ASERNIP-S REPORT NO. 38. July Australian Safety & Efficacy Register of New Interventional Procedures Surgical

Transcription

1 ASERNIP S Australian Safety and Efficacy Register of New Interventional Procedures-Surgical Systematic review of intraoperative ablation for the treatment of atrial fibrillation ASERNIP-S REPORT NO. 38 July 2004 Australian Safety & Efficacy Register of New Interventional Procedures Surgical The Royal Australasian College of Surgeons

2 A Systematic Review of Intraoperative Ablation for the Treatment of Atrial Fibrillation ISBN: X Published Date: July, 2004 This report should be cited in the following manner: Hazel SJ, et al. Systematic review of Intraoperative Ablation for the Treatment of Atrial Fibrillation. ASERNIP-S Report No.38. Adelaide, South Australia: ASERNIP-S, July, 2004 Copies of these reports can be obtained from: The Australian Safety and Efficacy Register of New Interventional Procedures - Surgical The Royal Australasian College of Surgeons PO Box 553, Stepney, South Australia 5069 AUSTRALIA Fax: College.asernip@surgeons.org

3 The Safety and Efficacy Classification for the Systematic Review of Intraoperative Ablation for the Treatment of Atrial Fibrillation was ratified by: The ASERNIP-S Management Committee on July 8, 2004 The Council of the Royal Australasian College of Surgeons on July 30, 2004

4 Table Of Contents Executive Summary... i The ASERNIP-S Classification System...iv Safety and Efficacy Classification... v Review Group Membership...vi 1.0 OBJECTIVE INTRODUCTION Pathogenesis of Atrial Fibrillation Conventional Therapies Medical Management of Atrial Fibrillation (AF) Electrical Cardioversion and Pacing of Atrial Fibrillation (AF) Catheter ablation of Atrial Fibrillation (AF) Surgical Treatment of Atrial Fibrillation (AF) Maze-III Challenges Intraoperative Ablation Techniques Summary METHODS Literature Search Protocol Inclusion Criteria Literature Search Strategies Literature Database Assessment Methods Outcome Measures DESCRIPTION AND METHODOGICAL ANALYSIS OF STUDIES Designation of Levels of Evidence and Critical Appraisal Cryotherapy Ablation Radiofrequency Ablation Microwave Ablation Laser Ablation Radiofrequency versus Microwave Ablation Maze-III RESULTS SAFETY Mortality Bleeding, blood loss, blood transfusion requirement Stroke/ transient ischaemic attack/ other thromboembolism Complications related to cardiac surgery Oesophageal injury Other major perioperative complications EFFICACY Sinus rhythm (SR) Atrial fibrillation (AF)... 77

5 5.2.3 Junctional rhythm Atrial flutter (AFl) Heart function Pacemakers Catheter ablation Electrical cardioversion Continued antiarrhythmic treatment Continued anticoagulant requirement Surgical times and lengths of hospital stay Ablation times Hospital and ICU stay Reoperation and readmission Exercise testing DISCUSSION Study Limitations Safety and efficacy of intraoperative ablation Efficacy Safety Factors influencing efficacy Energy source Lesion set Type of AF Measurement of SR/AF Atrial contraction Antiarrhythmic medication Safety Anticoagulant therapy and risk of stroke Oesophageal perforation Circumflex artery injury Length of CPB Possible indications and contraindications for intraoperative ablation Uptake of intraoperative ablation for AF Considerations for further research CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES...172

6 List of Tables 1 Databases searched Summary of the exclusion process for the methodological review papers Summary of the final exclusion process for the systematic review papers Included studies according to level of evidence and energy source Cryotherapy Ablation- Comparative non-randomised studies Cryotherapy Ablation Case Series Radiofrequency Ablation- RCT and Non-randomised Comparative Studies RFA Case Series Included Studies MWA RCT and Non-randomised Comparative Included Studies MWA Case Series Included Studies Maze-III included studies Mortality- Biatrial CA +CS versus CS Mortality- Left atrial CA +CS versus CS Mortality- Biatrial CA versus Maze-III Mortality- Kosakai maze versus CA Mortality- Kosakai maze RAA+ versus RAA Mortality- Biatrial versus left atrial CA Mortality- Biatrial versus right atrial CA Mortality- Biatrial CA Case Series Mortality- Left atrial CA Case Series Mortality- Biatrial RFA+MVS versus MVS RCT Mortality- Biatrial RFA+CS versus CS Mortality- Left atrial RFA versus CS Mortality- RFA versus Maze-III Mortality- Biatrial versus left atrial RFA Mortality- Biatrial RFA Case Series Mortality- Left atrial RFA Case Series Mortality- Left atrial MWA versus CS RCT Mortality- Left atrial MWA versus CS Mortality- Biatrial MWA Case Series Mortality- Left atrial MWA Case Series Bleeding- Biatrial CA+CS versus CS Bleeding- Left atrial CA+CS versus CS Bleeding- CA versus Maze-III Bleeding- Biatrial versus right atrial CA Bleeding and blood transfusion- Biatrial versus left atrial CA Blood loss- Kosakai maze versus biatrial CA Bleeding- Biatrial CA Case Series Bleeding and blood transfusion- Left atrial CA Case Series Bleeding- Left atrial RFA versus CS Bleeding- Biatrial versus left atrial CA Bleeding- Biatrial RFA Case Series Blood loss- Biatrial RFA Case Series Bleeding- Left atrial RFA Case Series Blood loss and transfusion- Left atrial RFA Case Series Bleeding- MWA versus CS Bleeding- Left atrial MWA Case Series Bleeding and blood loss- MWA versus RFA Stroke- Biatrial CA+CS versus CS Stroke and other thromboembolism- Biatrial CA versus Maze-III Stroke- Kosakai maze versus CA Stroke and transient ischaemic attack- Biatrial CA Case Series Stroke and transient ischaemic attack- Left atrial CS Case Series Stroke and other thromboembolism- Left atrial RFA versus CS Stroke and transient ischaemic attack- Left atrial RFA versus CS... 48

