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Research Article
Originally Published 26 February 2013
Free Access

Association Between Left Ventricular Ejection Fraction Post-Cardiac Resynchronization Treatment and Subsequent Implantable Cardioverter Defibrillator Therapy for Sustained Ventricular Tachyarrhythmias

Circulation: Arrhythmia and Electrophysiology

Abstract

Background—

Although cardiac resynchronization therapy (CRT) can improve left ventricular ejection fraction (LVEF), it is not known whether a specific level of improvement will predict future implantable cardioverter defibrillator (ICD) therapy.

Methods and Results—

CRT-defibrillator (CRT-D) was implanted in 423 patients at 1 institution between October 2, 2001 and January 19, 2007. A retrospective analysis was performed to evaluate the relationship between post–CRT-D LVEF and ICD therapy for ventricular tachyarrhythmias. A landmark population of 270 patients, with post–CRT-D LVEF measured and no ICD therapy within 1 year of device implantation, was followed for subsequent outcomes. Of these, 22 patients (8.2%) had subsequent appropriate ICD therapy over a median follow-up of 1.5 years. The estimated 2-year risk of appropriate ICD therapy is 3.0% (95% confidence interval [95% CI], 0%–6.3%), 2.1% (95% CI, 0%–5.0%), and 1.5% (95% CI, 0%–3.9%) for post–CRT-D LVEF of 45%, 50%, and 55%, respectively. In patients with a primary prevention indication for CRT-D, the estimated 2-year risk is 3.3% (95% CI, 0%–7.3%), 2.5% (95% CI, 0%–6.1%), and 1.9% (95% CI, 0%–5.1%) for post–CRT-D LVEF of 45%, 50%, and 55%, respectively.

Conclusions—

When a CRT responder demonstrates near normalization in LVEF to ≥45%, the incidence of ICD therapy for ventricular arrhythmias becomes low. Future studies are needed to determine whether an ICD is still needed in some of these patients at the time of generator replacement.

Introduction

Cardiac resynchronization therapy (CRT) has been shown to reduce heart failure symptoms and hospitalizations, and improve survival of patients with significant systolic heart failure, a wide QRS complex, and advanced heart failure symptoms despite optimal medical therapy.14 In some patients, CRT can improve the left ventricular ejection fraction (LVEF), but the degree of improvement is variable.5,6 Although in 25% to 30% of patients, there seems to be little to no clinical benefit from CRT,7 in a small subset of patients, CRT can result in near normalization of ventricular function. Such patients have been referred to as super-responders,8,9 defined arbitrarily as a post–CRT LVEF of ≥45%.8 Several studies have suggested that CRT can reduce the occurrence of ventricular arrhythmias,1014 but no data are available on the relationship of the post–CRT-D LVEF and subsequent occurrence of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). CRT-defibrillator (CRT-D) implantation guidelines depend on the LVEF as a measure of ventricular function. Thus, it would be important to know what the risk of sustained VT or VF is after changes in post–CRT LVEF, which may in the future affect decisions on whether CRT-D or CRT-pacemaker is given at time of generator replacement. The primary aim of this investigation is to examine the association between post–CRT-D LVEF and subsequent ICD therapy for sustained ventricular tachyarrhythmias; specifically to determine whether the probability of subsequent ICD therapy is low when post–CRT-D LVEF is near normalized. Secondary objectives are to describe characteristics of patients undergoing CRT implantation and their association with appropriate ICD therapy, and with near normalization of LVEF.
Clinical Perspective on p 264

Methods

Patient Selection

We conducted a retrospective analysis of 423 consecutive patients who received an implantable cardioverter defibrillator (ICD) with CRT (CRT-D) at The Care Group in Indianapolis, Indiana, from October 2, 2001 through January 19, 2007. A detailed chart review was conducted to collect demographic and clinical information about these patients and to gather follow-up data on device interrogations. Of the 423 patients who underwent CRT-D implantation during this timeframe, 4 were excluded because of the absence of follow-up information. A total of 419 patients were eligible for analysis; however, additional exclusions were necessary for specific analyses and are addressed below. Patients were censored at the closure date of the study (July 1, 2007), date of death, transplant, or the date when the LV lead dislodged or was programmed off. Criteria for CRT implantation were predetermined based on published guidelines.15 Specifically, patients were required to have systolic heart failure resulting from either ischemic or nonischemic cardiomyopathy, an LVEF of ≤35% with a New York Heart Association functional class III/IV on optimal medical therapy, and a QRS duration of ≥120 ms. The Institutional Review Board of both the St. Vincent Hospital and Duke University Medical Center approved the study.

