Abstract
Background
Repeated implantable cardioverter‐defibrillator (ICD) therapies cause myocardial damage and, thus, an increased risk of arrhythmias and mortality.
Hypothesis
Cardiac resynchronization therapy–defibrillator (CRT‐D) reduces the number of appropriate therapies in patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] <50%).
Methods
The retrospective study involved 175 consecutive patients (mean age, 64.6 ±10.4 years; 86.9% males) with reduced LVEF of 27.9% ±7.6% treated with an ICD (56.6%) or CRT‐D (43.4%), according to standard indications, between January 2009 and July 2014. Devices were placed for either primary (54.3%) or secondary prevention (45.7%). Mean follow‐up was 2.5 ±1.5 years. Predictors of first appropriate therapy were assessed using Cox regression analysis.
Results
Forty‐four (25.1%) patients received ≥1 appropriate therapy. Although patients treated with CRT‐D had lower LVEF and poorer New York Heart Association class, CRT‐D patients with LVEF improvement >35% at the end of follow‐up had a significantly lower risk of receiving a first appropriate therapy relative to those with an ICD (adjusted hazard ratio: 0.24, 95% confidence interval: 0.07–0.83, P = 0.025), independently of ischemic cardiomyopathy, baseline LVEF, and secondary prevention. There were no differences in mortality between the ICD and the CRT‐D groups.
Conclusions
Although patients receiving CRT‐D had a worse clinical profile, they received fewer device therapies in comparison with those receiving an ICD. This reduction is associated with a significant improvement in LVEF.
Keywords: Cardiac Resynchronization Therapy, Heart Failure, ICD Therapy
1. INTRODUCTION
Cardiac resynchronization therapy (CRT) reduces hospitalization for heart failure (HF) and improves survival in patients with left ventricular (LV) systolic dysfunction and wide QRS.1, 2, 3, 4, 5 These beneficial effects are related to LV reverse remodeling and an improvement of left ventricular ejection fraction (LVEF),6, 7, 8, 9, 10 but this improvement can be variable.11, 12 Quite often, CRT with an associated defibrillator (CRT‐D) is preferred to prevent sudden death due to ventricular arrhythmias (ventricular tachycardia [VT]).13 In Spain, the number of implanted CRT‐D devices increases every year. In 2016, CRT‐D devices represented 37.3% of all types of implantable cardioverter‐defibrillator (ICD) insertions.14
There is controversy regarding the effect of cardiac resynchronization therapy (CRT) on VT burden. Some studies have indicated no reduction or even an increase in the rate of VT, suggesting that epicardial pacing may increase transmural dispersion of repolarization and predispose to arrhythmias.15, 16, 17 By contrast, other studies6, 18, 19 have shown a reduction in the VT burden associated with an improvement of the LVEF. This dispute grew following the results of the Danish Study to Assess the Efficacy of ICDs in Patients With Non‐ischemic Systolic Heart Failure on Mortality (DANISH),20 because no differences in mortality were observed between medical treatment, including CRT, and prophylactic ICD, in patients with systolic HF not caused by coronary artery disease. These results suggest that for some lower‐risk‐profile patients (nonischemic cardiomyopathy and primary prevention), improvement of the LVEF with CRT could be enough to prevent VT.
The objective of the present study was to analyze predictors of appropriate and inappropriate therapies in a population of patients with systolic HF who have received an ICD or a CRT‐D in primary or secondary prevention.
2. METHODS
This was a single‐center, retrospective, observational study. Between January 2009 and July 2014, all consecutive patients with impaired LV systolic function (LVEF <50%) who received an ICD or a CRT‐D were included. Patients with preserved LV systolic function (LVEF ≥50%) in whom an ICD had been implanted were excluded, as well as patients with a follow‐up period of <6 months.
Indication for ICD followed the 2012 European Society of Cardiology (ESC) Guidelines,21 as follows: (1) in secondary prevention: in cases of sustained ventricular arrhythmias or recovered sudden cardiac death irrespective of LVEF; (2) in primary prevention: nonischemic cardiomyopathy with LVEF <35% despite optimal medical treatment and ischemic cardiomyopathy (in the absence of acute myocardial infarction in the past 4 weeks) with LVEF ≤35% and functional status of New York Heart Association (NYHA) class II to III. CRT‐D was indicated when LVEF ≤35% and (1) in sinus rhythm, NYHA class ≥II, left bundle branch block (LBBB) with QRS duration ≥120 ms (or in the absence of LBBB, QRS duration≥150 ms); (2) in atrial fibrillation (AF), NYHA class III to IV, and LBBB with QRS duration ≥120 ms.