7 56 Transient ischaemic attack- Biatrial versus left atrial RFA Stroke, other thromboembolisms and TIAs- Biatrial RFA Case Series Stroke, other thromboembolism and TIAs- Left atrial RFA Case Series Stroke- Biatrial MWA Case Series Stroke- Left atrial MWA Case Series Stroke- MWA versus RFA Mediastinitis- KM versus CA Wound infection- Biatrial CA Case Series Wound infection/sternal instability or mediastinitis- Biatrial RFA versus CS Mediastinitis- Biatrial RFA versus CS Mediastinitis- Biatrial versus left atrial RFA Wound infection- Biatrial RFA Case Series Wound infection- Left atrial RFA Case Series Pulmonary insufficiency- Kosakai maze versus CA Pulmonary insufficiency- Biatrial CA Case Series Pulmonary insufficiency- Biatrial RFA versus CS Pulmonary insufficiency- Left atrial RFA versus CS Pulmonary insufficiency- Biatrial RFA Case Series Pulmonary insufficiency- Left atrial RFA Case Series Low cardiac output- CA versus Maze-III Low cardiac output- Biatrial CA Case Series Low cardiac output- Biatrial CA Low cardiac output- Left atrial RFA versus CS Low cardiac output- Biatrial RFA Case Series Low cardiac output- Left atrial RFA Case Series Low cardiac output- Left atrial MWA Case Series Low cardiac output- MWA versus RFA Renal failure- CA versus Maze-III Renal failure- Kosakai maze versus CA Renal failure- Biatrial CA Case Series Renal failure- Biatrial CA Case Series IABP- Left atrial CA+CS versus CS IABP- CA versus Maze-III IABP- Left atrial CA Case Series IABP- Biatrial RFA Case Series IABP- MWA versus RFA Miscellaneous complications- Left atrial CA versus CS Miscellaneous complications- Kosakai maze versus CS Miscellaneous complications- Biatrial CA Case Series Miscellaneous complications- Left atrial CA Case Series Miscellaneous complications- Biatrial versus left atrial RFA Miscellaneous complications- Biatrial RFA Case Series Miscellaneous complications- Left atrial RFA Case Series Miscellaneous complications- Left atrial MWA Case Series Miscellaneous complications- MWA versus RFA Sinus rhythm- Biatrial CA+CS versus CS Sinus rhythm- Left atrial CA+CS versus CS Sinus rhythm- CA versus Maze-III Sinus rhythm- KM versus CA Sinus rhythm- KM-RAA versus KM+RAA Sinus rhythm- Biatrial versus left atrial CA Sinus rhythm- KM versus Maze-III Sinus rhythm- Biatrial CA Case Series Sinus rhythm- Left atrial CA Case Series Sinus rhythm- Biatrial RFA+MVS versus MVS RCT Sinus rhythm- Biatrial RFA versus CS... 70

8 112 Sinus rhythm- Left atrial RFA versus CS Sinus rhythm- RFA versus Maze-III Sinus rhythm- Biatrial versus left atrial RFA Sinus rhythm- Biatrial RFA Case Series Sinus rhythm- Left atrial RFA Case Series Sinus rhythm- Left atrial MWA versus CS RCT Sinus rhythm- Left atrial MWA versus CS Sinus rhythm- MWA Comparison of two lesion sets Sinus rhythm- Biatrial MWA Case Series Sinus rhythm- Left atrial MWA Case Series Sinus rhythm- MWA versus RFA Atrial fibrillation- Biatrial CA+CS versus CS Atrial fibrillation- Left atrial CA+CS versus CS Atrial fibrillation- CA versus Maze-III Atrial fibrillation- Kosakai maze versus CA Atrial fibrillation- Biatrial versus left atrial CA Atrial fibrillation- Biatrial CA Case Series Atrial fibrillation- Left atrial CA Case Series Atrial fibrillation- Biatrial RFA+MVS versus MVS RCT Atrial fibrillation- Biatrial RFA versus CS Atrial fibrillation- Left atrial RFA versus CS Atrial fibrillation- Biatrial versus left atrial RFA Atrial fibrillation- Biatrial RFA Case Series Atrial fibrillation- Left atrial RFA Case Series Atrial fibrillation- Left atrial MWA versus CS RCT Atrial fibrillation- Left atrial MWA versus CS Atrial fibrillation- Biatrial MWA Case Series Atrial fibrillation- Left atrial MWA Case Series Atrial fibrillation- MWA versus RFA Junctional rhythm- Biatrial CA+CS versus CS Junctional rhythm- Left atrial CA+CS versus CS Junctional rhythm- CA versus Maze-III Junctional rhythm- Biatrial versus left atrial CA Junctional rhythm- Biatrial CA Case Series Junctional rhythm- Left atrial RFA versus CS Junctional rhythm- Biatrial RFA Case Series Junctional rhythm- Left atrial RFA Case Series Junctional rhythm- MWA versus RFA Atrial flutter- Biatrial CA+CS versus CS Atrial flutter- CA versus Maze-III Atrial flutter- Biatrial CA Case Series Atrial flutter- Left atrial CA Case Series Atrial flutter- Left atrial RFA versus CS Atrial flutter- Biatrial versus left atrial RFA Atrial flutter- Biatrial RFA Case Series Atrial flutter- Left atrial RFA Case Series Atrial flutter- Left atrial MWA Case Series Atrial flutter- MWA versus RFA Atrial contraction- CA versus Maze-III Atrial contraction- Biatrial CA Case Series Atrial contraction- Left atrial CA Case Series Atrial contraction- Biatrial RFA+MVS versus MVS RCT Atrial contraction- Biatrial RFA versus CS Atrial contraction- Left atrial RFA versus CS Atrial contraction- Biatrial RFA versus Maze-III Atrial contraction- Biatrial versus left atrial RFA

