Reduction of inappropriate anti-tachycardia pacing therapies and shocks by a novel suite of detection algorithms in heart failure patients with cardiac resynchronization therapy defibrillators: a historical comparison of a prospective database

EP Europace, Sep 2016

Implantable cardioverter defibrillators improve survival of patients at risk for ventricular arrhythmias, but inappropriate shocks occur in up to 30% of patients and have been associated with worse quality of life and prognosis. In heart failure patients with cardiac resynchronization therapy defibrillators (CRT-Ds), we evaluated whether a new generation of detection and discrimination algorithms reduces inappropriate shocks.

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Reduction of inappropriate anti-tachycardia pacing therapies and shocks by a novel suite of detection algorithms in heart failure patients with cardiac resynchronization therapy defibrillators: a historical comparison of a prospective database

Europace Reduction of inappropriate anti-tachycardia pacing therapies and shocks by a novel suite of detection algorithms in heart failure patients with cardiac resynchronization therapy defibrillators: a historical comparison of a prospective database Maurizio Lunati 3 Alessandro Proclemer 1 Giuseppe Boriani 0 Maurizio Landolina 6 7 Emanuela Locati 3 Roberto Rordorf 7 Elisabetta Daleffe 1 Renato Pietro Ricci 5 Domenico Catanzariti 4 Luca Tomasi 9 Michele Gulizia 8 Maria Stella Baccillieri 2 Giulio Molon 10 Maurizio Gasparini 11 0 University of Bologna and Azienda Ospedaliera S.Orsola-Malpighi , Bologna , Italy 1 S. Maria della Misericordia Hospital , Udine , Italy 2 Ospedale P. Cosma , Camposampiero , Italy 3 'A De Gasperis' Cardiac Department, Niguarda Ca' Granda Hospital , Piazza Ospedale Maggiore, 3, 20162 Milano , Italy 4 Santa Maria del Carmine Hospital , Rovereto , Italy 5 San Filippo Neri Hospital , Rome , Italy 6 Ospedale Maggiore , Crema (Cremona) , Italy 7 Fondazione Policlinico S. Matteo IRCCS , Pavia , Italy 8 Ospedale Garibaldi Nesima , Catania , Italy 9 Azienda Ospedaliera Universitaria Integrata , Verona , Italy 10 Ospedale Sacro Cuore Don Calabria , Negrar , Italy 11 IRCCS Istituto Clinico Humanitas , Rozzano , Italy Aims Implantable cardioverter defibrillators improve survival of patients at risk for ventricular arrhythmias, but inappropriate shocks occur in up to 30% of patients and have been associated with worse quality of life and prognosis. In heart failure patients with cardiac resynchronization therapy defibrillators (CRT-Ds), we evaluated whether a new generation of detection and discrimination algorithms reduces inappropriate shocks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods We analysed 1983 Medtronic CRT-D patients (80% male, 67 + 10 years), 1368 with standard devices (Control CRTand results D) and 615 with new generation devices (New CRT-D). Expert electrophysiologists reviewed and classified the electrograms of all device-detected ventricular tachycardia/fibrillation episodes. Total follow-up was 3751 patients-years. Incidence of inappropriate shocks at 1 year was 2.8% [95% confidence interval (CI) ¼ 2.0 - 3.5] in Control CRT-D and 0.9% (CI ¼ 0.4 - 2.2) in New CRT-D (hazard ratio ¼ 0.37, CI ¼ 0.21 - 0.66, P , 0.001). In New CRT-D, inappropriate shocks were reduced by 77% [incidence rate ratio (IRR) ¼ 0.23, CI ¼ 0.16 - 0.35, P , 0.001] and inappropriate antitachycardia pacing by 81% (IRR ¼ 0.19, CI ¼ 0.11 - 0.335, P , 0.001). Annual rate per 100 patient-years for appropriate VF detections was 3.0 (CI ¼ 2.1 - 4.2) in New CRT-D and 3.2 (CI ¼ 2.1 - 5.0) in Control CRT-D (P ¼ 0.68), for syncope was 0.4 (CI ¼ 0.2 - 0.9) in New CRT-D and 0.7 (CI ¼ 0.5 - 1.0) in Control CRT-D (P ¼ 0.266), and for death was 1.0 (CI ¼ 0.6 - 1.6) in New CRT-D and 3.5 (CI ¼ 3.0 - 4.1) in Control CRT-D (P , 0.001). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion Detection and discrimination algorithms used in new generation CRT-D significantly reduced inappropriate shocks when compared with standard CRT-D. This result, with no compromise on VF sensitivity or risk of syncope, has important implications for patients' quality of life and prognosis. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - What’s new? † The clinical community is nowadays discussing about the best strategies to avoid unnecessary and/or inappropriate ICD shocks. † Strategies to reduce shocks comprise VT/VF detection limited to only faster rhythms or to sustained durations and programming of anti-tachycardia pacing to painlessly terminate slow and fast VT. † In our research, we demonstrated that combining a new generation of arrhythmia discrimination algorithms and evidence-based shock reduction programming results in a significant reduction of inappropriate shocks, ATP, and detections. † Our data confirm and complete PainFREE SST results; in particular, it characterizes the inappropriate shocks incidence in the pure population of CRT-ICD and compares this incidence with a historical population of patients with previous CRT-ICDs, which did not exploit the new generation of arrhythmia discrimination algorithms. † These results, obtained with no compromise on VF detection sensitivity or risk of syncope, have important prognostic implications because reduction of inappropriate therapies has been associated with improved survival and quality of life. Introduction Implantable cardioverter defibrillators (ICDs) are indicated in the treatment of patients at high risk of ventricular tachycardia/fibrillation (VT/VF) for both primary and secondary prevention of sudden cardiac death.1 Always ICD detection algorithms have favoured sensitivity to accurately detect life-threatening arrhythmias, over specificity. This historically resulted in inappropriate ICD therapies, i.e. therapies delivered on rhythms that are not ventricular tachyarrhythmias, in 8 – 40% of ICD patients.2,3 Inappropriate shocks have been associated with multiple adverse effects, impaired quality of life, worse prognosis, and increased mortality.2 – 4 Recently, the use of specific detection programming, such as long detection times or high rate VT or VF detection windows, and the use of anti-tachycardia pacing (ATP) to terminate rapid VTs have been proposed to reduce unnecessary or inappropriate ICD shock.5 – 10 Nevertheless, the incidence of inappropriate shocks 1 year after implant remains in the range of 2.6 – 3% even in the experimental arms of recent trials, such as the ‘Long Detection’ arm of Advance III9 and in the ‘High-Rate Therapy’ arm and in the ‘Delayed Therapy’ arm of MADIT RIT.10 The objective of our research was to evaluate whether novel sensing and discrimination features, SmartShockTM technology (Medtronic Inc., Minneapolis, MN, USA), improve device performance in the presence of lead failures, T wave oversensing, supraventricular tachycardias (SVTs), and non-sustained VT. In particular, we aimed to test whether these improved discrimination algorithms reduce inappropriate ICD shocks when compared with previous generation ICDs in patients with heart failure (HF), systolic dysfunction, and cardiac dyssynchrony, wearing ICDs with cardiac resynchronization therapy defibrillators (CRT-Ds) via biventricular pacing. This cohort of patients is of particular interest because CRT-D implant is increasing rapidly.11 Methods Project organization The patients included in the present analysis were followed up in a network of 80 Cardiology Centers, which participate in the Italian ClinicalService project [Clinical Trial Registration Information: http:// clinicaltrials.gov/ct2/show/NCT01007474]. This is a national cardiovascular data repository and medical care project that aimed at evaluating and improving the use of implantable cardiac devices in Italian clinical practice. The project was approved by each site’s Medical Ethics Committee or Medical Director and conforms to the principles outlined in the Declaration of Helsinki. Each patient provided informed consent for data collection and analysis. Patient population All patients received a biventricular triple-chamber CRT-D in accordance with ICD and CRT guidelines:1,12 i.e. HF in New York Heart Association (NYHA) class II, III, or IV, depressed ventricular function [left ventricular ejection fraction (LVEF) ≤35%], and wide QRS complex (≥120 ms). Project design and objectives The project consists of a historical comparison of a prospective database of 1983 Medtronic CRT-D patients: 615 patients with Protecta CRT-D (Medtronic Inc.), which utilize novel sensing and discrimination features (SmartShock technology), formed the new generation (New CRT-D) cohort, whereas 1368 patients with previous generation Medtronic CRT-D, not equipped with SmartShock technology, formed the historical Control CRT-D cohort. The main objective was to evaluate whether new detection and discrimination algorithms reduce inappropriate detections, ATP, and shocks when compared with algorithms in previous generation