Supplemental material

Title: Minimally Invasive Epicardial Surgical Ablation Alone Versus Hybrid Ablation for

Atrial Fibrillation: A Systematic Review and Meta-Analysis

Brief Title: Efficacy of Epicardial Versus Hybrid Ablation for AF

Authors: Charles M Pearman,1,3 Shi S Poon,1 Laura J Bonnett,4 Shouvik Haldar,5 Tom Wong,5

Neeraj Mediratta2 and Dhiraj Gupta1

Affiliations: 1. Department of Cardiology, Liverpool Heart and Chest Hospital; 2. Department of

Cardiothoracic Surgery, Liverpool Heart and Chest Hospital; 3. Division of

Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine

and Health, Manchester Academic Health Science Centre, The University of

Manchester; 4. Department of Biostatistics, University of Liverpool; 5. Heart Rhythm

Centre, NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and

Harefield NHS Foundation Trust, Institute of Cardiovascular Medicine and Science,

Imperial College London.

Correspondence: Charles Pearman, Department of Cardiology, Liverpool Heart and Chest Hospital,

Thomas Drive, Liverpool, L14 3PE, UK.

E: charles.pearman@manchester.ac.uk

Telephone: +44 151 228 1616

Fax: +44 151 600 1699

2

Supplemental Methods

The PRISMA1 and MOOSE2 guidelines for reporting of meta-analyses were followed. A protocol for

the meta-analysis was prospectively recorded in the PROSPERO registry (CRD42016043389).

Search strategy

Relevant studies were identified by interrogating the MEDLINE (via PubMed) and EMBASE (via OVID)

databases on 1st November 2016 including all dates to present. Search terms were ("atrial

fibrillation" OR "AF") AND ("surgical" OR "hybrid" OR "thoracoscopic" OR "pericardioscopic" OR

"endoscopic" or "minimally invasive" OR "minimal invasive" OR "less invasive") AND ("ablation" OR

"pulmonary vein isolation" OR "PVI" OR “radiofrequency”). Results were filtered including only

English language studies for which an abstract was present. To minimise duplication, the EMBASE

search was further limited to exclude MEDLINE-indexed journals. Additional studies were identified

by scanning reference lists of included studies and existing reviews.

Outcome measures

The pre-specified primary outcome was survival free from any atrial arrhythmia without

antiarrhythmic drugs (AADs). Secondary outcomes included survival free from any atrial arrhythmias

with or without AADs and survival free from AF with or without AADs. These measures were

assessed at 12 and 24 months post procedure. Additional secondary outcomes were the need for

repeat catheter ablation and the rate of major complications.

Eligibility and exclusion criteria and definitions

Randomised controlled trials, cohort studies and case series published in peer-reviewed journals

including at least one cohort of ≥10 patients undergoing minimally invasive epicardial ablation of

paroxysmal, persistent or longstanding persistent atrial fibrillation using radiofrequency energy were

eligible for inclusion. Smaller series (<10 patients) were not included as their low statistical power

was felt unlikely to influence overall results.

3

Studies were excluded if patients underwent concomitant cardiac surgery or routine sternotomy,

used non-radiofrequency energy sources, were not published as full-text articles, or contained

patients overlapping a study that had already been included. In the case of overlap, the study

containing the largest number of patients with the most robust definition of success was included

(see below).

Studies in which the planned treatment was a combination of minimally invasive surgical ablation

with endocardial catheter ablation, and in which both aspects of the ablation were completed in

>75 % of patients, were included in the ‘hybrid’ group. The endocardial ablation could be performed

either simultaneously with the epicardial ablation or as a staged procedure up to three months later,

as no difference in outcome has been shown between simultaneous and staged hybrid ablation.3

Studies in which catheter ablation was not performed routinely but was performed ad hoc in cases

of recurrent arrhythmia were included in the ‘epicardial only’ group. Studies that fell into neither of

these categories were excluded.

Lesion sets were grouped by the ablation lines performed: (1) pulmonary vein isolation without a

completed left atrial posterior wall isolation, (2) pulmonary vein isolation plus left atrial posterior

wall isolation but without additional right atrial ablation or (3) pulmonary vein isolation plus left

atrial posterior wall isolation and additional right atrial ablation (Dallas lesion set). Lesion sets were

further categorised by whether >50 % of subjects underwent ganglionic plexus ablation, or

underwent left atrial appendage exclusion.

