Download Redefining the Blanking Period After Catheter Ablation for

Original Article
Redefining the Blanking Period After Catheter
Ablation for Paroxysmal Atrial Fibrillation
Insights From the ADVICE (Adenosine Following Pulmonary Vein
Isolation to Target Dormant Conduction Elimination) Trial
Stephan Willems, MD; Paul Khairy, MD, PhD; Jason G. Andrade, MD;
Boris A. Hoffmann, MD; Sylvie Levesque, MSc; Atul Verma, MD;
Rukshen Weerasooriya, MBBS; Paul Novak, MD; Thomas Arentz, MD;
Isabel Deisenhofer, MD; Thomas Rostock, MD; Daniel Steven, MD; Lena Rivard, MD;
Peter G. Guerra, MD; Katia Dyrda, MD; Blandine Mondesert, MD; Marc Dubuc, MD;
Bernard Thibault, MD; Mario Talajic, MD; Denis Roy, MD; Stanley Nattel, MD;
Laurent Macle, MD; for the ADVICE Trial Investigators*
Downloaded from http://circep.ahajournals.org/ by guest on May 11, 2017
Background—Early recurrences (ERs) of atrial tachyarrhythmia are common after catheter ablation of atrial fibrillation. A
3-month blanking period is recommended by current guidelines. This study sought to investigate the significance of ER
during the first 3 months post ablation in predicting late recurrences and determine whether it varies according to timing.
Methods and Results—A total of 401 patients with paroxysmal atrial fibrillation undergoing pulmonary vein isolation were
followed for 12 months with transtelephonic monitoring in the ADVICE (Adenosine Following Pulmonary Vein Isolation
to Target Dormant Conduction Elimination) trial. Patients with atrial tachyarrhythmia ≥30 s within the 3-month blanking
period were stratified according to the timing of ER. A total of 179 patients (44.6%) experienced their last episode of
ER during the first (n=53), second (n=44), or third (n=82) month of the 3-month blanking period. One-year freedom
from symptomatic atrial tachyarrhythmia was 77.2% in patients without ER compared with 62.6%, 36.4%, and 7.8% in
patients with ER 1, 2, and 3 months post ablation, respectively (P<0.0001). Receiver operating curve analyses revealed
a strong correlation between the timing of ER and late recurrence (area under the curve 0.82, P<0.0001). Corresponding
hazard ratios for ER during the first, second, and third months were 1.84, 4.45, and 9.64, respectively.
Conclusions—This study validates the use of a blanking period after catheter ablation for paroxysmal atrial fibrillation but
calls into question the 90-day cut-off value. In particular, >90% of patients with ER during the third month post ablation
experience late recurrence by 1 year. However, pending further study, repeat ablation before 90 days cannot be routinely
advocated.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01058980. (Circ Arrhythm Electrophysiol. 2016;9:e003909. DOI: 10.1161/CIRCEP.115.003909)
Key Words: atrial fibrillation ◼ catheter ablation ◼ electrophysiology ◼ pulmonary vein ◼ tachycardia
C
atheter ablation is increasingly used to treat drug-refractory paroxysmal atrial fibrillation (AF), but recurrences
after initially successful pulmonary vein (PV) isolation (PVI)
are common.1 Notably, during the first 3 months after ablation, a substantial proportion of patients experience early
recurrences (ERs) of atrial tachyarrhythmias (ATs).2–5 The
relevance of ER to long-term recurrence risk is controversial; ERs are believed to often be because of transient local
inflammatory states unassociated with the risk of later AF
recurrence, and thus do not necessarily represent treatment
failure.3,4,6 It has, therefore, become common practice to use
a periprocedural blanking period, during which recurrences
are considered nonspecific and do not prompt reintervention.1 However, there is limited evidence on the impact of
ER-timing within the blanking period on clinical outcomes.7–9
Although the Heart Rhythm Society/European Heart Rhythm
Association/European Cardiac Arrhythmia Society expert
consensus recommends a 3 month post procedural blanking
period, emerging data suggest that electroanatomic changes
observed in the left atrium are limited to the first 4 to 8 weeks
post ablation.9
The ADVICE (Adenosine Following Pulmonary Vein
Isolation to Target Dormant Conduction Elimination) study
was designed to determine the use of an adenosine-guided
Received December 18, 2015; accepted July 18, 2016.
For the author affiliations, please see the Appendix.
*A list of all ADVICE Trial Investigators is given in the Appendix.
The Data Supplement is available at http://circep.ahajournals.org/lookup/suppl/doi:10.1161/CIRCEP.115.003909/-/DC1.
Correspondence to Laurent Macle, MD, Montreal Heart Institute, 5000 Bélanger, Montreal, Qc H1T 1C8, Canada. E-mail [email protected]
© 2016 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org
1
DOI: 10.1161/CIRCEP.115.003909
2 Willems et al Blanking Period After AF Ablation
WHAT IS KNOWN
• During the first three months after catheter ablation
for the treatment of atrial fibrillation, a substantial
proportion of patients experience early recurrences
of atrial tachyarrhythmias.
• The HRS/EHRA/ECAS expert consensus recommends a 3-month postprocedural blanking period
during which recurrences are considered nonspecific
and do not prompt reintervention.
WHAT THE STUDY ADDS
• This study provides empirical evidence in support of
Downloaded from http://circep.ahajournals.org/ by guest on May 11, 2017
a blanking period following pulmonary vein isolation for paroxysmal atrial fibrillation, during which
early recurrences may be considered nonspecific.
• However, it calls into question the 3-month cutoff
period advocated by current guidelines since >90%
of patients with arrhythmia recurrence during the
third month postablation experience late recurrence
by one year.
PVI strategy for paroxysmal AF.10,11 The present predefined
ADVICE substudy was designed to investigate the prevalence and significance of ER after AF ablation and provide
empirical evidence to define a blanking period.
