Ventricular Arrhythmia Risk Stratification Among Patients With Cardiac Resynchronization Therapy Devices

Abstract

Background: Patients with left ventricular (LV) dysfunction have a higher risk of ventricular arrhythmia (VA) compared with those without, and are candidates for implantable cardioverter defibrillator (ICD). Response to cardiac resynchronization therapy (CRT) decreases the risk of VA; however, selection of a suitable CRT device remains challenging.

Methods and Results: In 678 patients with a CRT/ICD device and LV dysfunction, we investigated 325 CRT and 142 ICD patients for primary prevention. VA was defined as lasting ≥30 s or being treated with an ICD. CRT non-responders were defined as patients without reduced LV end-systolic volume ≥15%. During the follow-up period, 98 (21%) patients had a VA event (CRT 71 [22%] vs. ICD 27 [19%]; P=0.49). The VA risk score was calculated by summing values for non-left bundle branch block, left atrial diameter >45 mm, persistent atrial fibrillation, male sex, LV ejection fraction <25%, and ischemic cardiomyopathy. Our results showed that the VA risk score stratified the risk of VA among CRT patients (P<0.01), but was not significant for ICD patients (P=0.24). Patients with a VA risk score ≥4 (divided by receiver operating characteristic analysis) had a higher risk of VA among CRT patients (log rank P<0.01); however, it was not significant for ICD patients (log rank P=0.71).

Conclusions: The VA risk score could be a useful indicator for VA among CRT candidates.

Central Figure.

Ventricular arrhythmia risk score among patients with cardiac resynchronization therapy and implantable cardioverter defibrillator devices. Left: The ventricular arrhythmia (VA) risk score stratified the risk of VA, and patients with a VA risk score ≥4 (red line) had a significantly higher risk of VA than those with VA <4 (green line) among cardiac resynchronization therapy (CRT) patients. Right: Among implantable cardioverter defibrillator (ICD) patients, there was no increased risk of VA according to the VA risk score, and no significant difference between patients with a VA risk score ≥4 (red line) and patients with a VA risk score <4 (green line).

Patients with left ventricular (LV) dysfunction have a high risk of lethal ventricular arrhythmia (VA), and implantable cardioverter defibrillators (ICD) present an effective preventative tool against sudden cardiac death.¹ Cardiac resynchronization therapy (CRT) improves cardiac contraction and hemodynamics, and CRT responders are reported to be at a lower risk of VA than non-responders.^2–4 The risk of VA among CRT patients may differ from ICD patients with LV dysfunction, and it can be difficult to select which CRT device to implant because patients with CRT indications are also candidates for ICD.⁵

Recently, Younis et al. reported that the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-ICD was useful in predicting the ventricular tachycardia/ventricular fibrillation (VT/VF) risk and the non-arrhythmic mortality risk.^6,7 However, the value of this scoring system is not certain because the Younis et al. study cohort primarily comprised ICD patients, and non-arrhythmic mortality is lower in CRT patients. Thus, the risk of VA among patients with LV dysfunction receiving CRT remains unknown. This study aimed to examine CRT-specific VA risk factors and construct a VA risk score for CRT patients.

Methods

Ethical Approval

This study was approved by the Institutional Review Board of the National Cerebral and Cardiovascular Center, Suita City, Japan (M26-150-13) and was conducted in accordance with the principles outlined in the Declaration of Helsinki. This is a retrospective study to analyze the anonymous data after patients’ agreement of treatment, and we applied an opt-out method to obtain informed consent.

Study Population

The present study included 678 patients who were implanted with a CRT device and an ICD device (n=422) and had a LV ejection fraction (LVEF) ≤35% (n=256) (Figure 1). The devices were implanted at National Cerebral and Cardiovascular Center between 2012 and 2021. All patients were hemodynamically stable and chose to have the device implanted. The indication criteria of CRT according to Japanese guidelines are as follows: QRS width ≥120 ms, LV ejection fraction ≤35%, and a New York Heart Association (NYHA) classification ranging from II to IV after optimal medical therapy. The indication for ICD was in accordance with Japanese guidelines.⁵ In this study, patients were excluded if they had a history of VA (n=178) or lacked follow-up data after device implantation (n=33). In total, 325 patients with CRT and 142 patients with ICD and LV dysfunction were analyzed.

