REACT DX registry: Real world REACTion to atrial high rate episodes detected in implantable cardioverter-defibrillator recipients with a DX lead

Abstract

BACKGROUND:

Atrial fibrillation (AF) is associated with significant morbidity and is predicted by atrial high rate events. The early detection of AF is paramount to timely interventions to reduce the morbidity of AF. The DX ICD system combined with Home Monitoring ${}^{\@setsize{\scriptsize}{9.5pt}{\viiipt}{\@viiipt}{\textregistered}}$ allows for continuous atrial rhythm monitoring without the need for a dedicated atrial lead.

OBJECTIVE:

To establish the reaction to and timing of reactions to the detection of atrial high rate episodes (AHRE).

METHODS:

A prospective cohort of DX ICD systems was followed up and the response to AHREs was collected and evaluated.

RESULTS:

A total of 234 patients were enrolled; an AHRE $\geqslant$ 6 min was detected in 13.7% of patients ( $n=$ 32) within a mean follow-up duration of 16 months. A high rate of oral anticoagulation (OAC) prescription was seen with the detection of AHREs in patients with a not-low risk CHA ${}_{2}$ DS ${}_{2}$ -VASc score. There was a delay in this prescription highlighting the potential to improve the timeliness of patient care in this group of patients.

CONCLUSIONS:

The DX ICD system provides rapid and ongoing atrial rhythm monitoring such that physicians are rapidly aware of AHRE without the need for a dedicated atrial lead, but local protocols are needed to improve the response time of anti-coagulation prescription.

Keywords

DX technology home monitoring atrial high rate events atrial fibrillation oral anticoagulation

1. Background

Atrial fibrillation (AF) is associated with an increased stroke risk, cardiovascular morbidity, heart failure exacerbations, cognitive decline as well as impacting on quality of life [1, 2, 3]. Furthermore, in patients with implantable cardioverter-defibrillators (ICDs) AF is the most common trigger for inappropriate shock delivery [4] and is associated with increased mortality [5]. Furthermore, it has been shown that single-chamber ICDs under-estimate the true AF incidence compared to dual-chamber ICDs and that additional screening with Holter monitors is required in single chamber ICDs to detect AF and address the thromboembolic risk in a timely fashion [6]. Furthermore, the early detection of AF by remote monitoring is important as it may instigate programming changes to the tachycardia detection algorithms [7].

There are well established guidelines for management of confirmed AF including instigation of oral anticoagulation (OAC) to address stroke risk, rate/rhythm control as appropriate as well as risk factor modification [2, 8]. Rate control is often the mainstay of therapy in asymptomatic patients, the elderly and those deemed to have permanent AF. Rate control is established with the administration of beta blockers, calcium channel blockers, digoxin or by performing AV nodal ablation as a last resort. Lenient rate control ( $<$ 110 bpm at rest) has been shown to be non-inferior to strict ( $<$ 80 bpm at rest) rate control with the exception of reduced biventricular pacing due to AF [9, 10]. There is increasing evidence of the benefits of maintaining sinus rhythm including reduced symptoms, admissions and potentially mortality [11, 12]. Rhythm control can be achieved pharmacologically or catheter ablation in conjunction with risk factor modification. Catheter ablation has been shown to have superior outcomes when compared to pharmacological therapy, but both approaches are augmented by risk factor modification [11, 12, 13, 14, 15].

The gold standard of AF detection is based on electrocardiogram (ECG) recordings (clinical AF), however as AF is often paroxysmal or asymptomatic AF diagnosis will underestimate the true incidence leaving a large ‘at risk’ population. More recently cardiac implantable electronic devices (CIEDs) with atrial leads such as pacemakers and ICDs have provided continuous atrial monitoring. This technology allows the automatic identification of patients with atrial high rate episodes (AHRE), it also overcomes the difficulty and patient acceptability of prolonged remote monitoring with wearable devices for the detection of AF [16].

The incidence of AHRE was defined in the ASSERT trial where 2580 patients with a newly implanted CIED (2451 pacemakers and 129 ICDs) without a history of atrial fibrillation were followed for a mean of 2.5 years [17]. Subclinical AHRE ( $>$ 6 min and $>$ 190 bpm) were detected in 10.1% of the patients within 3 months and in 34.7% after 2.5 years of follow up suggesting a progression over time of AHRE incidence and burden. AHRE were associated with an increased risk of clinical AF and ischaemic stroke or systemic embolism. However, despite much interest it is still unclear what threshold of AHRE burden and CHA ${}_{2}$ DS ${}_{2}$ -VASc score should prompt the initiation of OAC.