Methods
Study Population
Details of the ADVICE trial have been published previously.10,11
Briefly, the ADVICE study was a prospective randomized clinical
trial investigating whether a strategy incorporating targeted ablation
of PVs with dormant conduction unmasked by intravenous adenosine
would improve long-term efficacy of PVI procedures for paroxysmal
AF. Patients had to meet the following enrollment criteria: referral for
catheter ablation of paroxysmal AF (defined as self-terminating AF
within 7 days of onset), at least 3 symptomatic episodes of AF during the previous 6 months, failure of ≥1 class I or III antiarrhythmic
drugs, age >18 years, at least 1 electrocardiographically documented
episode of AF, and anticoagulation for >4 weeks or left atrial (LA)
thrombus ruled-out by transesophageal echocardiogram within 48
hours of the ablation procedure. Patients with any of the following
criteria were excluded: contraindication to oral anticoagulation therapy, previous ablation for AF, intracardiac thrombus, AF because of
reversible causes, LA size >55 mm, significant mitral valve disease,
and asthma or known adverse reaction to adenosine.
Catheter Ablation Procedure
After PVI by means of an open irrigated-tip radiofrequency ablation
catheter guided by a circular mapping catheter, provocative testing
with ≥12 mg of intravenous adenosine was sequentially performed in
each PV to evaluate the presence of dormant conduction. Adenosine
dosing was titrated to achieve at least 1 blocked P wave or a sinus
pause ≥3 s. Dormant conduction was defined by reappearance of PV
conduction recorded on the circular catheter for ≥1 beat. If dormant
conduction was observed, the patient was randomly assigned to (1)
additional targeted radiofrequency ablation in each affected PV until
dormant conduction could no longer be elicited or (2) no further ablation. If dormant conduction was not elicited in any PV, patients were
randomly assigned to (1) a registry group (with identical follow-up
to those with dormant conduction) or (2) routine follow-up (usual
medical care with no further follow-up in the context of the clinical
trial after hospital discharge).
Postablation Follow-Up
Antiarrhythmic drugs (except amiodarone) were allowed during
the first 3 months post ablation (blanking period). Other drugs,
including angiotensin-converting enzyme inhibitors (ACEi) and
angiotensin II receptor blockers (ARBs), were at the discretion of
the treating physician. All patients were followed for 1 year with
clinical visits and 24-hour ambulatory monitoring at 3, 6, and 12
months. A transtelephonic monitor (Braemar Event Recorder,
Baylis Medical Inc, Montreal, Canada) was provided to each patient immediately after the ablation procedure. Patients were required to record an electrocardiographic rhythm strip weekly at
least for the duration of the follow-up period, including the entire
blanking period, and were instructed to transmit additional recordings in the event of symptoms.
AT Recurrence
AT (AF, atrial flutter; atrial tachycardia) qualified as a recurrence
if it lasted ≥30 s and was documented by 12-lead ECG, electrocardiographic rhythm strips, or transtelephonic monitor recordings.1
Recurrence of symptomatic AT and recurrence of any AT (symptomatic or asymptomatic) were analyzed (on or off antiarrhythmic
drugs). Patients with documented AT within the first 3 months after ablation were stratified according to the timing of ER during.
The exact timing of the last ER within the 3-month blanking period
was recorded as a continuous variable and categorized according to
whether it occurred during the first, second, or third month. Late
recurrence (LR) was defined as AT ≥30 seconds in duration, 3 to 12
months post ablation.
Statistical Analyses
This study was a predefined secondary analysis of the ADVICE trial.
Continuous variables are presented as mean±SD or median and interquartile range (25th, 75th percentile) according to whether their distributions were normal or non-normal and were compared by Student
t tests or Mann–Whitney tests, respectively. Categorical variables are
presented as frequencies or percentages and were compared by χ2 tests.
All analyses were based on the intention-to-treat principle. Time to
first LR was plotted using the Kaplan–Meier product limit method and
compared by the log-rank test. Univariate and multivariate backward
logistic regression analyses were performed to identify factors associated with ER. The multivariate model considered factors associated
with a P value of <0.2 in univariate analyses, with forced retention
of the randomization group variable. Cox regression analyses were
performed to assess the impact of the presence and timing of ER on
LR, after verifying proportionality assumptions. A receiver operator
characteristic (ROC) curve analysis was performed to assess the correlation between the timing of ER and LR. The value with the greatest
discriminatory potential was selected on the basis of Youden Index.12
All statistical tests and confidence intervals were 2-sided, with a significance level of 0.05. Analyses were performed using SAS software
9.3 (SAS Institute Inc, Cary, NC). Data management and analyses were
performed at the Montreal Health Innovations Coordinating Center. All
patients provided informed consent, and the Montreal Heart Institute
Research Center Ethics Committee approved the study protocol.
Results
Early Recurrence
A total of 401 patients, 292 (72.8%) males, 59±10 years, were
followed for an average of 368±43 days. Overall, 197 (49.1%)
patients experienced an ER, which was symptomatic in 179
(44.6%) patients. Baseline clinical characteristics of patients
with and without symptomatic ER are detailed in Table 1.
Patients with ER had a larger LA size than those without ER
3 Willems et al Blanking Period After AF Ablation
Table 1. Baseline Characteristics of Patients With and Without Recurrence of Symptomatic Atrial Tachyarrhythmia
Characteristic
No Early Reccurence (n=222)
Early Reccurence (n=179)
Total (n=401)
P Value
Age, y
58.8±10.5
59.8±9.7
59.2±10.1
0.3288
Men, n (%)
160 (72.1)
132 (73.7)
292 (72.8)
0.7085
Duration of atrial fibrillation, y*
3.0 (1.3; 7.0)
4.0 (2.0; 8.0)
3.3 (1.5–7.0)
0.1343
Antiarrhythmic drugs failed in the past
2.6±1.2
2.6±1.1
2.6±1.2
0.5008
CHADS2 score, n (%)†
0
116 (52.2)
88 (49.1)
204 (50.9)
0.2387
1
72 (32.4)
73 (40.8)
145 (36.1)
0.2387
2
25 (11.3)
13 (7.3)
38 (9.5)
0.2387
≥3
9 (4.1)
5 (2.8)
14 (3.5)
0.2387
Hypertension, n (%)
93 (41.9)
73 (40.8)
166 (41.4)
0.8225
Ischemic heart disease, n (%)
28 (12.6)
13 (7.3)
41 (10.2)
0.0788
Congestive heart failure, n (%)
Downloaded from http://circep.ahajournals.org/ by guest on May 11, 2017
7 (3.2)
5 (2.8)
12 (3.0)
0.8335
13 (5.9)
12 (6.7)
25 (6.2)
0.7270
9 (4.1)
8 (4.5)
17 (4.2)
0.8375
Left atrial size, parasternal long axis, mm
39.2±4.4
40.9±5.8
39.9±5.1
0.0033
Left ventricular ejection fraction, %
59.9±5.9
59.5±7.3
59.8±6.5
0.6125
Diabetes mellitus, n (%)
Previous stroke or transient ischemic attack, n (%)
*Non-normally distributed continuous variables are expressed as median and interquartile range (25th–75th percentile).
