A Review of ICD Anti-Tachycardia Therapy Programming with Generic Programming for Primary and Secondary Prevention

Intracardiac defibrillator plays a pivotal role in preventing sudden cardiac death; however, inappropriate shock delivery remains an important source of morbidity and mortality. Advancements in device technology along with various shock reduction strategies play a key role in reducing inappropriate and unnecessary shocks. Anti-tachycardia pacing (ATP) is the first-line therapy prior to shock delivery. Several trials have validated the efficacy of ATP for both slow and fast ventricular tachycardia without significant increase in occurrence of arrhythmia-related syncope. In addition, trials also support that therapy for non-sustained tachycardia can be prevented by higher programmed zones and prolonged intervals to detect without higher risk of syncope. With this perspective, authors employ a customized programming for both primary and secondary prevention to reduce inappropriate therapies or unnecessary therapies, in particular, progression to shock but allow for spontaneous termination at slower ventricular tachycardia rates. The programming was instituted at the time of device implantation or at follow up.


Introduction
Implantable cardioverter-defibrillator (ICD) remains the main therapeutic option in reducing sudden cardiac death (SCD). Several randomized trials and registries have shown that ICD extends survival in patients with severe left ventricular function and mild-to-moderate heart failure [1][2][3][4]. The shocks delivered whether appropriate, inappropriate or unnecessary remain an important source of mortality and morbidity from proarrhythmic potential, heart failure, painful delivery of shock causing significant anxiety, depression and post-traumatic stress disorder [5][6][7][8][9][10][11].
Inappropriate ICD shocks are those delivered for a condition other than true ventricular arrhythmias, which most commonly include supraventricular arrhythmias with rapid rates, mechanical failure of ICD lead/system like lead conductor fracture resulting in noise detection and non-mechanical issues such as T-wave over sensing resulting in double-counting [3]. Unnecessary or potentially avoidable shocks are those where the ventricular tachycardia (VT) was to terminate spontaneously or could have been interrupted by appropriately timed pacing stimuli. Table 1 lists the major clinical trials and registries reporting the incidence of inappropriate shocks. We review some of the trials here.
The anti-arrhythmics versus implantable defibrillators (AVID) was a multi-centre trial which patients were randomized to receive ICD or anti-arrhythmic drug therapy; 492 patients were randomized to receive an ICD over a follow-up period of 22 ± 12 months. Inappropriate shocks in this cohort were due to supraventricular tachycardia in 18% and 3% were due to ICD malfunction or inappropriate sensing [12].
The Pain FREE Rx II trial was a prospective randomized control trial consisting of 634 patients with a mean follow up of 11 ± 3 months. All patients received ICDs and were randomized to anti-tachycardia pacing versus shock only programming [13]. There were 4230 spontaneous episodes retrieved from all implanted ICDs, 1837 had complete electrogram data and were included in the analysis. Of these, 491 episodes (27%) were determined to be inappropriately detected supraventricular tachycardia (SVT), and 4 (0.2%) were non-physiological artifact. Sweeny et al. performed a subgroup analysis of the PainFree trial and showed that the proportion of true ventricular detections that resulted in shocks was similar between primary and secondary prevention groups (40% versus 32%, respectively) [14]. The proportion of inappropriate ventricular detections due to SVT that resulted in shocks was also similar between primary and secondary prevention groups (44% versus 42%, respectively).
MIRACLE ICD was a prospective, randomized double-blind trial of 978 patients with a mean 10-month follow-up [15]. This trial evaluated the safety and efficacy of cardiac resynchronization combined defibrillator therapy (CRT-D) versus ICD only therapy in both primary and secondary prevention patients. The reported incidence of inappropriate shocks was 30% in primary prevention patients and 14% in secondary prevention patients.
In the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II), inappropriate shocks constituted 31.2% (184/590) of the total shock episodes [16]. The most common triggers were atrial fibrillation (44%) and supraventricular tachycardia (36%) with improper discrimination by the ICD device, followed by abnormal sensing (20%). The majority of inappropriate ICD therapy episodes were delivered for rhythms below or equal to 200 bpm; the mean ventricular rate triggering inappropriate shock for atrial fibrillation (AF) or SVT was 174 ± 22 bpm. Patients with inappropriate ICD shocks showed a significantly higher mortality during the follow-up (HR = 2.29, 95% CI: 1.11-4.71, p = 0.02) than patients with Clinical trial AVID [12] PainFREE [13] MIRACLE ICD [15] MADIT II [16] SCD-Heft [17] ALTITUDE ICD [18] ALTITUDE CRT-D [18] Leidin [19] Patient no.  Similar data could be extrapolated from the sudden cardiac death in heart failure trial (SCD-HeFT) [17]. In this trial, 2521 patients with primary prevention indication and with mild-tomoderate heart failure were randomized in equal proportions to receive placebo, amiodarone or a single-chamber ICD programmed to shock-only mode. Follow-up was for an average of 46 months. In 811 patients assigned to the ICD arm, the rate of inappropriate shocks was 17% as compared to 22.4% appropriate shocks during a 46-month follow-up. Patients with an inappropriate ICD therapy had a twofold increase in the risk of all-cause mortality (HR = 1.98, 95% CI: 1.29-3.05, p = 0.002).
The results from the randomized trials were confirmed in larger registries. The ALTura Impact on the Treatment of Abdominal Aortic Aneurysms Using a Novel D-stent EVAR Design (ALTITUDE) registry involved 39,396 ICD patients and 29,904 patients implanted CRTDs. Patients were implanted for both primary and secondary indications [18]. The 1-year incidence of inappropriate shocks was 8% and 6% and at 5 years increased to 16% and 17% for ICD and CRT-D patients, respectively. The two most common reasons for shock were atrial flutter/atrial fibrillation and sinus tachycardia or supraventricular arrhythmia. Inappropriate shock was due to noise, artifact or over sensing in 3% of the episodes.
The Leiden group published a large scale study in 1544 ICD patients and reported an 18% incidence of inappropriate ICD therapy over 41 months of follow-up. This study also confirmed the increased risk of death for both inappropriate and appropriate ICD therapy (HR1.60 for both, p = 0.01 for inappropriate; p < 0.01 for appropriate ICD therapy) [19].