The DX ICD system (BIOTRONIK SE &. Co. KG, Berlin, Germany) consists of a single-chamber ICD and a right ventricular lead with an integrated ‘floating’ atrial dipole providing a continuous atrial monitoring without the requirement for a dedicated atrial lead. This registry was designed to evaluate the ‘real-world’ incidence of AHREs in the ICD population, to understand the utilization of remote monitoring for AHRE without pre-defined instructions (e.g. standard operation procedures) and the reactions of treating physicians to AHREs detected.

2. Methods

The REACT DX registry is a prospective, non-randomized, non-controlled, multicentre investigation into the incidence of device-detected AHRE in an ICD population and the clinical reactions pertaining to the AHRE conducted in 14 hospitals. The local ethics committees approved the study and all patients gave written informed consent. The trial was registered in the publicly accessible database DRKS (Deutsches Register Klinischer Studien – ID: DRKS00010898). The registry was performed according to the principles of the Declaration of Helsinki and ISO14155.

For the purposes of the study a CHA ${}_{2}$ DS ${}_{2}$ -VASc score was used to determine thromboembolic risk, but appreciating that female sex is a risk modifier rather than a risk factor in isolation and does not change the anti-coagulation indication in the presence of AF [2, 18, 19, 20]. Thus, a score of 0 (male) or 1 (female) was considered ‘low’ thromboembolic risk, a score of 1 (male) or 2 (female) was considered a ‘single risk factor’ and a score of $\geqslant$ 2 (male) or $\geqslant$ 3 (female) was considered ‘high’ thromboembolic risk.

Spontaneous AHREs detected by the device were independently evaluated by the investigators and a clinical event committee. Events were included in the analysis if they were determined to be genuine atrial tachyarrhythmias with a duration of $\geqslant$ 6 mins and a rate $\geqslant$ 190 bpm.

Patients implanted with an ICD for primary or secondary prevention according to guidelines within one month prior to enrollment were eligible for the registry. Only patients with de novo ICD implantation were included. Additionally, sufficient coverage of mobile network for Home Monitoring ${}^{\@setsize{\scriptsize}{9.5pt}{\viiipt}{\@viiipt}{\textregistered}}$ (BIOTRONIK SE &. Co. KG, Berlin, Germany) had to be available. Patients with permanent atrial fibrillation, an indication for cardiac resynchronization therapy, life expectancy of less than six months, expected cardiac surgery within six months after enrollment, participation in another cardiac clinical investigation and age less than 18 years were excluded.

All ICDs implanted were BIOTRONIK DX devices including: Lumax 740 VR-T DX, Iforia 7 VR-T DX, Idova 7 VR-T DX, Itrevia 7 VR-T DX and Inventra 7 VR-T DX. The leads implanted included: Linox ${}^{\text{Smart}}$ DX S, Protego DF-1 ProMRI S DX ${}^{\@setsize{\scriptsize}{9.5pt}{\viiipt}{\@viiipt}{\textregistered}}$ (BIOTRONIK SE &. Co. KG, Berlin, Germany).

Subsequent to the implantation, six follow-up examinations were performed; pre-discharge, after 1, 3, 6, 9, 12 and 24 months. The 3- and 9-month follow-up were performed remotely. Additional follow-up was performed at the discretion of treating institution in response to remote-monitor detected AHRE. At each follow-up standard lead and device measurements were taken. P-wave amplitude (mV) was recorded at all visits.

The aim of the registry was to evaluate physicians’ reactions to AHRE detected with an integrated atrial dipole and the therapeutic consequences. The reactions to any AHRE were at the discretion of the treating physician. Reactions were classified as addressing the thromboembolic risk, alterations to the rate or rhythm control approach to the patient. Reactions were defined as: additional follow up, hospitalisation, medication change or procedure booking (such as echocardiography, cardioversion or ablation) and further classified as early (in response to the initial AHRE, timing defined by first patient contact after AHRE) or late (subsequent to the first patient contact after AHRE and prior to the study conclusion).