9 168 Atrial contraction- Biatrial RFA Case Series Atrial contraction- Left atrial RFA Case Series Atrial contraction- Left atrial MWA versus CS Atrial contraction- MWA1 versus MWA Atrial contraction- Left atrial MWA Case Series A/E ratio- CA versus Maze-III A/E ratio- Right atrial CA Case Series A/E ratio- Left atrial CA Case Series A/E ratio- Biatrial RFA Case Series A/E ratio- Left atrial RFA Case Series Atrial filling fraction- Biatrial CA Case Series Atrial filling fraction- Biatrial RFA versus CS Atrial filling fraction- Biatrial RFA Case Series Atrial filling fraction- Left atrial MWA Case Series Peak A-wave velocity- CA versus Maze-III Peak A-wave velocity- Biatrial CA Case Series Peak A-wave velocity- Biatrial CA Case Series Peak A-wave velocity- Biatrial RFA Case Series Peak A-wave velocity- Left atrial RFA Case Series Pacemakers- Biatrial CA+CS versus CS Pacemakers- Left atrial CA+CS versus CS Pacemakers- CA versus Maze-III Pacemakers- Kosakai maze versus CA Pacemakers- Biatrial versus left atrial CA Pacemaker- Biatrial CA Case Series Pacemaker- Left atrial CA Case Series Pacemaker- Biatrial RFA versus CS RCT Pacemaker- Biatrial RFA versus CS Pacemaker- RFA versus Maze-III Pacemaker- Biatrial versus left atrial RFA Pacemaker- Biatrial RFA Case Series Pacemaker- Left atrial RFA Case Series Pacemaker- Left atrial MWA versus CS Pacemaker- Biatrial MWA Case Series Pacemaker- Left atrial MWA Case Series Pacemaker- MWA versus RFA Catheter ablation- Left atrial CA+CS versus CS Catheter ablation- Left atrial CA Case series Catheter ablation- Biatrial RFA Case Series Catheter ablation- Left atrial RFA Case Series Catheter ablation- Left atrial MWA Case Series Electrical cardioversion- Biatrial CA+CS versus CS Electrical cardioversion- Left atrial CA+CS versus CS Electrical cardioversion- Biatrial CA Case Series Electrical cardioversion- Left atrial CA Case Series Electrical cardioversion- Left atrial RFA versus CS Electrical cardioversion- Biatrial versus left atrial RFA Electrical cardioversion- Biatrial RFA Case Series Electrical cardioversion- Left atrial RFA Case Series Electrical cardioversion- Left atrial MWA versus CS RCT Electrical cardioversion- Left atrial MWA Case Series Antiarrhythmic drugs- Biatrial CA+CS versus CS Antiarrhythmic drugs- Left atrial CA+CS versus CS Antiarrhythmic drugs- CA versus Maze-III Antiarrhythmic drugs- Biatrial versus left atrial CA Antiarrhythmic drugs- Biatrial CA Case Series

10 224 Antiarrhythmic drugs- Left atrial CA Case Series Antiarrhythmic drugs- Left atrial RFA versus CS Antiarrhythmic drugs- Biatrial RFA versus Maze-III Antiarrhythmic drugs- RFA versus cardioversion Antiarrhythmic drugs- Biatrial RFA Case Series Antiarrhythmic drugs- Left atrial RFA Case Series Antiarrhythmic drugs- Left atrial MWA versus CS RCT Antiarrhythmic drugs- Left atrial MWA versus CS Antiarrhythmic drugs- Left atrial MWA Case Series Anticoagulant- Biatrial CA+CS versus CS Anticoagulant- Biatrial CA versus Maze-III Anticoagulant- Left atrial CA Case Series Anticoagulant- Left atrial RFA versus CS Anticoagulant- RFA versus Maze-III Anticoagulant- Biatrial RFA Case Series CPB and cross clamping- Biatrial CA+CS versus CS CPB and cross clamping- Left atrial CA+CS versus CS CPB and cross clamping times- CA versus Maze-III CPB and cross clamping times- Kosakai maze versus CA CPB and cross clamping times- Kosakai-RAA versus Kosakai+RAA CPB and cross clamping times- Biatrial versus left atrial CA CPB and cross clamping times- Biatrial CA Case Series CPB and cross clamping times- Left atrial CA Case Series CPB and cross clamping times- Biatrial RFA+MVS versus MVS RCT CPB and cross clamping times- Biatrial RFA versus CS CPB and cross clamping times- Left atrial RFA+CS versus CS CPB and cross clamping times- RFA versus Maze-III CPB and cross clamping times- Biatrial versus left atrial RFA CPB and cross clamping times- Biatrial RFA Case Series CPB and cross clamping times- Left atrial RFA Case Series CPB and cross clamping times- Left atrial MWA+CS versus CS RCT CPB and cross clamping times- Biatrial MWA Case Series CPB and cross clamping times- Left atrial MWA Case Series CPB and cross clamping times- MWA versus RFA Ablation times- Left atrial CA Case Series Ablation times- Biatrial versus left atrial RFA Ablation times- Biatrial RFA Case Series Ablation times- Left atrial RFA Case Series Ablation times- Left atrial MWA Case Series Ablation times- MWA versus RFA Hospital stay- Biatrial CA+CS versus CS Hospital stay- Left atrial CA+CS versus CS ICU stay- Biatrial CA Case Series Hospital stay- Left atrial CA Case Series Hospital and ICU stay- Biatrial RFA versus CS Hospital stay- Left atrial RFA versus CS ICU stay- RFA versus Maze-III Hospital stay- Biatrial RFA Case Series Hospital and ICU stay- Left atrial RFA Case Series Hospital stay- MWA versus CS RCT Hospital and ICU stay- MWA versus RFA Re-operation- Biatrial CA+CS versus CS Re-operation- Left atrial CA+CS versus CS Re-operation- CA versus Maze-III Re-operation- Biatrial versus right atrial CA Re-operation- Biatrial CA Case Series

