Author + information
- Received March 27, 2014
- Revision received May 14, 2014
- Accepted May 17, 2014
- Published online December 1, 2014.
- Christof Kolb, MD, PhD∗∗ (, )
- Marcio Sturmer, MD†,
- Peter Sick, MD‡,
- Sebastian Reif, MD§,
- Jean Marc Davy, MD, PhD‖,
- Giulio Molon, MD¶,
- Jörg Otto Schwab, MD, PhD#,
- Giuseppe Mantovani, MD∗∗,
- Dan Dan, MD††,
- Carsten Lennerz, MD∗,
- Alberto Borri-Brunetto, MSc‡‡ and
- Dominique Babuty, MD, PhD§§
- ∗Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen, Faculty of Medicine, Technische Universität München, Munich, Germany
- †Sacre-Coeur Hospital, Université de Montréal, Montréal, Québec, Canada
- ‡Hospital of the Order of St. John of God, Prüfeninger Straße Clinic, Regensburg, Germany
- §Klinik für Kardiologie und Internistische Intensivmedizin, Städtisches Klinikum München-Bogenhausen, München, Germany
- ‖Département de Cardiologie et Maladies Vasculaires, Hôpital Arnaud de Villeneuve–CHU de Montpellier, Montpellier, France
- ¶Cardiology Department, Ospedale Sacro Cuore, Negrar, Italy
- #Department of Medicine, Cardiology, University Hospital, Bonn, Germany
- ∗∗Ospedale Civile, Desio, Italy
- ††Piedmont Heart Institute, Atlanta, Georgia
- ‡‡Sorin CRM SAS, Saluggia, Italy
- §§University Hospital, Tours, France
- ↵∗Reprint requests and correspondence:
Priv.-Doz. Dr. med. Christof Kolb, Klinik für Herz- und Kreislauferkrankungen, Abteilung für Elektrophysiologie, Deutsches Herzzentrum München, Lazarettstraße 36, 80636 München, Germany.
Objectives The OPTION (Optimal Anti-Tachycardia Therapy in Implantable Cardioverter-Defibrillator Patients Without Pacing Indications) trial sought to compare long-term rates of inappropriate shocks, mortality, and morbidity between dual-chamber and single-chamber settings in implantable cardioverter-defibrillators (ICDs) patients.
Background The use of dual-chamber ICDs potentially allows better discrimination of supraventricular arrhythmias and thereby reduces inappropriate shocks. However, it may lead to detrimental ventricular pacing.
Methods This prospective multicenter, single-blinded trial enrolled 462 patients with de novo primary or secondary prevention indications for ICD placement and with left ventricular ejection fractions ≤40% despite optimal tolerated pharmacotherapy. All patients received atrial leads and dual-chamber defibrillators that were randomized to be programmed either with dual-chamber or single-chamber settings. In the dual-chamber setting arm, the PARAD+ algorithm, which differentiates supraventricular from ventricular arrhythmias, and SafeR mode, to minimize ventricular pacing, were activated. In the single-chamber setting arm, the acceleration, stability, and long cycle search discrimination criteria were activated, and pacing was set to VVI 40 beats/min. Ventricular tachycardia detection was required at rates between 170 and 200 beats/min, and ventricular fibrillation detection was activated above 200 beats/min.
Results During a follow-up period of 27 months, the time to the first inappropriate shock was significantly longer in the dual-chamber setting arm (p = 0.012, log-rank test), and 4.3% of patients in the dual-chamber setting group compared with 10.3% in the single-chamber setting group experienced inappropriate shocks (p = 0.015). Rates of all-cause death or cardiovascular hospitalization were 20% for the dual-chamber setting group and 22.4% for the single-chamber setting group and satisfied the pre-defined margin for equivalence (p < 0.001).
