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Prevention of inappropriate therapy in implantable defibrillators: A meta-analysis of clinical trials comparing single-chamber and dual-chamber arrhythmia discrimination algorithms
International Journal of Cardiology 125 (2008) 352 – 357 www.elsevier.com/locate/ijcard
Prevention of inappropriate therapy in implantable defibrillators: A meta-analysis of clinical trials comparing single-chamber and dual-chamber arrhythmia discrimination algorithms ☆ Dominic A.M.J. Theuns ⁎, Maximo Rivero-Ayerza, Erik Boersma, Luc Jordaens Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands Received 20 November 2006; received in revised form 6 February 2007; accepted 17 February 2007 Available online 18 April 2007
Abstract Introduction: A proposed benefit of dual-chamber arrhythmia discrimination is a reduction in inappropriate therapy in implantable cardioverter-defibrillators (ICDs). The aim of this meta-analysis was to establish whether dual-chamber arrhythmia discrimination algorithms reduce inappropriate device therapy. Methods and results: Public domain databases, MEDLINE, EMBASE, and Cochrane Register of Controlled Trials, were searched from 1996 to 2006. Two investigators abstracted data independently. Pooled estimates were calculated using both fixed-effects and random-effects models. We retrieved 5 prospective studies comparing dual-chamber with single-chamber arrhythmia discrimination, accumulating data on 748 patients. Pooled per-patient based analysis demonstrated that the number of patients receiving inappropriate ICD therapy was not different between single- and dual-chamber devices (odds ratio [OR] 1.23; 95% CI, 0.83 to 1.81; p = 0.31). Per-episode based analysis demonstrated a favoring benefit for dual-chamber arrhythmia discrimination (OR 0.64; 95% CI, 0.52 to 0.78; p b 0.001). A mean reduction of 1.1 inappropriately treated atrial episodes per patient was observed with dual-chamber arrhythmia discrimination (p b 0.001). Conclusions: Dual-chamber arrhythmia discrimination is associated with a reduction in the number of inappropriate treated episodes. The number of patients who experience inappropriate therapy is not reduced by dual-chamber discrimination. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Implantable cardioverter-defibrillator; Inappropriate therapy; Meta-analysis; Atrial arrhythmias; Ventricular arrhythmias
1. Introduction The implantable cardioverter-defibrillator (ICD) has evolved to standard therapy for the prevention of sudden cardiac death in patients with reduced left ventricular function [1–5]. Despite the accuracy and effectiveness in the diagnosis and treatment of ventricular tachyarrhythmias, the ICD may also result in excess morbidity [6–9]. One of ☆
DAMJ Theuns received research grants from Biotronik (Netherlands) and Guidant (Netherlands). DAMJ Theuns is a consultant for Cameron Health (USA). L Jordaens received research grants and speaker fees from Biotronik, Guidant, Medtronic, Sorin, and St Jude Medical. ⁎ Corresponding author. Erasmus MC, Department of Electrophysiology, Bd416, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: +31 10 463 3991; fax: +31 10 463 4420. E-mail address: [email protected] (D.A.M.J. Theuns). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.02.041
the factors is inappropriate therapy for atrial tachyarrhythmias or other events. To avoid inappropriate therapy, several detection enhancements were developed to discriminate between atrial and ventricular tachyarrhythmias. In singlechamber devices, discrimination is based on sudden onset, RR interval stability, and electrogram morphology. Theoretically, dual-chamber ICDs have the opportunity to improve arrhythmia discrimination over single-chamber devices by the addition of atrial information. Some studies which compare single-chamber and dual-chamber devices reported small or even non-existent advantages of dual-chamber arrhythmia discrimination [10–12]. Recent studies support an actual benefit of dual-chamber devices over singlechamber devices [13–15]. However, conclusive evidence of improved arrhythmia discrimination by dual-chamber ICDs is still lacking. We performed a systematic review and meta-
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Table 1 Summary of included studies comparing single-chamber with dual-chamber arrhythmia discrimination Study
Kuhlkamp et al.
Study design Blinding Characteristic Number of patients Mean age (years) Men (%) CAD (%) LVEF (%) Prior history of atrial tachyarrhythmias (%) Mean follow-up (months) Number with DC-ICD
Non-randomized Parallel randomized Parallel randomized Cross-over randomized Parallel randomized Not Not Yes Yes Yes 94 65 NR 65 36 19 16 months 39
Deisenhofer et al.
92 61 90 68 NR 11 7.5 months 47
PINAPPs
60 59 78 78 30 25 12 months 31
1 + 1 Trial
102 65 NR 82 37 NR 6 months a 50
Detect SVT
400 65 80 81 32 29 6 months 201
CAD = coronary artery disease; DC-ICD = dual-chamber implantable cardioverter-defibrillator; LVEF = left ventricular ejection fraction; NR = not reported. a First phase of cross-over trial.