11 281 Re-operation- Left atrial CA Case Series Reoperation- RFA+MVS versus MVS Reoperation- Biatrial RFA versus CS Re-operation- Left atrial RFA versus CS Re-operation- Biatrial versus left atrial RFA Reoperation- Biatrial RFA Case Series Reoperation- Left atrial RFA Case Series Re-operation- Left atrial MWA Re-operation- MWA versus RFA Major efficacy outcomes Non-randomised comparative CA studies Major efficacy outcomes from RFA studies Major efficacy outcomes from MWA studies Major safety outcomes Non-randomised comparative CA studies Major safety outcomes from RFA studies Major safety outcomes from MWA studies List of Figures 1 Diagrammatic representation of Maze-III Median proportion of mortality Median proportion of patients in SR Median proportion of patients in AF Median proportion of patients with right atrial contraction Median proportion of patients with left atrial contraction Median proportion of patients requiring a pacemaker Cardiopulmonary bypass times Cross clamping times List of Appendices A Hierarchy of Evidence B Exclusions C Study Profile and Data Extraction Tables C.1 Cryotherapy ablation C.2 Radiofrequency ablation C.3 Microwave ablation C.4 Laser ablation D C.5 Microwave versus radiofrequency ablation Safety and Efficacy Tables D.1 Safety- Cryotherapy ablation D.2 Safety- Radiofrequency ablation D.3 Safety- Microwave ablation D.4 Safety- Laser ablation D.5 Safety- Microwave versus radiofrequency ablation D.6 Efficacy- Cryotherapy ablation D.7 Efficacy- Radiofrequency ablation D.8 Efficacy- Microwave ablation D.9 Efficacy- Laser ablation D.10 Efficacy-Microwave versus radiofrequency ablation D.11 Efficacy- Exercise testing D.12 Safety- Case reports E E.1 Methods of measurement of atrial contraction E.2 Use of antiarrhythmic medication E.3 Conditions for discontinuation of anticoagulant therapy E.4 Analysis of risk factors for recurrence of AF

12 Executive Summary Objective The aim of this review was to assess the safety and efficacy of intraoperative surgical ablation techniques for the treatment of atrial fibrillation (AF) compared to other surgical procedures, including cardiac surgery (CS) alone, or the Maze-III procedure, the current gold standard surgical treatment for AF. Methods Search strategy Studies were identified by searching MEDLINE, EMBASE, The Cochrane Library, Science Citation Index, PubMed, Clinical Trials Database (US), NHS Centre for Research and Dissemination, NHS Health Technology Assessment (UK), National Research Register (UK), National Institute of Health (US) and Meta Register of Controlled Trials, from inception to January 13, In addition, online abstracts for relevant conferences were searched, and additional articles identified through the reference sections of the retrieved studies. Studies using the Maze-III procedure were identified for benchmark data, including randomised controlled trials (RCTs) and nonrandomised comparative studies where the comparator was not intraoperative ablation, and case series. Study selection RCT, non-randomised comparative studies and case series were included in which intraoperative ablation, using any of the available energy sources (cryotherapy, radiofrequency, microwave, laser) and any standardised lesion pattern (left and/or right atrial), were performed. Patients were over 18 years of age with AF (paroxysmal, persistent or permanent); operations were via median sternotomy, with cardiopulmonary bypass (CPB). Case reports of major complications were also used. Patient safety outcomes included: blood loss, stroke, other thromboembolisms; wound infection, pulmonary insufficiency, low cardiac output, renal failure, oesophageal injury, circumflex artery injury and mortality. Efficacy outcomes included: heart rhythm, atrial function, pacemaker requirement, electrical cardioversion, operation, CPB and cross clamping time, hospital stay, reoperation, reintervention for catheter ablation, and continued antiarrhythmic and anticoagulant requirements. Data collection and analysis Data from the included studies were extracted by the ASERNIP-S Researcher using standardised data extraction tables developed a priori and checked by a second researcher. Relative risks (RR) for dichotomous outcome measures with 95% confidence intervals (CI) were calculated for some outcomes in individual i

