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(Circulation. 1999;99:2765-2770.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Double-Blind Placebo-Controlled Trial of Digoxin in Symptomatic Paroxysmal Atrial Fibrillation
From St George's Hospital Medical School, London, UK.
Correspondence to Dr Francis D. Murgatroyd, Department of Cardiology, Glenfield Hospital, Leicester LE3 9QP, UK. E-mail fmurgatroyd{at}compuserve.com
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
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Background—Digoxin is commonly prescribed in symptomatic paroxysmal atrial fibrillation (AF) but has never been evaluated in this condition.
Methods and Results—From a multicenter registry, 43 representative patients with frequent symptomatic AF episodes were recruited into a randomized, double-blind crossover comparison of digoxin (serum concentration, 1.29±0.35 nmol/L) and placebo. The study end point was the occurrence of 2 AF episodes (documented by patient-activated monitors), censored at 61 days. The median time to 2 episodes was 13.5 days on placebo and 18.7 days on digoxin (P<0.05). The relative risk (95% CI) of 2 episodes (placebo:digoxin) was 2.19 (1.07 to 4.50). A similar effect was seen on the median time to 1 episode: increased from 3.5 to 5.4 days (P<0.05), relative risk 1.69 (0.88 to 3.24). The mean±SD ventricular rates during AF recordings during placebo and digoxin treatment were 138±32 and 125±35 bpm, respectively (P<0.01). Twenty-four–hour ambulatory ECG recordings did not show significant differences in the frequency or duration of AF or in ventricular rate.
Conclusions—Digoxin reduces the frequency of symptomatic AF episodes. However, the estimated effect is small and may be due to a reduction in the ventricular rate or irregularity rather than an antiarrhythmic action.
Key Words: arrhythmia • fibrillation • antiarrhythmia agents • drugs
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Atrial fibrillation (AF) is the most common cardiac arrhythmia: in its permanent form, the prevalence is
2.3%
in people >40 years old and 5.9% in those >65 years
old.1 The paroxysmal form has been reported in 35% to
40% of patients attending hospital with AF,2 3 and in the
general population its prevalence may equal or even exceed that of
permanent AF. Antiarrhythmic therapy for paroxysmal AF generally aims
for a reduction in symptom frequency or severity; total abolition of
the arrhythmia is rarely possible. Few antiarrhythmic drugs
have been evaluated in this specific condition by randomized controlled
trials, and digitalis is the source of particular
controversy.4 The present study aimed to determine the
effect of digoxin in conventional doses on the frequency of
symptomatic episodes of paroxysmal AF. |
Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Study Population
The study population was recruited from 8 general hospitals and 1 regional cardiothoracic center. A registry was kept by each participating physician to determine whether the study group was representative of those patients likely to receive antiarrhythmic therapy for paroxysmal AF. This detailed the clinical features of outpatients seen by the participating physician who had at least 1 episode of AF, with return to sinus rhythm, in the preceding 6 months (irrespective of study eligibility).
Entry Criteria
Patients of either sex 
18 years old were eligible for
screening if they had a history of documented AF, with frequent
(1/mo), symptomatic, self-terminating episodes. Patients
taking antiarrhythmic drugs were eligible if they had met these
criteria before treatment and were willing to discontinue
treatment.
Exclusion Criteria
Patients were excluded if they had a history of AF requiring
cardioversion on >1 occasion or a history of thromboembolism or
symptoms such as syncope or angina judged by their physician to be
related to AF and to preclude the ethical administration of placebo.
Other exclusion criteria were uncorrected electrolyte imbalance; serum
potassium <3.8 mmol/L; abnormal thyroid function; renal, hepatic,
pulmonary, or cardiac insufficiency or valvular heart
disease that might cause progression to persistent AF; left atrial
diameter >45 mm; myocardial infarction, unstable angina, or
cardiac revascularization procedure in the
preceding 3 months; known or suspected accessory
atrioventricular pathway; history of second- or
third-degree atrioventricular block or sinus node
dysfunction; implanted cardiac pacemaker; hypertrophic
cardiomyopathy; or amiodarone or
investigational drugs in the preceding 3 months. Female patients who
were pregnant, lactating, or of childbearing potential and not using
contraception were excluded.
The protocol was in accordance with the Helsinki declaration of 1975 and was approved by the district medical ethics committee at each center. Informed written consent was obtained from all patients.
