Outcomes of Paroxysmal AF ablation Studies are Affected more by Study Design and Patient Mix than Ablation Technique
Short title: Trial design and outcomes in AF ablation
João Ferreira-Martinsc MRCP PhD, James Howardb MB BChir, Becker Al-khayattb MBBS,
Joseph Shalhoubd MBBS PhD, Afzal Sohaibc MBBS PhD, Matthew Shun-Shinb BM BCh,
Paul G Novaka MD, Rick Leathera MD, Laurence D Sternsa MD, Christopher Lanea MD,
Phang Boon Limb,c MBBS PhD, Prapa Kanagaratnamb,c PhD FRCP, Nicholas S Petersb,c MD
PhD FHRS, Darrel P Francisb,c1 MA MD, Markus B Sikkela,b MBBS PhD
aRoyal Jubilee Hospital, Victoria, Canada V8R 1J8
bNational Heart and Lung Institute, Imperial College London, London W12 0NN, UK
cDepartment of Cardiology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London W12 0HS, UK
dDepartment of Surgery & Cancer, Imperial College London, London SW7 2AZ, UK
1 Corresponding author
Prof Darrel FrancisInternational Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London59 North Wharf RoadLondon, W2 1LAUKEmail: [email protected]: +447973105394Fax: +442080825109
Total word count: 5024
M.B. Sikkel is supported by a National Institute of Health Research Clinical Lectureship award (#2670).ABSTRACT
1
Objective: We tested whether ablation methodology and study design can explain the
varying outcomes in terms of AF-free survival at 1 year.
Background:
There have been numerous paroxysmal AF ablation trials, which are heterogeneous in
their use of different ablation techniques and study design. A useful approach to
understanding how these factors influence outcome is to dismantle the trials into
individual arms and reconstitute them as a large meta-regression.
Methods: Data was collected from 66 studies (6941 patients). With freedom from AF as
the dependent variable, we performed meta-regression using the individual study arm
as the unit.
Results: Success rates did not change regardless of the technique used to produce
pulmonary vein isolation. Neither were adjunctive lesion sets associated with any
improvement in outcome.
Studies that included more males and fewer hypertensive patients were found more
likely to report better outcomes. ECG method selected to assess outcome also plays an
important role. Outcomes were worse in studies that used regular telemonitoring (by
23%, p<0.001) or in patients who had implantable loop recorders (by 21%, p=0.006),
rather than less thorough periodic Holter monitoring.
Conclusions: Outcomes of AF ablation studies involving pulmonary vein isolation are not
affected by the technologies used to produce PVI. Neither do adjunctive lesion sets
change the outcome. Achieving high success rates in these studies appears to be
dependent more on patient mix and on the thoroughness of AF detection protocols.
2
This should be carefully considered when quoting success rates of AF ablation
procedures which are derived from such studies.
Key words: paroxysmal atrial fibrillation, ablation, pulmonary vein isolation
3
Abbreviations list
AF – atrial fibrillation
AT – atrial tachycardia
CFAE – complex fractionated atrial electrograms
GP – ganglionated plexi
HIFU - high intensity focal ultrasound
ILR – internal loop recorder
LA – left atrium
PAF – paroxysmal atrial fibrillation
PV – pulmonary vein
PVI – pulmonary vein isolation
RF – radiofrequency
WACA – wide area circumferential ablation
4
Introduction
Percutaneous catheter ablation is now well established in international guidelines as an
effective therapy for paroxysmal atrial fibrillation (AF) 1,2. However, there is a wide range
of success rates (20%-100% at 12 months)3,4 and this is frequently attributed to technical
differences in the ablation process5-7.
No analysis has ever systematically addressed the possibility that the disparate design of
trials might also contribute to the disparate results. In part this is because the disparities
are so extensive that conventional trial-by-trial analysis is unable to extract the effects.
In this analysis, we perform an arm-by-arm meta-regression in which the multi-level
heterogeneity becomes a strength rather than a weakness. Treating the individual arms
(with their design and corresponding outcome) as the unit of analysis, we quantify:
Whether adjunctive ablation strategies such as CFAE, GP ablation or additional
lines might be additive to PVI in improving success rate of PAF ablation;
Whether different methods of producing PVI (e.g. cryoablation vs ostial RF vs
wide area RF) give rise to differing success rates;
Whether any of these strategies lead to reduction in RF time or procedure time;
and
Whether studies with different characteristics (e.g. longer vs shorter blanking
periods, different methods of AF detection) would alter success rates.
The last point alludes to the possibility that factors that have nothing to do with
technique have the potential to influence study outcomes. In AF ablation trials, the
“success” of a study is usually quoted as the recurrence-free survival at 6-12 months.
How such recurrence is defined is as variable as the techniques used in these studies
with variable definitions of recurrence (AF vs AF plus atrial tachycardia) 8,9, durations of
blanking period 8,10, and the means by which recurrence is detected (e.g. using periodic
Holter monitoring vs using long-term implantable-loop recorder to detect recurrence)
5
8,11. Whether such methodological details are important in defining outcomes is vital to
put results of ablation studies into context.
Methods
Search strategy and data extraction
Two reviewers (JFM and BA) independently searched the Medline and the Cochrane
Central Register of Randomised Controlled Trials databases using the search terms
“paroxysmal atrial fibrillation ablation”. Abstracts were screened by both reviewers,
who independently extracted data from the full texts. A third author (MS) resolved any
conflicts. Inclusion criteria were: (1) randomized and non-randomized trials published in
English; (2) patient population with paroxysmal atrial fibrillation; (3) at least one
intervention arm including some form of left atrial ablation. Study titles and abstracts
were initially screened. Those not excluded at this stage underwent full text screening.
From each study report, the following parameters were extracted: number of patients in
each intervention arm; characteristics of included patients; procedure characteristics,
including specific methodologies and procedure duration; and blanking period and its
duration. Included and excluded reports are shown in the PRISMA diagram (Figure 1).
Outcome selection
The primary outcome was the percentage of patients free from AF in each study arm. In
most cases the 12-month timepoint was chosen. Where this was not available, the
nearest available timepoint was selected. The 12-month timepoint was chosen as it was
commonly available in almost all studies and was felt to be a clinically relevant
timepoint by which the majority of recurrences would have been expected to occur.
Data analysis and synthesis
Where possible, continuous variables were reported as mean (+/- standard deviation)
and categorical variables as proportions (%). A funnel plot (Supplemental Figure 1)
6
showed that a large number of trials fell outside the predicted standard error margins
but without evidence of asymmetry, suggesting no important publication bias. With
percentage success (freedom from AF) as the dependent variable, we performed meta-
regression using the restricted maximum likelihood method, with study-level
heterogeneity factored using a random-effects model. Using this, we examined the
effects of baseline clinical (age, gender, hypertension, LA diameter), procedural
characteristics (CFAE, GP, lines, WACA, cryoballoon, single-shot RF, laser balloon, force-
sensing, HIFU), non-procedural study characteristics (e.g. anti-arrhythmic use), and
methods of endpoint assessment (blanking period; method of assessment of arrhythmia
recurrence such as telemonitoring or implantable loop recoder [ILR]; definition of
recurrence such as inclusion of atrial tachycardias (AT) and minimum duration of AF/AT).
Statistical analyses were performed using R 12 with the metafor 13 package. Plots were
created using ggplot2 14.
Results
Medline and Cochrane database searches yielded 493 and 349 studies, respectively
(total 842). Seven hundred and thirty-four studies were excluded on initial screening
and 119 studies underwent full text review and 11 further studies relating to references
found in these studies which had not been found by the initial search also underwent
full review. Sixty-six manuscripts met criteria for onward analysis after excluding
duplicate studies, conference abstracts, studies with patients affected by
persistent/permanent AF, studies including further ablations after the index procedure,
follow-up period shorter than 3 months and studies which did not perform LA ablation
(please refer to Figure 1 and Supplemental Table 1 for specific details). With regards to
follow-up, 676 (9.7%) of the patients had follow-up between 3 and 6 months. 514 (7.4%)
had follow-up between 6 and 12 months and 5751 (82.9%) of the patients had follow-up
of at least 12 months. Only study arms which included ablation were considered in the
final analysis. In these 111 arms, a total of 6941 patients were studied, with a follow up
of 20.1 ± 15.4 months (3 to 72 months) and total follow-up 11,631 patient-years.
7
For the reader unfamiliar with metaregression, interpretation of the analyses requires
some explanation. Each of figures 2-6 represents a separate meta-regression analysis in
which the outcome (e.g. AF-free survival) is explained by a variety of variables used to
build the statistical model. The effect of each of these variables is then separated from
each of the others in the model. There is no “control” group since all the data is placed
into a single model but the comparison, for example in the first row of Figure 2, is
effectively between “CFAE” vs “no CFAE” regardless of what other lesion sets are
performed.
Adjunctive strategies to PVI do not enhance success rate in PAF ablation
Among the 3 adjunctive strategies to PVI studied (CFAE, GP ablation and Additional
Ablation Lines), none improved success rate (Figure 2). Use of adjuvant anti-arrhythmic
drugs classes I/III post ablation showed a trend to improved success rate which did not
reach significance (95%CI -0.8 to 23.5%, p=0.07, Figure 2).