13 RCTs where it helped the interpretation of results. For non-randomised studies, median values were calculated for sets of comparable interventions. Results A total of 69 studies using intraoperative ablation were identified, plus 15 studies with Maze-III surgery as a benchmark. There were 30 studies using cryotherapy ablation (CA): 14 non-randomised comparative studies (four CA versus CS, five CA versus Maze-III, four studies with internal comparisons and one questionnaire study) and 16 case series. A total of 29 studies used radiofrequency ablation (RFA): one RCT comparing biatrial RFA versus CS, nine non-randomised comparative studies (five RFA versus CS, one RFA versus cardioversion, one RFA versus Maze-III and two biatrial versus left atrial RFA) and 19 case series. One RCT compared left atrial microwave ablation (MWA) versus CS, two non-randomised comparative studies compared left atrial MWA versus CS, and five case series used MWA. Finally, one case series used laser ablation and one nonrandomised comparative study compared RFA versus MWA. No studies comparing intraoperative ablation with medical management were located. Evidence was mostly limited by the many variations of energy sources and ablation patterns used in the included studies. The primary efficacy outcome was conversion to normal sinus rhythm (SR), which was greater with CA, RFA and MWA versus CS alone. In the RCTs, the relative risk (RR) of patients being in SR at 12 months follow-up after RFA compared with MV surgery alone was 3.82 (95% CI: 1.35 to 10.81, p=0.01) in Khargi et al. (2001), while at three months follow-up in Schuetz et al. (2003) the RR was 3.24 (95% CI: 1.09 to 9.65, p=0.03). Conversion to SR was at least 68% for all the different energy sources and lesion sets. There were no consistent differences in efficacy between CA versus Maze-III, and insufficient evidence for this comparison using other energy sources. In the one study comparing different energy sources, there were no significant differences in efficacy between RFA versus MWA. Addition of ablation significantly increased CPB and cross clamping times versus CS alone. Left atrial versus biatrial CA or RFA generally appeared to decrease CPB and cross clamping times without influencing efficacy. Atrial function results were difficult to interpret due to the varying criteria used to assess effective atrial contraction. There were no consistent differences in mortality when ablation was compared to CS or Maze-III surgery, and there did not appear to be any greater risk of bleeding with CA or RFA versus CS. Not enough evidence was presented to make any conclusions about stroke incidence. Small numbers of oesophageal perforation and circumflex artery stenosis, both of which may be lethal, were reported, mostly in case reports. All of the oesophageal perforations were associated with unipolar non-irrigated RFA. ii

14 Conclusion and recommendations On the basis of the evidence presented in this systematic review, The ASERNIP-S Review Group agreed on the following classifications and recommendations concerning the safety and efficacy of intraoperative ablation for the treatment of AF: Classification Evidence rating- The available evidence was assessed as being poor. Safety- There was insufficient evidence to determine if intraoperative ablation was more or less safe than cardiac surgery alone, or the Maze-III procedure. Associated risks relating to longer bypass times, plus the possibility of oesophageal perforation and circumflex artery injuries, are potential concerns. There were no studies comparing intraoperative ablation with medical management of AF, therefore safety could not be evaluated. Efficacy- Intraoperative ablation is at least as efficacious as cardiac surgery alone, or the Maze-III procedure. There were no studies comparing intraoperative ablation with medical management of AF, therefore efficacy could not be evaluated. ASERNIP-S Recommendations A randomised controlled trial of intraoperative ablation should be performed, designed and powered sufficiently to measure long term survival and stroke rate. The comparator would be cardiac surgery alone. Surgeons performing intraoperative ablation for the treatment of AF should also participate in a national audit. Important note The information contained in this report is a distillation of the best available evidence located at the time the searches were completed as stated in the protocol. Please consult with your medical practitioner if you have further questions relating to the information provided, as the clinical context may vary from patient to patient. iii

15 The ASERNIP-S Classification System Evidence Rating The evidence for ASERNIP-S systematic reviews is classified as Good, Average or Poor, based on the quality and availability of this evidence. High quality evidence is defined here as having a low risk of bias and no other significant flaws. While high quality randomised controlled trials are regarded as the best kind of evidence for comparing interventions, it may not be practical or ethical to undertake them for some surgical procedures, or the relevant randomised controlled trials may not yet have been carried out. This means that it may not be possible for the evidence on some procedures to be classified as good. Good Most of the evidence is from a high quality systematic review of all relevant randomised trials or from at least one high quality randomised controlled trial of sufficient power. The component studies should show consistent results, the differences between the interventions being compared should be large enough to be important, and the results should be precise with minimal uncertainty. Average Most of the evidence is from high quality quasi-randomised controlled trials, or from nonrandomised comparative studies without significant flaws, such as large losses to followup and obvious baseline differences between the comparison groups. There is a greater risk of bias, confounding and chance relationships compared to high-quality randomised controlled trials, but there is still a moderate probability that the relationships are causal. An inconclusive systematic review based on small randomised controlled trials that lack the power to detect a difference between interventions and randomised controlled trials of moderate or uncertain quality may attract a rating of average. Poor Most of the evidence is from case series, or studies of the above designs with significant flaws or a high risk of bias. A poor rating may also be given if there is insufficient evidence. iv

16 Safety and Efficacy Classification SAFETY At least as safe compared to comparator * procedure(s) This grading is based on the systematic review showing that the new intervention is at least as safe as the comparator. Safety cannot be determined This grading is given if the evidence is insufficient to determine the safety of the new intervention. Less safe compared to comparator * procedure(s) This grading is based on the systematic review showing that the new intervention is not as safe as the comparator. EFFICACY At least as efficacious compared to comparator * procedure(s) This grading is based on the systematic review showing that the new intervention is at least as efficacious as the comparator. Efficacy cannot be determined This grading is given if the evidence is insufficient to determine the efficacy of the new intervention. Less efficacious compared to comparator * procedure(s) This grading is based on the systematic review showing that the new intervention is not as efficacious as the comparator. RESEARCH RECOMMENDATIONS It may be recommended that an audit or a controlled (ideally randomised) clinical trial be undertaken in order to strengthen the evidence base. CLINICAL RECOMMENDATIONS Additional recommendations for use of the new intervention in clinical practice may be provided to ensure appropriate use of the procedure by sufficiently qualified/experienced centres and on specific patient types (where appropriate). * A comparator may be the current gold standard procedure, an alternative procedure, a nonsurgical procedure or no treatment (natural history). v

