Clinical Predictors of Recurrent Ventricular Arrhythmias in Secondary Prevention Implantable Cardioverter Defibrillator Recipients With Coronary Artery Disease　― Lower Left Ventricular Ejection Fraction and Incomplete Revascularization ―

Abstract

Background: The implantable cardioverter defibrillator (ICD) is a standard prevention therapy for patients at high risk for sudden cardiac death (SCD) due to life-threatening ventricular arrhythmia (VA), that is, ventricular fibrillation and ventricular tachycardia. However, clinical predictors of recurrent VA in secondary prevention ICD recipients with coronary artery disease (CAD) remain unknown.

Methods and Results: We followed up 96 consecutive patients with CAD undergoing ICD implantation for secondary prevention of SCD. Long-term rates and clinical predictors of appropriate ICD therapy (ICD-Tx) for VA were analyzed. Appropriate ICD-Tx occurred in 41 (42.7%) patients during a median follow-up of 2.4 years (interquartile range, 0.9-6.1). These patients had significantly greater left ventricular end-diastolic diameter (62.3±1.3 vs. 54.6±1.1 mm, P<0.001), lower left ventricular ejection fraction (LVEF; 36.3±2.0% vs. 45.7±1.8%, P<0.001), and more incomplete revascularization (ICR; 70.7% vs. 45.5%, P=0.014) than those without appropriate ICD-Tx. Multivariable analysis showed that LVEF (hazards ratio [HR], 0.950; 95% CI: 0.925–0.975; P<0.001) and ICR (HR, 2.293; 95% CI: 1.133–4.637; P=0.021) were significant predictors of appropriate ICD-Tx for VA.

Conclusions: Lower LVEF and ICR were independent predictors of recurrent VA in secondary prevention ICD recipients with CAD.

Life-threatening ventricular arrhythmia (VA; ventricular fibrillation [VF] and ventricular tachycardia [VT]) is an important prognostic factor for patients with coronary artery disease (CAD). The Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) demonstrated that prophylactic use of an implantable cardioverter defibrillator (ICD) reduced all-cause death in patients with a prior myocardial infarction (MI) and severely reduced left ventricular ejection fraction (LVEF).¹ Similarly, many clinical trials have shown the ICD to be a powerful and useful standard prevention therapy for patients with CAD at high risk for sudden cardiac death (SCD) due to life-threatening VA.^2–6 In MADIT II, appropriate ICD therapy (ICD-Tx), that is, cardioversion or anti-tachycardia pacing (ATP) for VA, was observed in 23.5% of 719 patients with ischemic heart disease during a median follow-up of 1.6 years. In contrast, these patients had significantly higher mortality than those without appropriate ICD-Tx.⁷ In addition, frequent ICD-Tx might impair quality of life, causing significant psychological distress.⁸ Thus, determining predictors of appropriate ICD-Tx for VA is of utmost importance. Clinical predictors of recurrent VA in secondary prevention ICD recipients with CAD, however, remain unknown. The purpose of this study was therefore to identify clinical predictors of ICD-Tx for VA in such patients.

Methods

Patients and Data Collection

We followed 96 consecutive CAD patients with prior MI who underwent ICD or cardiac resynchronization therapy and defibrillator (CRT-D) implantation for secondary prevention of SCD due to VA at Niigata University Medical and Dental Hospital and Tachikawa General Hospital between 2000 and 2015. The local ethics committee of Niigata University School of Medical and Dental Sciences approved this study. Baseline clinical characteristics and laboratory data, including medical history, physical examination, routine blood test, electrocardiography, echocardiography, and coronary angiography, were collected.

Criteria for Prior MI

Any 1 of the following criteria met the diagnosis for prior MI: pathological Q waves with or without symptoms in the absence of non-ischemic causes, imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract in the absence of a non-ischemic cause, and pathological findings of prior MI.⁹

Echocardiography

Two-dimensional and color Doppler echocardiography were performed before ICD or CRT-D implantation. Measurements of LV systolic and diastolic chamber dimensions were obtained from 2-D imaging according to the recommendations of the American Society of Echocardiography.¹⁰ LVEF was calculated using the formula of Teichholz.

