Europace Advance Access published online on August 8, 2007
Europace, doi:10.1093/europace/eum154
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Electrophysiological study and ‘slow’ ventricular tachycardia predict appropriate therapy: results from a single-centre implantable cardiac defibrillator follow-up
1 Cardiology Clinic Y, University Hospital Bispebjerg, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark; 2 Cardiology Department P, University Hospital Gentofte, Niels Andersens Vej, DK-2900 Hellerup, Denmark
Manuscript submitted 14 March 2007. Accepted after revision 3 July 2007.
* Corresponding author. Tel: +45 3940 4161; fax: +45 3531 3226. E-mail address: rw04{at}bbh.regionh.dk
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Abstract |
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Aims To account for appropriate and inappropriate therapies and cardiac death (CD) in a cohort of consecutive implantable cardiac defibrillator (ICD) eligible patients and to identify baseline predictors of these outcomes.
Methods and results During follow-up of 288 consecutive ICD-treated patients, clinical, biochemical, echocardiographic, arteriographic, and electrophysiological (EP) data at baseline were individually matched with survival data and electrograms retrieved during device interrogation. Predictors of therapy and CD were identified by multivariate analyses. Eighty-eight per cent of cases were secondary prevention and 12% were primary prevention. About 770 patient-years of ICD follow-up were analysed. Median follow-up was 22.7 months. Forty-eight per cent of patients had appropriate therapy for at least one ventricular tachyarrhythmia. Seventy per cent of tachycardias were successfully treated with anti-tachy pacing alone. Overall risk of therapy was higher for patients with ischaemic heart disease (IHD) than with non-IHD (51 vs. 37%; P = 0.049). Low left ventricular ejection fraction (LVEF), positive EP study, and ‘slow’ ventricular tachycardia predicted appropriate therapy. Cardiac death was predicted by nephropathy, low LVEF, amiodarone use, and supraventricular tachycardia (SVT). Inappropriate therapy affected 12.2% of patients and was predicted by known SVT and IHD.
Conclusion Electrophysiological study and slow VT predicted appropriate therapy. Amiodarone use predicted CD. Inappropriate therapy remains an important issue largely predictable by SVT.
Key Words: ICD, Appropriate therapy, Inappropriate therapy, Cardiac death, Electrophysiology study
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Introduction |
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Implantable cardiac defibrillator (ICD) therapy has become first choice strategy to prevent sudden cardiac death (CD) from malignant ventricular tachyarrhythmia in high-risk patients.1
Until recently, ICDs were preferentially implanted on a secondary prevention indication—patients with a clinical presentation of sustained ventricular tachycardia (VT) or cardiac arrest—but accumulating evidence has expanded the indications to primary prevention as well.2,3 Uncovering predictors of therapy, CD, and inappropriate therapy is of paramount importance for improving future quality of care. Previous studies addressed this important topic—either by retrospective analysis of baseline and follow-up data from the treatment arm in prospective randomized trials or simply by follow-up data from implanting centres.4–6 In these studies of patients with ischaemic heart disease (IHD) and non-ischaemic heart disease (N-IHD), the most consistent predictors of ICD therapy and CD were high age, low left ventricular ejection fraction (LVEF), and poor New York Heart Association (NYHA) function class,5 whereas electrophysiological (EP) study played no role.6 The PROFIT investigators recently supported the data in a mixed (IHD and N-IHD) patient cohort, although the role of EP study was not addressed.7 A recently published substudy of MADIT-II data showed that EP-inducibility predicted ICD therapy for VT, but not for ventricular fibrillation (VF).8 As the role of EP study remains unsettled, the present study aims to clarify the role of EP study as well as other baseline variables as predictors of appropriate therapy for ventricular tachyarrhythmia, CD, and inappropriate therapy at long-term follow-up in a mixed population of consecutive ICD-treated patients from a single tertiary-care centre. |