†The CHADS2 score is a measure of the risk of stroke in patients with atrial fibrillation, with scores ranging from 0 to 6 and higher scores indicating a greater risk.
Congestive heart failure, hypertension, an age of ≥75 years, and diabetes mellitus are each assigned 1 point, and previous stroke or transient ischemic attack is
assigned 2 points; the score is calculated by summing all the points for a given patient.
(40.9±5.8 versus 39.2±4.4 mm, P=0.0033), with otherwise
similar baseline characteristics, including AF duration, prevalence of underlying heart disease, and the CHADS2 score.
Factors Associated With ER
Univariate and multivariate predictors of ER are detailed in
Table 2. In multivariate analyses, randomization group (odds
ratio, 0.41 for additional ablation versus no further ablation
for dormant PV conduction; 95% confidence interval [{0.25–
0.70}; overall P=0.0010], LA size [odds ratio, 1.09 per mm;
95% confidence interval, 1.04–1.14; P=0.0002], and ACEi or
ARB at discharge [odds ratio, 0.57; 95% confidence interval,
0.35–0.92; P=0.0220]) were independently associated with
ER. Antiarrhythmic drug therapy post ablation had no impact
on risk of developing ER.
Significance of ER and Timing Within the Blanking
Period
At 12 months after a single ablation procedure, freedom from
symptomatic AT after the blanking period (30.7% versus
77.2%; P<0.0001) and freedom from any AT (30.5% versus
76.7%; P<0.0001) was significantly lower in patients with ER
(at any time during the blanking period) compared with those
without ER (Figure 1). Specifically, 12-month freedom from
symptomatic AT after a single ablation procedure was 28.7% in
patients with symptomatic ER consisting of AF only, 62.5% in
patients with symptomatic ER consisting of atrial tachycardia/
atrial flutter only, and 24.2% in patients with symptomatic ER
with both AF and atrial tachycardia/atrial flutter (P<0.0001;
Figure I in the Data Supplement). Freedom from symptomatic
AT off antiarrhythmic drugs (28.8% versus 70.4%; P<0.0001)
was also significantly lower in patients with ER (at any time
during the blanking period) compared with those without ER
(Figure II in the Data Supplement).
Of the 179 patients with ER, the timing of the latest ER
was during the first month post ablation in 53 patients, during
the second month in 44 patients, and during the third month in
82 patients. The risk of LR varied significantly according to the
timing of the ER, with a clearly graded effect (Figure 2). Oneyear freedom from symptomatic AT with or without antiarrhythmic drugs after a single procedure was 77.2% in patients
without ER compared with 62.6%, 36.4%, and 7.8% in patients
with ER 1, 2, and 3 months post ablation (P<0.0001). Oneyear freedom from symptomatic AT off antiarrhythmic drugs
after a single ablation procedure was 70.4% in patients without
ER compared with 58.7%, 36.4%, and 6.1% in patients with
ER 1, 2, and 3 months post ablation (P<0.0001). All 2-by-2
comparisons were statistically significant. Similar results were
obtained when the end point of recurrence of any AT (symptomatic or asymptomatic) was analyzed (P<0.0001).
The impact of the number of months with symptomatic ER
(1 month only, 2 months, or all 3 months) during the 3-month
blanking period on the incidence of LR was also studied. At
12 months, freedom from symptomatic AT after a single ablation procedure was 48.2% in patients with ER during only 1
month of the blanking period, 20.7% in patients with ER in
any 2 months of the blanking period, and 3.1% in patients
with ER during all 3 months of the 3-month blanking period
(P<0.0001; Figure III in the Data Supplement).
ROC analysis for assessing the correlation between the
timing of ER and LR is displayed in Figure 3 (area under
4 Willems et al Blanking Period After AF Ablation
Table 2. Univariate and Multivariate Logistic Regression Analyses for Early RecurrencesUnivariate
Odds Ratio
95% Confidence
Interval
P Value
Ablation until adenosine neg vs no further ablation
0.522
(0.325–0.836)
0.0012
Ablation until adenosine neg vs registry group
1.278
(0.773–2.113)
0.0012
Registry group vs no further ablation
0.408
(0.245–0.679)
0.0012
Right isthmus linear ablation
1.299
(0.775–2.177)
0.3214
Left atrial roof linear ablation
1.244
(0.248–6.241)
0.7905
Left mitral isthmus linear ablation
2.497
(0.225–27.762)
0.4565
Non PV foci ablation
1.669
(0.369–7.554)
0.5064
Any non-PVI ablation (during procedure)
1.309
(0.802–2.139)
0.2817
Conscious sedation vs general anesthesia*
1.349
(0.903–2.015)
0.1443
Adjunctive electroanatomic mapping systems
0.925
(0.428–1.998)
0.8429
At least 1 vein with PV dissociation observed
1.160
(0.773–1.743)
0.4732
At least 1 vein with PVI performed partially or completely
during AF*
1.882
(1.243–2.850)
0.0028
At least 1 vein with spontaneous reconnection
1.062
(0.693–1.630)
0.7815
Age, y
1.010
(0.990–1.030)
0.3282
Sex, male
1.088
(0.698–1.696)
0.7092
Hypertension
0.955
(0.640–1.425)
0.8226
Structural heart disease
0.950
(0.641–1.408)
0.7976
Time since first diagnosis of paroxysmal AF, y*
1.148
(0.946–1.393)
0.1622
No. of antiarrhythmic drugs used in the past
1.060
(0.894–1.257)
0.4999
Left atrial size,* mm
1.068
(1.023–1.115)
0.0028
Left atrial volume, mm
1.013
(0.976–1.052)
0.4823
Average duration of AF episode in past 6 mo (≥6 h vs <6 h)*
1.385
(0.916–2.094)
0.1226
Valvular disease
0.616
(0.112–3.401)
0.5782
Diabetes mellitus
1.155
(0.514–2.598)
0.7272
AF induced by adenosine
1.701
(0.700–4.132)
0.2410
Tobacco*
0.676
(0.438–1.042)
0.0759
Antiarrhythmic drug at discharge
1.064
(0.717–1.579)
0.7586
Body mass index, kg/m
0.981
(0.938–1.025)
0.3963
Left ventricular ejection fraction at baseline, %
0.991
(0.960–1.024)
0.6018
Weight, kg
0.998
(0.987–1.010)
0.7642
ACEi/ARB at discharge*
0.733
(0.484–1.110)
0.1429
β-Blocker at discharge
1.274
(0.856–1.897)
0.2326
Ablation until adenosine neg vs no further ablation
0.413
(0.245–0.699)
0.0010
Ablation until adenosine neg vs registry group
1.012
(0.579–1.768)
0.0010
Registry group vs no further ablation
0.409
(0.232–0.721)
0.0010
Left atrial size, mm
1.090
(1.041–1.142)
0.0002
ACEi/ARB at discharge
0.565
(0.347–0.921)
0.0220
Variable
Randomization group*
Downloaded from http://circep.ahajournals.org/ by guest on May 11, 2017
3
2
Multiple logistic regression for early recurrent event
Randomization group
ACEi indicates angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; neg,
negative; PV, pulmonary vein; and PVI, PV isolation.
