HEALTH TECHNOLOGY ASSESSMENT

HEALTH TECHNOLOGY ASSESSMENT VOLUME 19 ISSUE 65 AUGUST 2015 ISSN 1366-5278 Dua-chamber pacemakers for treating symptomatic bradycardia due to sick sinus syndrome without atrioventricuar bock: a systematic review and economic evauation Steven J Edwards, Charotta Karner, Nicoa Trevor, Victoria Wakefied and Fatima Saih DOI 10.3310/hta19650

Dua-chamber pacemakers for treating symptomatic bradycardia due to sick sinus syndrome without atrioventricuar bock: a systematic review and economic evauation Steven J Edwards, * Charotta Karner, Nicoa Trevor, Victoria Wakefied and Fatima Saih BMJ Technoogy Assessment Group, London, UK *Corresponding author Decared competing interests of authors: none Pubished August 2015 DOI: 10.3310/hta19650 This report shoud be referenced as foows: Edwards SJ, Karner C, Trevor N, Wakefied V, Saih F. Dua-chamber pacemakers for treating symptomatic bradycardia due to sick sinus syndrome without atrioventricuar bock: a systematic review and economic evauation. Heath Techno Assess 2015;19(65). Heath Technoogy Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch ) and Current Contents / Cinica Medicine.

Heath Technoogy Assessment NICE TAR and DAR ISSN 1366-5278 (Print) ISSN 2046-4924 (Onine) Impact factor: 5.116 Heath Technoogy Assessment is indexed in MEDLINE, CINAHL, EMBASE, The Cochrane Library and the ISI Science Citation Index. This journa is a member of and subscribes to the principes of the Committee on Pubication Ethics (COPE) (www.pubicationethics.org/). Editoria contact: nihredit@southampton.ac.uk The fu HTA archive is freey avaiabe to view onine at www.journasibrary.nihr.ac.uk/hta. Print-on-demand copies can be purchased from the report pages of the NIHR Journas Library website: www.journasibrary.nihr.ac.uk Criteria for incusion in the Heath Technoogy Assessment journa Reports are pubished in Heath Technoogy Assessment (HTA) if (1) they have resuted from work for the HTA programme, and (2) they are of a sufficienty high scientific quaity as assessed by the reviewers and editors. Reviews in Heath Technoogy Assessment are termed systematic when the account of the search appraisa and synthesis methods (to minimise biases and random errors) woud, in theory, permit the repication of the review by others. HTA programme The HTA programme, part of the Nationa Institute for Heath Research (NIHR), was set up in 1993. It produces high-quaity research information on the effectiveness, costs and broader impact of heath technoogies for those who use, manage and provide care in the NHS. Heath technoogies are broady defined as a interventions used to promote heath, prevent and treat disease, and improve rehabiitation and ong-term care. The journa is indexed in NHS Evidence via its abstracts incuded in MEDLINE and its Technoogy Assessment Reports inform Nationa Institute for Heath and Care Exceence (NICE) guidance. HTA research is aso an important source of evidence for Nationa Screening Committee (NSC) poicy decisions. For more information about the HTA programme pease visit the website: http://www.nets.nihr.ac.uk/programmes/hta This report The research reported in this issue of the journa was commissioned and funded by the HTA programme on behaf of NICE as project number 13/48/01. The protoco was agreed in November 2013. The assessment report began editoria review in Juy 2014 and was accepted for pubication in October 2014. The authors have been whoy responsibe for a data coection, anaysis and interpretation, and for writing up their work. The HTA editors and pubisher have tried to ensure the accuracy of the authors report and woud ike to thank the reviewers for their constructive comments on the draft document. However, they do not accept iabiity for damages or osses arising from materia pubished in this report. This report presents independent research funded by the Nationa Institute for Heath Research (NIHR). The views and opinions expressed by authors in this pubication are those of the authors and do not necessariy refect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Heath. If there are verbatim quotations incuded in this pubication the views and opinions expressed by the interviewees are those of the interviewees and do not necessariy refect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Heath. Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Pubished by the NIHR Journas Library (www.journasibrary.nihr.ac.uk), produced by Prepress Projects Ltd, Perth, Scotand (www.prepress-projects.co.uk).