Implantation Procedure and ICD Programming

Experienced board certified electrophysiologists implanted all devices. The specific location of the LV lead, device selection, and programming were decided by the implanting physician. Vendors used at this particular institution include Medtronic, St. Jude Medical, and Guidant.

Therapies

Therapies included antitachycardia pacing (ATP) or high-voltage shocks. Appropriate (sustained ventricular arrhythmias) and inappropriate (supraventricular arrhythmias or interference/noise) therapies were based on chart-documented interpretations of the individual implanting electrophysiologists.

End points

The primary end point of this analysis is time to appropriate ICD therapy defined as ATP and high-voltage shocks for ventricular arrhythmias. The secondary end point is near normalization of the post–CRT-D LVEF defined as LVEF of ≥45%. The time of the follow-up post–CRT-D LVEF assessment was at the discretion of the attending electrophysiologist.

Statistical Analysis

Baseline characteristics were examined for all patients (n=419) and for patients with a primary prevention indication who had a post–CRT-D LVEF assessment (n=289). Percentages are provided for categorical variables, and medians with interquartile ranges (IQR) are provided for continuous variables.
Given that post–CRT-D LVEF was measured at the discretion of the physician, the timing of these measurements was highly variable. Thus, we could not assess post–CRT-D LVEF at a consistent time point. To mitigate this issue in the study of association between post–CRT-D LVEF and subsequent ICD therapy, we used a landmark analysis. We defined a landmark time point of 1 year, included only the subset of individuals with a post–CRT-D LVEF measured before 1 year and no previous ICD therapy (n=270; 62 patients without a post–CRT-D LVEF and 87 patients experiencing appropriate ICD therapy within the first year were excluded). Follow-up for subsequent outcomes began at 1 year, and time-to-event was modeled by the Cox proportional hazards model. The advantage of this approach is that the population is well defined as being event free at 1 year after device implantation and with post–CRT-D LVEF measurements occurring relatively close to the procedure. Generally, post–CRT-D LVEF was analyzed as a continuous variable and tested for linearity. In Figure 1A and 1B, the corresponding 2-year probability (measured from the 1-year landmark) of receiving appropriate ICD therapy is presented on the y-axis across the range of continuous post–CRT-D LVEF values because probability is a more clinically meaningful measure than the log hazard. Additionally, we report estimated event probabilities and confidence intervals (CIs) for specific values of post–CRT-D LVEF (45%, 50%, and 55%) based on the continuous relationship with outcome. Where specifically stated, post–CRT-D LVEF was evaluated as a categorical variable with levels <45% and ≥45%, representing near normalization. Analyses were repeated in the subset of patients with primary prevention indication for ICD therapy (n=226).
Figure 1. Estimated probability of appropriate implantable cardioverter defibrillator (ICD) therapy from the Cox proportional hazard model in the 1-year landmark population, where post–CRT-D LVEF was included as a continuous (linear) variable for (A) all patients (n=270) and (B) those with a primary prevention indication (n=226). CI indicates confidence interval; CRT-D, cardiac resynchronization therapy defibrillator; and LVEF, left ventricular ejection fraction.
The secondary aim of evaluating baseline characteristics was addressed in the full sample (n=419). Unadjusted Kaplan–Meier plots and log rank P values were examined to assess time from device implantation to initial therapy for VT/VF, stratified by indication, ischemic cardiomyopathy, and sex. Univariable and multivariable Cox proportional hazards models were generated to assess the relationship between baseline candidate variables and time to appropriate ICD therapy. Logistic regression modeling was used to explore the relationship between baseline variables and the near normalization of the post–CRT-D LVEF, among subjects with post–CRT-D LVEF measurement (n=357; 62 patients were excluded from this specific analysis because of the absence of post–CRT-D LVEF measurement). Final models include statistically significant baseline covariates based on stepwise selection (α=0.05). Candidate variables included ischemic cardiomyopathy, coronary artery disease, sex, baseline LVEF, age, New York Heart Association, heart failure class, history of myocardial infarction, previous revascularization with percutaneous coronary intervention or coronary artery bypass grafting, history of atrial fibrillation, QRS duration, conduction abnormalities, and baseline medication usage. We assessed the assumption of proportional hazards for the covariates and found that the post–CRT-D LVEF did not violate the assumption using our landmark view at 1 year. In the baseline models, there were violations for use of an angiotensin receptor blocker and use of an angiotensin-converting enzyme inhibitor (ACE-I), but not for the other covariates. Despite these violations, these 2 variables achieved statistical significance. Cubic polynomial spline curves were examined to assess violations of the linearity assumption for continuous variables.16 No violations were detected; consequently, no transformations were required to satisfy this assumption. Finally, using the logistic regression model for near normalization of post–CRT-D LVEF, we examined how the probability of achieving a post–CRT-D LVEF ≥45 changes across baseline LVEF values, assuming the patient has nonischemic cardiomyopathy. We generated these estimates using 2 models, 1 that is based on all patients and 1 that is based on patients with a primary prevention indication.