*Variables included in the multiple logistic regression model.
5 Willems et al Blanking Period After AF Ablation
Downloaded from http://circep.ahajournals.org/ by guest on May 11, 2017
Figure 1. A, Freedom from symptomatic atrial tachyarrhythmia (AT) after a single ablation procedure and (B) freedom from any AT after a
single ablation procedure; in patients with and without early recurrence of AT. CI indicates confidence interval.
the curve, 0.8218; P<0.0001). The point on the ROC curve
associated with the greatest discriminatory potential was 50
days (Youden index 0.58). Freedom from LR and hazard
ratios according to whether ER occurred during the first,
second, or third month of the blanking period are summarized in Table 3.
Discussion
Main Findings
The main findings of this study are (1) ER occurs in >40% of
patients when follow-up is based on regular transtelephonic
recordings, (2) factors independently associated with ER are
presence of dormant conduction left unablated, LA enlargement, and absence of ACEi or ARB therapy post ablation, (4)
ER is associated with a significantly increased rate of recurrence of AT during the long-term follow-up, and (5) a gradient
of risk is observed according to the timing of ER. Specifically,
recurrences during the third month of the conventional blanking period are highly predictive of LR and should not, therefore, be dismissed as nonsignificant.
Incidence of ERs After AF Ablation
ER after AF ablation occurs frequently and is postulated to
be related to transient phenomena because of the ablation
6 Willems et al Blanking Period After AF Ablation
Downloaded from http://circep.ahajournals.org/ by guest on May 11, 2017
Figure 2. A, Freedom from symptomatic atrial tachyarrhythmia (AT) after a single ablation procedure in patients with early recurrence
of AT 1, 2, and 3 mo post ablation and (B) freedom from symptomatic AT off antiarrhythmic drugs after a single ablation procedure in
patients with early recurrence of AT 1, 2, and 3 mo post ablation.
procedure. In our study, 44.6% of patients experienced ER
of symptomatic AT during the 3 months post ablation blanking period, consistent with prevalence rates between 16%
and 65% in earlier studies.1,2 The pooled average ER rate was
38% in trials that relied on sporadic ECG and Holter recordings instead of routine transtelephonic monitoring for detection.2,7 It has been noted that the incidence of ER progressively
decreases over time and is highest shortly after ablation. In
the STAR AF I substudy, which included a substantial proportion of patients with persistent AF (36%), ER was observed
in 50%, primarily based on Holter recordings.13 ER has also
been described after cryoballoon ablation for AF, despite the
fact that this energy source is thought to be associated with a
less marked inflammatory reaction compared with radiofrequency.14 In a recent STOP-AF (Sustained Treatment of Paroxysmal Atrial Fibrillation) substudy, the incidence of ER was
52% using transtelephonic monitoring data.15
Predictors of ER After AF Ablation
Various predictors for early arrhythmia recurrence after ablation have been proposed.2,5 These include clinical characteristics, pattern of AF, echocardiographic parameters, such as
LA enlargement, markers of inflammation, and procedural
characteristics. In this study, a lower prevalence of ER was
independently associated with smaller LA size, an ablation
7 Willems et al Blanking Period After AF Ablation
acute and chronic electric remodeling in AF.22,23 Interestingly,
antiarrhythmic agents at discharge did not confer a beneficial
effect on ER in our study, a finding consistent with some but
not all earlier studies.3,24–26 Although the impact of empirical
antiarrhythmic drugs on ER remains controversial, no effect
on longer-term outcomes has been observed.26,27
Relevance of ER-Timing
Downloaded from http://circep.ahajournals.org/ by guest on May 11, 2017
Figure 3. Receiving operator characteristics analysis to assess
the correlation between timing of early recurrence and late
recurrence.
strategy of eliminating dormant PV conduction, and the use of
ACEi or ARB at discharge. LA size, previously reported as a
predictor for ER,4,6,7,16 may reflect atrial structural remodeling
and hemodynamic burden, and it is also the strongest predictor of a favorable long-term outcome after a single ablation
procedure.17 Eliminating dormant conduction, when present,
markedly improves long-term outcomes, as demonstrated
by the main ADVICE trial.10 A lower prevalence of ER is,
therefore, consistent with higher efficacy associated with this
strategy. In the STAR AF I trial, the index ablation strategy
associated with the best long-term outcomes was also associated with a lower prevalence of ER.13 Nonrandomized studies
evaluating the impact of ACEi or ARB on ER and LR after
AF ablation have reported conflicting results.18–20 However,
our findings are consistent with a recent randomized trial of
120 patients, which reported a significant reduction in ER and
LR with valsartan post-PVI.21 Most patients treated with ACEi
or ARB in the ADVICE trial had hypertension (ie, 121/143;
84.6%). Experimental studies have provided a biologically
plausible rationale, demonstrating that ACEi and ARB prevent
Table 3. LR According to Timing of the Last Episode of ER
Within the Blanking Period
Freedom
From LR, %
Hazard
Ratio*
95% CI*
P Value
No ER
77.2
…
…
…
ER during the first
month
62.6
1.84
1.09–3.12
0.0230
ER during the
second month
36.4
4.45
2.83–6.99
<0.0001
7.8
9.64
6.68–13.91
<0.0001
ER during the third
month
CI indicates confidence interval; ER, early recurrence; and LR, late recurrence.