According to HRS/EHRA/ECAS guidelines,4 major complications are defined as “… a complication that

results in permanent injury or death, requires intervention for treatment, or prolongs or requires

hospitalization for more than 48 hours.” As the detail in reporting of complications varied greatly we

defined combined major complications as a composite of death, stroke/TIA, major bleeding,

pericardial effusion requiring drainage, atrio-oesophageal fistula, and conversion to sternotomy.

4

For studies which met our inclusion criteria but in which data were ambiguous or could not be

extracted, authors were contacted by email and offered two weeks to respond. In some cases

authors provided details of additional follow-up not reported in the original manuscript. These

studies have been indicated in the results section.

Data extraction, synthesis and statistical methods

Abstracts were reviewed by a single investigator (CP, clinician), and a random sample of these were

checked for agreement (SP, clinician). Data were extracted independently by two investigators (CP,

SP) using a custom-written tool in Visual Basic for Applications within Microsoft Excel. Discrepancies

were agreed by consensus and adjudicated by a third reviewer (DG, clinician). Where studies

reported multiple definitions of success, the definition most likely to find recurrent AF was included

in this analysis (e.g. any recurrence of AF on loop recorder included over point prevalence of AF at

discrete timepoint). Where such data were included in the published studies, additional unplanned

catheter ablations were counted as treatment failures. A complete list of data fields extracted can be

found in Supplemental Table 1. The lesion set used was simplified into the closest match for three

base categories (Supplemental Table 2) with or without the use of ganglionic plexus ablation and left

atrial appendage exclusion. Study quality and risk of bias within studies were assessed using a

modified version of published criteria5,6 for measuring the quality of case series (Supplemental Table

3). Risk of publication bias across studies was assessed using Funnel plots and Eggers’ test.7

Data analysis was performed by a statistician (LB). Pooled estimates were obtained for each

outcome for epicardial-alone and hybrid ablation via the generalised inverse variance method using

a fixed effects model on the original scale of measurement. A random effects model using the

DerSimonian and Laird method was used in the case of significant heterogeneity (I2 statistic >50 %)7.

Differences between epicardial-alone and hybrid ablations were judged to be different if 95 % CIs for

the respective pooled estimates did not overlap. Baseline demographics were compared using two-

tailed T-tests for normally distributed continuous data and Chi-squared tests for categorical data.

5

95 % binomial CIs for outcomes involving a proportion were calculated using standard

methodology.8 For studies where no events were observed a small fixed value was added to each

null entry to avoid dividing by a zero count which would yield a computational error.7 The fixed value

used for assessing the primary and secondary outcomes was 0.5. Specific sensitivity analyses were

performed to ensure that this fixed value was not influencing results by using fixed values of 0.05

and 1.

Meta-regression was used to examine the impact of several clinical covariates on the effect size of

both primary outcomes, via the ‘metafor’ package within R. Analyses were performed using R

version 3.2.3.9

6

Supplementary Figure 1: Survival Free From Any Atrial Arrhythmias With or Without Antiarrhythmic

Drugs at 12 Months

AADs = antiarrhythmic drugs.

7

Supplementary Figure 2: Survival Free From Any Atrial Arrhythmias With or Without Antiarrhythmic

Drugs at 24 Months

AADs = antiarrhythmic drugs.

8

Supplementary Figure 3: Survival Free From Atrial Fibrillation With or Without Antiarrhythmic Drugs

at 12 Months

AADs = antiarrhythmic drugs.

9

Supplementary Figure 4: Survival Free From AF With or Without Antiarrhythmic Drugs at at 24

Months

AADs = antiarrhythmic drugs.

10

Supplementary Figure 5: Incidence of Major Complications

11

Supplementary Figure 6: Incidence of Additional Unplanned Catheter Ablation at 12 Months

12

Supplemental Tables

Supplementary Table 1: Complete List of all Data Fields Collected

Author Year of Publication

AF free survival at 12 months ON AAD (numerator and denominator)

Journal Research group

AF free survival at 12 months OFF AAD (numerator and denominator)

Dates patients recruited Study type

Any atrial arrhythmia free survival at 12 months ON AAD (numerator and denominator)

Procedure Access

Any atrial arrhythmia free survival at 12 months OFF AAD (numerator and denominator)

Energy Source Epicardial alone / Hybrid

AF free survival at 24 months ON AAD (numerator and denominator)

n Follow up (months, mean)

AF free survival at 24 months OFF AAD (numerator and denominator)

Age (years, mean) Male sex (numerator)