Results

Patient Characteristics

The baseline characteristics of eligible patients are presented in Table 1. The median age of patients was 72 years. The median follow-up period for end point assessment and last known alive in this study was 2.64 years, IQR 1.84 to 3.20 years. The majority of patients (71%) were men, 61% had ischemic cardiomyopathy, and 81% had a primary prevention indication for ICD therapy. Of the 77 patients taking nitrates, 8 patients (10.4%) had nonischemic cardiomyopathy and 69 patients (89.6%) had ischemic heart disease. The median QRS duration for all patients was 154 ms.
Table 1. Baseline Characteristics
CharacteristicsTotal
N419
Age, y; median (Q1–Q3)72 (64–78)
Men, n (%)299 (71)
Primary prevention, n (%)341 (81)
Ischemic, n (%)254 (61)
Previous PCI, n (%)143 (34)
Previous CABG, n (%)166 (40)
LVEF (pre-CRT), median (Q1–Q3)20 (15–25)
QRS (pre-CRT), median (Q1–Q3)154 (133–174)
NYHA (pre-CRT), n (%) 
II10 (2)
II/II4 (1)
III354 (84)
III/IV32 (8)
IV19 (5)
CAD, n (%)272 (65)
AFIB, n (%)172 (41)
Previous MI, n (%)221 (53)
β-Blocker, n (%)396 (95)
Diuretics, n (%)338 (81)
ARB, n (%)107 (26)
ACE-I, n (%)238 (57)
Aldosterone inhibitor, n (%)118 (28)
Aspirin, n (%)294 (70)
Nitrates, n (%)77 (18)
Statins, n (%)263 (63)
AAD, n (%)100 (24)
Amiodarone, n (%)91 (22)
Sotalol, n (%)6 (1)
Moricizine, n (%)2 (1)
Mexiletine, n (%)4 (1)
Dofetilide, n (%)3 (1)
LBBB, n (%)260 (62)
RBBB, n (%)35 (8)
IVCD, n (%)34 (8)
Paced, n (%)86 (21)
ACE-I indicates angiotensin-converting enzyme inhibitor; AAD, anti-arrhythmic drugs; AFIB, atrial fibrillation; ARB, angiotensin receptor blocker; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CRT, cardiac resynchronization therapy; IVCD, interventricular conduction delay; LBBB, left bundle-branch block; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; and RBBB, right bundle-branch block.