Indication for ICD or CRT-D for Secondary Prevention

The indication for ICD or CRT-D for secondary SCD prevention was based on the Guidelines of the Japanese Circulation Society.¹¹

Coronary Angiography and Definition of Anatomic Complete Revascularization

Coronary angiography was performed in all patients before ICD or CRT-D implantation. Characteristics of coronary artery lesions were determined according to the American Heart Association/American College of Cardiology lesion classification.¹² Anatomic complete revascularization (CR) was defined as treatment of all >1.5-mm-diameter coronary artery segments and ≥50% diameter stenosis.¹³

Appropriate ICD-Tx and Follow-up

Patients underwent ICD or CRT-D interrogation every 1–3 months as well as at emergency visits as necessary. Appropriate ICD-Tx was defined as cardioversion or ATP for VA. The endpoint of follow-up was occurrence of the first appropriate ICD-Tx for VA.

Statistical Analysis

Continuous variables are described as mean±SEM and categorical variables as number of patients. Continuous variables were compared using 2-sided Student’s t-test. Categorical variables were compared using the chi-squared test or Fisher’s exact test. Freedom from appropriate ICD-Tx curves were calculated using the Kaplan-Meier method, and comparison between patient groups was done using the log-rank test. The risk of appropriate ICD-Tx was estimated by calculating hazard ratios (HR) and their 95% CI using the Cox regression method. A multivariable model was built using a forward selection procedure based on likelihood ratio (P_in<0.10). P<0.05 was considered significant. All statistical analyses were performed using IBM SPSS Statistics for Windows, version 23.0 (IBM, Armonk, NY, USA).

Results

Baseline Patient Characteristics

Of 96 CAD patients with ICD or CRT-D for secondary prevention of SCD, appropriate ICD-Tx occurred in 41 (42.7%) during a median follow-up of 2.4 years (IQR, 0.9–6.1 years). First recurrent VT and VF were observed in 34 (82.9%) and in 7 patients (17.1%), respectively. Seventeen out of 34 patients with VT were treated with ATP and the other 17 patients with VT, and 7 patients with VF needed cardioversion as the first appropriate ICD-Tx for VA. Baseline clinical characteristics are summarized in Table 1. There were no significant differences in the proportion of New York Heart Association functional class ≥III or the history of VA between the appropriate and no ICD-Tx groups. Patients with appropriate ICD-Tx had significantly greater LV end-diastolic diameter (LVDd; 62.3±1.3 vs. 54.6±1.1 mm, P<0.001), lower LVEF (36.3±2.0% vs. 45.7±1.8%, P<0.001), and a higher prevalence of incomplete revascularization (ICR; 70.7% vs. 45.5%, P=0.014) than those without appropriate ICD-Tx. There were no significant differences between the 2 groups in coronary risk factors, medication, laboratory data, infarct-related vessels, number of diseased vessels, methods for revascularization, or number of incompletely revascularized vessels.

