Current status and role of programmed ventricular stimulation in patients without sustained ventricular arrhythmias and reduced ejection fraction: Analysis of the Japan cardiac device treatment registry database

Abstract Background The aim of this study was to clarify the current status and role of programmed ventricular stimulation in patients without sustained ventricular arrhythmias and reduced left ventricular ejection fraction (LVEF). Methods The follow‐up data of the Japan cardiac device treatment registry (JCDTR) was analyzed in 746 patients with LVEF ≦35% and no prior history of sustained ventricular arrhythmias who underwent de novo implantable cardioverter‐defibrillator (ICD) or cardiac resynchronization therapy with a defibrillator (CRT‐D) implantation between January 2011 and August 2015. Results Electrophysiological study (EPS) with programmed ventricular stimulation had been performed before the device implant in 118 patients (15.8%, EPS group). During the mean follow‐up of 21 ± 12 months, the rate of freedom from any death and appropriate defibrillator therapy was not significantly different between EPS group (n = 118) and No EPS group (n = 628). NYHA class II‐IV, and QRS duration were negatively associated with performing EPS. Among patients in the EPS group, the rate of ventricular tachycardia (VT)/ventricular fibrillation (VF) induction was 48%. The inducibility was not a predictor of appropriate defibrillator therapy, whereas BNP ≧535 pg/mL and no use of amiodarone were significantly associated with a risk of the appropriate therapy. Conclusion EPS for induction of VT/VF had been performed in about 16% of patients with reduced LVEF before primary prevention ICD/CRT‐D implantation. Elevated BNP levels and no use of amiodarone, but not inducibility of VT/VF, appeared to be associated with appropriate defibrillator therapy in these populations.


| INTRODUC TI ON
Implantable cardioverter-defibrillator (ICD) implantation, in combination with guideline-directed medical therapy (GDMT), is an established therapy for primary prevention of sudden cardiac death in symptomatic heart failure with reduced ejection fraction. In the late 1990s and early 2000s, electrophysiological study (EPS) with programmed ventricular stimulation had been performed to identify patients at risk of ventricular arrhythmias, 1-3 especially of an ischemic etiology, 1,2 whereas the results of randomized controlled trials underscored the use of ICDs for primary prevention of sudden cardiac death in patients with reduced left ventricular ejection fraction (LVEF) without performing the EPS. 4,5 Therefore, the significance of EPS in patients receiving the contemporary GDMT with reduced LVEF remains unknown.
The present study is aimed to evaluate the current status and significance of the EPS in patients with no prior history of sustained ventricular arrhythmias and LVEF ≦35% by analyzing the Japan cardiac device treatment registry (JCDTR) database.

| Study population
The JCDTR was established in 2006 by the Japanese Heart Rhythm Society (JHRS) for a survey of actual conditions in patients undergoing de novo implantation of Cardiac Implantable Electronic Devices (CIEDs) including implantable cardioverter-defibrillator (ICD)/cardiac resynchronization therapy with a defibrillator (CRT-D)/cardiac resynchronization therapy with a pacemaker (CRT-P). 6 In general, the electrophysiologic testing protocol used 400-ms and 600-ms drive trains followed by one to three ventricular extrastimuli and rapid burst pacing from the right ventricular apex and then from the right ventricular outflow tract. Extrastimuli were decremented down to a coupling interval no shorter than 180 ms. 10 In cases where no sustained ventricular tachyarrhythmia was induced, the protocol was repeated during isoproterenol challenge with the discretion of the attending physician. A sustained ventricular arrhythmia was defined as one lasting 30 seconds or requiring termination sooner because of hemodynamic compromise.
The present study analyzed the data of patients having a defibrillator (ICD or CRT-D) with LVEF ≦35% and no prior history of sustained ventricular arrhythmias whose implantation date was from January 2011 to August 2015. Among them, the follow-up data were available in 746 patients as of 16 September 2015. These 746 patients were analyzed in the present study.