17 Review Group Membership Protocol Surgeon Mr James Edwards Department of Cardiothoracic Surgery Royal Adelaide Hospital North Terrace Adelaide SA 5000 Advisory Surgeon Mr Hugh Paterson Department of Cardiothoracic Surgery Westmead Hospital PO Box 533 Wentworthville NSW 2145 Surgeon from Another Specialty Mr Russell Stitz Unit 24/2 nd Floor Wesley Medical Centre 40 Chasely Street Auchenflower Qld 4066 Invited Member Professor John Horowitz Department of Cardiology The Queen Elizabeth Hospital 28 Woodville Rd Woodville South SA 5011 ASERNIP-S Surgical Director Professor Guy Maddern ASERNIP-S Royal Australasian College of Surgeons PO Box 553 Stepney SA 5069 ASERNIP-S Researchers Dr Susan Hazel Ms Rebecca Morgan Dr Marie Andrew vi

18 1.0 OBJECTIVE The primary objective was to assess the safety and efficacy of intraoperative ablation techniques for the treatment of atrial fibrillation. Intraoperative ablation was compared to other surgical therapeutic techniques or medical management, on the basis of a systematic assessment of the literature. Energy sources included radiofrequency, microwave, cryotherapy, laser and ultrasound. Comparative surgical techniques included the Maze III procedure, isolated cardiac surgery, and medical management. 2.0 INTRODUCTION 2.1 Pathogenesis of atrial fibrillation Atrial fibrillation (AF) is the most common form of cardiac arrhythmia, affecting the atria (upper chambers) of the heart. Electrical impulses are usually transmitted uniformly to all parts of the atria, but in AF the excitation and recovery of the atria are chaotic. As a result the atria fibrillate instead of undergoing effective contraction. Atrial fibrillation is associated with three serious sequelae: 1) an irregular heartbeat, causing patient discomfort and anxiety, 2) loss of synchronous contraction decreases efficient heart pump action, resulting in varying levels of congestive heart failure, and 3) sluggish blood flow in the left atrium, which increases the likelihood of thromboembolism. Standardised nomenclature exists for classifying AF. If a patient has two or more episodes of AF it is considered recurrent, and may be subclassified as paroxysmal, persistent, or permanent (Levy et al. 2003). Paroxysmal AF can last for up to seven days (more typically less than 48 hours), and reverts spontaneously to SR. Persistent AF continues for more than seven days, does not terminate spontaneously, but can be converted to SR by pharmacologic or electrical cardioversion. Permanent AF occurs when the AF does not spontaneously revert to SR, and interventions to try to convert to SR are ineffective, or not attempted. For every decade of age, the incidence of AF doubles, from an incidence of 0.5% at 50 to 59 years of age to almost 9% at 80 to 89 years (Kannel et al. 1998). Based on almost four decades of Framingham Study data, the prevalence of AF is also increasing. In this study, data have been prospectively collected since 1948 from 5209 residents of Framingham, Massachusetts, USA (Benjamin et al. 1998). There were 3.2% of men aged 65 to 84 years with AF in , which had increased to 9.1% by 1987 to 1989 (Kannel et al. 1998). Men have a greater risk of developing AF than women, even after adjustment for age and other predisposing conditions. Hypertension and diabetes are significant independent predictors of AF, while risk of AF is greater in patients with heart failure, valvular heart disease, and myocardial infarction. Atrial fibrillation is an independent predictor of mortality (Maisel and Stevenson, 2003; Wyse et al. 2001), and is associated with a 1.5-fold to 2-fold increase in total and cardiovascular mortality (Benjamin et al. 1998; Kannel et al. 1998). Patients with AF are also at a higher risk of having a stroke. It has been estimated that as many as 15% of all strokes in the US may be related to AF (Rockson and Albers 2004). Additionally, when AF is present following cardiac surgery, it is a major determinant of postoperative stroke (Lahtinen et al. 2004). 1