Possible mechanism of increased risk of death with ICD shocks
It may be hypothesized that there is a direct mechanical or hemodynamic effect of the inappropriate ICD therapies themselves or that some of the inappropriate ICD therapies lead to fatal pro-arrhythmia due to an increase in sympathetic discharge, which in turn leads to raterelated changes in ventricular refractoriness and worsened myocardial ischemia [20].
It is likely that it is not the inappropriate shock per se that is detrimental, but the sequelae that hastens the adverse clinical outcome.
It has been suggested that high shock fields are associated with changes in electrophysiological properties of the heart and can be the primary source of activation wave fronts that may give rise to idioventricular rhythms after the shock and perhaps may even perpetuate ventricular fibrillation [21]. The cellular injury from intra-cardiac shock delivery whether it be appropriate or not is reflected in a rise in cardiac troponin I [22]. Though the result may be a rescue from acute ventricular arrhythmia, studies have shown a relationship with increased mortality and morbidity from progression to heart failure as a consequence of the myocardial stunning [5][6][7][8][9][10][11].
Minimizing the need for shock delivery overall will, therefore, ultimately prevent the downstream complications.

Shock reducing strategies
There have been several technological advancements to improve ICD therapy delivery and to avoid inappropriate and unnecessary ICD therapies. The shock reduction programming strategies may be divided into the following categories: • Optimizing ventricular tachyarrhythmia discrimination by applying advanced detection algorithms in all therapy zones.
• Delaying onset of anti-tachycardia therapies either by prolonged detection intervals or setting higher tachycardia detection limits.
• Using anti-tachycardia pacing (ATP) as first-line therapy whenever possible prior to shock delivery.