analysis of controlled studies that compared the performance of dual-chamber and single-chamber arrhythmia discrimination, with the purpose of establishing whether dual-chamber arrhythmia discrimination algorithms reduce inappropriate device therapy. 2. Methods 2.1. Search strategy Controlled clinical trials comparing single-chamber with dual-chamber arrhythmia discrimination algorithms implemented in ICDs were identified. Public domain databases including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for all published articles from January 1996 to June 2006 related to arrhythmia discrimination by the ICD. The search was restricted to humans and English language literature. The data limits were chosen because the dual-chamber ICD was not in clinical use before 1996. Search items included: implantable cardioverterdefibrillator; clinical trials; detection; algorithms;, and arrhythmias. To identify studies reported only at scientific meetings, we performed searches of secondary sources including references of initially identified articles and proceedings from international cardiology meetings. 2.2. Eligibility and data abstraction Studies considered for inclusion met the following criteria: the design was a controlled trial comparing single-
chamber with dual-chamber arrhythmia discrimination; the outcome was an inappropriate therapy delivered for atrial tachyarrhythmias; the follow-up time was 6 months or longer. To be included, the duration of the first follow-up phase of randomized cross-over trials had to be at least 6 months. We contacted sponsors or principal investigators to obtain additional data not reported considered important for our analysis. All qualifying studies were assessed for completeness of follow-up, and objectivity of the outcome assessment. Eligibility assessment and data abstraction were both performed independently by 2 investigators (DAMJT and MRA). Data regarding ICD study design, patient characteristics (number, mean age, percent men, ejection fraction), device type, duration of follow-up, number of patients experiencing inappropriate therapy, number of misclassified episodes of atrial tachyarrhythmias, and number of inappropriately treated episodes were abstracted from each study. 2.3. Data analysis A meta-analysis of summary statistics from the individual trials was performed. For each study, data regarding inappropriate therapy for atrial tachyarrhythmias in both single-chamber and dual-chamber ICDs were used to calculate odds ratios (ORs). The ORs from each included trial were pooled using both fixed and random-effects model that used weighting based on inverse variance calculated according to DerSimonian and Laird [16]. Evidence of statistical heterogeneity among the trial-specific ORs was identified using χ2 test,
Table 2 Programmed arrhythmia discrimination parameters Study
Manufacturer
Single-chamber
Dual-chamber
Kuhlkamp et al. [10] Deisenhofer et al. [11] 1 + 1 Trial [14] PINAPPs [12] Detect SVT [15]
Guidant Biotronik, ELA, Guidant, Medtronic, St Jude Medical ELA Biotronik, Guidant St Jude Medical
Onset; stability Onset; stability Onset; stability Onset; stability Onset; stability; MD
Onset; stability; V NA; Afib threshold Onset; stability; DC algorithm Onset; stability; PARAD Onset; stability; V NA; Afib threshold; SMART Stability; MD; rate branch
DC = dual-chamber; MD = morphology discrimination.
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Table 3 Sensitivity analysis of arrhythmia discrimination studies a Study removed
RR
95% CI
Heterogeneity (p value)
Kuhlkamp et al. Deisenhofer et al. PINAPPs 1 + 1 Trial Detect SVT
0.90 0.90 0.95 1.23 0.85
0.62–1.31 0.62–1.31 0.66–1.38 0.83–1.81 0.51–1.43
0.04 0.04 0.02 0.78 0.03
a Removal of each study (shown in column 1) followed by re-analysis of the relative ratio (RR) for inappropriate therapy (column 2) and 95% confidence intervals (CI) (column 3) in the remaining studies is shown. The level of significant heterogeneity is shown in column 4.
with p ≤ 0.10 deemed statistically significant. Where no significant statistical heterogeneity was identified, the fixed effect was used preferentially as the summary measure. Sensitivity analysis was performed to assess the contribution of each study to the pooled estimate by excluding individual studies one at a time and the pooled estimate was recalculated for the remaining studies. When pooled analysis still resulted in a significant heterogeneity, the random-effects model was used. Data analysis was performed with Cochrane Review Manager for Windows (release 4.2.8, the Cochrane Collaboration, Copenhagen, Denmark). 3. Results 3.1. Search results A total of 554 references from all databases were found. A total of 458 potentially relevant reports of clinical trials with implantable defibrillators were screened, and 394 were excluded based on titles and abstracts. For detailed evaluation, full-text versions of the remaining 64 reports were retrieved. Of these, 5 reports of 5 controlled studies were included for this analysis.
discrimination. These trials were the 1 + 1 Trial [14], the Prevention of INAPPropriate Therapy study (PINAPPs) [12], the Detect SupraVentricular Tachycardia (Detect SVT) study [15], the study by Deisenhofer et al. [11], and the study by Kuhlkamp et al. [10]. The Atrial Sensing To Reduce Inappropriate Defibrillation (ASTRID) study was excluded from further analysis as patients who were randomized to the single-chamber group had purely rate-only detection and no activated single-chamber arrhythmia discrimination. In total, this meta-analysis represented a composite of 748 patients. Of these patients, 380 patients had single-chamber arrhythmia discrimination and 368 patients had dualchamber arrhythmia discrimination. Baseline characteristics and the design of the included studies are summarized in Table 1. The mean age of the study population ranged between 59 and 65 years. The majority of patients were male and presented with coronary artery disease. No differences in baseline characteristics were observed between patients randomized for single-chamber arrhythmia discrimination and those randomized for dual-chamber arrhythmia discrimination. The programmed parameters of arrhythmia discrimination are summarized in Table 2. The mean programmed cutoff for arrhythmia detection was similar for both groups (392 ± 24 ms for single-chamber devices vs 413 ± 57 ms for dual-chamber devices). The included studies were all prospective in design. The primary endpoint was inappropriate therapy in the majority of the studies [10–12]. In the 1 + 1 Trial, inappropriate therapy was part of a combined endpoint [14]. The Detect SVT study [15] used inappropriate detections as primary endpoint. This was a secondary endpoint in the PINAPPs study [12]. All studies excluded patients with permanent atrial fibrillation, sinus node dysfunction, AV block, or other indications for permanent pacemaker implantation.