Editor-in-Chief of Heath Technoogy Assessment and NIHR Journas Library Professor Tom Waey Director, NIHR Evauation, Trias and Studies and Director of the HTA Programme, UK NIHR Journas Library Editors Professor Ken Stein Chair of HTA Editoria Board and Professor of Pubic Heath, University of Exeter Medica Schoo, UK Professor Andree Le May Chair of NIHR Journas Library Editoria Group (EME, HS&DR, PGfAR, PHR journas) Dr Martin Ashton-Key Consutant in Pubic Heath Medicine/Consutant Advisor, NETSCC, UK Professor Matthias Beck Chair in Pubic Sector Management and Subject Leader (Management Group), Queen s University Management Schoo, Queen s University Befast, UK Professor Aieen Carke Professor of Pubic Heath and Heath Services Research, Warwick Medica Schoo, University of Warwick, UK Dr Tessa Criy Director, Crysta Bue Consuting Ltd, UK Dr Peter Davidson Director of NETSCC, HTA, UK Ms Tara Lamont Scientific Advisor, NETSCC, UK Professor Eaine McCo Director, Newcaste Cinica Trias Unit, Institute of Heath and Society, Newcaste University, UK Professor Wiiam McGuire Professor of Chid Heath, Hu York Medica Schoo, University of York, UK Professor Geoffrey Meads Professor of Heath Sciences Research, Facuty of Education, University of Winchester, UK Professor John Norrie Heath Services Research Unit, University of Aberdeen, UK Professor John Powe Consutant Cinica Adviser, Nationa Institute for Heath and Care Exceence (NICE), UK Professor James Raftery Professor of Heath Technoogy Assessment, Wessex Institute, Facuty of Medicine, University of Southampton, UK Dr Rob Riemsma Reviews Manager, Keijnen Systematic Reviews Ltd, UK Professor Heen Roberts Professor of Chid Heath Research, UCL Institute of Chid Heath, UK Professor Heen Snooks Professor of Heath Services Research, Institute of Life Science, Coege of Medicine, Swansea University, UK Professor Jim Thornton Professor of Obstetrics and Gynaecoogy, Facuty of Medicine and Heath Sciences, University of Nottingham, UK Pease visit the website for a ist of members of the NIHR Journas Library Board: www.journasibrary.nihr.ac.uk/about/editors Editoria contact: nihredit@southampton.ac.uk NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 Abstract Dua-chamber pacemakers for treating symptomatic bradycardia due to sick sinus syndrome without atrioventricuar bock: a systematic review and economic evauation Steven J Edwards, * Charotta Karner, Nicoa Trevor, Victoria Wakefied and Fatima Saih BMJ Technoogy Assessment Group, London, UK *Corresponding author sedwards@bmj.com Background: Bradycardia [resting heart rate beow 60 beats per minute (b.p.m.)] can be caused by conditions affecting the natura pacemakers of the heart, such as sick sinus syndrome (SSS) and atrioventricuar (AV) bocks. Peope suffering from bradycardia may present with papitations, exercise intoerance and fainting. The ony effective treatment for patients suffering from symptomatic bradycardia is impantation of a permanent pacemaker. Objective: To appraise the cinica effectiveness and cost-effectiveness of dua-chamber pacemakers compared with singe-chamber atria pacemakers for treating symptomatic bradycardia in peope with SSS and no evidence of AV bock. Data sources: A databases (MEDLINE, EMBASE, Cochrane Centra Register of Controed Trias, Heath Technoogy Assessment database, NHS Economic Evauations Database) were searched from inception to June 2014. Methods: A systematic review of the cinica and economic iterature was carried out in accordance with the genera principes pubished by the Centre for Reviews and Dissemination. Randomised controed trias (RCTs) evauating dua-chamber and singe-chamber atria pacemakers and economic evauations were incuded. Pairwise meta-anaysis was carried out. A de novo economic mode was deveoped. Resuts: Of 493 references, six RCTs were incuded in the review. The resuts were predominanty infuenced by the argest tria DANPACE. Dua-chamber pacing was associated with a statisticay significant reduction in reoperation [odds ratio (OR) 0.48, 95% confidence interva (CI) 0.36 to 0.63] compared with singe-chamber atria pacing. The difference is primariy because of the deveopment of AV bock requiring upgrade to a dua-chamber device. The risk of paroxysma atria fibriation was aso reduced with dua-chamber pacing compared with singe-chamber atria pacing (OR 0.75, 95% CI 0.59 to 0.96). No statisticay significant difference was found between the pacing modes for mortaity, heart faiure, stroke, chronic atria fibriation or quaity of ife. However, the risk of deveoping heart faiure may vary with age and device. The de novo economic mode shows that dua-chamber pacemakers are more expensive and more effective than singe-chamber atria devices, resuting in a base-case incrementa cost-effectiveness ratio (ICER) of 6506. The ICER remains beow 20,000 in probabiistic sensitivity anaysis, structura sensitivity anaysis and most scenario anayses and one-way sensitivity anayses. The risk of heart faiure may have an impact on the decision to use dua-chamber or singe-chamber atria pacemakers. Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. v

ABSTRACT Resuts from an anaysis based on age (> 75 years or 75 years) and risk of heart faiure indicate that dua-chamber pacemakers dominate singe-chamber atria pacemakers (i.e. are ess expensive and more effective) in oder patients, whereas dua-chamber pacemakers are dominated by (i.e. more expensive and ess effective) singe-chamber atria pacemakers in younger patients. However, these resuts are based on a subgroup anaysis and shoud be treated with caution. Concusions: In patients with SSS without evidence of impaired AV conduction, dua-chamber pacemakers appear to be cost-effective compared with singe-chamber atria pacemakers. The risk of deveoping a compete AV bock and the ack of toos to identify patients at high risk of deveoping the condition argue for the impantation of a dua-chamber pacemaker programmed to minimise unnecessary ventricuar pacing. However, considerations have to be made around the risk of deveoping heart faiure, which may depend on age and device. Study registration: This study is registered as PROSPERO CRD42013006708. Funding: The Nationa Institute for Heath Research Heath Technoogy Assessment programme. vi NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 Contents List of tabes List of figures List of boxes Gossary List of abbreviations Pain Engish summary Scientific summary xi xvii xix xxi xxiii xxv xxvii Chapter 1 Description of heath probem 1 Bradycardia 1 Sick sinus syndrome 1 Atrioventricuar bock 1 Aetioogy and pathoogy 2 Incidence and prevaence 2 Diagnosis 2 Prognosis and impact of heath probem 2 Measurements of disease 3 Current service provision 3 Current guideines 3 Current pacemaker usage in the NHS 4 Description of technoogy under assessment 4 Pacemakers 4 Impant procedure and foow-up 5 Compications 6 Costs associated with intervention 6 Chapter 2 Definition of the decision probem 7 Decision probem 7 Popuation 7 Intervention and comparator 7 Outcomes 7 Overa aims and objectives of assessment 7 Chapter 3 Assessment of cinica effectiveness 9 Methods for reviewing effectiveness 9 Identification of studies 9 Incusion and excusion criteria 9 Data abstraction strategy 10 Critica appraisa strategy 10 Methods of data synthesis 10 Stakehoders submissions 11 Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. vii

