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Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices
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JJCC-1948; No. of Pages 8 Journal of Cardiology xxx (2019) xxx–xxx
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Original article
Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices Nobuhiko Ueda (MD)a,b, Tsukasa Kamakura (MD PhD FJCC)a,*, Takashi Noda (MD PhD)a, Kenzaburo Nakajima (MD)a,b, Naoya Kataoka (MD PhD)a, Mitsuru Wada (MD)a,b, Kenichiro Yamagata (MD PhD)a, Kohei Ishibashi (MD PhD)a, Yuko Inoue (MD PhD)a, Koji Miyamoto (MD PhD)a, Satoshi Nagase (MD PhD)a, Takeshi Aiba (MD PhD)a, Chisato Izumi (MD PhD FJCC)a, Teruo Noguchi (MD PhD)a, Satoshi Yasuda (MD PhD FJCC)a,b, Kengo Kusano (MD PhD FJCC)a,b a b
Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan Department of Advanced Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 5 August 2019 Received in revised form 27 September 2019 Accepted 5 October 2019 Available online xxx
Background: Atrial tachyarrhythmias (ATAs) have a significant negative impact on the prognosis of patients implanted with cardiac resynchronization therapy (CRT) devices. New-generation atrial antitachycardia pacing (Reactive ATP, Medtronic Inc., Minneapolis, MN, USA) is effective in managing ATAs in patients implanted with pacemakers. The purpose of this study was to evaluate the efficacy and safety of Reactive ATP in patients implanted with CRT devices. Methods: This was a single-center retrospective study involving 72 CRT patients with a history of ATAs [44 patients with a device capable of Reactive ATP (ATP group) and 28 patients with a device without ATP function (Control group)]. The atrial fibrillation (AF) burden, the biventricular pacing rate, and clinical outcomes were compared between the two groups. Results: At baseline, there was no significant difference in the AF burden and biventricular pacing rate between the ATP and Control groups. During the 832 489 days of the follow-up period, 23 of the 44 patients (52%) received a total of 2862 ATP deliveries and the median ATP success rate was 23.6% (interquartile range: 12.5–50.0%) in the ATP group. The AF burden was significantly decreased only in the ATP group 6 months after ATP was programmed (from 6.1 18.2% to 2.0 5.4%, p = 0.0083) and maintained low throughout the follow-up period. Moreover, there were no Reactive ATP-related complications observed. Patients in the ATP group showed a significantly lower incidence of heart failure (HF) hospitalization (log-rank, p = 0.041) and ventricular arrhythmias (log-rank, p = 0.039) than those reported in the Control group. Conclusions: Reactive ATP successfully and safely reduced AF burden, and was associated with a lower incidence of HF hospitalization in patients implanted with CRT devices. © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Cardiac resynchronization therapy Atrial tachyarrhythmias Heart failure Ventricular arrhythmias Reactive atrial antitachycardia pacing
Introduction Cardiac resynchronization therapy (CRT) is an important component of the total management of patients with heart failure
* Corresponding author at: Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 6-1 Kishibe-shinmachi, Suita, Osaka 564-8565, Japan. E-mail address: [email protected] (T. Kamakura).
(HF). CRT improves the symptoms, quality of life, functional status, and mortality in patients with HF [1,2]. Atrial fibrillation (AF) and HF often develop concurrently and result in significant morbidity and mortality [3,4]. Approximately one-third of the patients who receive CRT suffer from AF, which attenuates the efficacy of CRT due to atrioventricular asynchrony and the loss of a sufficient biventricular (BiV) pacing delivery [5–8]. Thus, the management of atrial tachyarrhythmias (ATAs) in patients implanted with CRT devices is crucial.
https://doi.org/10.1016/j.jjcc.2019.10.001 0914-5087/© 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001
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Reentrant ATAs are potentially susceptible to termination by means of antitachycardia pacing (ATP) [9,10]. Reactive ATP (Medtronic Inc., Minneapolis, MN, USA) is a new-generation ATP that attempts to terminate ATAs in response to changes in the rate or regularity, when the episode may be most amenable to termination by pacing [11]. The MINimizE Right Ventricular pacing to prevent AF and HF (MINERVA) randomized trial reported that Reactive ATP was associated with a lower risk of progression to permanent AF in patients implanted with a pacemaker [11]. Recently, Reactive ATP was significantly associated with a reduced risk of ATAs even in the patients with defibrillator and resynchronization device [12]. However, there are no data regarding the impact of Reactive ATP on clinical outcomes such as HF hospitalization or ventricular arrhythmia (VA) in HF patients implanted with CRT devices. Therefore, the purpose of this study was to investigate the efficacy and safety of Reactive ATP in managing ATAs in patients implanted with CRT devices. Methods Study population This was a single-center, retrospective study. We investigated 72 consecutive patients with a history of ATAs and implanted with a CRT device. The ATP group consisted of 44 consecutive patients in whom Reactive ATP was programmed from 2013 to 2017. The Control group consisted of 28 consecutive patients implanted with CRT devices, without an ATP function during the same period. Device selection was decided by the treating physician. Reactive
ATP was programmed in all patients with CRT devices capable of Reactive ATP. Patients with permanent AF, a left ventricular assist device, or inappropriate AF detection due to oversensing were excluded. Study patients were registered using opt-out (http:// www.ncvc.go.jp/hospital/pub/clinical-research/untersuchung/ post_56.html). The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee (M26150-6). Reactive ATP and device programming The ATP settings were identical to those used in the MINERVA trial [11]. In brief, a mean atrial cycle length 350 ms was indicative of ATAs, and a delay of 1 min between the onset of ATA and ATP delivery was programmed. The ATA zone was subdivided into a series of narrower regions, namely the ATA zone (100–350 ms) divided into five 50 ms subzones for regular rhythms, and into three 50 ms and 100 ms subzones for irregular rhythms (i.e., 100– 200 ms, 200–300 ms, and 300–350 ms). Each subzone was supplied with a separate set of atrial ATP therapies that were 10 Ramp sequences, 10 Burst + sequences, and 10 Ramp sequences. If the rhythm shifted into a different subzone because of a change in the cycle length or regularity, the device delivered therapies from those available in the new subzone (Fig. 1). An ATP therapy was considered successful if the sinus rhythm was confirmed within 20 s after the last ATP delivery [13]. ATP was programmed on the day of the first clinic follow-up visit after CRT implantation. Atrial leads were placed in the right atrial appendage in all
Fig. 1. Representative case of successful Reactive ATP delivery. Interval plot (A) and number of Reactive ATP attempts in the ATA detection subzones (B) for a specific ATA episode successfully terminated by Reactive ATP. Irregular and disorganized ATA, suggestive of AF, was detected and the first ATP therapy was delivered (solid box). However, AF continued for >7 h and 114 ATP therapies were delivered. Subsequently, the AF was suddenly organized into regular AT, and successfully terminated through atrial ATP (dotted box) (C). ATP, antitachycardia pacing; ATA, atrial tachyarrhythmia; AF, atrial fibrillation; AT, atrial tachycardia.
Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001
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Table 1 Comparisons of the characteristics between the patients in the Reactive ATP and Control groups. Clinical characteristics
Total (n = 72)
ATP group (n = 44)
Control group (n = 28)
p-value
Age, (years) Male, n (%) CRT-D / CRT-P, n (%) Secondary prevention, n (%) ICM/NICM, n (%) Medical History ATA, n (%) AF/AFL/AT, n (%) AF burden at baseline (%) AV block, n (%) History of VAs, n (%) History of PV isolation, n (%) History of cardiac surgery, n (%) Hypertension, n (%) Diabetes mellitus, n (%) Previous stroke or TIA, n (%) NYHA class II/III/IV before CRT implantation, n (%) CHADS2 score Medications AAD class III, n (%) b-blocker, n (%) Echocardiographic findings LVEF (%) Left atrial dimension (mm) Left atrial volume index (ml/m2) E/e’ Electrocardiographic findings QRS width (ms) LBBB / RBBB / IVCD / pacing, n (%)
67.0 14.0 55 (76) 62 (86) / 10 (14) 21 (34) 16 (22) / 56 (78)
64.6 14.9 31 (70) 42 (95) / 2 (5) 17 (40) 11 (25) / 33 (75)
70.9 11.6 24 (86) 20 (71) / 8 (29) 4 (20) 5 (18) / 23 (82)
0.062 0.13 0.004 0.10 0.47
72 (100) 65 (90) / 14 (19) / 23 (32) 6.0 18.8 17 (24) 32 (44) 3 (4) 12 (17) 28 (39) 19 (26) 7 (10) 35 (49) / 25 (35) / 12 (16)
44 (100) 38 (86) / 9 (21) / 17 (39) 6.1 18.2 10 (23) 22 (50) 3 (7) 5 (11) 14 (32) 10 (23) 5 (11) 20 (45) / 14 (32) / 10 (23)
28 (100) 27 (96) / 5 (18) / 6 (21) 5.9 20.0 7 (25) 10 (36) 0 (0) 7 (25) 14 (50) 9 (32) 2 (7) 15 (54) / 11 (39) / 2 (7)
1.00
2.0 1.1
1.9 1.1
2.1 1.0
0.44
45 (63) 69 (96)
30 (68) 43 (98)
15 (54) 26 (93)
0.21 0.32
28.6 10.4 44.5 7.1 63.4 22.0 13.9 8.3
28.2 10.2 44.7 8.1 62.7 21.2 15.0
29.3 11.0 44.2 5.2 64.5 23.5 12.0
0.65 0.78 0.74 0.18
161 36.9 17 (24) / 15 (20) / 23 (32) / 17 (24)
156.3 36.5 11 (25) / 9 (20) / 17 (39) / 7 (16)
168.4 36.9 6 (21) / 6 (21) / 6 (21) / 10 (37)
0.17 0.06
0.96 0.83 0.23 0.08 0.14 0.12 0.38 0.55 0.19
CRT-D, cardiac resynchronization therapy defibrillator; CRT-P, cardiac resynchronization therapy pacemaker; ICM, ischemic cardiomyopathy; NICM, non-ischemic cardiomyopathy; ATA, atrial tachyarrhythmia; AF, atrial fibrillation; AFL, atrial flutter; AT, atrial tachycardia; AV, atrioventricular; PV, pulmonary vein; VA, ventricular arrhythmia; TIA, transient ischemic attack; NYHA, New York Heart Association; AAD, antiarrhythmic drugs; LVEF, left ventricular ejection fraction; E/e’, the ratio of the early transmitral flow velocity and the early mitral annular velocity; LBBB, left bundle branch block; RBBB, right bundle branch block; IVCD, intraventricular conduction disturbance.
patients. CRT optimization was performed by the decision of each physician. Clinical data Clinical data were collected from all patients including the age, gender, underlying heart disease, New York Heart Association (NYHA) functional class, comorbidity, history of ATAs, and medications. In addition, echocardiographic data, such as the left ventricular ejection fraction (LVEF), left atrial dimension, ratio of the early transmitral flow velocity, and early mitral annular velocity (E/e’) were collected. The number of ATA episodes lasting 1 min, AF burden, atrial pacing rate, and BiV pacing rate during the follow-up period were also collected from all patients. In the ATP group, the number of ATP deliveries and success rate of ATP were evaluated. We also evaluated the incidence of the progression to persistent AF (i.e. AF episodes lasting 7 days), HF hospitalization, VA which lasted 30 s or treated by ATP or shock, and complications associated with the delivery of Reactive ATP. A CRT responder was defined as a patient with improvement of LVEF 10% and/or a reduction of LV end systolic volume 15% compared with the data of implantation at 6 months after CRT device implantation, which was the same as the definition of a positive CRT response [14,15]. The patients were followed up every 3–6 months for clinical review and device interrogation. The follow-up period commenced on the day of the first clinic visit after CRT implantation. Baseline data were defined as AF burden and BiV pacing rate from CRT implantation to the first clinic visit.
Statistical analysis The numeric values are presented as means standard deviation, or median and interquartile range (IQR), as appropriate. The categorical data were expressed as counts and percentages. Categorical differences between groups were evaluated using the chi-squared test or Fisher exact test, as appropriate. Continuous variables were compared using the Wilcoxon rank-sum test or the Kruskal–Wallis test. For a comparison between the AF burden and BiV pacing rate prior to and after ATP programming, we used the Wilcoxon signed-rank test. A value of p < 0.05 denoted statistical significance. Multivariate analysis was not performed to identify the risk factors for HF hospitalization and VAs due to the small sample size. All analyses were performed using the JMP 12 software (SAS Institute Inc., Cary, NC, USA). Results Clinical characteristics The clinical characteristics of the patients are shown in Table 1. There were no significant differences in the clinical characteristics between patients in the ATP and Control groups, except for the number of cardiac resynchronization therapy pacemaker (CRT-P) patients. The average duration from CRT implantation to the first clinic visit was 33.3 9.9 days in the ATP group and 35.3 13.2 days in the Control group, respectively (p = 0.45). At baseline, the AF burden was 6.1 18.2% and 5.9 20.0% in the ATP and Control groups, respectively
Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001
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Fig. 2. (A) Mean atrial tachycardia/atrial fibrillation (AT/AF) burden during the follow-up period. The AT/AF burden was significantly decreased from 6.1 18.2% to 2.0 5.4%, 6 months after programming (p = 0.0083). The AF burden was maintained lower than the baseline value throughout the follow-up period; however, the differences were not statistically significant. In contrast, there were no significant changes in the AT/AF burden observed in the Control group. Average and standard deviation are shown. (B) Number of atrial tachyarrhythmia episodes with duration 1 min per person. Although the difference was not statistically significant, the ATP group tended to have ATAs with shorter duration. Average and standard deviation are shown. (C) Median biventricular (BiV) pacing rate during the follow-up period. There were no significant changes in the BiV pacing rate in either of the groups. However, there was a tendency toward maintaining a high BiV pacing rate in the ATP group versus the Control group. Median and IQR are shown. AT, atrial tachycardia; AF, atrial fibrillation; ATP, antitachycardia pacing; ATA, atrial tachyarrhythmia.
