HEALTH TECHNOLOGY ASSESSMENT

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1 HEALTH TECHNOLOGY ASSESSMENT VOLUME 18 ISSUE 10 FEBRUARY 2014 ISSN Enhancements to angiopasty for periphera arteria occusive disease: systematic review, cost-effectiveness assessment and expected vaue of information anaysis Emma L Simpson, Benjamin Kearns, Matthew D Stevenson, Anna J Cantre, Chris Littewood and Jonathan A Michaes DOI /hta18100

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3 Enhancements to angiopasty for periphera arteria occusive disease: systematic review, cost-effectiveness assessment and expected vaue of information anaysis Emma L Simpson, Benjamin Kearns, Matthew D Stevenson, Anna J Cantre, Chris Littewood and Jonathan A Michaes* The University of Sheffied, Schoo of Heath and Reated Research (ScHARR), Sheffied, UK *Corresponding author Decared competing interests of authors: none Pubished February 2014 DOI: /hta18100 This report shoud be referenced as foows: Simpson EL, Kearns B, Stevenson MD, Cantre AJ, Littewood C, Michaes JA. Enhancements to angiopasty for periphera arteria occusive disease: systematic review, cost-effectiveness assessment and expected vaue of information anaysis. Heath Techno Assess 2014;18(10). Heath Technoogy Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch ) and Current Contents / Cinica Medicine.

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5 Heath Technoogy Assessment HTA/HTA TAR ISSN (Print) ISSN (Onine) Five-year impact factor: Heath Technoogy Assessment is indexed in MEDLINE, CINAHL, EMBASE, The Cochrane Library and the ISI Science Citation Index and is assessed for incusion in the Database of Abstracts of Reviews of Effects. This journa is a member of and subscribes to the principes of the Committee on Pubication Ethics (COPE) ( Editoria contact: nihredit@southampton.ac.uk The fu HTA archive is freey avaiabe to view onine at Print-on-demand copies can be purchased from the report pages of the NIHR Journas Library website: 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 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: This report The research reported in this issue of the journa was funded by the HTA programme as project number 09/116/01. The contractua start date was in January The draft report began editoria review in Juy 2012 and was accepted for pubication in December 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 This work was produced by Simpson 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 ( produced by Prepress Projects Ltd, Perth, Scotand (

6 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 Heath Sciences, 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 Honorary Professor, Business Schoo, Winchester University and Medica Schoo, University of Warwick, UK Professor Jane Norman Professor of Materna and Feta Heath, University of Edinburgh, 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 Professoria Research Associate, University Coege London, UK Professor Heen Snooks Professor of Heath Services Research, Institute of Life Science, Coege of Medicine, Swansea University, UK Pease visit the website for a ist of members of the NIHR Journas Library Board: Editoria contact: nihredit@southampton.ac.uk NIHR Journas Library