*No ER is the reference category.
The concept of a blanking period is predicated on the assumption that early AT recurrences are because of a different (transient) mechanism from later recurrences and do not necessarily
represent treatment failure. Here, we found that freedom from
AT at 12 months was markedly lower in patients with ER compared with those without. Importantly, our analyses indicate
that the prognostic importance of ER varies according to the
time of onset, with a clear gradient of effect. Similarly, Themistoclakis et al7 found a strong inverse correlation between the
timing of ER within a 3-month blanking period and LR in a
large nonrandomized study (ie, odds ratio, 20, 54, and 1052 for
ER in the first, second, and third month, respectively).
Our study provides support for incorporating a blanking
period post catheter ablation, with ROC analyses revealing
a strong correlation between the timing of ER and LR (area
under the curve, 0.82; P<0.0001). At the same time, our findings challenge the conventional 3-month blanking period supported by the Heart Rhythm Society/European Heart Rhythm
Association/European Cardiac Arrhythmia Society expert
consensus panel.1 Recurrence within the third month post
ablation was associated with an HR of 9.64 in predicting LR,
with <10% remaining free from LR by 1 year of follow-up.
Although a blanking period of 50 days yielded the greatest
discriminatory potential by ROC analysis (Youden index) in
the ADVICE trial, this approach is based on a statistical concept that does not account for how the blanking period is used
in clinical practice. It makes no assumption about the relative significance of false positives versus false negatives.12 It
simply represents the point on the ROC curve that maximizes
the vertical distance from the line of equality (diagonal line).
The observation that not all ERs are predictive of LR suggests
different pathogenic mechanisms according to time since the
index ablation procedure. Mechanistically, a 50-day blanking period is coherent with recent data suggesting that 4 to 8
weeks are required for the completion of LA electroanatomic
changes post ablation.9
From a practical perspective, our findings may inform
management decisions about ER after AF ablation.
Recurrences within the third month post ablation should not
be considered nonspecific because the overwhelming majority (>90%) of such patients will subsequently experience
recurrent AT. Pending definitive clinical trial evidence from
head-to-head comparisons of blanking periods, earlier repeat
ablation cannot be routinely advocated. As such, treatment
decisions should be individualized. For example, in highly
symptomatic patients with multiple recurrences, it may be
reasonable to perform a repeat ablation procedure before the
end of the standard 90-day blanking period. However, the
potential risks and cost of an unnecessary early repeat ablation
should be weighed considering that 8% of patients with ER
during the third month post ablation remain free of arrhythmia
8 Willems et al Blanking Period After AF Ablation
at 12 months without further ablation. It may be hypothesized
that recurrences in the latter part of the conventional 90-day
blanking period post ablation are more likely to represent PV
reconnection, as opposed to acute inflammatory or remodeling
effects.28–30 Indeed, a recent study of patients undergoing systematic PV mapping 2 months post ablation found that ER in
the second month after PVI was strongly associated with PV
reconnection, as opposed to ER confined to the first month.9
Conclusions
Downloaded from http://circep.ahajournals.org/ by guest on May 11, 2017
This predefined substudy of the ADVICE trial provides empirical evidence in support of a blanking period after PVI for
paroxysmal AF, during which ER may be considered nonspecific. However, it calls into question the 3-month cut-off
value advocated by current guidelines because ER during the
third month post ablation is nearly always associated with LR.
Randomized trials are required to assess the impact of a conventional versus shorter blanking period on clinical outcomes
after catheter ablation for AF.
Appendix
Affiliations
From the Montreal Heart Institute, Université de Montréal, Montreal
Health Innovations Coordinating Centre (MHICC), Canada (P.K.,
J.G.A., S.L., L.R., P.G.G., K.D., B.M., M.D., B.T., M.T., D.R., S.N.,
L.M.); Department of Medicine, Université de Montréal, Canada
(P.K., J.G.A., S.L., L.R., P.G.G., K.D., B.M., M.D., B.T., M.T., D.R.,
S.N., L.M.); Hollywood Private Hospital, University of Western Australia, Perth, Australia (R.W.); Royal Jubilee Hospital, Victoria, Australia (P.N.); Southlake Regional Health Centre, Newmarket, Canada
(A.V.), University Hospital Eppendorf, Hamburg, Germany (S.W.,
B.A.H.); Herz-Zentrum, Bad Krozingen, Germany (T.A.); Deutsches
Herz-Zentrum München, Munich, Germany (I.D.); University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany
(T.R.); and Herzzentrum Uniklinik Köln, Germany (D.S.).
ADVICE Trial Investigators
Laurent Macle: Montreal Heart Institute, Université de Montréal,
Montreal, Canada; Rukshen Weerasooriya: Hollywood Private Hospital, Perth, Australia; Paul Novak: Royal Jubilee Hospital, Victoria,
Canada; Atul Verma: Southlake Regional Health Center, Newmarket, Canada; Stephan Willems: Universitäres Herzzentrum, Hamburg, Germany; Thomas Arentz: Universitäts Herzzentrum, Bad
Krozingen, Germany; Isabel Deisenhofer: Deutsches Herzzentrum,
Munich, Germany; Yorgo Veenhuyzen: Libin Cardiovascular Institute, Calgary, Canada; Christophe Scavée: Cliniques Universitaires
St-Luc, Brussels, Belgium; Ratika Parkash: QE II Health Sciences
Centre, Halifax, Canada; Isabelle Nault: IUCPQ, Quebec, Canada;
Jean-François Roux: CHUS Fleurimont, Sherbrooke, Canada; Allan
Skanes: London Health Science Center, London, Canada; David
Birnie: Ottawa Heart Institute, Ottawa, Canada; Pierre Jaïs: Hôpital
Haut-Lévêque, Bordeaux, France; Helmut Pürerfellner: KH der Elizabethinen, Linz, Austria; Vidal Essebag; McGill University Health
Center, Montreal, Canada; Girish Nair, Carlos Morillo: McMaster
University, Hamilton, Canada.