Conclusions Therapy with dual-chamber settings for ICD discrimination combined with algorithms for minimizing ventricular pacing was associated with reduced risk for inappropriate shock compared with single-chamber settings, without increases in mortality and morbidity. (Optimal Anti-Tachycardia Therapy in Implantable Cardioverter-Defibrillator [ICD] Patients Without Pacing Indications [OPTION]; NCT00729703)
Implantable cardioverter-defibrillator (ICD) therapy prevents sudden cardiac death and prolongs survival in patients who undergo implantation for primary and secondary prevention of sudden cardiac death (1–4). The benefits of the therapy and the expansion of indications for ICDs since their introduction have led to a significant increase in the number of ICD recipients and in lives saved by ICD therapy (5).
However, inappropriate therapies, most commonly caused by supraventricular tachyarrhythmias (SVTs), remain a significant adverse effect of ICD therapy, affecting up to 40% of patients during long-term follow-up (6–10). Besides the pain and discomfort caused by inappropriate shocks, they are also associated with anxiety, depression, impaired quality of life, proarrhythmia, low treatment satisfaction, and possibly mortality (11–13).
Important efforts have been made in defining optimal programming methods for accurate rhythm detection and minimizing inappropriate ICD interventions. However, so far, there is no consensus on the most appropriate programming methodology (14–17). Likewise, the question of whether dual-chamber ICD therapy with dual-chamber settings can reduce the risk for inappropriate shocks in comparison with single-chamber therapy with single-chamber settings remains unanswered. Several investigators have reported a trend toward fewer inappropriate shocks with dual-chamber setting (18), whereas others have reported no differences between the therapies (19–22). Moreover, additional factors should be considered when choosing single- versus dual-chamber ICD settings, including the risk for complications (23), as well as the detrimental effect of unnecessary ventricular pacing (24). Therefore, the potential superiority of dual-chamber over single-chamber ICD settings in terms of inappropriate shocks can be assessed only in the light of optimal tachyarrhythmia discrimination algorithms combined with optimized bradycardia parameters for minimized ventricular pacing (25).
The OPTION (Optimal Anti-Tachycardia Therapy in Implantable Cardioverter-Defibrillator Patients Without Pacing Indications) trial was designed to compare long-term outcomes in ICD recipients with dual-chamber settings with those in patients with single-chamber settings. All patients received atrial leads and dual-chamber devices, the only difference being the pacing mode setting. The programming in both groups was optimized to minimize ventricular pacing and to reduce inappropriate shocks using discrimination algorithms along with standardized antitachycardia pacing (ATP) therapies.
The rationale and design of OPTION have been published previously (25). The OPTION trial is a prospective, randomized, multicenter, 2-arm, single-blinded, parallel-group trial. A total of 462 patients were enrolled at 54 centers in Europe and North America between June 2006 and April 2009. Eligible patients were recipients of de novo ICDs for primary or secondary prevention of sudden cardiac death with left ventricular ejection fractions ≤40% despite optimal tolerated heart failure therapy. Major exclusion criteria were an indication for permanent pacemaker or resynchronization therapy; the diagnosis of hypertrophic obstructive cardiomyopathy or acute myocarditis; history of percutaneous coronary intervention, troponin-positive acute coronary syndrome, myocardial infarction, or coronary artery bypass grafting within the previous month; and permanent atrial tachyarrhythmias or cardioversion of these within the previous month.
The investigational plan was approved by the institutional review board or ethics committee at each study center. All patients provided written informed consent. Before implantation, patients were randomized to either standard single-chamber settings or dual-chamber settings, as described later, according to a 4-block permutation randomization list. Follow-up visits were scheduled at 3 months after implantation and at 6-month intervals thereafter up to 27 months.
The primary endpoint of this study was 2-fold: the time to first occurrence of inappropriate ICD shock and the occurrence of all-cause death or cardiovascular hospitalization (including hospitalization for congestive heart failure, symptomatic atrial fibrillation (AF), cardioversion of AF, stroke, and undetected or untreated ventricular tachycardia).
Secondary endpoints were rates of appropriate and inappropriate ICD shocks, all-cause mortality, cardiovascular mortality, hospitalization for cardiovascular reasons, and mean and median cumulative percent of ventricular pacing and system-related complications.