Post–CRT-D LVEF and the Risk of Appropriate ICD Therapy

Post–CRT-D LVEF was measured in 357 patients. Among these, the median time from implantation to post–CRT-D LVEF measurement was 217 (IQR, 15–609) days; 177 (IQR, 15–596) days for patients whose post–CRT-D LVEF was <45% and 352 (IQR, 131–684) days for patients whose post–CRT-D LVEF ≥45%. The number of patients whose post–CRT-D LVEF increased to ≥45% was 58 (16.2%). Of these, 4 patients (6.9%) received appropriate therapy. Further limiting the cohort to patients with a primary prevention indication (n=289), the number of patients whose post–CRT-D LVEF increased to ≥45% was 49 (17%). Of these, 1 patient received appropriate therapy. The number of patients with a post–CRT-D LVEF ≥55% was 18 (5%). Of these patients, none received appropriate ICD therapy, regardless of whether the indication for the device was primary or secondary prevention. Of the 299 patients with post–CRT-D LVEF <45%, 60 patients (20%) had appropriate ICD therapy and 16 patients (5%) had inappropriate ICD therapy. Of patients with a primary prevention ICD with a post–CRT-D LVEF <45% (n=240), 35 patients (15%) had appropriate ICD therapy and 10 patients (4%) had inappropriate ICD therapy. Of those with a secondary prevention ICD with an LVEF <45% (n=59), 25 patients (42%) had appropriate ICD therapy and 6 patients (10%) had inappropriate ICD therapy.
In 34 patients, the exact programming details at the time of ICD therapy were available for analysis. Ten patients received shock therapy; 2 of them after ATP failure. In the 9 Guidant devices, initial and redetect intervals, respectively, were 1 second (n=7), 2.5 and 1 second (n=1), and 18/24 and 6/8 (n=1). In the 1 Medtronic device, initial and redetect intervals were 12/16 and 6/8, respectively. Programming before ATP therapy in 24 patients was 2.5 and 1 second, respectively, for initial and redetect intervals for Guidant (n=20); 12 intervals for both initial and redetect for St. Jude (n=2); and 16 initial and 12 redetect intervals for Medtronic (n=2).
In the 1-year landmark analysis (n=270), 22 patients received appropriate therapy, all of whom with post–CRT-D LVEF <45%. Figure 1A shows the results of the landmark analysis, where a Cox proportional hazard model was used to estimate the 2-year risk of appropriate ICD therapy over the range of continuous post–CRT-D LVEF values. Although no evidence of nonlinearity was detected, the P value for the log hazard linearity assessment was 0.357. This showed that the risk of appropriate ICD therapy within 2 years decreases as the post–CRT-D LVEF increases such that once the post–CRT-D LVEF exceeds 45%, the risk of appropriate ICD therapy becomes very low; specifically, the 2-year risk of appropriate ICD therapy is 3.0% (95% CI, 0%–6.3%), 2.1% (95% CI, 0%–5.0%), and 1.5% (95% CI, 0%–3.9) for a post–CRT-D LVEF of 45%, 50%, and 55%, respectively. Limiting this analysis to patients with a primary prevention device, the 2-year risk of appropriate ICD therapy is 3.3% (95% CI, 0%–7.3%) for a post–CRT-D LVEF of 45%, 2.5% (95% CI, 0%–6.1%) for a post–CRT-D LVEF of 50%, and 1.9% (95% CI, 0%–5.1%) for a post–CRT-D LVEF of 55% (Figure 1B). Although no evidence of nonlinearity was detected, the P value for the log hazard linearity assessment was 0.404.

Factors Associated With Appropriate ICD Therapy

The relationship between time to appropriate ICD therapy and the pathogenesis of cardiomyopathy (ischemic versus nonischemic), as well as indication for ICD therapy (primary versus secondary), and sex are provided in Figures 2 and 3. Female sex and primary prevention indication were associated with a lower risk of appropriate ICD therapy. In a multivariable Cox proportional hazards model, factors that were significantly associated with a lower risk of appropriate ICD therapy were a primary prevention indication (hazard ratio, 0.27; 95% CI, 0.16–0.44; P<0.01), use of an ACE-I at baseline (hazard ratio, 0.52; 95% CI, 0.30–0.91; P=0.02), use of an angiotensin receptor blocker at baseline (hazard ratio, 0.32; 95% CI, 0.15–0.70; P<0.01), and use of nitrates (hazard ratio, 2.04; 95% CI, 1.18–3.53; P=0.01).
Figure 2. Comparison of appropriate implantable cardioverter defibrillator (ICD) therapy in patients with ischemic (isch) and nonischemic (nonisch) cardiomyopathy and in those with primary and secondary prevention indications for cardiac resynchronization therapy defibrillator therapy.
Figure 3. Comparison of appropriate implantable cardioverter defibrillator (ICD) therapy in men and women patients.

