3.3 High rate versus delayed therapy
Basal characteristics of the two randomized groups did not differ between the groups (supplementary table 1). Patients in the high-rate programming group had more frequently obstructive sleep apnea (19% versus 5%, p=0.040) and less frequently history of stroke or TIA (6% versus 21%, p=0.038). No other characteristics differ between the groups.
Regarding primary endpoint, no programming strategy was better than the other (HR 0.901, 95% CI 0.311-2.614, p=0.849 for delayed detection programming). Also, for secondary endpoints no differences were found.
DISCUSSION
The concept of optimal ICD programming has evolved in recent years from quick detection and treatment of VT/VF to a more permissive strategy, in order to reduce avoidable shocks11. Demonstration of an increased defibrillation threshold when VF was prolonged14, concerns about undersensing and underdetection of VF and its use in secondary prevention patients with a higher risk of arrhythmic events were responsible for the idea of programming of short interval for detection and treatment of rapid tachycardia.
Nowadays, concepts have changed and the adverse effects of avoidable therapies were emphasized. As such, an evidence-based programming is recommended11. However, manufacturer-specific translations of recommendations into clinical practice is not straightforward and obtaining a universal (or almost universal) programming to apply in clinical practice is not easy. However, for clinicians who deal with defibrillator programming on a daily basis, it would be more practical to have only one programming that could be used across all manufacturers.
We have shown in the present study, that it was possible to program defibrillators from all the five manufacturers with one of two tachycardia configurations, based on high-rate or delayed detection. Both strategies were effective and safe. As expected, due to the reduced number of patients assigned in each arm no conclusion about the benefit of one programming over the other could be obtained. Despite this fact, when comparing the new programming group with a historical group of patients treated in the same institution, some conclusions were drawn. When comparing our interventional group (new programming) with our historical group (conventional programming), the primary outcome (all therapies) was significantly reduced by the new programming strategy. By analyzing secondary outcomes, the reduction in the number of appropriate ATP mostly accounted for these results. However, all shocks (appropriate and inappropriate together) were also reduced. There was a trend for a benefit regarding inappropriate shocks (HR 0.155, p=0.079), while appropriate shocks were not minimized.
“Appropriate” ATPs were reduced in the new programming group. This is expectable since ATPs were exclusively delivered in the FV zone (figure 1) while charging and it is also consistent with previous studies4-10. Despite the fact that ATP can be effective and avoids shocks15, it can also be responsible for acceleration and degeneration to polymorphic VT or VF. According to previous studies, ATP programming can cause acceleration of VT or degeneration to VF in 1.2% to 21% of patients15-16, being responsible for shock delivery and even incessant electrical storm. The potential adverse effects of using ATP only during charge, such as syncope, did not occur. Avoidable” ATPs were almost eradicated in the new programming group, suggesting that many episodes of nonsustained VT that would have terminated spontaneously were treated prematurely in the conventional programming group.
Inappropriate shocks affected 4% of patients in the new programming group, a proportion similar to other studies3-9, comparing to 9% in the conventional programming group. There was a trend for a reduction in inappropriate shocks with the new programming (HR 0.155, p=0.079), which would be expected considering previous studies3-9. The absence of statistical significance is probably related to the reduced number of events.
The total number of shocks was significantly reduced, but not the number of appropriate shocks, which occurred in 5.6% of all patients. The rate was independent of the programming, probably because they are unavoidable, since these patients are at a high risk of SCD. The same occurred in other studies, in which a minority of patients received appropriate ICD shocks (3-6%) and no significant difference in the risk of appropriate shocks was observed with new programming3-9.
On the other hand, some reports raised the question of ineffectiveness of ICD when specific tachycardia configurations are used. Differences in sensing and detection methods among manufacturers may limit the applicability of generic programming recommendations. An update of the previous expert consensus statement was released in 201913, including manufacturer-specific translations into clinical practice. Despite these recent concerns and the fact that many patients were programmed with tachycardia configuration different from those used in randomized trials, potential adverse effects did not occur. The risks of applying these tachycardia settings, such as syncope and arrhythmic death, were minimal. No syncopal episodes were detected but two sudden deaths occurred, one of them in the new programming group. In both patients it was not possible to have access to the EGM and autopsy was not performed, so an arrhythmic cause for death was possible but not certain. The patient belonging to the new programming group was randomized to the high rate arm so his tachycardia configuration was in accordance with MADIT-RIT, which efficacy and safety have been previously demonstrated. Togerson et al reported that in most patients in whom failure of ICDs to treat VF occurred, ICD programming deviated from values validated in manufacturer-specific clinical trials, although complying with the more generic recommendations of the Consensus Statement12. This is not what happened in our case since the patient had a programming in accordance with a previous randomized trial4-5. In the patient who died suddenly in the conventional programming group, it was not possible to access tachycardia settings.
The number of deaths was high in our study (18%), comparing with previous ones. Our population was older and had a higher incidence of hypertension, diabetes and AF, which can explain this result. However, the majority of patients died from non-cardiovascular causes. Probably related to this fact, we found no benefits in mortality with new programming. Others had found otherwise10 and hypothesized that the significant reduction in appropriate and inappropriate ATP and shocks may have contributed to the observed mortality reduction. In fact, these studies change our concepts about tachycardia programming by demonstrating a benefit in mortality rates with ICD programming. In the present study, such an observation could not be done. Nevertheless, the benefit of the reduction of all therapies is per si enough to advice for such programming. Although not translating into a survival benefit in our study, inappropriate shocks are painful and associated with increased anxiety and depression17, so every effort should be made to reduce them.
Finally, the role of medical therapy in reducing the risk of SCD is well established. Thus, recent studies highlighting the benefit of defibrillators are influenced by the increasing use of these drugs comparing to studies performed some years ago18. In the present study, patients were receiving adequate medical therapy: 96% were taking ACEI/ARB/ARNI; 90% beta-blockers, 46% mineralocorticoid receptor antagonists (MRA). These proportions are comparable to controlled trials and better than recent registries19. Only the proportion of patients under MRA was higher in the new programming group (55% versus 37%, p=0.016). Although MRA reduce the risk of SCD20, this difference is unlikely to influence our results in what concerns device therapies.
The present study highlights the benefits of having a structured protocol to program all patients with a defibrillator implanted for primary prevention. Our principal finding is that it was possible to program tachycardia settings across all device manufacturers, while the reduction of all defibrillator therapies without safety concerns was achieved.
LIMITATIONS
It was not a pure prospective study since it was performed a comparison with historical controls in which the tachycardia settings were unknown and not standard. However, since patients from the historical control group were included after 2014, the ICD programming was probably in line with the programming guidelines published in 201511. It’s entirely possible that a proportion of the patients in this group already received some form of contemporary programming, so the difference between the conventional and novel program in groups could be underestimated. If the historical group had been earlier, the benefit would probably have been higher.
Also, in order to avoid selection bias that might result from the exclusion of the so called “good patients” (namely those without previous therapies), some of our study patients were also included in the early historical control group. However, even with the inclusion of these patients, who had defibrillators for a longer time and were free from previous episodes of ICD therapies, we had found significant differences in the studied endpoints.
It was not possible to determine the total number of ventricular events for each group in order to understand if the number of ICD therapies has been reduced due to less arrhythmic events or because of the new programming configurations. This information was not available in the conventional programming group.
Finally, due to the small number of randomized patients the analyses of the relationship between device programming and endpoints in the high rate and delayed detection groups had limited power.