Any atrial arrhythmia free survival at 24 months ON AAD (numerator and denominator)

LA diameter (mm, mean) LV ejection fraction (%, mean)

Any atrial arrhythmia free survival at 24 months OFF AAD (numerator and denominator)

BMI (kg/m2, mean) CHADS score (mean)

Additional catheter ablations in 12 months (numerator and denominator)

Prior catheter ablation (numerator) Arrhythmia recurrence definition Paroxysmal AF (n) Monitoring during f/u (description) Persistent AF (n) Surgery - Complications - Death (n) Longstanding persistent AF (n) Surgery - Complications - Stroke/TIA (n) Duration of AF (years, mean) Surgery - Complications - Perforations (n) Surgical ablation procedure duration (minutes, mean) Surgery - Complications - Pericardial effusions

requiring drainage (n) Surgical ablation length of stay (days, mean) Surgery - Complications - Sternotomies (n) Lesion set during surgical ablation - pulmonary veins Surgery - Complications - Phrenic nerve injury (n) Lesion set during surgical ablation - roof and floor lines Surgery - Complications - Permanent PM (n) Lesion set during surgical ablation - ganglionic plexus ablation

Surgery - Complications - Infection (n)

Lesion set during surgical ablation - left atrial appendage exclusion

Surgery - Complications - Major bleeding (n)

Lesion set during surgical ablation - other (list) Surgery - Complications - Atriooesophageal fistula (n)

Conduction block checked? Surgery - Complications - Haemothorax (n) Catheter ablation procedure duration (minutes, mean) Surgery - Complications - Pneumothorax (n) Catheter ablation length of stay (days, mean) Surgery - Complications - Pleural effusion (n) Lesion set during catheter ablation - pulmonary veins Surgery - Complications - Others (list) Lesion set during catheter ablation - cavotricuspid isthmus

Catheter ablation - Complications - Death (n)

Lesion set during catheter ablation - superior vena cava Catheter ablation - Complications - Stroke (n) Lesion set during catheter ablation - other (list) Catheter ablation - Complications - Pericardial

effusions requiring drainage (n) Pulmonary vein reconnection at catheter ablation (numerator)

Catheter ablation - Complications - Major bleeding (n)

Pulmonary vein reconnection at catheter ablation (denominator)

Catheter ablation - Complications - Minor bleeding (n)

No ablation performed at planned catheter ablation (numerator)

Catheter ablation - Complications - Others (list)

No ablation performed at planned catheter ablation (denominator)