Table 1. Baseline Clinical Characteristics

	All patients (n=96)	ICD-Tx (n=41)	No ICD-Tx (n=55)	P-value
Age (years)	69.4±1.3	70.0±1.9	69.0±1.7	0.701
Sex (F/M)	18/78	5/36	13/42	0.155
NYHA functional class ≥III	14 (14.6)	8 (19.5)	6 (10.9)	0.237
History of VA				0.243
VT	64 (66.7)	30 (73.2)	34 (61.8)
VF	32 (33.3)	11 (26.8)	21 (38.2)
High-voltage device type				0.633
ICD	92 (95.8)	40 (97.6)	52 (94.5)
CRT-D	4 (4.2)	1 (2.4)	3 (5.5)
Coronary risk factors
Hypertension	49 (51.0)	21 (51.2)	28 (50.9)	0.976
Diabetes mellitus	30 (31.3)	12 (29.3)	18 (32.7)	0.718
Dyslipidemia	51 (53.1)	22 (53.7)	29 (52.7)	0.928
Smoking history	50 (52.1)	23 (56.1)	27 (49.1)	0.497
Medication
ACEI and/or ARB	75 (78.1)	31 (75.6)	44 (80.0)	0.607
β-blockers	68 (70.8)	29 (70.7)	39 (70.9)	0.985
Aldosterone antagonists	35 (36.5)	15 (36.6)	20 (36.4)	0.982
Class III anti-arrhythmia drugs	48 (50.0)	19 (46.3)	29 (52.7)	0.536
Laboratory data
BNP (pg/mL)	318.2±57.0	392.8±108.6	270.0±62.4	0.298
Creatinine (mg/dL)	1.2±0.1	1.4±0.2	1.1±0.1	0.172
CRP (mg/dL)	1.21±0.29	1.12±0.32	1.27±0.44	0.775
Echocardiographic parameters
LVDd (mm)	58.0±0.9	62.3±1.3	54.6±1.1	<0.001
LVDd <58 or ≥58 mm				<0.001
LVDd <58 mm		12 (29.2)	35 (63.6)
LVDd ≥58 mm		29 (70.7)	17 (30.9)
LVEF (%)	41.6±1.4	36.3±2.0	45.7±1.8	<0.001
LVEF ≥35% or <35%				0.001
LVEF ≥35%		19 (46.3)	43 (78.2)
LVEF <35%		22 (53.7)	11 (20.0)
Infarct-related vessel
LMT	4 (4.2)	1 (2.4)	3 (5.5)	0.830
LAD	57 (59.4)	25 (61.0)	32 (58.2)	0.783
LCX	24 (25.0)	10 (24.4)	14 (25.5)	0.905
RCA	41 (42.7)	19 (46.3)	22 (40.0)	0.534
No. diseased vessels				0.269
1	54 (56.3)	22 (53.7)	32 (58.2)
2	21 (21.9)	7 (17.1)	14 (25.5)
3	21 (21.9)	12 (29.3)	9 (16.4)
Methods for revascularization
PCI	60 (62.5)	23 (56.1)	37 (67.3)	0.263
CABG	9 (9.4)	2 (4.9)	7 (12.7)	0.342
PCI and CABG	8 (8.3)	3 (7.3)	5 (9.1)	1.000
ICR	54 (56.3)	29 (70.7)	25 (45.5)	0.014
No. incompletely revascularized vessels [% of incomplete revascularization]				0.140
1	31 [57.4]	17 [58.6]	14 [56.0]
2	14 [25.9]	5 [17.2]	9 [36.0]
3	9 [16.7]	7 [24.1]	2 [8.0]
Incompletely revascularized arteries				0.607
LAD	14 (14.6)	8 (19.5)	6 (10.9)
LCX	9 (9.4)	4 (9.8)	5 (9.1)
RCA	8 (8.3)	5 (12.2)	3 (5.5)
LAD and LCX	6 (6.3)	2 (4.9)	4 (7.3)
LAD and RCA	4 (4.2)	3 (7.3)	1 (1.8)
LCX and RCA	4 (4.2)	0 (0.0)	4 (7.3)
LAD, LCX, and RCA	9 (9.4)	7 (17.1)	2 (3.6)

Data given as mean±SEM or n (%). ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; BNP, brain natriuretic peptide; CABG, coronary artery bypass grafting; CRP, C-reactive protein; CRT-D, cardiac resynchronization therapy with defibrillator; ICD, implantable cardioverter defibrillator; ICD-Tx, ICD therapy; ICR, incomplete revascularization; LAD, left anterior descending coronary artery; LCX, left circumflex artery; LMT, left main trunk; LVDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; RCA, right coronary artery; VA, ventricular arrhythmia; VF, ventricular fibrillation; VT, ventricular tachycardia.

Long-Term Rates of Appropriate ICD-Tx for VA

At 1, 3, and 5 years of follow-up the cumulative rate of appropriate ICD-Tx was 26.0%, 53.1%, and 64.6%, respectively (Figure 1). In addition, the long-term rate of appropriate ICD-Tx was stratified according to LVDd (≥58 vs. <58 mm), LVEF (<35% vs. ≥35%), and revascularization (ICR vs. CR). The long-term rate of appropriate ICD-Tx in patients with LVDd ≥58 mm was significantly higher than that in patients with LVDd <58 mm (log-rank test, P<0.001; Figure 2A). The long-term rate of appropriate ICD-Tx in patients with LVEF <35% was also significantly higher than that in patients with LVEF ≥35% (log-rank test, P<0.001; Figure 2B). Although not statistically significant, the long-term rate of appropriate ICD-Tx in patients with ICR showed a tendency to be higher than that in those with CR (log-rank test, P=0.072; Figure 2C).