Devices and Programming
All patients received dual-chamber ICDs (OVATIO DR model 6550, Sorin Group, Milan, Italy). In the dual-chamber setting arm, the discrimination algorithm PARAD+ was activated. This algorithm differentiates supraventricular from ventricular arrhythmias on the basis of ventricular rate stability, rate-onset analysis, atrioventricular association analysis, long cycle search, and determination of the chamber of origin in the case of 1:1 tachycardia (26–29). In the single-chamber setting arm, the acceleration (onset), stability, and long cycle search discrimination criteria were activated. Ventricular tachycardia detection was required at rates between 170 and 200 beats/min (353 to 300 ms) with the delivery of 2 pre-defined sequences of ATP followed by shocks. Ventricular fibrillation detection was activated above 200 beats/min, with shock therapy programmed on being preceded by 1 ATP for arrhythmias at heart rates between 200 and 240 beats/min (300 to 250 ms). A slow ventricular tachycardia zone was set at 120 beats/min in both groups. This zone (500 to 353 ms) was used as a monitor zone for the single-chamber setting group, while ATP with no shock was recommended for the dual-chamber setting group (24).
In the dual-chamber setting group, SafeR minimized ventricular pacing mode (30) was activated with a basic rate of 60 beats/min. In the single-chamber setting arm, a ventricular backup pacing of VVI 40 beats/min was used.
Data Collection and Evaluation
Data were collected by paper case report forms and electronic files derived from Holter devices at each follow-up visit. All data considered for the present analysis were monitored. Adverse events and hospitalizations were documented on specific case report forms and were independently reviewed by a data safety monitoring board consisting of 4 electrophysiologists and heart failure experts responsible for evaluating, validating, and classifying all adverse events. In addition, a blinded events committee of 5 experts validated the appropriateness of shocks on the basis of the analysis of the electrographic recording ascertained from the device’s memory. The assessment was performed blinded to treatment arm, on the basis of the same information regarding atrioventricular association analysis (also available in the single-chamber setting group), electrographic configuration, arrhythmia onset, and regularity.
As the study had 2 primary endpoints, the significance level for each primary endpoint was set at 0.025. For all other tests, the significance level was set at 0.05. Different pre-specified analyses were applied to assess the primary endpoint: Kaplan-Meier analysis for the time of first occurrence of inappropriate shock with a log-rank test to validate the difference and a Student t test for equivalence testing after normal approximation to assess whether the difference in the occurrence of specific cardiovascular events or death between randomization groups was less than 17%. Time-to-event and survival curves were estimated by using the Kaplan-Meier approach and are displayed as descriptive graph (11).
For other dichotomous variables, the chi-square test and the Fisher exact test were used as appropriate. Continuous variable were compared using the Student t test when normal distribution was confirmed; otherwise the Wilcoxon rank test was used.
To identify potential predictors of inappropriate shocks, univariate and multivariate (using logistic model) analyses were carried out. Only predictors with p values <0.10 (on univariate analysis) were added in the multivariate model.
All endpoint analyses were carried out on the basis of the intention-to-treat principle. Patients with missing outcome data were considered in the analysis as follows: censored at the time of last follow-up for survival analysis or assuming none experienced the outcome of interest for dichotomous variables.
The statistical software used for the analyses was SAS version 9.2 (SAS Institute Inc., Cary, North Carolina).
A total of 462 patients were included in the OPTION trial, and 453 received study devices. The dual-chamber setting group consisted of 230 patients, and 223 patients were assigned to the single-chamber setting group (Figure 1). The clinical characteristics of the 2 groups at baseline are given in Table 1.