The success of PVI is independent of the ablation methodology
There are different methodologies for performing PVI. We compared seven different
methods (WACA, cryoballoon, single-shot RF, laser balloon, force-sensing, HIFU and
robot) in this meta-regression to basic ablation, which was defined as antral PVI using
radiofrequency, i.e. an absence of the other techniques included in the metaregression
(Figure 3). Wide area circumferential ablation (WACA) was not associated with a
significantly different outcome in comparison to antral radiofrequency ablation (95% CI -
3.3 to 12%, p=0.267). Similarly, none of the other 6 methodologies studied (cryoballoon,
single-shot RF, laser balloon, force-sensing, HIFU, robotic navigation) were associated
with a better outcome (Figure 3). Together, the results presented in Figure 2 and 3
indicate that, among the paroxysmal AF techniques, the effectiveness of PVI is not
enhanced by the use of any adjunctive techniques nor by the specific approaches used
to achieve it.
8
Procedure and fluoroscopy times vary by ablation methodology
For procedures of similar efficacy, procedural and fluoroscopy times are relevant
considerations.
WACA has become the most widely used point-by-point method to produce PVI.
Procedure time did not significantly differ from an antral approach (95% CI -6.4 to 4.8,
p=0.784, Figure 4.1, Supplemental Table 3), but it was associated with significantly
reduced fluoroscopy exposure (-2.08min, 95% CI -3.34 to -0.83, p<0.001, Figure 4.2,
Supplemental Table 4). Although statistically significant, such a difference is unlikely to
be clinically significant.
Of the single-shot technologies, only single-shot RF was associated with shorter times,
both procedure time (by 63 mins, CI -71.6 to -55.3 mins, p<0.001, Figure 4.1) and
fluoroscopy time (by 11 mins, CI -12.9 to -9.0 mins, p<0.001, Figure 4.2).
No other techniques were associated with shorter procedure time. Laser balloon
ablation was associated with increased procedure time (Figure 4.1). In addition to WACA
and single-shot RF, robotic navigation also reduced fluoroscopy time (Figure 4.2).
Freedom from AF varies by the characteristics of patients enrolled
Most study arms contained a substantial proportion of patients with hypertension
(mean 40.6% across all study arms). The higher the proportion of patients with
hypertension, the lower the AF-free survival. The presence of hypertension in a patient
reduces the chance of AF-free survival by 24% in that individual (95% CI -48.3 to 0.5%,
p=0.046, Figure 5).
Gender mix also had a significant affect on outcome. Studies including more males had
better outcomes. Extrapolating to the individual patient level, a male patient stands a
9
42.8% better chance at being AF free after 1 year as compared to a female patient post
ablation (95% CI 11.5 to 74.2%, p=0.007, Figure 5).
Neither age nor LA dimensions had a significant impact on outcomes (Figure 5).
Impact of protocols for detecting recurrence
We tested whether success rates were associated with duration of blanking period, the
inclusion of freedom from AT (rather than just AF) in the primary outcome, whether
patients needed to be free from antiarrhythmic drugs to count as successful, the
thoroughness of ECG monitoring methods, and how many seconds of AF were required
to define recurrence.
For freedom from AF at 6 months, the blanking period was found to be a significant
factor with an improvement in freedom from AF of 5.4% per month blanked (95% CI -1.1
to 9.9%, p=0.013, Supplemental Figure 2).
By the 12-month timepoint, however, blanking period is no longer significant in affecting
the outcomes of AF ablation studies (Figure 6). Thoroughness of ECG sampling in the
search for AF recurrences was important throughout the follow up period. By 12
months, trials whose protocols included frequent ECG sampling rather than Holter
monitoring, reported a poorer arrhythmia-free survival, by 23% for telemonitoring (95%
CI 11.4 to 33.2%, p<0.001) and by 21% for ILR (95% CI 6.7 to 33.5%, p=0.006, Figure 6).
Discussion
In terms of technique, multiple strategies targeting ablation of tissue that either triggers
or sustains AF have been used 15. Pulmonary vein isolation (PVI) is the commonest
employed technique aimed at stopping pulmonary vein ectopy from triggering AF 16.
Other aspects of atrial substrate sometimes targeted include complex fractionated atrial
electrograms (CFAE) and ganglionated plexi (GP) 17-19. Additional linear ablation lesions
10
have been proposed to further enhance the success of the procedure 8,20,21, potentially
by preventing left atrial macro-reentrant tachycardias which can degenerate into AF.
Furthermore, PVI itself has evolved as a technique since its first description, although it
is not clear whether these changes have resulted in improved freedom from AF for the
patient 22-24.
This analysis of 111 arms of 66 trials including 6941 patients shows that different
techniques for achieving PVI or adjunctive strategies on top of PVI do not translate into
better or worse outcomes. Secondly, these techniques differ in terms of fluoroscopy
times and procedure times despite outcomes being similar. Finally, patient selection and
the protocol for defining recurrence have a large effect on outcomes.
Additional Lesion sets do not Improve Outcome Compared to PVI Alone
Additional ablation targets such as CFAE 9,25,26, ganglionated plexus ablation and
additional lines 9,15,27 were not associated with improved outcomes (Figure 2). Although
the results of PVI are not perfect, our analysis suggests that adding these alternatives do
not convincingly improve success in the ablation of paroxysmal AF.
This does not mean that these alternative targets must be irrelevant. It is possible that
PVI might, through an accident of anatomy, be coincidentally ablating them too. This is
particularly a possibility for ganglionated plexi, which may well be involved in the
pathogenesis of PAF 28,29 and be disrupted by PVI 30.
Another possible reason for ineffectiveness of other approaches might be that they
enhance arrhythmia by as much as they reduce it, leaving a neutral effect. For example,
both CFAE and lines can slow conduction enough to enable macro-reentrant AT circuits 31,32.
11
Choice of ablation technology affects procedure and fluoroscopy time, but not success
rate
We found no difference between the ablation technologies in their AF-free survival. In
particular, wider area ablation (WACA) 10 does not, across the data as a whole, seem to
be associated with improved success, in comparison with antral ablation, at least in
paroxysmal AF ablation.
Nor were any of the single-shot ablation techniques, i.e. cryoballoon, single-shot RF,
laser balloon and high frequency ultrasound balloon (HIFU), associated with a better
outcome. This is consistent with the FIRE AND ICE trial, published after our analysis was
completed, which showed no difference in success between cryoballoon and WACA 33.
The fact that FIRE AND ICE shows similar results to our analysis also adds some
credibility to the methodology we use here.
Although success rates are similar across the technologies, procedural times were
notably shorter for single-shot RF (by 63 minutes), and longer with CFAE (by 61 minutes)
and laser-balloon ablation (by 60 minutes). Fluoroscopy times were slightly shorter for
WACA, and this probably relates to these studies being done in the modern setting of
electroanatomical mapping whilst some of the ostial RF studies were performed before
its widespread use. In addition, fluoroscopy time was shorter with single-shot RF and
robotic ablation, but longer where adjunctive lesions such as CFAE and lines were
performed.
Since outcomes are similar with all these techniques, the procedure and fluoroscopy
times may be useful in selecting the right technology for AF ablation if aiming for
maximum efficiency with the least exposure to harmful radiation for the patient and
electrophysiology lab staff.
Patients characteristics alter success rates of AF ablation studies
12
It is now accepted that modifiable or non-modifiable risk factors can increase an
individual’s risk of AF development. Accumulating evidence also suggests that aggressive
modification of the modifiable risk factors can also decrease the risk of PAF recurrence34.
Our meta-regression analysis identified arterial hypertension as having a negative
impact on the relative success of paroxysmal AF ablation, an effect possibly due to
ongoing electrical and structural remodeling of the atria and associated electrical
instability. Consistent with this finding, intensive post-ablation blood pressure treatment
has been shown to markedly decrease the risk of AF recurrence34.
Seemingly at odds with the fact that male gender is a recognized predisposing factor for
AF development, our meta-regression showed that studies containing a high proportion
of males had significantly better outcomes. This suggests that men with AF have more to
gain from PVI than women. This corresponds with recent studies which reported a lower
success rate and a higher complication rate among women post catheter AF ablation35,36.
It has also been suggested that women are referred for catheter ablation not only less
frequently but also at later stages than men, despite being more symptomatic, having a
lower quality of life and being less tolerant of anti-arrhythmic drugs36.
The changes in outcome associated with being male (42% improvement in outcome)
and hypertensive (24% reduction in success) are quoted on a per patient basis in Figure
5. Equally relevant when looking at results of studies, is to think about how this would
affect the results of a study based on percentage of patients with these characteristics
recruited. For example, per 20% increase in the proportion of females versus males in a
study, one can expect an 8.6% reduction in AF-free survival. Per 20% reduction in the
proportion of hypertensive patients, we can expect a 4.9% improvement in the final
outcome of a study arm.
13
Complex effect of blanking period on outcomes
Eighty percent of the trials had blanking periods, for the good clinical rationale that
transient post-procedural inflammation37 could elicit early recurrences which were not
reflective of the long-term treated state.
Unlike other parameters tested in this study, the effect of blanking period on outcomes
depends on when you look. By 12 months, the blanking period makes little difference.