Patients were followed up clinically and every 6 months at the ICD Clinic. Baseline clinical characteristics, indications for ICD and CRT‐D implantation, and clinical events during follow‐up were collected from medical notes. Details on appropriate and inappropriate therapies (shock or antitachycardia pacing) were collected from patients' ICD follow‐up visits. Devices were programmed according to the discretion of the responsible physician.
2.1. Statistical analysis
Continuous variables were reported using mean ±SD. Categorical variables were described using proportions. Patients characteristics according to the type of device implanted (ICD or CRT‐D) were compared using the χ2 or Student t test. LVEF at baseline and at the end of follow‐up were compared using the t test for paired data. The time until the first appropriate therapy according to the type of device was estimated by Kaplan–Meier curves and was compared by the log‐rank test.
To analyze predictors of appropriate therapies throughout the follow‐up, a Cox regression analysis of time to first appropriate therapy was performed with potential predictors of developing appropriate therapies as independent variables. To select from the potential variables, initially we performed separate univariate analysis and then a model that included the variables with statistical significance in the univariate analysis (P < 0.2) or that were considered clinically relevant.
3. RESULTS
3.1. Baseline characteristics
Of the 175 patients included, 99 (56.6%) received an ICD and 76 (43.4%) received a CRT‐D. Patients' characteristics are shown in Table 1. Although the prevalence of hypertension, diabetes, dyslipidemia, cerebrovascular disease, chronic kidney disease, and pulmonary disease did not differ significantly between the 2 groups, patients in the CRT‐D group had a worse clinical profile suggesting more advanced HF. Specifically, CRT‐D patients were older, had lower LVEF and hemoglobin, and had significantly higher prevalence of NYHA class III or IV and AF. By contrast, ischemic cardiomyopathy was more frequent in ICD patients. Finally, ICD was more often used in secondary prevention, whereas CRT‐D was more commonly implanted in primary prevention.
Table 1.
Baseline characteristics (n = 175)
| ICD, n = 99 | CRT‐D, n = 76 | P Value | |
|---|---|---|---|
| Demographics | |||
| Age, y | 62.5 ±11.3 | 67.4 ±8.5 | 0.002 |
| Male sex | 90 (90.9) | 62 (81.6) | 0.070 |
| Indication | |||
| Primary prevention | 39 (39.4) | 56 (73.7) | |
| Secondary prevention | 60 (60.6) | 20 (26.3) | <0.001 |
| Comorbidities | |||
| HTN | 62 (62.6) | 54 (71.1) | 0.242 |
| DM | 27 (27.3) | 30 (39.5) | 0.088 |
| Dyslipidemia | 54 (54.5) | 44 (57.9) | 0.658 |
| Stroke | 12 (12.1) | 12 (15.8) | 0.484 |
| Pulmonary disease | 27 (27.3) | 23 (30.3) | 0.664 |
| Hb, g/dL | 13.4 ± 2.1 | 12.7 ± 1.5 | 0.030 |
| Cr, mg/dL | 1.20 ± 0.81 | 1.33 ±0.49 | 0.223 |
| Cardiomyopathy | |||
| Ischemic etiology | 66 (66.7) | 31 (40.8) | 0.001 |
| LVEF, % | 29.9 ± 8.4 | 25.3 ± 5.5 | <0.001 |
| NYHA class III–IV | 14 (14.1) | 39 (51.3) | <0.001 |
| AF/flutter | 23 (23.2) | 28 (36.8) | 0.050 |
| QRS >120 ms | 29 (29.3) | 66 (95.7) | <0.001 |
| LBBB | 18 (18.2) | 63 (87.5) | <0.001 |
| Medications | |||
| ACEI/ARB | 78 (78.8) | 65 (85.5) | 0.253 |
| MRA | 45 (45.5) | 38 (50.7) | 0.495 |
| β‐Blocker | 73 (73.7) | 66 (86.8) | 0.034 |
| Diuretics | 50 (50.5) | 67 (88.2) | <0.001 |
| Amiodarone | 4 (4.0) | 3 (4.0) | 0.975 |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; Cr, creatinine; CRT‐D, cardiac resynchronization therapy–defibrillator; DM, diabetes mellitus; Hb, hemoglobin; HTN, hypertension; ICD, implantable cardioverter‐defibrillator; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; SD, standard deviation.
Data are presented as n (%) or mean ± SD.