Acknowledgments
Data management and analyses were performed at the Montreal
Health Innovations Coordinating Centre (Montreal, Canada).
Sources of Funding
The ADVICE trial was funded by the Canadian Institutes of Health
Research (CIHR) with support from the investigator initiated study
programs of St. Jude Medical and Biosense-Webster, and a personal contribution from M. Lachapelle, Montreal Heart Institute
Foundation.
Disclosures
Dr Macle reports receiving lecture fees from St. Jude Medical,
Biosense-Webster, Medtronic, Bayer, Boehringer-Ingelheim, Bristol
Myers Squibb, and Pfizer and grant support from St. Jude Medical and
Biosense-Webster. Dr Khairy reports receiving consulting fees from
Boehringer-Ingelheim and grant support from Boehringer-Ingelheim,
Actelion, Bayer, Medtronic, and St. Jude Medical. Dr Weerasooriya
reports receiving lecture fees from Bayer, Boehringer-Ingelheim, and
Pfizer. Dr Novak reports receiving lecture fees from Medtronic and
Boehringer Ingelheim and research support from St. Jude Medical,
Biosense-Webster, Medtronic, and Biotronik. Dr Verma reports having served on advisory boards for and receiving grant support from
Bayer, Boehringer-Ingelheim, Medtronic, Biosense-Webster, and
St. Jude Medical. Dr Willems reports receiving lecture fees from St.
Jude Medical, Biosense-Webster, Boston Scientific, Bristol Myers
Squibb, and Sanofi-Aventis and having served on advisory boards for
Boehringer-Ingelheim and Bayer. Dr Deisenhofer reports receiving
lecture fees from Biosense-Webster, St. Jude Medical, BoehringerIngelheim, and Astra-Zeneca. Dr Andrade reports receiving lecture
fees from Medtronic, Bayer, and Biosense-Webster; consulting
fees from Medtronic, Bayer, and Biotronik; and grant support from
Medtronic. The other authors report no conflicts.
References
1. Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns
HJ, Damiano RJ Jr, Davies DW, DiMarco J, Edgerton J, Ellenbogen K,
Ezekowitz MD, Haines DE, Haissaguerre M, Hindricks G, Iesaka Y,
Jackman W, Jalife J, Jais P, Kalman J, Keane D, Kim YH, Kirchhof P, Klein
G, Kottkamp H, Kumagai K, Lindsay BD, Mansour M, Marchlinski FE,
McCarthy PM, Mont JL, Morady F, Nademanee K, Nakagawa H, Natale
A, Nattel S, Packer DL, Pappone C, Prystowsky E, Raviele A, Reddy V,
Ruskin JN, Shemin RJ, Tsao HM, Wilber D; Heart Rhythm Society Task
Force on Catheter and Surgical Ablation of Atrial Fibrillation. 2012 HRS/
EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints,
and research trial design: a report of the Heart Rhythm Society (HRS) Task
Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed
in partnership with the European Heart Rhythm Association (EHRA), a
registered branch of the European Society of Cardiology (ESC) and the
European Cardiac Arrhythmia Society (ECAS); and in collaboration with
the American College of Cardiology (ACC), American Heart Association
(AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the
Society of Thoracic Surgeons (STS). Endorsed by the governing bodies
of the American College of Cardiology Foundation, the American Heart
Association, the European Cardiac Arrhythmia Society, the European
Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia
Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart
Rhythm. 2012;9:632–696.e21. doi: 10.1016/j.hrthm.2011.12.016.
2. Andrade JG, Khairy P, Verma A, Guerra PG, Dubuc M, Rivard L, Deyell
MW, Mondesert B, Thibault B, Talajic M, Roy D, Macle L. Early recurrence of atrial tachyarrhythmias following radiofrequency catheter ablation of atrial fibrillation. Pacing Clin Electrophysiol. 2012;35:106–116.
doi: 10.1111/j.1540-8159.2011.03256.x.
3. Oral H, Knight BP, Ozaydin M, Tada H, Chugh A, Hassan S, Scharf C,
Lai SW, Greenstein R, Pelosi F Jr, Strickberger SA, Morady F. Clinical
significance of early recurrences of atrial fibrillation after pulmonary vein
isolation. J Am Coll Cardiol. 2002;40:100–104.
4. Jiang H, Lu Z, Lei H, Zhao D, Yang B, Huang C. Predictors of early recurrence and delayed cure after segmental pulmonary vein isolation for paroxysmal atrial fibrillation without structural heart disease. J Interv Card
Electrophysiol. 2006;15:157–163. doi: 10.1007/s10840-006-9003-y.
5. Liang JJ, Elafros MA, Chik WW, Santangeli P, Zado ES, Frankel DS,
Supple GE, Schaller RD, Lin D, Hutchinson MD, Riley MP, Callans DJ,
Marchlinski FE, Dixit S. Early recurrence of atrial arrhythmias following
pulmonary vein antral isolation: Timing and frequency of early recurrences predicts long-term ablation success. Heart Rhythm. 2015;12:2461–
2468. doi: 10.1016/j.hrthm.2015.07.015.
9 Willems et al Blanking Period After AF Ablation
Downloaded from http://circep.ahajournals.org/ by guest on May 11, 2017
6. O’Donnell D, Furniss SS, Dunuwille A, Bourke JP. Delayed cure despite
early recurrence after pulmonary vein isolation for atrial fibrillation. Am J
Cardiol. 2003;91:83–85.