The average follow-up duration was 23.4 ± 7.9 months. During the trial, a total of 47 patients crossed over from one treatment group to the other: 39 crossed over from the single-chamber setting group to the dual-chamber setting group and 8 from the dual-chamber setting group to the single-chamber setting group. Known reasons for crossover from the single-chamber setting to dual-chamber setting arm included the occurrence of inappropriate therapies in 13 patients, clinical causes in 5 patients, and programming errors in 8 patients. The switch from the dual-chamber setting arm to the single-chamber setting arm was explained by lead issues in 2 patients and programming errors in 3 patients.
The time to first inappropriate shock was significantly longer in the dual-chamber setting group compared with the single-chamber setting group (p = 0.012, log-rank test) (Figure 2A). The hazard ratio was 2.5 (95% confidence interval [CI]: 1.2 to 5.3) in favor of dual-chamber setting therapy.
The endpoint of all-cause death or cardiovascular hospitalizations occurred in 46 patients (20.0%) in the dual-chamber setting group and 50 (22.4%) in the single-chamber setting group (Table 2). The pre-specified equivalence analysis with a margin of 17% confirmed the equivalence of dual-chamber setting therapy to single-chamber setting therapy (p < 0.001). Figure 2B illustrates the occurrence of the events over time.
A total of 88 patients (19.9%) received at least 1 ICD shock: 37 (16.1%) in the dual-chamber setting group and 51 (22.9%) in the single-chamber setting group (Table 3). The difference in rates of patients with shocks was driven by a lower frequency of patients with SVT-triggered inappropriate shocks in the dual-chamber setting group (1.3%) compared with the single-chamber setting group (7.6%) (p = 0.001). The rates of patients with only appropriate shocks were similar in both groups (11.7% and 12.6% in the dual-chamber setting and single-chamber setting groups, respectively).
Inappropriate shocks were delivered throughout the 27-month follow-up period at a rate of 7.3%, with no clustering at any specific time point. A total of 6 patients in the dual-chamber setting group (2.6%) and 17 patients in the single-chamber setting group (7.6%) received at least 1 inappropriate shock over 12 months (p = 0.015), as did 10 patients in the dual-chamber setting group (4.3%) and 23 patients in the single-chamber setting group (10.3%) at the end of the 27-month period (p = 0.015) (Table 3). The number of patients needed to treat to prevent 1 patient from experiencing an inappropriate shock was 17.
The reasons for inappropriate shocks in the 2 treatment groups included SVTs, responsible for 73.6% of the events, and lead failure or oversensing in 25.5% of the events (Table 4). In patients in the dual-chamber setting arm, lead failure or oversensing was the major reason for inappropriate shocks (70.8%). In patients in the single-chamber setting arm, SVTs triggered 86.6% of all inappropriate shocks, compared with 29.2% of inappropriate shocks in the dual-chamber setting group. A univariate analysis was performed to assess the impact of different factors (age, sex, left ventricular ejection fraction, coronary artery disease, New York Heart Association functional class, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, spironolactone, class III drugs, treatment arm, implantation indication, and history of AF) on the occurrence of inappropriate shocks. Among these, only treatment arm, implantation indication, and history of AF were added in a logistic multivariate model and identified as independent predictors (dual-chamber setting vs. single-chamber setting odds ratio: 0.36; 95% CI: 0.17 to 0.80; p = 0.012; primary vs. secondary prevention of sudden cardiac death odds ratio: 0.38; 95% CI: 0.18 to 0.80; p = 0.011; AF history absence vs. presence odds ratio: 0.27; 95% CI: 0.11 to 0.63; p = 0.003).
The rates of all-cause mortality were not statistically different (p = 0.688) between the groups: 21 patients died in the dual-chamber setting group (9.1%) and 18 patients in the single-chamber setting group (8.1%). A breakdown of causes for cardiovascular hospitalization is provided in Table 2.
Remarkably, ventricular pacing did not differ significantly between the groups, with a median of 0% in both groups (p = 0.635) and means of 3.9 ± 13.8% in the dual-chamber setting group and 2.4 ± 8.6% in the single-chamber setting group. Atrial pacing in the dual-chamber setting group was on average 26.7 ± 26.3% (median 17.2%).