CONTENTS Resuts 11 Quantity and quaity of research avaiabe 11 Randomised controed tria characteristics 12 Assessment of effectiveness 21 Genera we-being and functiona status 35 Mutidimensiona measures 36 Discussion 37 Summary of quantity and quaity of research avaiabe 37 Summary of assessment of cinica effectiveness 38 Generaisabiity of resuts 39 Concusions 39 Chapter 4 Assessment of cost-effectiveness 41 Systematic review of existing cost-effectiveness evidence 41 Narrative summary of incuded UK economic evauations 44 Narrative summary of incuded non-uk economic evauations 54 Narrative summary of incuded costing studies 60 Summary and concusions of avaiabe cost-effectiveness evidence 61 Independent economic assessment 62 Overview 62 Comparison to scope 62 Popuation 62 Interventions and comparators 63 Mode structure 63 Overview of mode parameters, sources and assumptions 65 Treatment effectiveness 69 Mortaity 71 Adverse events 73 Heath-reated quaity-of-ife data 73 Narrative summary of incuded heath-reated quaity-of-ife studies 76 Quaity-of-ife data seected for the economic mode 80 Costs 81 Approach to uncertainty 85 Base case resuts 87 Resuts of the sensitivity anaysis 88 Summary of the Technoogy Assessment Group s de novo economic evauation 94 Discussion of the Technoogy Assessment Group s de novo economic evauation 97 Chapter 5 Assessment of factors reevant to the NHS and other parties 99 End-of-ife criteria 99 Chapter 6 Discussion 101 Statement of principa findings 103 Strengths and imitations of the assessment 104 Strengths 104 Weaknesses 104 Uncertainties 104 Other reevant factors 104 Chapter 7 Concusions 105 Impications for service provision 105 Suggested research priorities 105 viii NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 Acknowedgements 107 References 109 Appendix 1 Literature search strategies 119 Appendix 2 Data abstraction 135 Appendix 3 Quaity assessment 177 Appendix 4 Tabe of excuded studies 199 Appendix 5 One-way sensitivity anaysis 203 Appendix 6 Cacuation of ong-term care costs associated with heart faiure 205 Appendix 7 Monthy probabiity of reoperation by treatment arm 207 Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ix

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 List of tabes TABLE 1 Definition of generic antibradycardia pacing codes (NASPE/BPEG) 4 TABLE 2 Incusion criteria, based on the decision probem, for studies evauating cinica effectiveness 10 TABLE 3 Summary of studies incuded in the review of the cinica effectiveness iterature 13 TABLE 4 Dua-chamber pacemaker programming 15 TABLE 5 Patient baseine characteristics of incuded parae RCTs 16 TABLE 6 Patient baseine characteristics of incuded crossover RCTs 17 TABLE 7 Outcomes of interest reported in incuded trias 18 TABLE 8 Summary of risk of bias assessments of parae RCTs incuded in review 19 TABLE 9 Summary of risk of bias assessments of crossover RCTs incuded in review 20 TABLE 10 Percentages of atria pacing and VP 23 TABLE 11 Resuts of a-cause mortaity by tria arm in Niesen et a. 26 TABLE 12 Resuts of reported measures of HF 27 TABLE 13 Resuts of anaysis and sensitivity anaysis of AF in Niesen et a. 28 TABLE 14 Resuts of anaysis of chronic and paroxysma AF based on data from the DANPACE tria (effect estimate generated by TAG) 28 TABLE 15 Resuts of unadjusted and adjusted anaysis of chronic and paroxysma AF in the DANPACE tria 29 TABLE 16 PQ-interva at baseine in the DANPACE tria and Niesen et a. 29 TABLE 17 Resuts of stroke by tria arm in Niesen et a. 33 TABLE 18 Resuts of reported measures of exercise capacity 33 TABLE 19 Resuts of unadjusted and adjusted anaysis of reoperations in the DANPACE tria 34 TABLE 20 Resuts per indication for reoperation in the DANPACE tria 34 TABLE 21 Compications at impantation in Abertsen et a. 34 TABLE 22 Resuts for genera we-being: VAS 35 Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xi