3.2. Qualitative findings
3.3. Arrhythmia discrimination based on a per-patient analysis
Our search identified 6 controlled clinical studies comparing dual-chamber with single-chamber arrhythmia
When data from all studies were pooled using a fixedeffects model, dual-chamber arrhythmia discrimination was
Fig. 1. Patients who received inappropriate therapy pooled in a fixed-effects model. For each study, the number of inappropriately treated patients (n) and the number assigned (N) are shown. The point estimates of the odds ratio (OR) for individual studies are represented by squares with 95% confidence intervals (CIs) shown as bars. The midpoint of the black diamond represents the overall pooled estimate of the OR, which is 0.85. The 95% CI is represented by the horizontal tips of the black diamond. DC-ICD = dual-chamber implantable cardioverter-defibrillator; Detect SVT = Detect SupraVentricular Tachycardia trial; df = degrees of freedom; PINAPPs = Prevention of INAPPropriate Therapy study; SC-ICD = single-chamber implantable cardioverter-defibrillator.
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Fig. 2. The number of atrial tachyarrhythmias, which were inappropriately treated, pooled in a fixed-effects model. For each study, the number of inappropriately treated atrial episodes (n) and the total number of atrial episodes (N) are shown. The point estimates of the odds ratio (OR) for individual studies are represented by squares with 95% CIs shown as bars. The midpoint of the black diamond represents the overall pooled estimate of the OR, which is 0.35. The 95% CI is represented by the horizontal tips of the black diamond. Abbreviations as in Fig. 1.
not associated with a significant reduction in the number of patients who received inappropriate therapy relative to single-chamber discrimination (OR 0.97; 95% CI, 0.68 to 1.38; p = 0.85). We found statistical evidence of heterogeneity among trial-specific ORs (Chi-square 9.47; p = 0.05). To assess the impact of statistical heterogeneity on the pooled effect estimate, we performed sensitivity analysis (Table 3). After the exclusion of the 1 + 1 Trial, no evidence of statistical heterogeneity (Chi-square 1.10; p = 0.78) was present. When the remaining 4 studies were pooled, the analysis showed no significant reduction in the number of patients who received inappropriate therapy with dualchamber arrhythmia discrimination (OR 1.18; 95% CI 0.83 to 1.81; p = 0.31 Fig. 1). Among the dual-chamber group, 68 patients (21%) received inappropriate device therapy compared with 59 patients (18%) treated with singlechamber devices. 3.4. Arrhythmia discrimination based on a per-episode analysis Data on the number of inappropriate treated atrial tachyarrhythmias were reported in the 1 + 1 Trial, PINAPPs, and the Detect SVT study. When pooling data from these studies together (2207 episodes of atrial tachyarrhythmias) using a fixed-effects model, dual-chamber arrhythmia discrimination significantly reduced inappropriately treated
episodes by 36% (OR 0.64; 95% CI 0.52 to 0.78; p b 0.001) compared with single-chamber arrhythmia discrimination (Fig. 2). With dual-chamber arrhythmia discrimination, 257 episodes (20%) were inappropriately treated versus 262 episodes (27%) with single-chamber discrimination. No evidence of statistical heterogeneity was observed between the studies regarding this effect (p = 0.14). Similarly, analysis based on the mean number of inappropriate therapies per patient confirmed a benefit from dual-chamber arrhythmia discrimination (Fig. 3). A reduction of 1.1 (95% CI −1.7 to − 0.5) in the mean of inappropriately treated episodes per patient was observed (p b 0.001). 4. Discussion This meta-analysis demonstrated a significant reduction in the number of inappropriately treated atrial episodes with dual-chamber arrhythmia discrimination. Pooling controlled studies together, dual-chamber arrhythmia discrimination was associated with a 36% reduction in inappropriately treated episodes as compared with single-chamber arrhythmia discrimination. However, the number of patients who received inappropriate therapy was not affected by dual- or single-chamber arrhythmia discrimination. In the included studies, 21% of the patients in the dual-chamber group received inappropriate therapy compared with 18% of patients with single-chamber arrhythmia discrimination. It
Fig. 3. Change in the mean number of inappropriate therapies per patient from dual-chamber arrhythmia discrimination. The squares indicate the point estimate for individual studies, with 95% CIs shown as bars. The midpoint of the black diamond represents the overall pooled estimate, which is 0.91. The 95% CI is represented by the horizontal tips of the black diamond. Abbreviations as in Fig. 1.
