Journal of the American Heart Association ORIGINAL RESEARCH Long-Term Outcomes Among a Nationwide Cohort of Patients Using an Implantable Cardioverter-Defibrillator: UMBRELLA Study Final Results Sem Briongos-Figuero , MD; Arcadio García-Alberola, MD, PhD; Jerónimo Rubio, MD, PhD; José María Segura, MD, PhD; Aníbal Rodríguez, MD, PhD; Rafael Peinado, MD, PhD; Javier Alzueta, MD, PhD; José B. Martínez-Ferrer , MD, PhD; Xavier Viñolas, MD, PhD; Joaquín Fernández de la Concha, MD, PhD; Ignasi Anguera, MD, PhD; María Martín, EngD; Laia Cerdá, Pharm B; Luisa Pérez, MD, PhD; on behalf of the UMBRELLA Investigators* BACKGROUND: Large-scale studies describing modern populations using an implantable cardioverter-defibrillator (ICD) are lacking. We aimed to analyze the incidence of arrhythmia, device interventions, and mortality in a broad spectrum of real-world ICD patients with different heart disorders. METHODS AND RESULTS: The UMBRELLA study is a prospective, multicenter, nationwide study of contemporary patients using an ICD followed up by remote monitoring, with a blinded review of arrhythmic episodes. From November 2005 to November 2017, 4296 patients were followed up. After 46.6±27.3 months, 16 067 episodes of sustained ventricular arrhythmia occurred in 1344 patients (31.3%). Appropriate ICD therapy occurred in 27.3% of study population. Patients with ischemic cardiomyo- Downloaded from http://ahajournals.org by on March 28, 2023 pathy (hazard ratio [HR], 1.51; 95% CI, 1.29–1.78), dilated cardiomyopathy (HR, 1.28; 95% CI, 1.07–1.53), and valvular heart disease (HR, 1.94; 95% CI, 1.43–2.62) exhibited a higher risk of appropriate ICD therapies, whereas patients with hypertrophic cardiomyopathy (HR, 0.72; 95% CI, 0.54–0.96) and Brugada syndrome (HR, 0.25; 95% CI, 0.14–0.45) showed a lower risk. All-cause death was 13.4% at follow-up. Ischemic cardiomyopathy (HR, 3.09; 95% CI, 2.58–5.90), dilated cardiomyopathy (HR, 3.33; 95% CI, 2.18–5.10), and valvular heart disease (HR, 3.97; 95% CI, 2.25–6.99) had the worst prognoses. Delayed high-rate detection was enabled in 39.7% of patients, and single-zone programming occurred in 52.6% of primary prevention patients. Both parameters correlated with lower risk of first appropriate ICD therapy, with no excess risk of mortality. The rate of inappropriate shocks at follow-up was low (6%) and did not differ among type of ICD but was lower in SmartShock-capable devices. CONCLUSIONS: Irrespective of the cause, contemporary ICD patients with heart failure–related disorders had a similar risk of ICD life-saving interventions and death. Current ICD programming recommendations still need to be implemented. REGISTRATION: URL: https://www.clini​caltr​ials.gov; Unique identifier: NTC01561144. Key Words: all-cause death ■ appropriate implantable cardioverter-defibrillator therapy ■ implantable cardioverter-defibrillator ■ inappropriate shock ■ sustained ventricular arrhythmia Correspondence to: Sem Briongos-Figuero, MD, Servicio de Cardiología. Hospital Universitario Infanta Leonor, Gran Vía del Este, 28030 Madrid, Spain. E-mail: semdoc@hotmail.com Supplementary Material for this article is available at https://www.ahajo​urnals.org/doi/suppl/​10.1161/JAHA.120.018108 *A complete list of the UMBRELLA Investigators can be found in the Appendix at the end of the article. For Sources of Funding and Disclosures, see page 13. © 2020 The Authors and Medtronic Iberica S.A. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. JAHA is available at: www.ahajournals.org/journal/jaha J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.0181081 Briongos-Figuero et al UMBRELLA Study disease being linked to SCD.1 Thus, an implantable CLINICAL PERSPECTIVE cardioverter-defibrillator (ICD) is recommended to pre- vent SCD in patients at high risk of VA. In this setting, What Is New? the survival benefit is achieved mainly by proper detec- • The present study comprises a large cohort tion and subsequent treatment of life-threatening VA. of 4296 implantable cardioverter-defibrillation Current recommendations for ICD therapy in patients (ICD) patients with 8 different heart disorders, with left ventricular systolic dysfunction are robust be- implanted according to current guidelines and cause they were derived from randomized trials (RTs).2 followed up for 46.6±27.3 months. However, many cardiac diseases are not included or • A reliable incidence of arrhythmic events and are underrepresented in RTs, and the risk of SCD has ICD interventions by disease cause was identi- been inferred from small observational studies by re- fied by a blinded review of the stored arrhythmic porting the incidence of VA and ICD interventions.3–6 episodes collected through the remote monitor- Large observational real-world studies describing ICD ing system. populations implanted with modern devices are lack- What Are the Clinical Implications? ing. Therefore, homogeneous information derived from • The long-term prognosis of heart failure in pa- a wide and diverse population after long-term follow-up tients using an ICD seems to be similar regard- is needed to analyze the real incidence of arrhythmia, less of the disease cause. mortality, and adverse events among patients using an • Contemporary primary prevention ICD patients ICD. with channelopathies and inherited cardiomyo- The UMBRELLA observational study intended pathies showed a low risk of life-threatening to bridge this gap and to provide further knowledge ventricular arrhythmia and death, suggesting about real clinical practice and SCD risk stratification. that a better risk stratification would be desir- The UMBRELLA study aims to collect a large and con- able in these subgroups. temporary ICD population implanted under current • Delayed high-rate detection was enabled in clinical guidelines and followed up by remote device <40% of patients and correlated with a lower risk of appropriate ICD interventions, showing monitoring. The primary objective of the UMBRELLA that better implementation of current program- study was to assess the incidence of arrhythmias in ming recommendations is required in modern- a cohort of patients implanted with Medtronic ICDs in era patients using an ICD. Spain, as well as to analyze the arrhythmic risk and Downloaded from http://ahajournals.org by on March 28, 2023 mortality prognosis according to their clinical profiles and ICD indication. The secondary objective was to investigate the existence of additional parameters that could identify ICD patients at higher risk of malignant Nonstandard Abbreviations and Acronyms VA. ARVC  rrhythmogenic right ventricular a The incidence of arrhythmias in the UMBRELLA cardiomyopathy study population after 2 years of recruitment was pub- BS Brugada syndrome lished previously.7 Herein, we report the results of the DCM dilated cardiomyopathy entire cohort at the end of follow-up. HCM hypertrophic cardiomyopathy ICM ischemic cardiomyopathy IS inappropriate shock METHODS LQTS long-QT syndrome Study Design PP primary prevention The UMBRELLA study is a multicenter, observational, RT randomized trial nationwide study of patients implanted with Medtronic SCD sudden cardiac death ICDs (Medtronic, Inc) and prospectively followed up SP secondary prevention through the Medtronic remote device monitoring sys- SVA sustained ventricular arrhythmia tem (CareLink). The study, which was sponsored by VA ventricular arrhythmia Medtronic Ibérica S.A. and registered