Factors Associated With a Near Normalization Response

Baseline characteristics of patients with a primary prevention device and a post–CRT-D LVEF assessment are shown in Table 2. In a multivariable logistic regression model assessing baseline variables, only 2 factors were significant; namely, nonischemic cardiomyopathy (odds ratio, 2.24; CI, 1.18–4.25; P=0.013) and a higher LVEF at baseline (odds ratio per 5% increase = 1.43; CI, 1.12–1.84; P=0.004). The χ2 for the baseline LVEF is 8.17 versus a χ2 of 6.14 for nonischemic cardiomyopathy; therefore, the baseline LVEF seems to have a stronger association with near normalization response than nonischemic cardiomyopathy. For patients with nonischemic cardiomyopathy and a primary prevention indication, a pre-LVEF of 30% and 35% yielded a predicted probability of post–CRT-D LVEF ≥45% of 37% and 48%, respectively. Taking patients with either a secondary or primary indication for the device, a pre-LVEF of 30% and 35% yielded a predicted probability of near normalization of LVEF of 36% and 45%, respectively.
Table 2. Baseline Characteristics of Patients With Primary Prevention Device and a Post–CRT-D LVEF Assessment
ParametersTotal
N289
Age, y; median (Q1–Q3)71 (64–77)
Men, n (%)207 (72)
Ischemic, n (%)170 (59)
Previous PCI, n (%)100 (35)
Previous CABG, n (%)112 (39)
LVEF (pre-CRT), median (Q1, Q3)20 (15–25)
QRS (pre-CRT), median (Q1, Q3)155 (132–176)
NYHA (pre-CRT), n (%) 
II6 (2)
II/III2 (1)
III247 (85)
III/IV21 (7)
IV13 (5)
CAD, n (%)185 (64)
AFIB, n (%)114 (40)
Previous MI, n (%)150 (52)
β-Blocker, n (%)279 (97)
Diuretics, n (%)223 (77)
ARB, n (%)77 (27)
ACE-I, n (%)165 (57)
Aldosterone inhibitor, n (%)84 (29)
Aspirin, n (%)196 (68)
Nitrates, n (%)56 (19)
Statins, n (%)178 (62)
AAD, n (%)51 (18)
Amiodarone, n (%)50 (17)
Mexiletine, n (%)1 (<1)
LBBB, n (%)180 (62)
RBBB, n (%)21 (9)
IVCD, n (%)25 (9)
Paced, n (%)61 (21)
ACE-I indicates angiotensin-converting enzyme inhibitor; AAD, anti-arrhythmic drugs; AFIB, atrial fibrillation; ARB, angiotensin receptor blocker; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CRT, cardiac resynchronization therapy; IVCD, interventricular conduction delay; LBBB, left bundle-branch block; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; and RBBB, right bundle-branch block.

Discussion

The current study evaluated whether or not improvement of mechanical left ventricular function as measured by the post–CRT-D LVEF would correlate with electric stability, defined as the occurrence of appropriate ICD therapy for sustained ventricular tachyarrhythmias after CRT-D implantation, and to identify patient characteristics that would help predict such a favorable response. We also sought to identify whether a specific post–CRT-D LVEF, if any, would show marked electric stability.
In this study, we provide 2 main findings. First, we showed a definite relationship between the post–CRT-D LVEF and the subsequent risk of appropriate ICD therapy (Figure 1). Specifically, when a patient’s LVEF improves to 45%, the 2-year risk of appropriate ICD therapy using a 1-year landmark analysis approaches 3.0% in the overall cohort and 3.3% in patients with a primary prevention device. Second, a near normalization response to CRT could be predicted only by a higher LVEF at baseline and nonischemic cardiomyopathy. In addition, men were more likely than women to receive appropriate ICD therapy (Figure 3), and patients with a primary prevention indication have a significantly lower risk of future therapies after CRT as previously shown (Figure 2).17
This study demonstrates that when a patient receives a primary prevention CRT-D, is event free at 1 year, and has near normalization of their LVEF to ≥45%, the subsequent incidence of sustained VT or VF during follow-up is very low. In fact, no events were observed in that subgroup, and the estimated event rate based on categorization of post–CRT-D LVEF would be 0. In the continuous analysis of post–CRT-D LVEF, the estimated event rate still remained below 3.3% for post–CRT-D LVEF >45%. Although several studies have shown a reduction in the risk of ventricular arrhythmias1014,18,19 with CRT, no previous study has provided quantitative data on the relationship between the level of post–CRT-D LVEF and subsequent sustained VT or VF. This is particularly relevant because the guidelines for implantation of CRT devices are based, in part, on a critically low LVEF. In this study, we show that as the post–CRT-D LVEF increases, the risk of appropriate ICD therapy decreases. We demonstrate a linear relationship between post–CRT-D LVEF and appropriate ICD therapy and a very low risk of sustained ventricular arrhythmias when the post–CRT-D LVEF is ≥45%. Why such a relationship exists requires further study, but it is likely attributable to both ventricular reverse remodeling and hemodynamic and neurohormonal changes.
In our study, 4 factors were significantly and independently associated with a lower risk of appropriate ICD therapy; namely, a primary prevention indication for the device, use of an ACE-I, use of an angiotensin receptor blocker, and use of nitrates at baseline. The majority of patients using nitrates (89.6%) had ischemic cardiomyopathy; thus, it seems that the underlying substrate, rather than the use of nitrates, engenders appropriate shocks.
It is not surprising that in the unadjusted univariate analysis, men were more likely than women to receive appropriate ICD therapy. The risk of sudden cardiac death is lower in women than men.20 However, it should not be concluded that women do not benefit from ICD therapy. Although studies have suggested a lack of survival benefit of primary prevention ICD therapy in women, the number of women in those studies was too small to allow any meaningful conclusions.2123 Even pooling data from 5 clinical trials of primary prevention ICDs in 1 study yielded 934 women; this number was significantly lower than the 3810 men included.23 Thus, until more robust data are published on this issue, women should continue to be considered for this therapy.
Approximately 70% of patients who undergo CRT implantation seem to be responders, and yet there is still another subset of patients who nearly normalize their LVEF. These patients in our study were identified in a multivariable analysis as those with nonischemic cardiomyopathy and also patients who had a higher pre–CRT-D LVEF. A recent study from Rickard et al24 demonstrated that only baseline left bundle-branch block was strongly associated with a near normalization of LVEF to CRT. However, van Bommel et al25 also noted an association of female sex and nonischemic cardiomyopathy with this response to CRT. In a study of only nonischemic cardiomyopathy patients, no baseline characteristics predicted a hyper-responder.26 Further research is needed in this important area to define more precisely the patients most likely to have a marked improvement in LVEF, for they are also the ones unlikely to have sustained ventricular tachyarrhythmia after CRT.
It is important to note that inappropriate ICD therapies occurred in only 5% of patients. This contrasts markedly with the 9% to 25% of inappropriate therapies quoted in other studies.25,27,28 These data would suggest either a difference in baseline programming or improved discrimination algorithms with the devices selected for implantation.

Clinical Implications

Our findings have important clinical implications. If after CRT implantation, the LVEF improves to ≥45%, and especially to 55%, a patient may be a good candidate for a CRT-pacemaker at generator replacement, especially if the initial indication was for primary prevention and no appropriate therapies occurred. This would also assume that the marked improvement in LVEF is stable over time, which requires further research. What does seem clear from our study as well as others, and makes physiological sense, is that the presence of substantial ischemic scar burden typically precludes a near normalization response to CRT treatment. The ability to prescribe CRT-pacemaker without compromising survival benefit would have a substantial impact on the economic burden that this important treatment of heart failure places on healthcare systems.

Limitations

We recognize that this study has its limitations. This was a retrospective study looking at the treatment of patients with heart failure with device therapy of a single center. However, the implanting electrophysiologists are a very experienced group at a high-volume practice. The patients were not selected at random, and were chosen at the implanting physician’s discretion based on current standard of care. Likewise, the implanting electrophysiologists individually chose medical therapy, programming, LV lead position, device selection, and the timeframe for reassessing the post–CRT-D LVEF. Although, these factors represent potential bias, they could also be construed as real-world scenarios, making them clinically relevant and applicable to everyday practice. A further limitation is the nonsystematic times after implant to measuring the follow-up LVEF. Additionally, the sample size was small, the power to detect nuanced relationships, such as nonlinearity with post–CRT-LVEF was low and the probability of appropriate ICD therapy was estimated with wide CIs. These results should be confirmed in a larger study. Finally, programming strategies for detection of VT or VF have evolved over recent years with a general trend toward prolonging the initial time to delivering therapy.29,30 Detection of VF was 18 of the last 24 R-R intervals in 1 study29 and 30 of 40 beats in another study.30 It is possible that some of the patients in our study may not have received therapy if these settings were used.

Conclusions

Based on our findings, increased post–CRT-D LVEF correlates with a reduction in sustained VT or VF during follow-up with minimal occurrence in patients who achieve near normalization of the post–CRT-D LVEF. Further study is necessary to determine whether such patients require CRT-D versus CRT-pacemaker treatment at device replacement.

Clinical Perspective

Indications for cardiac resynchronization therapy (CRT) include a low left ventricular ejection fraction (LVEF) and significant heart failure. The majority of patients have relief of their heart failure symptoms with CRT, but improvement in LVEF is quite variable, with some patients obtaining near normalization of ventricular function. No data are available on the specific relationship of the post–CRT LVEF and the subsequent occurrence of sustained ventricular tachycardia or ventricular fibrillation. In our study, a CRT-defibrillator (CRT-D) was implanted in 423 patients, and LVEF before and after implantation was evaluated to examine the relationship of post–CRT LVEF and implantable cardioverter defibrillator therapy. The estimated 2-year risk of appropriate implantable cardioverter defibrillator therapy was 3.0%, 2.1%, and 1.5% for post–CRT-D LVEF of 45%, 50%, and 55%, respectively. The estimated 2-year risk was 3.3%, 2.5%, and 1.9% for post–CRT-D LVEF of 45%, 55%, and 55%, respectively, in patients with a primary prevention indication for CRT-D. Only 5% of 299 patients with post–CRT-D LVEF <45% had inappropriate implantable cardioverter defibrillator therapy. Thus, when the post–CRT LVEF demonstrates near normalization to ≥45%, appropriate implantable cardioverter defibrillator therapy for ventricular tachycardia or ventricular fibrillation is very low. Future studies are needed to determine whether patients with LVEF >45% at the time of generator replacement require CRT-D or CRT pacing.

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Go to Circulation: Arrhythmia and Electrophysiology
Go to Circulation: Arrhythmia and Electrophysiology
Circulation: Arrhythmia and Electrophysiology
Pages: 257 - 264
PubMed: 23443618

History

Received: 7 March 2012
Accepted: 20 January 2013
Published online: 26 February 2013
Published in print: April 2013

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Keywords

  1. cardiac resynchronization therapy
  2. heart failure
  3. left ventricular ejection fraction
  4. sudden cardiac death
  5. ventricular tachycardia

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Affiliations

Joseph A. Manfredi, MD
From the AnMed Arrhythmia Specialists, Anderson, SC (J.A.M.); Duke Clinical Research Institute (L.K.S., L.T.), and Division of Cardiology (S.M.A.-K.), Duke University Medical Center, Durham, NC; and the St. Vincent Medical Group, Indianapolis, IN (R.I.F., B.P., D.R., R.V., L.W.G., K.G., E.N.P.).
Sana M. Al-Khatib, MD, MHS
From the AnMed Arrhythmia Specialists, Anderson, SC (J.A.M.); Duke Clinical Research Institute (L.K.S., L.T.), and Division of Cardiology (S.M.A.-K.), Duke University Medical Center, Durham, NC; and the St. Vincent Medical Group, Indianapolis, IN (R.I.F., B.P., D.R., R.V., L.W.G., K.G., E.N.P.).
Linda K. Shaw, MS
From the AnMed Arrhythmia Specialists, Anderson, SC (J.A.M.); Duke Clinical Research Institute (L.K.S., L.T.), and Division of Cardiology (S.M.A.-K.), Duke University Medical Center, Durham, NC; and the St. Vincent Medical Group, Indianapolis, IN (R.I.F., B.P., D.R., R.V., L.W.G., K.G., E.N.P.).
Laine Thomas, PhD
From the AnMed Arrhythmia Specialists, Anderson, SC (J.A.M.); Duke Clinical Research Institute (L.K.S., L.T.), and Division of Cardiology (S.M.A.-K.), Duke University Medical Center, Durham, NC; and the St. Vincent Medical Group, Indianapolis, IN (R.I.F., B.P., D.R., R.V., L.W.G., K.G., E.N.P.).
Richard I. Fogel, MD
From the AnMed Arrhythmia Specialists, Anderson, SC (J.A.M.); Duke Clinical Research Institute (L.K.S., L.T.), and Division of Cardiology (S.M.A.-K.), Duke University Medical Center, Durham, NC; and the St. Vincent Medical Group, Indianapolis, IN (R.I.F., B.P., D.R., R.V., L.W.G., K.G., E.N.P.).
Benzy Padanilam, MD
From the AnMed Arrhythmia Specialists, Anderson, SC (J.A.M.); Duke Clinical Research Institute (L.K.S., L.T.), and Division of Cardiology (S.M.A.-K.), Duke University Medical Center, Durham, NC; and the St. Vincent Medical Group, Indianapolis, IN (R.I.F., B.P., D.R., R.V., L.W.G., K.G., E.N.P.).
David Rardon, MD
From the AnMed Arrhythmia Specialists, Anderson, SC (J.A.M.); Duke Clinical Research Institute (L.K.S., L.T.), and Division of Cardiology (S.M.A.-K.), Duke University Medical Center, Durham, NC; and the St. Vincent Medical Group, Indianapolis, IN (R.I.F., B.P., D.R., R.V., L.W.G., K.G., E.N.P.).
Rosh Vatthyam, MD
From the AnMed Arrhythmia Specialists, Anderson, SC (J.A.M.); Duke Clinical Research Institute (L.K.S., L.T.), and Division of Cardiology (S.M.A.-K.), Duke University Medical Center, Durham, NC; and the St. Vincent Medical Group, Indianapolis, IN (R.I.F., B.P., D.R., R.V., L.W.G., K.G., E.N.P.).
Lee W. Gemma, MD
From the AnMed Arrhythmia Specialists, Anderson, SC (J.A.M.); Duke Clinical Research Institute (L.K.S., L.T.), and Division of Cardiology (S.M.A.-K.), Duke University Medical Center, Durham, NC; and the St. Vincent Medical Group, Indianapolis, IN (R.I.F., B.P., D.R., R.V., L.W.G., K.G., E.N.P.).
Keith Golden, MD
From the AnMed Arrhythmia Specialists, Anderson, SC (J.A.M.); Duke Clinical Research Institute (L.K.S., L.T.), and Division of Cardiology (S.M.A.-K.), Duke University Medical Center, Durham, NC; and the St. Vincent Medical Group, Indianapolis, IN (R.I.F., B.P., D.R., R.V., L.W.G., K.G., E.N.P.).
Eric N. Prystowsky, MD
From the AnMed Arrhythmia Specialists, Anderson, SC (J.A.M.); Duke Clinical Research Institute (L.K.S., L.T.), and Division of Cardiology (S.M.A.-K.), Duke University Medical Center, Durham, NC; and the St. Vincent Medical Group, Indianapolis, IN (R.I.F., B.P., D.R., R.V., L.W.G., K.G., E.N.P.).