(p = 0.96). There was no significant difference in the incidence of CRT responder between the ATP and Control groups [25 patients (57%) vs. 18 patients (64%), respectively, p = 0.53]. No patients underwent atrioventricular node ablation. Efficacy of Reactive ATP During the 832 489 days of the follow-up period, 23 patients (52%) in the ATP group and 13 patients (46%) in the Control group experienced a total of 5977 and 4694 ATA episodes lasting 1 min, respectively. There was no significant difference in the number of ATA episodes lasting 1 min per person between the two groups (260 495 vs. 361 573 episodes per person, respectively, p = 0.58). Median time to the first AF episode was 120 days (IQR: 12– 428 days) in the ATP group and 38 days (IQR: 12–163.5 days) in the Control group, respectively. In the ATP group, 23 of the 44 patients (52%) received a total of 2862 ATP deliveries. The median Reactive ATP efficacy during the follow-up period was 23.6% (IQR: 12.5–50.0%). The AF burden was significantly decreased in the ATP group 6 months after the Reactive ATP was programmed (from 6.1 18.2% to 2.0 5.4%, p = 0.0083). In contrast, there was no significant difference observed in the Control group (Fig. 2A). The AF burden in the ATP group was maintained lower than that
reported in the Control group throughout the follow-up period. The ATP group tended to have shorter episodes of ATAs than the Control group (Fig. 2B). The BiV pacing rate was maintained higher in the ATP group than that observed in the Control group; however, the difference was not statistically significant (Fig. 2C). A representative case, in which Reactive ATP was effective, is shown in Fig. 3. In this patient, successful management of the ATAs by Reactive ATP led to a decrease in the AF burden and an improvement in the BiV pacing rate. Predictors of ATP efficacy For the identification of clinical factors that predicted high ATP efficacy, we divided the patients in the ATP group into two subgroups according to the median ATP success rate (24%): high ATP efficacy (24%) and low ATP efficacy (<24%) groups. There were no significant differences in the baseline characteristics between these two groups (Table 2). Clinical outcome During the follow-up period, 21 patients (ATP: 11, control: 10) died (10 patients due to cardiac death), 23 patients (ATP: 11,
Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001
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Fig. 3. Representative case. This patient was a 68-year-old male with ischemic cardiomyopathy. He had undergone radiofrequency catheter ablation of atrial flutter and atrial tachycardia (AT); however, AT recurred. After the Reactive ATP was programmed, the ATAs were successfully terminated (ATP success rate: 67.2%), the AT/AF burden was decreased from 35.6% to 1.2%, and the BiV pacing rate was increased from 92.6% to 98.2% (A, B). ATP, antitachycardia pacing; ATA, atrial tachyarrhythmia; AF, atrial fibrillation; BiV, biventricular.
Table 2 Comparisons of the characteristics between the patients in the high and low antitachycardia pacing (ATP) efficacy groups divided by the median ATP success rate.
Age (years) Male, n (%) ICM / NICM, n (%) AT or AFL, n (%) CHADS2 score NYHA class II / III / IV before CRT implantation, n (%) AAD class III, n (%) b-blocker, n (%) LVEF (%) Left atrial dimension (mm) E/e’ Atrial pacing rate (%) CRT responder
High ATP efficacy (24%) (n = 11)
Low ATP efficacy (<24%) (n = 12)
p-value
61.4 20.1 7 (64) 4 (36) / 7 (64) 5 (45) 1.7 0.8 6 (55) / 3 (27)/2 (18) 8 (73) 10 (91) 27.0 12.3 44.3 9.0 13.5 7.8 69.9 27.1 4 (36)
60.1 7.4 6 (50) 1 (8) / 11 (92) 6 (50) 1.4 0.7 4 (33)/5(42)/3 (25) 8 (67) 12 (100) 25.9 11.1 46.5 7.9 11.7 3.7 61.1 28.3 7 (58)
0.84 0.51 0.10 0.83 0.32 0.59 0.75 0.22 0.83 0.56 0.52 0.46 0.29
ATP, antitachycardia pacing; ICM, ischemic cardiomyopathy; NICM, non-ischemic cardiomyopathy; AFL, atrial flutter; AT, atrial tachycardia; NYHA, New York Heart Association; AAD, antiarrhythmic drugs; LVEF, left ventricular ejection fraction; E/e’, the ratio of the early transmitral flow velocity and the early mitral annular velocity; CRT, cardiac resynchronization therapy.
control: 12) experienced HF hospitalization, 25 patients (ATP: 12, control: 13) had VA, and 12 patients (ATP: 9, control: 3) progressed to persistent AF. The patients in the ATP group had a significantly lower incidence of HF hospitalization (log-rank, p = 0.041) and VA (log-rank, p = 0.039) than those in the Control group (Fig. 4A, B). There were no significant differences in the incidence of progression to persistent AF and all-cause death between the two groups (Fig. 4C, D). Univariate analysis revealed that the use of Reactive ATP was a predictor of freedom from HF hospitalization and VAs (Table 3A, B).
battery drainage was evaluated based on the estimated battery longevity. No patients experienced 400 ATP deliveries. Battery drainage during 717 251 days of the follow-up period was not significantly different between patients with and without ATP deliveries (1.23 0.49 year per 1 year in patients with ATP deliveries vs. 1.19 0.43 year per 1 year in patients without ATP deliveries, p = 0.84).
Safety evaluation of Reactive ATP
Main findings
There were no severe complications such as unexpectedly rapid battery drainage and episodes of induced VAs. No patients complained of chest symptoms related to atrial pacing. In 28 patients implanted with Viva XT CRT-D or VivaTM CRT-P,
To the best of our knowledge, this is the first study to evaluate the efficacy and safety of Reactive ATP for the management of ATAs in patients implanted with CRT devices due to a severely depressed cardiac function. This study showed that Reactive ATP significantly
Discussion
Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001
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Fig. 4. (A) Kaplan–Meier analyses of the freedom from heart failure (HF) hospitalization during the follow-up period. The ATP group showed a significantly lower incidence of HF hospitalization versus the Control group (log-rank, p = 0.041). (B) Kaplan–Meier analyses of the freedom from ventricular arrhythmia (VA). The ATP group showed a significantly lower incidence of VA versus the Control group (log-rank, p = 0.039). (C) Kaplan–Meier analyses of the freedom from all-cause death. There was no significant difference in the incidence of all-cause death between the two groups (log-rank, p = 0.23). (D) Kaplan–Meier analysis of the freedom from progression to persistent atrial fibrillation (AF). There was no significant difference in the incidence of progression to persistent AF (log-rank, p = 0.44). ATP, antitachycardia pacing.