CRT-Ds. Secondary objectives comprised the comparison of the New CRT-D group with the Control CRT-D group in terms of appropriate detection, therapies and shocks, syncope, and mortality. An independent Episode Review Committee, composed by expert electrophysiologists, reviewed all arrhythmic episodes detected by the device as VT/VF, particularly the electrograms stored prior to VT/VF detection, after detection, and after therapy or VT/VF termination. The committee identified appropriate detections and inappropriate detection mechanisms and classified ICD therapies as appropriate or inappropriate in accordance with the detection classification. Follow-up and data collection All patients were followed for at least 6 months according to each centre’s clinical practice through standard in-hospital visits. Device interrogations and clinical evaluations were performed at each in-hospital visit. Data collection included information about VT/VF and SVT episodes, device programming, cardiovascular medications, and cardiovascular adverse events. Device programming and discrimination algorithms Device detection and therapy parameters were programmed according to each centre’s clinical practice. In the Control CRT-D cohort, SVT discrimination utilized PR Logic.5,6 This algorithm includes three criteria: a criterion designed to identify rapidly conducted atrial fibrillation (AF), atrial flutter, or atrial tachycardia; a criterion to identify sinus tachycardia; and another 1:1 SVTs criterion, designed to identify other 1:1 SVTs, in which atrial and ventricular activation is roughly simultaneous. At least, two of these criteria were programmed in 97% of the patients. The New CRT-Ds were programmed taking advantage of the SmartShock technology,13 which comprises four algorithms developed to reduce inappropriate shocks: (i) the WaveletTM algorithm differentiates VT from SVT on the basis of QRS morphology, (ii) T-wave discrimination algorithm identifies T-wave oversensing, (iii) right ventricular lead noise algorithm discriminates sensed rhythms that are due to lead noise from those that are from VT/VF, and (iv) Confirmation + algorithm identifies non-sustained VT which spontaneously terminate. Safety of the New CRT-D algorithms has been already proven by showing that SmartShock algorithms (i) did not delay detection of induced VF 14; (ii) were associated with 98.8% relative sensitivity on true spontaneous ventricular arrhythmias; and (iii) appropriately withheld therapy in 98.6% episodes.15 New CRT-D and Control CRT-D had very similar programming in terms of VF detection interval, which was between 290 and 330 ms in 95.1 and 94.6% of patients (P ¼ 0.929), respectively, and of fast ventricular tachycardia (FVT) window which was programmed in 75.9 and 75.7% of patients (P ¼ 0.995), respectively. Conversely, the VF number of intervals to detect (NID) was different (P , 0.001) with most [401 (65.2%)] New CRT-D patients programmed with NID ¼ 18/24, whereas Control CRT-D patients were programmed with NID ¼ 12/16 in 1096 (80.1%) cases and with NID ¼ 18/24 in 252 (18.4%) cases. Another difference (P , 0.001) between New CRT-D and Control CRT-D was that the VT window was programmed in 30.6 and 52.3%, respectively. Statistical analysis Continuous variables are reported as means and standard deviations or medians and interquartile ranges, as appropriate. Categorical data are reported as counts and percentage. The rate of events (number of detections, ATP, shocks, syncopes, or deaths over time) was computed per 100 person-years and reported separately for each group, together with their 95% confidence intervals (CIs). Rates were compared by means of either a mixed Poisson model or a negative binomial regression model (if over-dispersion was present). Incident rate ratios (IRRs) and CIs were used to compare the two groups. The analyses of time-to-the-first event were described by means of Kaplan – Meier curves and compared between the groups by means of the log-rank test. Cox models were fitted and hazard ratios (HRs) with CI were computed. The proportional hazard assumptions were tested by means of Schoenfeld residuals. Multivariate analysis was used to identify predictors of inappropriate shocks and to account for differences in the baseline characteristics of New CRT-D and Control CRT-D patients. Propensity score analysis16 was also used to compare event rates between two subgroups of New CRT-D and Control CRT-D patients having similar distributions of baseline