at www.clini​caltr​ VHD valvular heart disease ials.gov (NTC01561144), was performed in 44 hospi- tals distributed among 14 of the 17 regions in Spain. Institutional ethics committee approval was acquired A broad spectrum of cardiovascular disorders have according to national requirements, and written in- an increased risk of life-threatening ventricular ar- formed consent was mandatory for patient enroll- rhythmia (VA) and sudden cardiac death (SCD), ment. The enrollment period started in August 2011 with up to 50% of deaths related to cardiovascular and ended in November 2017. For each patient, the J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.0181082 Briongos-Figuero et al UMBRELLA Study protocol allowed use of the device information from the network. Two committee members reviewed each implant date until study exit or end of follow-up. Thus, event in a blinded manner, classifying the type of remote transmissions stored in the CareLink system arrhythmia and the effectiveness of the delivered before patient enrollment could be included in the therapy. If the 2 members disagreed on the classifi- study as a contribution to the follow-up of the patient’s cation, the event was referred to a third reviewer. If no device. agreement was reached, the event was reassigned As an observational study, ICD programming was to a new pair of reviewers and, if needed, to a sixth performed according to regular clinical practice at reviewer. If consensus was not reached at this point, each site. the event was finally classified in a joint meeting of all The analytic methods and study materials that sup- committee members. port the findings of this study will be made available to Arrhythmic episodes were classified as sustained other researchers from the corresponding author on VA (SVA), non-SVA, and nonventricular episodes. SVA reasonable request. was defined as ventricular episodes lasting ≥30 sec- onds and/or requiring ICD therapy, and was further Patient Selection classified into sustained monomorphic ventricular Patients were eligible for inclusion in the UMBRELLA tachycardia (VT) or sustained polymorphic VT/ventric- study if they were at least 18 years old and implanted ular fibrillation (VF). Non-SVA was defined as VA lasting with a Medtronic ICD. In addition, patients were also <30 seconds and terminated before the delivery of any required to be followed up by the remote monitor- ICD therapy. Nonventricular episodes were classified ing system. Single-, dual-, and triple-chamber ICDs as atrial fibrillation (AF), sinus tachycardia, other regu- were permitted. The protocol allowed the inclusion lar supraventricular tachycardia, T-wave oversensing, of patients at the moment of implantation (“de novo” false detection, or noise. procedure or device replacement) as well as pa- Appropriate ICD therapy was defined as any ther- tients implanted with the device before the moment apy (antitachycardia pacing or high-energy shocks) enrollment. delivered to treat SVA episodes. Inappropriate shock (IS) was defined as any shock delivered to nonsus- tained ventricular episodes or nonventricular episodes. Data Collection and Follow-Up All of the arrhythmic events described in this article The follow-up period ran from the date of the first come from the adjudication of the expert committee. Downloaded from http://ahajournals.org by on March 28, 2023 ICD implant (November 11, 2005) to the end of study follow-up and data collection (November 30, 2017). Subgroup Analysis and Outcomes For each patient, a baseline form was used to col- The entire cohort was clustered into subgroups ac- lected data on demographics, cardiovascular history, cording to the underlying heart disease and ICD indi- and implant procedure information related to the first cation. The resulting study subgroups were ischemic device registered in the study database. All device cardiomyopathy (ICM), nonischemic dilated cardiomy- information was automatically stored and collected opathy (DCM), hypertrophic cardiomyopathy (HCM), through the remote monitoring system database. valvular heart disease (VHD), long-QT syndrome Information on adverse events, including deaths, or (LQTS), Brugada syndrome (BS), arrhythmogenic right study exits was collected when applicable on sep- ventricular cardiomyopathy (ARVC), and adult congeni- arate forms. Data on cause-specific mortality were tal heart disease. further classified into SCD, non-SCD, heart failure The study outcomes were SVA, first appropriate (HF) death, noncardiac death, or death of unknown ICD therapy, all-cause death, and IS. origin. A specific quality process was followed regularly throughout the study to ensure consistency in the Statistical Analysis collected data. Furthermore, twice a year, an analysis Continuous variables are expressed as mean±SD, was performed of the patients who had not made any and categorical data are expressed as numbers and CareLink transmission within the previous 7 months. percentages. Parametric tests were used for compari- sons: Student t test and χ2 test for continuous and cat- egorical variables, respectively. Cumulative incidence Electrogram Analysis and Classification of was described using the Kaplan-Meier method, and Arrhythmic Events comparisons between the estimated curves were per- A committee, composed of 6 expert electrophysiolo- formed using the log-rank test. gists, analyzed all electrograms from the arrhythmic Cox proportional hazards regression analysis was events that occurred in study patients. The elec- used to identify unadjusted risk factors for the study trograms were automatically stored in the CareLink outcomes. After proportional hazard assumptions J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.0181083 Briongos-Figuero et al UMBRELLA Study were tested, a multivariable Cox regression analysis was performed to assess independent predictors of appropriate ICD therapy, all-cause death, and IS. The multivariate Cox regression model was adjusted for age, sex, hypertension, diabetes mellitus, hypercho- lesterolemia, smoking, history of AF, previous stroke, chronic kidney disease, family history of SCD, left ven- tricular ejection fraction (LVEF), QRS width, and heart disease, as well as the following ICD characteristics: type of device, ICD indication, detection zones en- abled, and delayed high-rate detection programming. SmartShock technology was also included in the mul- tivariate analysis of IS outcome. Data are expressed as hazard ratios (HRs) and 95% CIs. Analyses were performed using IBM Statistical Package for Social Sciences, version 25.0 (IBM SPSS, Inc, Chicago, IL). A 2-sided P<0.05 was considered significant for all tests. RESULTS Population Characteristics A total of 4618 patients were enrolled in the study, with 74.7% (n=3449) corresponding to first implants. Figure 1 shows the patient distribution according to available follow-up. A total of 322 patients (7%) were implanted and then included in the CareLink system but had no record of a remote transmission being made. As no follow-up information could be obtained, Downloaded from http://ahajournals.org by on March 28, 2023 these patients were excluded from the analysis. Thus, the final study sample was composed of 4296 patients (follow-up population) in whom at least one remote Figure 1. Flow diagram of patient distribution. transmission was performed. The mean follow-up was 46.6±27.3 months (median, 44 months; maximum, 143 