and safely reduced the AF burden, which was associated with a reduction in HF hospitalization. Management of ATAs in CRT patients The incidence of AF in patients implanted with CRT devices is 30–35% for paroxysmal AF and 20–25% for permanent AF [16,17]. AF exhibits loss of atrioventricular synchronicity and a higher risk for insufficient CRT delivery because of an uncontrolled heart rate, which causes hemodynamic deterioration [7,18]. The irregular rhythm of AF may facilitate the induction of VA due to short-longshort sequences [19]. These degenerative effects may result in a high incidence of HF hospitalization, occurrence of VA, and poor prognosis in CRT patients with ATAs [20–22]. The control of ATAs is important to maximize the efficacy of the CRT in patients with AF [23]. Recently, the Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) trial showed that maintaining the sinus rhythm through catheter ablation for AF was associated with a lower incidence of HF hospitalization in HF patients with cardiac implantable electronic devices and low LVEF [24]. The AF burden was significantly reduced only in the ablation group. This indicates that the reduction of the AF burden may play an important role in preventing HF. Moreover, the control of ATAs may lead to the reduction of the occurrence of VAs in patients with
reduced LVEF. Gasparini et al. [25] reported that ablation of the atrioventricular junction resulted in a lower incidence of appropriate implantable cardioverter defibrillator (ICD) therapies in CRT patients with AF. This observation may be explained by the fact that ablation of the atrioventricular junction prevents shortlong-short sequences. Efficacy of ATP in cardiac implantable electronic devices Atrial ATP can be an effective option for the control of ATAs in patients implanted with cardiovascular electronic devices. The efficacy of first-generation atrial ATP therapies in patients implanted with pacemakers is controversial, owing to the limitation of 30 ATP attempts [9,26] and its inability to terminate long-lasting ATAs. Reactive ATP, a second-generation atrial ATP, allows multiple deliveries of programmed atrial ATP therapies during ATAs in response to changes in the length of the atrial rhythm cycle or regularity. In addition, it opportunistically applies atrial ATP therapy when the episode is most vulnerable to pacing [27]. This feature is expected to increase the chances of ATA termination because disorganized ATAs can change to organized ATA [28]. Reactive ATP reduces the AF burden and incidence of progression to permanent AF in patients implanted with a pacemakers, defibrillators, and resynchronization devices [11,12]. However,
Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001
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JJCC-1948; No. of Pages 8 N. Ueda et al. / Journal of Cardiology xxx (2019) xxx–xxx Table 3 (A) Univariate analysis for the prediction of heart failure hospitalization during follow-up. (B) Univariate analysis for the prediction of ventricular arrhythmia during follow-up. Univariate analysis
Age Male ICM / NICM Hypertension Diabetes CHADS2 score NYHA class III or IV before CRT implantation AAD class III b-blocker LVEF (1% increase) Left atrial dimension (1 mm increase) E/e’ Atrial pacing rate (%) CRT responder Reactive ATP
HR
95%CI
p-value
1.01 1.07 1.32 0.84 0.56 0.91 1.95
0.97–1.04 0.43–3.24 0.48–3.20 0.35–1.93 0.16–1.49 0.59–1.34 0.85–4.84
0.73 0.89 0.56 0.69 0.26 0.64 0.12
7.58 0.78 0.93 1.02 0.99 1.00 0.51 0.43
2.22–47.4 0.16–13.9 0.88–0.98 0.96–1.08 0.92–1.04 0.99–1.01 0.22–1.17 0.19–0.99
0.0004 0.81 0.0043 0.46 0.63 0.92 0.11 0.049
Univariate analysis
Age Male ICM / NICM History of VAs Hypertension Diabetes CHADS2 score NYHA class III or IV before CRT implantation AAD class III b-blocker LVEF (1% increase) Left atrial dimension (1 mm increase) E/e’ Atrial pacing rate (%) CRT responder Reactive ATP
HR
95%CI
p-value
0.99 1.21 1.25 1.04 0.58 0.76 0.80 0.84
0.96–1.02 0.49–3.62 0.48–2.86 0.49–2.41 0.23–1.30 0.28–1.79 0.52–1.18 0.38–1.85
0.41 0.70 0.63 0.83 0.19 0.54 0.27 0.66
1.34 0.42 0.98 0.98 1.00 0.99 0.66 0.45
0.60–3.29 0.12–2.64 0.94–1.02 0.93–1.03 0.95–1.05 0.98–1.00 0.30–1.48 0.20–0.98
0.49 0.30 0.36 0.46 0.86 0.037 0.31 0.046
ICM, ischemic cardiomyopathy; NICM, non-ischemic cardiomyopathy; NYHA, New York Heart Association; AAD, antiarrhythmic drugs; LVEF, left ventricular ejection fraction; E/e’, the ratio of the early transmitral flow velocity and the early mitral annular velocity; CRT, cardiac resynchronization therapy; ATP, antitachycardia pacing; HR, hazard ratio; CI, confidence interval; VA, ventricular arrhythmia.
there have been no data regarding the clinical impact of Reactive ATP on the clinical outcomes such as HF hospitalization or VA in patients implanted with CRT devices. In the current study, Reactive ATP reduced the AF burden throughout the 2 years of the follow-up period, which possibly led to a reduction in HF hospitalization. Univariate analysis showed that the use of Reactive ATP was a predictor of HF hospitalization as well as the previously known predictors of HF hospitalization such as LVEF. In contrast to the MINERVA trial, the mean success rate of ATP was lower in CRT patients, and the reduction in AF burden was not associated with the prevention of persistent AF. This suggests that Reactive ATP is less effective in CRT patients than in those with a pacemaker. However, this modality can play an important role in CRT patients because reduction in AF burden helps to maintain cardiac hemodynamics by maintaining atrioventricular synchronicity and high BiV pacing rate. The lower efficacy rate in CRT patients may be due to a more damaged and enlarged left atrium than that observed in patients with pacemakers. Regarding the predictors of high ATP efficacy, the MINERVA trial reported that Reactive ATP was highly effective for regular AT with
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a long cycle length [27]. We compared the clinical characteristics between the high and low ATP efficacy groups to investigate predictors of high ATP efficacy in CRT patients. However, none of the clinical factors, including history of atrial tachycardia, atrial flutter, and antiarrhythmic drugs, were associated with high ATP efficacy. Further studies are warranted to evaluate the predictors of high ATP efficacy. Furthermore, this study showed the safety of Reactive ATP in patients with a reduced heart function. There were no severe complications related to the delivery of ATP, such as the induction of VA. The decrease in battery longevity was relatively small. This may also prompt to activate Reactive ATP in patients with CRT devices. Limitations Firstly, this was a single-center, retrospective study. The small number of patients may limit the interpretation of the results. In addition, this study was not randomized, which might affect the results. Although we cannot rule out the potential bias with our data, baseline characteristics are almost identical between the two groups including AF burden at baseline. We could also observe the benefit of Reactive ATP in the univariate analysis including risk factors for HF hospitalization and VA development. Secondly, the battery drainage was relatively small in a limited number of patients unless frequent ATP therapies were delivered. However, the risk of battery consumption should be kept in mind especially in patients with frequent ATP deliveries. Further prospective, multicenter studies, including a larger number of patients with CRT devices, are warranted to confirm these findings. Conclusions Reactive ATP reduced the AF burden and HF hospitalization in patients implanted with CRT devices. Reactive ATP can be an effective and safe option for the management of ATAs in CRT patients. Funding This study was supported by the intramural research fund (254-7, Kengo Kusano) for cardiovascular diseases of the National Cerebral and Cardiovascular Center and trust research and joint research funds of Medtronic Japan Co., Ltd. Disclosures Kengo Kusano and Takashi Noda received honoraria for lectures by Medtronic Japan Co., Ltd. References [1] Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003;289:2685–94. [2] Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–49. [3] Senni M, Tribouilloy CM, Rodeheffer RJ, Jacobsen SJ, Evans JM, Bailey KR, et al. Congestive heart failure in the community a study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 1998;98:2282–9. [4] Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003;91:2D–8D. [5] Dickstein K, Bogale N, Priori S, Auricchio A, Cleland JG, Gitt A, et al. The European cardiac resynchronization therapy survey. Eur Heart J 2009;30:2450–60. [6] Fein AS, Wang Y, Curtis JP, Masoudi FA, Varosy PD, Reynolds MR. Prevalence and predictors of off-label use of cardiac resynchronization therapy in patients