Methods |
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Complete medical records including follow-up data of all 288 patients receiving an ICD and follow-up between 1996 and 2004 at our department—providing tertiary-level cardiology care to approximately 1 million citizens—were reviewed. The medical history, clinical, biochemical, echocardiographic, arteriographic, EP study data at baseline, records of therapy, and stored electrograms (EGMs) retrieved at regular and event-driven device interrogation were obtained and computerized. Indications for ICD implantation generally adhered to available evidence and guidelines over time; thus of the 288 ICDs, 254 (88%) were on a secondary prevention indication, whereas the remaining 34 (12%) were on a primary prevention indication. All ICD implantations were performed by transvenous access and fluoroscopy-guided endocardial lead placement. The devices, manufactured by Guidant Inc., Medtronic Inc., St Jude Medical Inc., and ELA Medical, were equipped with anti-tachy pacing (ATP) as well as with DC shock delivery features. Baseline programming of the device was at the discretion of the implanting physician. In the database, baseline variables for each patient were matched with detailed data retrieved during device interrogation at scheduled and event-driven visits. All interrogation data previously downloaded to discs were reviewed and EGMs from all stored episodes were ‘manually’ analysed. Therapy was classified as ‘appropriate’ if ATP and/or shock therapy was administered because of sustained VT or VF. The tachycardia was classified as fast VT (fVT)/VF in case of VF or VT with cycle length (CL)
300 ms at the initiation of device therapy (i.e. ATP or shock). ‘Slow’ VT was defined as tachycardia (300 ms < CL 600 ms) deemed by the investigators to be of ventricular origin. For patients dying during follow-up (n = 58), the hospital records and death certificates, retrieved from the Danish Board of Health, were reviewed to classify the cause and mode of death as either non-cardiac (N-CD) or cardiac (CD), which was then subclassified as sudden CD (SCD) or non-sudden CD (NSCD), according to a modified Hinkle–Thaler system adopted from Greenberg et al.9 Device therapy delivered as either ATP or DC shock was termed ‘inappropriate’ when EGM documentation showed that therapy was triggered by either supraventricular tachycardia (SVT), oversensing, or myopotentials/lead defects.
Statistics
By use of the software package Statistica® version 5.1 (Statsoft Inc., OK, USA), clinical, biochemical, and EP variables at baseline were subjected to univariate tests (log-rank and Cox's F-test where appropriate) to identify variables predicting appropriate therapy, CD, and inappropriate therapy using the Kaplan–Meier method of estimation from censored observations.10 Then variables that significantly predicted appropriate therapy, CD, and inappropriate therapy were subjected to multivariate analysis, using the Cox proportional hazard model of covariates to identify independently significant predictors. The model was applied to both the mixed patient group (IHD + N-IHD) and the subgroup classified with IHD. The significance level was P = 0.05. Although the distribution of ATP and DC shocks is inherently skewed (i.e. therapy tends to be clustered in susceptible individuals), the objective of the current analysis being occurrence and time to first therapy, inappropriate therapy and death avoided the need of general estimation equation adjustment.
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Results |
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Baseline clinical variables are shown in Table 1. Of 288 patients, one died from pulmonary embolism on the day of implantation and one was lost to follow-up, leaving 286 patients for further analyses. Two hundred and fifteen patients were diagnosed with IHD, whereas the remaining 71 were diagnosed with N-IHD, as listed in Table 1. Seven hundred and seventy patient-years of EGMs were retrieved from the implanted devices at follow-up. Median duration of follow-up was 22.7 months (quartile range 9.7–46.6).