months). The baseline characteristics of the follow- (47.7%). After blinded analysis of the electrograms, up population and study subgroups are summarized in 11 405 were catalogued as non-SVA or nonven- Table 1 and Tables S1 and S2. tricular episodes. Therefore, 1344 patients (31.3% of follow-up population) experienced 16 067 episodes of SVA; 1054 episodes (6.6%) were catalogued by ICD Type and Programming the committee as VF/sustained polymorphic VT and Device models used in the UMBRELLA study are de- 15 013 (93.4%) were catalogued as sustained mono- picted in Table S3. ICD programming extracted from the morphic VT. The overall cumulative incidence of SVA first remote transmission is given in Table 2. Briefly, many was 23% (95% CI, 22%–24%) at 1 year, 34% (95% CI, primary prevention (PP) patients had a VT zone enabled 33%–35%) at 3 years, and 54% (95% CI, 53%–55%) (47.4%), and delayed high-rate detection programming at 6 years. The incidence rates of SVA, appropriate was only enabled in 39.7% (n=1704) of follow-up popu- ICD therapy, and all-cause death on the basis of the lation. Delayed high-rate programming was defined ac- underlying heart disease and ICD indication are given cording to current consensus8 and comprised patients in Table 3. with a cutoff rate ≤320 ms and number of intervals to An appropriate ICD therapy was delivered to detect ≥30/40 within the VF zone. Nevertheless, ad- 85.7% (n=13 767) episodes of SVA in 1173 patients herence to programming recommendations increased (event rate, 27.3%). A total of 1334 episodes of the through the study period (Table S4). untreated SVA occurred in a monitor zone (58.4%). The remaining 966 events (41.6%) corresponded to SVA and Appropriate ICD Therapies episodes of SVA that terminated before the delivery of At study closure, a total of 27 472 stored arrhyth- the programmed therapy. Among the treated events, mic episodes had been collected in 2048 patients 346 episodes (2.7%) of sustained monomorphic VT J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.0181084 Downloaded from http://ahajournals.org by on March 28, 2023 Table 1. Baseline Characteristics at Implantation in the Follow-Up Population and Study Subgroups Characteristic Follow-Up Population ICM DCM VHD HCM ARVC LQTS BS ACHD Briongos-Figuero et al No. (%) 4296 (100) 2150 (50) 1166 (27.1) 119 (2.8) 294 (6.8) 71 (1.7) 43 (1) 143 (3.3) 60 (1.4) Age, mean±SD, y 61.9±12.9 65.6±10.1 62.1±12.1 63.5±12.6 52.6±15.1 47.4±11.9 51.1±18.5 50.3±12.6 45.6±14.2 Sex (men) 3527 (82.1) 1938 (90.2) 878 (75.3) 90 (75.6) 216 (73.5%) 51 (71.8) 12 (27.9) 120 (83.9) 34 (56.7) Hypertension 2275 (54.4) 1358 (65) 598 (52.4) 60 (52.2) 109 (37.7) 14 (20.6) 11 (25.6) 24 (16.8) 11 (18.3) Diabetes mellitus 1178 (28.3) 758 (36.4) 312 (27.5) 24 (21.1) 30 (10.3) 0 (0) 3 (2.3) 9 (5.6) 4 (6.7) Hypercholesterolemia 2040 (52.5) 1291 (65.8) 462 (43.8) 40 (39.6) 111 (41.6) 16 (24.6) 6 (12.5) 33 (25.6) 13 (22) Smoking status 1415 (37.7) 852 (45.2) 345 (33.8) 21 (21.4) 69 (26) 10 (15.9) 3 (7.7) 40 (32.5) 10 (16.9) History of atrial fibrillation 1235 (29.4) 608 (29) 401 (35.1) 62 (53) 89 (30.5) 3 (4.3) 7 (16.3) 5 (3.5) 13 (21.7) Previous stroke 252 (6.8) 145 (7.9) 60 (5.9) 9 (9) 17 (6.1) 1 (1.7) 3 (7.9) 2 (1.6) 3 (5.1) Chronic kidney disease 633 (15.3) 380 (18.4) 183 (16.3) 17 (14.8) 19 (6.6) 3 (4.3) 3 (7) 4 (2.8) 4 (6.7) Family history of SCD 356 (8.7) 48 (2.4) 93 (8.3) 3 (2.7) 104 (36.4) 15 (22.1) 10 (23.8) 44 (31.9) 14 (23.7) LV ejection fraction, % ≤35 2841 (66.4) 1633 (76.3) 996 (85.6) 64 (53.8) 34 (11.6) 11 (15.5) 1 (2.3) 1 (0.7) 25 (41.7) 36–50 631 (14.7) 379 (17.7) 131 (11.3) 27 (22.7) 35 (11.9) 11 (15.5) 5 (11.6) 5 (3.5) 9 (15) >50 806 (18.9) 128 (5.9) 36 (3.1) 28 (23.5) 224 (76.5) 49 (69) 37 (86) 137 (95.8) 26 (43.3) QRS width, ms <120 2202 (52.4) 1154 (53.7) 389 (34) 42 (35.9) 196 (68.3) 65 (91.5) 35 (81.4) 127 (90.1) 23 (40.4) 120–150 877 (20.9) 479 (22.3) 249 (21.7) 32 (27.4) 48 (16.7) 5 (7) 5 (11.6) 11 (7.8) 9 (15.8) >150 1119 (26.7) 466 (21.7) 507 (44.3) 43 (36.8) 43 (15) 1 (1.4) 3 (7) 3 (2.1) 25 (43.9) Previous heart failure 2973 (69.8) 1564 (73.1) 986 (85.4) 89 (75.4) 133 (45.2) 26 (36.6) 11 (25.6) 23 (16.1) 40 (66.7) Type of device VR 2027 (47.2) 1107 (51.5) 356 (30.5) 46 (38.7) 137 (46.6) 48 (67.6) 16 (37.2) 133 (93) 23 (38.3) DR 972 (22.6) 511 (23.8) 168 (14.4) 20 (16.8) 142 (48.3) 23 (32.4) 26 (60.5) 10 (7) 21 (35) CRT-D 1297 (30.2) 532 (24.7) 642 (55.1) 53 (44.5) 15 (5.1) 0 (0) 1 (2.3) 0 (0) 16 (26.7) Primary prevention 2758 (64.2) 1342 (62.4) 899 (77.1) 53 (44.5) 228 (77.6) 22 (31) 4 (9.3) 110 (76.9) 37 (61.7) Data are given as number (percentage) unless otherwise noted. ACHD indicates adult congenital heart disease; ARVC, arrhythmogenic right ventricular cardiomyopathy; BS, Brugada syndrome; CRT-D, cardiac resynchronization therapy-defibrillator; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; ICM, ischemic cardiomyopathy; LQTS, long-QT syndrome; LV, left ventricular; SCD, sudden cardiac death; and VHD, valvular heart disease. J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.0181085 UMBRELLA Study Briongos-Figuero et al UMBRELLA Study Table 2. ICD Programming Follow-Up Population Primary Prevention Secondary Prevention Variable (N=4296) (N=2758) (N=1538) P Value Detection zones enabled Single zone* 1853 (43.2) 1451 (52.6) 402 (26.2) <0.001 Multiple zones 2440 (56.8) 1305 (47.4) 1135 (73.8) VF detection interval, ms 302.7±19.4 302.9±18.7 302.4±20.4 0.396 NID <0.001 <30/40 2490 (58) 1508 (54.7) 982 (63.8) ≥30/40 1805 (42) 1249 (45.3) 555 (36.2) Fast VT detection zone enabled† 1557 (36.3) 879 (31.9) 678 (44.1) <0.001 Fast VT detection interval, ms† 266.5±29.4 263.7±26 270±32.9 <0.001 VT detection interval, ms‡ 361.6±25.3 358.7±20.4 366.7±31.5 <0.001 NID‡ 0.617 ≤16 1395 (57.2) 740 (56.7) 655 (57.7) ≥20 1045 (42.8) 565 (43.3) 480 (42.3) SmartShock technology–capable device 2930 (72.1) 1890 (72.6) 1040 (71.0) 0.267 Data are given as number (percentage) or mean±SD. ICD indicates implantable cardioverter-defibrillator; NID, number of intervals to detect; VF, ventricular fibrillation; and VT, ventricular tachycardia. *Patients with fast VT zone enabled through VF zone, but without any other VT zone activated, were also considered as single-zone detection patients. † Through VF detection zone. ‡ Applies only to multiple-zone detection programming patients. received high-energy shocks, 11 074 (85.7%) received with lower risk. Among causative subgroups, an in- antitachycardia pacing, and 1508 (11.6%) received dependently higher risk of appropriate ICD therapy both therapies, whereas 615 episodes (73.3%) of was found in patients with DCM, VHD, and ARVC, sustained polymorphic VT/VF received high-energy whereas patients with BS exhibited a lower risk. Downloaded from http://ahajournals.org by on March 28, 2023 shocks, 63 (7.5%) received antitachycardia pacing, Among ICD settings, delayed high-rate detection in and 161 (19.2%) received both therapies. The overall PP patients (Figure 3A) and single-zone program- cumulative incidence of appropriate ICD therapy was ming were associated with a lower risk of first appro- 14% (95% CI, 13%–15.2%) at 1 year, 26% (95% CI, priate ICD therapy. 