7.Themistoclakis S, Schweikert RA, Saliba WI, Bonso A, Rossillo A,
Bader G, Wazni O, Burkhardt DJ, Raviele A, Natale A. Clinical predictors and relationship between early and late atrial tachyarrhythmias after
pulmonary vein antrum isolation. Heart Rhythm. 2008;5:679–685. doi:
10.1016/j.hrthm.2008.01.031.
8. Joshi S, Choi AD, Kamath GS, Raiszadeh F, Marrero D, Badheka A,
Mittal S, Steinberg JS. Prevalence, predictors, and prognosis of atrial fibrillation early after pulmonary vein isolation: findings from 3 months of
continuous automatic ECG loop recordings. J Cardiovasc Electrophysiol.
2009;20:1089–1094. doi: 10.1111/j.1540-8167.2009.01506.x.
9. Das M, Wynn GJ, Morgan M, Lodge B, Waktare JE, Todd DM, Hall
MC, Snowdon RL, Modi S, Gupta D. Recurrence of atrial tachyarrhythmia during the second month of the blanking period is associated with
more extensive pulmonary vein reconnection at repeat electrophysiology study. Circ Arrhythm Electrophysiol. 2015;8:846–852. doi: 10.1161/
CIRCEP.115.003095.
10. Macle L, Khairy P, Verma A, Weerasooriya R, Willems S, Arentz T, Novak
P, Veenhuyzen G, Scavée C, Skanes A, Puererfellner H, Jaïs P, Khaykin
Y, Rivard L, Guerra PG, Dubuc M, Thibault B, Talajic M, Roy D, Nattel
S; ADVICE Study Investigators. Adenosine Following Pulmonary Vein
Isolation to Target Dormant Conduction Elimination (ADVICE): methods and rationale. Can J Cardiol. 2012;28:184–190. doi: 10.1016/j.
cjca.2011.10.008.
11.Macle L, Khairy P, Weerasooriya R, Novak P, Verma A, Willems S,
Arentz T, Deisenhofer I, Veenhuyzen G, Scavée C, Jaïs P, Puererfellner
H, Levesque S, Andrade JG, Rivard L, Guerra PG, Dubuc M, Thibault
B, Talajic M, Roy D, Nattel S; ADVICE trial investigators. Adenosineguided pulmonary vein isolation for the treatment of paroxysmal atrial
fibrillation: an international, multicentre, randomised superiority trial.
Lancet. 2015;386:672–679. doi: 10.1016/S0140-6736(15)60026-5.
12.Böhning D, Böhning W, Holling H. Revisiting Youden’s index as a
useful measure of the misclassification error in meta-analysis of diagnostic studies. Stat Methods Med Res. 2008;17:543–554. doi:
10.1177/0962280207081867.
13. Andrade JG, Macle L, Khairy P, Khaykin Y, Mantovan R, De Martino G,
Chen J, Morillo CA, Novak P, Guerra PG, Nair G, Torrecilla EG, Verma A.
Incidence and significance of early recurrences associated with different ablation strategies for AF: a STAR-AF substudy. J Cardiovasc Electrophysiol.
2012;23:1295–1301. doi: 10.1111/j.1540-8167.2012.02399.x.
14.Hernández-Romero D, Marín F, Roldán V, Peñafiel P, Vilchez JA,
Orenes-Piñero E, Giner JA, Valdés M, García-Alberola A. Comparative
determination and monitoring of biomarkers of necrosis and myocardial
remodeling between radiofrequency ablation and cryoablation. Pacing
Clin Electrophysiol. 2013;36:31–36. doi: 10.1111/pace.12017.
15.Andrade JG, Khairy P, Macle L, Packer DL, Lehmann JW, Holcomb
RG, Ruskin JN, Dubuc M. Incidence and significance of early recurrences of atrial fibrillation after cryoballoon ablation: insights from the
multicenter Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP
AF) Trial. Circ Arrhythm Electrophysiol. 2014;7:69–75. doi: 10.1161/
CIRCEP.113.000586.
16. Lee SH, Tai CT, Hsieh MH, Tsai CF, Lin YK, Tsao HM, Yu WC, Huang
JL, Ueng KC, Cheng JJ, Ding YA, Chen SA. Predictors of early and
late recurrence of atrial fibrillation after catheter ablation of paroxysmal
atrial fibrillation. J Interv Card Electrophysiol. 2004;10:221–226. doi:
10.1023/B:JICE.0000026915.02503.92.
17. Miyazaki S, Kuwahara T, Kobori A, Takahashi Y, Takei A, Sato A, Isobe M,
Takahashi A. Impact of adenosine-provoked acute dormant pulmonary vein
conduction on recurrence of atrial fibrillation. J Cardiovasc Electrophysiol.
2012;23:256–260. doi: 10.1111/j.1540-8167.2011.02195.x.
18. Ishikawa K, Yamada T, Yoshida Y, Takigawa M, Aoyama Y, Inoue N,
TatematsuY, Nanasato M, Kato K, Tsuboi N, Hirayama H. Renin-angiotensin
system blocker use may be associated with suppression of atrial fibrillation recurrence after pulmonary vein isolation. Pacing Clin Electrophysiol.
2011;34:296–303. doi: 10.1111/j.1540-8159.2010.02949.x.
19.Mohanty S, Mohanty P, Trivedi C, Gianni C, Bai R, Burkhardt JD,
Gallinghouse JG, Horton R, Sanchez JE, Hranitzky PM, Al-Ahmad A,
Bailey S, Di Biase L, Natale A. Association of pretreatment with angiotensin-converting enzyme inhibitors with improvement in ablation outcome
in atrial fibrillation patients with low left ventricular ejection fraction.
Heart Rhythm. 2015;12:1963–1971. doi: 10.1016/j.hrthm.2015.06.007.
20. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream therapies
for management of atrial fibrillation: review of clinical evidence and
implications for European Society of Cardiology guidelines. Part II: secondary prevention. Europace. 2011;13:610–625. doi: 10.1093/europace/
eur023.
21. Cui Y, Ma C, Long D, Wang L, Cao X, Zhang G. Effect of valsartan on
atrial fibrillation recurrence following pulmonary vein isolation in patients. Exp Ther Med. 2015;9:631–635. doi: 10.3892/etm.2014.2143.