Study Design
The study was of a multicenter, double-blind, placebo-controlled
crossover design (Figure 1
). The study
end point was the interval to 2 symptomatic episodes of AF,
documented by patient-activated ECG recordings,
censored at 61 days. The principal comparison was between the intervals
to the second documented AF episode on digoxin and placebo. Also
studied were the interval to the first documented episode, the
ventricular rates during the documented portions of AF
episodes, the number and duration of AF episodes on Holter
recordings and their mean heart rates, and reported adverse
events and side effects.
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Screening Phase
Patients meeting the entry criteria underwent a 31-day screening
phase after the withdrawal of antiarrhythmic medication for 5
half-lives. This included ß-blockers, verapamil, and
diltiazem: if these were prescribed for hypertension or angina,
substitution was required. A 3-month discontinuation was required for
amiodarone and investigational drugs. During screening,
patients were instructed to transmit ECG recordings at the
onset of and after each symptomatic episode. Patients in
whom 1 symptomatic, self-terminating episode of AF was
documented during screening were randomized into the evaluation
phase.
Evaluation Phase
The evaluation phase of the study had 2 limbs. In each,
evaluation was commenced only after loading/washout and documentation
of an appropriate digoxin level. Each treatment continued until 2
symptomatic episodes of AF, separated by sinus rhythm, had
been documented or for a maximum of 61 days. Each treatment was
discontinued after a single AF episode if it was judged by the
physician to be of sufficient clinical severity (in terms of symptoms,
duration, or hemodynamic disturbance) to
constitute treatment failure. Patients without any documented
symptomatic episodes of AF during active or placebo
treatment were replaced and not entered into principal statistical
analysis. Recruitment continued until 40 patients had completed
both phases.
Randomization and Dosing
Randomization was carried out in blocks of 4 at each center.
Patients were instructed to take 1 to 4 tablets daily, each containing
125 µg digoxin (Lanoxin) or matching placebo, supplied by the
Wellcome Foundation Ltd. For each patient, initial dosing was
determined by a nomogram based on renal function.5 After
7 days of loading/washout, and 6 hours after the most recent dose,
serum digoxin concentration was measured (TDx, Abbott Laboratories,
Inc) by a nonblinded central laboratory. The laboratory instructed the
trial coordinator to alter dosing in patients with serum concentrations
outside the desired range (1.0 to 2.6 nmol/L, 0.8 to 2.0 µg/L). Blood
sampling was repeated 7 days after changes in digoxin dose, and
further dose adjustments were made if necessary. To keep both patients
and investigators blinded, the laboratory issued an equivalent number
of dose adjustment instructions for patients currently taking placebo.
Unused tablets were counted at the end of each phase to assess
compliance.
ECG Documentation of Symptomatic Arrhythmias
Thirty-two second ECG recordings were made by patients
using a precordial event recorder (Cardiomemo, Instrumedix
Inc). Patients were instructed to transmit a recording at the
onset of each episode of symptoms and again after the episode ceased.
To encourage compliance, patients also made weekly transmissions in the
absence of symptoms. At the coordinating hospital, telephone
transmissions were recorded onto chart paper at 25 mm/s
(Lifesigns Receiving Station, Instrumedix Inc). Recordings were
checked immediately for diagnostic quality, and repeat
recordings were requested if necessary. Recordings were
reviewed by a blinded observer. AF was diagnosed in the presence of 5
consecutive irregular RR intervals with no evidence of organized atrial
activity. The heart rate for each recording was calculated as
an average over all beats that clearly demonstrated AF.
Ambulatory Recording
Twenty-four–hour ambulatory recordings were made at the
start of each evaluation phase after loading/washout. Three-channel
(modified V5, V1, and aVF)
recorders were used to maximize P-wave visibility (model 8500,
Marquette Electronics, Inc). Tapes were digitized (Laser Holter XP,
Marquette Electronics, Inc), then scrutinized to confirm R-wave
labeling and exclude artifact. The exact timing of onset and
termination of each episode of AF (defined as above) was manually
marked by operators blinded to treatment. The data were merged with an
RR interval file to obtain listings of the exact time, duration, and RR
intervals for each episode of sinus rhythm and AF. The details and
validation of this method have been published in full
elsewhere.6
Statistical Methods
The study size calculation was based on the premise that
arrhythmic episodes occur independently with a fixed probability for
each patient in any given time.7 The target number of 40
completed patients was calculated to give 90% power to detect a 3-fold
increase in mean interval between attacks.