24.7%–27.7%) at 3 years, and 36% (95% CI, 34.4%– 38.2%) at 6 years. A higher risk of first appropriate ICD therapy was observed in patients with VHD (HR, All-Cause Death 1.94; 95% CI, 1.43–2.62; P<0.001), ARVC (HR, 1.84; At the end of follow-up, 590 deaths (event rate, 13.4% 95% CI, 1.28–2.66; P=0.001), ICM (HR, 1.51; 95% CI, of follow-up population) had been reported. The 1.29–1.78; P<0.001), and DCM (HR, 1.28; 95% CI, causes of death are given in Table S5. The cumula- 1.07–1.53; P=0.005), whereas patients with HCM (HR, tive incidence of all-cause death was 5% (95% CI, 0.72; 95% CI, 0.54–0.96; P=0.027) and BS (HR, 0.25; 4%–6%) at 1 year, 13% (95% CI, 12%–14%) at 3 years, 95% CI, 0.14–0.45; P<0.001) were at significantly and 25% (95% CI, 24%–26%) at 6 years. Patients with lower risk (Figure 2A). A trend toward lower risk was ICM (HR, 3.90; 95% CI, 2.58–5.90; P<0.001), DCM seen in LQTS (HR, 0.49; 95% CI, 0.22–1.09; P=0.082), (HR, 3.33; 95% CI, 2.18–5.10; P<0.001), and VHD (HR, whereas no differences in risk were observed in adult 3.97; 95% CI, 2.25–6.99; P<0.001) had worse progno- congenital heart disease (HR, 1.30; 95% CI, 0.85– ses (Figure 2C), and prognosis was significantly bet- 1.99; P=0.218). Furthermore, the risk of appropriate ter in patients with BS (HR, 0.11; 95% CI, 0.01–0.67; ICD therapy was higher in secondary prevention (SP) P=0.017). ICD indication lacked a statistical relationship patients than in PP patients (HR, 2.27; 95% CI, 2.02– with mortality (HR, 1.19; 95% CI, 0.91–1.41; P=0.076). 2.54; P<0.001). The event incidence rate was 40.1% The event rate was 14.7% in PP patients and 13.9% in versus 20.4%, respectively (Figure 2B). SP patients (Figure 2D). In the multivariate analysis (Table 4), age, sex, In the multivariate analysis, sex, increasing age, previous AF, SP, LVEF ≤35%, and QRS width (120– previous AF, chronic kidney disease, diabetes mellitus, 150 ms) emerged as clinical predictors of appropriate and impaired LVEF emerged as independent predic- ICD therapy, whereas the implantation of a cardiac tors of all-cause death (Table 4). No excess risk of mor- resynchronization therapy-defibrillator correlated tality was associated with any ICD setting. J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.0181086 Briongos-Figuero et al UMBRELLA Study Table 3. Incidence of Study End Points, According to the Underlying Heart Disease and ICD Indication Appropriate ICD Variable SVA P Value Therapy P Value All-Cause Death P Value ICM (n=2150) 730 (34.0) 658 (30.6) 371 (17.3) Primary prevention (n=1342) 349 (26.0) <0.001* 310 (23.1) <0.001* 235 (17.5) 0.686* Secondary prevention (n=808) 381 (47.2) 348 (43.1) 136 (16.8) DCM (n=1166) 355 (30.4) 306 (26.2) 167 (14.3) Primary prevention (n=904) 223 (24.8) <0.001* 187 (20.8) <0.001* 131 (14.6) 0.656* Secondary prevention (n=268) 132 (49.4) 119 (44.6) 36 (13.4) HCM (n=294) 65 (22.1) 49 (16.7) 9 (3.1) Primary prevention (n=228) 38 (16.7) <0.001* 25 (10.1) <0.001* 5 (2.2) 0.108* Secondary prevention (n=66) 27 (40.9) 26 (39.4) 4 (6.1) VHD (n=119) 49 (41.2) 43 (36.1) 19 (16) Primary prevention (n=53) 17 (33.1) 0.071 16 (30.2) 0.226* 8 (15.1) 0.816* Secondary prevention (n=66) 32 (48.5) 27 (40.9) 11 (16.7) ARVC (n=71) 31 (43.7) 27 (38) 1 (1.4) Primary prevention (n=22) 7 (31.8) 0.178* 6 (27.3) 0.211* 1 (4.5) 0.310* Secondary prevention (n=49) 24 (49) 21 (42.9) 0 (0) LQTS (n=43) 8 (18.6) 5 (11.6) 1 (2.3) Primary prevention (n=4) 0 (0) 0.424* 0 (0) 0.598* 0 (0) 0.746* Secondary prevention (n=39) 8 (20.5) 5 (12.8) 1 (2.6) BS (n=143) 13 (9.1) 10 (7) 1 (0.7) Primary prevention (n=110) 5 (4.5) 0.002* 3 (2.7) 0.001* 1 (0.9) 0.583* Secondary prevention (n=33) 8 (24.2) 7 (21.2) 0 (0) ACHD (n=60) 23 (38.3) 19 (31.7) 5 (8.3) Primary prevention (n=37) 11 (29.7) 0.082* 8 (21.6) 0.034* 3 (8.1) 0.936* Downloaded from http://ahajournals.org by on March 28, 2023 Secondary prevention (n=23) 12 (52.2) 11 (47.8) 2 (8.7) Data are given as number (percentage). ACHD indicates adult congenital heart disease; ARVC, arrhythmogenic right ventricular cardiomyopathy; BS, Brugada syndrome; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter-defibrillator; ICM, ischemic cardiomyopathy; LQTS, long-QT syndrome; SVA, sustained ventricular arrhythmia; and VHD, valvular heart disease. *Comparison of the proportion of primary vs secondary prevention patients within the same cardiomyopathy subgroup. Inappropriate Shocks In the multivariate analysis (Table 4), previous AF A total of 1375 patients (32% of follow-up population) was the only clinical predictor of IS, whereas increasing had 11 405 episodes catalogued as non-SVA or non-VA. age correlated with a lower risk. Among ICD settings, Inappropriate ICD therapy was given in 13.2% (n=1503) single-zone programming was independently related of these episodes, but only 257 patients (6%) experi- to a lower risk of IS. enced an IS. The most frequent cause of an IS was AF and other supraventricular tachycardia (Table S6). The incidence of IS was higher in patients with HCM DISCUSSION (9.4%; P=0.007), and a trend toward higher risk was Our study comprises the largest contemporary co- seen in patients with ARVC (10.7%; P=0.065), but it was hort of ICD patients implanted according to current lower in patients with BS (1.3%; P=0.015) and ICM (5%; clinical guidelines and followed up over a long pe- P=0.008). No significant differences were found in pa- riod of time. We had several key findings. First, left tients with DCM (6.8%; P=0.153), VHD (4.9%; P=0.477), ventricular systolic dysfunction, and subsequent adult congenital heart disease (3.1%; P=0.214), and HF, remains the most frequent indication for ICD im- LQTS (2%; P=0.232). The incidence of IS did not dif- plantation, with PP as the leading strategy. Second, fer according to type of device (6.4% versus 6.2% ICD patients with HF-related disorders had a similar versus 5.2% for VR, DR, and cardiac resynchroniza- risk of life-threatening VA, appropriate ICD thera- tion therapy-defibrillator, respectively; P=0.321) or ICD pies, and death, regardless of the cause (ischemic, indication (6.8% for PP versus 5.5% for SP; P=0.081), dilated, or valvular heart disease). SP patients were but it was lower in patients implanted with SmartShock- more prone to VA and appropriate ICD therapies, capable devices (4% versus 8.7%; P=0.002; Figure 3B). but survival was similar to PP patients. In addition, J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.0181087 Briongos-Figuero et al UMBRELLA Study BS Event free survival (First ICD therapy) LQTS Event free survival (All-cause death) BS ARVC LQTS ACHD HCM HCM ACHD VHD P<0.001 DCM P<0.001 DCM + ICM + ICM ARVC VHD A C Nº at risk Nº at risk ICM 2139 1612 1243 872 616 388 ICM 2139 1927 1636 1276 983 683 429 256 111 DCM 1159 897 695 498 341 198 DCM 1159 1061 901 706 528 331 197 109 49 HCM 294 247 200 147 113 85 HCM 294 269 238 188 153 115 74 43 19 VHD 119 88 61 40 25 14 VHD 119 111 86 61 44 29 20 13 7 ACHD 60 47 39 34 29 19 ACHD 60 60 57 48 42 29 15 13 7 ARVC 70 49 42 36 25 16 ARVC 70 68 64 56 41 32 21 11 5 BS 139 125 112 102 77 59 BS 139 132 120 110 87 67 49 36 24 LQTS 42 36 31 22 17 15 LQTS 42 40 36 27 22 20 11 3 2 Event free survival (First ICD therapy) Primary prevention + Secondary prevention Event free survival (All-cause death) Primary prevention P<0.001 + Secondary prevention P=0.076 B D Downloaded from http://ahajournals.org by on March 28, 2023 Nº at risk Nº at risk Primary prevention 2748 2230 1762 1272 920 577 Primary prevention 2752 2494 2107 1629 1240 842 512 302 132 Secondary prevention 1526 1045 794 569 388 261 Secondary prevention 1523 1392 1207 970 752 522 339 208 105 Figure 2. Kaplan-Meier curves for first appropriate implantable cardioverter-defibrillator (ICD) therapy according to underlying heart disease (A) and ICD indication (B); and for all-cause death according to underlying heart disease (C) and ICD indication (D). ACHD indicates adult congenital heart disease; ARVC, arrhythmogenic right ventricular cardiomyopathy; BS, Brugada syndrome; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; ICM, ischemic cardiomyopathy; LQTS, long-QT syndrome; and VHD, valvular heart disease. prophylactic ICD patients with channelopathies and review of stored arrhythmic events classified by a inherited cardiomyopathies presented a low risk of blinded committee of experts. life-threatening VA. Finally, delayed high-rate and single-zone detection programming were poorly implemented in patients with daily clinical ICD, and SVA and Appropriate ICD Therapies they were confirmed as essential programming The incidence of SVA and appropriate ICD interven- strategies. tions has declined over the past years. In major ICD To the best of our knowledge, this is the first large- trials, the incidence of appropriate therapies ranged scale study of ICD carriers including patients with no from 17% to 31% in PP to 54% to 64% in SP stud- restriction on ICD indication or underlying heart dis- ies.9 Similar rates were reported in observational ease. This point allows us to compare the evolution registries10,11 with short-term follow-up that did not in- of different populations using an ICD in a real-life sce- clude channelopathies or inherited cardiomyopathies. nario. The rigorous follow-up allowed by the remote More modern real-world studies reported a lower rate monitoring guarantees a reliable incidence of arrhyth- of life-threatening VA. In the DANISH ICD registry,12 mia and ICD interventions and offers the opportunity to only 13.5% of the 1609 ischemic patients carrying explore the impact that currently recommended pro- a prophylactic ICD received an appropriate therapy. gramming strategies have on outcomes. A strength of Nevertheless, the authors admit some underreporting the UMBRELLA study is that it provides a systematic of therapies, which is rare in the UMBRELLA study J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.0181088 Briongos-Figuero et al UMBRELLA Study Table 4. Multivariate Cox Regression Analysis of the Study End Points End Point Variable HR (95% CI) P Value First appropriate ICD therapy Clinical parameters Age 1.01 (1.00–1.01) 0.023 Sex (men) 1.57 (1.26–1.94) <0.001 AF 1.29 (1.12–1.49) <0.001 Secondary prevention 1.96 (1.67–2.31) <0.001 QRS width, ms >150 0.98 (0.81–1.21) 0.896 120–150 1.32 (1.09–1.61) 0.005 <120 REF LVEF, % ≤35 1.53 (1.18–1.97) 0.001 36–50 1.21 (0.92–1.58) 0.168 >50 REF Type of device CRT-D 0.76 (0.61–0.94) 0.011 Dual-chamber ICD 1.03 (0.88–1.21) 0.711 Single-chamber ICD REF ICD settings Single-zone programming 0.69 (0.59–0.81) <0.001 Delayed high-rate detection* 0.76 (0.61–0.94) 0.012 Causative subgroups DCM 1.30 (1.02–1.66) 0.036 VHD 1.54 (1.08–2.20) 0.018 ARVC 1.72 (1.14–2.61) 0.010 Downloaded from http://ahajournals.org by on March 28, 2023 BS 0.32 (0.15–0.67) 0.003 All-cause death Clinical parameters Age 1.05 (1.04–1.06) <0.001 AF 1.31 (1.09–1.59) 0.004 Sex (men) 1.43 (1.07–1.93) 0.016 CKD 1.75 (1.43–2.15) <0.001 DM 1.63 (1.35–1.96) <0.001 LVEF, % ≤35 2.44 (1.65–3.62) <0.001 36–50 1.79 (1.14–2.80) 0.011 >50 REF Inappropriate shock Clinical parameters Age 0.98 (0.97–0.99) 0.001 AF 2.40 (1.73–3.32) <0.001 ICD settings Single-zone programming 0.71 (0.51–0.97) 0.035 AF indicates atrial fibrillation; ARVC, arrhythmogenic right ventricular cardiomyopathy; BS, Brugada syndrome; CKD, chronic kidney disease; CRT-D, cardiac resynchronization therapy-defibrillator; DCM, dilated cardiomyopathy; DM, diabetes mellitus; HR, Hazard ratio; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; REF, reference group; and VHD, valvular heart disease. *Among primary prevention patients. because of the automatic storage of all arrhythmic The incidence of appropriate therapies in the events. A contemporary but retrospective study from UMBRELLA study ranges from 7% in patients with Amara et al13 demonstrated 22.3% of appropriate BS to 38% in patients with ARVC. Our cohort is com- therapies after a 3-year follow-up in a cohort of PP posed of 8 different cardiomyopathies, includes PP ICD-only patients. and SP, and has long-term follow-up. This kind of J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.0181089 Briongos-Figuero et al UMBRELLA Study Event free survival (First ICD therapy) p < 0.001 p = 0.477 Delayed high-rate (PP) Non delayed high-rate (PP) Delayed high-rate (SP) A Non delayed high-rate (SP) Nº at risk No delayed high rate (PP) 1566 1305 1111 916 697 458 Delayed high rate (PP) 1185 928 655 357 223 119 No delayed high rate (SP) 1006 715 566 451 324 227 Delayed high rate (SP) 516 326 224 117 64 34 Event free survival (Inappropriate shock) + With Smartshock™ Technology Downloaded from http://ahajournals.org by on March 28, 2023 o Without Smarshock™ Technology p = 0.002 B Nº at risk With Smarshock 2909 2466 1947 1318 861 449 Without Smarshock 1134 1062 999 904 785 613 Figure 3. Kaplan-Meier curves for first appropriate implantable cardioverter-defibrillator (ICD) therapy, according to delayed high-rate detection stratified by ICD indication (A), and for inappropriate shock, according to SmartShock technology (B). PP indicates primary prevention; and SP, secondary prevention. comparison has never been performed. VHD, ARVC, ≤35% was associated with a 1.5-fold increased risk, and DCM predicted a higher risk of appropriate whereas cardiac resynchronization therapy-defibril- ICD therapies, whereas BS correlated with lower lator patients, who have the chance for improved risk, which indicates the importance of a patholog- LVEF, were at significantly lower risk. This is some- ical myocardial substrate on the risk of SCD. LVEF what striking, as concerns about the benefit of ICD J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.01810810 Briongos-Figuero et al UMBRELLA Study in DCM are still present.14 Our results suggest that patients using an ICD is influenced mainly by patient patients with DCM, when carefully selected, are at comorbidities and LVEF. high risk of life-threatening VA and may obtain a Predictors of death found in the UMBRELLA study similar benefit as other high-risk populations (ICM/ are in agreement with the results of developed risk ARVC). In addition, the high arrhythmia risk found models.17–19 Increasing age, AF, chronic kidney dis- in patients with VHD agrees with published data on ease, diabetes mellitus, and impaired LVEF are well-es- PP patients.15 Left ventricle overload and remodel- tablished predictors of death in patients using an ICD. ing attributable to valvular dysfunction seem to offer Nevertheless, most of the models were performed with another pathological substrate for the occurrence of cohorts of PP and ischemic patients. life-threatening VA. ICD shocks are life saving, but they are also as- Other Subgroups sociated with an increased risk of complications and In the UMBRELLA study, the risk of arrhythmic death. We found that 14.3% of episodes of SVA did events and death was low among HCM, LQTS, and not receive an ICD intervention, which supports the BS carriers of a prophylactic ICD. As RTs are lack- existence of non–life-threatening episodes of SVA. ing, recommendations for ICD implantation have Current consensus recommends shock reduction been derived from