However, earlier on in the follow up, the blanking period can make quite a large
difference. With respect to 6-month outcomes, every extra month of blanking period
yielded 5.4% fewer recurrence events (Supplemental Figure 2). Designing a protocol
with a 3-month rather than a 1-month blanking period will raise success rates at 6
months by 10.8%, an effect that will dissipate by 12 months. This is consistent with data
suggesting that blanking period recurrences, are predictive of later recurrences38 such
that ignoring blanking period recurrences, particularly in months 2 and 3, is unlikely to
improve success rates in the long run. So although these later blanking period
recurrences may not predict further recurrence by the time 6 month outcomes are
measured, by 12 months they almost certainly do.
More thorough ECG follow-up reduces success rates
Studies use a variety of approaches to detect and define AF recurrence, ranging from a
single Holter monitor to continuous monitoring with an ILR. Quite rightly, each
individual trial only made comparisons between its arms of comparable design, but
outcomes are often compared between trials without adjusting for, or even mentioning,
differences in recurrence detection protocols.
Our data indicate that designing a study to rely on a Holter monitor rather than an ILR or
telemonitoring improves apparent success rate by around 20%. This is in stark
comparison to the absence of influence of technical factors such as method of
producing PVI or adjunctive lesion sets.
14
Limitations
This is not a randomized trial, but rather a meta-regression treating each arm of
published studies as a unit of analysis. It is effectively an observational study. However,
it provides a solution to the practical problem that, although one might suppose that
these non-procedural aspects may have some impact on outcome, as clinicians we have
no idea what the likely magnitudes of such outcomes will be. This study provides an
understanding of these effect sizes.
In addition, we are limited by the data available to us. As an example, there may be
limited variation in physiological parameters such as mean LA size in this group of PAF
patients, limiting our ability to detect a difference in outcomes in this metaregression. A
further example is that some technologies that we have grouped together may not be
completely homogeneous, such as first vs second generation cryoballoons.
We could only study variables disclosed by the authors of the manuscripts. There may
be other variables that are important but were not disclosed, or even not documented.
All we can tell is the apparent effect size of the non-procedural variables that happen to
have been presented are much larger than the effect size of the choice of procedure.
Conclusion
The key practical finding from this analysis is that when we look at the highly varied
results in outcomes of AF ablation studies, study methodology is a bigger determinant
than any modifications to the technique. Clearly performing a pulmonary vein isolation
is important, but how this is done, and the performance of adjunctive lesion sets are
less important to the final outcome than patient characteristics and protocol for
defining AF recurrence. Adjunctive lesion sets and some methods of producing PVI add
15
to procedure and fluoroscopy time without enhancing efficacy across the study arms
assessed.
Non-procedural aspects show much greater potential to increase observed success rate.
Per 20% increase in the proportion of males versus females in a study, one can expect
an 8.6% improvement in final AF-free survival. Per 20% reduction in the proportion of
hypertensive patients, we can expect a 4.9% improvement in success. Finally, using less
thorough methods of follow-up (e.g. Holter monitoring) can result in an apparent 21-
23% improvement in success compared to more thorough methods such as ILR or
telemonitoring.
Acknowledgements
We would like to acknowledge the BRC, BHF, and ElectroCardioMathsProgramme of the
Imperial Centre for Cardiac Engineering.
Author contributions:
João Ferreira-Martins: Concept/design, Data analysis/interpretation, Drafting article,
Critical revision of article, Approval of article.
James Howard: Concept/design, Data analysis/interpretation, Critical revision of article,
Approval of article, Statistics.
Becker Al-khayatt: Concept/design, Data analysis/interpretation, Drafting article, Critical
revision of article, Approval of article.
Joseph Shalhoub: Data analysis/interpretation, Critical revision of article, Approval of
article.
Afzal Sohaib: Data analysis/interpretation, Critical revision of article, Approval of article.
Matthew Shun-Shin: Data analysis/interpretation, Critical revision of article, Approval of
article.
16
Paul G Novak: Data analysis/interpretation, Critical revision of article, Approval of
article.
Rick Leather:Data analysis/interpretation, Critical revision of article, Approval of article.
Laurence D Sterns: Data analysis/interpretation, Critical revision of article, Approval of
article.
Christopher Lane: Data analysis/interpretation, Critical revision of article, Approval of
article.
Phang Boon Lim: Data analysis/interpretation, Critical revision of article, Approval of
article.
Prapa Kanagaratnam: Data analysis/interpretation, Critical revision of article, Approval
of article.
Nicholas S Peters: Data analysis/interpretation, Critical revision of article, Approval of
article.
Darrel P Francis: Concept/design, Data analysis/interpretation, Drafting article, Critical
revision of article, Statistics Approval of article.
Markus B Sikkel: Concept/design, Data analysis/interpretation, Drafting article, Critical
revision of article, Statistics Approval of article.
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26. Deisenhofer I, Estner H, Reents T, et al. Does electrogram guided substrate ablation add to the success of pulmonary vein isolation in patients with paroxysmal atrial fibrillation? A prospective, randomized study. Journal of cardiovascular electrophysiology. 2009;20(5):514-521.
27. Link MS, Haissaguerre M, Natale A. Ablation of Atrial Fibrillation: Patient Selection, Periprocedural Anticoagulation, Techniques, and Preventive Measures After Ablation. Circulation. 2016;134(4):339-352.
19
28. Pokushalov E, Romanov A, Shugayev P, et al. Selective ganglionated plexi ablation for paroxysmal atrial fibrillation. Heart rhythm. 2009;6(9):1257-1264.
29. Pokushalov E, Romanov A, Artyomenko S, et al. Ganglionated plexi ablation directed by high-frequency stimulation and complex fractionated atrial electrograms for paroxysmal atrial fibrillation. Pacing and clinical electrophysiology : PACE. 2012;35(7):776-784.
30. Malcolme-Lawes LC, Lim PB, Wright I, et al. Characterization of the left atrial neural network and its impact on autonomic modification procedures. Circulation Arrhythmia and electrophysiology. 2013;6(3):632-640.
31. Wong KC, Paisey JR, Sopher M, et al. No Benefit of Complex Fractionated Atrial Electrogram Ablation in Addition to Circumferential Pulmonary Vein Ablation and Linear Ablation: Benefit of Complex Ablation Study. Circulation Arrhythmia and electrophysiology. 2015;8(6):1316-1324.
32. Sawhney N, Anousheh R, Chen W, Feld GK. Circumferential pulmonary vein ablation with additional linear ablation results in an increased incidence of left atrial flutter compared with segmental pulmonary vein isolation as an initial approach to ablation of paroxysmal atrial fibrillation. Circulation Arrhythmia and electrophysiology. 2010;3(3):243-248.
33. Kuck KH, Brugada J, Furnkranz A, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. The New England journal of medicine. 2016;374(23):2235-2245.
34. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. Journal of the American College of Cardiology. 2014;64(21):2222-2231.
35. Zylla MM, Brachmann J, Lewalter T, et al. Sex-related outcome of atrial fibrillation ablation: Insights from the German Ablation Registry. Heart rhythm. 2016;13(9):1837-1844.
36. Beck Md H, A BCM. Sex Differences In Outcomes Of Ablation Of Atrial Fibrillation. Journal of atrial fibrillation. 2014;6(6):1024.
37. Arya A, Hindricks G, Sommer P, et al. Long-term results and the predictors of outcome of catheter ablation of atrial fibrillation using steerable sheath catheter navigation after single procedure in 674 patients. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2010;12(2):173-180.
38. Lellouche N, Jais P, Nault I, et al. Early recurrences after atrial fibrillation ablation: prognostic value and effect of early reablation. Journal of cardiovascular electrophysiology. 2008;19(6):599-605.
20
Figure 1
21
Figure 2
22
Figure 3
23
Figure 4.1
24
Figure 4.2
25
Figure 5
26
Figure 6
27
Figure Legends
Figure 1. Flow diagram of literature search and study selection. N, number of studies.
Figure 2. The effect of adjunctive strategies in addition to PVI on AF-free survival.
None of the adjunctive strategies resulted in significant improvements over the basic
PVI lesion set. Routine use of anti-arrhythmic drugs class I/III post-ablation came closest
to reaching significance p=0.07 with a trend towards greater success. CFAE, complex
fractionated atrial electrograms; GP, ganglionated plexi; PVI, pulmonary vein isolation.
Figure 3. The effect of PVI methodology on arrhythmia-free survival. The success of PVI
is independent of the specific methodologies available to achieve it. HIFU, high-intensity
focal ultrasound; PVI, pulmonary vein isolation; RF, radiofrequency; WACA, wide area
circumferential ablation.
Figure 4.1. The effect of ablation methodology on procedure time. CFAE and laser
balloon increase procedure time, and single-shot RF reduces procedure time. CFAE,
complex fractionated atrial electrograms; GP, ganglionated plexi; HIFU, high-intensity
focal ultrasound; RF, radiofrequency; WACA, wide area circumferential ablation.
Figure 4.2. The effect of ablation methodology on fluoroscopy time. Performing CFAE
or lines increased fluoroscopy time. Use of single-shot RF or robot reduces fluoroscopy
time. CFAE, complex fractionated atrial electrograms; GP, ganglionated plexi; HIFU, high-
intensity focal ultrasound; RF, radiofrequency; WACA, wide area circumferential
ablation.
Figure 5. The effect of patient characteristics on arrhythmia-free survival. Each
hypertensive patient recruited had a 24.4% greater chance of recurrence. Male gender
conferred greater success. Age and LA diameter did not affect success. LA, left atrium.