LIST OF TABLES TABLE 23 Resuts for mutidimensiona QoL measures 36 TABLE 24 Incusion and excusion criteria for the systematic review of economic evauations and costing studies 42 TABLE 25 Summary of outcome data used in NICE s TA88 48 TABLE 26 Summary of costs used in NICE s TA88 49 TABLE 27 Summary of utiity vaues used in NICE s TA88 49 TABLE 28 Summary of outcome data used in anaysis by Sutton et a. (data adapted from tabe 3; p. 577) 52 TABLE 29 Cost and sources used to inform cost benefit anaysis by Sutton et a. 53 TABLE 30 Cost-effectiveness resuts of Oddershede et a. 55 TABLE 31 Summary of cost-effectiveness resuts (physioogica pacing vs. VP) presented by O Brien et a. 57 TABLE 32 Costs used in the anayses carried out by Rinfret et a. (data adapted from tabe 1; p. 166) 58 TABLE 33 Summary of resuts presented by Ray et a. 60 TABLE 34 Comparison of the TAG s anaysis with the NICE scope 62 TABLE 35 Reasons for reoperation in patients enroed in the DANPACE tria (data adapted from tabe 3 of Niesen et a.) 65 TABLE 36 Summary of parameters and accompanying distributions used to inform the TAG s economic mode 66 TABLE 37 Probabiity of cinica sequeae derived from the DANPACE tria 70 TABLE 38 A-cause mortaity data used in the TAG s economic mode 71 TABLE 39 Probabiity of fata stroke based on data presented by Carter et a. 72 TABLE 40 Probabiity of fata event used in the TAG s base-case economic evauation 72 TABLE 41 Incusion and excusion criteria for the systematic review of HRQoL evidence 74 TABLE 42 Summary of incuded HRQoL studies 75 TABLE 43 Summary of resuts reported by Feischmann et a. 76 TABLE 44 Age- and sex-adjusted TTO utiities presented by Feischmann et a. by pacing mode 77 xii NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 TABLE 45 Baseine, pre-crossover and post-crossover utiity data presented by Link et a. 78 TABLE 46 Change in measures of QoL observed in the MOST 78 TABLE 47 Summary of HRQoL estimates presented by Lopez-Jimenez et a. 79 TABLE 48 Heath state utiity vaues used in the base case mode 80 TABLE 49 Summary of unit costs used to inform procedure costs within the TAG s economic mode 81 TABLE 50 Summary of unit costs used to inform HF and stroke episode costs within the TAG s economic mode 82 TABLE 51 Prevaence of CVD, by sex and age, UK 2007 to 2010 (data adapted from tabe 2.20, Townsend et a.) 83 TABLE 52 Summary of unit costs used to inform ong-term costs of stroke used within the TAG s economic mode 84 TABLE 53 Cacuation of per person cost of primary care and hospitaisation for peope with AF based on costs reported by Stewart et a. 84 TABLE 54 Cacuation of monthy cost of ora anticoaguation used in the base-case mode 85 TABLE 55 Probabiity distributions used for mode parameters 85 TABLE 56 Scenario anayses carried out by the TAG 87 TABLE 57 Base-case resuts 88 TABLE 58 Structura sensitivity anaysis using a 5-year time horizon 89 TABLE 59 Structura sensitivity anaysis using Kapan Meier data as the basis for reoperation 91 TABLE 60 Scenario anayses using aternative sources for parameter estimates or testing assumptions used within the base case 92 TABLE 61 Summary of cumuative effect of a sensitivity anayses found to increase the ICER from the base case 94 TABLE 62 Additiona scenario anayses investigating the impact of HF compared with the base case resuts 95 TABLE 63 Summary of resuts comparing the cost-effectiveness of dua-chamber pacemakers with singe-chamber atria pacemakers for treating symptomatic bradycardia due to SSS without AV bock 95 Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xiii