small observational reports.3–6 strategies based on high-rate cutoffs, delayed pro- Several stratification methods have been proposed gramming, and single-zone detection.8 These rec- to determine the minimum risk of SCD that could jus- ommendations were derived from trials performed tify a prophylactic ICD. A 5-year risk of SCD ≥6% mainly in patients with HF. In the UMBRELLA study, supposes a class IIa recommendation for an ICD in high-rate cutoffs were commonly programmed patients with HCM,3 and BS patients with 2 risk fac- through the VF zone, but number of intervals to de- tors had a 5-year risk of arrhythmic events of 10.2% tect <30/40 was present in 58% of patients and VT in a recently developed score.6 In the UMBRELLA zones were enabled in many PP patients. This may study population of patients with HCM, LQTS, and be explained by the 12-year period of patient enroll- BS, the risk of appropriate ICD therapy after a mean ment in which recommendations were continuously follow-up of 46 months ranged from 0% to 10.1%, evolving. in PP setting. Therefore, in the absence of RTs, bet- Our results endorse the usefulness of single-zone ter stratification methods are necessary to select PP detection and the combination of high-rate intervals Downloaded from http://ahajournals.org by on March 28, 2023 candidates with enough 5-year risk of SCD to sup- with delayed detection. This setting was associated port the implantation of an ICD. with 24% lower risk of appropriate ICD therapies among PP patients. Thus, despite an increase in the adoption of delayed programming throughout the Inappropriate Shocks study period, current programming recommenda- Current programming recommendations led to a re- tions still need to be implemented in patients using duction of IS rates to <5%.8 This tendency was con- an ICD. firmed in the UMBRELLA study, with an annual rate of 1.53%. Our results also agree with contemporary recommendations, as single-zone detection correlated All-Cause Death with 29% lower risk of IS. Mortality was lower in the UMBRELLA study than AF was the leading cause of IS and correlated with in other observational reports,11–13,16 which may be a 2.4-fold increased risk, but we also found that age related to the inclusion of low-risk populations. Our was associated with a lower risk of IS. Although elderly study reinforces the idea that ICM has an unfavora- patients are more prone to developing AF, the prob- ble prognosis. In addition, the prognosis of DCM was ability of rapid ventricular conduction may be lower. similar to ICM; thus, death in patients with left ven- Thus, IS reduction strategies should be enhanced tricular systolic dysfunction seems to be barely influ- among younger patients using an ICD. enced by the cause of HF. Another important finding In theory, dual-chamber devices have more power is that patients with VHD were not only at high risk to discriminate between supraventricular tachycardia of life-threatening VA, but also death. Therefore, they and VA, but several studies have failed to demonstrate probably represent a subgroup of patients with HF this.8 We think that our heterogeneous population sup- who may obtain a similar benefit from ICD as other poses a barrier to identifying any potential benefit. We patients with left ventricular systolic dysfunction.15 reported an independently lower risk of IS among du- However, the relationship between a high risk of ma- al-chamber ICDs in the UMBRELLA study population lignant VA and death is not always present, as with of PP patients with HF.20 SmartShock technology con- ARVC, which is mainly an electrical disease. Taken sists of 6 discrimination algorithms that are nominally together, the results indicate that the risk of death in activated to distinguish between true VA and other J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.01810811 Briongos-Figuero et al UMBRELLA Study rhythms. As observed in previous reports,21 the use Rodríguez, Hospital Universitario De Canarias (Tenerife); of SmartShock technology in modern-era ICD patients Luis Álvarez, Hospital Universitario Nuestra Señora with real-world programming led to a low IS rate in the De La Candelaria (Tenerife); Juanjo Olalla, Hospital UMBRELLA study. Universitario Marqués De Valdecilla (Santander); Javier Jiménez Díaz, Hospital General De Ciudad Real (Ciudad Limitations Real); Javier Balaguer, Hospital General Y Universitario De Guadalajara (Guadalajara); Miguel Ángel Arias, This study has limitations inherent to the observa- Hospital Virgen De La Salud (Toledo); Jerónimo Rubio, tional design. The UMBRELLA study is a single-brand Hospital Clinico Universitario De Valladolid (Valladolid); ICD study and, as such, extrapolation of the conclu- Marisa Fidalgo, Hospital De León (León); Francisco- sions to other brands should be made with caution. Javier García, Hospital Universitario De Burgos Nevertheless, characteristics of the UMBRELLA study (Burgos); Xavier Viñolas, Hospital De La Santa Creu I population are similar to the characteristics of patients Sant Pau (Barcelona); Josep Brugada, Hospital Clínico included in the last Spanish ICD Registry22 (Table S7), De Barcelona (Barcelona); Ignasi Anguera, Hospital which enrolled >90% of the devices implanted in our De Bellvitge (Barcelona); Roger Villuendas, Hospital country. Therefore, we believe our sample might rep- Germans Trias I Pujol (Barcelona); Rosa Porro, Hospital resent a real picture of the Spanish population using San Pedro De Alcántara (Cáceres); Joaquín Fernández an ICD. ICD programming evolved throughout the de la Concha, Hospital Infanta Cristina (Badajoz); Luisa 12-year period of patient inclusion. We did not study Pérez, Complejo Hospitalario Universitario A Coruña (A temporal trends in programming because this topic Coruña); Enrique García Campo, Complejo Hospitalario is currently being analyzed in another study by our Universitario De Vigo (Pontevedra); Ignacio Fernández group. Although we included several populations that Lozano, Hospital Universitario Puerta De Hierro are underrepresented in RTs, the small size of these (Majadahonda); Adolfo Fontenla, Hospital 12 De Octubre subgroups and the lack of specific predictors of death (Madrid); Julián Villacastín, Hospital Clínico San Carlos (ie, wall thickness in HCM) limit the power to extract (Madrid); Ángel Arenal, Hospital General Universitario stronger conclusions. Gregorio Marañón (Madrid); Roberto Muñoz Aguilera, Hospital Infanta Leonor (Madrid); Antonio Hernández, CONCLUSIONS Hospital Universitario Ramón Y Cajal (Madrid); Rafael Peinado, Hospital Universitario La Paz (Madrid); Arcadio Downloaded from http://ahajournals.org by on March 28, 2023 This contemporary nationwide study involved a broad García Alberola, Hospital Clínico Universitario Virgen ICD population with long-term follow-up. We observed De La Arrixaca (Murcia); Fernando Pérez Lorente, a decrease in the incidence of SVA, appropriate ICD Hospital General Universitario Reina Sofía (Murcia); therapies, IS, and death compared with previous ob- Nuria Basterra, Hospital de Navarra (Navarra); María servational and randomized studies. Patients with Fe Arcocha, Hospital de Basurto (Vizcaya); Andrés myocardial substrate derived from an impaired LVEF Bodegas, Hospital de Cruces (Baracaldo); Francisco (ICM, DCM, and VHD) were at higher risk of appropri- Zumalde, Hospital de Galdakao-Usansolo (Vizcaya); ate ICD interventions and death than those with chan- José