13

Supplemental Table 2: Lesion Set Classification

1 PVI without completed LA box +/− GPl +/− LAA

2 PVI + roof + floor +/− GP +/− LAA +/− mitral line (Left atrial MAZE)

3 PVI + additional right and left atrial ablation lines +/− GP +/− LAA (Dallas, CM IV)

14

Supplementary Table 3: Risk of Bias Assessment

1 Were selection/eligibility criteria adequately reported?

2 Was the selected population representative of that seen in normal practice?

3 Were criteria for assessing outcome explicitly defined?

4 Was loss to follow-up reported or explained?

5 Were at least 90 % of those included at baseline followed up?

6 Were patients recruited prospectively?

7 Were patients recruited consecutively?

8 Did the study report relevant prognostic factors?

15

Supplementary Table 4: List of Excluded Studies with Reasons Author (Date) Reference Journal Reason for exclusion Bartus (2012) 10 Pol Arch Med Wewn Overlap [Gersak (2012)] Beller (2016) 11 Methodist Debakey Cardiovasc J Overlap [Mahapatra (2011)] Bisleri (2013) 12 Eur J Cardiothorac Surg Overlap [Muneretto (2012)] Castella (2010) 13 J Thorac Cardiovasc Surg Overlap [Boersma (2012)] Cui (2010) 14 J Thorac Cardiovasc Surg Overlap [Wang (2014)] De Maat (2014) 15 Europace Overlap [De Maat (2013)] De Maat (2015) 16 Europace Overlap [De Maat (2013)] De Maat (2015) 17 Biomed Res Int Overlap [De Maat (2013)] Fengsrud (2015) 18 Multimed Man Cardiothorac Surg Overlap [Fengsrud (2016)] Gersak (2012) 19 J Cardiovasc Electrophysiol Overlap [Gersak (2016)] Gersak (2014) 20 J Thorac Cardiovasc Surg Overlap [Gersak (2016)] Han (2009) 21 Circ Arrhythm Electrophysiol Overlap [Kasirajan (2012)] Hu (2014) 22 J Thorac Cardiovasc Surg Overlap [Wang (2014)] Kiser (2010) 23 Heart Surg Forum Overlap [Gehi (2013)] Kiser (2011) 24 Innovations (Phila) Overlap [Gehi (2013)] Krul (2011) 25 Circ Arrhythm Electrophysiol Overlap [Krul (2014)] Kumar (2015) 26 Neth Heart J Overlap [Krul (2014)] Kurfirst (2014) 27 Interact Cardiovasc Thorac Surg Overlap [Bulava (2015)] La Meir (2011) 28 J Card Surg Overlap [Krul (2014)] La Meir (2012) 29 Interact Cardiovasc Thorac Surg Overlap [Krul (2014)] La Meir (2013) 30 Int J Cardiol Overlap [Krul (2014)] Ma (2012) 31 Innovations (Phila) Overlap [Ma (2015)] Ma (2016) 32 Heart Vessels Overlap [Ma (2015)] Mei (2014) 33 J Thorac Cardiovasc Surg Overlap [Ma (2015)] Muneretto (2012) 34 J Thorac Cardiovasc Surg Overlap [Muneretto (2012)] Pison (2012) 35 J Am Coll Cardiol Overlap [Pison (2014)] Sharma (2016) 36 Pacing Clin Electrophysiol Overlap [Kasirajan (2012)] Toplisek (2015) 37 Pacing Clin Electrophysiol Overlap [Gersak (2016)] Wang (2011) 38 PLoS One Overlap [Ma (2015)] Wang (2011) 39 Ann Thorac Surg Overlap [Ma (2015)] Yilmaz (2010) 40 Eur J Cardiothorac Surg Overlap [Boersma (2012)] Zembala (2012) 41 Kardiol Pol Overlap [Gersak (2012)] Zheng (2014) 42 J Card Surg Overlap [Ma (2015)] Ad (2016) 43 J Thorac Cardiovasc Surg <12 month follow up data Ahlsson (2013) 44 Interact Cardiovasc Thorac Surg <12 month follow up data de Groot (2012) 45 Minim Invasive Ther Allied Technol <12 month follow up data Edgerton (2009) 46 Ann Thorac Surg <12 month follow up data Edgerton (2009) 47 Heart Rhythm <12 month follow up data Guo (2015) 48 Ann Acad Med Singapore <12 month follow up data Sirak (2008) 49 Ann Thorac Surg <12 month follow up data van Laar (2016) 50 Multimed Man Cardiothorac Surg <12 month follow up data Budera (2015) 51 Cor Vasa <12 month follow up data Beukema (2009) 52 Interact Cardiovasc Thorac Surg Data at specified timepoints not available Beyer (2009) 53 J Thorac Cardiovasc Surg Data at specified timepoints not available Ip (2012) 54 J Interv Card Electrophysiol Data at specified timepoints not available Kumar (2016) 55 J Am Heart Assoc Data at specified timepoints not available Matsutani (2008) 56 Circ J Data at specified timepoints not available Nasso (2011) 57 J Thorac Cardiovasc Surg Data at specified timepoints not available Pison (2014) 58 Ann Cardiothorac Surg Data at specified timepoints not available Wolf (2014) 59 Ann Cardiothorac Surg Data at specified timepoints not available Wudel (2008) 60 Ann Thorac Surg Data at specified timepoints not available Ad (2011) 61 Ann Thorac Surg Concomitant cardiac surgery Coolbear (2011) 62 N Z Med J Concomitant cardiac surgery Holmes (2016) 63 Innovations (Phila) Concomitant cardiac surgery Lee (2010) 64 Innovations (Phila) Concomitant cardiac surgery Lee (2011) 65 Innovations (Phila) Concomitant cardiac surgery Massimiano (2013) 66 Ann Thorac Surg Concomitant cardiac surgery McCarthy (2010) 67 J Thorac Cardiovasc Surg Concomitant cardiac surgery Sternik (2011) 68 Tex Heart Inst J Concomitant cardiac surgery Gaita (2013) 69 Ann Thorac Surg Non-RF energy source Metzner (2012) 70 Heart Rhythm Non-RF energy source Straka (2016) 71 Interact Cardiovasc Thorac Surg Non-RF energy source Song (2011) 72 J Card Surg Open chest procedure

16

Supplementary Table 5: Study Demographics

Author (date) Reference Epicardial alone / Hybrid

n Age Male LA

diameter (mm)