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JJCC-1948; No. of Pages 8 Journal of Cardiology xxx (2019) xxx–xxx
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Original article
Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices Nobuhiko Ueda (MD)a,b, Tsukasa Kamakura (MD PhD FJCC)a,*, Takashi Noda (MD PhD)a, Kenzaburo Nakajima (MD)a,b, Naoya Kataoka (MD PhD)a, Mitsuru Wada (MD)a,b, Kenichiro Yamagata (MD PhD)a, Kohei Ishibashi (MD PhD)a, Yuko Inoue (MD PhD)a, Koji Miyamoto (MD PhD)a, Satoshi Nagase (MD PhD)a, Takeshi Aiba (MD PhD)a, Chisato Izumi (MD PhD FJCC)a, Teruo Noguchi (MD PhD)a, Satoshi Yasuda (MD PhD FJCC)a,b, Kengo Kusano (MD PhD FJCC)a,b a b
Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan Department of Advanced Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 5 August 2019 Received in revised form 27 September 2019 Accepted 5 October 2019 Available online xxx
Background: Atrial tachyarrhythmias (ATAs) have a significant negative impact on the prognosis of patients implanted with cardiac resynchronization therapy (CRT) devices. New-generation atrial antitachycardia pacing (Reactive ATP, Medtronic Inc., Minneapolis, MN, USA) is effective in managing ATAs in patients implanted with pacemakers. The purpose of this study was to evaluate the efficacy and safety of Reactive ATP in patients implanted with CRT devices. Methods: This was a single-center retrospective study involving 72 CRT patients with a history of ATAs [44 patients with a device capable of Reactive ATP (ATP group) and 28 patients with a device without ATP function (Control group)]. The atrial fibrillation (AF) burden, the biventricular pacing rate, and clinical outcomes were compared between the two groups. Results: At baseline, there was no significant difference in the AF burden and biventricular pacing rate between the ATP and Control groups. During the 832 489 days of the follow-up period, 23 of the 44 patients (52%) received a total of 2862 ATP deliveries and the median ATP success rate was 23.6% (interquartile range: 12.5–50.0%) in the ATP group. The AF burden was significantly decreased only in the ATP group 6 months after ATP was programmed (from 6.1 18.2% to 2.0 5.4%, p = 0.0083) and maintained low throughout the follow-up period. Moreover, there were no Reactive ATP-related complications observed. Patients in the ATP group showed a significantly lower incidence of heart failure (HF) hospitalization (log-rank, p = 0.041) and ventricular arrhythmias (log-rank, p = 0.039) than those reported in the Control group. Conclusions: Reactive ATP successfully and safely reduced AF burden, and was associated with a lower incidence of HF hospitalization in patients implanted with CRT devices. © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Cardiac resynchronization therapy Atrial tachyarrhythmias Heart failure Ventricular arrhythmias Reactive atrial antitachycardia pacing
Introduction Cardiac resynchronization therapy (CRT) is an important component of the total management of patients with heart failure
* Corresponding author at: Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 6-1 Kishibe-shinmachi, Suita, Osaka 564-8565, Japan. E-mail address: [email protected] (T. Kamakura).
(HF). CRT improves the symptoms, quality of life, functional status, and mortality in patients with HF [1,2]. Atrial fibrillation (AF) and HF often develop concurrently and result in significant morbidity and mortality [3,4]. Approximately one-third of the patients who receive CRT suffer from AF, which attenuates the efficacy of CRT due to atrioventricular asynchrony and the loss of a sufficient biventricular (BiV) pacing delivery [5–8]. Thus, the management of atrial tachyarrhythmias (ATAs) in patients implanted with CRT devices is crucial.
https://doi.org/10.1016/j.jjcc.2019.10.001 0914-5087/© 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001
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Reentrant ATAs are potentially susceptible to termination by means of antitachycardia pacing (ATP) [9,10]. Reactive ATP (Medtronic Inc., Minneapolis, MN, USA) is a new-generation ATP that attempts to terminate ATAs in response to changes in the rate or regularity, when the episode may be most amenable to termination by pacing [11]. The MINimizE Right Ventricular pacing to prevent AF and HF (MINERVA) randomized trial reported that Reactive ATP was associated with a lower risk of progression to permanent AF in patients implanted with a pacemaker [11]. Recently, Reactive ATP was significantly associated with a reduced risk of ATAs even in the patients with defibrillator and resynchronization device [12]. However, there are no data regarding the impact of Reactive ATP on clinical outcomes such as HF hospitalization or ventricular arrhythmia (VA) in HF patients implanted with CRT devices. Therefore, the purpose of this study was to investigate the efficacy and safety of Reactive ATP in managing ATAs in patients implanted with CRT devices. Methods Study population This was a single-center, retrospective study. We investigated 72 consecutive patients with a history of ATAs and implanted with a CRT device. The ATP group consisted of 44 consecutive patients in whom Reactive ATP was programmed from 2013 to 2017. The Control group consisted of 28 consecutive patients implanted with CRT devices, without an ATP function during the same period. Device selection was decided by the treating physician. Reactive
ATP was programmed in all patients with CRT devices capable of Reactive ATP. Patients with permanent AF, a left ventricular assist device, or inappropriate AF detection due to oversensing were excluded. Study patients were registered using opt-out (http:// www.ncvc.go.jp/hospital/pub/clinical-research/untersuchung/ post_56.html). The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee (M26150-6). Reactive ATP and device programming The ATP settings were identical to those used in the MINERVA trial [11]. In brief, a mean atrial cycle length 350 ms was indicative of ATAs, and a delay of 1 min between the onset of ATA and ATP delivery was programmed. The ATA zone was subdivided into a series of narrower regions, namely the ATA zone (100–350 ms) divided into five 50 ms subzones for regular rhythms, and into three 50 ms and 100 ms subzones for irregular rhythms (i.e., 100– 200 ms, 200–300 ms, and 300–350 ms). Each subzone was supplied with a separate set of atrial ATP therapies that were 10 Ramp sequences, 10 Burst + sequences, and 10 Ramp sequences. If the rhythm shifted into a different subzone because of a change in the cycle length or regularity, the device delivered therapies from those available in the new subzone (Fig. 1). An ATP therapy was considered successful if the sinus rhythm was confirmed within 20 s after the last ATP delivery [13]. ATP was programmed on the day of the first clinic follow-up visit after CRT implantation. Atrial leads were placed in the right atrial appendage in all
Fig. 1. Representative case of successful Reactive ATP delivery. Interval plot (A) and number of Reactive ATP attempts in the ATA detection subzones (B) for a specific ATA episode successfully terminated by Reactive ATP. Irregular and disorganized ATA, suggestive of AF, was detected and the first ATP therapy was delivered (solid box). However, AF continued for >7 h and 114 ATP therapies were delivered. Subsequently, the AF was suddenly organized into regular AT, and successfully terminated through atrial ATP (dotted box) (C). ATP, antitachycardia pacing; ATA, atrial tachyarrhythmia; AF, atrial fibrillation; AT, atrial tachycardia.
Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001
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Table 1 Comparisons of the characteristics between the patients in the Reactive ATP and Control groups. Clinical characteristics
Total (n = 72)
ATP group (n = 44)
Control group (n = 28)
p-value
Age, (years) Male, n (%) CRT-D / CRT-P, n (%) Secondary prevention, n (%) ICM/NICM, n (%) Medical History ATA, n (%) AF/AFL/AT, n (%) AF burden at baseline (%) AV block, n (%) History of VAs, n (%) History of PV isolation, n (%) History of cardiac surgery, n (%) Hypertension, n (%) Diabetes mellitus, n (%) Previous stroke or TIA, n (%) NYHA class II/III/IV before CRT implantation, n (%) CHADS2 score Medications AAD class III, n (%) b-blocker, n (%) Echocardiographic findings LVEF (%) Left atrial dimension (mm) Left atrial volume index (ml/m2) E/e’ Electrocardiographic findings QRS width (ms) LBBB / RBBB / IVCD / pacing, n (%)
67.0 14.0 55 (76) 62 (86) / 10 (14) 21 (34) 16 (22) / 56 (78)
64.6 14.9 31 (70) 42 (95) / 2 (5) 17 (40) 11 (25) / 33 (75)
70.9 11.6 24 (86) 20 (71) / 8 (29) 4 (20) 5 (18) / 23 (82)
0.062 0.13 0.004 0.10 0.47
72 (100) 65 (90) / 14 (19) / 23 (32) 6.0 18.8 17 (24) 32 (44) 3 (4) 12 (17) 28 (39) 19 (26) 7 (10) 35 (49) / 25 (35) / 12 (16)
44 (100) 38 (86) / 9 (21) / 17 (39) 6.1 18.2 10 (23) 22 (50) 3 (7) 5 (11) 14 (32) 10 (23) 5 (11) 20 (45) / 14 (32) / 10 (23)
28 (100) 27 (96) / 5 (18) / 6 (21) 5.9 20.0 7 (25) 10 (36) 0 (0) 7 (25) 14 (50) 9 (32) 2 (7) 15 (54) / 11 (39) / 2 (7)
1.00
2.0 1.1
1.9 1.1
2.1 1.0
0.44
45 (63) 69 (96)
30 (68) 43 (98)
15 (54) 26 (93)
0.21 0.32
28.6 10.4 44.5 7.1 63.4 22.0 13.9 8.3
28.2 10.2 44.7 8.1 62.7 21.2 15.0
29.3 11.0 44.2 5.2 64.5 23.5 12.0
0.65 0.78 0.74 0.18
161 36.9 17 (24) / 15 (20) / 23 (32) / 17 (24)
156.3 36.5 11 (25) / 9 (20) / 17 (39) / 7 (16)
168.4 36.9 6 (21) / 6 (21) / 6 (21) / 10 (37)
0.17 0.06
0.96 0.83 0.23 0.08 0.14 0.12 0.38 0.55 0.19
CRT-D, cardiac resynchronization therapy defibrillator; CRT-P, cardiac resynchronization therapy pacemaker; ICM, ischemic cardiomyopathy; NICM, non-ischemic cardiomyopathy; ATA, atrial tachyarrhythmia; AF, atrial fibrillation; AFL, atrial flutter; AT, atrial tachycardia; AV, atrioventricular; PV, pulmonary vein; VA, ventricular arrhythmia; TIA, transient ischemic attack; NYHA, New York Heart Association; AAD, antiarrhythmic drugs; LVEF, left ventricular ejection fraction; E/e’, the ratio of the early transmitral flow velocity and the early mitral annular velocity; LBBB, left bundle branch block; RBBB, right bundle branch block; IVCD, intraventricular conduction disturbance.
patients. CRT optimization was performed by the decision of each physician. Clinical data Clinical data were collected from all patients including the age, gender, underlying heart disease, New York Heart Association (NYHA) functional class, comorbidity, history of ATAs, and medications. In addition, echocardiographic data, such as the left ventricular ejection fraction (LVEF), left atrial dimension, ratio of the early transmitral flow velocity, and early mitral annular velocity (E/e’) were collected. The number of ATA episodes lasting 1 min, AF burden, atrial pacing rate, and BiV pacing rate during the follow-up period were also collected from all patients. In the ATP group, the number of ATP deliveries and success rate of ATP were evaluated. We also evaluated the incidence of the progression to persistent AF (i.e. AF episodes lasting 7 days), HF hospitalization, VA which lasted 30 s or treated by ATP or shock, and complications associated with the delivery of Reactive ATP. A CRT responder was defined as a patient with improvement of LVEF 10% and/or a reduction of LV end systolic volume 15% compared with the data of implantation at 6 months after CRT device implantation, which was the same as the definition of a positive CRT response [14,15]. The patients were followed up every 3–6 months for clinical review and device interrogation. The follow-up period commenced on the day of the first clinic visit after CRT implantation. Baseline data were defined as AF burden and BiV pacing rate from CRT implantation to the first clinic visit.
Statistical analysis The numeric values are presented as means standard deviation, or median and interquartile range (IQR), as appropriate. The categorical data were expressed as counts and percentages. Categorical differences between groups were evaluated using the chi-squared test or Fisher exact test, as appropriate. Continuous variables were compared using the Wilcoxon rank-sum test or the Kruskal–Wallis test. For a comparison between the AF burden and BiV pacing rate prior to and after ATP programming, we used the Wilcoxon signed-rank test. A value of p < 0.05 denoted statistical significance. Multivariate analysis was not performed to identify the risk factors for HF hospitalization and VAs due to the small sample size. All analyses were performed using the JMP 12 software (SAS Institute Inc., Cary, NC, USA). Results Clinical characteristics The clinical characteristics of the patients are shown in Table 1. There were no significant differences in the clinical characteristics between patients in the ATP and Control groups, except for the number of cardiac resynchronization therapy pacemaker (CRT-P) patients. The average duration from CRT implantation to the first clinic visit was 33.3 9.9 days in the ATP group and 35.3 13.2 days in the Control group, respectively (p = 0.45). At baseline, the AF burden was 6.1 18.2% and 5.9 20.0% in the ATP and Control groups, respectively
Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001
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Fig. 2. (A) Mean atrial tachycardia/atrial fibrillation (AT/AF) burden during the follow-up period. The AT/AF burden was significantly decreased from 6.1 18.2% to 2.0 5.4%, 6 months after programming (p = 0.0083). The AF burden was maintained lower than the baseline value throughout the follow-up period; however, the differences were not statistically significant. In contrast, there were no significant changes in the AT/AF burden observed in the Control group. Average and standard deviation are shown. (B) Number of atrial tachyarrhythmia episodes with duration 1 min per person. Although the difference was not statistically significant, the ATP group tended to have ATAs with shorter duration. Average and standard deviation are shown. (C) Median biventricular (BiV) pacing rate during the follow-up period. There were no significant changes in the BiV pacing rate in either of the groups. However, there was a tendency toward maintaining a high BiV pacing rate in the ATP group versus the Control group. Median and IQR are shown. AT, atrial tachycardia; AF, atrial fibrillation; ATP, antitachycardia pacing; ATA, atrial tachyarrhythmia.