| Device programming
In general, device programming was as follows. VF zone detected ventricular events faster than 185-200 beats/min with at least one train of anti-tachycardia pacing (ATP) before shock, and the VT zone detected ventricular events faster than 150-170 beats/min with at least three trains of ATP before shock. After the multicenter automatic defibrillator implantation trial-reduce inappropriate therapy (MADIT-RIT) trial was published in 2012, 11 the VF zone ≧200-250 beats/min with ATP plus shock and VT zone ≧170 beats/min with delayed therapy (a 60-second delay) or only monitoring were recommended. The discrimination algorithms were used at the physician's discretion.

| Outcomes
The analyzed events were (a) death from any cause, (b) heart failure death, (c) appropriate and inappropriate defibrillator therapies.
Appropriate defibrillator therapy was defined as an anti-tachycardia pacing or shock for tachyarrhythmia determined to be either ventricular tachycardia (VT) or ventricular fibrillation (VF). The diagnosis of the cause of death was made by attending physicians.

| Statistical analysis
All data are expressed as mean ± SD. Simple between-group analysis was conducted using Student's t-test. Categorical variables were compared using Fisher's exact test. Kaplan-Meier curves were constructed to estimate event-free outcomes in the two study groups with comparison using the log-rank test. A logistic regression analysis was used to estimate the factors associated with performing EPS before CIEDs implant. Among the variables that reached a significance level of P < .1 in univariate models, multivariate analysis was performed. In patients who underwent EPS, a multivariate Cox proportional-hazards regression model with a stepwise selection was used to estimate significant factors for appropriate defibrillator therapy. The sensitivity and   Table 1. These data were derived from the status of each patient just before the device implantation. With regard to gender and the etiology of heart disease, there was no difference between the two groups. In No EPS group, age was higher, LVEF was lower, NYHA class was worse, and QRS duration was longer than those in EPS group. There was a significant increase in the percentage of CRT-D implantation in No EPS group (79.3%) as compared to EPS group (46.6%). Patients in No EPS group had a lower history of non-sustained ventricular tachycardia (NSVT) than those in EPS group. BNP and creatinine were higher and hemoglobin was lower in No EPS group than in EPS group. .324

Pharmacological therapy in EPS and No EPS groups is shown in
Note: Data are given as number (%).
Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker. Kaplan-Meier estimates of event-free survival in the two groups are shown in Figure 1. The rate of event free survival for death from any cause was 95.5% at 1-year and 88.2% at 2-year in EPS group, and 89.2% at 1-year and 82.0% at 2-year in No EPS group (P = .267) ( Figure 1A). Similarly, with regard to heart failure death, there was no significant difference between the two groups ( Figure 1B) Figure 1C). There was no significant difference in the risk of inappropriate defibrillator therapy between the two groups ( Figure 1D). The variables associated with not performing EPS before the ICD/CRT-D implantation obtained by multivariate models were NYHA class II-IV (P = .030), and QRS duration (P = .002) ( Table 3).