The study end point was the time to the second documented attack of AF (t2), censored after 61 days. This was initially examined with Kaplan-Meier product-limit survival estimates. To make use of the paired data, the difference in t2 between the first and second treatment periods (t2a-t2b) was calculated. The null hypothesis that t2a-t2b did not differ according to treatment order (digoxin-placebo and placebo-digoxin) was examined by use of the Mann-Whitney test. For a numerical estimate of treatment effect, the Cox proportional hazards model, adapted to the analysis of failure times in crossover studies,8 was used (hazards being treatment and treatment period). Identical analyses were made of the intervals to the first documented attacks of AF. Mean heart rates during recordings were compared by parametric methods for crossover trials. Data resulting from ambulatory recordings were analyzed by nonparametric methods. Statistical analysis used SPSS for Windows (v6.0, SPSS Inc) and a program written for SAS/Stat software (v6.07, SAS Institute Inc). A 2-tailed P<0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Patients
One hundred ninety patients with
1 episode of AF in the
preceding 6 months were registered during recruitment. Of these, 113
failed to meet the entry criteria for the following reasons:
insufficient symptom frequency (33), digoxin contraindicated (6),
withdrawal of antiarrhythmic therapy contraindicated (12), withdrawal
of amiodarone considered inappropriate (10), history of
cerebral embolism (2), reversible cause for AF (3), pacemaker (3),
patient refusal (22), physician declined because of probable poor
compliance (13), or unspecified reasons (13). The remaining 77
patients were screened: randomization continued until 40 patients
completed the double-blind phase with documentation of at least 1
episode of AF. Two patients had no symptomatic episodes of
AF during double-blind treatment, and a third withdrew consent on the
day of randomization: these 3 patients were replaced, so that 43
patients were randomized. Table 1
summarizes clinical and echocardiographic features of
the patients in the registry and randomized phases, which showed no
significant differences. Echocardiography was not
mandatory for the registry, but data were available in 144 patients
(76%). Thirty-eight patients had a history of prior antiarrhythmic
drug treatments: digoxin (32), Vaughan Williams
class 1 (24), ß-blocker (19), amiodarone or sotalol (19), and
verapamil/diltiazem (13). These treatments were continuing
in 22 patients up to screening for the present study; prior
treatments had been discontinued due to inefficacy (43), side effects
(27), or unspecified reasons (25).
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Digoxin Dosing and Levels
Of the 40 patients evaluated, 20 had been randomized to each
treatment order. During active treatment, 11 patients required an
increase from the initial dose to achieve desired plasma levels; no
patient required dose reduction. Final daily doses were 250 µg in 5
patients, 375 µg in 28 patients, and 500 µg in 7 patients. The
mean±SD digoxin level on the final dose of active treatment was
1.29±0.35 nmol/L (1.01±0.27 µg/L). Plasma digoxin levels
measured during placebo treatment were all <0.1 nmol/L. Residual
tablet counts confirmed >95% compliance in all patients.
Patient-Activated Recordings
Digoxin was associated with a decrease in the frequency of
documented symptomatic AF. The median interval before 2
transmitted attacks of AF was 13.5 days on placebo and 18.7 days on
digoxin (P=0.041). The numbers of patients transmitting 0,
1, and 2 (the maximum) AF episodes were 0, 4, and 36 on placebo and 3,
5, and 32 on digoxin, respectively (P=NS). The estimated
relative risk (95% CI) of 2 symptomatic AF
recurrences on placebo compared with digoxin was 2.19 (1.07 to
4.50). Similarly, the median interval before the first attack was 3.5
days on placebo and 5.4 days on digoxin (P=0.037; relative
risk, 1.69 [0.88 to 3.24]). Survival curves for the time to the first
and second documented attacks of AF, based on Kaplan-Meier
product-limit estimates, are shown in Figure 2. To illustrate the estimated relative
risks, average event-free survival curves were constructed for the
times to the first and second attacks, and each was corrected for the
estimated effects of active and placebo treatment8
(Figure 3). In this model, the "median
survival time" (at which 50% of patients would be expected to have
had a first attack) was increased from 3.2 (95% CI, 2.0 to 5.4) to 6.4
(5.0 to 10.1) days, and the median survival time to the second attack
from 13.1 (95% CI, 10.2 to 15.6) to 26.7 (16.8 to 43.1) days. The
mean±SD heart rate during transmissions on placebo treatment was
137.9±32.1 bpm, and that on active treatment was 125.0±35.2 bpm. The
estimated effect of treatment on heart rate was a reduction of 15.0 bpm
(95% CI, 4.5 to 25.6 bpm, P=0.007).
