be evaluated only during follow-up. As 91% of patients with high PVC burden (≥13%) and SSA qualified for removal of the indication during follow-up, these patients can be considered the target population for the strategy of withholding the implant. Other predictors of LVEF improvement after PVC abolition reported in the literature are an epicardial PVC origin and the QRS width of the PVC (26). However, these associations were not observed in larger studies (15). In the present study, neither the SOO (right vs. left) nor the QRS width were independent predictors of response, suggesting that the lack of persistent PVC burden reduction instead of the SOO is the strongest variable to be taken into account. Limitations The main limitation of the study is the absence of a control group. Programmed stimulation to induce ventricular arrhythmias was not part of the study protocol; therefore, PP-ICD indication based on the electrophysiology study was not evaluated. A 24-hour Holter monitoring may be insufficient to assess the exact PVC burden before

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and after ablation, due to the day-to-day variability of ectopy. However, this method is the most commonly used to determine the PVC burden, in the literature as well as in clinical practice. Distortion in LVEF measurements caused by ectopic beats cannot always be excluded. However, this study shows that improvement in LVEF is associated with consistent improvements in functional and neurohormonal status, and therefore provides further evidence that improvement in LVEF after ablation is not just the apparent result of PVC abolition. Finally, a contrast-enhanced cardiac magnetic resonance was not systematically performed and influence of myocardial scar in the evolution after PVC ablation could not be evaluated. CONCLUSION In patients with frequent PVC and PP-ICD indication, ablation improves LVEF and allows removal of the indication in most cases. A baseline PVC burden ≥13% is the best cut-off for removing PP-ICD indication after ablation. Withholding the ICD and reevaluating within the first 6 months post-ablation seems to be an appropriate and safe strategy. Further study is needed to confirm these findings.

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L.

Long-term

left

ventricular

reverse

remodelling

with

cardiac resynchronization therapy: results from the CARE-HF trial. Eur J Heart Fail. 2009;11:480-8. 20.- Lakkireddy D, Di Biase L, Ryschon K, et al. Radiofrequency ablation of premature ventricular ectopy improves the efficacy of cardiac resynchronization therapy in nonresponders. J Am Coll Cardiol. 2012;60:1531-9. 21.- Ellis ER, Shvilkin A, Josephson ME. Nonreentrant ventricular arrhythmias in patients with structural heart disease unrelated to abnormal myocardial substrate. Heart Rhythm. 2014;11:946-52.

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22.- El Kadri M, Yokokawa M, Labounty T, et al. Effect of ablation of frequent premature ventricular complexes on left ventricular function in patients with nonischemic cardiomyopathy. Heart Rhythm. 2015;12:706-13. 23.- Leyva F, Taylor RJ, Foley PW, Umar F, Mulligan LJ, Patel K, Stegemann B, Haddad T, Smith RE, Prasad SK. Left ventricular midwall fibrosis as a predictor of mortality and morbidity after cardiac resynchronization therapy in patients with nonischemic cardiomyopathy. J Am Coll Cardiol. 2012;60:1659-67. 24.- Tavazzi L, Volpi A. Remarks about postinfarction prognosis in light of the experience with the Gruppo Italiano per lo Studio della Sopravvivenza nell’ Infarto Miocardico (GISSI) trials. Circulation. 1997; 95: 1341–1345. 25.- Yokokawa M, Good E, Crawford T, Chugh A, Pelosi F Jr, Latchamsetty R, Jongnarangsin K, Armstrong W, Ghanbari H, Oral H, Morady F, Bogun F. Recovery from left ventricular dysfunction after ablation of frequent premature ventricular complexes. Heart Rhythm. 2013;10:172-5. 26.- Yokokawa M, Kim HM, Good E, et al. Impact of QRS duration of frequent premature ventricular complexes on the development of cardiomyopathy. Heart Rhythm. 2012;9:1460-4.

Clinical Perspective In patients with frequent premature ventricular complex and primary prevention cardioverter-defibrillator (PP-ICD) indication, ablation improves LVEF and allows removal of the indication in the majority of cases. In these patients, withholding the ICD and re-evaluating this indication post-ablation appears to be an appropriate and safe strategy. Baseline PVC burden and persistence of PVC abolition post-ablation are independently associated with the probability of removal of the ICD indication. In view of these results, patients with severe LV dysfunction meeting PP-ICD criteria should be

20

screened for the presence of frequent PVC as part of the clinical decision-making process. Further study is needed to confirm these findings.

Figure 1.

Patient classification based on the presence of a previously diagnosed

structural heart disease (SHD) and changes in left ventricular ejection fraction (LVEF) during follow-up. Before premature ventricular complex (PVC) ablation, it is only possible to classify patients as with or without previously diagnosed structural heart disease. After completing the follow-up, patient can be classified in 4 groups: patients with a previously diagnosed SHD (PVC-worsened cardiomyopathy); patients with no previously diagnosed SHD and normalized LVEF (>50%) after PVC abolition (PVCinduced cardiomyopathy); patients with no previously diagnosed SHD and improved but not normalized LVEF after PVC abolition [non-ischemic heart disease (NIHD) worsened by PVC]; and patients without previously diagnosed SHD and without complete PVC abolition. PVC: premature ventricular complex; SHD: structural heart disease; NIHC: non-ischemic heart disease; CM: cardiomyopathy.