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can be argued that some of the studies included in the pooled per-patient analysis are confounded by variables affecting the rate of inappropriate therapy. Accurate atrial sensing is a prerequisite for optimal performance of dual-chamber arrhythmia discrimination [17]. In the studies by Kuhlkamp et al. [10] and Deisenhofer et al. [11], atrial sensing errors were common (41% and 75%, respectively), while in the Detect SVT study [15] atrial sensing errors accounted only for 5% of the misclassifications. However, it must be stated that the result of the pooled per-patient analysis was not sensitive to the exclusion of these studies. Given that dual-chamber arrhythmia discrimination does not affect the number of inappropriately treated patients, the total amount of inappropriately treated atrial episodes is less for patients with devices with dual-chamber arrhythmia discrimination. The summary estimate demonstrated a 36% reduction in inappropriately treated atrial episodes with dualchamber arrhythmia discrimination. Programming detection and therapy mainly causes the rate of inappropriate therapy. In the included studies, the mean programmed cutoff for arrhythmia detection was similar for both groups. Another factor affecting the rate of inappropriate therapy is the frequency and distribution of atrial tachyarrhythmias [18]. Data used in this meta-analysis were not suited to determine which type of atrial arrhythmia encountered more difficulty of appropriate classification by arrhythmia discrimination. The overall finding of this meta-analysis reassures the evidence that dual-chamber arrhythmia discrimination increases detection specificity without jeopardizing sensitivity. On the other hand, the proportion of patients with inappropriate therapy is still approximately 20%, despite sophisticated arrhythmia discrimination. This finding still raises the question of which device to select for the patient with an indication for ICD therapy. 4.1. Device selection and clinical practice The indication for ICD therapy has expanded on the basis of the results of the second Multicenter Automatic Defibrillator Implantation Trial (MADIT II) [4] and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) [5]. Although there are clear guidelines for the indication of ICD therapy [19], device selection is still a matter of debate. The most important factors to be considered in device and mode selection remain the complications of the additional atrial lead, and the negative effect of ventricular pacing [20–23]. The Dual Chamber and VVI Implantable Defibrillator (DAVID) trial demonstrated that active right ventricular pacing in dual-chamber ICDs resulted in an exacerbation of heart failure [20]. In the Mode Selection Trial (MOST) study [22], patients programmed to DDD mode, a high percentage of ventricular pacing was associated with an increased risk of heart failure hospitalization. These results have led to the recommendation, in the absence of a pacing indication, to implant a singlechamber device [19].
The indication for implantation of a dual-chamber ICD might be the likelihood of inappropriate therapy in patients with a history of atrial tachyarrhythmias, which is deemed appropriate by ACC/AHA/NASPE guidelines [19]. Having shown an important reduction in the amount of inappropriately treated atrial episodes by dual-chamber arrhythmia discrimination and considering that this reduction will improve quality of life for the ICD patient, the question whether each ICD patient should receive a dual-chamber device gains relevance. However, ICD technology is still evolving. As device technology has improved, morphologybased algorithms for arrhythmia discrimination have been implemented in both single- and dual-chamber ICDs. Despite the improved algorithms, inappropriate ICD therapy still remains a clinical challenge. 4.2. Study limitations Our meta-analysis was dominated by one large series of patients [15], however there was no significant heterogeneity between this study and the smaller studies. Furthermore, each included study was weighted based on inverse variance according to DerSimonian and Laird [16]. Another possible limitation of this analysis is the influence of publication bias. This type of bias can never be completely avoided, although extensive searching may minimize it. Despite the fact that funnel plots were used, its usefulness is limited due to the small number of included studies. Another possible limitation might be the advancing ICD technology. Current devices can apply morphology discrimination in conjunction with interval-based arrhythmia discrimination algorithms. However, the interval-based algorithms, which were included in this analysis, will still be available in devices, irrespective of morphology-based discrimination. Another limitation is the absence of the type of atrial tachyarrhythmia, which is presented to the arrhythmia discrimination algorithm. This may affect the performance of the applied algorithms. Given the nature of trial reports we examined, we were unable to analyze the limitations of the applied arrhythmia discrimination algorithms for specific atrial tachyarrhythmias. Such an analysis can be performed only in a meta-analysis with the use of individual-patient data. 5. Conclusion This meta-analysis shows that dual-chamber arrhythmia discrimination significantly reduces the number of inappropriately treated atrial episodes compared to single-chamber devices. However, the amount of patients receiving inappropriate therapy was similar between groups. Acknowledgement The authors thank Dr P.A. Friedman and Dr M. Glikson for sharing unpublished results of the Detect SVT Study. We
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thank Dr D. Bänsch and mr. R. Ocklenburg for giving additional data of the 1 + 1 Trial. References [1] Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996;335:1933–40. [2] A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med 1997;337:1576–83. [3] Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999;341:1882–90. [4] Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–83. [5] Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. [6] Nunain SO, Roelke M, Trouton T, et al. Limitations and late complications of third-generation automatic cardioverter-defibrillators. Circulation 1995;91:2204–13. [7] Rosenqvist M, Beyer T, Block M, den Dulk K, Lindemans F, Minten J. Adverse events with transvenous implantable cardioverter-defibrillators: a prospective multicenter study. European 7219 Jewel ICD investigators. Circulation 1998;98:663–70. [8] Gradaus R, Block M, Brachmann J, et al. Mortality, morbidity, and complications in 3344 patients with implantable cardioverter defibrillators: results from the German ICD Registry EURID. Pacing Clin Electrophysiol 2003;26:1511–8. [9] Alter P, Waldhans S, Plachta E, Moosdorf R, Grimm W. Complications of implantable cardioverter defibrillator therapy in 440 consecutive patients. Pacing Clin Electrophysiol 2005;28:926–32. [10] Kuhlkamp V, Dornberger V, Mewis C, Suchalla R, Bosch RF, Seipel L. Clinical experience with the new detection algorithms for atrial fibrillation of a defibrillator with dual chamber sensing and pacing. J Cardiovasc Electrophysiol 1999;10:905–15. [11] Deisenhofer I, Kolb C, Ndrepepa G, et al. Do current dual chamber cardioverter defibrillators have advantages over conventional single chamber cardioverter defibrillators in reducing inappropriate therapies? A randomized, prospective study. J Cardiovasc Electrophysiol 2001;12:134–42.