LIST OF TABLES TABLE 64 MEDLINE In-Process & Other Non-Indexed Citations (via Ovid) and MEDLINE (via Ovid) searched from 1946 to present (initiay searched 6 January 2014 and updated 12 May 2014) 119 TABLE 65 EMBASE (via Ovid) searched from inception to present (initiay searched 6 January 2014 and updated 12 May 2014) 121 TABLE 66 The Cochrane Library searched from inception to present (initiay searched 7 January 2014 and updated 15 May 2014) 123 TABLE 67 MEDLINE (via Ovid) In-Process & Other Non-Indexed Citations and MEDLINE (via Ovid) searched from 1946 to present (initiay searched 16 December 2013 and updated 6 June 2014) 124 TABLE 68 EMBASE (via Ovid) searched from 1974 to 3 December 2013 (initiay searched 16 December 2013 and updated 6 June 2014) 126 TABLE 69 MEDLINE (via Ovid) In-Process & Other Non-Indexed Citations and MEDLINE (via Ovid) 1946 to present (initiay searched 17 December 2013 and updated 6 June 2014) 128 TABLE 70 EMBASE (via Ovid) 1974 to 4 December 2013 (initiay searched 17 December 2013 and updated 6 June 2014) 130 TABLE 71 Abertsen et a. data extraction for cinica effectiveness 135 TABLE 72 The DANPACE tria, data extraction for cinica effectiveness 138 TABLE 73 Niesen et a. data extraction for cinica effectiveness 142 TABLE 74 Gaik et a. data extraction for cinica effectiveness 145 TABLE 75 Lau et a. data extraction for cinica effectiveness 147 TABLE 76 Schwaab et a. data extraction for cinica effectiveness 149 TABLE 77 Caro et a. data extraction for economic evauations 152 TABLE 78 Castenuovo et a. data extraction for economic evauations 153 TABLE 79 Carke et a. data extraction for economic evauations 154 TABLE 80 Deniz et a. data extraction for economic evauations 155 TABLE 81 Mahoney data extraction for economic evauations 156 TABLE 82 O Brien et a. data extraction for economic evauations 157 TABLE 83 Oddershede et a. data extraction for economic evauations 157 TABLE 84 Osman et a. data extraction for economic evauations 159 TABLE 85 Ray et a. data extraction for economic evauations 160 xiv NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 TABLE 86 Rinfret et a. data extraction for economic evauations 161 TABLE 87 Sutton et a. data extraction for economic evauations 162 TABLE 88 Wiegand et a. data extraction for economic evauations 164 TABLE 89 Summary of studies incuded in the review that report HRQoL data 165 TABLE 90 Quaity assessment of Abertsen et a. 177 TABLE 91 Quaity assessment of the DANPACE tria 178 TABLE 92 Quaity assessment of Niesen et a. 179 TABLE 93 Quaity assessment of Gaik et a. 180 TABLE 94 Quaity assessment of Lau et a. 180 TABLE 95 Quaity assessment of Schwaab et a. 181 TABLE 96 The NICE reference case assessment of Caro et a. 182 TABLE 97 The NICE reference case assessment of Castenuovo et a. 183 TABLE 98 The NICE reference case assessment of Carke et a. 184 TABLE 99 The NICE reference case assessment of Deniz et a. 185 TABLE 100 The NICE reference case assessment of Mahoney 186 TABLE 101 The NICE reference case assessment of O Brien et a. 187 TABLE 102 The NICE reference case assessment of Osman et a. 188 TABLE 103 The NICE reference case assessment of Ray et a. 189 TABLE 104 The NICE reference case assessment of Rinfret et a. 190 TABLE 105 The NICE reference case assessment of Sutton et a. 191 TABLE 106 The NICE reference case assessment of Wiegand et a. 192 TABLE 107 The Phiips checkist assessment of Caro et a. 193 TABLE 108 Phiips checkist assessment of Castenuovo et a. 194 TABLE 109 Phiips checkist assessment of Deniz et a. 195 TABLE 110 Phiips checkist assessment of Rinfret et a. 196 TABLE 111 Phiips checkist assessment of Sutton et a. 197 TABLE 112 Excuded studies from the cinica effectiveness review 199 Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xv

LIST OF TABLES TABLE 113 Excuded studies from the economic evauations review 201 TABLE 114 Excuded studies from the HRQoL review 202 TABLE 115 Resuts of the OWSA 203 TABLE 116 Hospita and community heath services infation indices 206 TABLE 117 Monthy probabiity of reoperation by treatment arm 207 xvi NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 List of figures FIGURE 1 Preferred Reporting Items for Systematic Reviews and Meta-Anayses (PRISMA) fow diagram for the cinica effectiveness review 12 FIGURE 2 Resuts from anaysis of change in pacing mode 22 FIGURE 3 Resuts from anaysis of a-cause mortaity 25 FIGURE 4 Subgroup anayses of a-cause mortaity in the DANPACE tria 26 FIGURE 5 Subgroup anayses of paroxysma AF in the DANPACE tria 30 FIGURE 6 Resuts from anaysis of stroke 32 FIGURE 7 Identified economic evauation and costing studies 42 FIGURE 8 Overview of mode structure used in NICE s TA88 46 FIGURE 9 Overview of TAG s economic mode structure 64 FIGURE 10 Identified HRQoL studies, December 2013 and June 2014 searches 74 FIGURE 11 Time-to-event curve for freedom from reoperation from the DANPACE tria 86 FIGURE 12 Scatterpot of cost-effectiveness resuts for dua-chamber pacemakers vs. singe-chamber atria pacemakers using a time horizon of 10 years (dark-green ine indicates threshod of 20,000 per additiona QALY, ight-green ine indicates threshod of 30,000 per additiona QALY) 88 FIGURE 13 Cost-effectiveness acceptabiity curve for dua-chamber pacemakers vs. singe-chamber atria pacemakers using a time horizon of 10 years 89 FIGURE 14 Scatterpot of cost-effectiveness resuts for dua-chamber pacemakers vs. singe-chamber atria pacemakers using a time horizon of 5 years (dark-green ine indicates threshod of 20,000 per additiona QALY, ight-green ine indicates threshod of 30,000 per additiona QALY) 90 FIGURE 15 Cost-effectiveness acceptabiity curve for dua-chamber pacemakers vs. singe-chamber atria pacemakers using a time horizon of 5 years 90 FIGURE 16 Tornado diagram of parameters to which the cost-effectiveness of dua-chamber pacemakers vs. singe-chamber atria pacemakers is most sensitive 91 FIGURE 17 Time trends in UK prevaence data, Townsend et a. 205 FIGURE 18 Extrapoation of previous 4 years of CVD prevaence data 205 Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xvii

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 List of boxes BOX 1 Summary of studies incuded foowing review of the pubished economic iterature 43 BOX 2 Unpanned overnight hospita stays and compications foowing same-day new pacemaker impantation as reported by Osman et a. 51 BOX 3 Heath Technoogy Assessment database (HTA, Cochrane) 127 BOX 4 NHS Economic Evauations Database (NHS EED, Cochrane) 127 BOX 5 Heath Technoogy Assessment database (HTA, Cochrane) 132 BOX 6 NHS Economic Evauations Database (NHS EED, Cochrane) 133 Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xix