28
Figure 6. The effect of follow-up protocols on arrhythmia-free survival. By 12 months,
the duration of a blanking period had little impact on AF free survival (unlike results at 6
months – see text). Utilization of telemonitoring and ILR also significantly reduced AF-
free survival. AT included: whether atrial tachycardia, as well as AF recurrences, counted
towards the primary outcome; Drug-free: whether patients had to be off class I/III
agents to be classed recurrence-free; ILR: implantable loop recorder; Seconds of AF:
whether number of seconds of AF required to be deemed a recurrence made a
difference to the outcome.
29
Supplemental material
Supplement Figure 1. Funnel plot: the symmetric configuration of the Funnel plot
suggests no important publication bias of the trials included in the meta-analysis.
30
Supplement Figure 2. Metaregression showing impact of study characteristics
on freedom from AF at 6 months. Unlike at 12 months, blanking period has a
significant impact of 5.4% per month blanked at this timepoint.
31
Supplement Figure 3. AF-free survival by ablation technique and year of
publication in included studies (A – G). RF, radiofrequency; PVI, pulmonary vein
isolation; HIFU, high-intensity focal ultrasound; WACA, wide area circumferential
ablation.
32
Group Number of study arms
Number of patients
Control: RF antral PVI ablation
16 866
RF antral PVI + CFAE 3 261RF antral PVI + GP 2 116
RF antral PVI + additional lines 15 919RF antral PVI + AAD 5 381
Supplemental Table 1. Number of study arms and patients analysed in manuscript
Figure 2.
Group Number of trial arms
Number of patients
Control:RF antral PVI ablation
16 866
WACA 39 2687Cryoablation 7 478
Single shot RF 7 471Laser balloon 3 297Force sensing 3 222
HIFU 1 22Robot 2 52
Supplemental Table 2. Number of study arms and patients analysed in manuscript
Figure 3.
33
Group Number of study arms
Number of patients
Study year
RF antral PVI 10 535 2003 – 2014WACA 29 1973 2008 – 2016CFAE 3 261 2006 – 2011
GP 1 34 2010Lines 11 919 2006 - 2014
Cryoablation 6 442 2008 – 2014Single shot RF 5 277 2010 – 2015Laser balloon 3 297 2009, 2013Force sensing 3 222 2014
HIFU 1 22 2009Robot 2 53 2009, 2010
Supplemental Table 3. Procedure time: number of study arms, number of patients and study publication year.
Group Number of study arms
Number of patients
Study year
RF antral PVI 10 414 2003 – 2014WACA 30 2081 2008 – 2016CFAE 3 261 2006 – 2011
GP 2 116 2010, 2013Lines 10 548 2006 – 2014
Cryoablation 6 442 2008 – 2014Single shot RF 5 277 2010 – 2015Laser balloon 3 297 2009, 2013Force sensing 3 222 2014
HIFU 1 22 2009Robot 2 53 2009, 2010
Supplemental Table 4. Fluoro time: number of study arms, number of patients and study publication year.
34
Search strategy
A Pubmed search using the terms (MESH) "atrial fibrillation" OR "atrial" AND "fibrillation" OR "atrial fibrillation" OR
"paroxysmal" AND "atrial" AND "fibrillation" OR "paroxysmal atrial fibrillation" AND “ablation” was performed with the filter
“Clinical Trials” and with publication dates between 1st January 1985 and 12th June 2015 (date of literature search). The
search terms paroxysmal atrial fibrillation ablation were used on Cochrane Central Register of Controlled Trials with the filter
“Trials” and with publication dates between 1st January 1985 and 3rd June 2015 (date of literature search).
Supplemental Table 3
Study reference Abstract screen Full text screen reason for exclusion
Dagres 2001excluded RF ablation of accessory pathways
Cosedis Nielsen 2012 Included Included
Nam 2012 Included excluded randomization after PVI
Han 2014excluded persistent AF
Cosedis Nielsen 2012excluded duplicate
Chen 2011 Included Included Morillo 2014 (RAAFT-2) Included Included
Looi 2013excluded focus on QoL
Wang 2011excluded population with early recurrence subject to reablation
Verma 2015excluded persistent AF
35
Sawhney 2010 Included Included
Fiala 2008excluded mixed population pAF and persistent AF
Gillis 2009excluded study design
Morillo 2014 (RAAFT-2)excluded duplicate
Luik 2010excluded study design Freeze AF
Oral 2004excluded
focused on subgroup of pts with inducible AF post initial ablation
Pokushalov 2009 Included Included Zhao 2013 Included Included Providencia 2014 Included Included
Providencia 2014excluded duplicate
Brignole 2002 Includedexcluded AV node ablation+ pacemaker for AF
Pokushalov 2013excluded
Andrade 2014 Includedexcluded substudy of STOP AF trial
Papone 2006 Included Included
Calo 2012 Includedexcluded Right atrium Ganglionated plexi ablation only
Di Biase 2009 Included Included Oral 2003 Included Included
Bogachev-Prokophiev 2014excluded surgical ablation
Nuhrich 2014excluded
focused on subgroup of patients with intraprocedure sustained AF
Stazi 2014excluded ischaemic preconditioning
Steinwender 2010excluded
focused on subgroup of patients screened with CT for anatomical specificities
Stabile 2006excluded mixed population pAF and persistent AF
Chen 2011 exclude duplicate
36
d
Duncan 2012excluded no follow-up of AF recurrence
Brignole 1999 Includedexcluded AV node ablation
Caponi 2010excluded mixed population pAF and persistent AF
Bogachev-Prokophiev 2012excluded conference abstract
Katritsis 2013 Included Included
Shim 2014excluded conference abstract
Vassilikos 2011excluded no follow-up of AF recurrence
Pokushalov 2013excluded focused on subgroup of pts with failed AF ablation
Brignole 2003excluded review
Zhao 2013excluded duplicate
Kojodjojo 2010excluded mixed population pAF and persistent AF
Corrado 2010excluded mixed population pAF and persistent AF
Linhart 2009excluded case control study
Packer 2013excluded mixed population pAF and persistent AF
Calo 2006excluded mixed population pAF and persistent AF
Gu 2011excluded
subpopulation of T2DM treated or not with pioglitazone
Wang 2011excluded duplicate
Nori 2009excluded mixed population pAF and persistent AF
Gaita 2008excluded mixed population pAF and persistent AF
Lutomsky 2008 exclude no follow-up of AF recurrence
37
dMcCready 2014 Included Included Wilber 2010 Included Included
Chin 2014excluded focused on LA size measurement post ablation
Bogachev-Prokophiev 2014excluded duplicate (Bogachev-Prokophiev)
Baran 2013excluded echo for LA thrombus
Deisenhofer 2009 Included Included
Duncan 2012excluded
Kim 2010 Included Included
Pokushalov excluded
Gavin 2012 Included Included Bulava 2010 Included Included
Lemke 2003excluded mixed population pAF and persistent AF
Gilis 2000 Includedexcluded AV node ablation
Pokushalov 2013excluded
mixed population pAF and persistent AF/conference abstract
Baman 2009excluded mixed population pAF and persistent AF
Beukema 2012 Included Included
Tang 2008 Includedexcluded
retrospective study assessing the eficacy of PVI in trigered PAF
Padeletti 2003 Includedexcluded Right atrial ablation +/- right atrial appendage pacing
Reynolds 2010excluded focus on QoL
Sebag 2013excluded persistent AF
Koch 2012 MACPAF studyexcluded no follow-up of AF recurrence
Hocini 2005excluded no follow-up of AF recurrence
38
Calo 2012excluded duplicate
Liu 2006 Includedexcluded
Stepwise left atrial linear ablation tailored by inducibilty of AF after systemic SPVI
Buer 2006excluded
Haeusler 2010excluded
Mallow 2013excluded
Rizzo 2012excluded
Marshall 1999 Includedexcluded AV node ablation
Mun 2012 Included Included
Bassiounyexcluded persistent AF/conference abstract
Roux 2009excluded only 6 weeks follow-up
Tamborero 2009 Includedexcluded
mixed population (paroxysmal/persistent/longstanding)
Stabile 2001excluded mixed population pAF and chronic AF
Chierchia 2011excluded no follow-up of AF recurrence
Brignole 1997 Includedexcluded AF inducibility before/after PVI and outcome
Adlbrecht 2013 Includedexcluded paper not available
Solheim 2012excluded mixed population pAF and persistent AF
Kriatselis (abst) 2012excluded conference abstract
Richter 2011excluded
patient stratification according to healing biomarkers post PVI
Luria 2008excluded atrial flutter ablation
to ACexcluded Computed tomography vs TOE
39
Della Bella 2009excluded mixed population pAF and persistent AF
DiBiase 2009excluded study of oesophageal fistulas
Cheema 2006 excluded mixed population pAF and persistent AF
Pokushalov 2013excluded duplicate
Wang 2007 Includedexcluded paper not available
Verma 2010excluded mixed population pAF and persistent AF
Kriatselis 2014 Included Included
Maly 2008excluded paper not available
Mantovan 2013excluded STAR AF substudy
Koch 2012 MACPAF studyexcluded duplicate
Koch 2011 MACPAF study abstract