characteristics. The baseline variables that were considered in the multivariate analyses and in the propensity score analyses were age, CRT-D implant indication, AF history, hypertension, myocardial infarction, diabetes, AV block, left bundle branch block, LVEF, and use of amiodarone, digitalis, and beta-blocking agents. All tests were two-sided and a two-tailed P-value of 0.05 was considered statistically significant. SAS 9.3 (SAS Institute Inc., Cary, NC, USA) was used for statistical analysis. Results Patients’ baseline characteristics are shown in Table 1. Median follow-up was 39 months (interquartile range ¼ 24 – 52 months) in Control CRT-D and 20 months (interquartile range ¼ 6– 48 months) in New CRT-D. Total follow-up was 3751 patients-years. Inappropriate ICD shock incidence The Kaplan – Meier incidence of inappropriate shocks was significantly lower in New CRT-D, as shown in Figure 1; in particular, at 1 year it was 0.9% (CI ¼ 0.4 – 2.2) in New CRT-D and 2.8% (CI ¼ 2.0 – 3.5) in Control CRT-D [HR ¼ 0.37 (CI ¼ 0.21 – 0.66), P , 0.001]. Number, annual rate, and IRR of patients and episodes with inappropriate shocks, comparing New CRT-D and Control CRT-D, is shown in Table 2 for all-cause shocks and for the specific mechanisms of inappropriate detections. In particular, inappropriate shocks occurred in 14 New CRT-D (1 patient suffered inappropriate shocks for two different causes) and 91 Control CRT-D patients (5 patients suffered inappropriate shocks for two different causes). Also, the total number of inappropriate shocks was significantly reduced in New CRT-D patients compared with Control CRT-D patients, with an annual rate of 2.1 (CI ¼ 1.5 – 2.9) and 9.1 (CI ¼ 8.3 – 10.0) shocks per 100 patient-years [IRR ¼ 0.23 (CI ¼ 0.16 – 0.35), P , 0.001], respectively. Predictors of inappropriate ICD shocks At multivariable analysis, inappropriate shocks were significantly associated with several patient characteristics such as wearing a new generation CRT-D [IRR ¼ 0.10 (CI ¼ 0.04 – 0.25), P , 0.001], age [IRR ¼ 0.98 (CI ¼ 0.96 – 0.99), P ¼ 0.030], AF [IRR ¼ 2.52 (CI ¼ 1.67 – 3.80), P , 0.001], myocardial infarction [IRR ¼ 0.34 (CI ¼ 0.21 – 0.54), P , 0.001], and left bundle branch block [IRR ¼ 4.18 (CI ¼ 2.10 – 8.32), P , 0.001]. Inappropriate ICD shock incidence adjusted for baseline characteristics The two CRT-D cohorts showed statistical differences in a few baseline characteristics, as shown in Table 1; incidence of inappropriate detections, ATP, and shocks, adjusted at multivariable analyses, confirmed that New CRT-D patients had a lower risk of inappropriate detections and therapies when compared with Control CRT-D (Table 3). Propensity score analysis, performed to exclude that the reduction of inappropriate shocks in the New CRT-D cohort was due to the imbalance in baseline characteristics, identified two homogeneous subgroups of 161 New CRT-D patients and 161 Control CRT-D patients and estimated an IRR of episodes with inappropriate shocks equal to 0.38, i.e. 62% relative reduction, associated with New CRT-D patients, with an adjusted P ¼ 0.044, and an IRR of the total number of inappropriate shocks equal to 0.27, i.e. 73% relative reduction, associated with New CRT-D patients, with an adjusted P ¼ 0.005. Inappropriate ICD shock incidence adjusted for ICD programming A multivariable analysis, accounting for VT window programming and considering only patients with NID ¼ 18/24, in order to NYHA, New York Heart Association; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; ACE, angiotensin-converting enzyme. exclude the effect of NID programming differences in New CRT-D vs. Control CRT-D, confirmed that New CRT-D patients had a lower risk of inappropriate ATP and shocks when compared with Control CRT-D (Table 4). Secondary objectives We observed no differences in the rates of appropriate VF detections between New CRT-D and Control CRT-D patients [3.0 (CI ¼ 2.1 – 4.2) per 100 patient-years vs. 3.2 (CI ¼ 2.1 – 5.0) per 100 patient-years, IRR ¼ 0.92 (CI ¼ 0.62 – 1.36), P ¼ 0.68]. Conversely, when evaluating all appropriate ventricular tachyarrhythmia detections, i.e. VF, FVT, and VT, we observed less detections and therapies in the New CRT-D cohort compared with Control CRT-D patients, in particular, the annual rate for detections was 4.2 (CI ¼ 3.1 – 5.8) per 100 patient-years in New CRT vs. 11.0 (CI ¼ 9.8 – 12.3) per 100 patient-years in Control CRT-D, IRR ¼ 0.38 (CI ¼ 0.29 – 0.51) (P , 0.001), the annual rate for appropriate