Statistical analysis

Continuous data were expressed as mean $\pm$ standard deviation and assessed with the Mann-Whitney U test. Normal distribution was assessed with the Kolmogorov-Smirnov-Test. Categorical data were reported as numbers and percentage and assessed with the Pearson Chi-square test or Fisher’s exact tests were used as appropriate. All tests were two-tailed and a $p$ -value $<$ 0.05 was defined as statistically significant. Statistical analysis was performed using SPSS Statistics 27 (IBM Corp., Armonk, NY, USA).

3. Results

3.1 Study population

In total 234 patients across 14 sites were enrolled in the registry. Enrolment was from November 2012 to June 2016. Follow-up duration was 489.2 $\pm$ 187.8 days. During the study period 11 patients died, 2 patients were lost to follow-up and 13 patients withdrew informed consent.

The average age of the study population was 60.7 years and 85.0% of patients were male. The indication was primary prevention in 76.9% of patients, the remained were secondary prevention (Table 1). The mean CHA ${}_{2}$ DS ${}_{2}$ -VASc score was 2.7 $\pm$ 1.5 and there was a documented history of previous AF in 17.9% (42/234) of patients at enrolment. Coronary artery disease was present in 65.8% of patients, hypertension in 73.5% and diabetes in 29.9% (Table 2). No embolic events occurred during the follow up period in the AHRE group, there were however two stroke in the non-AHRE group.

Table 1
Baseline characteristics

Patient characteristics	Total Patients with DX ( $n=$ 234)	Patients with AHRE ( $n=$ 32)	Patients without AHRE ( $n=$ 202)	$p$ -value
Age [ears]	60.7 $\pm$ 12.6	63.7 $\pm$ 9.9	60.2 $\pm$ 12.9	0.169
Male sex	199 (85%)	32 (100%)	167 (82.7%)	0.006 ${}^{*}$
Height [cm]	175.1 $\pm$ 7.9	176.8 $\pm$ 5.9	174.8 $\pm$ 8.2	0.233
BMI [kg/qm]	28.4 $\pm$ 5.4	29.1 $\pm$ 6.2	28.2 $\pm$ 5.3	0.607
ICD indication				0.861
a) Primary prevention	180 (76.9%)	25 (78.1%)	155 (76.7%)
b) Secondary prevention	54 (23.1%)	7 (21.8%)	47 (23.3%)
LVEF [%]	33.6 $\pm$ 12.7	29.7 $\pm$ 11.2	34.0 $\pm$ 12.8	0.059
NYHA class				0.350
I	24 (13.8%)	2 (6.3%)	22 (10.9%)
II	84 (48.%)	11 (34.4%)	73 (36.1%)
III	63 (36.2%)	9 (28.1%)	54 (26.7%)
IV	3 (1.7%)	1 (3.1%)	2 (0.9%)
CHA2DS2-VASc score	2.7 $\pm$ 1.5	3.1 $\pm$ 1.5	2.6 $\pm$ 1.5	0.161
Follow up period (time between	489.2 $\pm$ 187.8	528.2 $\pm$ 175.7	482.9 $\pm$ 189.2	0.381
enrolment and last visit) [days]

AHRE $=$ Atrial High Rate Episode, BMI $=$ Body Mass Index, ICD $=$ Implantable Cardioverter Defibrillator, LVEF $=$ Left Ventricular Ejection Fraction, NYHA $=$ New York Heart Association, values are mean $\pm$ SD, ${}^{*}$ significant.