excluded conference abstract
Crawford 2008excluded focused on subgroup of pts with failed AF ablation
Wieczorek 2010 Includedexcluded uncontrolled, limited follow-up data
Lu 2014 excluded conference abstract
Budera 2012excluded mixed population pAF and persistent AF
Romanov 2011excluded conference abstract
Nielson 2011 MANTRA-PAF Study
excluded conference abstract
Leong-Sit 2011 Includedexcluded
included patients with previous AF ablation; details aof current AF ablation mnot available
Pappone 2011 APAF study Includedexcluded extension of study Papone 2006
Pokushalov 2010excluded conference abstract
40
Nielsen 2012excluded conference abstract
Zhao 2012excluded conference abstract
Theis 2014excluded conference abstract
Schade 2013excluded
focused on subgroup of patients with failed AF ablation
Arbelo 2014 Included Included
Kim 2012excluded conference abstract
Lu 2013excluded conference abstract
DiBiase 2014excluded
no follow-up of AF recurrence/ only bleeding/thromboembolic complications
Pokushalov 2011excluded focused on subgroup of pts with failed AF ablation
Bassiouny 2011excluded conference abstract
Richmond 2008excluded mixed population pAF and persistent AF
Caponi 2010excluded mixed population pAF and persistent AF
Kang 2014excluded conference abstract
DeRuvo 2012excluded conference abstract
Rostock 2006excluded mixed population pAF and persistent AF
Proclemer 1999 Includedexcluded AV node ablation
Bencsik 2009excluded mixed population pAF and persistent AF
Pokushalov 2012excluded surgical ablation
Verma 2014excluded persistent AF
Lan 2009 Included Included Nedios 2011 exclude mixed population pAF and persistent AF
41
d
Sciarra 2013excluded conference abstract
Jais 2008 (A4 study) Included Included
Turco 2007excluded conference abstract
Lambiase 2013excluded conference abstract
Fichtner 2014excluded conference abstract
Sra 2007excluded mixed population pAF and persistent AF
Park 2014excluded conference abstract
Tuohy 2014excluded conference abstract
Hwang 2009 Included Included
Jons 2009excluded study design
Pokushalov 2009excluded conference abstract
Verma 2007excluded mixed population pAF and persistent AF
Sairaku 2012excluded retrospective study
Heart Rhythm Congress, 2011.excluded Europace proceedings
Letsas 2014excluded mixed population pAF and persistent AF
Duncan 2010excluded conference abstract
Rilling 2013excluded mixed population pAF and persistent AF
Lim 2013excluded conference abstract/persistent AF
Romanov 2012excluded conference abstract
Crawford 2010excluded
study focused on outcomes of patient subgroups based on AF non-inducibility
42
Tse 2005excluded focused on platelet activation
Tsao 2005excluded
patient population who had MRI before and after ablation
chen 1999 Includedexcluded electrophysiologic study of PVs
Podd 2012excluded conference abstract
Stabile 2003excluded mixed population pAF and persistent AF
Martinek 2009excluded oesophageal damge post ablation
Khaykin 2009excluded mixed population pAF and persistent AF
Nilsson 2006excluded mixed population pAF and persistent AF
Kaba 2014excluded summary of RAAFT-2 trial
Wang 2008 Included Included
Fiala 2008excluded duplicate
Kautzner 2009 Included Included
Walfridsson 2015excluded MANTRA-PAF substudy focusing on QoL
Walfridsson 2014excluded duplicate
Suleiman 2012excluded mixed population pAF and persistent AF
Stazi 2013excluded conference abstract
Kamalvand 1997excluded atrial tacgyarrythmias and pacing
Malmborg 2013excluded conference abstract
Long 2006excluded duplicate
Lin 2001excluded no follow-up
Shimano 2008 exclude mixed population pAF and persistent AF
43
dDeftereos 2014 Included Included
Wang 2014 Includedexcluded paper not available
Oral 2004 Includedexcluded
focused on asymptomatic AF recurrences ~2years after ablation procedure
Biase 2014excluded mixed population pAF and persistent AF
Romavov 2011excluded conference abstract
Finlay 2012excluded mixed population pAF and persistent AF
Forleo 2009excluded mixed population pAF and persistent AF
Wieczorek 2013excluded focused on subgroup of pts with failed AF ablation
Koyama 2010 Included Included
Martinek 2012excluded no follow-up
Lim 2012excluded mixed population pAF and persistent AF
Hunter 2013excluded no follow-up
Piorkowski 2011excluded mixed population pAF and persistent AF
Knecht 2010excluded mixed population pAF and persistent AF
Rillig 2013excluded study design
McLellan 2013excluded conference abstract
Nuehrich 2013excluded conference abstract
Nolker 2012excluded mixed atrial arrhythmias
Pak 2008excluded
focused on subgroup of PAF patients with unilateral arrhythmogenic PVs
Wu 2008excluded not in english
44
Gillis 1999 Includedexcluded
focused on atrial pacing before ablation - no ablation data on paper
Nilsson 2013excluded conference abstract
Tang 2009excluded
focused on patients with previous AF ablation and AF recurrence based on OSA risk
Lin 2012 Included Included
Pokushalov 2013excluded focused on subgroup of pts with failed AF ablation
Di Biase 2013excluded conference abstract
Sheikh 2006 Included Included
Kim 2014excluded conference abstract
Khaykin 2009excluded cost comparison study
Gillis 2000excluded duplicate
De Potter 2010excluded case-control/mixed paroxysmal/persistent AF
Willems 2006excluded persistent AF
Yamaji 2013excluded conference abstract
Schmidt 2009excluded ablation in pts with therapeutic INR
Liu 2005excluded not in english
Liu 2005excluded mixed population pAF and persistent AF
Lickfett 2013excluded atrial flutter
Doi 2013excluded no follow-up
Pontoppidan 2009excluded mixed population pAF and persistent AF
Neuzil 2013excluded no follow-up
Brunelli 2011 exclude mixed population pAF and persistent AF
45
d
Hayashi 2014excluded randomization after PVI
Katritsis 2011 Included Included
Atienza (2013) RADAR-AF trialexcluded conference abstract
Andrade 2012 STAR AF trialexcluded mixed population pAF and persistent AF
Mantovan 2013 (STAR AF substudy)
excluded mixed population pAF and persistent AF
Raatikainen 2013 MANTRA-PAFexcluded conference abstract
Tsao 2010excluded no follow-up
Sheng 2013excluded systematic review/conference abstract
Walfridsson 2013excluded conference abstract
Duncan 2010excluded conference abstract
Kettering 2008excluded study on ablation complications (oesophageal fistula)
Suleiman 2012excluded duplicate
Shu 2014excluded conference abstract
Tada 2002excluded no follow-up
Khan 2008excluded no follow-up
Fichtner 2013 Included Included
Pokushalov 2014excluded conference abstract
Gutleben 2013excluded conference abstract
Pokushalov 2014excluded conference abstract
Steven 2013 Included Included
46
Duff 2003excluded permanent AF
Steven 2010 Included Included
Mont 2014 (SARA study)excluded persistent AF
Ahmed 2013excluded study design
Kowal 2011excluded conference abstract
Oral 2003excluded review
Duncan 2010excluded conference abstract
Knecht 2008 Included Included
Lin 2012excluded
Di Biase 2011 Included Included
Mohanty 2013excluded conference abstract
Lee 2000excluded mixed population pAF and chronic AF
Dixit 2008excluded mixed population pAF and chronic AF
Fichtner 2011excluded conference abstract
Fitts 1998excluded study design
Schmidt 2010 Included Included
Gillis 2003excluded AV node ablation
Nalliah 2013excluded conference abstract
Podd 2012excluded conference abstract
Arentz 2007excluded mixed population pAF and persistent AF
Haeusler 2013excluded focused on ischaemic brain lesions post ablation
47
Bittner 2011excluded mixed population pAF and persistent AF
Duncan 2011excluded conference abstract
Oral 2008excluded inducibility of AF by isoproterenol
Bailin 2001excluded no ablation
Dixit 2006excluded mixed population pAF and persistent AF
Miyanaga 2009excluded no follow-up of AF recurrence
Dong 2009excluded no follow-up of AF recurrence
Tamborero 2010excluded mixed population pAF and persistent AF
Kriatselis 2014excluded conference abstract
Liu 2014excluded conference abstract
Di Biase 2013excluded conference abstract
Shurrab 2013excluded conference abstract
Fitts 2000 Includedexcluded AV node ablation
Steven 2013excluded conference abstract
Kumagai 2005 Included excluded comparison of mapping strategies
Pratola 2011excluded mixed population pAF and persistent AF
Giannopoulos 2015excluded conference abstract
Takigawa 2013excluded focused on effect of non-isolation of PV carina
Fassini 2005excluded mixed population pAF and persistent AF
Atarashi 2007 exclude mixed population pAF and persistent AF
48
d
Epstein 2002excluded no follow-up
Pokushalov 2012excluded conference abstract