ATP was 2.5 (CI ¼ 1.6 – 3.7) per 100 patient-years vs. 7.3 (CI ¼ 6.3 – 8.3) per 100 patient-years, IRR ¼ 0.32 (CI ¼ 0.23 – 0.46) (P , 0.001), and the annual rate for appropriate shock was 1.5 (CI ¼ 0.8 – 2.5) per 100 patient-years vs. 4.3 (CI ¼ 3.6 – 5.2) per 100 patient-years, IRR ¼ 0.32 (0.22 – 0.48) (P , 0.001). A total of 7 syncopes in 9 patients were reported in the New CRT-D arm and 32 in 36 patients in the Control CRT-D arm, among which 0 and 2, respectively, were considered to be related to VT/VF episodes or ICD treatment. The annual rate of syncope was similar in the two compared groups [0.4 (CI ¼ 0.2 – 0.9) per 100 patientyears in New CRT-D patients and 0.7 (CI ¼ 0.5 – 1.0) in Control CRT-D patients (IRR ¼ 0.63 (CI ¼ 0.28 – 1.42), P ¼ 0.266)]. Also at propensity score analyses, the risk of syncope was similar in the two groups (IRR ¼ 0.75, P ¼ 0.675). The mortality rate was 1.0 (CI ¼ 0.6 – 1.6) per 100 patient-years in the New CRT-D patients and 3.5 (CI ¼ 3.0 – 4.1) in the Control CRT-D patients. At multivariate analyses, AT/AF history and Control CRT-D cohort resulted associated with mortality. Discussion ICDs have been established to be the most effective therapy in the prevention and treatment of sudden cardiac death.1 Despite efforts to improve ICD technology and detection algorithms, a significant number of episodes are still inappropriately treated.2,3 Inappropriate shocks have been associated with impaired quality of life, psychological distress, reduction of battery life, and worse prognosis.2 – 4 The proportion of subjects with inappropriate shocks at 1 year in clinical practice is 3 – 4%.2,3,6,7,9,10 These findings outline the need for enhanced shock reduction strategies. Main research findings Detection and discrimination algorithms in a new generation of CRT-Ds significantly reduced inappropriate detections and 0.20 ks0.18 c ho0.16 s ICD0.14 tea0.12 i rrop0.10 p iap0.08 n fo0.06 e cn0.04 e d iIcn0.02 0.00 Follow-up (months) 12 24 36 48 Figure 1 Kaplan – Meier incidence of inappropriate ICD shocks in the New CRT-D and Control CRT-D patients’ cohorts. therapies and in particular inappropriate shocks when compared with the historical physician-tailored Control CRT-D cohort. Therefore, our research confirmed the clinical benefit of combining a new generation of arrhythmia discrimination algorithms and evidence-based shock reduction programming; such VT/VF detection limited to only faster rhythms or to sustained durations and programming of ATP to painlessly terminate slow and fast VT. Inappropriate shock prevention in new generation devices The percentage of patients with inappropriate shocks at 1 year was 0.9% in the New CRT-D cohort (Figure 1), which favourably compares with the findings of the PainFREE observational study,15 which tested the same discrimination algorithms on 1071 Protecta CRT-ICD patients and 948 dual-chamber ICD patients and found a 1-year inappropriate ICD shock incidence equal to 1.5%. Importantly, the 2.8% 1-year incidence of inappropriate ICD shocks estimated in our Control CRT-D cohort represents a state-of-the-art outcome, being similar to the results obtained in the study arms of two recent randomized trials,9,10 with detection and treatment programming specifically devoted to inappropriate shock reduction; inappropriate ICD shock incidence at 1 year was 2.6% in the Long Detection arm of ADVANCE III study9 and 3% in the High-Rate Therapy arm and in the Delayed Therapy arm of MADIT RIT study.10 The comparison of inappropriate shock incidences in our New CRT-D cohort and in the ADVANCE III and MADIT RIT trials suggests that in new generation ICDs, the novel discrimination algorithms may avoid inappropriate shocks in 2 of 3 patients every 100 patients. Importantly, beyond the reduction of patients with inappropriate shocks, the novel algorithms yielded a 66% reduction of episodes with inappropriate shocks and a 60% reduction in the number of shocks (Table 2, last 2 rows). It is worthwhile to outline that our research represents real life and included all-comers CRT-D patients, whereas often randomized clinical trials have strict eligibility criteria; for example, AF history was present in 31% of the patients in our research and only in 10% of ADVANCE III9 and MADIT RIT10 trials, and AF is known as the most frequent cause of inappropriate shocks.2,3,4,17 Out of the 91 Control CRT-D patients who suffered inappropriate shocks, AF was the cause of inappropriate detection in 54 (59%) patients and in 