Table 2

Medical history

Medical history	Total Patients with DX ( $n=$ 234)		Patients with AHRE ( $n=$ 32)		Patients without AHRE ( $n=$ 202)		$p$ -value
Conorary artery disease	154	(65.8%)	21	(65.6%)	133	(65.4%)		0.981
a) Myocardial infarction	75	(32.1%)	9	(28.1%)	66	(32.7%)		0.564
b) Coronary artery bypass graft	47	(20.1%)	8	(25%)	39	(19.3%)		0.417
c) Percutaneous coronary intervention	104	(44.4%)	15	(46.9%)	89	(44.1%)		0.682
Dilated cardiomyopathy	78	(33.3%)	14	(43.7%)	64	(31.7%)		0.179
Hypertrophic obstructive cardiomyopathy	12	(5.1%)	1	(3.1%)	11	(5.4%)		0.999
Hypertension	172	(73.5%)	28	(87.5%)	144	(71.3%)		0.053
(Inherited) arrhythmogenic disease	15	(6.4%)	3	(9.3%)	12	(5.9%)		0.439
a) Long QT-syndrome	5	(2.1%)	0	(0%)	5	(2.5%)		0.505
b) Short QT-syndrome	0	(0%)	0	(0%)	0	(0%)	n/a
c) ARVC	4	(1.7%)	0	(0%)	4	(1.9%)		0.516
d) Other	5	(2.1%)	2	(6.25%)	3	(1.5%)		0.242
Diabetes mellitus	70	(29.9%)	13	(40.6%)	57	(28.2%)		0.154
Valvular heart disease	80	(34.2%)	13	(40.6%)	67	(33.2%)		0.409
Renal insufficiency	50	(21.4%)	7	(21.9%)	43	(21.3%)		0.940
Atrial fibrillation at inclusion	42	(17.9%)	16	(50%)	26	(12.9%)	$<$	0.001 ${}^{*}$
a) Paroxysmal	28	(12.0%)	10	(31.3%)	18	(8.9%)
b) persistent	14	(6.0%)	6	(18.7%)	8	(3.9%)

ARVC $=$ Arrhythmogenic right ventricular cardiomyopathy, ${}^{*}$ significant, n/a $=$ not available.

AHREs $\geqslant$ 6 mins were detected in 13.7% (32/234) patients, of these patients 50% (16/32) had a history of atrial fibrillation. Of these 32 patients 1 would be considered low-risk for embolic events, 3 had a single risk factor (excluding female sex) and 28 were high embolic risk. There was a greater proportion of male patients in the cohort who developed AHRE compared to those who did not (100% vs 83%, $p=$ 0.006). Otherwise, the demographics and medical history was similar between the overall study population and the AHRE group.

The mean time to detection of AHRE was significantly longer for patients with no previous diagnosis of AF (183 $\pm$ 124 days) vs. those with known AF (62 $\pm$ 108 days), $p=$ 0.003 (Fig. 1). There were no strokes during the follow up period in either group.

Figure 1.

Box plot comparing time to first occurrence of AHRE (in days) between group with history of AF and without history of AF; w/o $=$ without, w $=$ with.

3.2 DX-Lead performance

The p-wave amplitude remained stable with a mean value to 5.29 mV at the 12-month follow up (Fig. 2).

Figure 2.

Mean p-wave amplitude in mV over time from implant to 12-month follow up; PHD $=$ prehospital discharge, mo $=$ month, FU $=$ follow-up.

Figure 3.

The 16 patients with no prior history of AF and newly detected AHRE plotted as their AHRE duration against CHA ${}_{2}$ DS ${}_{2}$ -VASc score with subsequent oral anticoagulation status. The red area in the chart (lower right corner) represents those who should be considered for OAC and the green region represents those who should have ongoing monitoring according to ESC guidelines (figure adapted from ESC guidelines [2]). Numbers in the circle represent the patients number. Patient #17 was treated with a left atrial appendage occlusion device, OAC was initiated in Patient #25 after study conclusion.

Figure 4.

Sankey diagram demonstrating the physician response to AHRE in patients with prior documented AF with regards to initiating rate/rhythm control at the time of AHRE detection and during follow up.

Figure 5.

Sankey diagram demonstrating the physician response to AHRE in patients with no prior documented AF with regards to initiating rate/rhythm control at the time of AHRE detection and during follow up.

3.3 Anticoagulation response to AHRE

Of the 16 patients with a previous diagnosis of AF 14 were already established on OAC. The remaining two patients, OAC was initiated in one patient after the first AHRE, and in one patient only after the end of the study period. Of the 16 patients with no previous AF diagnosis and newly detected AHRE one was previously established on an OAC; after the first AHRE a further 11 were commenced on an OAC with a mean reaction time of 24 days (defined as the time from AHRE episode to change in management). Of the remaining four, one was placed on OAC after the end of the study period, one received a left atrial occlusion device and two were considered precipitated events (one post-operative and one in the context of sepsis). Of the patients with no previous AF 81% (13/16) were high risk for thromboembolic events and of these approximately half (7/13) had an AHRE episode $>$ 1 hr where OAC should be considered according to the 2020 ESC guidelines (the same recommendation as the 2016 ESC guidelines, current during the study period) for management of atrial fibrillation, the remaining 9 patients would be recommended to have ongoing clinical monitoring (Fig. 3) [2, 20].