Pokushalov 2012excluded duplicate
Nalliah 2014excluded conference abstract
Brunelli 2013excluded conference abstract
Ko 2013excluded conference abstract
Pontone 2014excluded conference abstract
Pontone 2014excluded duplicate
Al-Azawy 2013excluded conference abstract
Stavrakis 2013excluded conference abstract
Pokushalov 2012excluded mixed population pAF and persistent AF
Bertaglia 2013 Included Included
Katritsis 2014 Includedexcluded paper not available
Di Biase 2013excluded conference abstract
Bänsch 2013excluded mixed population pAF and persistent AF
Liakishev 2013excluded not in english
Deftereos 2012excluded paper not available
Simpson 2001excluded mixed population pAF and chronic AF
Naccarelli 2014excluded design study
Pokushalov 2015 exclude conference abstract
49
d
Drewirz 2007excluded not in english
Nalliah 2014excluded conference abstract
Nalliah 2014excluded duplicate
Nalliah 2014excluded duplicate
Scaglione 2012excluded focused on cerebral lesions post ablation
Tondo 2005excluded mixed population pAF and persistent AF
Metzner 2012excluded no follow-up
Podd 2012excluded conference abstract
van Breugel 2014excluded no follow-up of AF recurrence
Yamane 2007excluded mixed population pAF and persistent AF
Yamada 2009 Includedexcluded paper not available
Katritsis 2004 Includedexcluded Multiple ablations
Stabile 2014excluded no follow-up of AF recurrence
Chierchia 2012excluded no follow-up of AF recurrence
Jaïs 2002excluded no ablation
Bertaglia 2013 Includedexcluded paper not available
Lampe 2012excluded
effects of AV ablation + pacing vs DDD PPM for CHB in HF progression
Aras 2013excluded conference abstract
Fitts 2000excluded
focused on rate of atrial tachyarrhythmia detection by PPM
50
Di Biase 2012excluded conference abstract
Waldo 1999excluded dicussion paper
Tse 2001 Includedexcluded AV node ablation
Knecht 2010excluded conference abstract
Perez-Castellano 2014 Included Included
Jiang 2009excluded no follow-up of AF recurrence
Lau 1995excluded mixed atrial tachyaarhythmias (SVTs)
Stavrakis 2014excluded conference abstract
Marshall 1999excluded overlapp with paper 89
Gao 2007excluded not in english
Gordon 2014excluded paper not available
Ullah 2014excluded conference abstract
Macle 2012excluded study design
Kimura 2014excluded mixed population pAF and persistent AF
Herrera 2012excluded no follow-up
Bittkau 2012excluded conference abstract
Mulder 2013 Included Included
Dorian 1996excluded no ablation
Chilukuri 2011excluded mixed population pAF and persistent AF
Herrera 2012excluded duplicate
Derval 2010 exclude conference abstract
51
d
Haeusler 2011excluded no ablation
Deftereos 2012excluded review
Lyan 2013excluded conference abstract
Kay 1989excluded mixed population pAF and persistent AF
RAAFT-2excluded erratum
Zhang 2007excluded not in english
Bauer 2006excluded no follow-up of AF recurrence
Navistar® 2004excluded no abstract
Manolis 1998excluded no abstract
Fiala 2008 Included Included
Verma 2015excluded duplicate
Stavrakis 2015excluded no follow-up for AF recurrence
Scherr 2015excluded persistent AF
Atienza 2014excluded mixed population pAF and persistent AF
Giannopoulos 2014excluded
subpopulation of hypertensive pts undergoing AF ablation +/- minoxidil
Rolf 2014excluded mixed population pAF and persistent AF
Straube 2014excluded maximum 7 days follow-up
Zellerhoff 2014 Included Included
Nuhrich 2014excluded duplicate
Miller 2014excluded mixed population pAF and persistent AF
52
Wutzler 2014excluded no follow-up for AF recurrence
Uhm 2014excluded no follow-up for AF recurrence
Natale 2014 Included Included
McCready 2014excluded duplicate
Providencia 2014excluded mixed population pAF and persistent AF
Wang 2014excluded mixed population pAF and persistent AF
Oza 2014excluded no follow-up for AF recurrence
Kim 2014excluded no follow-up for AF recurrence
Kimura 2014excluded mixed population pAF and persistent AF
Pokushalov 2014excluded subpopulation of hypertensive pts
Adachi 2014excluded no ablation
DiBiase 2014excluded duplicate
Arbelo 2014excluded mixed population pAF and persistent AF
De Greef 2014excluded mixed population pAF and persistent AF
Bisbal 2014excluded mixed population pAF and persistent AF
Kimura 2014excluded duplicate
Park 2014excluded mixed population pAF and persistent AF
De Ville 2014excluded no follow-up for AF recurrence
Efremidis 2014excluded focused on QoL
Manganiello 2014excluded mixed population pAF and persistent AF
53
Yorgun 2014excluded mixed population pAF and persistent AF
Schmidt 2014excluded mixed population pAF and persistent AF
Krul 2014excluded patient population with previously failed PVI
Sairaku 2014excluded no follow-up for AF recurrence/focus on INR
Kriatselis 2014excluded duplicate
Song 2014excluded non-PAF
Kawakami 2014excluded no follow-up of AF recurrence
kaitani 2014 Includedexcluded
role of ATP in late re-conduction in pts undergoing second AF ablation
Deftereos 2014excluded duplicate
Seitz 2014excluded mixed population pAF and persistent AF
Lakkireddy 2014excluded focused on bleeding complications
Stabile 2014excluded duplicate
Takigawa 2014excluded impact of haemodysis in AF ablation
van Breugel 2014excluded duplicate
Morillo 2014 (RAAFT-2)excluded duplicate
Marrouche 2014excluded mixed population pAF and persistent AF
Andrade 2014excluded duplicate
Verma 2014excluded duplicate
Mont 2014 (SARA study)excluded duplicate
Bogachev-Prokophiev 2014 exclude duplicate
54
d
Jang 2014excluded chronic AF
Han 2014excluded duplicate
Stazi 2014excluded duplicate
Wang 2014excluded duplicate
Ejima 2014 Includedexcluded atrial remodeling and AF recurrence
Takigawa 2014excluded mixed population pAF and persistent AF
Kirchhof 2014excluded mixed population pAF and persistent AF
De Maat 2014excluded mixed population pAF and persistent AF
Perez-Castellano 2014excluded duplicate
Schmidt 2014excluded no follow-up for AF recurrence
Loghin 2014 Included Included
Katritsis 2013excluded duplicate
Pokushalov 2013excluded duplicate
Aytemir 2013excluded mixed population pAF and persistent AF
Miyazaki 2013excluded no follow-up for AF recurrence
Malmborg 2013excluded mixed population pAF and persistent AF
Linhart 2013excluded mixed population pAF and persistent AF
Ichiki 2013excluded
focus on cerebral microthromboembolism after catheter AF ablation
Brunelli 2013excluded no follow-up for AF recurrence
Efremidis 2013 exclude duplicate
55
d
Brooks 2013 Includedexcluded mixed population pAF and persistent AF
Sebag 2013excluded duplicate
Mantovan 2013excluded duplicate
Verma 2013excluded
focus on asymptomatic cerebral embolism after catheter AF ablation
Hong 2013excluded focus on left atrial remodeling in lone AF
De Bortoli 2013excluded non-PAF
Kobza 2013excluded mixed population pAF and persistent AF
Haines 2013excluded
retrospective study focused on dabigatran vs warfarin complications post AF ablation
Reddy 2013excluded
mixed population pAF and persistent AF/pts with GORD/IBS vs those without
Pokushalov 2013excluded duplicate
Al-Khatib 2013excluded
mixed population pAF and persistent AF/focus on apixaban
Sohns 2013excluded mixed population pAF and persistent AF
Neumann 2013 Included Included
Malcolme-Lawes 2013 Includedexcluded cardiac MRI
Doi 2013excluded duplicate
Ferrero-de Loma-Osorio 2013excluded mixed population pAF and persistent AF
Hussein 2013excluded
look at Spontaneous dissociated firing from the pulmonary veins during ablation
Steven 2013excluded duplicate
Fichtner 2013excluded duplicate
Dukkipati 2013 Included Included
56
Chun 2013excluded pts grouped by age. Mixed PAF and persistent
Ahmed 2013excluded duplicate
Packer 2013excluded duplicate
Adlbrecht 2013excluded duplicate
Neuzil 2013excluded duplicate
Zhao 2013excluded duplicate
Schernthaner 2013excluded mixed population pAF and persistent AF
Hunter 2013excluded duplicate
Schade 2013excluded duplicate
Pokushalov 2013excluded duplicate
Bertaglia 2013excluded duplicate
Mardigyan 2013excluded survey
Narayan 2013excluded mixed population pAF and persistent AF
Blanche 2013excluded mixed population pAF and persistent AF
Bänsch 2013excluded duplicate
Wieczorek 2013excluded no follow-up for AF recurrence
Lickfett 2013excluded duplicate
Uchiyama 2013 Included Included
Wójcik 2013excluded mixed population pAF and persistent AF
Wójcik 2013excluded
mixed population pAF and persistent AF (not the same as 109)
57
Lo 2013excluded mixed population AF and paroxysmal SVT
Wi 2013excluded mixed population pAF and persistent AF
Takigawa 2013excluded duplicate