In the total study population, 6 patients (1.3%) had atrial lead complications, including dislodgment, perforation, and loss of capture (Table 5). Twenty-one patients (4.6%) had ventricular lead–related complications, including fracture or insulation defect, dislodgment, high ventricular threshold or loss of capture, and lead perforation. Overall, 9 patients (2.0%) had hematoma, 9 patients (2.0%) had infections, and 6 patients (1.3%) had pneumothoraces. No significant difference was observed between groups (even disqualifying the atrial lead–related events in the single-chamber setting group).
The OPTION trial is the first prospective, randomized study evaluating inappropriate shock occurrence with dual-chamber settings and single-chamber settings during long-term follow-up in an ICD population. It shows a significant reduction of inappropriate shocks in the dual-chamber setting versus the single-chamber setting arm, with equivalent rates of cardiovascular events and death in both arms.
Conceptually, because of the information on atrial rhythm, dual-chamber ICDs are expected to discriminate more precisely between supraventricular and ventricular tachyarrhythmias compared with single-chamber ICD. Recent analyses of large-scale trials point toward few inappropriate shocks with dual-chamber ICDs, which may be less than with conventional single-chamber ICDs (17,18). However, the presumed superiority of dual-chamber ICD has never been shown in prospective, randomized trials for inappropriate shocks on per patient analysis (19–22). The lack of statistical significance in these studies may be attributed to inadequate sample sizes of early studies, study design, devices and algorithms used, and device programming (single-zone vs. multiple-zone programming). The results of our trial add an important piece of evidence for the reduction of inappropriate shocks with dual-chamber ICDs (2.6% vs. 7.6% at 1 year, p = 0.015; 4.3% vs. 10.3% at study end, p = 0.012).
The yearly rate of inappropriate shocks in OPTION (2.6% in the dual-chamber setting group) was of the same magnitude as in the recently conducted MADIT-RIT (Multicenter Automated Defibrillation Trial–Reduction in Inappropriate Therapy) trial (31) and lower than in several earlier large-scale trials, in which rates of 11% to 13% were reported (12–20). However, recent studies have reported very low overall rates of inappropriate shocks, which may be attributed to shorter follow-up periods, to specific device settings, including a higher tachycardia therapy cutoff rate, and to longer detection times (32–35). Moreover, it should be noted that the high crossover rate observed in our study from dual-chamber to single-chamber therapy may have even diluted the magnitude of the difference between the groups in this intention-to-treat analysis. The rate of appropriate shocks in this trial was not significantly different between the groups, at 11.7% and 12.6% in the dual-chamber setting and single-chamber setting groups, respectively.
A second factor to be considered when deciding between a dual-chamber or single-chamber device is the detrimental effect of unnecessary right ventricular pacing on morbidity and mortality, which was observed in the early days of dual-chamber ICD therapy (24,36). In the meantime, this risk has been substantially reduced by the introduction of algorithms to minimize ventricular pacing (37–39). The devices implanted within the OPTION trial were all equipped with SafeR, a well-established algorithm to minimize ventricular pacing, with proved effectiveness in randomized clinical trials (30,38). In the OPTION trial, no statistically significant differences in the percent of ventricular pacing was observed between the dual-chamber setting and single-chamber setting groups, with a median ventricular pacing percent of 0%. Furthermore, there were equivalent rates of death or cardiovascular events in both groups. Thus, dual-chamber ICD therapy combined with the SafeR algorithm provides a net benefit by reducing inappropriate shocks without increasing cardiovascular morbidity and mortality.
Finally, it is generally believed that the implantation of dual-chamber ICDs requires greater expertise. There are reports of an increased incidence of implantation- and device-related complications with dual-chamber ICDs in current clinical care (23), recently confirmed by Peterson et al. (40). In contrast to that and in agreement with the DATAS (Dual Chamber and Atrial Tachyarrhythmias Adverse Events Study) (41), the OPTION trial showed no elevated incidence of device-related or implantation-related adverse events in the dual-chamber group, even disregarding the atrial lead–related complications in the single-chamber group.