B. Martínez Ferrer, Hospital Universitario De nelopathies and HCM. Áraba (Álava); José María Porres, Hospital Universitario A better SCD risk stratification is necessary in PP Donostia (Guipúzcoa); José Moreno Arribas, Hospital ICD patients with channelopathies and inherited car- Clínico San Juan (Alicante); Ricardo Ruiz, Hospital diomyopathies. A strategy based on delayed high-rate Clínico Universitario De Valencia (Valencia); Aurelio detection and single-zone programming still needs to Quesada, Hospital General Universitario De Valencia be implemented in modern-era patients using an ICD. (Valencia); Juan Gabriel Martínez, Hospital General Universitario De Alicante (Alicante); María José Sancho- Tello, Hospital Universitario Y Politécnico De La Fe APPENDIX (Valencia). Principal investigators and participating centers of the UMBRELLA study: Ricardo Pavón, Hospital Nuestra Señora De Valme (Sevilla); José María Arizón, Hospital ARTICLE INFORMATION Universitario Reina Sofía (Córdoba); Miguel Álvarez López, Received October 6, 2020; accepted October 28, 2020. Hospital Universitario Virgen De Las Nieves (Granada); Affiliations Javier Alzueta, Hospital Virgen De La Victoria (Málaga); From the Hospital Universitario Infanta Leonor, Madrid, Spain (S.B.-F.); Ernesto Díaz Infante, Hospital Universitario Virgen Universidad Complutense de Madrid, Madrid, Spain (S.B.-F.); Hospital Macarena (Sevilla); David Calvo, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain (A.G.-A.); Hospital Clínico Universitario de Valladolid, Valladolid, Spain (J.R.); Hospital Reina Sofía de Córdoba, Central De Asturias (Asturias); Juan Carlos Rodríguez, Córdoba, Spain (J.M.S.); Hospital Universitario de Canarias, Santa Cruz de Hospital Insular De Gran Canaria (Gran Canaria); Aníbal Tenerife, Spain (A.R.); Hospital Universitario La Paz, Madrid, Spain (R.P.); J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.01810812 Briongos-Figuero et al UMBRELLA Study Hospital Universitario Virgen de la Victoria, Málaga, Spain (J.A.); Hospital 9. Germano JJ, Reynolds M, Essebag V, Josephson ME. Frequency and Universitario de Áraba, Álava, Spain (J.B.M.-F.); Hospital Santa Creu i Sant causes of implantable cardioverter-defibrillator therapies: is device ther- Pau, Barcelona, Spain (X.V.); Hospital Infanta Cristina, Badajoz, Spain (J.F.d.); apy proarrhythmic? Am J Cardiol. 2006;97:1255–1261. Hospital Universitario de Bellvitge, Barcelona, Spain (I.A.); Medtronic Ibérica, 10. van Welsenes GH, van Rees JB, Borleffs CJW, Cannegieter SC, Bax JJ, Madrid, Spain (M.M., L.C.); and Complexo Hospitalario Universitario de A van Erven L, Schalij MJ. Long-term follow-up of primary and second- Coruña, A Coruña, Spain (L.P.). ary prevention implantable cardioverter defibrillator patients. Europace. 2011;13:389–394. Acknowledgments 11. MacFadden DR, Crystal E, Krahn AD, Mangat I, Healey JS, Dorian P, The authors appreciate the efforts made by the investigators of the Birnie D, Simpson CS, Khaykin Y, Pinter A, et al. Sex differences in im- UMBRELLA study and Medtronic personnel who have contributed to the plantable cardioverter-defibrillator outcomes: findings from a prospec- success of this project. tive defibrillator database. Ann Intern Med. 2012;156:195–203. DOI: 10.7326/0003-4819-156-3-20120​2070-00007. Sources of Funding 12. Weeke P, Johansen JB, Jorgensen OD, Nielsen JC, Moller M, Videbaek The UMBRELLA study was supported by Medtronic Iberica. R, Hojgaard MV, Riahi S, Jacobsen PK. Mortality and appropriate and inappropriate therapy in patients with ischaemic heart disease and Disclosures implanted cardioverter-defibrillators for primary prevention: data from Dr Briongos-Figuero reports personal fees and nonfinancial support from the Danish ICD Register. Europace. 2013;15:1150–1157. DOI: 10.1093/ Medtronic Iberica and personal fees from Boston Scientific. Dr García- europ​ace/eut017. Alberola reports grants from Medtronic. Dr Rubio reports personal fees 13. Amara N, Boveda S, Defaye P, Klug D, Treguer F, Amet D, Perier M- from Medtronic, St. Jude, and Boston Scientific. Dr Segura reports per- C, Gras D, Algalarrondo V, Bouzeman A, et al. Implantable cardio- sonal fees from Medtronic and grants from Boston Scientific. Dr Peinado verter-defibrillator therapy among patients with non-ischaemic vs. reports personal fees from Medtronic and grants from Medtronic, Boston ischaemic cardiomyopathy for primary prevention of sudden cardiac Scientific, and Abbot. Dr Martínez-Ferrer reports personal fees and non- death. Europace. 2018;20:65–72. financial support from Medtronic. Drs Martín and Cerdá are employees of 14. Køber L, Thune JJ, Nielsen JC, Haarbo J, Videbæk L, Korup E, Jensen Medtronic. G, Hildebrandt P, Steffensen FH, Bruun NE, et al. Defibrillator implan- tation in patients with nonischemic systolic heart failure. N Engl J Med. Supplementary Material 2016;375:1221–1230. DOI: 10.1056/NEJMo​a1608029. Tables S1–S7 15. 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Fontenla A, Martinez-Ferrer JB, Alzueta J, Vinolas X, Garcia-Alberola 21. Auricchio A, Schloss EJ, Kurita T, Meijer A, Gerritse B, Zweibel S, A, Brugada J, Peinado R, Sancho-Tello MJ, Cano A, Fernandez- AlSmadi FM, Leng CT, Sterns LD. Low inappropriate shock rates in pa- Lozano I. Incidence of arrhythmias in a large cohort of patients with tients with single- and dual/triple-chamber implantable cardioverter-de- current implantable cardioverter-defibrillators in Spain: results from the fibrillators using a novel suite of detection algorithms: PainFree SST UMBRELLA Registry. Europace. 2016;18:1726–1734. trial primary results. Heart Rhythm. 2015;12:926–936. DOI: 10.1016/j. 8. Wilkoff BL, Fauchier L, Stiles MK, Morillo CA, Al-Khatib SM, Almendral hrthm.2015.01.017. J, Aguinaga L, Berger RD, Cuesta A, Daubert JP, et al. 2015 HRS/ 22. Fernandez Lozano I, Osca Asensi J, Alzueta RJ. Spanish Implantable EHRA/APHRS/SOLAECE expert consensus statement on optimal Cardioverter-Defibrillator Registry: 15th Official Report of the Spanish implantable cardioverter-defibrillator programming and testing. Heart Society of Cardiology Electrophysiology and Arrhythmias Section Rhythm. 2016;13:e50–e86. (2018). Rev Esp Cardiol (Engl Ed). 2019;72:1054–1064. J Am Heart Assoc. 2021;10:e018108. DOI: 10.1161/JAHA.120.01810813 SUPPLEMENTAL MATERIAL Downloaded from http://ahajournals.org by on March 28, 2023 Table S1. Baseline characteristics according to date of ICD implant. 