| D ISCUSS I ON
In patients with coronary artery disease, LVEF ≦40%, and asymptomatic NSVT, the inducibility of sustained ventricular tachyarrhythmias was associated with a significantly higher risk of sudden death or cardiac arrest. 1 More recently, induction of VT/VF during programmed ventricular stimulation was an independent prognostic factor for future appropriate ICD therapy in patients with nonischemic cardiomyopathy and no history of spontaneous VT/VF. 12 However, the predictive value of ventricular arrhythmia inducibility for subsequent VT/VF was not significant in patients with a LVEF ≦30% (or 35%). 2,3,10 For example, among patients with coronary artery disease and LVEF <30%, the percentage of deaths that were arrhythmic was not significantly different in those with inducible tachyarrhythmia vs those without (55% vs 48%, P = .20). 2 To the best of our knowledge, the present study has demonstrated for the first time in a contemporary cohort study, (a) the inducibility was not a predictor of appropriate defibrillator therapy in patients with reduced LVEF (≦35%) and (b) the rate of sustained VT/VF inducibility was 48% in those patients. The high inducibility (41% 10 and 38% 3 ) had been reported in patients whose LVEF was ≦30% or ≦35%.
According to the indication of health insurance in Japan, induction of VT/VF is generally required to approve ICD implantation for primary prevention of sudden cardiac death regardless the sever- There were some differences of basic characteristics and pharmacological therapy between patients with and without performing EPS (Tables 1 and 2). For example, the use of β-blockers was lower despite worse NYHA-class and lower LVEF. Since the use of β-blockers in patients receiving a CRT-D was about 80% and it did not differ between non-university and university hospitals, 13 the clinical practice appears to be homogeneous in facilities participating in the JCDTR. Significant risk factors for failing a trial of β-blocker therapy in patients with chronic heart failure were worse NYHA status and worse left ventricular function. 14 The former was a predictor of not performing EPS (Table 3), and can be a reason for paradoxical decrease in the rate of β-blocker therapy in No EPS group.
In patients with prior myocardial infarction, sustained VT/VF and LVEF ≧35%, amiodarone was not inferior to ICD implantation with regard to the survival benefit. 15 Mortality in patients with nonischemic cardiomyopathy, LVEF ≦35%, and asymptomatic NSVT who were treated with amiodarone or an ICD were not statistically significant in the Amiodarone vs Implantable Cardioverter-Defibrillator Trial (AMIOVIRT). 16 Amiodarone in combination with β-blockers was effective for preventing ICD shocks compared with β-blocker alone in patients with inducible or spontaneous occurring VT/VF. 17 These results are in agreement with our observation that amiodarone significantly reduced the risk of appropriate defibrillator therapy in primary prevention ICD/CRT-D patients. However, we should be prudent for the use of amiodarone, because it had no effect on allcause mortality in patients with symptomatic heart failure (NYHA class II or III) and LVEF ≦35%, 4  Abbreviations: 95% CI, 95% confidence interval; LVEF, left ventricular ejection fraction; OR, odds ratio.

TA B L E 3 Logistic regression analyses for factors associated with performance of EPS in patients with primary prevention and LVEF of ≦35%
Elevated BNP levels were superior to EPS for predicting future appropriate defibrillator therapy ( Figure 3A). Elevated baseline and follow-up BNP levels were reported to be independent predictors of increased risk for subsequent VT/VF in symptomatic heart failure patients enrolled in MADIT-CRT. 19 The present study underscore this finding with an cutoff value of baseline BNP≧535 pg/mL for the prediction. Measurement of BNP is a simple, less invasive, and less expensive test compared with EPS, thus may be a useful marker of VT/VF in patients with reduced LVEF.

| Study limitations
There are several limitations to be considered in this study.  (Table 1), reverse remodeling with CRT may change the heart failure status and reduce the incidence of VT/VF. 20,21 Fifth, information regarding the presence or absence of NSVT, which is likely to be a surrogate marker of severe heart failure, 22 is not mandatory for the registration of data

| Conclusions
Inducibility of VT/VF by EPS, which had been performed in 15.8% of patients with LVEF ≦35% before primary prevention ICD/CRT-D implantation in Japan, was not a significant predictor of subsequent appropriate defibrillator therapy. Patients with symptomatic heart failure (NYHA class II-IV) and QRS prolongation, which indicate prerequisites for a CRT candidate, are unlikely to receive the EPS.
Elevated BNP levels ≧535 pg/mL may be useful for predicting future VT/VF events in patients receiving primary prevention ICD/ CRT-D.

ACK N OWLED G M ENTS
The authors thank the members of the JHRS who registered data in the JCDTR on a voluntary basis. As of March 20, 2020, 393 facilities in Japan had enrolled at least one patient. The list of the facilities that enrolled more than 100 patients (114 facilities in alphabetical order) is below.