(p = 0.96). There was no significant difference in the incidence of CRT responder between the ATP and Control groups [25 patients (57%) vs. 18 patients (64%), respectively, p = 0.53]. No patients underwent atrioventricular node ablation. Efficacy of Reactive ATP During the 832 489 days of the follow-up period, 23 patients (52%) in the ATP group and 13 patients (46%) in the Control group experienced a total of 5977 and 4694 ATA episodes lasting 1 min, respectively. There was no significant difference in the number of ATA episodes lasting 1 min per person between the two groups (260 495 vs. 361 573 episodes per person, respectively, p = 0.58). Median time to the first AF episode was 120 days (IQR: 12– 428 days) in the ATP group and 38 days (IQR: 12–163.5 days) in the Control group, respectively. In the ATP group, 23 of the 44 patients (52%) received a total of 2862 ATP deliveries. The median Reactive ATP efficacy during the follow-up period was 23.6% (IQR: 12.5–50.0%). The AF burden was significantly decreased in the ATP group 6 months after the Reactive ATP was programmed (from 6.1 18.2% to 2.0 5.4%, p = 0.0083). In contrast, there was no significant difference observed in the Control group (Fig. 2A). The AF burden in the ATP group was maintained lower than that
reported in the Control group throughout the follow-up period. The ATP group tended to have shorter episodes of ATAs than the Control group (Fig. 2B). The BiV pacing rate was maintained higher in the ATP group than that observed in the Control group; however, the difference was not statistically significant (Fig. 2C). A representative case, in which Reactive ATP was effective, is shown in Fig. 3. In this patient, successful management of the ATAs by Reactive ATP led to a decrease in the AF burden and an improvement in the BiV pacing rate. Predictors of ATP efficacy For the identification of clinical factors that predicted high ATP efficacy, we divided the patients in the ATP group into two subgroups according to the median ATP success rate (24%): high ATP efficacy (24%) and low ATP efficacy (<24%) groups. There were no significant differences in the baseline characteristics between these two groups (Table 2). Clinical outcome During the follow-up period, 21 patients (ATP: 11, control: 10) died (10 patients due to cardiac death), 23 patients (ATP: 11,
Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001
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Fig. 3. Representative case. This patient was a 68-year-old male with ischemic cardiomyopathy. He had undergone radiofrequency catheter ablation of atrial flutter and atrial tachycardia (AT); however, AT recurred. After the Reactive ATP was programmed, the ATAs were successfully terminated (ATP success rate: 67.2%), the AT/AF burden was decreased from 35.6% to 1.2%, and the BiV pacing rate was increased from 92.6% to 98.2% (A, B). ATP, antitachycardia pacing; ATA, atrial tachyarrhythmia; AF, atrial fibrillation; BiV, biventricular.
Table 2 Comparisons of the characteristics between the patients in the high and low antitachycardia pacing (ATP) efficacy groups divided by the median ATP success rate.
Age (years) Male, n (%) ICM / NICM, n (%) AT or AFL, n (%) CHADS2 score NYHA class II / III / IV before CRT implantation, n (%) AAD class III, n (%) b-blocker, n (%) LVEF (%) Left atrial dimension (mm) E/e’ Atrial pacing rate (%) CRT responder
High ATP efficacy (24%) (n = 11)
Low ATP efficacy (<24%) (n = 12)
p-value
61.4 20.1 7 (64) 4 (36) / 7 (64) 5 (45) 1.7 0.8 6 (55) / 3 (27)/2 (18) 8 (73) 10 (91) 27.0 12.3 44.3 9.0 13.5 7.8 69.9 27.1 4 (36)
60.1 7.4 6 (50) 1 (8) / 11 (92) 6 (50) 1.4 0.7 4 (33)/5(42)/3 (25) 8 (67) 12 (100) 25.9 11.1 46.5 7.9 11.7 3.7 61.1 28.3 7 (58)
0.84 0.51 0.10 0.83 0.32 0.59 0.75 0.22 0.83 0.56 0.52 0.46 0.29
ATP, antitachycardia pacing; ICM, ischemic cardiomyopathy; NICM, non-ischemic cardiomyopathy; AFL, atrial flutter; AT, atrial tachycardia; NYHA, New York Heart Association; AAD, antiarrhythmic drugs; LVEF, left ventricular ejection fraction; E/e’, the ratio of the early transmitral flow velocity and the early mitral annular velocity; CRT, cardiac resynchronization therapy.
control: 12) experienced HF hospitalization, 25 patients (ATP: 12, control: 13) had VA, and 12 patients (ATP: 9, control: 3) progressed to persistent AF. The patients in the ATP group had a significantly lower incidence of HF hospitalization (log-rank, p = 0.041) and VA (log-rank, p = 0.039) than those in the Control group (Fig. 4A, B). There were no significant differences in the incidence of progression to persistent AF and all-cause death between the two groups (Fig. 4C, D). Univariate analysis revealed that the use of Reactive ATP was a predictor of freedom from HF hospitalization and VAs (Table 3A, B).
battery drainage was evaluated based on the estimated battery longevity. No patients experienced 400 ATP deliveries. Battery drainage during 717 251 days of the follow-up period was not significantly different between patients with and without ATP deliveries (1.23 0.49 year per 1 year in patients with ATP deliveries vs. 1.19 0.43 year per 1 year in patients without ATP deliveries, p = 0.84).
Safety evaluation of Reactive ATP
Main findings
There were no severe complications such as unexpectedly rapid battery drainage and episodes of induced VAs. No patients complained of chest symptoms related to atrial pacing. In 28 patients implanted with Viva XT CRT-D or VivaTM CRT-P,
To the best of our knowledge, this is the first study to evaluate the efficacy and safety of Reactive ATP for the management of ATAs in patients implanted with CRT devices due to a severely depressed cardiac function. This study showed that Reactive ATP significantly
Discussion
Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001
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Fig. 4. (A) Kaplan–Meier analyses of the freedom from heart failure (HF) hospitalization during the follow-up period. The ATP group showed a significantly lower incidence of HF hospitalization versus the Control group (log-rank, p = 0.041). (B) Kaplan–Meier analyses of the freedom from ventricular arrhythmia (VA). The ATP group showed a significantly lower incidence of VA versus the Control group (log-rank, p = 0.039). (C) Kaplan–Meier analyses of the freedom from all-cause death. There was no significant difference in the incidence of all-cause death between the two groups (log-rank, p = 0.23). (D) Kaplan–Meier analysis of the freedom from progression to persistent atrial fibrillation (AF). There was no significant difference in the incidence of progression to persistent AF (log-rank, p = 0.44). ATP, antitachycardia pacing.