Figure 1.

Kaplan-Meier curve for freedom from appropriate implantable cardioverter defibrillator (ICD) therapy in all patients.

Figure 2.

Kaplan-Meier curves for freedom from appropriate implantable cardioverter defibrillator (ICD) therapy according to (A) left ventricular end-diastolic diameter (LVDd) <58 mm or LVDd ≥58 mm; (B) left ventricular ejection fraction (LVEF) ≥35% or LVEF <35%; and (C) complete revascularization (CR) or incomplete revascularization (ICR).

Clinical Predictors of Appropriate ICD-Tx

Univariable and multivariable analyses of prognostic predictors of appropriate ICD-Tx are shown in Table 2. In model A, on multivariable analysis using a Cox proportional hazards regression model with forward selection, LVEF (HR, 0.950; 95% CI: 0.925–0.975; P<0.001) and ICR (HR, 2.293; 95% CI: 1.133–4.637; P=0.021) were significant predictors of appropriate ICD-Tx for VA. In model B, multivariable analysis using a Cox proportional hazards regression model with forward selection showed that creatinine (HR, 1.294; 95% CI: 1.020–1.641; P=0.034), LVEF <35% (HR, 3.713; 95% CI: 1.920–7.180; P<0.001), and ICR (HR, 2.406; 95% CI: 1.179–4.910; P=0.016) were significant predictors of appropriate ICD-Tx for VA.

Table 2. Prognostic Indicators of Appropriate ICD Therapy

	Univariable HR (95% CI)†	P-value	Multivariable HR‡ (95% CI)†	P-value
Model A
Female	0.390 (0.152–1.002)	0.050
Creatinine (mg/dL)	1.263 (1.014–1.573)	0.037
LVDd (mm)	1.054 (1.026–1.082)	<0.001
LVEF (%)	0.957 (0.934–0.981)	0.001	0.950 (0.925–0.975)	<0.001
ICR	1.838 (0.977–3.605)	0.077	2.293 (1.133–4.637)	0.021
Model B
Female	0.390 (0.152–1.002)	0.050
Creatinine (mg/dL)	1.263 (1.014–1.573)	0.037	1.294 (1.020–1.641)	0.034
LVDd ≥58 mm	3.329 (1.695–6.540)	<0.001
LVEF <35%	2.892 (1.557–5.370)	0.001	3.713 (1.920–7.180)	<0.001
ICR	1.838 (0.977–3.605)	0.077	2.406 (1.179–4.910)	0.016

^†Per 1-unit increment. In model B, LVDd (≥58 vs. <58 mm) and LVEF (<35% vs. ≥35%) were included as categorical variables. The cut-off of 58 mm in LVDd was selected based on the mean of LVDd. The cut-off of 35% in LVEF was determined in the MADIT trial.^{2 ‡}Hazards ratio by additional forward selection method, noted only for selected variables in the final equation. Abbreviations as in Table 1.

Discussion

We have demonstrated that lower LVEF and ICR are independent predictors of recurrent VA in secondary prevention ICD recipients with CAD.

Long-Term Rates of Appropriate ICD-Tx for VA

Few studies have reported on the long-term rates of appropriate ICD-Tx for VA limited to secondary prevention ICD recipients with CAD. Olimulder et al reported that appropriate ICD-Tx occurred in 9 (31.0%) of 29 patients during a median follow-up of 1.8 years.¹⁴ Borleffs et al also reported appropriate ICD-Tx in 216 (47.4%) of 456 patients during a median follow-up of 4.5 years.¹⁵ In the present study, the rates were 25.3% and 42.3% at 1.8 year and 4.5 years, respectively, similar to that in the aforementioned studies. In addition, the cumulative rate of appropriate ICD-Tx ≤6 months after ICD or CRT-D implantation was 11%, which was also high, similar to the 17% rate reported by Borleffs et al.¹⁵

Lower LVEF as a Clinical Predictor of Appropriate ICD-Tx

As in some previous studies,^16–18 in the present study lower LVEF was a strong predictor of ICD-Tx for VA. LVEF is the well-known gold standard risk stratification for the occurrence of life-threatening VA, and ICD is also known to exhibit a particularly high SCD preventive effect in patients with LVEF <30–35%.^1,2 Similarly, in the present study the appropriate ICD-Tx rate in patients with LVEF <35% was significantly higher than that in patients with LVEF ≥35%.