19 Although there is frequently a co-existence of AF and heart failure, valvular heart disease, and myocardial infarction, surgical treatment of these conditions does not always cure the AF. For example, in 100 consecutive AF patients having mitral valve surgery, only 26% spontaneously reverted to SR (Kalil et al. 1999). Furthermore, AF is not an innocent bystander in patients having cardiac surgery for other reasons, as the presence of preoperative AF in patients who underwent CABG was found to be both a marker for the high-risk patients, and also in itself significantly reduced long-term survival (Quader et al. 2004). The pathophysiology of AF has been extensively studied, but the complex nature of the arrhythmia means many factors remain unknown. Normally contraction of the heart is controlled by electrical signals, originating from the sinus node (natural heart pacemaker) in the upper right atrium. The electrical signal follows natural electrical pathways through the atria, causing them to contract, and passes to the ventricles through the atrioventricular node. However, in AF the electrical circuits in the atria become uncoordinated and chaotic. Permanent AF does not require a stimulus to continue, as the atria are always fibrillating. By contrast when AF is in the early stages or is intermittent (paroxysmal), there may be discrete areas of arrhythmia origin. With improvements in the methods used to measure the electrical activity of the heart, these areas can now be mapped. Haissaguerre et al. (1998) demonstrated that AF often originates from a site within the orifice of one or more of the pulmonary veins. Despite this at least 10% of patients with intermittent AF have a triggering mechanism that does not involve the pulmonary veins (Haisaguerre et al. 1998; Schmitt et al. 2004), and even if the pulmonary veins are ablated, other arrhythmic foci can be unmasked. One of the problems with chronic AF is that the changes in atrial electrophysiology produced by AF, in turn make the atria more vulnerable to AF (Wijffels et al. 1995). During permanent AF, the electrical circuits sustain themselves, with changes in the atria including electrical and anatomical remodelling, such as atrial enlargement (size and thickness) and stretching (Allessie 1999). 2.2 Conventional therapies The following procedures are used in the treatment of AF: Medical management of atrial fibrillation (AF) Rate or rhythm control The medical management of AF focuses on control of either heart rate, or heart rhythm. Recently a randomised, multicentre comparison of rate versus rhythm control study was completed, called the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial. In a total of over 4000 patients, management with rhythm control offered no survival advantage over rate control, and may have a higher risk of adverse drug effects (Wyse et al. 2002). It will be interesting to evaluate the longer-term effect of these findings on the medical management of patients with AF. The antiarrhythmic drugs that are used in patients with AF have been classified into the following groups: Class I: block the sodium channel e.g. lidocaine, quinidine, procainamide. Class II: act indirectly on electrophysiological parameters by blocking beta-adrenergic receptors e.g. propanolol, metoprolol Class III: act by poorly understood mechanisms. These drugs prolong repolarisation, or increase the refractory period (time the heart cannot respond to another electrical signal) in the heart, with little effect on the rate of depolarisation. e.g. amiodarone, sotalol. They are the 2

20 most frequently used antiarrhythmic drugs for the treatment of AF in patients with heart failure (Wolbrette 2003). Class IV: relatively selective AV nodal calcium-channel blockers, e.g. verapamil. Miscellaneous group: e.g. digoxin, adenosine. Antiarrhythmics drugs are associated with significant side effects, for example amiodarone is associated with corneal microdeposits, gastrointestinal changes, and skin photosensitivity and discolouration (Martino et al. 2001). In addition, class III antiarrhythmic agents can have potentially life threatening pro-arrhythmic effects (Wolbrette 2003). Anticoagulant therapy Since AF significantly increases the risk of stroke and other thromboembolisms, patients with AF are routinely treated with long-term anticoagulation. The most commonly used anticoagulants are warfarin and aspirin, with newer agents including low-molecular weight heparin and thrombin inhibitors. A recent Cochrane Review of 14 studies concluded that warfarin, and aspirin to a lesser extent, help reduce the risk of stroke in patients with AF, although warfarin in particular carries an associated risk of haemorrhage (Segal et al. 2003). Specific blood coagulation levels (known as an international normalised ratio or INR) are necessary to significantly reduce both the incidence, and severity and risk of death from stroke (Hylek et al. 2003). However, anticoagulation is contraindicated in people who are at high risk for bleeding including patients : over 75 years of age; with over consumption of alcohol; with hypertension; and having a risk of bleeding for other reasons eg. liver failure (Fitzmaurice, Biann and Lip 2002). In patients with concomitant heart disease, medical management either 1) does not address the underlying heart disease, or 2) is contraindicated in the presence of structural heart disease, such as mitral stenosis, poor ventricular function, or a dilated left atrium. In addition, some patients are intolerant of the medication and/or the remaining physical symptoms associated with AF Electrical cardioversion and pacing of atrial fibrillation (AF) External electrical cardioversion under general anaesthesia is safe and effective as a treatment for AF, with success rates of 65% to 90% (Peters et al. 2002). Unfortunately longer term success rates are lower, with only 47% of patients with serial electrical cardioversion remaining in SR after a median follow-up of seven years (Crijns et al. 1996). Internal cardioversion under sedation, (percutaneous electrode catheters deliver synchronized lowenergy shocks between the right atrium and coronary sinus, or left pulmonary artery) can restore SR in up to 90% of patients when external cardioversion has failed (Schmitt et al. 1996). This type of internal cardioversion has also been developed for use as an implantable atrial defibrillator. Major limitations include frequent recurrences of arrhythmia, and patient intolerance to repeated painful cardioversion shocks (Geller et al. 2003). Atrial pacing can be effective for secondary prevention of AF in some patients, but there are no clear predictors of which patients will benefit the most from this therapy (Packer et al. 2003). Current studies have been limited by variations in the population studies, differences in pacing protocols, and a lack of uniform end points (Saliba 2003) and the use of pacing as a primary therapy for the prevention of recurrent AF have not been validated. 3