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 Gossary Atria fibriation Atria fibriation/futter is a heart rhythm disorder (arrhythmia). It usuay invoves a rapid heart rate, in which the upper heart chambers (atria) are stimuated to contract in a very disorganised and abnorma manner. Atrioventricuar bock Defective conduction at the atrioventricuar node. Bradycardia Sow heart rate. Bradycardia may become pathoogica with decreased heart output. Symptoms of bradycardia may be specific (syncope) or chronic and non-specific (dizziness, fatigue and heart faiure). Cost-effectiveness acceptabiity curve A graphica representation of the probabiity of an intervention being cost-effective over a range of monetary vaues for society s wiingness to pay for an additiona unit of heath gain. Incrementa cost-effectiveness ratio An expression of the additiona cost of heath gain associated with an intervention reative to an appropriate comparator. Expressed as the difference in mean costs (reative to the comparator) divided by the difference in mean effects. Sometimes expressed with confidence intervas. Internationa normaised ratio A measure of the degree of anticoaguation achieved using warfarin (intrinsic heart rate = 1.0 is equivaent to no anticoaguation). Kapan Meier curves Aso caed product imit method. A non-parametric method of compiing ife or surviva tabes, deveoped by Kapan and Meier in 1958. It combines cacuated probabiities of surviva and estimates to aow for censored observations, which are assumed to occur randomy. The intervas are defined as ending each time an event (e.g. death, withdrawa) occurs and are therefore unequa. New York Heart Association functiona scae A scae used to cassify patients cardiac disease according to the severity of their symptoms into four categories based on the imitations on physica activity, with cass I patients having no imitation of physica activity and cass IV patients having symptoms of heart faiure at rest and inabiity to carry out any physica activity without discomfort. Physioogica pacing Pacing mode that reproduces the natura sequence of atrioventricuar contractions. This is achieved with the preservation of atrioventricuar synchrony and rate response. Quaity-adjusted ife-year A term originay deveoped in cancer studies to baance poor quaity of ife (possiby with ong ife expectancy) with good quaity of ife (possiby with short ife expectancy). Quaity of ife A concept incorporating a the factors that might impact on an individua s ife, incuding factors such as the absence of disease or infirmity as we as other factors which might affect physica, menta and socia we-being. Rate moduation/rate responsiveness A feature of pacemakers in which the pacing rate varies according to the physica demands of the patient. Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxi

GLOSSARY Sick sinus syndrome This term covers a spectrum of arrhythmias with different underying mechanisms, manifested as bradycardia, tachycardia (fast heart rate) or a mix of the two, but aso as chronotropic incompetence (the inabiity of the heart to increase its rate appropriatey with increased activity, eading to exercise intoerance). Tachyarrhythmia Abnormay fast heart rhythm. Tachycardia Increased heart rate. xxii NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 List of abbreviations 6MWT 6-minute waking test IHR intrinsic heart rate 12-GHQ ABHI ACC AF AHA AV BMI BNF BPEG b.p.m. 12-Item Genera Heath Questionnaire Association of British Heathcare Industries American Coege of Cardioogy atria fibriation American Heart Association atrioventricuar body mass index British Nationa Formuary British Pacing and Eectrophysioogy Group beats per minute IPD kpm LV LVEF MeSH MOST MTA NASPE NHS EED NICE individua patient data kiopond metre eft ventrice eft ventricuar ejection fraction medica subject heading MOde Seection Tria mutipe technoogy appraisa The North American Society of Pacing and Eectrophysioogy NHS Economic Evauations Database Nationa Institute for Heath and Care Exceence BTS bradycardia tachycardia syndrome NOAC nove ora anticoaguant CHF congestive heart faiure NYHA New York Heart Association CI confidence interva OR odds ratio CRD CTOPP CVD ECG EED EQ-5D ESC GP HF HR HRG HRQoL HTA ICER Centre for Reviews and Dissemination Canadian Tria of Physioogica Pacing cardiovascuar disease eectrocardiography Economic Evauations Database European Quaity of Life-5 Dimensions European Society of Cardioogy genera practitioner heart faiure hazard ratio Heathcare Resource Group heath-reated quaity of ife Heath Technoogy Assessment incrementa cost-effectiveness ratio OWSA OXVASC PASE PSS QALY QoL RCT SA SAS SD SE SF-36 SND SSI SSS one-way sensitivity anaysis OXford VASCuar study Pacemaker Seection in the Edery study Persona Socia Services quaity-adjusted ife-year quaity of ife randomised controed tria sinoatria Specific Activity Scae standard deviation standard error Short Form Questionnaire-36 items sinus node dysfunction somatic symptoms inventory sick sinus syndrome Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxiii

LIST OF ABBREVIATIONS TA technoogy appraisa VAS visua anaogue scae TAG Technoogy Assessment Group VP ventricuar pacing TTO time trade-off WTP wiingness to pay xxiv NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 Pain Engish summary Bradycardia means that the heart rate is unusuay sow, beating at fewer than 60 beats per minute. Peope with bradycardia may have troube exercising, have irreguar or pounding heart beats or may even faint. Bradycardia can be caused by diseases that stop the heart s natura pacemaker working propery, caed sick sinus syndrome (SSS) and atrioventricuar (AV) bock. The ony effective treatment for peope with bradycardia is having an operation to fit an artificia pacemaker. Artificia pacemakers are connected to one or two chambers of the heart. After impantation, it might eventuay be necessary to have a second operation to change the pacemaker s battery or repace the pacemaker. The risk of compications of surgery is higher with second surgery than with initia impantation. The aim of this project was to ook at the benefits and harms of dua-chamber pacemakers compared with singe-chamber pacemakers for peope with bradycardia caused by SSS but without AV bock. This project aso ooks at whether or not these pacemakers are ikey to be considered good vaue for money for the NHS. Based on the best avaiabe evidence, it is ikey that peope with a dua-chamber pacemaker need fewer reoperations and have fewer unusua heart beats than peope with singe-chamber pacemaker. There may aso be an important difference in how peope s hearts worsen at pumping bood around the body at the right pressure, which seems to vary with age and pacemaker type. The economic evauation shows that dua-chamber pacemakers are more expensive and more effective than singe-chamber atria pacemakers. Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxv

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 Scientific summary Background Bradycardia is defined as a resting heart rate beow 60 beats per minute (b.p.m.). A sow heart rate is common and is not necessariy associated with a physica iness. However, conditions affecting the eectrica conduction system of the heart ead to pathoogica bradycardia. Peope suffering from symptomatic bradycardia may present with dizziness, confusion, papitations, breathessness, exercise intoerance and syncope (backout or fainting). Pathoogica bradycardia has many causes, incuding sick sinus syndrome (SSS), which might or might not be associated with comorbid atrioventricuar (AV) bock; AV bock can occur independenty from SSS. SSS is caused by dysfunction of the sinus node, the heart s natura pacemaker. SSS encompasses a spectrum of arrhythmias with different underying mechanisms. The ony effective treatment for patients suffering from symptoms is impantation of a permanent pacemaker. Pacemaker impantation does not cure or affect the prognosis of SSS; thus, pacemakers are impanted with the aim of aeviating symptoms and improving the patient s quaity of ife (QoL). During 2012 13 in Engand, more than 20,000 peope had a singe- or a dua-chamber pacemaker impanted. SSS was the fourth most prevaent primary diagnosis (9.5%) necessitating impantation of a singe- or a dua-chamber pacemaker. Reoperation after impantation may be required because of a compication, such as ead dispacement or infection, but it can aso be because of a need for pacemaker upgrade (singe to dua) or the end of battery ife. The compication rate associated with a reoperation is substantiay higher than that associated with initia impantation. Current guidance is that peope with SSS in whom, after fu evauation, there is no evidence of impaired AV bock receive a singe-chamber atria pacemaker. However, it is uncear if there is any difference between singe-chamber atria pacing and dua-chamber pacing in outcomes for peope with SSS and no AV bock. Objectives The aim of this review was to appraise the cinica effectiveness and cost-effectiveness of dua-chamber pacemakers compared with singe-chamber atria pacemakers for treating symptomatic bradycardia in peope with SSS in whom there is no evidence of impaired AV conduction. This report is a partia update of the Nationa Institute for Heath and Care Exceence (NICE) s technoogy appraisa (TA) number 88 in reation to this indication [Nationa Institute for Heath and Care Exceence (NICE). Dua-Chamber Pacemakers for Symptomatic Bradycardia due to Sick Sinus Syndrome and/or Atrioventricuar Bock. London: NICE; 2005. URL: www.nice.org.uk/guidance/ta88/documents (accessed June 2014).] Methods Cinica effectiveness review methods Evidence for the cinica effectiveness of dua-chamber and singe-chamber atria pacemakers was identified by searching mutipe eectronic bibiographic databases from inception to January 2014, and an updated search was run in May 2014. The databases searched were MEDLINE (via Ovid), EMBASE (via Ovid), Heath Technoogy Assessment (HTA) database and NHS Economic Evauations Database (NHS EED). Search terms incuded medica subject headings and text terms for pacemakers. Search terms for the condition (i.e. bradycardia and SSS) were not incuded. Ony randomised controed trias (RCTs) were considered for incusion in the review. Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxvii

SCIENTIFIC SUMMARY Potentiay reevant fu pubications were assessed independenty by two reviewers for incusion or excusion against pre-specified criteria. The quaity of the cinica effectiveness data was assessed independenty by two reviewers in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and was recorded using the Cochrane Risk of Bias Too. Randomised controed trias evauating permanent impantabe dua-chamber pacemakers programmed to dua-chamber pacing against permanent impantabe pacemakers (singe or dua) programmed to atria pacing in peope with symptomatic bradycardia due to SSS without AV bock were eigibe for incusion in the review. Outcome measures of interest were a-cause mortaity, heart faiure (HF), atria fibriation (AF), stroke, exercise capacity, cognitive function, requirement for further surgery, adverse effects of pacemaker impantation, and heath-reated quaity of ife (HRQoL). Review methods Extracted data and quaity assessments for each study were presented in structured tabes and as a narrative summary. Where sufficient comparabe data were avaiabe for each outcome measure, pairwise meta-anaysis was performed. Methods of anaysis/synthesis Treatment effects were anaysed as odds ratios (ORs) for dichotomous data and as the mean difference for continuous outcomes. Cost-effectiveness systematic review Mutipe eectronic databases were searched: MEDLINE (via Ovid), EMBASE (via Ovid), HTA database and NHS EED. In addition, experts in the fied were contacted with a request for detais of reevant pubished and unpubished studies of which they might have knowedge. The website of NICE was searched for recenty pubished TAs in pacing that had not aready been identified via database searches. Reference ists of key identified studies were reviewed for additiona potentiay reevant studies. Search strategies for MEDLINE and EMBASE incuded terms for popuation (pacing) and interventions (dua-chamber pacemakers) of interest and reevant terms to capture economic evauations/costing studies. The search strategy for HTA and NHS EED combined terms for the target condition (AV bock and SSS) with terms for the intervention (pacemaker). A databases were searched from inception. The searches were carried out in December 2013 and updated in June 2014. No restrictions on anguage or setting were appied. The tites and abstracts of papers identified through the searches were independenty assessed for incusion by two heath economists. Resuts were described narrativey, and quaity assessed against the NICE reference case, and Phiips et a. s checkist [Phiips Z, Ginney L, Scupher M, Caxton K, Goder S, Riemsma R, et a. Review of guideines for good practice in decision-anaytic modeing in heath technoogy assessment. Heath Techno Assess 2004;8(36)]. A Markov cohort mode was deveoped. The mode structure was derived from that used in a previous HTA that evauated the cost-effectiveness of dua-chamber pacemakers versus singe-chamber atria pacemakers in peope with SSS and no AV bock (NICE TA88). The mode uses a monthy cyce ength with a time horizon of 10 years. Anayses were undertaken from the perspective of the NHS and Persona Socia Services, with costs and benefits discounted at 3.5% per annum. Mode outputs are reported as incrementa cost-effectiveness ratios (ICERs). xxviii NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19650 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 65 Resuts Cinica effectiveness resuts The systematic review of cinica effectiveness identified six RCTs of reevance to this review. Three studies were of a parae-group design and three were crossover trias. The parae RCTs a compared device against device, whereas the crossover trias evauated variation in pacing mode programme. The quaity of the trias was generay good, with appropriate tria design and methodoogy. The crossover trias incuded in this review invoved a sma number of peope (12 21 peope) and were of short duration (up to 3 months), which imited the outcomes that coud be captured and the power to detect any differences between the pacing modes. The parae-group RCTs were arger (50 1415 patients) and had onger foow-up (from 1 to 5.4 years mean foow-up) than the crossover trias. There was imited opportunity to combine the resuts using meta-anaysis from the six RCTs identified from the pubished iterature. When this was possibe, the resuts tended to foow the argest tria (DANPACE). Mortaity Meta-anaysis of two parae RCTs identified no statisticay significant difference between dua-chamber and singe-chamber atria pacing in a-cause mortaity [OR 0.97, 95% confidence interva (CI) 0.67 to 1.41]. However, the meta-anaysis of mortaity is unikey to have sufficient power to identify a statisticay significant difference. Heart faiure There was variation across the three parae RCTs in the measures used to capture the incidence of HF. A three RCTs found no statisticay significant difference between dua-chamber pacing and singe-chamber atria pacing in risk of HF. Subgroup anaysis of data from the argest tria (DANPACE) showed that younger patients ( 75 years) receiving singe-chamber atria pacing were at a ower risk of deveoping HF than those receiving dua-chamber pacing [hazard ratio (HR) 0.72, 95% CI 0.53 to 1.00]. By contrast, oder peope (> 75 years) with singe-chamber atria pacing were at a higher risk of HF than those with dua-chamber pacing (HR 1.34, 95% CI 1.00 to 1.80). Atria fibriation Two RCTs reported conficting resuts for AF. In one RCT (177 peope), dua-chamber pacing was associated with a statisticay significant increase in AF (OR 3.19, 95% CI 1.05 to 9.67), whereas, in a second RCT (1415 peope; DANPACE), dua-chamber pacing was associated with a statisticay significant decrease in paroxysma AF (OR 0.75, 95% CI 0.59 to 0.96) but no statisticay significant difference in chronic AF. There may be mutipe underying factors eading to disparity in the resuts reported by two RCTs, incuding differences in baseine characteristics and differences in interventions (programming of AV deay). Of the identified studies, the argest RCT (DANPACE) was deemed to be more robust; thus, it is reasonabe to have more confidence in this RCT than the smaer study. Stroke Meta-anaysis of data from two RCTs indicates no statisticay significant difference between dua-chamber pacing and singe-chamber atria pacing in the risk of stroke (OR 0.93, 95% CI 0.60 to 1.45). Exercise capacity Limited data (reativey sma number of patients with imited foow-up) were avaiabe on exercise capacity. Singe-chamber atria pacing was associated with sma, but statisticay significant, improvements in exercise capacity in one parae and one crossover tria. However, a second short-term crossover tria identified no statisticay significant difference between devices in improvement in exercise capacity. Further surgery In the arge RCT (DANPACE), reoperation was necessary in significanty fewer peope with dua-chamber pacing than with singe-chamber atria pacing (OR 0.48, 95% CI 0.36 to 0.63). Queen s Printer and Controer of HMSO 2015. This work was produced by Edwards et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxix