ICDS
Right ventricular pacing is an independent predictor for ventricular tachycardia/ventricular fibrillation occurrence and heart failure events in patients with an implantable cardioverter–defibrillator
1 Department of Cardiovascular Medicine, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany; 2 Department of Thoracic and Cardiovascular Surgery, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
Manuscript submitted 25 October 2007. Accepted after revision 12 January 2008.
* Corresponding author. Tel: +49 511 5323817; fax: +49 511 5328475. E-mail address: gunnarklein{at}yahoo.de
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Abstract |
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Aims: There is increasing evidence that right ventricular (RV) pacing may have detrimental effects by increasing morbidity and mortality for heart failure in implantable cardioverter–defibrillator (ICD) patients. In this study we prospectively tested the hypothesis that cumulative RV pacing increases ventricular tachycardia/ventricular fibrillation (VT/VF) occurrence (primary endpoint) and hospitalization and mortality for heart failure (secondary endpoint) in a predominantly secondary prophylactic ICD patient population.
Methods and results: Two hundred and fifty patients were divided into two groups according to the median of cumulative RV pacing (
2 vs. >2%) and prospectively followed-up for occurrence of primary and secondary endpoints for 18 ± 4 months. Established predictors for VT/VF occurrence and heart failure events such as age, left ventricular ejection fraction (EF), QRS duration, history of atrial fibrillation, and NT-proBNP were collected at enrolment. Multivariate Cox regression analysis revealed that cumulative RV pacing > 2% and EF < 40% were independent predictors for VT/VF occurrence and heart failure events. Kaplan–Meier analysis showed that patients with >2% cumulative RV pacing more frequently suffered from VT/VF occurrence and heart failure hospitalization.
Conclusion: Cumulative RV pacing > 2% and EF < 40% are independent predictors for VT/VF occurrence and mortality and hospitalization for heart failure in predominantly secondary prophylactic ICD patients. Our data show that algorithms capable of reducing cumulative RV pacing should be used more frequently in clinical practice.
Key Words: ICD, Heart failure, Right ventricular pacing, VT/VF
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Introduction |
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There is strong evidence that implantable cardioverter/defibrillators (ICDs) improve survival in patients with primary and secondary prophylactic ICD indications.1
–4 In several trials, however, patients treated with an ICD more often experienced heart failure events.1,5 The Dual-Chamber and VVI-Implantable Defibrillator (DAVID) Trial demonstrated that patients with a reduced ejection fraction (EF) and without any indication for antibradycardia pacing suffered from increased heart failure morbidity, when provided with a dual-chamber ICD programmed at a high lower rate limit (DDDR-70).6 Furthermore, the combined endpoint of death or hospitalization for heart failure was higher in patients programmed DDDR-70. The aim of this study was to prospectively assess the impact of cumulative right ventricular (RV) pacing on the occurrence of ventricular tachycardia/ventricular fibrillation (VT/VF) episodes and only secondarily on morbidity and mortality for heart failure in ICD patients. Determining this deleterious interaction may have consequences in ICD programming, as several algorithms are already available, which, to a certain extent, avoid or reduce RV pacing. Furthermore, identifying harmful side effects secondary to ICD therapy is crucial in improving its benefits with respect to mortality and morbidity of heart failure patients.
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Methods |
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Study design
This is a single-centre prospective cohort study of consecutive ICD patients designed to identify the pre-specified impact of RV pacing as a predictor of VT/VF occurrence (primary endpoint) and hospitalization and mortality for heart failure (secondary endpoint). For inclusion in the study, patients had to meet the 2002 American College of Cardiology/American Heart Association Guidelines for ICD implantation (Class I–IIb).7
Enrollment began in March 2003 and ended in March 2004. At entry into the study, clinical characteristics were collected through medical record review and interrogation of the patients. At enrollment cumulative RV apical pacing over the last 6 months was collected from the ICD and documented for each patient. Cumulative RV pacing was the percentage of ventricular-paced beats. Further data on pre-specified and well-established predictors of VT/VF occurrence in ICD patients such as age,8–10 left ventricular EF,11,12 QRS duration,13 NYHA class,14 NT-proBNP level,15,16 and history of atrial fibrillation17,18 were collected at study begin. EF was determined either by echocardiography or left ventricular angiography. Congestive heart failure severity was categorized according to NYHA class at baseline interview. NT-proBNP was measured using an electrochemiluminescence immunoassay ‘ECLIA’ (Roche Diagnostics).19
Follow-up
Subsequently patients were followed-up for a minimum of 12 months (18 ± 4) after enrollment. Patients were monitored for ICD therapies (only sustained VT/VF episodes either treated by anti-tachycardia pacing or shock were included) and clinical endpoints (death, hospitalization due to heart failure) during routine follow-up visits every 6 months. Hospitalization due to heart failure was defined as NYHA Class IV (pulmonary edema) or ankle edema, making intravenous therapy necessary. Appropriate device therapy was confirmed by two electrophysiologists (G.K./A.G.) by analysis of stored electrograms as we previously described.16,17,20 During follow-up visits, the electrophysiologists were blinded to the patients' 2 EF, NYHA class, and QRS duration and baseline cumulative RV pacing percentage.
Statistical analysis
Baseline descriptive statistics are presented as mean ± SD or median (range) for continuous variables and numbers with percentages for categorical variables. Linear variables were dichotomized according to the median value. Cumulative event proportions were calculated by the Kaplan–Meier analysis, and outcome differences of patients were assessed by log-rank test. Cox regression analysis was performed to evaluate associations between risk factors at enrollment and appropriate ICD therapy. Adjusted hazard ratios of clinical characteristics (e.g. age, LVEF, NYHA class, atrial fibrillation, AV-Block, QRS duration, BNP level), baseline drug therapy, and cumulative RV pacing were calculated with Cox proportional hazards regression models. P values of less than 0.05 were considered statistically significant. All statistical analyses were performed using SPSS for Windows 12.0 (SPSS, Inc., Chicago, IL, USA).
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Results |
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Baseline characteristics
In this prospective cohort study, 245 ICD patients were enrolled. Baseline clinical and demographic features of all patients are summarized in Table 1. At inclusion patients were predominantly males and on average 63 ± 13 years old. Sixty-three percent of the patients had a coronary artery disease and 21% suffered from non-ischaemic dilated cardiomyopathy, arrhythmogenic RV cardiomyopathy (ARVC), or suspected ARVC in 7%. The remaining patients (8.5%) had hypertensive cardiomyopathy or valvular heart disease. Indication for ICD therapy was primary prophylactic in 7% and secondary prophylactic in 93% of the cases. Twenty-seven percent of the patients received a dual-chamber ICD and 73% a single-chamber ICD. Eighty-two percent of the ICDs were programmed in VVI mode and 18% in DDD mode with a mean lower rate limit of 47 ± 8 bpm. Three percent of the patients had a sinus node disease and 9% suffered from high-degree AV block. Lowest VT detection zone was 174 ± 18 bpm.
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Distribution of RV pacing percentage is shown in Figure 1. Median of cumulative RV pacing was 2%, which was determined and documented at enrollment. Correspondingly, patients were divided into two groups: Group 1 (n = 121) with cumulative RV pacing
2% and Group 2 (n = 124) with >2% cumulative RV pacing. Patients with 2% RV pacing were younger, had a better EF, a narrower QRS, and a lower prevalence of intermittent or permanent high-degree AV block (P < 0.05). Patients had a mean follow-up of 549 ± 118 days.
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Cumulative right ventricular pacing is an independent predictor for occurrence of ventricular tachycardia/ventricular fibrillation
Of 245 patients included in this study, 46 patients suffered from 427 sustained episodes of VT/VF, subsequently receiving ICD therapy. Mean time to VT/VF occurrence was significantly shorter in patients with a cumulative RV pacing >2% compared with patients with a cumulative RV pacing
2% (511 ± 144 vs. 547 ± 129 days; P < 0.05). Kaplan–Meier analysis showed that patients with cumulative RV pacing above median (>2%), EF < 40%, or a history of atrial fibrillation had a significantly higher probability of experiencing a VT/VF episode (Figure 2A–C). Multivariate Cox regression analysis including age, QRS duration, coronary artery disease, NYHA class, AV block, NT-proBNP, cumulative RV pacing, EF, and history of atrial fibrillation revealed that cumulative RV pacing, EF, and history of atrial fibrillation were independent predictors for the occurrence of VT/VF episodes (Table 2).
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Cumulative right ventricular pacing is an independent predictor for death or hospitalization due to heart failure
Among 245 patients 44 suffered from the secondary endpoint of death or hospitalization due to heart failure. Time to secondary endpoint was significantly shorter in patients with a cumulative RV pacing >2% compared with patients with a cumulative RV pacing
2% (474 ± 171 vs. 524 ± 143 days; P = 0.015). Kaplan–Meier analysis revealed that patients with a cumulative RV pacing >2% or an NT-proBNP above median (405 ng/L) had a significantly higher probability of suffering a heart failure endpoint (Figures 3A, B and 4). Multivariate Cox regression analysis including age, QRS duration, coronary artery disease, NYHA class, AV block, NT-proBNP, cumulative RV pacing, EF, and history of atrial fibrillation revealed that cumulative RV pacing and NT-proBNP were independent predictors for heart failure events (Table 2).
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Discussion |
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This prospective study demonstrates that cumulative RV pacing >2% is an independent predictor for occurrence of ventricular arrhythmias in predominantly secondary prophylactic ICD patients. VT/VF occurrence increased with incremental RV pacing. Furthermore, RV pacing >2% and NT-proBNP are independent predictors for the combined endpoint of hospitalization and death due to heart failure in ICD patients.
Several previous primary and secondary prophylactic ICD trials have presented indices for the detrimental effects of RV pacing in patients with left ventricular dysfunction,1,3,4 mostly concerning heart failure events and not VT/VF incidence. In a post hoc analysis of the MADIT-II trial, which included patients with previous myocardial infarction and LVEF 30%, patients paced >50% of the time more frequently suffered from heart failure events had a higher mortality and received more often appropriate ICD therapies.21 In the DAVID Trial, dual-chamber pacing increased the combined endpoint of death and hospitalization due to heart failure compared with ventricular back-up pacing in patients with reduced LVEF.6 Sharma et al. showed in a post hoc analysis of the DAVID trial that patients with DDDR RV pacing 40% had a similar outcome as those with VVI backup pacing. DDDR RV pacing >40% was a univariate predictor of death and hospitalization for heart failure. However, the patients with DDDR RV pacing 40% showed a trend toward better outcomes than the VVI group. This finding may be explained by the fact that these patients received atrial rate support without detrimental RV pacing, as reported by the authors. No data were provided on VT/VF occurrence in this analysis. Smit et al. studied the effect of RV pacing on heart failure events in asymptomatic (NYHA class I) patients. Cumulative RV pacing >50% was associated with an increase in heart failure events and was an independent predictor of ICD shocks.22 In a recent post hoc analysis of the INTRINSIC RV study, Olshansky et al. reported that more than 50% of RV pacing was associated with heart failure hospitalization and mortality and the occurrence of appropriate ICD shocks. This finding is consistent with our observations. However, ICD patients with some RV pacing (10–19%) had lower event rates than those with very low RV pacing (0–9%). Furthermore, ventricular tachycardias treated with ICD shock occurred more often in patients with 0–9% RV pacing in comparison to those with 10–19% RV pacing.23 Differences in patient’s selection and study design might explain this difference in outcome (Figure 4). All patients in the study by Olshansky et al. had a dual-chamber ICD implanted, which was programmed DDDR. In contrast, 82% of our patients had a VVI backup pacing programmed. Apart from this, ventricular tachycardias treated with antitachycardia pacing were not included by Olshansky et al.
In contrast to previous studies, we did not only include VT/VF episodes terminated by ICD shock, but also those terminated by antitachycardia pacing. Furthermore, we prospectively decided to choose the median of RV pacing (2%) as the cut-off value. It is surprising that even this low cut-off value of 2% cumulative RV pacing differentiates between high risk and low risk for VT/VF occurrence. A possible explanation might be that RV pacing causes mechanical dyssynchrony resulting in haemodynamic deterioration.24 Furthermore, RV pacing results in alterations in cardiac sympathetic activity, histopathology, and ion channel expression and function.25 In experimental models, it has been shown that RV pacing induces asymmetric hypertrophy, fibre disarray, and increased myocardial catecholamine concentrations.26–28 Ultimately, these changes may be responsible for an increase in arrhythmia occurrence in patients with depressed ventricular function. Moreover, higher VT/VF incidence in patients with higher cumulative RV pacing is supported by data from Himmrich et al., showing that pauses followed by ventricular pacing were significantly associated with pacemaker-induced ventricular tachycardias (PITs).29 This interaction was further supported by the observation that no PIT occurred after reducing pacing by rate hysteresis or backup pacing. Although our study was not designed to look for the incidence of PITs, we did not find pauses followed by ventricular pacing to be a predominant mechanism for VT/VF induction in our patients. Thus, the above-mentioned mechanism of left ventricular dyssynchrony by RV pacing might be the most important reason for the observed difference in arrhythmia occurrence in our study.
Nevertheless, this prospective study clearly points out that reduction of cumulative RV pacing as far as possible should be achieved in ICD patients. In single-chamber devices programming, minimal lower rate limit or rate hysteresis can reduce cumulative RV pacing. Use of algorithms capable of reducing RV pacing either by AV hysteresis or by mode-switching from DDD to AAI in dual-chamber devices may be helpful in daily practice.
Furthermore, in patients dependent on ventricular pacing biventricular device implantation or upgrade should be considered. The PAVE study compared RV pacing with biventricular pacing in patients undergoing AV-node ablation for atrial fibrillation. Patients provided with a biventricular device showed an increase in exercise tolerance and had a better EF. This effect was emphasized in patients with impaired left ventricular function.30 Recently, Leclercq et al. showed that upgrading from RV pacing to biventricular pacing significantly improved symptoms of heart failure and exercise tolerance in chronically paced patients with advanced heart failure and mechanical dyssynchrony.31 However, as yet it would be premature to assume that upgrading from single- or dual-chamber to biventricular devices can definitely reduce VT/VF burden. Future studies are needed to prove this concept.
In summary, we conclude that cumulative RV pacing above a very low threshold of 2% leads to a higher incidence of VT/VF episodes in ICD patients. Therefore, algorithms capable of reducing cumulative RV pacing should be used more intensively in clinical practice.
Conflict of interest: none declared.
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Footnotes |
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Both authors contributed equally to the study. 
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Reference |
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