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Ambulatory Recordings
Ambulatory recordings were considered separately, and the
analysis included the 2 patients who did not transmit
symptomatic AF episodes. Of the 42 pairs of
recordings, 41 made on digoxin (mean duration, 24.6±0.5 hours)
and 37 made on placebo (mean duration, 24.8±0.5 hours) were of
sufficient quality throughout to be included in analysis. These
contained 1076 episodes of AF, whose duration ranged from 5 beats to
the entire duration of the recording. The number of episodes
per recording varied from 0 to 138. To avoid skewing by those
recordings showing large numbers of AF episodes, measures of
heart rate were calculated as the mean over all the AFs in each
recording.
The principal results of this analysis are shown in Table 2. No significant difference was detected
between digoxin and placebo in terms of the number of AF episodes,
their duration, the mean ventricular rate during AF
overall, or the mean ventricular rate at the start of AF
episodes. The analysis also failed to detect differences
between placebo and digoxin when limited to AF episodes of >30
seconds' duration and when daytime (8 AM to 8
PM) and nighttime (10 PM to 6 AM)
episodes were analyzed separately.
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Treatment Failures and Side Effects
On 3 occasions, treatment was discontinued on clinical grounds
after a single attack of AF: this occurred twice on placebo medication
and once on digoxin. Two patients reported gastrointestinal
disturbances: this was minor in the first, but the second
patient stopped study medication after 28 days of monitoring and 1
documented attack of AF: his data were censored at that point. In both
patients, side effects occurred during active treatment: their digoxin
levels were 1.5 and 2.2 nmol/L, respectively. No other side effects
were reported.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Digitalis glycosides have been used to treat AF for more than 2 centuries.9 However, their only known clinical benefits are a reduction in resting ventricular rate in patients with chronic AF and a modest inotropic effect: there is no evidence of a primary antiarrhythmic action. Retrospective studies suggest that digoxin does not affect the ventricular response during paroxysmal AF episodes,10 11 and randomized studies have found it ineffective in terminating acute AF.12 13 The vagotonic action of digitalis may even be proarrhythmic at the atrial level14 : cholinergic stimuli cause a nonuniform reduction in conduction velocity and effective refractory period and are used to facilitate AF induction in smaller animals.15 16 Increased arrhythmia frequency has been attributed to digoxin in individuals with paroxysmal AF,17 but controlled data have hitherto been lacking.
The principal goal of antiarrhythmic drug therapy in AF is to improve symptoms. Accordingly, the frequency of symptomatic AF episodes was the main object of study in this trial. Although subjective measures such as symptom diaries, physicians' impressions of symptomatic status, and even the continuance of therapy have been used as primary study end points,18 19 20 21 ECG documentation of symptomatic episodes is advantageous. In the present study, event recorders were used: these were preferred to Holter monitoring, because the latter is not practical over extended periods and correlates poorly with symptoms.22 23 24 Because of the large interindividual variation in attack frequency, the end point selected was a fixed number of episodes rather than a fixed monitoring period, and a crossover design was used to increase statistical power.25 26 27 The design selected a representative group of patients, able to document recurrent symptomatic paroxysmal AF, for whom neither digitalis nor placebo treatment would be contraindicated. To avoid bias, previous treatment with digitalis or other drugs was neither required nor a contraindication.
The study found that digoxin reduced the frequency of
symptomatic attacks of paroxysmal AF. The relative risks
(placebo:digoxin) for the times to first and second attacks were 1.69
and 2.19, respectively. If seen uniformly in the population studied,
this effect would correspond to a doubling of the median event-free
survival times (Figure 3
).
The estimated effect of digoxin, although statistically significant, is
small compared with that of other drugs. Flecainide was evaluated in
symptomatic paroxysmal AF in a trial of similar design and
sample size.25 The increase in median interval between
actual attacks was >400% with flecainide and was 50% with digoxin
in the present study. Likewise, a study with a broadly similar
design found the relative risk of first arrhythmia
recurrence to be 6.8 on placebo compared with high-dose
propafenone26 : the same calculations8 showed
a relative risk of 1.7 for the times to first recurrence with
digoxin in the present study. It should be noted that the
Kaplan-Meier curves illustrating treatment effect in the flecainide
study came from the raw data, whereas those used in the propafenone
study were derived from the treatment by France et al8 : a
comparison of Figures 2 and 3 highlights the difference
between data treatments.