Figure 2. Left ventricular ejection fraction and NYHA class progression during followup in patients with and without successful sustained ablation LVEF: left ventricular ejection fraction; SSA: successful sustained ablation; NYHA: New York Heart Association.

Figure 3. Decline in primary prevention ICD indications during follow-up. IHD: ischemic heart diseases.

Figure 4. Figure 4 shows the number of patients with primary prevention (PP) implantable cardioverter-defibrillator (ICD) implant indication along the follow-up, according to baseline premature ventricular complex (PVC) burden and the persistence of PVC abolition after ablation. Note that at the end of follow-up, ICD implantation 21

was still indicated in only one of the patients with high PVC burden and successful sustained ablation, but was indicated in all patients with a PVC burden <13%, regardless of ablation success.

Figure 5. Association between absolute reduction of the baseline PVC burden [baseline PVC burden (%) –average 6-month and 12-month PVC burden (%)] and changes in LVEF during follow-up. PVC: premature ventricular complex; LVEF: left ventricular ejection fraction.

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Table 1: Baseline characteristics. No PMI (n=55)

PMI (n=11)

Total (n=66)

P value

Age (years)

52±14

60±7

53±13

0.08

Sex (male)

23 (42%)

10 (91%)

33 (50%)

0.003

LVEF (%)

28±4

29±2

28±4

0.2

LVESD (mm)

48±6

46±6

48±6

0.48

LVEDD (mm)

61±6

62±6

61±6

0.6

Beta-blocker therapy

54 (98%)

10 (91%)

64 (97%)

0.17

ACEI therapy

52 (94%)

11 (100%)

63 (95%)

0.69

Amiodarone therapy

20 (36%)

4 (36%)

24 (36%)

0.63

Months under optimal MT

58±62

15±18

21±33

<0.001

PVC Holter (%)

19±11

28±10

21±12

0.03

BNP (pg/mL)

137±220

235±188

151±216

0.3

I

0

2(18%)

2 (3%)

0.17

II

37 (67%)

6 (55%)

43 (65%)

III

18 (33%)

3 (27%)

21 (32%)

IV

0

0

0

NYHA

PMI: prior myocardial infarction; LVEF: left ventricular ejection fraction; LVESD: left ventricular endsystolic diameter; LVEDD: left ventricular end-diastolic diameter; ACEI: angiotensin-converting enzyme inhibitor; BNP: brain natriuretic peptide; MT: medical treatment; PVC: premature ventricular complex; NYHA: New York Heart Association.

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Table 2. Predictors of successful sustained ablation. Univariate and multivariate models.

Sex (male) Age LVEF (%) NYHA Class Baseline PVC burden Summit Location (left ventricle) SHD Monomorphic PVC BNP (pg/mL)

Univariate OR (95% CI) 1.39 (0.45-4.3) 0.93 (0.88-0.98) 1.02 (0.89-1.17) 0.39 (0.13-1.17) 0.99 (0.95-1.05) 0.08 (0.01-0.9) 1.2 (0.37-3.8) 0.56 (0.42-0.75) 18.6 (3.3-104) 0.99(0.991-0.999)

P-value 0.56 0.005 0.75 0.1 0.9 0.04 0.75 0.002 0.001 0.014

Multivariate OR (95% CI)

P-value

0.88 (0.8-0.97)

0.013

19 (1.5-236)

0.002

LVEF: left ventricular ejection fraction; NYHA: New York Heart Association; PVC: premature ventricular complex; SHD: structural heart disease; BNP: brain natriuretic peptide

Table 3. Predictors of removing primary prevention ICD indication during follow-up. Univariate and multivariate models. Univariate

Multivariate

Sex (male)

Respons e 62%

No Response 33%

Age Baseline PVC burden

54 ± 14 26 ± 8

51 ± 10 10 ± 9

QRS width Location (left ventricle) IHD

172 ± 16

182 ± 15

OR (95% CI) 2.96 (0.99-8.8) 1.02 (0.981.07) 1.3 (1.16-1.47) 0.96 (0.920.99)

57% 24%

14% 4%

12.2 (2.5-59.5) 7.2 (0.86-60.1)

0.002 0.067

70%

43%

3 (0.94-9.5)

0.06

SSA

Pvalue 0.051

OR (95% CI)

Pvalue

0.23 <0.001 1.33 (1.16-1.53) <0.001 0.2

20.3(1.03402.5)

0.015

SSA: successful sustained ablation; IHD: ischemic heart disease.

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Figure 1

Figure 2

Figure 3

Figure 4

Figure 5