LV ejection fraction

(%)

BMI (kg/m2)

CHADS score

Prior catheter

ablation (%)

Paroxysmal AF (%)

Persistent AF (%)

LS persistent

AF (%)

Abo-Salem (2013) 73 Epicardial alone 33 63.8 63.6 % 43.3 55.8 31.7 0 9.1 % 39.4 % 60.6 % 0.0 % Bagge (2009) 74 Epicardial alone 43 58 67.4 % 45 67.4 % 65.1 % 14.0 % 20.9 % Bauer (2009) 75 Epicardial alone 54 58 75.9 % 42 27.8 % 66.7 % 0.0 % 33.3 % Beaver (2016) 76 Epicardial alone 12 67 41.7 % 3.25 16.7 % 41.7 % 58.3 % 0.0 % Boersma (2011) 77 Epicardial alone 61 56.1 73.8 % 42.5 57.7 27.8 73.8 % 73.8 % 26.2 % 0.0 % Compier (2016) 78 Epicardial alone 25 58 76.0 % 45 26 1.2 12.0 % 0.0 % 0.0 % 100.0 % De Maat (2013) 79 Epicardial alone 86 54 77.9 % 42 56 27 17.4 % 86.0 % 14.0 % 0.0 % Doty (2012) 80 Epicardial alone 32 61 71.9 % 62.5 % 43.8 % 56.3 % 0.0 % Driessen (2016) 81 Epicardial alone 240 59.9 72.9 % 42.2 49.6 27.3 23.3 % 40.8 % 59.2 % 0.0 % Edgerton (2010) 82 Epicardial alone 52 60.3 67.3 % 48 54.2 19.2 % 100.0 % 0.0 % 0.0 % Fengsrud (2016) 83 Epicardial alone 15 66.6 86.7 % 47 54 29.7 0.0 % 0.0 % 0.0 % 100.0 % Gersak (2012) 84 Epicardial alone 32 56.7 81.3 % 48 55.1 0.0 % 40.6 % 59.4 % Geuzebroek (2016) 85 Epicardial alone 82 59.9 70.7 % 45 29.2 37.8 % 50.0 % 37.8 % 12.2 % Janusauskas (2016) 86 Epicardial alone 91 53 76.9 % 43 55 11.0 % 0.0 % 85.7 % 14.3 % Kasirajan (2012) 87 Epicardial alone 118 64 61.0 % 43 55 29 1 29.7 % 67.8 % 29.7 % 2.5 % Krul (2014) 88 Epicardial alone 36 59 83.3 % 50 29 1 47.2 % 47.2 % 52.8 % 0.0 % Ma (2016) 89 Epicardial alone 107 61.1 64.5 % 43.9 57.7 24 1.9 15.9 % 54.2 % 45.8 % 0.0 % Mcclelland (2007) 90 Epicardial alone 21 61 66.7 % 42 56 52.4 % 23.8 % 19.0 % Oudeman (2015) 91 Epicardial alone 20 55 35.0 % 10.0 % 100.0 % 0.0 % 0.0 % Pojar (2014) 92 Epicardial alone 41 57.6 75.6 % 45.3 30.3 12.2 % 58.5 % 22.0 % 19.5 % Pokushalov (2013) 93 Epicardial alone 32 56 71.9 % 46 55 28 0.6 100.0 % 62.5 % 37.5 % 0.0 % Probst (2015) 94 Epicardial alone 60 61 80.0 % 49 29 21.7 % 15.0 % 21.7 % 63.3 % Romanov (2016) 95 Epicardial alone 176 57 79.0 % 47 57 28 0.0 % 0.0 % 100.0 % 0.0 % Santini (2012) 96 Epicardial alone 22 63 86.4 % 47 61 1 72.7 % 27.3 % 72.7 % 0.0 % Sirak (2012) 97 Epicardial alone 229 67.5 54.6 % 52 29.3 % 1.3 % 2.6 % 96.1 % Wagner (2015) 98 Epicardial alone 15 52.5 66.7 % 58.1 46.6 38 20.0 % 0.0 % 0.0 % 100.0 % Wang (2014) 99 Epicardial alone 103 56.2 63.1 % 54.9 63 0.0 % 0.0 % 0.0 % 100.0 % Wang (2014) 100 Epicardial alone 66 52 57.6 % 45 64 100.0 % 0.0 % 0.0 % Weimar (2012) 101 Epicardial alone 89 60 70.8 % 60 27.3 29.2 % 34.8 % 23.6 % 41.6 % Zheng (2013) 102 Epicardial alone 139 58.3 65.5 % 40.1 63.5 25.4 5.0 % 77.7 % 12.2 % 10.1 % Bulava (2015) 103 Hybrid 51 62 62.7 % 48.1 63 30.5 0.0 % 0.0 % 0.0 % 100.0 % de Asmundis (2016)