All patients in the OPTION study were provided with dual-chamber devices. This could slightly overestimate the rates of inappropriate shocks due to AF induced by local irritation from the lead. This study design was chosen because the information from the atrial lead was crucial to determine accurately the appropriateness of the therapy, which represented a central component of our primary endpoint. Moreover, it should be noted that the slow ventricular tachycardia zone setting was different between the groups: this zone was used as a monitor zone for the single-chamber group, while ATP with no shock was recommended for the dual-chamber group. Such a difference must be considered in addition to the treatment difference that is under randomized investigation.
Given the small number of inappropriate shocks in the dual-chamber setting group, further subgroup analysis with respect to patients who may benefit most from dual-chamber implantation was not possible.
The crossover rate was higher than in some other studies. However, it is not assumed that this has contributed to the positive finding of the trial, because the vast majority of patients switched to the dual-chamber setting group. This has rather diluted the magnitude of the difference between the groups in the intention-to-treat analysis.
The OPTION trial analyzed a specific setting of algorithms enabled by Sorin devices, so the results may not be transferable to dual-chamber ICDs from other manufacturers, which warrants further investigation.
The OPTION trial showed that therapy with dual-chamber setting discrimination combined with algorithms for minimizing ventricular pacing is associated with reduced long-term risk for inappropriate shock compared with single-chamber settings. The reduction of inappropriate shocks was obtained without an increase in mortality, morbidity, or device-related complications.
The authors thank Rolf Ocklenburg, MSc, for his contribution to this study; Pierre-Henri Siot for his statistical expertise; and Pelle Stolt, PhD, and Anne Rousseau-Plasse, PhD, for their editorial assistance.
The OPTION study was supported by Sorin CRM (Clamart, France). Dr. Kolb has received lecture honoraria and travel support from Biotronik, Boston Scientific, Medtronic, St. Jude Medical, and Sorin; is a consultant for Biotronik and Sorin; and has performed clinical studies supported by Biotronik, Medtronic, Sorin, and St. Jude Medical. Dr. Sturmer has received speaking honoraria from Medtronic; has received consulting honoraria from Boston Scientific and Medtronic; and has performed clinical studies supported by Sorin, Medtronic, Biotronik, and St. Jude Medical. Dr. Sick has received a research grant from Sorin. Dr. Reif has received travel support from Sorin; and has performed clinical studies supported by Biotronik, Medtronic, Sorin, and St. Jude Medical. Prof. Davy has received travel support from Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical; is a consultant for Sorin, Boston Scientific, and Medtronic; and has performed clinical studies supported by Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical. Dr. Molon has received travel support from Boston Scientific and Medtronic; is a consultant for Boston Scientific and Medtronic; and has performed clinical studies supported by Boston Scientific, Medtronic, Sorin, and St. Jude Medical. Dr. Schwab has received speaking honoraria and research support from Medtronic, Biotronik, St. Jude Medical, Boston Scientific, and Sorin. Dr. Mantovani has performed clinical studies supported by Medtronic and Sorin. Dr. Dan has received honoraria and travel support from Sorin, Medtronic, and St. Jude Medical; is a consultant for St. Jude Medical and Medtronic; and has performed clinical studies and received research grants from Medtronic, Sorin, St. Jude Medical, and Biotronik. Dr. Lennerz has received travel support from St. Jude Medical. Mr. Borri-Brunetto receives a salary as a Sorin employee. Dr. Babuty has received travel support from Biotronik, Boston Scientific, Medtronic, St. Jude Medical, and Sorin; and has performed clinical studies supported by Biotronik, Medtronic, Sorin, and St. Jude Medical.
- Abbreviations and Acronyms
- atrial fibrillation
- antitachycardia pacing
- implantable cardioverter-defibrillator
- supraventricular tachyarrhythmia
- Received March 27, 2014.
- Revision received May 14, 2014.
- Accepted May 17, 2014.
- American College of Cardiology Foundation
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