132/253 (52%) episodes with inappropriate shocks. Despite AF history was more frequent (41.5%) in New CRT-D patients compared with Control CRT-D patients (26.7%, P , 0.001), inappropriate shocks due to AF in New CRT-D were significantly less, with a reduction of 62% shocked patients and 77% shocked episodes (Table 2). In the studied new generation CRT-D, a QRS morphology analysis algorithm, which uses the wavelet decomposition of electrogram signals to compare the morphology of tachycardia complexes with a previously collected normal sinus rhythm template, has been associated with significant reduction of inappropriate therapies for SVT.18 Finally, multivariable analysis confirmed the efficacy of the new or improved detection and discrimination algorithms featured in new generation of CRT-D by showing that these devices were associated with a significantly lower risk of inappropriate shocks [IRR ¼ 0.10 (CI ¼ 0.04 – 0.25), P , 0.001]. Secondary objectives New CRT-D and Control CRT-D cohorts did not differ as for appropriate VF detection rates and syncopes. This observation, together with previous findings,14,15 is reassuring as it suggests that optimization of inappropriate detection algorithms was obtained with no compromise in terms of VF sensitivity or risk of syncopes. New CRT-Ds were also associated with lower rates of appropriate detections and therapies for FVT/VT episodes. This could be explained by differences in the compared patients’ cohorts and by differences in device programming for VT and FVT detection and therapies. In particular, the longer NIDs programmed in New CRT-D compared with Control CRT-D likely resulted in a reduction of unnecessary detection and therapies. The finding of a low mortality rate in New CRT-D patients should be regarded with caution, given the observational nature of our research. A recent meta-analysis,19 considering four randomized trials6,9,10,20 and two observational studies,7,8 has shown that therapy reduction programming, based on prolonging the time required to detect a sustained ventricular arrhythmia, resulted in a large, significant, and consistent reduction in mortality. The huge reduction of inappropriate therapies and of unnecessary therapies on appropriate detections found in New CRT-D patients could have contributed, together with other factors, to the observed low mortality. Clinical implications In the last 15 years, clinical and technological research has been particularly focused on reducing unnecessary and inappropriate ICD shocks.2,5 – 10,13 – 15,18,20 First, ATPs have been proposed in the PainFREE studies2,5 to avoid unnecessary shocks; secondly, strategic programming has been tested in clinical practice both in observational and in randomized studies6 – 8; finally, delayed detection, permitting non-sustained and slower arrhythmias to self-terminate, has been shown to be safe and effective in reducing both unnecessary and inappropriate shocks.9,10 Recently, the PROVIDE study20 has shown that a combination of programmed parameters utilizing high detection rates, long detection intervals, empiric ATP, and optimized SVT discriminators reduces ICD therapies without increasing arrhythmic syncope and is associated with reduction in all-cause mortality. Now our research shows the synergistic effect of state-of-the-art ICD programming and novel detection algorithms. Therefore, we suggest that specific detection programming, such as longer detection times or shorter VT/VF detection windows, as those proposed by recent trials,9,10 may provide even better inappropriate shock prevention when applied on top of optimal detection and discrimination capabilities as those studied in our research. Improved detection capabilities have the advantage that can be applied in all patients, whereas specific programming settings, such as VT and VF detection windows, should be programmed on the basis of patients’ characteristics; indeed, the benefit of eliminating a slow VT detection zone in order to reduce the probability of inappropriate therapies should be balanced against the risk of failing to treat VT. Minimization of ICD inappropriate shocks does clear the way for more patients to benefit from ICD life-saving technology. Research limitations The major limitation of our clinical research is that, deriving from a project aiming observation of device use in standard clinical practice, it has an observational non-randomized design. Besides, the limitations of multicentre observational studies, such