21 2.2.3 Catheter ablation of atrial fibrillation (AF) Percutaneous catheters can be used to deliver energy to focal areas of the heart. The energy sources most commonly used have been radiofrequency or cryotherapy. Mapping techniques are essential during the procedure, to diagnose the precise area of the heart initiating the arrhythmia. As many as 90% of patients with AF with one focus can be cured, while only 50% of patients with three or more foci will convert to normal SR (Peters et al. 2002). Complications of catheter ablation can include: systemic embolism, pulmonary vein stenosis, pericardial effusion, cardiac tamponade, and phrenic nerve paralysis (Fuster et al. 2001). Development of both the catheter-based energy sources, and mapping of the electrical activity of the heart, may expand the use of these techniques in the future. While catheter ablation is a curative approach, a last resort for patients with refractory AF is catheter ablation of the atrioventricular node (AV), a palliative approach. Ablation of the AV node means the patient will require a permanent pacemaker (Peters et al. 2002). Long-term survival does not appear to be significantly affected by the ablation of the AV node (Ozcan et al. 2001). Although it is associated with improved quality of life, particularly in the most symptomatic patients (Lee et al. 1998), this technique has obvious disadvantages. The patient has to rely on a pacemaker for life; and the atria continue to fibrillate, meaning the risk of stroke remains Surgical treatment of atrial fibrillation (AF) Cardiac Surgery In the majority of patients who have AF associated with an underlying heart disease, surgical correction of the heart disease will not result in conversion to normal SR. Therefore, surgical techniques designed to treat AF have been developed as an adjunct to the primary cardiac surgical procedure, although they may also be used in isolation. Maze Procedure The original surgical technique devised by James Cox was known as the Maze-I procedure (Cox 1991). The Maze-I procedure involved a maze-like pattern of surgical incisions in the right and left atria, acting as electrically insulating scars to prevent transmission of the arrhythmia. It was modified to become the Maze-II procedure due to late effects on the sinoatrial node affecting control of heart rate (i.e. chronotropic problems), and intra-atrial conduction delays resulting in reduced left atrial contraction. Changes to the incisions in the Maze-II meant exposure for the left atrial incisions was extremely difficult, and the Maze-II did not appear to correct all the problems associated with the Maze-I (Cox et al. 1995a). Therefore the Maze-III was developed, with two minor modifications of the Maze-II: a left atrial incision was moved posteriorly, and the atrial septotomy was also moved posteriorly. This resulted in significant technical and functional improvements, and the Maze-III became the gold standard for the surgical treatment of AF. 4

22 The incisions which make up the Maze-III procedure are outlined in Figure 1. There are incisions to both the right and left atria, and excision of the right and left atrial appendages. In addition, cryotherapy is used to ablate tissue at the: 1) tricuspid end of the T incision in the right atrial free wall, 2) level of the tricuspid annulus, 3) coronary sinus, and 4) end of the mitral valve incision. Figure 1: Diagrammatic representation of Maze-III. The mitral and tricuspid valves are lightly shaded; the incisions hatched; and circles represent the cryoablation sites. RAA: right atrial appendage; LAA: left atrial appendage In a total of 198 patients operated on using the Maze-III procedure, the Kaplan-Meier estimate of freedom from AF was 92% at 14 years follow-up in patients who had a lone procedure (n=112), and 97% at 10 years follow-up in patients who had a concomitant cardiac procedure (n=86) (Prasad et al. 2003). The risk of stroke was also significantly reduced: in 306 patients who had the maze procedure (all variants) between 1987 and 1999, only two perioperative strokes (0.7%) occurred, and in 265 patients followed up to 11.5 years after surgery, only one late minor stroke occurred (Cox et al. 1999). Since 19% of these patients had a thromboembolic event prior to the maze surgery, this result is even more impressive. 5

23 2.2.5 Maze-III challenges The Maze-III procedure has provided excellent clinical results, but in spite of this it has not been widely performed around the world. The major problems with the Maze-III procedure that have prevented greater uptake have been: 1) the high level of technical difficulty, 2) the increased bypass and cross-clamping times, and 3) the significant risk of bleeding from the numerous incisions in the atria. In an effort to make the surgery easier and to reduce operation times and the risk of bleeding, alternative energy sources have been developed to replace the surgical incisions of the Maze- III. 2.3 Intraoperative ablation techniques It has been recently suggested surgery for AF has reached a tipping point (Martin et al. 2003) with the development of new technologies, and increased understanding of the pathophysiology of AF. The energy sources that have been developed for intraoperative ablation are as follows: Cryotherapy Ablation (CA) Cryotherapy ablation (CA) utilizes a probe to deliver a very cold substance to the tissue, causing rapid cooling to -60 o C. The lesions do not damage tissue collagen, hence preserving the myocardial architecture. This minimises thrombus formation, and the risk of perioperative bleeding and perforation of the atrial wall is lower than with a cut-and-sew technique. It is also easy for the surgeon to monitor lesion formation, as the spreading iceball is visible. A current limitation of cryoablation is the rigidity of the probes, reducing flexibility and ease of operation. A newer cryoprobe (SurgiFrost, CryoCath Technologies Inc, Quebec, Canada) uses inert argon gas as a refrigerant, and reaches temperatures as low as -144 o C (Doll et al. 2004). The probe temperature is controlled by the flow and pressure of argon gas, and is adjustable by the surgeon. Radiofrequency Ablation (RFA) Radiofrequency energy destroys myocardial tissue by heating at the electrode-tissue interface, and creating a superficial burn. Radiofrequency energy can be used with either unipolar or bipolar probes. The RF catheters can also vary in whether they are saline-irrigated or dry probes. In saline-irrigated RFA the surface temperature is cooled and direct heating is directed below the surface, resulting in greater lesion depth and increased likelihood of a transmural lesion. The power (Watts), saline irrigation speed (ml per minute) electrode diameter, and application time are the main factors determining the total amount of delivered RF energy. With dry RFA there is a greater risk of surface charring, and a restricted depth of tissue penetration. Microwave Ablation (MWA) Microwave energy causes the vibration and rotation of the dipoles of water molecules, generating heat by friction. Microwave probes create a single linear line of tissue coagulation, and do not cause boiling, charring, smoking, or perforation (Williams et al. 2002). The energy can be transmitted through blood, desiccated tissue, and scars. Factors influencing the penetration depth of the microwave energy include: 1) dielectric properties of the tissue 2) frequency of the microwave energy, and 3) antenna design. Energy delivery times are typically less than one minute, and microwave energy may result in deeper lesions with more even penetration compared to radiofrequency energy. Microwave energy is considered safe to 6