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[12] Theuns DA, Klootwijk AP, Goedhart DM, Jordaens LJ. Prevention of inappropriate therapy in implantable cardioverter-defibrillators: results of a prospective, randomized study of tachyarrhythmia detection algorithms. J Am Coll Cardiol 2004;44:2362–7. [13] Dorian P, Philippon F, Thibault B, et al. Randomized controlled study of detection enhancements versus rate-only detection to prevent inappropriate therapy in a dual-chamber implantable cardioverterdefibrillator. Heart Rhythm 2004;1:540–7. [14] Bansch D, Steffgen F, Gronefeld G, et al. The 1 + 1 Trial. A prospective trial of a dual- versus a single-chamber implantable defibrillator in patients with slow ventricular tachycardias. Circulation 2004;110: 1022–9. [15] Friedman PA, McClelland RL, Bamlet WR, et al. Dual-chamber versus single-chamber detection enhancements for implantable defibrillator rhythm diagnosis: the Detect SupraVentricular Tachycardia study. Circulation 2006;113:2871–9. [16] DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88. [17] Glikson M, Swerdlow CD, Gurevitz OT, et al. Optimal combination of discriminators for differentiating ventricular from supraventricular tachycardia by dual-chamber defibrillators. J Cardiovasc Electrophysiol 2005;16:732–9. [18] Wilkoff BL, Kuhlkamp V, Volosin K, et al. Critical analysis of dualchamber implantable cardioverter-defibrillator arrhythmia detection: results and technical considerations. Circulation 2001;103:381–6. [19] Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). Circulation 2002;106:2145–61. [20] Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002;288:3115–23. [21] Nielsen JC, Kristensen L, Andersen HR, Mortensen PT, Pedersen OL, Pedersen AK. A randomized comparison of atrial and dual-chamber pacing in 177 consecutive patients with sick sinus syndrome: echocardiographic and clinical outcome. J Am Coll Cardiol 2003;42: 614–23. [22] Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003;107:2932–7. [23] Steinberg JS, Fischer A, Wang P, et al. The clinical implications of cumulative right ventricular pacing in the multicenter automatic defibrillator trial II. J Cardiovasc Electrophysiol 2005;16:359–65.
Prevention of inappropriate therapy in implantable defibrillators: A meta-analysis of clinical trials comparing single-chamber and dual-chamber arrhythmia discrimination algorithms ☆ Dominic A.M.J. Theuns ⁎, Maximo Rivero-Ayerza, Erik Boersma, Luc Jordaens Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands Received 20 November 2006; received in revised form 6 February 2007; accepted 17 February 2007 Available online 18 April 2007
Abstract Introduction: A proposed benefit of dual-chamber arrhythmia discrimination is a reduction in inappropriate therapy in implantable cardioverter-defibrillators (ICDs). The aim of this meta-analysis was to establish whether dual-chamber arrhythmia discrimination algorithms reduce inappropriate device therapy. Methods and results: Public domain databases, MEDLINE, EMBASE, and Cochrane Register of Controlled Trials, were searched from 1996 to 2006. Two investigators abstracted data independently. Pooled estimates were calculated using both fixed-effects and random-effects models. We retrieved 5 prospective studies comparing dual-chamber with single-chamber arrhythmia discrimination, accumulating data on 748 patients. Pooled per-patient based analysis demonstrated that the number of patients receiving inappropriate ICD therapy was not different between single- and dual-chamber devices (odds ratio [OR] 1.23; 95% CI, 0.83 to 1.81; p = 0.31). Per-episode based analysis demonstrated a favoring benefit for dual-chamber arrhythmia discrimination (OR 0.64; 95% CI, 0.52 to 0.78; p b 0.001). A mean reduction of 1.1 inappropriately treated atrial episodes per patient was observed with dual-chamber arrhythmia discrimination (p b 0.001). Conclusions: Dual-chamber arrhythmia discrimination is associated with a reduction in the number of inappropriate treated episodes. The number of patients who experience inappropriate therapy is not reduced by dual-chamber discrimination. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Implantable cardioverter-defibrillator; Inappropriate therapy; Meta-analysis; Atrial arrhythmias; Ventricular arrhythmias
1. Introduction The implantable cardioverter-defibrillator (ICD) has evolved to standard therapy for the prevention of sudden cardiac death in patients with reduced left ventricular function [1–5]. Despite the accuracy and effectiveness in the diagnosis and treatment of ventricular tachyarrhythmias, the ICD may also result in excess morbidity [6–9]. One of ☆
DAMJ Theuns received research grants from Biotronik (Netherlands) and Guidant (Netherlands). DAMJ Theuns is a consultant for Cameron Health (USA). L Jordaens received research grants and speaker fees from Biotronik, Guidant, Medtronic, Sorin, and St Jude Medical. ⁎ Corresponding author. Erasmus MC, Department of Electrophysiology, Bd416, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: +31 10 463 3991; fax: +31 10 463 4420. E-mail address: [email protected] (D.A.M.J. Theuns). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.02.041
the factors is inappropriate therapy for atrial tachyarrhythmias or other events. To avoid inappropriate therapy, several detection enhancements were developed to discriminate between atrial and ventricular tachyarrhythmias. In singlechamber devices, discrimination is based on sudden onset, RR interval stability, and electrogram morphology. Theoretically, dual-chamber ICDs have the opportunity to improve arrhythmia discrimination over single-chamber devices by the addition of atrial information. Some studies which compare single-chamber and dual-chamber devices reported small or even non-existent advantages of dual-chamber arrhythmia discrimination [10–12]. Recent studies support an actual benefit of dual-chamber devices over singlechamber devices [13–15]. However, conclusive evidence of improved arrhythmia discrimination by dual-chamber ICDs is still lacking. We performed a systematic review and meta-
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353
Table 1 Summary of included studies comparing single-chamber with dual-chamber arrhythmia discrimination Study
Kuhlkamp et al.