The explanation for the observed effect of digoxin on the frequency of arrhythmic symptoms is of interest. A direct atrial antiarrhythmic action cannot be excluded, but no such effect has been described experimentally or clinically. As discussed earlier, digoxin might even be expected to promote AF. The inotropic action of digoxin on the ventricles may cause an indirect effect on atrial electrophysiology by reducing wall stress, but there is no evidence to support this.
A more plausible explanation is that the arrhythmia itself is
unaffected by digoxin but that any reduction in ventricular
rate or irregularity during AF causes more attacks to be
asymptomatic. The ventricular rate appears to
be an important determinant of symptoms in paroxysmal
AF.28 Although 2 studies failed to demonstrate that
digitalis slows the ventricular rate during AF episodes,
both were retrospective and therefore possibly biased and may have been
underpowered, because their data were few and
unpaired.10 11 During both flecainide and placebo
treatment, Anderson et al25 found that the
ventricular rate during symptomatic AF episodes
was 10 bpm lower in patients taking digoxin than in others. In the
present study, the documented rate during symptomatic
AF episodes was reduced by 15 bpm.
Analysis of ambulatory recordings showed large
variances in heart rate and arrhythmia burden (ie, total
minutes of AF, Table 2) but failed to detect any effect of
digoxin on these parameters, whether the analysis
covered entire recordings or was limited to daytime, nighttime,
or the onset of AF episodes. It is possible that the
symptomatic benefit from digoxin derives from more subtle
effects. We have previously noted that during AF, digoxin causes
significant reductions in both the irregularity of RR intervals at high
rates and the overall variability of RR interval
distributions.29 30 Although these findings provide a
plausible explanation for symptom reduction, they do not account for
the reduced ventricular rate seen during
patient-activated recordings. It remains possible that
the symptomatic effect derives from a reduction in
ventricular rate that was simply not detected by ambulatory
monitoring. Thus, despite the large number of AF episodes recorded,
this study highlights the inadequacy of ambulatory monitoring in the
detection of modest changes in arrhythmia frequency or
ventricular rate against a background of great
interindividual and intraindividual variability. Such treatment effects
would not be detectable by ambulatory monitoring other than in patients
with exceptionally frequent arrhythmia, whose mechanism appears
to be unusual.31 The study also highlights our poor
understanding of the determinants of symptom severity in this
condition.
Limitations
This study examined a small patient group, with a lower age and
less structural heart disease than the AF population as a
whole.32 However, published epidemiological data relate
largely to patients with permanent AF. Our registry indicates that the
study group was indeed representative of patients
attending hospital with symptoms caused by paroxysmal AF. As discussed
above, although this study did not detect a significant effect on
arrhythmia burden or ventricular rate by ambulatory
monitoring, such an effect cannot be excluded.
Conclusions
Digoxin reduces the frequency of symptomatic episodes
of paroxysmal AF. This may be due to a reduction in the
ventricular rate or irregularity during AF, rather than a
true antiarrhythmic action. Its benefit is marginal compared with that
of other drugs. However, digoxin does not appear to be detrimental and
need not be discontinued in patients with paroxysmal AF if indicated
for other reasons.
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Acknowledgments |
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This study was funded by grant PG/91032 from the British Heart Foundation.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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CRAFT-1 Participants
Bournemouth General Hospital: Nicholas Curzen* (*principal investigator), Adrian Rozkovec, Andrew Duncan. Royal Sussex County Hospital: Peter Stafford,* Richard Vincent, Douglas Chamberlain, Steven Holmberg, Sally Anderson. Crawley Hospital: Julia Kendall,* Richard Bailey, James Sneddon, Margaret Franklin. Frimley Park Hospital: Malcolm Boyd,* Catherine Packham, Elizabeth Gattwood. Royal Surrey County Hospital: Thomas Foley,* Valerie Hole. Hemel Hempstead Hospital: Jehad Aldeghather,* John Bayliss, Barbara Thatcher. St George's Hospital: Charles Pumphrey, David Redwood, Alistair Slade, Mary Venning. Poole General Hospital: Brenda Howarth,* Andrew MacLeod, Nick Pare. East Surrey Hospital, Redhill, East Sussex: Arshad Ali,* John Lyons, Audrey Watson.
Drug assay and dosing: Terence Lee, David Holt. Central pharmacy: Christopher Cairns. Transtelephonic ECG reception: Dympna O'Farrell, Sharon Welby, Julie Critchley, and the Staff of the Cardiac High Dependency Unit, St George's Hospital.
Received September 29, 1998; revision received March 4, 1999; accepted March 16, 1999.
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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