as potential bias in patient selection or patient treatment, apply to our research. Indeed, the differences in baseline characteristics and device programming between the two compared groups were considerable. However, we believe that the acknowledged limitations were mitigated by the fact that data were collected prospectively, the research endpoints were prespecified, the analysis plan was designed before the data set was opened, and finally both multivariable and propensity score analyses were performed to account for patients characteristic and device programming differences in the two research arms. These methods allowed us also to verify that lead type, in particular Sprint Fidelis, which historically has been associated with higher incidence of inappropriate shocks, among other variables, did not impact findings of the presented research. Although primary endpoint, being derived from device diagnostics, was not affected by data collection limitations, we cannot exclude underreporting in syncopes and deaths. Due to the data collection and reporting platform, all used ICDs were Medtronic systems; this may limit a general applicability of research results. Conclusions Improved detection and discrimination algorithms significantly reduced incidences and annual rates of inappropriate shocks, ATP, and detections when compared with algorithms used in a standard CRT-D. This result, obtained with no compromise on VF detection sensitivity or risk of syncope, has important prognostic implications because reduction of inappropriate therapies has been associated with improved survival.19 Acknowledgement The authors thank Andrea Grammatico and Silvia Bisetti for scientific advice and Lorenza Mangoni and Paola Di Stefano for statistical analysis. Conflict of interest: M.L. received modest consultancy and speaker’s fees from Medtronic, St Jude Medical, Sorin, Boston Scientific, and Biotronik. G.B. has minor consultancy fees from Boston Scientific and Medtronic. M.L. received modest speaker fees from Medtronic and St Jude Medical and an advisory board relationship with Medtronic and St Jude Medical. R.P.R. has minor consultancy fees from Biotronik and Medtronic. G.M. has consultancy and speaker’s fees from Boston, St Jude Medical, and Medtronic. The other authors have no relationship to disclose with regard to the present research. Funding This research was performed within the framework of the Italian ClinicalServicew project, a national cardiovascular data repository and medical care project funded by Medtronic Italia, an affiliate of Medtronic Inc. No other funding sources were involved in the research. The authors are responsible for the design and conduct of this research. 1. Zipes DP , Camm AJ , Borggrefe M , Buxton AE , Chaitman B , Fromer M et al. ACC/ AHA/ ESC 2006 Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death-executive summary: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society . Eur Heart J 2006 ; 27 : 2099 - 140 . 2. Sweeney MO , Wathen MS , Volosin K , Abdalla I , DeGroot PJ , Otterness MF et al. Appropriate and inappropriate ventricular therapies, quality of life, and mortality among primary and secondary prevention implantable cardioverter defibrillator patients: results from the Pacing Fast VT REduces Shock ThErapies (PainFREE Rx II) trial . Circulation 2005 ; 111 : 2898 - 05 . 3. Van Rees JB , Borleffs CJ , de Bie MK , Stijnen T , van Erven L , Bax JJ et al. Inappropriate implantable cardioverter defibrillator shocks: incidence, predictors, and impact on mortality . J Am Coll Cardiol 2011 ; 57 : 556 - 62 . 4. Poole JE , Johnson GW , Hellkamp AS , Anderson J , Callans DJ , Raitt MH et al. Prognostic importance of defibrillator shocks in patients with heart failure . N Engl J Med 2008 ; 359 : 1009 - 17 . 5. Wathen MS , DeGroot PJ , Sweeney MO , Stark AJ , Otterness MF , Adkisson WO et al. 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Lunati, Maurizio, Proclemer, Alessandro, Boriani, Giuseppe, Landolina, Maurizio, Locati, Emanuela, Rordorf, Roberto, Daleffe, Elisabetta, Ricci, Renato Pietro, Catanzariti, Domenico, Tomasi, Luca, Gulizia, Michele, Baccillieri, Maria Stella, Molon, Giulio, Gasparini, Maurizio. Reduction of inappropriate anti-tachycardia pacing therapies and shocks by a novel suite of detection algorithms in heart failure patients with cardiac resynchronization therapy defibrillators: a historical comparison of a prospective database, EP Europace, 2016, 1391-1398, DOI: 10.1093/europace/euv420