Study design Blinding Characteristic Number of patients Mean age (years) Men (%) CAD (%) LVEF (%) Prior history of atrial tachyarrhythmias (%) Mean follow-up (months) Number with DC-ICD
Non-randomized Parallel randomized Parallel randomized Cross-over randomized Parallel randomized Not Not Yes Yes Yes 94 65 NR 65 36 19 16 months 39
Deisenhofer et al.
92 61 90 68 NR 11 7.5 months 47
PINAPPs
60 59 78 78 30 25 12 months 31
1 + 1 Trial
102 65 NR 82 37 NR 6 months a 50
Detect SVT
400 65 80 81 32 29 6 months 201
CAD = coronary artery disease; DC-ICD = dual-chamber implantable cardioverter-defibrillator; LVEF = left ventricular ejection fraction; NR = not reported. a First phase of cross-over trial.
analysis of controlled studies that compared the performance of dual-chamber and single-chamber arrhythmia discrimination, with the purpose of establishing whether dual-chamber arrhythmia discrimination algorithms reduce inappropriate device therapy. 2. Methods 2.1. Search strategy Controlled clinical trials comparing single-chamber with dual-chamber arrhythmia discrimination algorithms implemented in ICDs were identified. Public domain databases including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for all published articles from January 1996 to June 2006 related to arrhythmia discrimination by the ICD. The search was restricted to humans and English language literature. The data limits were chosen because the dual-chamber ICD was not in clinical use before 1996. Search items included: implantable cardioverterdefibrillator; clinical trials; detection; algorithms;, and arrhythmias. To identify studies reported only at scientific meetings, we performed searches of secondary sources including references of initially identified articles and proceedings from international cardiology meetings. 2.2. Eligibility and data abstraction Studies considered for inclusion met the following criteria: the design was a controlled trial comparing single-
chamber with dual-chamber arrhythmia discrimination; the outcome was an inappropriate therapy delivered for atrial tachyarrhythmias; the follow-up time was 6 months or longer. To be included, the duration of the first follow-up phase of randomized cross-over trials had to be at least 6 months. We contacted sponsors or principal investigators to obtain additional data not reported considered important for our analysis. All qualifying studies were assessed for completeness of follow-up, and objectivity of the outcome assessment. Eligibility assessment and data abstraction were both performed independently by 2 investigators (DAMJT and MRA). Data regarding ICD study design, patient characteristics (number, mean age, percent men, ejection fraction), device type, duration of follow-up, number of patients experiencing inappropriate therapy, number of misclassified episodes of atrial tachyarrhythmias, and number of inappropriately treated episodes were abstracted from each study. 2.3. Data analysis A meta-analysis of summary statistics from the individual trials was performed. For each study, data regarding inappropriate therapy for atrial tachyarrhythmias in both single-chamber and dual-chamber ICDs were used to calculate odds ratios (ORs). The ORs from each included trial were pooled using both fixed and random-effects model that used weighting based on inverse variance calculated according to DerSimonian and Laird [16]. Evidence of statistical heterogeneity among the trial-specific ORs was identified using χ2 test,
Table 2 Programmed arrhythmia discrimination parameters Study
Manufacturer
Single-chamber
Dual-chamber
Kuhlkamp et al. [10] Deisenhofer et al. [11] 1 + 1 Trial [14] PINAPPs [12] Detect SVT [15]
Guidant Biotronik, ELA, Guidant, Medtronic, St Jude Medical ELA Biotronik, Guidant St Jude Medical
Onset; stability Onset; stability Onset; stability Onset; stability Onset; stability; MD
Onset; stability; V NA; Afib threshold Onset; stability; DC algorithm Onset; stability; PARAD Onset; stability; V NA; Afib threshold; SMART Stability; MD; rate branch
DC = dual-chamber; MD = morphology discrimination.
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Table 3 Sensitivity analysis of arrhythmia discrimination studies a Study removed
RR
95% CI
Heterogeneity (p value)
Kuhlkamp et al. Deisenhofer et al. PINAPPs 1 + 1 Trial Detect SVT
0.90 0.90 0.95 1.23 0.85
0.62–1.31 0.62–1.31 0.66–1.38 0.83–1.81 0.51–1.43
0.04 0.04 0.02 0.78 0.03
a Removal of each study (shown in column 1) followed by re-analysis of the relative ratio (RR) for inappropriate therapy (column 2) and 95% confidence intervals (CI) (column 3) in the remaining studies is shown. The level of significant heterogeneity is shown in column 4.
with p ≤ 0.10 deemed statistically significant. Where no significant statistical heterogeneity was identified, the fixed effect was used preferentially as the summary measure. Sensitivity analysis was performed to assess the contribution of each study to the pooled estimate by excluding individual studies one at a time and the pooled estimate was recalculated for the remaining studies. When pooled analysis still resulted in a significant heterogeneity, the random-effects model was used. Data analysis was performed with Cochrane Review Manager for Windows (release 4.2.8, the Cochrane Collaboration, Copenhagen, Denmark). 3. Results 3.1. Search results A total of 554 references from all databases were found. A total of 458 potentially relevant reports of clinical trials with implantable defibrillators were screened, and 394 were excluded based on titles and abstracts. For detailed evaluation, full-text versions of the remaining 64 reports were retrieved. Of these, 5 reports of 5 controlled studies were included for this analysis.
discrimination. These trials were the 1 + 1 Trial [14], the Prevention of INAPPropriate Therapy study (PINAPPs) [12], the Detect SupraVentricular Tachycardia (Detect SVT) study [15], the study by Deisenhofer et al. [11], and the study by Kuhlkamp et al. [10]. The Atrial Sensing To Reduce Inappropriate Defibrillation (ASTRID) study was excluded from further analysis as patients who were randomized to the single-chamber group had purely rate-only detection and no activated single-chamber arrhythmia discrimination. In total, this meta-analysis represented a composite of 748 patients. Of these patients, 380 patients had single-chamber arrhythmia discrimination and 368 patients had dualchamber arrhythmia discrimination. Baseline characteristics and the design of the included studies are summarized in Table 1. The mean age of the study population ranged between 59 and 65 years. The majority of patients were male and presented with coronary artery disease. No differences in baseline characteristics were observed between patients randomized for single-chamber arrhythmia discrimination and those randomized for dual-chamber arrhythmia discrimination. The programmed parameters of arrhythmia discrimination are summarized in Table 2. The mean programmed cutoff for arrhythmia detection was similar for both groups (392 ± 24 ms for single-chamber devices vs 413 ± 57 ms for dual-chamber devices). The included studies were all prospective in design. The primary endpoint was inappropriate therapy in the majority of the studies [10–12]. In the 1 + 1 Trial, inappropriate therapy was part of a combined endpoint [14]. The Detect SVT study [15] used inappropriate detections as primary endpoint. This was a secondary endpoint in the PINAPPs study [12]. All studies excluded patients with permanent atrial fibrillation, sinus node dysfunction, AV block, or other indications for permanent pacemaker implantation.
3.2. Qualitative findings
3.3. Arrhythmia discrimination based on a per-patient analysis
Our search identified 6 controlled clinical studies comparing dual-chamber with single-chamber arrhythmia
When data from all studies were pooled using a fixedeffects model, dual-chamber arrhythmia discrimination was
Fig. 1. Patients who received inappropriate therapy pooled in a fixed-effects model. For each study, the number of inappropriately treated patients (n) and the number assigned (N) are shown. The point estimates of the odds ratio (OR) for individual studies are represented by squares with 95% confidence intervals (CIs) shown as bars. The midpoint of the black diamond represents the overall pooled estimate of the OR, which is 0.85. The 95% CI is represented by the horizontal tips of the black diamond. DC-ICD = dual-chamber implantable cardioverter-defibrillator; Detect SVT = Detect SupraVentricular Tachycardia trial; df = degrees of freedom; PINAPPs = Prevention of INAPPropriate Therapy study; SC-ICD = single-chamber implantable cardioverter-defibrillator.
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Fig. 2. The number of atrial tachyarrhythmias, which were inappropriately treated, pooled in a fixed-effects model. For each study, the number of inappropriately treated atrial episodes (n) and the total number of atrial episodes (N) are shown. The point estimates of the odds ratio (OR) for individual studies are represented by squares with 95% CIs shown as bars. The midpoint of the black diamond represents the overall pooled estimate of the OR, which is 0.35. The 95% CI is represented by the horizontal tips of the black diamond. Abbreviations as in Fig. 1.
not associated with a significant reduction in the number of patients who received inappropriate therapy relative to single-chamber discrimination (OR 0.97; 95% CI, 0.68 to 1.38; p = 0.85). We found statistical evidence of heterogeneity among trial-specific ORs (Chi-square 9.47; p = 0.05). To assess the impact of statistical heterogeneity on the pooled effect estimate, we performed sensitivity analysis (Table 3). After the exclusion of the 1 + 1 Trial, no evidence of statistical heterogeneity (Chi-square 1.10; p = 0.78) was present. When the remaining 4 studies were pooled, the analysis showed no significant reduction in the number of patients who received inappropriate therapy with dualchamber arrhythmia discrimination (OR 1.18; 95% CI 0.83 to 1.81; p = 0.31 Fig. 1). Among the dual-chamber group, 68 patients (21%) received inappropriate device therapy compared with 59 patients (18%) treated with singlechamber devices. 3.4. Arrhythmia discrimination based on a per-episode analysis Data on the number of inappropriate treated atrial tachyarrhythmias were reported in the 1 + 1 Trial, PINAPPs, and the Detect SVT study. When pooling data from these studies together (2207 episodes of atrial tachyarrhythmias) using a fixed-effects model, dual-chamber arrhythmia discrimination significantly reduced inappropriately treated
episodes by 36% (OR 0.64; 95% CI 0.52 to 0.78; p b 0.001) compared with single-chamber arrhythmia discrimination (Fig. 2). With dual-chamber arrhythmia discrimination, 257 episodes (20%) were inappropriately treated versus 262 episodes (27%) with single-chamber discrimination. No evidence of statistical heterogeneity was observed between the studies regarding this effect (p = 0.14). Similarly, analysis based on the mean number of inappropriate therapies per patient confirmed a benefit from dual-chamber arrhythmia discrimination (Fig. 3). A reduction of 1.1 (95% CI −1.7 to − 0.5) in the mean of inappropriately treated episodes per patient was observed (p b 0.001). 4. Discussion This meta-analysis demonstrated a significant reduction in the number of inappropriately treated atrial episodes with dual-chamber arrhythmia discrimination. Pooling controlled studies together, dual-chamber arrhythmia discrimination was associated with a 36% reduction in inappropriately treated episodes as compared with single-chamber arrhythmia discrimination. However, the number of patients who received inappropriate therapy was not affected by dual- or single-chamber arrhythmia discrimination. In the included studies, 21% of the patients in the dual-chamber group received inappropriate therapy compared with 18% of patients with single-chamber arrhythmia discrimination. It
Fig. 3. Change in the mean number of inappropriate therapies per patient from dual-chamber arrhythmia discrimination. The squares indicate the point estimate for individual studies, with 95% CIs shown as bars. The midpoint of the black diamond represents the overall pooled estimate, which is 0.91. The 95% CI is represented by the horizontal tips of the black diamond. Abbreviations as in Fig. 1.