3.2. Complications of device implantation
A total of 28 (16%) patients experienced device‐related complications, considering those related to the implantation and those arising during the follow‐up period. The total number of patients with complications was 16 (21.1%) in the CRT‐D group and 12 (12.1%) in the ICD group (P = 0.110). The frequency of wound hematoma, pneumothorax, and infective endocarditis did not differ significantly between both groups. However, lead displacement (13.2% vs 5.1%, respectively; P = 0.06) and need for reimplantation (17.1% vs 7.1%, respectively; P = 0.04) were more frequent in CRT‐D patients than in ICD patients. Complications of device implantation are listed in Supporting Information, Table S1, in the online version of this article.
3.3. Follow‐up
During the 2.5 ±1.5 years of follow‐up, 25 (14.3%) patients died, with no significant differences between the 2 groups (ICD: 11.1% vs CRT‐D: 18.1%; P = 0.171). In addition, no differences were observed in the occurrence of admission for HF, acute coronary syndrome, or ventricular arrhythmia. However, LVEF at the end of follow‐up was significantly higher in CRT‐D patients (ICD: 31.90% vs CRT‐D: 36.67%; P = 0.002). This effect was also patent when analyzing changes in LVEF from baseline to the end of follow‐up (ICD: + 2.03 vs CRT‐D: + 11.39%; P < 0.001). The improvement of LVEF in CRT‐D patients supposes that of the 76 patients who received a CRT‐D, 38 (50%) increased LVEF to >35% at the end of follow‐up. During the follow‐up period, VT ablation was more frequent in patients with ICD (ICD: 16.2% vs CRT‐D: 2.6%; P = 0.003). Clinical events during follow‐up are described in Table 2.
Table 2.
Clinical events during follow‐up (n = 175)
| ICD, n = 99 | CRT‐D, n = 76 | P Value | |
|---|---|---|---|
| Follow‐up, y | 2.55 ± 1.49 | 2.50 ±1.62 | 0.815 |
| LVEF at the end of follow‐up, % | 31.90 ± 10.43 | 36.67 ± 9.75 | 0.002 |
| Difference between LVEF at the end of follow‐up and baseline LVEF | + 2.03 ± 9.45 | + 11.39 ±9.82 | <0.001 |
| Hospitalization | |||
| HF | 14 (14.1) | 14 (18.4) | 0.444 |
| ACS | 2 (2.0) | 2 (2.6) | 0.789 |
| Ventricular arrhythmia | 12 (12.1) | 4 (5.3) | 0.119 |
| Syncope | 13 (12.1) | 8 (10.5) | 0.599 |
| Antiarrhythmic treatment | |||
| VT ablation | 16 (16.2) | 2 (2.6) | 0.003 |
| Amiodarone | 31 (31.3) | 16 (21.1) | 0.129 |
| Other antiarrhythmic drugs | 5 (5.1) | 1 (1.3) | 0.178 |
| Cardiac transplant | 1 (1.0) | 1 (1.4) | 0.835 |
| Mortality | 11 (11.1) | 14 (18.4) | 0.171 |
| SCD | 3 (27.3) | 0 (0.0) | |
| HF | 5 (45.5) | 7 (50.0) | |
| ACS | 1 (9.1) | 1 (7.1) | |
| Electrical storm | 0 (0.0) | 1 (1.7) | |
| Extracardiac cause | 1 (9.1) | 5 (35.7) | |
| Unknown cause | 1 (9.1) | 0 (0.0) |
Abbreviations: ACS, acute coronary syndrome; CRT‐D, cardiac resynchronization therapy–defibrillator; HF, heart failure; ICD, implantable cardioverter‐defibrillator; LVEF, left ventricular ejection fraction; SCD, sudden cardiac death; SD, standard deviation; VT, ventricular arrhythmia.Data are presented as n (%) or mean ± SD.
3.4. Device therapies
Device therapies during follow‐up are described in Table 3. Appropriate therapies were delivered in 10 (13.2%) patients with CRT‐D and in 34 (34.3%) of patients with ICD (P = 0.001). In addition, the rate of appropriate therapies was also significantly lower in CRT‐D patients (CRT‐D: 5.8 vs ICD: 16.6 therapies per 100 patient‐years; P = 0.003). The Kaplan–Meier analysis of time from device implantation to first appropriate therapy, stratified by ICD, CRT‐D with no improvement in LVEF, and CRT‐D with LVEF improvement up to 35%, showed a significant reduction of appropriate therapies delivered in CRT‐D patients (Figure 1). Nonetheless, the total number of patients that received inappropriate therapies and the rate of inappropriate therapies per 100 patient‐years were similar between ICD and CRT‐D patients.
Table 3.