Rilling 2013excluded duplicate
Metzner 2013 Included Included
Haeusler 2013excluded duplicate
Wieczorek 2013excluded duplicate
Derejko 2013excluded mixed population pAF and persistent AF/HOCM pts
Wang 2013 Included Included
Scharf 2012excluded mixed population pAF and persistent AF
Chierchia 2012excluded duplicate
Nolker 2012excluded duplicate
Wang 2012excluded mixed population pAF and persistent AF
Shivkumar 2012excluded mixed population pAF and persistent AF
Sairaku 2012excluded duplicate
Andrade 2012 STAR AF trialexcluded duplicate
Budera 2012excluded duplicate
Reddy 2012 Includedexcluded some patients had more than 1 ablation
Lin 2012excluded duplicate
Martinek 2012excluded duplicate
Deftereos 2012 exclude duplicate
58
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Cosedis Nielsen 2012excluded duplicate
Lim 2012excluded duplicate
Lampe 2012excluded duplicate
Koch 2012 MACPAF studyexcluded duplicate
Pokushalov 2012excluded focused on pts with resistant hypertension
Narayan 2012excluded mixed population pAF and persistent AF
Arbelo 2012excluded
mixed population pAF and lone AF/no follow-up AF recurrence
Scaglione 2012excluded duplicate
Beukema 2012excluded duplicate
von Bary 2012 Includedexcluded
does not distinguish outcomes od 2 different ablation techniques. Results based on LA dimensions
Solheim 2012excluded duplicate
Liu 2012 Includedexcluded focus on inducibility of AF after ablation
Pozzoli 2012excluded 3 weeks follow-up only
Pison 2012excluded survey
Chierchia 2012 Included Included
Rivard 2012excluded persistent AF
Pokushalov 2012 Included Included
Dukkipati 2012 Includedexcluded 2 ablations
Santini 2012excluded mixed population pAF and persistent AF
Duncan 2012excluded duplicate
59
Kasirajan 2012excluded mixed population pAF and persistent AF
Miller 2012excluded mixed population pAF and persistent AF
Bayrak 2012excluded mixed population pAF and persistent AF
Cheung 2012excluded mixed population pAF and persistent AF
Berkowitsch 2012excluded mixed population pAF and persistent AF
Golden 2012excluded mixed population pAF and persistent AF
Metzner 2012excluded duplicate
Lakkireddy 2012excluded
mixed population pAF and persistent AF/focus in anticoagulation
Erdei 2012 Included Included
Macle 2012excluded duplicate
Pokushalov 2012excluded duplicate
Mun 2012excluded duplicate
Finlay 2012excluded duplicate
Calo 2012excluded duplicate
Herrera 2012excluded duplicate
Suleiman 2012excluded duplicate
Mulder 2012 Included Included
Tang 2012 Includedexcluded paper not available
Hunter 2012excluded mixed population pAF and persistent AF
Gavin 2012excluded duplicate
Pappone 2011 APAF study exclude duplicate
60
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Pokushalov 2011excluded duplicate
Nedios 2011excluded duplicate
Chilukuri 2011excluded duplicate
Meinertz 2011excluded AF management in primary care in Germany
Gu 2011excluded duplicate
Bittner 2011excluded duplicate
to ACexcluded duplicate
Chen 2011excluded duplicate
Narducci 2011excluded
mixed population pAF and persistent AF/no follow-up/focus on tissue inflammation
Wang 2011excluded duplicate
Bonnemeier 2011excluded mixed population pAF and persistent AF
Katritsis 2011excluded duplicate
Kidouchi 2011excluded multiple atrialarrhythmias
Piorkowski 2011excluded duplicate
Pratola 2011excluded duplicate
Haeusler 2011excluded duplicate
Di Biase 2011excluded duplicate
Chierchia 2011excluded duplicate
Spertus 2011excluded QoL questionnaire
61
Leong-Sit 2011excluded duplicate
Nagashima 2011excluded mixed population pAF and persistent AF
Chao 2011 Includedexcluded
focus on renal function and recurrence of AF after ablation
Kettering 2011excluded persistent AF
Osmancik 2011excluded mixed population pAF and persistent AF
Reynolds 2010excluded duplicate
Reddy 2010excluded no follow-up/acute safety study
Schmidt 2010excluded duplicate
Gaita 2010excluded mixed population pAF and persistent AF
Koyama 2010excluded duplicate
Patel 2010excluded mixed population pAF and persistent AF
Edgerton 2010excluded non-randomized
Kojodjojo 2010excluded duplicate
Kim 2010excluded duplicate
Bulava 2010excluded duplicate
Park 2010excluded mixed population pAF and persistent AF
Caponi 2010excluded duplicate
Haeusler 2010excluded duplicate
Di Biase 2010excluded mixed population pAF and persistent AF
Veasey 2010 exclude mixed population pAF and persistent AF
62
d
Sawhney 2010excluded duplicate
Yamaguchi 2010excluded mixed population pAF and persistent AF
Verma 2010excluded duplicate
Tamborero 2010excluded duplicate
Luik 2010excluded duplicate
Beukema 2010excluded mixed population pAF and persistent AF
Tuan 2010excluded mixed population pAF and persistent AF
Knecht 2010excluded duplicate
Wieczorek 2010excluded duplicate
Nam 2010excluded mixed population pAF and persistent AF
Kirch 2010excluded QoL study/no ablation
Di Donna 2010excluded subpopulation of pts with HOCM
Pokushalov 2010excluded persistent AF
Rillig 2010excluded mixed population pAF and persistent AF
Chierchia 2010excluded no follow-up/study to assess effusion post ablation
Tsao 2010excluded duplicate
Neumann 2010excluded mixed population pAF and chronic AF
Steinwender 2010excluded duplicate
Bertaglia 2010excluded mixed population pAF and persistent AF
63
Wilber 2010excluded duplicate
Schrickel 2010excluded no follow-up/study on acute silent cerebral embolism
De Potter 2010excluded duplicate
Patel 2010excluded
mixed population pAF and persistent AF/females only study on complications
Steven 2010excluded duplicate
Corrado 2010excluded duplicate
Crawford 2010excluded duplicate
Wieczorek 2010 Included Included
Chierchia 2009excluded duplicate
Yamada 2009excluded duplicate
Klinkenberg 2009excluded no follow-up/effects of adenosin after ablation
Linhart 2009excluded duplicate
Jiang 2009excluded mixed population pAF and persistent AF
Baman 2009excluded duplicate
Cagli 2009excluded duplicate
Shamiss 2009excluded duplicate
Jensen-Urstad 2009excluded AF ablation in WPW syndrome patients
Nori 2009excluded mixed population pAF and persistent AF
Hwang 2009excluded atrial tachycardia
Khaykin 2009excluded duplicate
64
Schmidt 2009 Included Included
Abecasis 2009excluded mixed population pAF and persistent AF
Bhargava 2009excluded mixed population pAF and persistent AF
Joshi 2009excluded mixed population pAF and persistent AF
Fredersdorf 2009excluded mixed population pAF and persistent AF
Ninomiya 2009excluded
no follow-up/acute effect of ATP in reconduction post ablation
Roux 2009excluded duplicate
Pokushalov 2009excluded duplicate
Hof 2009excluded mixed population pAF and persistent AF
Meissner 2009excluded mixed population pAF and persistent AF
Han 2009excluded mixed population pAF and persistent AF
Chun 2009excluded no follow-up/effect of rapid pacing of RV
Bencsik 2009excluded duplicate
Pratola 2009excluded no follow-up
Schmidt 2009excluded duplicate
Reddy 2009 Included Included
Jons 2009excluded duplicate
Chilukuri 2009excluded
questionnaire on obstructive sleep apnoea and outcomes of AF ablation
Martinek 2009excluded duplicate
Edgerton 2009excluded mixed population pAF and persistent AF
Sohara 2009 exclude mixed population pAF and persistent AF
65
d
Pontoppidan 2009excluded duplicate
Yokoyama 2009excluded no follow-up
Van belle 2009excluded no follow-up
Kettering 2009excluded mixed population pAF and persistent AF
Miyanaga 2009excluded duplicate
Deisenhofer 2009excluded duplicate
Schmidt 2009excluded mixed population pAF and persistent AF
Di Biase 2009excluded duplicate
DiBiase 2009excluded duplicate
Yoshida 2009 Includedexcluded multiple ablations
Della Bella 2009excluded duplicate
Park 2009excluded mixed population pAF and persistent AF
Dong 2009excluded duplicate
Laurent 2009excluded ablation of atrial flutter
Beyer 2009excluded mixed population pAF and persistent AF
Kautzner 2009excluded duplicate
Tamborero 2009excluded duplicate
Kumagai 2009excluded mixed population pAF and persistent AF
Kriatselis 2009excluded mixed population pAF and persistent AF
66
Tang 2009excluded duplicate
Khaykin 2009excluded duplicate
Forleo 2009excluded duplicate
Jais 2008 (A4 study)excluded duplicate
Knecht 2008excluded duplicate
Malmborg 2008excluded mixed population pAF and persistent AF
Van Belle 2008 Included Included
Luria 2008excluded duplicate
Gaita 2008excluded duplicate
Yoshida 2008excluded mixed population pAF and persistent AF
Muller 2008excluded mixed population pAF and chronic AF
Piorkowski 2008excluded mixed population pAF and persistent AF
Shimano 2008excluded duplicate