104 Hybrid 64 59.7 87.5 % 50.3 52.8 28.3 1.03 29.7 % 0.0 % 32.8 % 67.2 % Edgerton (2016) 105 Hybrid 24 63.8 91.7 % 51.5 52.6 30.8 1.13 0.0 % 0.0 % 0.0 % 100.0 % Gehi (2013) 106 Hybrid 101 62.9 78.2 % 51 50.2 1.1 35.6 % 16.8 % 46.5 % 36.6 % Gersak (2016) 107 Hybrid 76 56.6 47 59.2 28.9 5.3 % 15.8 % 78.9 % Krul (2014) 88 Hybrid 36 60 75.0 % 44 27 1 61.1 % 52.8 % 47.2 % 0.0 % La Meir (2012) 108 Hybrid 19 61.2 84.2 % 50 47.4 % 26.3 % 21.1 % 52.6 % Mahapatra (2011) 109 Hybrid 15 59.5 53.3 % 52.3 47 100.0 % 0.0 % 60.0 % 40.0 % Muneretto (2012) 110 Hybrid 24 63.2 58.3 % 50.5 51.2 0.0 % 12.5 % 87.5 % On (2015) 111 Hybrid 79 54 94.9 % 44 59 1.5 12.7 % 10.1 % 21.5 % 68.4 % Osmancik (2016) 112 Hybrid 33 60.2 72.7 % 46.9 54.4 32.8 0.0 % 0.0 % 69.7 % 30.3 % Richardson (2016) 3 Hybrid 83 63 81.9 % 49 55 0.0 % 1.2 % 98.8 % 0.0 %

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Supplementary Table 6: Lesion Sets

Author (date) Reference Epicardial alone / Hybrid

Access Energy Source Overall lesion set

category Ganglionic

plexus ablation LAA exclusion

Conduction block verified

Abo-Salem (2013) 73 Epicardial alone Mini-thoracotomy Bipolar RF PVI + + -

Bagge (2009) 74 Epicardial alone Thoracoscopic Bipolar RF PVI + + -

Bauer (2009) 75 Epicardial alone Mini-thoracotomy Bipolar RF PVI + box + + +

Beaver (2016) 76 Epicardial alone Thoracoscopic Bipolar RF PVI - + -

Boersma (2011) 77 Epicardial alone Thoracoscopic Bipolar RF PVI + + +

Compier (2016) 78 Epicardial alone Thoracoscopic Bipolar RF PVI + box - + +

De Maat (2013) 79 Epicardial alone Mixed Bipolar RF PVI - - +

Doty (2012) 80 Epicardial alone Mini-thoracotomy Monopolar RF PVI + box + + +

Driessen (2016) 81 Epicardial alone Thoracoscopic Bipolar RF PVI + box + RA - + +