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Appropriate therapy
An aggregate of 3069 ventricular tachyarrhythmias were successfully treated. In 925 instances (30%), shock therapy was eventually required or programmed as initial therapy to terminate the arrhythmia, whereas 70% were terminated by ATP alone. In the overall patient population, 48% received at least one appropriate therapy (Figure 1A), with DC shock constituting 59% of first therapies. Within the first year after ICD implantation, 35% of the patients received appropriate therapy, and in 28%, this therapy was triggered by VF or fast VT (Figure 1A). One patient received therapy for very slow VT (CL 480–540 ms.), whereas the remaining slow VTs had CLs between 300 and 400 ms. Cumulated over the observational period, 51% of the IHD patients received at least one appropriate therapy over time and 37% within the first year. Correspondingly, a cumulated 37% of NIHD patients received appropriate therapy during the observation period and 27% within the first year. This difference between IHD and NIHD was significant in univariate analysis (P = 0.049; Table 2 and Figure 1B). In the small group of primary prevention ICDs, 29% received appropriate therapy vs. 51% in the secondary prevention group (P = 0.008, data not shown). Analyses of predictors of appropriate therapy are shown in Table 2. In summary, in the overall population, LVEF
30%, positive EP study (Figure 1C), and slow VT as qualifying arrhythmia were all mutually independent predictors of therapy. Separate analysis of the IHD group (data not shown) revealed that both LVEF 30% and positive EP study predicted therapy in univariate analysis. However, owing to sizeable covariance, neither independently predicted therapy in multivariate analysis (NS). Still, concomitant positive EP study and LVEF 30% predicted appropriate therapy among IHD patients.
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Mortality
Fifty-eight patients died during follow-up, translating into a cumulated mortality rate of 20% (Figure 2A). Mode of death was N-SCD in 31 patients (53%), SCD in 10 patients (17%), and N-CD in 17 patients (29%) with no statistical difference between IHD and NIHD patients (P = 0.19). Analyses of predictors of CD are shown in Table 2. In summary, in the overall population, S-creatinine > 125 µM, LVEF
30%, baseline use of amiodarone, and known paroxysmal or permanent SVT were strong independent predictors of CD. Baseline digoxin use predicted CD in univariate analysis, but lost significance in multivariate test because of significant covariance with SVT, which was the stronger predictor. In the IHD subgroup (data not shown), LVEF 30%, S-creatinine > 125 µM, and baseline use of amiodarone all independently predicted CV death.
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Inappropriate therapy
Anti-tachy pacing and/or DC shock due to atrial fibrillation, SVT, or abnormal sensing totalled 143 inappropriate therapies and affected 12.2% of the patients receiving at least one inappropriate therapy. In contrast to appropriate therapy, repeated inappropriate therapy in the same patient was rare. Known SVT and IHD at baseline independently predicted inappropriate therapy (Figure 2B).
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Discussion |
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This single-centre study of consecutive ICD patients examines baseline determinants of ICD therapy, CD, and inappropriate therapy. The study population detailed in Table 1 compares with other ICD-treated cohorts,11
although the fraction of patients diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) (4.2%) and long QT-syndrome (1.7%) tends to be smaller than in previous studies of consecutive ICD patients.4,7 The reason for this discrepancy is unclear, but might be viewed in light of the ‘diluting’ effect of widening ICD indications.
Overall, 48% of patients—51% in secondary prevention vs. 29% in primary prevention (P = 0.008)—received one or more appropriate therapies over a median of 22.7 months. The difference was expected because of the known lower risk of arrhythmia in primary prevention patients. The incidence of therapy in the primary prevention group resembles the 
24% incidence of appropriate therapy observed during a mean follow-up of 20 months in the MADIT II primary prevention cohort.6 First therapies in individual patients constituting primarily DC shocks, whereas any succeeding therapy was primarily ATP, might be explained by efforts to reprogram the system after DC shock to obtain less aggressive subsequent treatment. Although the ‘risk’ of ICD therapy was high in both the primary and secondary prevention setting, it is important to note that as some of the treated VT episodes would undoubtedly have terminated spontaneously, the observed incidence of ICD therapy does not translate into avoided SCD, as pointed out earlier.8
An interesting finding is that positive EP study independently predicted appropriate therapy in the overall patient population—hazard ratio (HR) = 1.36 and together with a low LVEF predicted therapy in the IHD group. However, important caveats regarding our findings are warranted. First, as the calculated empirical positive and negative predictive values of EP study were only 63 and 67%, respectively (data not shown), this does not support EP study as a guide for individual patient selection for ICD therapy. Secondly, as the majority of ICDs was prescribed for secondary prevention, it is not feasible to extrapolate to the primary prevention setting, which is currently the main clinical challenge. Thus, it should be emphasized that this study does not clarify the role of EP testing in decision-making regarding ICD prescription.
Another interesting finding is that slow VT as qualifying spontaneous arrhythmia predicted appropriate therapy (HR = 1.35), compared with patients presenting with spontaneous fVT/VF. This concords with the findings of Nielsen et al.4 and is not readily explainable. We hypothesize that VF in most settings is an exceptional, less reproducible event than VT. Interestingly, the increased amount of ICD therapy in the EP-positive group does not translate into increased CD (Table 2), an effect that might be ascribed a mortality reducing effect of ICDs.
With respect to mortality, it is intriguing that known SVT and amiodarone use at baseline independent of decreased kidney function and low LVEF predicted CD. The increased mortality among patients with known SVT and amiodarone users is not reflected in the incidence of appropriate therapy in these patients (Table 2). Supraventricular tachycardia seems, in this setting, merely to be an independent marker of disease severity.12 In that context, one might hypothesize this to be true primarily in permanent SVT vs. paroxysmal SVT. Our data do not substantiate this; however, by comparing permanent vs. paroxysmal SVT patients, the mortality rates were 28 and 19%, respectively (P = 0.15). Regarding amiodarone, the most likely explanation for the association with increased mortality would be that amiodarone use in these patients—such as SVT—might represent confounding risks of CD. It is in this regard a drawback that NYHA classification was not available in our study. In addition, one might speculate that proarrhythmia and/or increased defibrillation thresholds could play a role.13,14
The incidence of inappropriate therapy was substantially lower than in earlier ICD cohorts, but comparable with the recently published incidence by Friedman et al.15 Surprisingly, in that study, dual-chamber detection did not significantly reduce the burden of inappropriate therapy. In our cohort, 45 patients (16%), most of whom had a history of paroxysmal SVT, had dual-chamber lead ICDs with a presumed potential to better detect SVTs and avoid misinterpretation as malignant ventricular arrhythmias. Despite that, the risk of inappropriate therapy was tripled in patients with known SVT when compared with patients with no history of SVT (Table 2). In the current setting of expanding indications for ICD implantation to patients at lower risk of appropriate therapy, strategies to further decrease the incidence of inappropriate therapy in order to maintain patient's quality of life are increasingly important. Taken together, increased alertness to documented SVT or a history pointing to SVT may warrant considerations of dual lead implantation for diagnostic purposes or further tailoring of drug therapy in these patients.
The limitations of retrospective studies pertain to this study as well. Thus, although the current patient cohort represents consecutive patients, they nevertheless constitute a non-randomized study population. Therefore, the baseline predictors of therapy and CD uncovered here provide no direct impact on the decision for ICD implantation. Although the included baseline parameters were remarkably complete, it is important to emphasize that parameters not included due to incomplete sampling such as NYHA class, QRS duration, heart rate, and the promising Microvolt T-Wave Alternans feature might allow a more thorough modelling of the relative importance of baseline characteristics, as indicated by Bloomfield et al.16 Importantly, detailed data on ICD programming at baseline and during follow up, which may influence the pattern of ICD therapy, were not consistently available. For instance, findings at EP testing or a spontaneous slow VT might bias the programming of therapy zones, leaving the patients more prone to both appropriate and inappropriate therapies. However, the low incidence of inappropriate therapy indicates that device programming was relatively conservative. Thus, the obvious decrease in the rate of inappropriate therapy 4 months after ICD implantation (Figure 2B) might suggest that special attention to optimization of device programming and/or tailoring of anti-arrhythmic drug therapy took place.
In conclusion, the present data support a predictive role of EP study and slow VT for appropriate therapy, although the clinical utility of these findings remain uncertain. The burden of inappropriate therapy tends to decrease since the early days of the ICD era. Further tailoring of device programming and medical treatment, especially in patients with a history of SVT and IHD, might further reduce inappropriate therapy in future patients.
Conflict of interest: none declared.
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