Satomi 2008 Included Included
Richmond 2008excluded duplicate
Corrado 2008excluded mixed population pAF and persistent AF
Fiala 2008excluded duplicate
Neumann 2008excluded mixed population pAF and persistent AF
Khadjooi 2008excluded effects of CRT in AF and SR
Jongnarangsin 2008excluded mixed population pAF and chronic AF
Shah 2008 exclude mixed population pAF and persistent AF
67
d
Wu 2008excluded duplicate
Fiala 2008excluded duplicate
Kettering 2008excluded duplicate
Wang 2008excluded duplicate
Lutomsky 2008excluded duplicate
Pak 2008excluded duplicate
Oral 2008excluded duplicate
Khan 2008excluded duplicate
Mortada 2008excluded anticoagulation for AF ablation
Perea 2008excluded mixed population pAF and persistent AF
Chang 2008excluded SVT and AF/ no follow-up
Tang 2008excluded duplicate
Chen 2008excluded mixed population pAF and persistent AF
Yamada 2008excluded AF ablation in Brugada syndrome patients
Verma 2008excluded mixed population pAF and persistent AF
Dixit 2008excluded duplicate
Maly 2008excluded duplicate
Phillips 2008excluded no follow-up
Crawford 2008excluded duplicate
68
Liakishev 2013excluded duplicate
Moreira 2008excluded mixed population pAF and atrial flutter
Yao 2007excluded mixed population pAF and persistent AF
McClelland 2007excluded mixed population pAF and persistent AF
Pruitt 2007excluded mixed population pAF and persistent AF
Narayan 2007excluded mixed population pAF and persistent AF
Knecht 2007excluded mixed population pAF and flutter
Issa 2007excluded no follow-up/AV node ablation + PPM
Wang 2007excluded duplicate
Arentz 2007excluded duplicate
Gaita 2007excluded mixed population pAF and persistent AF/HOCM pts
Chang 2007excluded no follow-up
Yamane 2007excluded duplicate
Haïssaguerre 2007excluded mixed population pAF and persistent AF
Sra 2007excluded mixed population pAF and persistent AF
Suwalski 2007 Includedexcluded surgical PVI with VATS
Gao 2007excluded duplicate
Kurosaki 2007excluded mixed population pAF and persistent AF
Atarashi 2007excluded duplicate
Verma 2007 exclude duplicate
69
d
Nakagawa 2007excluded mixed population pAF and persistent AF
Turco 2007excluded mixed population pAF and persistent AF
Solheim 2007excluded mixed population pAF and persistent AF
Papone 2006excluded duplicate
Willems 2006excluded duplicate
Bauer 2006excluded duplicate
Liu 2006excluded duplicate
Richter 2006excluded mixed population pAF and persistent AF
Sheikh 2006excluded duplicate
Kistler 2006excluded mixed population pAF and persistent AF
Cheema 2006excluded mixed population pAF and persistent AF
Di Biase 2013excluded duplicate
Dixit 2006excluded duplicate
Heist 2006excluded no follow-up
Nilsson 2006excluded duplicate
Wongcharoen 2006excluded no follow-up
Scanavacca 2006 Includedexcluded no PVI
Estner 2006excluded mixed population pAF and persistent AF
Yu 2006excluded not in english
70
Calo 2006excluded duplicate
Obergassel 2006excluded pts with HOCM
Oral 2006 Included Included
Akpinar 2006excluded mixed population pAF and persistent AF
Cheema 2006 excluded duplicate
Risius 2006excluded no follow-up
Stabile 2006excluded mixed population pAF and persistent AF
Hocini 2005excluded duplicate
Tojo 2005excluded no follow-up
Kumagai 2005excluded duplicate
Mantovan 2005excluded mixed population pAF and persistent AF
Jiang 2005 Includedexcluded CT guided AF ablation
Reant 2005excluded mixed population pAF and chronic AF
Fassini 2005excluded duplicate
Liu 2005excluded duplicate
Tse 2005excluded duplicate
Lickfett 2005excluded ablation of atrial flutter
Ninet 2005excluded mixed population pAF and persistent AF
Mack 2005excluded mixed population pAF and persistent AF
Rao 2005excluded persistent and permanent AF
71
Liu 2005excluded duplicate
Molloy 2005excluded mixed population pAF and persistent AF
Kocheril 2005 Includedexcluded right atrial ablation
Cappato 2005excluded survey
Tsao 2005excluded duplicate
Tondo 2005excluded duplicate
Oral 2004excluded duplicate
Mokadam 2004excluded mixed population pAF and persistent AF
Sacher 2004excluded not in english
Tanner 2004excluded ablation of atrial tachycardias
Brembilla-Perrot 2004excluded
effect of transoesophageal pacing in the diagnostic evaluation of patient with unexplained syncope
Oral 2004excluded duplicate
Katritsis 2014excluded duplicate
Schwartzman 2004excluded
study of pulmonry veins as source of arrhythmogenic atrial ectopy
Gillinov 2004excluded mixed population pAF and persistent AF
Pappone 2004 Includedexcluded effect of vagal denervation + PVI
Jansens 2004 Includedexcluded paper not available
Calo 2004excluded mixed population pAF and persistent AF
Todd 2003excluded longstanding AF
Gillis 2003 exclude duplicate
72
d
Oral 2003excluded no follow-up
Lemke 2003excluded duplicate
Arentz 2003excluded mixed population pAF and persistent AF
Oral 2003excluded duplicate
Weerasooriya 2003excluded no follow-up
Duff 2003excluded duplicate
Raman 2003excluded mixed population pAF and persistent AF
Wang 2003excluded paper not available
Tada 2003 Includedexcluded focused on QoL
Berkowitsch 2013 Includedexcluded focused on QoL
Hocini 2003excluded AF pts with sinus pauses (>=3sec) after fast AF
Oral 2003excluded duplicate
Tse 2003excluded mixed population pAF and persistent AF
Stabile 2003excluded mixed population pAF and persistent AF
Sanchez 2003excluded no follow-up
Lin 2003 Includedexcluded ablation of non PV ectopies
Padeletti 2003excluded duplicate
Patel 2003excluded no follow-up
Brignole 2003excluded duplicate
73
Marchlinski 2003excluded mixed population pAF and persistent AF
Dill 2003excluded focus on PV stenosis post ablation
Pürerfellner 2003excluded focus on PV stenosis post ablation
Camm 2003excluded no ablation
Stabile 2003excluded duplicate
Jaïs 2002excluded duplicate
Brembilla-Perrot 2003excluded not in english
Goya 2002excluded PAF post AF ablation
Tada 2002excluded duplicate
Epstein 2002excluded duplicate
Takahashi 2002excluded no follow-up
Brignole 2002excluded duplicate
Katritsis 2002excluded no follow-up
Oral 2002excluded mixed population pAF and persistent AF
Brembilla-Perrot 2002excluded not in english
Brembilla-Perrot 2002excluded not in english
Pappone 2001excluded mixed population pAF and persistent AF
Tse 2001excluded duplicate
Simpson 2001excluded duplicate
Bailin 2001 exclude duplicate
74
d
Hindricks 2001excluded no follow-up
Stabile 2001excluded duplicate
Sueda 2001excluded chronic AF
Dagres 2001excluded duplicate
Ashar 2000excluded no follow-up
Padeletti 2000excluded chronic AF
Pappone 2000excluded mixed population pAF and persistent AF
Gasparini 2000excluded mixed population pAF and chronic AF
Chan 2000excluded focus in coagulum formation during ablation
Gasparini 2000excluded mixed population pAF and persistent AF
Hocini 2000excluded no follow-up
Tai 2000excluded no ablation
Gilis 2000excluded duplicate
Tsai 2000 Includedexcluded ablation of SVC ectopies
Fitts 2000excluded duplicate
Lee 2000excluded duplicate
Jais 2000 Includedexcluded paper not available
chen 1999excluded duplicate
Gasparini 1999excluded focus on thromboembolic events
75
Waldo 1999excluded duplicate
Gillis 1999excluded duplicate
Proclemer 1999excluded duplicate
Marshall 1999excluded duplicate
Hsieh 1999 Includedexcluded paper not available
Gillis 2009excluded duplicate
Marshall 1999excluded duplicate
Brignole 1999excluded duplicate
Furlanello 1999excluded AF in athletes
Kuck 1998excluded no ablation
Fitts 1998excluded duplicate
Herz 1998excluded not in english
Chen 1998excluded no follow-up
Kalman 1997excluded ablation of atrial flutter
Kim 1997excluded mixed population pAF and atrial flutter
Brignole 1997excluded duplicate
Leitch 1997excluded EP study
Kamalvand 1997excluded duplicate
Schuchert 1997excluded not in english
Chen 1996 exclude AV ablation
76
d
Dorian 1996excluded duplicate
Tai 1995excluded ablation of AV accessory pathways
Lau 1995excluded duplicate
Xang 1995excluded ablation of atrial flutter
Iesaka 1994excluded ablation of AV accessory pathways
Kay 1989excluded duplicate
Pokushalov 2010excluded mixed population pAF and persistent AF
Eitel 2011 Included Included Podd 2015 Included Included mixed population pAF and persistent AFPood 2016 Included Included Bjorkenheim 2016 Included Included Kuck et al 2016 Included Included Verma et al 2010 Included Included
Martinek 2007excluded mixed population pAF and persistent AF
Kapa 2013excluded mixed population pAF and persistent AF
Veasey et al 2010excluded mixed population pAF and persistent AF
Yang et al 2016excluded mixed population pAF and persistent AF
77
78