Therapies according to device type (n = 175)
| ICD, n = 99 | CRT‐D, n = 76 | P Value | |
|---|---|---|---|
| Patients with appropriate therapies | 34 (34.3) | 10 (13.2) | 0.001 |
| Appropriate ATP | 29 (29.3) | 5 (6.6) | <0.001 |
| Appropriate shock | 24 (24.2) | 8 (10.5) | 0.020 |
| Rate of appropriate therapy (per 100 patients‐year) | 16.6 (11.8–23.3) | 5.8 (3.1–10.7) | 0.003 |
| Appropriate ATP | 13.8 (9.5–20) | 2.7 (1.1–6.5) | <0.001 |
| Appropriate shock | 9.9 (6.5–15.1) | 4.5 (2.3–9) | 0.042 |
| Patients with inappropriate therapies | 10 (10.1) | 7 (9.2) | 0.844 |
| Rate of inappropriate therapy (per 100 patients‐year) | 4.2 (2.3–7.9) | 4.0 (1.9–8.5) | 0.880 |
Abbreviations: ATP, antitachycardial pacing; CRT‐D, cardiac resynchronization therapy–defibrillator; ICD, implantable cardioverter‐defibrillator; IQR, interquartile range.
Data are presented as n (%) or median (IQR).
Figure 1.
Kaplan‐Meier analysis of time from device implantation to first appropriate therapy, stratified by ICD, CRT‐D with no improvement in LVEF, and CRT‐D with LVEF improvement up to 35%. Abbreviations: CRT‐D, cardiac resynchronization therapy–defibrillator; ICD, implantable cardioverter‐defibrillator; LVEF, left ventricular ejection fraction
3.5. Predictors of appropriate therapies
Predictors of appropriate therapies are listed in Table 4. Responders to CRT‐D are divided into 2 categories, those with an improvement of LVEF >35% and those with LVEF ≤35% at the end of follow‐up. When device indication was in secondary prevention, the unadjusted hazard ratio [HR] of first appropriate therapy was 1.97 (95% confidence interval [CI]: 1.07–3.61, P = 0.029). By contrast, the risk of receiving a first appropriate therapy decreased in patients who received a CRT‐D and LVEF improved >35% when compared with those with an ICD (unadjusted HR: 0.21, 95% CI: 0.06–0.68, P = 0.009). After adjusting for implant indication, baseline LVEF, sex, and the presence of ischemic cardiomyopathy with multivariate analysis, CRT‐D patients with LVEF improvement >35% at the end of follow‐up still had a significantly lower risk of receiving a first appropriate therapy relative to those with an ICD (adjusted HR: 0.24, 95% CI: 0.07–0.83, P = 0.025). This suggests that responders to CRT‐D had a beneficial effect on reducing appropriate therapies even in patients with ischemic cardiomyopathy or in secondary prevention. However, in multivariate analysis, secondary prevention was associated with a trend toward increased risk of receiving a first appropriate therapy (adjusted HR: 1.38, 95% CI: 0.70–2.70, P = 0.349).
Table 4.
Predictors of first appropriate therapy
| Unadjusted HR (95% CI) | Adjusted HR (95% CI) | |
|---|---|---|
| Female sex | 0.35 (0.08–1.45) | 0.37 (0.09–1.56) |
| Secondary prevention | 1.97 (1.07–3.61) | 1.38 (0.70–2.70) |
| CRT‐D | ||
| CRT‐D with LVEF at the end of follow‐up ≤35% | 0.52 (0.23–1.17) | 0.53 (0.22–1.27) |
| CRT‐D with LVEF at the end of follow‐up >35% | 0.21 (0.06–0.68) | 0.24 (0.07–0.83) |
| Baseline LVEF | 1.03 (0.99–1.07) | 1 (0.96–1.05) |
| Ischemic etiology | 1.14 (0.63–2.09) | 0.72 (0.30–1.80) |
Abbreviations: CI, confidence interval; CRT‐D, cardiac resynchronization therapy–defibrillator; HR, hazard ratio; LVEF, left ventricular ejection fraction.
4. DISCUSSION
There are 4 main findings of the present study. First is the significant reduction of first appropriate therapy seen in CRT‐D patients when compared with those who received an ICD, despite having a worse clinical profile. Second, the reduction of appropriate therapies in the CRT‐D group was independent of implant indication and the presence of ischemic heart disease. Third, the decrease of CRT‐D therapies was associated with an improvement of LVEF during follow‐up. Fourth, we did not observe any differences in device‐related complications and in the rate of inappropriate therapies between CRT‐D and ICD patients.
Although there is strong evidence that CRT improves LVEF and reduces hospitalization and HF mortality, there is still controversy regarding the effect of CRT on VT burden. This effect could be of special importance, considering that ICD therapies are a marker of increased risk of death.22
Some studies have indicated no reduction or even an increase in the VT burden with CRT. In the Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE‐ICD) trial,1 there were no significant differences in the occurrence of appropriate therapies between CRT‐D and ICD groups in patients with moderate to severe HF symptoms. Similar results were obtained in patients with mild HF in the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study.23 The estimated event rate for a first treated VT episode was not significantly different between the activated CRT (CRT‐on) group and the activated ICD (CRT‐off) group. However, among CRT‐on patients, those with reverse remodeling showed a reduced incidence of VT burden compared with those without remodeling. Authors hypothesized that the neutral effect observed might be due to the competing antiarrhythmic effect of reverse remodeling and proarrhythmic effect of epicardial pacing.
By contrast, other studies have shown a reduction in the VT burden associated with an improvement of the LVEF.6, 24, 25 In a recent meta‐analysis by Chaterjee,26 the estimated rate of ICD therapies was significantly lower in patients with post‐CRT LVEF ≥35% when compared with patients with post‐CRT <35%. The results of our study are in line with Chaterjee's meta‐analysis, in which CRT was associated with a reduction of ICD therapies. Interestingly, in our study, patients in the CRT‐D group seemed to exhibit a worse clinical profile at the time of implantation, suggesting more advanced HF. CRT‐D patients were older, had lower LVEF and lower levels of hemoglobin, and the prevalence of NYHA class III or IV and AF were significantly higher. However, despite having a significantly higher risk profile, CRT‐D patients did not experience more clinical events during follow‐up. In fact, we did not observe any difference in mortality between CRT‐D and ICD patients, and the risk of receiving a first appropriate therapy was significantly lower in the CRT‐D group. According to the results of Chaterjee's meta‐analysis, the reduction of appropriate therapies was strongly associated with an improvement of the LVEF.
After the publication of the DANISH study,20 the debate about choosing between a CRT‐pacemaker and CRT‐D has increased. In favor of CRT‐pacemaker is the reduction of VT burden and sudden cardiac death by improving LVEF, at least in patients with nonischemic cardiomyopathy, and the lower cost of the device. However, the trend is still to implant a CRT‐D (80% of cases in the United States and 75% overall).27 Further studies are warranted to elucidate by how much the use of CRT prevents patients from developing ventricular arrhythmias, to avoid the implantation of the defibrillator function. In addition, CRT without ICD avoids morbidity related to inappropriate therapies. A cost‐effectiveness assessment of CRT compared with CRT‐D is also needed.
4.1. Study limitations
The first limitation of the present study is the retrospective design of the analysis. However, all patients included were consecutive. Second, this is a single‐center study and the number of patients included is relatively small. The small sample size resulted in a poor statistical power to analyze the effect of changes in LVEF in CRT‐D patients with >2 categories. In this sense, we considered clinically relevant to divide CRT‐D patients into those who experienced an improvement of LVEF >35% and those with LVEF ≤35% at the end of follow‐up, because ICD therapy is recommended when LVEF is ≤35% in primary prevention. Third, different device‐programming strategies in primary or secondary prevention may have influenced the time to first appropriate therapy and have not been evaluated in this study. Finally, in our study, CRT‐D was indicated in patients with LBBB and wide QRS (QRS duration >120 ms), according to 2012 ESC guidelines.21 Later in 2016, CRT indication criteria changed to QRS duration >130 ms,28 after patients had already been included in the study.
5. CONCLUSION
In patients with impaired LV systolic function, CRT‐D reduces the time to first appropriate therapy when compared with patients with ICD, irrespective of a worse clinical profile. This effect is associated with an improvement of LVEF and it is independent of implantation indication and the presence of ischemic cardiomyopathy. According to these findings, the use of ICD should be reconsidered in subjects whose LVEF is expected to improve with CRT‐Pacemaker.
Conflicts of interest
The authors declare no potential conflicts of interest.
Supporting information
Table S1. Complications of device implantation (n = 175)
Galve E, Oristrell G, Acosta G, et al. Cardiac resynchronization therapy is associated with a reduction in ICD therapies as it improves ventricular function. Clin Cardiol. 2018;41:803–808. 10.1002/clc.22958
Funding information This work was funded by CIBERCV and co‐financed by the European Regional Development Fund (ERDF‐FEDER).
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Associated Data
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Supplementary Materials
Table S1. Complications of device implantation (n = 175)