22. Nakashima H, Kumagai K, Urata H, Gondo N, Ideishi M, Arakawa K.
Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation. Circulation. 2000;101:2612–2617.
23. Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Saku K. Effects
of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol. 2003;41:2197–2204.
24. Hayashi M, Miyauchi Y, Iwasaki YK, Yodogawa K, Tsuboi I, Uetake S,
Hayashi H, Takahashi K, Shimizu W. Three-month lower-dose flecainide
after catheter ablation of atrial fibrillation. Europace. 2014;16:1160–1167.
doi: 10.1093/europace/euu041.
25.Roux JF, Zado E, Callans DJ, Garcia F, Lin D, Marchlinski FE, Bala
R, Dixit S, Riley M, Russo AM, Hutchinson MD, Cooper J, Verdino R,
Patel V, Joy PS, Gerstenfeld EP. Antiarrhythmics after ablation of atrial
fibrillation (5A Study). Circulation. 2009;120:1036–1040. doi: 10.1161/
CIRCULATIONAHA.108.839639.
26. Darkner S, Chen X, Hansen J, Pehrson S, Johannessen A, Nielsen JB,
Svendsen JH. Recurrence of arrhythmia following short-term oral
AMIOdarone after CATheter ablation for atrial fibrillation: a doubleblind, randomized, placebo-controlled study (AMIO-CAT trial). Eur
Heart J. 2014;35:3356–3364. doi: 10.1093/eurheartj/ehu354.
27. Leong-Sit P, Roux JF, Zado E, Callans DJ, Garcia F, Lin D, Marchlinski
FE, Bala R, Dixit S, Riley M, Hutchinson MD, Cooper J, Russo AM,
Verdino R, Gerstenfeld EP. Antiarrhythmics after ablation of atrial fibrillation (5A Study): six-month follow-up study. Circ Arrhythm Electrophysiol.
2011;4:11–14. doi: 10.1161/CIRCEP.110.955393.
28. Verma A, Kilicaslan F, Pisano E, Marrouche NF, Fanelli R, Brachmann
J, Geunther J, Potenza D, Martin DO, Cummings J, Burkhardt JD, Saliba
W, Schweikert RA, Natale A. Response of atrial fibrillation to pulmonary
vein antrum isolation is directly related to resumption and delay of pulmonary vein conduction. Circulation. 2005;112:627–635. doi: 10.1161/
CIRCULATIONAHA.104.533190.
29.Ouyang F, Antz M, Ernst S, Hachiya H, Mavrakis H, Deger FT,
Schaumann A, Chun J, Falk P, Hennig D, Liu X, Bänsch D, Kuck KH.
Recovered pulmonary vein conduction as a dominant factor for recurrent
atrial tachyarrhythmias after complete circular isolation of the pulmonary
veins: lessons from double Lasso technique. Circulation. 2005;111:127–
135. doi: 10.1161/01.CIR.0000151289.73085.36.
30.Willems S, Steven D, Servatius H, Hoffmann BA, Drewitz I,
Müllerleile K, Aydin MA, Wegscheider K, Salukhe TV, Meinertz T,
Rostock T. Persistence of pulmonary vein isolation after robotic remote-navigated ablation for atrial fibrillation and its relation to clinical outcome. J Cardiovasc Electrophysiol. 2010;21:1079–1084. doi:
10.1111/j.1540-8167.2010.01773.x.
Downloaded from http://circep.ahajournals.org/ by guest on May 11, 2017
Redefining the Blanking Period After Catheter Ablation for Paroxysmal Atrial
Fibrillation: Insights From the ADVICE (Adenosine Following Pulmonary Vein Isolation
to Target Dormant Conduction Elimination) Trial
Stephan Willems, Paul Khairy, Jason G. Andrade, Boris A. Hoffmann, Sylvie Levesque, Atul
Verma, Rukshen Weerasooriya, Paul Novak, Thomas Arentz, Isabel Deisenhofer, Thomas
Rostock, Daniel Steven, Lena Rivard, Peter G. Guerra, Katia Dyrda, Blandine Mondesert, Marc
Dubuc, Bernard Thibault, Mario Talajic, Denis Roy, Stanley Nattel and Laurent Macle
for the ADVICE Trial Investigators*
Circ Arrhythm Electrophysiol. 2016;9:
doi: 10.1161/CIRCEP.115.003909
Circulation: Arrhythmia and Electrophysiology is published by the American Heart Association, 7272 Greenville
Avenue, Dallas, TX 75231
Copyright © 2016 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-3149. Online ISSN: 1941-3084
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circep.ahajournals.org/content/9/8/e003909
Data Supplement (unedited) at:
http://circep.ahajournals.org/content/suppl/2016/08/11/CIRCEP.115.003909.DC1
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation: Arrhythmia and Electrophysiology can be obtained via RightsLink, a service of the Copyright
Clearance Center, not the Editorial Office. Once the online version of the published article for which
permission is being requested is located, click Request Permissions in the middle column of the Web page
under Services. Further information about this process is available in the Permissions and Rights Question and
Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation: Arrhythmia and Electrophysiology is online at:
http://circep.ahajournals.org//subscriptions/
SUPPLEMENTARY MATERIAL
SUPPLEMENTARY FIGURE LEGENDS
Supplementary Figure 1.
Freedom from symptomatic atrial tachyarrhythmia (AT) after a single ablation procedure in
patients with and without early recurrence of AT by arrhythmia type (atrial fibrillation (AF) only,
atrial tachycardia/atrial flutter only, both AF and atrial tachycardia/atrial flutter).
Supplementary Figure 2.
Freedom from symptomatic atrial tachyarrhythmia (AT) off antiarrhythmic drugs after a single
ablation procedure in patients with and without early recurrence of AT.
Supplementary Figure 3.
Freedom from symptomatic atrial tachyarrhythmia (AT) after a single ablation procedure in
patients with early recurrence of AT during one, any two, or all three months of the post-ablation
blanking period.
SUPPLEMENTARY FIGURES
Supplementary Figure 1
Supplementary Figure 2
Supplementary Figure 3