Edgerton (2010) 82 Epicardial alone Mini-thoracotomy Bipolar RF PVI + + +

Fengsrud (2016) 83 Epicardial alone Thoracoscopic Monopolar RF PVI + box - - +

Gersak (2012) 84 Epicardial alone Mixed Monopolar RF PVI + box + RA - - +

Geuzebroek (2016) 85 Epicardial alone Thoracoscopic Bipolar RF PVI + box - + +

Janusauskas (2016) 86 Epicardial alone Mini-thoracotomy Bipolar RF PVI - + -

Kasirajan (2012) 87 Epicardial alone Mini-thoracotomy Bipolar RF PVI + + -

Krul (2014) 88 Epicardial alone Thoracoscopic Bipolar RF PVI + box + + -

Ma (2015) 89 Epicardial alone Thoracoscopic Bipolar RF PVI + + -

Mcclelland (2007) 90 Epicardial alone Mini-thoracotomy Bipolar RF PVI + - +

Oudeman (2015) 91 Epicardial alone Mini-thoracotomy Bipolar RF PVI + + +

Pojar (2014) 92 Epicardial alone Thoracoscopic Bipolar RF PVI + box - + +

Pokushalov (2013) 93 Epicardial alone Thoracoscopic Bipolar RF PVI + box + + +

Probst (2015) 94 Epicardial alone Thoracoscopic Bipolar RF PVI + box + + +

Romanov (2016) 95 Epicardial alone Thoracoscopic Bipolar RF PVI + box + - +

Santini (2011) 96 Epicardial alone Mini-thoracotomy Bipolar RF PVI + + +

Sirak (2012) 97 Epicardial alone Thoracoscopic Bipolar RF PVI + box + + +

Wagner (2015) 98 Epicardial alone Thoracoscopic Bipolar RF PVI + box - + +

Wang (2014) 99 Epicardial alone Thoracoscopic Bipolar RF PVI - + +

Wang (2014) 100 Epicardial alone Thoracoscopic Bipolar RF PVI + + -

Weimar (2012) 101 Epicardial alone Thoracoscopic Bipolar RF PVI + box + + +

Zheng (2013) 102 Epicardial alone Thoracoscopic Bipolar RF PVI + + +

Bulava (2015) 103 Hybrid Thoracoscopic Bipolar RF PVI + box + RA + + +

de Asmundis (2016) 104 Hybrid Thoracoscopic Bipolar RF PVI + box + RA - + +

Edgerton (2016) 105 Hybrid Transdiaphragmatic Monopolar RF PVI + box + RA - - +

Gehi (2013) 106 Hybrid Transdiaphragmatic Monopolar RF PVI + box + RA - - +

Gersak (2016) 107 Hybrid Transdiaphragmatic Monopolar RF PVI + box + RA - - +

Krul (2014) 88 Hybrid Thoracoscopic Bipolar RF PVI + box + RA + + -

La Meir (2012) 108 Hybrid Thoracoscopic Monopolar RF PVI + box + - +

Mahapatra (2011) 109 Hybrid Thoracoscopic Bipolar RF PVI + box + RA + + +

Muneretto (2012) 110 Hybrid Thoracoscopic Monopolar RF PVI + box + RA - - +

On (2015) 111 Hybrid Thoracoscopic Bipolar RF PVI + box + RA - + +

Osmancik (2016) 112 Hybrid Thoracoscopic Mixed PVI + box + RA + - +

Richardson (2016) 3 Hybrid Thoracoscopic Bipolar RF PVI + box + RA + + +

18

Supplementary Table 7: Complications (non-hierarchical)