3.4 Rhythm management in response to AHRE

Patients with a previous diagnosis of AF were either on rate control (68.8%, 11/16) or on rhythm control (31.2%, 5/16) drugs at enrolment. In response to the first device-detected AHRE two patients underwent electrical cardioversion thus indicating a change to a rhythm control approach with an average reaction time of 25 days. Longer-term, a further five patients were managed with a rhythm control approach (two ablation and three with anti-arrhythmic drugs (AADs)). The mean reaction time for these patients was 262 days (Fig. 4).

Initially, patients without AF were not following a rhythm or rate control regime, in response to the first device-detected AHRE one patient was placed on an AAD (reaction time 28 days). The longer-term management involved 50% (8/16) of patients being placed managed with rate (4/16) or rhythm control (4/16) with a mean reaction time of 338 days. Rate control was established with betablockers in three cases and AV nodal ablation in one case. Rhythm control was established with AADs in two patients, electrical cardioversion in one and ablation in one patient (Fig. 5).

Figure 6.

Proposed protocol for responding to AHRE events detected by Remote Monitoring. Interventions in reaction to AHRE are based on stroke risk (High risk $=$ CHA ${}_{2}$ DS ${}_{2}$ -VASc $\geqslant$ 2 (m) or $\geqslant$ 3 (f), Single risk factor $=$ CHA ${}_{2}$ DS ${}_{2}$ -VASc 1 (m) or 2 (f), Low risk $=$ CHA ${}_{2}$ DS ${}_{2}$ -VASc 0 (m) or 1 (f)) and AHRE duration.

4. Conclusions

To the best of our knowledge, this is the first study to prospectively evaluate the physician response to device-detected AHRE from an integrated atrial dipole DX ICD system. All previous studies have only used devices with a dedicated atrial lead introducing selection bias as the decision to add an atrial lead to a system is based on clinical factors and thus excludes the majority of ICD patients without a pacing indication. Importantly the p-wave amplitude (mean value 5.29 mV) remained stable over the study period permitting accurate diagnosis of AHRE.

During the study period an additional 16 patients were identified as having AHRE by the use of the DX ICD system, these AHRE may not have been detected with a standard single chamber ICD. This thus demonstrates a potential advantage of the DX ICD system given that the implant procedure does not come with any additional complications.

The rate of AHRE during follow up in our cohort was lower than previously suggested in studies such as the ASSERT trial (10.1% at 3 months and 34.7% at 2.5 years); this is likely explained due to the difference in patient selection; the ASSERT trial consisted of 2451 pacemaker patients and only 129 ICD patients suggesting that their population are older and have established sinus node or conduction disease which is linked to the development of atrial tachyarrhythmias. Other studies including pacemaker patients show similar AHRE incidence from 13–30% [21, 22, 23]. However, ICD specific studies and those with sub-group analysis of ICD cohorts show a much lower AHRE incidence cf. pacemaker patients similar to our cohort (3.6–13.8%) [23, 24]. With a low incidence of AF in the ICD population it is hard to justify a dedicated additional lead, and its associated increased complication rate, just for AF detection, however given the morbidity associated with the thromboembolic complications of AF rhythm monitoring when available as an integral component of the ventricular lead is advantageous.

There were two cerebral embolic events in the group without AHRE detected; this could be due to under-detection of AHRE/AF in this group. Given the p-wave amplitudes recorded (mean $>$ 5 mV throughout follow up) we believe this unlikely; it is possible that these two patients’ strokes were of a non-AF aetiology such as carotid disease or cerebral arterial atherosclerosis.