Notes

Correspondence to Eric N. Prystowsky, MD, The St. Vincent Medical Group, 8333 Naab Road, Indianapolis, IN 46260. E-mail [email protected]

Disclosures

Dr Manfredi declares a potential conflict of interest speaking for St. Jude and Boston Scientific. Dr Padanilam declares a potential conflict of interest speaking for Medtronic and Boehringer Ingelheim. Dr Fogel declares a potential conflict interest speaking for Medtronic and serving as expert witness for St. Jude and Biotronik. Dr Prystowsky declares a potential conflict of interest as a consultant for Medtronic, and St. Vincent Hospital receives fellowship support from Medtronic, St. Jude, and Boston Scientific. The other authors have no conflicts to report.

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  1. Risk of ventricular arrhythmias following implantable cardioverter‐defibrillator generator change in patients with recovered ejection fraction: Implications for shared decision‐making, Journal of Cardiovascular Electrophysiology, 34, 6, (1405-1414), (2023).https://doi.org/10.1111/jce.15913
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  2. 2023 HRS/APHRS/LAHRS guideline on cardiac physiologic pacing for the avoidance and mitigation of heart failure, Heart Rhythm, 20, 9, (e17-e91), (2023).https://doi.org/10.1016/j.hrthm.2023.03.1538
    Crossref
  3. 2023 HRS / APHRS / LAHRS guideline on cardiac physiologic pacing for the avoidance and mitigation of heart failure , Journal of Arrhythmia, 39, 5, (681-756), (2023).https://doi.org/10.1002/joa3.12872
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  4. Incidence of ventricular arrhythmias after biventricular defibrillator replacement: impact on safety of downgrading from CRT-D to CRT-P, Minerva Cardiology and Angiology, 70, 4, (2022).https://doi.org/10.23736/S2724-5683.20.05352-9
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  5. CRT-D replacement strategy: results of the BioCONTINUE study, Journal of Interventional Cardiac Electrophysiology, 66, 5, (1201-1209), (2022).https://doi.org/10.1007/s10840-022-01440-5
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  6. Incidence of Ventricular Arrhythmias and 1‐Year Predictors of Mortality in Patients Treated With Implantable Cardioverter‐Defibrillator Undergoing Generator Replacement, Journal of the American Heart Association, 10, 4, (2021)./doi/10.1161/JAHA.120.018090
    Abstract
  7. Predictors of appropriate shock after generator replacement in patients with an implantable cardioverter defibrillator, Pacing and Clinical Electrophysiology, 44, 5, (911-918), (2021).https://doi.org/10.1111/pace.14236
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  8. Reassessment of clinical variables in cardiac resynchronization defibrillator patients at the time of first replacement: Death after replacement of CRT (DARC) score, Journal of Cardiovascular Electrophysiology, 32, 6, (1687-1694), (2021).https://doi.org/10.1111/jce.15031
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  9. Risk of ventricular arrhythmia in cardiac resynchronization therapy responders and super-responders: a systematic review and meta-analysis, EP Europace, 23, 8, (1262-1274), (2021).https://doi.org/10.1093/europace/euaa414
    Crossref
  10. Primary Prevention Implantable Cardioverter-Defibrillator Therapy in Heart Failure with Recovered Ejection Fraction, Journal of Cardiac Failure, 27, 5, (585-596), (2021).https://doi.org/10.1016/j.cardfail.2021.02.006
    Crossref
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Association Between Left Ventricular Ejection Fraction Post-Cardiac Resynchronization Treatment and Subsequent Implantable Cardioverter Defibrillator Therapy for Sustained Ventricular Tachyarrhythmias
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