Author (date) Reference Epicardial alone / Hybrid

n Death Stroke /

TIA Pericardial effusions requiring drainage

Sternotomies Major

bleeding Atrio-oesophageal

fistulae

Abo-Salem (2013) 73 Epicardial alone 33 2 (6.1 %) 0 0 0 0 0 Bagge (2009) 74 Epicardial alone 43 0 1 (2.3 %) 0 0 6 (14 %) 0 Bauer (2009) 75 Epicardial alone 54 0 0 0 0 0 0 Beaver (2016) 76 Epicardial alone 12 0 0 0 1 (8.3 %) 0 0 Boersma (2011) 77 Epicardial alone 61 0 0 1 (1.6 %) 1 (1.6 %) 1 (1.6 %) 0 Compier (2016) 78 Epicardial alone 25 1 (4 %) 1 (4 %) 1 (4 %) 0 0 0 De Maat (2013) 79 Epicardial alone 86 0 1 (1.2 %) 3 (3.5 %) 3 (3.5 %) 0 0 Doty (2012) 80 Epicardial alone 32 0 0 0 0 1 (3.1 %) 0 Driessen (2016) 81 Epicardial alone 240 1 (0.4 %) 1 (0.4 %) 1 (0.4 %) 1 (0.4 %) 9 (3.8 %) 0 Edgerton (2010) 82 Epicardial alone 52 0 0 0 0 0 0 Fengsrud (2016) 83 Epicardial alone 15 0 0 0 0 0 0 Gersak (2012) 84 Epicardial alone 32 1 (3.1 %) 0 0 1 (3.1 %) 0 0 Geuzebroek (2016) 85 Epicardial alone 82 0 0 1 (1.2 %) 0 0 0 Janusauskas (2016) 86 Epicardial alone 91 0 2 (2.2 %) 1 (1.1 %) 3 (3.3 %) 1 (1.1 %) 0 Kasirajan (2012) 87 Epicardial alone 118 0 0 0 3 (2.5 %) 0 0 Krul (2014) 88 Epicardial alone 36 0 0 1 (2.8 %) 1 (2.8 %) 0 0 Ma (2015) 89 Epicardial alone 107 0 0 0 0 0 0 Mcclelland (2007) 90 Epicardial alone 21 0 0 0 0 0 0 Oudeman (2015) 91 Epicardial alone 20 0 0 0 0 0 0 Pojar (2014) 92 Epicardial alone 41 0 0 0 0 0 0 Pokushalov (2013) 93 Epicardial alone 32 0 0 1 (3.1 %) 1 (3.1 %) 1 (3.1 %) 0 Probst (2015) 94 Epicardial alone 60 0 3 (5 %) 0 3 (5 %) 3 (5 %) 0 Romanov (2016) 95 Epicardial alone 176 0 6 (3.4 %) 0 5 (2.8 %) 0 0 Santini (2011) 96 Epicardial alone 22 0 0 0 1 (4.5 %) 0 0 Sirak (2012) 97 Epicardial alone 229 0 0 0 2 (0.9 %) 0 0 Wagner (2015) 98 Epicardial alone 15 0 0 0 0 0 0 Wang (2014) 99 Epicardial alone 103 0 0 0 0 0 0 Wang (2014) 100 Epicardial alone 66 - - - - - - Weimar (2012) 101 Epicardial alone 89 0 1 (1.1 %) 0 0 0 0 Zheng (2013) 102 Epicardial alone 139 1 (0.7 %) 2 (1.4 %) 0 1 (0.7 %) 0 0 Bulava (2015) 103 Hybrid 51 0 0 1 (2 %) 2 (3.9 %) 0 0 de Asmundis (2016) 104 Hybrid 64 0 0 2 (3.1 %) 2 (3.1 %) 0 0 Edgerton (2016) 105 Hybrid 24 3 (12.5 %) 2 (8.3 %) 1 (4.2 %) 0 0 1 (4.2 %) Gehi (2013) 106 Hybrid 101 2 (2 %) 1 (1 %) 2 (2 %) 0 2 (2 %) 1 (1 %) Gersak (2016) 107 Hybrid 76 2 (2.6 %) 1 (1.3 %) 1 (1.3 %) 0 0 2 (2.6 %) Krul (2014) 88 Hybrid 36 0 0 0 1 (2.8 %) 0 0 La Meir (2012) 108 Hybrid 19 0 0 0 0 0 0 Mahapatra (2011) 109 Hybrid 15 0 0 0 0 0 0 Muneretto (2012) 110 Hybrid 24 0 0 0 0 0 0 On (2015) 111 Hybrid 79 0 3 (3.8 %) 2 (2.5 %) 0 0 1 (1.3 %) Osmancik (2016) 112 Hybrid 33 0 1 (3 %) 0 0 6 (18.2 %) 0 Richardson (2016) 3 Hybrid 83 1 (1.2 %) 0 1 (1.2 %) 0 7 (8.4 %) 0

19

Supplementary Table 8: Sensitivity Analysis

Analysis n series

(Epicardial alone, hybrid)

Epicardial alone (mean, CI)

Hybrid (mean, CI)

12 months

All studies included 30,11 72 % (66–77 %) 63 % (51–75 %)

Only thoracoscopic access and bipolar RF 24,6 73 % (67–79 %) 75 % (65–85 %)

Only <20 % paroxysmal AF (9,10) 9,10 73 % (62–85 %) 63 % (51–76 %)

Only guideline adherent success definition 18,8 74 % (68–81 %) 62 % (47–78 %)

Only >7 days ambulatory monitoring 11,8 75 % (67–84 %) 61 % (45–77 %)

24 months

All studies included 11,6 68 % (58–79 %) 57 % (34–80 %)

Only thoracoscopic access and bipolar RF 9,2 72 % (61–83 %) 77 % (66–88 %)

Only <20 % paroxysmal AF (9,10) 4,6 73 % (55–91 %) 57 % (34–80 %)

Only guideline adherent success definition 9,4 72 % (62–83 %) 54 % (22–86 %)

Only >7 days ambulatory monitoring 2,5 85 % (66–100 %) 56 % (29–82 %)

20

Supplementary Table 9: Comparison of Modes of Access

Thoracoscopic

(mean, SD)

Mini-thoracotomy (mean, SD)

Transdiaphragmatic (mean, SD)

p

Length of stay (days) 5.6 (2.0) 5.8 (2.7) 5 (NA) 0.55

Combined major complications

6.2 % (7.9 %) 2.7 % (2.9 %) 18.5 % (15.0 %) 0.59

21

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