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can be argued that some of the studies included in the pooled per-patient analysis are confounded by variables affecting the rate of inappropriate therapy. Accurate atrial sensing is a prerequisite for optimal performance of dual-chamber arrhythmia discrimination [17]. In the studies by Kuhlkamp et al. [10] and Deisenhofer et al. [11], atrial sensing errors were common (41% and 75%, respectively), while in the Detect SVT study [15] atrial sensing errors accounted only for 5% of the misclassifications. However, it must be stated that the result of the pooled per-patient analysis was not sensitive to the exclusion of these studies. Given that dual-chamber arrhythmia discrimination does not affect the number of inappropriately treated patients, the total amount of inappropriately treated atrial episodes is less for patients with devices with dual-chamber arrhythmia discrimination. The summary estimate demonstrated a 36% reduction in inappropriately treated atrial episodes with dualchamber arrhythmia discrimination. Programming detection and therapy mainly causes the rate of inappropriate therapy. In the included studies, the mean programmed cutoff for arrhythmia detection was similar for both groups. Another factor affecting the rate of inappropriate therapy is the frequency and distribution of atrial tachyarrhythmias [18]. Data used in this meta-analysis were not suited to determine which type of atrial arrhythmia encountered more difficulty of appropriate classification by arrhythmia discrimination. The overall finding of this meta-analysis reassures the evidence that dual-chamber arrhythmia discrimination increases detection specificity without jeopardizing sensitivity. On the other hand, the proportion of patients with inappropriate therapy is still approximately 20%, despite sophisticated arrhythmia discrimination. This finding still raises the question of which device to select for the patient with an indication for ICD therapy. 4.1. Device selection and clinical practice The indication for ICD therapy has expanded on the basis of the results of the second Multicenter Automatic Defibrillator Implantation Trial (MADIT II) [4] and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) [5]. Although there are clear guidelines for the indication of ICD therapy [19], device selection is still a matter of debate. The most important factors to be considered in device and mode selection remain the complications of the additional atrial lead, and the negative effect of ventricular pacing [20–23]. The Dual Chamber and VVI Implantable Defibrillator (DAVID) trial demonstrated that active right ventricular pacing in dual-chamber ICDs resulted in an exacerbation of heart failure [20]. In the Mode Selection Trial (MOST) study [22], patients programmed to DDD mode, a high percentage of ventricular pacing was associated with an increased risk of heart failure hospitalization. These results have led to the recommendation, in the absence of a pacing indication, to implant a singlechamber device [19].
The indication for implantation of a dual-chamber ICD might be the likelihood of inappropriate therapy in patients with a history of atrial tachyarrhythmias, which is deemed appropriate by ACC/AHA/NASPE guidelines [19]. Having shown an important reduction in the amount of inappropriately treated atrial episodes by dual-chamber arrhythmia discrimination and considering that this reduction will improve quality of life for the ICD patient, the question whether each ICD patient should receive a dual-chamber device gains relevance. However, ICD technology is still evolving. As device technology has improved, morphologybased algorithms for arrhythmia discrimination have been implemented in both single- and dual-chamber ICDs. Despite the improved algorithms, inappropriate ICD therapy still remains a clinical challenge. 4.2. Study limitations Our meta-analysis was dominated by one large series of patients [15], however there was no significant heterogeneity between this study and the smaller studies. Furthermore, each included study was weighted based on inverse variance according to DerSimonian and Laird [16]. Another possible limitation of this analysis is the influence of publication bias. This type of bias can never be completely avoided, although extensive searching may minimize it. Despite the fact that funnel plots were used, its usefulness is limited due to the small number of included studies. Another possible limitation might be the advancing ICD technology. Current devices can apply morphology discrimination in conjunction with interval-based arrhythmia discrimination algorithms. However, the interval-based algorithms, which were included in this analysis, will still be available in devices, irrespective of morphology-based discrimination. Another limitation is the absence of the type of atrial tachyarrhythmia, which is presented to the arrhythmia discrimination algorithm. This may affect the performance of the applied algorithms. Given the nature of trial reports we examined, we were unable to analyze the limitations of the applied arrhythmia discrimination algorithms for specific atrial tachyarrhythmias. Such an analysis can be performed only in a meta-analysis with the use of individual-patient data. 5. Conclusion This meta-analysis shows that dual-chamber arrhythmia discrimination significantly reduces the number of inappropriately treated atrial episodes compared to single-chamber devices. However, the amount of patients receiving inappropriate therapy was similar between groups. Acknowledgement The authors thank Dr P.A. Friedman and Dr M. Glikson for sharing unpublished results of the Detect SVT Study. We
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