2005-2009 2010-2014 2015-2017 N (%) 344 (8) 2744 (63.9) 1208 (28.1) Age (years), mean (± SD) 61.5 ± 13.7 61.9 ± 13.2 62.3 ± 12.0 Sex (male) 290 (84.3) 2259 (82.4) 978 (81.0) Hypertension 158 (47.7) 1449 (54.4) 668 (56.3) Diabetes 72 (21.9) 742 (28.0) 364 (30.8) Hypercholesterolaemia 157 (49.5) 1315 (52.0) 568 (54.7) Smoking status 115 (39.9) 867 (35.4) 433 (42.8) History of atrial fibrillation 116 (34.8) 745 (27.9) 374 (31.4) Previous stroke 18 (6.0) 167 (6.8) 67 (7.0) Chronic kidney disease 42 (12.9) 410 (15.6) 181 (15.4) Family history of SCD 29 (9.0) 241 (9.3) 86 (7.3) LV ejection fraction ≤ 35% 217 (63.5) 1807 (66.1) 817 (68.0) 36-50% 57 (16.7) 399 (14.6) 175 (14.6) > 50% 68 (19.9) 528 (19.3) 210 (17.5) QRS width <120 ms 160 (47.6) 1398 (52.0) 644 (54.9) 120-150 ms 72 (21.4) 575 (21.4) 230 (19.6) >150 ms 104 (31.0) 717 (26.7) 298 (25.4) Previous heart failure 152 (76.8) 1088 (82.8) 481 (83.2) Type of device VR 159 (46.2) 1237 (45.1) 631 (52.1) DR 77 (22.4) 682 (24.9) 213 (17.6) Downloaded from http://ahajournals.org by on March 28, 2023 CRT-D 108 (31.4) 825 (30.1) 364 (30.1) Primary prevention 210 (61.0) 1735 (63.2) 818 (67.7) Data are given as n (%) unless otherwise noted. CRT-D: cardiac resynchronization therapy defibrillator; LV: left ventricle; SCD: sudden cardiac death; SD: standard deviation. Table S2. Number of patients in whom baseline data are available. Baseline characteristics Valid data, n (%) Age 4296 (100) Sex 4296 (100) Hypertension 4184 (97.4) Diabetes 4166 (97) Hypercholesterolaemia 3884 (90.4) Smoking status 3752 (87.3) History of atrial fibrillation 4198 (97.7) Previous stroke 3702 (86.2) Chronic kidney disease 4132 (96.2) Family history of SCD 4090 (95.2) LV ejection fraction 4278 (99.6) QRS width 4198 (97.7) Previous heart failure 4259 (99.1) Type of device 4296 (100) ICD indication (primary vs. secondary 4296 (100) prevention) ICD programming Detection zones enabled 4293 (99.9) Downloaded from http://ahajournals.org by on March 28, 2023 VF detection interval 4295 (99.9) NID within VF detection zone 4295 (99.9) Fast VT detection zone enabled 4293 (99.9) Fast VT detection interval* 1557 (100) VT detection interval 4295 (99.9) NID within VT detection zone** 2440 (100) SmartShock™ Technology capable device 4065 (94.6%) ICD: Implantable cardioverter-defibrillator; LV: left ventricle; NID: number of intervals to detect; SCD: sudden cardiac death; VF: ventricular fibrillation; VT: ventricular tachycardia. *Data correspond to total of patients with a fast VT zone enabled. **Data correspond to total of multizone patients. Table S3. Devices included in UMBRELLA study. Single-chamber Models without SmartShock® Technology n EnTrust D154VRC 47 Maximo II VR D264VRM 55 Maximo II VR D284VRC 141 Secura VR D214VRM 35 Secura VR D234VRC 179 Virtuoso II VR D294VRC 58 Virtuoso VR D164VWC 130 Subtotal 645 (29%) Models with SmartShock® Technology Evera MRI S VR DVMC3D4 234 Evera MRI XT VR DVMB2D4 140 Evera S VR DVBC3D1 67 Evera S VR DVBC3D4 171 Evera XT VR DVBB2D1 42 Evera XT VR DVBB2D4 24 Protecta VR D364VRG 135 Protecta VR D364VRM 293 Protecta XT VR D354VRG 115 Protecta XT VR D354VRM 121 Downloaded from http://ahajournals.org by on March 28, 2023 Visia AF MRI S VR DVFC3D4 70 Visia AF MRI XT VR DVFB2D4 102 Visia AF MRI™ S VR 5 Visia AF MRI™ XT VR 4 Visia AF S VR DVAC3D1 7 Visia AF XT VR DVAB2D1 12 Subtotal 1542 (71%) TOTAL 2187 Dual-chamber Models without SmartShock® Technology n EnTrust D154ATG 20 Maximo II DR D264DRM 17 Maximo II DR D284DRG 44 Secura DR D214DRM 12 Secura DR D234DRG 103 Virtuoso DR D164AWG 57 Virtuoso II DR D294DRG 55 Intrinsic ICD 7288 1 Subtotal 309 (30%) Models with SmartShock® Technology n Evera MRI S DR DDMC3D1 1 Evera MRI S DR DDMC3D4 54 Evera MRI XT DR 7 Evera MRI XT DR DDMB2D4 140 Evera S DR DDBC3D1 39 Evera S DR DDBC3D4 68 Evera XT DR DDBB2D1 38 Evera XT DR DDBB2D4 23 Protecta DR D364DRG 61 Protecta DR D364DRM 105 Protecta XT DR D354DRG 93 Downloaded from http://ahajournals.org by on March 28, 2023 Protecta XT DR D354DRM 89 Subtotal 718 (70%) TOTAL 1027 Cardiac Resynchronization Therapy-Defibrillators Models without SmartShock® Technology n Concerto C174AWK 63 Concerto II CRT-D D294TRK 28 Consulta CRT-D D214TRM 60 Consulta CRT-D D234TRK 194 Maximo II CRT-D D264TRM 12 Maximo II CRT-D D284TRK 52 Subtotal 409 (29%) Models with SmartShock® Technology n Amplia MRI™ CRTD 8 Amplia MRI™ Quad CRTD 20 Brava CRT-D DTBC2D1 60 Brava CRT-D DTBC2D4 39 Brava Quad CRT-D DTBC2Q1 5 Brava Quad CRT-D DTBC2QQ 134 Claria MRI™ CRTD 17 Claria MRI™ Quad CRTD 45 Compia MRI™ CRTD 7 Compia MRI™ Quad CRTD 13 Protecta CRT-D D364TRG 46 Protecta CRT-D D364TRM 72 Protecta XT CRT-D D354TRG 109 Downloaded from http://ahajournals.org by on March 28, 2023 Protecta XT CRT-D D354TRM 87 Viva Quad S CRT-D DTBB2Q1 1 Viva Quad S CRT-D DTBB2QQ 27 Viva Quad XT CRT-D DTBA2Q1 7 Viva Quad XT CRT-D DTBA2QQ 171 Viva S CRT-D DTBB2D1 10 Viva S CRT-D DTBB2D4 10 Viva XT CRT-D DTBA2D1 51 Viva XT CRT-D DTBA2D4 56 Subtotal 995 (71%) TOTAL 1404 Table S4. Device programming according to date of ICD implant. 2005-2009 2010-2014 2015-2017 p value (N=344) (N=2744) (N=1208) Detection zones enabled < 0.001 • Single-zone * 119 (34.6) 1116 (40.7) 618 (51.2) • Multi-zone 225 (65.5) 1627 (59.3) 588 (48.8) VF detection interval, ms 302.7 ± 21.4 303.5 ± 19.2 301.0 ± 18.9 0.001 NID < 0.001 • < 30/40 314 (91.3) 1998 (72.8) 178 (14.6) • ≥ 30/40 30 (8.7) 746 (27.2) 1023 (85.3) Fast VT detection zone enabled** 119 (34.6) 951 (34.7) 487 (40.4) 0.002 Fast VT detection interval**, ms 270.59 ± 31.7 267.3 ± 31 263.6 ± 24.8 0.014 VT detection interval†, ms 368.4 ± 31.1 362.4 ± 25.4 357.9 ± 22.4 < 0.001 NID † < 0.001 • ≤16 181 (80.4) 1014 (62.3) 200 (34.0) • ≥20 44 (19.6) 613 (37.7) 388 (66.0) SmartShock™ Technology-capable device 40 (16.6) 1740 (66.4) 1150 (95.5) < 0.001 Data are given as n (%) or mean±standard deviation. ICD: Implantable cardioverter-defibrillator; NID: Downloaded from http://ahajournals.org by on March 28, 2023 number of intervals to detect; VF: ventricular fibrillation; VT: ventricular tachycardia. * Patients with fast VT zone enabled through VF zone, but without any other VT zone activated were also considered as single-zone detection patients. ** Through VF detection zone. † Applies only to multi-zone detection programming patients. Table S5. Causes of death. Cause of death N (%) Heart failure 214 (36.3%) Sudden cardiac death 26 (4.4%) Non-cardiovascular 190 (32.2%) Unknown 160 (27.1%) Total deaths 590 (100%) Downloaded from http://ahajournals.org by on March 28, 2023 Table S6. Causes of inappropriate shock. Cause of inappropriate shock Episodes, n (%) Atrial fibrillation 254 (42.3%) Other SVT* 95 (15.9%) Non-sustained MVT 52 (8.6%) T-wave oversensing 95 (15.9%) Noise 60 (10%) Sinus tachycardia 24 (4%) False detection 7 (1.2%) Possible SVT 13 (2.1%) Total episodes 600 (100%) MVT: monomorphic ventricular tachycardia; SVT: supraventricular tachycardia. *i.e., atrial flutter, atrial tachycardia, atrioventricular node re-entry tachycardia. Downloaded from http://ahajournals.org by on March 28, 2023 Table S7. Comparison between the UMBRELLA population and the patients enrolled in the last Spanish ICD registry. UMBRELLA Spanish ICD population registry 22 Age (years), mean(± SD) 61.9±12.9 62.4±13.5 Sex (male) 82.1 82 Hypertension 54.4 57 Diabetes 28.3 30 Hypercholesterolaemia 52.5 48 Smoking status 37.7 35 History of atrial fibrillation 29.4 27 Previous stroke 6.8 6 Chronic kidney disease 15.3 15 Family history of SCD 8.7 9 LV ejection fraction ≤ 35% 66.4 54 36-50% 14.7 27.4 > 50% 18.9 18.5 QRS width <120 ms 52.4 N/R 120-150 ms 20.9 N/R >150 ms 26.7 N/R* Downloaded from http://ahajournals.org by on March 28, 2023 Previous heart failure 69.8 N/R Type of device VR 47.2 50.1 DR 22.6 13.4 CRT-D 30.2 30.6 Primary prevention 64.2 65.7 Underlying heart disease ICM 50 52.9 DCM 27.3 26.1 HCM 7.4 7.1 ARVC 1.9 1.1 VHD 2.8 1.6 BS 3.5 2.3 LQTS 1.1 0.6 ACHD 1.4 N/R Data are given as % unless otherwise noted. ACHD: adult congenital heart disease; ARVC: arrhythmogenic right ventricular cardiomyopathy; BS: Brugada syndrome; CRT-D: cardiac resynchronization therapy defibrillator; DCM: dilated cardiomyopathy; HCM: hypertrophic cardiomyopathy; ICD: implantable cardioverter-defibrillator; ICM: ischaemic cardiomyopathy; LQTS: long QT syndrome; LV: left ventricle; N/R: not reported; SCD: sudden cardiac death; SD: standard deviation; VHD: valvular heart disease. *39% of patients had QRS > 140 ms.