and safely reduced the AF burden, which was associated with a reduction in HF hospitalization. Management of ATAs in CRT patients The incidence of AF in patients implanted with CRT devices is 30–35% for paroxysmal AF and 20–25% for permanent AF [16,17]. AF exhibits loss of atrioventricular synchronicity and a higher risk for insufficient CRT delivery because of an uncontrolled heart rate, which causes hemodynamic deterioration [7,18]. The irregular rhythm of AF may facilitate the induction of VA due to short-longshort sequences [19]. These degenerative effects may result in a high incidence of HF hospitalization, occurrence of VA, and poor prognosis in CRT patients with ATAs [20–22]. The control of ATAs is important to maximize the efficacy of the CRT in patients with AF [23]. Recently, the Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) trial showed that maintaining the sinus rhythm through catheter ablation for AF was associated with a lower incidence of HF hospitalization in HF patients with cardiac implantable electronic devices and low LVEF [24]. The AF burden was significantly reduced only in the ablation group. This indicates that the reduction of the AF burden may play an important role in preventing HF. Moreover, the control of ATAs may lead to the reduction of the occurrence of VAs in patients with
reduced LVEF. Gasparini et al. [25] reported that ablation of the atrioventricular junction resulted in a lower incidence of appropriate implantable cardioverter defibrillator (ICD) therapies in CRT patients with AF. This observation may be explained by the fact that ablation of the atrioventricular junction prevents shortlong-short sequences. Efficacy of ATP in cardiac implantable electronic devices Atrial ATP can be an effective option for the control of ATAs in patients implanted with cardiovascular electronic devices. The efficacy of first-generation atrial ATP therapies in patients implanted with pacemakers is controversial, owing to the limitation of 30 ATP attempts [9,26] and its inability to terminate long-lasting ATAs. Reactive ATP, a second-generation atrial ATP, allows multiple deliveries of programmed atrial ATP therapies during ATAs in response to changes in the length of the atrial rhythm cycle or regularity. In addition, it opportunistically applies atrial ATP therapy when the episode is most vulnerable to pacing [27]. This feature is expected to increase the chances of ATA termination because disorganized ATAs can change to organized ATA [28]. Reactive ATP reduces the AF burden and incidence of progression to permanent AF in patients implanted with a pacemakers, defibrillators, and resynchronization devices [11,12]. However,
Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001
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JJCC-1948; No. of Pages 8 N. Ueda et al. / Journal of Cardiology xxx (2019) xxx–xxx Table 3 (A) Univariate analysis for the prediction of heart failure hospitalization during follow-up. (B) Univariate analysis for the prediction of ventricular arrhythmia during follow-up. Univariate analysis
Age Male ICM / NICM Hypertension Diabetes CHADS2 score NYHA class III or IV before CRT implantation AAD class III b-blocker LVEF (1% increase) Left atrial dimension (1 mm increase) E/e’ Atrial pacing rate (%) CRT responder Reactive ATP
HR
95%CI
p-value
1.01 1.07 1.32 0.84 0.56 0.91 1.95
0.97–1.04 0.43–3.24 0.48–3.20 0.35–1.93 0.16–1.49 0.59–1.34 0.85–4.84
0.73 0.89 0.56 0.69 0.26 0.64 0.12
7.58 0.78 0.93 1.02 0.99 1.00 0.51 0.43
2.22–47.4 0.16–13.9 0.88–0.98 0.96–1.08 0.92–1.04 0.99–1.01 0.22–1.17 0.19–0.99
0.0004 0.81 0.0043 0.46 0.63 0.92 0.11 0.049
Univariate analysis
Age Male ICM / NICM History of VAs Hypertension Diabetes CHADS2 score NYHA class III or IV before CRT implantation AAD class III b-blocker LVEF (1% increase) Left atrial dimension (1 mm increase) E/e’ Atrial pacing rate (%) CRT responder Reactive ATP
HR
95%CI
p-value
0.99 1.21 1.25 1.04 0.58 0.76 0.80 0.84
0.96–1.02 0.49–3.62 0.48–2.86 0.49–2.41 0.23–1.30 0.28–1.79 0.52–1.18 0.38–1.85
0.41 0.70 0.63 0.83 0.19 0.54 0.27 0.66
1.34 0.42 0.98 0.98 1.00 0.99 0.66 0.45
0.60–3.29 0.12–2.64 0.94–1.02 0.93–1.03 0.95–1.05 0.98–1.00 0.30–1.48 0.20–0.98
0.49 0.30 0.36 0.46 0.86 0.037 0.31 0.046
ICM, ischemic cardiomyopathy; NICM, non-ischemic cardiomyopathy; NYHA, New York Heart Association; AAD, antiarrhythmic drugs; LVEF, left ventricular ejection fraction; E/e’, the ratio of the early transmitral flow velocity and the early mitral annular velocity; CRT, cardiac resynchronization therapy; ATP, antitachycardia pacing; HR, hazard ratio; CI, confidence interval; VA, ventricular arrhythmia.
there have been no data regarding the clinical impact of Reactive ATP on the clinical outcomes such as HF hospitalization or VA in patients implanted with CRT devices. In the current study, Reactive ATP reduced the AF burden throughout the 2 years of the follow-up period, which possibly led to a reduction in HF hospitalization. Univariate analysis showed that the use of Reactive ATP was a predictor of HF hospitalization as well as the previously known predictors of HF hospitalization such as LVEF. In contrast to the MINERVA trial, the mean success rate of ATP was lower in CRT patients, and the reduction in AF burden was not associated with the prevention of persistent AF. This suggests that Reactive ATP is less effective in CRT patients than in those with a pacemaker. However, this modality can play an important role in CRT patients because reduction in AF burden helps to maintain cardiac hemodynamics by maintaining atrioventricular synchronicity and high BiV pacing rate. The lower efficacy rate in CRT patients may be due to a more damaged and enlarged left atrium than that observed in patients with pacemakers. Regarding the predictors of high ATP efficacy, the MINERVA trial reported that Reactive ATP was highly effective for regular AT with
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a long cycle length [27]. We compared the clinical characteristics between the high and low ATP efficacy groups to investigate predictors of high ATP efficacy in CRT patients. However, none of the clinical factors, including history of atrial tachycardia, atrial flutter, and antiarrhythmic drugs, were associated with high ATP efficacy. Further studies are warranted to evaluate the predictors of high ATP efficacy. Furthermore, this study showed the safety of Reactive ATP in patients with a reduced heart function. There were no severe complications related to the delivery of ATP, such as the induction of VA. The decrease in battery longevity was relatively small. This may also prompt to activate Reactive ATP in patients with CRT devices. Limitations Firstly, this was a single-center, retrospective study. The small number of patients may limit the interpretation of the results. In addition, this study was not randomized, which might affect the results. Although we cannot rule out the potential bias with our data, baseline characteristics are almost identical between the two groups including AF burden at baseline. We could also observe the benefit of Reactive ATP in the univariate analysis including risk factors for HF hospitalization and VA development. Secondly, the battery drainage was relatively small in a limited number of patients unless frequent ATP therapies were delivered. However, the risk of battery consumption should be kept in mind especially in patients with frequent ATP deliveries. Further prospective, multicenter studies, including a larger number of patients with CRT devices, are warranted to confirm these findings. Conclusions Reactive ATP reduced the AF burden and HF hospitalization in patients implanted with CRT devices. Reactive ATP can be an effective and safe option for the management of ATAs in CRT patients. Funding This study was supported by the intramural research fund (254-7, Kengo Kusano) for cardiovascular diseases of the National Cerebral and Cardiovascular Center and trust research and joint research funds of Medtronic Japan Co., Ltd. Disclosures Kengo Kusano and Takashi Noda received honoraria for lectures by Medtronic Japan Co., Ltd. References [1] Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003;289:2685–94. [2] Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–49. [3] Senni M, Tribouilloy CM, Rodeheffer RJ, Jacobsen SJ, Evans JM, Bailey KR, et al. Congestive heart failure in the community a study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation 1998;98:2282–9. [4] Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003;91:2D–8D. [5] Dickstein K, Bogale N, Priori S, Auricchio A, Cleland JG, Gitt A, et al. The European cardiac resynchronization therapy survey. Eur Heart J 2009;30:2450–60. [6] Fein AS, Wang Y, Curtis JP, Masoudi FA, Varosy PD, Reynolds MR. Prevalence and predictors of off-label use of cardiac resynchronization therapy in patients
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Please cite this article in press as: Ueda N, et al. Efficacy and safety of new-generation atrial antitachycardia pacing for atrial tachyarrhythmias in patients implanted with cardiac resynchronization therapy devices. J Cardiol (2019), https://doi.org/10.1016/j. jjcc.2019.10.001