ICR as a Clinical Predictor of Appropriate ICD-Tx

We further showed that anatomic ICR, defined as the presence of ≥1 residual stenosis of coronary artery segments >1.5 mm in diameter and ≥50% diameter stenosis, is an independent predictor of appropriate ICD-Tx for VA. In various heart diseases, myocardial ischemia has been suggested to be an important trigger for VA.¹⁹ In addition, CR is associated with significantly decreased mortality, MI, and repeat coronary revascularization.²⁰ The impact of ICR on recurrent VA in secondary prevention ICD recipients with CAD, however, is unknown, and, to the best of our knowledge, this is the first study showing that anatomic ICR is a clinical predictor of ICD-Tx for VA in secondary prevention ICD recipients with CAD. VA in patients with prior MI is usually due to reentry in the border zone of a post-infarction scar, which consists of strands of viable myocytes interspersed with fibrous tissue.²¹ In contrast, the Ventricular Arrhythmia in Chronic Total Coronary Occlusion (VACTO) secondary study investigators recently reported that: (1) the presence of chronic total coronary occlusion (CTO) was an independent predictor of recurrent VA in secondary prevention ICD recipients with ischemic cardiomyopathy and was associated with poorer survival on long-term follow-up; and (2) better collateral flow in the CTO artery was associated with a tendency toward a higher VA recurrence rate.²² This suggests that the mechanism of the recurrent VA in patients with CAD is involved not only in the reentry, but also in the ischemia. Although the mechanism (e.g., reentry vs. triggered activity) or origin of VA in the present study is unclear, the findings are in line with the results of previous studies demonstrating that ischemia, or ICR, is closely associated with arrhythmogenesis and electrical instability. As a result, the rate of ICD-Tx for VA has increased.

Study Limitations

The present study has several limitations. First, this was an observational study and the results should be interpreted with caution. Second, we considered the coronary status only immediately before ICD implantation. In addition, no patients had undergone CR during follow-up. Therefore, patients who had a new stenotic or occluded lesion at the time of ICD-Tx for VA could have been missed. Finally, although anatomic ICR was found to be an independent predictor of recurrent VA in secondary prevention ICD recipients with CAD, we could not show that physiologic ICR, as assessed on stress thallium-201 myocardial scintigraphy, was an independent predictor of ICD-Tx for VA (data not shown). Garcia et al. concluded that CR was associated with a significant reduction in mortality, MI, and repeat coronary revascularization regardless of how CR is defined (e.g., anatomic vs. physiologic).²⁰ Although it is not intended to deny physiological evaluation using myocardial scintigraphy,²³ the limit of ischemic evaluation is also known in patients with multivessel CAD.²⁴ In the present study, 42.6% of patients with anatomic ICR had multivessel CAD, so the possibility that the ischemia was not able to be picked up accurately, remained. Recently, it has been reported that functional SYNTAX score, assessed by fractional flow reserve (FFR), is more capable of risk stratification for adverse events in patients with CAD than anatomic SYNTAX score.²⁵ The association between VA and physiologic ICR, however, remains unknown. A future consideration is to establish accurate evaluation of myocardial ischemia using FFR and so forth, and to elucidate the association between myocardial ischemia and VA.

Conclusions

Lower LVEF and ICR were independent predictors of recurrent VA in secondary prevention ICD recipients with CAD. These results could help identify echocardiographic and angiographic factors that influence ICD-Tx for VA, and may improve management for secondary prevention ICD recipients with CAD. Whether CR has a beneficial impact on VA reduction, however, remains unknown. Further study is needed to determine the impact of CR on ICD-Tx for VA.

Disclosures

The authors declare no conflicts of interest.

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