We found that the majority of physician responses to AHRE are reasonable, with the majority of high-risk patients with AHRE commencing OAC, but there is a small delay, or reaction time, from AHRE occurrence to implementing the response. The two high-risk patients who were not anticoagulated in response to their AHRE did receive a LAA occlusion device (in the case of OAC contra-indication) or anticoagulation after the conclusion of the study, respectively. This highlights the priority in physician’s minds to protection from thromboembolic complications of AF, but most reactions occurred at the point of the next scheduled follow up suggesting that the Home Monitoring ${}^{\@setsize{\scriptsize}{9.5pt}{\viiipt}{\@viiipt}{\textregistered}}$ system is not being used optimally with regards to AHRE detection and monitoring as suggested in the 2020 ESC management of atrial fibrillation guidelines [2]. The recommendation for ongoing monitoring of low risk patients or those with a low AHRE burden can be facilitated by the DX ICD system, especially with the long-term stability of the p-wave sensing seen previously and during our study [24]. There are many possibly causes of this delay, including staffing issues, Home Monitoring ${}^{\@setsize{\scriptsize}{9.5pt}{\viiipt}{\@viiipt}{\textregistered}}$ alert programming and a lack of institutional protocols to address remote monitor alerts for AHREs.

In contrast, the majority of rhythm/rate management decisions occurred with a significantly greater delay compared to OAC initiation. This is understandable as the decision to alter rate/rhythm approaches requires a shared decision-making approach with patient engagement best done in a clinic environment and likely requiring ongoing monitoring and additional data points. This additional data is readily gathered from the DX ICD system with continuous atrial rhythm monitoring. The paradigm regarding rhythm control is different from that of OAC initiation due to the significant consequences of un-anticoagulated, high thrombotic risk AF explaining the shorter reaction time for this intervention.

The complexity in the decision around oral anticoagulation for a given AHRE event lies in the lack of clear evidence, despite much interest and study, that a particular cut off in duration or burden with any given thromboembolic risk profile clearly identifies those who will benefit from OAC and those who will not. There is evidence of higher thromboembolic risk in paroxysmal vs. persistent AF suggesting a dose response effect [25, 26, 27], though this too has been contested [28]. It is not clear if this dose-response effect extends to much shorter durations of atrial arrhythmias i.e. AHREs. Though caution is warranted in prescribing OAC outside of clinical AF with no benefit for stroke or heart failure patients without AF [29, 30, 31] the risk of stroke in patients with AHRE does appear to be elevated with an annualized stroke risk of 1.7% [17]. Importantly this risk needs to be balanced against that of the bleeding risks with OAC which are approximately 2% [32]. Given this lack of definitive evidence or guideline directions to aid developing institutional protocols; we propose the following approach to AHRE detected by Home Monitoring ${}^{\@setsize{\scriptsize}{9.5pt}{\viiipt}{\@viiipt}{\textregistered}}$ in patients without a prior diagnosis of AF (Fig. 6):

Our study is limited by its observational nature, however this is also its strength as it highlights the real-world reactions of physicians to the discovery of AHRE as well as the application of Home Monitoring ${}^{\@setsize{\scriptsize}{9.5pt}{\viiipt}{\@viiipt}{\textregistered}}$ in the detection of AHRE.

The DX ICD system with an integrated atrial sensing dipole offers permanent atrial rhythm monitoring while keeping the simplicity of a single-chamber ICD.

In combination with Home Monitoring ${}^{\@setsize{\scriptsize}{9.5pt}{\viiipt}{\@viiipt}{\textregistered}}$ a DX ICD system is an effective and convenient way to detect AHRE in a timely fashion. Furthermore, the DX ICD system allows for ongoing monitoring of AF events and burden without the requirement for a dedicated lead potentially reducing long-term lead related complication. There is a delay between system-based detection of AHRE, its real-life recognition in daily practice, and the initiation of OAC. Simple institution protocols such as the one that we suggest may improve the speed at which we can react to such events and ‘close the loop’ with the patients and their management.

Footnotes

Acknowledgments

The authors would like to thank Dr. Alexander Schirdewan, who passed away, for his initial conception of the study and valuable contribution to the steering committee. They also thank Ulrike von Hehn for her statistical support.

Conflict of interest

NK received lecture fees from BIOTRONIK, AstraZeneca, Pfizer, Novartis and has advisory contracts with BIOTRONIK, Cardiac Dimensions, Boston Scientific. NW and JFK received financial support from BIOTRONIK. RB, TH and KR are employees of BIOTRONIK. MO, HI, TR, CK, SK, StK, RT, DB, CL have no conflict of interest to declare.

Funding

This study was sponsored by BIOTRONIK SE & Co. KG, Berlin, Germany.

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