Figure 1.

Study flow chart. CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; VA, ventricular arrhythmia.

Clinical data at baseline were collected from all patients at the time of implantation and included age, sex, underlying heart disease, medical history (including diabetes and chronic kidney disease), medications (β-blocker and amiodarone), echocardiographic parameters, and 12-lead electrocardiogram results. Left bundle branch block (LBBB) was defined according to the American Heart Association scientific statement.⁸ Diabetes was defined according to the American Diabetes Association’s 2011 guidelines,⁹ and chronic kidney disease was defined according to the Kidney Disease: Improving Global Outcomes’ (KDIGO) 2012 guidelines.¹⁰

CRT and ICD Implantation and Programming

A CRT and ICD device were implanted transvenously after obtaining written informed consent from all patients. A right ventricular (RV) lead was positioned at the RV septal apex, and an LV lead was implanted in a suitable branch of the coronary vein at a site that produced an acceptable pacing threshold without diaphragmatic pacing.

VA

VA was evaluated using an intracardiac electrogram, which included pre-episode, detection, and post-therapy sections with 3-channel signals from the atrial, RV, and LV electrodes or the RV far-field signal. VA was defined as lasting >30 s or requiring treatment with a CRT and ICD device, including devices that used anti-tachycardia pacing (ATP) and shock therapy. ICD device detection programming was performed in at least 1 zone of ventricular tachycardia and ventricular fibrillation.

Clinical Outcome and Definition of CRT Non-Responder

The primary outcome was VA, as described in the section above. CRT non-responders were defined as patients without a reduction of LV end-systolic volume ≥15%,¹¹ compared with baseline at 6 months after CRT device implantation.

Follow-up

All follow-up examinations were performed at a single center in Japan. Follow-up information was obtained from the device follow-up charts, hospital records, and outpatient evaluations.

Statistical Analyses

The results are summarized as mean±standard deviation, or as median and interquartile range (IQR) for continuous data as appropriate. Categorical data are expressed as counts and percentages. Categorical differences between groups were evaluated using the chi-square test or Fisher’s exact test, as appropriate. Groups were compared and displayed using Kaplan-Meier survival analysis with the log-rank test. Continuous variables were compared using the Wilcoxon rank-sum test or Kruskal-Wallis test. A receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off value for the prediction of VA. The threshold for statistical significance was set as P<0.05. All analyses were performed using JMP 14 software (SAS Institute, Cary, NC, USA).

Results

Baseline Clinical Characteristics

The clinical characteristics of the study cohorts are presented in Table 1. The median age of patients was 67 years (IQR 56–76), 354 (76%) patients were male, and 129 (28%) patients with ischemic heart disease were included. The mean LVEF for all patients was 25% (IQR 19–32%). Compared with the ICD patients, CRT patients had a higher prevalence of non-ischemic cardiomyopathy (NICM) and LBBB morphology including RV pacing, and the left atrial diameter was larger in this group.

Table 1.

Clinical Characteristics of Patients With CRT and ICD Devices

Clinical characteristic	All (n=467)	CRT (n=325)	ICD (n=142)	P value
Age (years)	67 [56–76]	69 [60–77]	62 [46–69]	<0.01
Sex, male	354 (76)	243 (75)	111 (78)	0.43
Medical history
ICM/NICM	129 (28)/338 (72)	80 (25)/245 (75)	49 (35)/93 (65)	0.03
Diabetes	161 (34)	115 (35)	46 (32)	0.53
CKD	230 (49)	161 (50)	69 (49)	0.85
NYHA III or IV	317 (68)	228 (70)	89 (62)	0.11
Medication
β-blockers	391 (84)	261 (80)	130 (92)	<0.01
Amiodarone	92 (20)	63 (19)	29 (21)	0.77
LVEF (%)	25 [19–32]	24 [19–32]	27 [21–33]	0.18
LA diameter	45 [41–51]	46 [41–52]	44 [40–50]	0.02
LBBB/RV pacing	85 (18)/87 (19)	82 (25)/85 (26)	3 (2)/2 (1)	<0.01
QRS duration (ms)	146 [117–171]	160 [138–179]	111 [102–120]	<0.01
Persistent AF	93 (20)	73 (22)	20 (14)	0.03

Unless indicated otherwise, data are presented as n (%), or median [IQR]. AF, atrial fibrillation; CKD, chronic kidney disease; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; ICM, ischemic cardiomyopathy; LA, left atrial; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; NICM, non-ischemic cardiomyopathy; NYHA, New York Heart Association; RV, right ventricular.

Clinical Characteristics of the Patients With and Without VA

During the median follow-up time of 866 days (IQR 364–1,647) after device implantation, 98 (21%) patients had a VA event (CRT 71 [22%] vs. ICD: 27 [19%] patients; P=0.49). The clinical characteristics of patients with and without VA among the cohorts of CRT and ICD devices are shown in Table 2. Among CRT cohorts, patients with VA were mostly males (60 [85%] vs. 183 [72%]; P=0.03), had persistent AF (27 [38%] vs. 46 [18%]; P<0.01), a larger LA diameter (50 [43–54] vs. 45 [40–51]; P<0.01), and a lower prevalence of LBBB or RV pacing morphology (22 [31%] vs. 145 [57%]; P<0.01) compared with the patients without VA.

Table 2.

Clinical Characteristics of Patients With and Without VA Among the Cohorts With CRT and ICD Devices

Clinical characteristic	CRT/VA (+) (n=71)	CRT/VA (−) (n=254)	P value	ICD/VA (+) (n=27)	ICD/VA (−) (n=115)	P value
Age (years)	68 [61–75]	70 [60–77]	0.25	60 [48–69]	62 [46–70]	0.89
Sex, male	60 (85)	183 (72)	0.03	23 (85)	88 (77)	0.31
Medical history
ICM/NICM	21 (30)/50 (70)	59 (23)/195 (77)	0.28	8 (30)/19 (70)	41 (36)/74 (64)	0.55
Diabetes	27 (38)	88 (35)	0.60	14 (52)	32 (28)	0.02
CKD	38 (53)	123 (48)	0.44	10 (37)	59 (51)	0.18
NYHA III or IV	56 (79)	172 (68)	0.06	19 (70)	70 (61)	0.35
Medication
β-blockers	58 (82)	203 (80)	0.74	26 (96)	104 (90)	0.28
Amiodarone	20 (28)	43 (17)	0.04	5 (19)	24 (21)	0.77
LVEF (%)	22 [17–30]	25 [19–32]	0.13	23 [18–29]	28 [21–33]	0.28
LA diameter	50 [43–54]	45 [40–51]	<0.01	46 [40–55]	44 [40–48]	0.03
LBBB or RV pacing	22 (31)	145 (57)	<0.01	2 (7)	3 (3)	0.27
QRS duration (ms)	150 [127–178]	162 [142–180]	0.15	114 [108–119]	110 [101–121]	0.51
Persistent AF	27 (38)	46 (18)	<0.01	8 (30)	12 (10)	0.02

Unless indicated otherwise, data are presented as n (%), or median [IQR]. VA, ventricular arrhythmia. Other abbreviations as in Table 1.

VA Risk Score

We constructed the VA risk score by summing the factors observed among CRT patients that differed between those with and without VA: non-LBBB, left atrial diameter >45 mm, persistent atrial fibrillation, and male sex, in addition to ischemic cardiomyopathy and LVEF<25%. The risk of a VA event significantly increased with an increasing VA risk score among CRT patients; however, this was not significant for ICD patients (P=0.24; Figure 2). The ROC analysis for the prediction of VA revealed that the area under the curve was 0.68 (P<0.01) among CRT patients, and the optimal cut-off point was a VA risk score 4 (sensitivity 0.52, specificity 0.74). There was no significant optimal cut-off point for the VA risk score among ICD patients using ROC analysis.

Figure 2.

Distribution of ventricular arrhythmia event. The prevalence of ventricular arrhythmia (VA) events according to VA risk score among cardiac resynchronization therapy (CRT) and implantable cardioverter defibrillator (ICD) patients. VA events increased with an increasing VA risk score among CRT patients; however, there was no such association for ICD patients.

VA Risk Score and VA Events Among CRT and ICD Patients

Kaplan-Meier analysis showed that patients with a VA risk score ≥4 had a higher risk of VA among CRT patients (log-rank, P<0.01); however, this was not significant for ICD patients (log-rank, P=0.71; Figure 3). Although there was no significant difference in the risk of VA between CRT and ICD patients (log-rank, P=0.36), the CRT patients with VA risk score ≥4 had a higher risk of VA than ICD patients (CRT patients with VA risk score ≥4 vs. ICD: log-rank, P<0.01; CRT patients with VA risk score ≥4 vs. CRT patients with VA risk score <4: log-rank, P<0.01; CRT patients with VA risk score <4 vs. ICD: log-rank, P=0.43; Figure 4).

Figure 3.

Kaplan-Meier analysis. A Kaplan-Meier survival curve evaluating the effect of ventricular arrhythmia (VA) risk score (VA risk ≥4 or VA risk <4) among (A) cardiac resynchronization therapy, and (B) implantable cardioverter defibrillator patients. (A) Kaplan-Meier analysis revealed that patients with a VA risk score ≥4 (red line) had a higher risk of VA than patients with a VA risk score <4 (blue line). (B) There was no significant difference between patients with a VA risk score ≥4 (red line) and patients with a VA risk <4 (blue line).

Figure 4.

Kaplan-Meier analysis. A Kaplan-Meier survival curve evaluating (A) the difference of device type, and (B) the effect of ventricular arrhythmia (VA) risk score (VA risk ≥4 or VA risk <4) among (CRT) and implantable cardioverter defibrillator (ICD) patients. (A) There was no significant difference between patients with CRT (blue) and patients with ICD (green line). (B) Kaplan-Meier analysis revealed that CRT patients with a VA risk score ≥4 (red line) had a higher risk of VA than ICD patients (green line) and CRT patients with a VA risk score <4 (blue line).

VA Risk Score and CRT Non-Responder

After CRT device implantation, 116 (39%) patients did not respond to CRT among 298 patients with available follow-up data. The prevalence of CRT non-responders significantly increased with an increasing VA risk score among CRT patients (P<0.01; Figure 5). The prevalence of CRT non-responders was significantly higher in patients with a VA risk score ≥4 (49 [50%] vs. 67 [33%]; P<0.01).

Figure 5.

Distribution of cardiac resynchronization therapy (CRT) non-responders. The prevalence of CRT non-responders according to ventricular arrhythmia (VA) risk score among CRT patients. Prevalence of CRT non-responders increases with increasing VA risk score among CRT patients.

Discussion

Main Findings

In this study, we examined the VA risk factor among CRT and ICD patients. The major findings of our study were as follows: (1) VA risk score stratified the risk of VA among CRT patients and not for ICD patients; (2) patients with a VA risk score ≥4 had higher risk of VA among CRT patients; and (3) the VA risk score was a predictor of non-response in CRT patients.

Difference in Risk With and Without the CRT Effect

Patients with LV dysfunction are at a greater mortality risk due to VA,¹ and there is persistent arrhythmic risk even among recovered LVEF patients.¹² In the Sudden Cardiac Death in Heart Failure Trial, patients who had an improvement in LVEF >35% accrued a similar relative reduction in mortality with ICD therapy as those whose LVEF remained >35%.¹³

In contrast, CRT responders were at a decreased risk of VA compared with non-responders,² and patients who achieved LVEF normalization and LVEF subnormalization were at a decreased risk of VA in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) analysis.³ In a previous study, CRT for primary prophylaxis significantly reduced the incidence of VA, which was not seen in patients for the secondary prophylaxis.⁴ In this study, CRT non-responders had higher VA risk compared with patients with ICD (log rank, P=0.013) and CRT responders (log rank, P<0.001). Therefore, since the risk of VA is different between patients with LV dysfunction who receive CRT and ICD, it is important to examine the effect of CRT for prediction of VA risk.

VA Risk Score and CRT

Several factors have been reported to be connected to the risk associated with VA. Previous studies have shown that non-sustained VT,¹⁴ age,⁶ sex,¹⁵ atrial arrhythmia,^16–18 NYHA class, blood urea nitrogen, B-type natriuretic peptide, diabetes mellitus,¹⁹ QRS duration,^20,21 and lower systolic pressure²² increase the risk of VA among patients with an ICD device and LV dysfunction.

The risk of VA is heterogeneous among patients with underlying heart disease and depends on the indication for CRT. In this study, male sex, LA diameter, LBBB morphology, and persistent AF, which were also predictors of CRT non-responders, were predictors of VA. In previous reports, non-LBBB morphology^23–25 and LA volume²⁶ were predictors of CRT non-responders. There are limited data that indicate the relationship between the CRT-specific VA risk score and CRT responder, and we have developed a VA risk score to predict subsequent VA in patients with CRT. In this study, as the VA risk score was only correlated with CRT patients, our results showed that this scoring system is a suitable risk score for patients with CRT.

Clinical Implications

Our results suggest that patients with high VA risk scores and CRT should be considered for CRT defibrillator implantation, whereas patients without VA risk factors may be considered for CRT pacemaker implantation, because we found that the incidence of VA was low in only 1 patient (7% of 14 patients during the 2.4 years of follow-up). As this risk score could be useful in predicting CRT non-responders, patients with high VA risk scores may warrant considering other options for HF or VA therapy, such as medical therapy (including titration of heart failure drugs²⁷), MitraClip²⁸ ablation for VA, and antiarrhythmic drugs.²⁹

Study Limitations

First, this was a single-center retrospective study, and the relatively small number of patients was the primary limitation. Second, although the prevalence of non-LBBB and non-ischemic cardiomyopathy was higher than that reported in previous studies,^30,31 a previous study demonstrated that only 13.8% of patients were classified as having a LBBB with reference to all definitions,³² compared with 18% observed in the present study. Third, we did not perform the external validation of this risk score. Further prospective multicenter studies including a larger number of patients using CRT devices are warranted to confirm our findings.

Conclusions

The VA risk score stratified the incidence of VA and CRT non-responders. Among CRT patients, those with a VA risk ≥4 had a higher risk of VA, which was not the case for ICD patients. We found that the VA risk score is a useful indicator for the risk of VA among CRT candidates.

Acknowledgments

We thank Editage (www.editage.com) for English language editing.

Sources of Funding

This study was supported by the Intramural Research Fund (25-4-7; K.K.) for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center. N.U. and T. Noda were partially supported by JSPS KAKENHI (grant numbers 23K15177 and 22K08092, respectively).

Disclosures

N.U. received honoraria from Medtronic Japan Co., Ltd for providing lectures. K.I. received honoraria for teaching lectures from BIOTRONIK Japan and Medtronic Japan Co., Ltd. T. Noda received honoraria for lectures from Medtronic Japan Co., Ltd, and BIOTRONIK Japan, Inc., and belongs to a department endowed by BIOTRONIK Japan. S.N. is affiliated with a department endowed by Japan Medtronic Inc. K.K. received honoraria from BIOTRONIK Japan and Medtronic Japan and research grants from Medtronic Japan. None of these disclosures were directly associated with this study.

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