Clinical evidence and the rationale to support ATP therapy
Monomorphic VT can be interrupted when an appropriately timed pacing stimulus is delivered into the excitable gap of a re-entrant circuit where a collision with the orthodromic wave front results in termination of the tachycardia.
An alternative explanation is that the paced stimuli result in myocardial depolarization during the relative refractory period. This pre-excites the preceding wave front, thereby altering myocardial excitability and extinguishing the propagation re-entrant VT [23].
The duration of the excitable gap and the conduction time from the pacing stimulus site to the re-entrant circuit are the main factors influencing penetration of the excitable gap and termination of the arrhythmia [24].
Ventricular conduction time is influenced by anatomic and functional barriers as well as the influence of the sympathetic nervous system [25]. The efficacy of the ATP is improved with adequate beta blockade and is not adversely influenced by other anti-arrhythmic drugs as is the case with defibrillation thresholds [26].

Customized programming
Several trials have validated the efficacy of ATP in terminating slower cycle length of VT.
The Pain FREE Rx II trial was the first trial that extended the use of ATP for fast VT (FVT) with heart rates of 188-250 beats/min. This study also used longer intervals to detect VT as compared to the previous conventional programming (Figure 1) [13,27]. The result was that 73% of FVT episodes were successfully terminated by the ATP.
It also showed that FVT made up 76% of all ventricular arrhythmias that would have conventionally been treated by shock alone according to conventional ICD programming.
Acceleration of FVT occurred in patients programmed to receive ATP as well as those in the shock only group: 4/273 monomorphic VT episodes (2%) in the ATP arm versus 2/145 (1%) in the shock arm. There were also three episodes of syncope during treatment for FVT (ATP, n = 2; shock, n = 1). This study, therefore, established the safety and efficacy of ATP for both slow and FVT as first-line therapy in ICDs with a non-significant occurrence or difference in arrhythmia-related syncope in either therapy arm.
The next stage in the evolution of device therapy programming was to defer treatment (VT detection) till absolutely necessary. In this regard, the Primary Prevention Parameters Evaluation (PREPARE) trial (Figure 2) [28] evaluated a prolonged detection interval duration of 30/40 ventricular beats and an increased tachycardia detection interval (TDI) of 182 beats/ min. Supraventricular detection discrimination algorithms and ATP were also optimized in this programming strategy. Arrhythmic syncope was only 1.6% in the test programming strategy. All-cause mortality in the PREPARE study group was also relatively low (Kaplan-Meier estimated 12-month mortality of 4.9%). Thus, the overall safety behind the rationale of this programming was acceptable. The multicenter automatic defibrillator implantation trial-reduce inappropriate therapy (MADIT-RIT) trial compared three arms: (a) conventional ICD detection of VT with a (b) prolonged detection interval and (c) a higher tachycardia detection interval (Figure 3) [29].
The results validated the safety of both the active test arms. There was a 79% reduction in the incidence of therapy in the high-rate group than in the conventional therapy group and delayed therapy (longer detection interval programming) was associated with a 76% reduction in overall therapy delivery. Mortality was reduced by 55% in the high-rate group (p = 0.01) and by 44% in the delayed-therapy group (p = 0.06). Despite withholding therapies till absolutely needed, there was a mortality improvement in these active programming options.
The incidence of syncope was similar between the groups and was not clinically significant: high rate strategy and delayed therapy versus conventional arm (p = 0.39, p = 0.80).
Both delayed therapy and higher rate programming were shown to be safe and efficacious. The ADVANCE III (Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III) [30] reinforced the findings from the MADIT-RIT trial and included both primary and secondary prevention patients, with or without atrial fibrillation, in whom single-, dualand triple-chamber ICD were implanted [30]. Thus, this randomized control trial applied an extended detection interval strategy to a heterogeneous cohort of ICD recipients and more likely to resemble a real world setting (Figure 4).
This delayed arrhythmia detection strategy resulted in a reduction in the combined end point of all ICD therapies (ATPs and shocks) with 346 delivered therapies (42 therapies per 100 person-years) in test group (extended-detection interval) versus 557 in the control group (standard-detection interval) (67 therapies per 100 person-years); p < 0.001.
The incidence of arrhythmic syncope was low in both groups and did not differ significantly with rates of 3.1 versus 1.9 per 100 patient-years (p = 0.220 in the extended detection and standard detection groups, respectively). The syncopal episodes were not associated with any additional adverse outcomes. The mortality rates were 5.5 versus 6.3 per 100 patient-years (p = 0.50) in extended detection and standard detection, respectively. Both were low and comparable to what was reported in the MADIT-RIT trial.
Similarly the PROVIDE (Programming Implantable Cardioverter Defibrillators in Patients with Primary Prevention Indication to Prolong Time to First Shock) trial was a programming strategy with combination of higher detection rates, prolonged detection intervals, optimized SVT discriminators and empiric ATP therapy compared to conventional parameters in patients receiving ICDs for primary prevention (Figure 5) [31]. The primary end point was time to first shock delivery. The median time to first shock was significantly longer at 13.1 months in experimental group versus 7.8 months in the control group. In addition, the 2-year shock rate was 12.4% in the experimental group compared to 19.4% in the control group. An overall reduction in both appropriate and inappropriate shock and ATP was observed. The decrease in ICD therapies was associated with a 30% relative reduction in all-cause mortality.
The incidence of arrhythmic syncope was not significantly different between the two groups with overall incidence of 1.7% over 2 years of follow-up. With this perspective, we can summarize the overall current trends in ICD programming:

3.
Use of advanced discriminators in all zones

4.
Use of tiered therapies with ATP as first line therapy before shock delivery.
The aim of these strategies is to reduce inappropriate therapies (ITS) particularly progression to shock and not to over treat ventricular arrhythmias but to allow for spontaneous termination at ventricular rates that are safe to do so. There has been no data to suggest that implanting dual chamber ICDs is more advantageous in ventricular arrhythmia over single chamber devices in any of the studies we have mentioned. However, there are some practical reasons where one may choose to implant an atrial lead as well to enhance discrimination algorithms [32].
• In patients who require pacing for bradycardia, AV sequential pacing would be preferable.
• In patients with bradycardia-induced or pause-dependent ventricular tachyarrhythmia (such as patients with long QT syndrome and torsades de pointes).
• In patients with documented history of paroxysmal atrial arrhythmias (atrial EGMS will help distinguish the chamber of onset of the tachycardia). • In patients with hypertrophic cardiomyopathy as they are prone to atrial arrhythmias but may also require pacing.
With this in mind, we employ the following customized ICD programming (Tables 2 and 3) for both primary and secondary prevention of SCD in our patients.  In doing so, the work flow both in the implant suite and at the follow-up device visit is facilitated and the programming can be delegated to our allied professional nurses and cardiac technicians.

Conclusion
With the complexity and sophistication of ICD algorithms, the programming of these cardiac devices has become a discipline and challenge in its own right. We have found that it has been difficult to maintain predictability and consistency in the programming of ICDs in our centre, hence a need arose to develop a programming template. This was derived from current trends in programming and is mentioned here in an extensive review of the literature. There is an obvious limitation in which each of the studies has been manufacturer specific. We have tried to identify the principles on which the programming was based and then developed a generic template. This was however still done with due consultation with the manufacturers to ensure applicability and safety with the specific algorithms. There have also been very few studies that deal with programming of secondary prevention of ICDs. We have strived to maintain a compromise between all manufacturers to reach a consensus on programming for primary prevention of ICDs.