7 DOI: /hta18100 HEALTH TECHNOLOGY ASSESSMENT 2014 VOL. 18 NO. 10 Abstract Enhancements to angiopasty for periphera arteria occusive disease: systematic review, cost-effectiveness assessment and expected vaue of information anaysis Emma L Simpson, Benjamin Kearns, Matthew D Stevenson, Anna J Cantre, Chris Littewood and Jonathan A Michaes* The University of Sheffied, Schoo of Heath and Reated Research (ScHARR), Sheffied, UK *Corresponding author Background: There have been rapid technoogica deveopments aimed at improving short- and ong-term resuts of percutaneous transumina baoon angiopasty (PTA) in periphera arteria occusive disease (PAD). Objectives: To assess current cinica effectiveness and cost-effectiveness evidence of additiona techniques to standard PTA for PAD, deveop a heath economic mode to assess cost-effectiveness and to identify where further research is needed. Data sources: Reevant eectronic databases, incuding MEDLINE, EMBASE and The Cochrane Library were searched from inception to 2011, between May and October Methods: Systematic reviews were conducted of cinica effectiveness and cost-effectiveness. The popuation was participants with symptomatic PAD undergoing endovascuar treatment for disease dista to the inguina igament. Interventions were modifications of and adjuncts to PTA in the periphera circuation, compared with conventiona PTA. Outcomes incuded measures of cinica effectiveness and costs. Data were extracted from randomised controed trias (RCTs), which were quaity assessed using standard criteria. Where appropriate, meta-anayses using fixed- and random-effects methods produced reative risks (RRs). A discrete-event simuation mode was deveoped to assess the reative cost-effectiveness of the interventions from a NHS perspective over a ifetime. The patient popuations of intermittent caudication (IC) and critica imb ischaemia (CLI) were modeed separatey. Univariate and probabiistic sensitivity anayses were undertaken. Resuts: In tota, 40 RCTs were incuded, many of which had sma sampe sizes. Significanty reduced restenosis rates were shown in meta-anayses of sef-expanding stents (SES) {RR 0.67 [95% confidence interva (CI) 0.52 to 0.87]}, endovascuar brachytherapy (EVBT) [RR 0.63 (95% CI 0.48 to 0.83)] at 12 months and drug-coated baoons (DCBs) at 6 months [RR 0.40 (95% CI 0.23 to 0.69)], and singe studies of stent-graft or drug-euting stent (DES), compared with PTA; a singe study showed improvements with DES versus bare-meta stents (BMSs). Compared with PTA, waking capacity was not significanty affected by cutting baoon, baoon-expandabe stents or EVBT; in SES, there was evidence of improvement in waking capacity after up to 12 months. The use of DCBs dominated both the assumed standard practice of PTA with baiout BMS and a other interventions because it owered ifetime costs and improved quaity of ife (QoL). These resuts were seen for both patient popuations (IC and CLI). Sensitivity anayses showed that the resuts were robust to different assumptions about the cinica benefits attributabe to the interventions, suggesting that the use of DCBs is cost-saving. Limitations: Differing definitions of restenosis made direct comparison across trias difficut. There were few data avaiabe for waking capacity and QoL. Queen s Printer and Controer of HMSO This work was produced by Simpson 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

8 ABSTRACT Concusions: The evidence showed a significant benefit to reducing restenosis rates for sef-expanding and DESs, stent-graft, EVBT and DCBs. If it is assumed that patency transates into beneficia ong-term cinica outcomes, then DCB and bai-out DES are most ikey to be the cost-effective enhancements to PTA. A RCT comparing current recommended practice (PTA with bai-out BMS) with DCB and bai-out DES coud assess ong-term foow-up and cost-effectiveness. Data reating patency status to the need for reintervention and to the probabiity of symptoms returning shoud be coected, as shoud heath-reated QoL measures [European Quaity of Life-5 Dimensions (EQ-5D) and maximum waking distance]. Study registration: This study is registered as PROSPERO CRD Funding: The Nationa Institute for Heath Research Heath Technoogy Assessment programme. vi NIHR Journas Library

9 DOI: /hta18100 HEALTH TECHNOLOGY ASSESSMENT 2014 VOL. 18 NO. 10 Contents List of tabes...ix List of figures...xiii Gossary...xv List of abbreviations.... xvii Scientific summary...xix Chapter 1 Background 1 Cinica presentation 1 Anatomica distribution 2 Treatment pathway 2 Limitations of current techniques 3 Chapter 2 Definition of decision probem 5 Purpose of assessment 5 Pace of the intervention in the treatment pathway 5 Incuded interventions 5 Absorbabe stents 5 Sef-expanding stents 5 Baoon-expandabe stents 5 Drug-euting stents 5 Stent-graft 5 Atherectomy 5 Cutting baoon 6 Cryopasty 6 Radiation 6 Drug-coated baoon 6 Laser angiopasty 6 Excuded interventions 6 Pharmacoogica interventions 6 Combined surgica procedures 6 Other techniques 6 Interventions above the inguina igament (aortoiiac segment) 7 Reevant comparators 7 Popuation 7 Methods for assessment 7 Review stage 1 7 Review stage 2 7 Deveopment of a heath economic mode 7 Queen s Printer and Controer of HMSO This work was produced by Simpson 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

10 CONTENTS Chapter 3 Systematic review of the cinica effectiveness of enhancements to angiopasty 9 Methods 9 Identification of studies 9 Incusion criteria 10 Excusion criteria 10 Resuts 11 Quantity and quaity of studies 11 Cinica effectiveness resuts 15 Discussion 53 Chapter 4 Assessment of cost-effectiveness 55 Systematic review of existing cost-effectiveness evidence 55 Searches 55 Resuts 55 Summary 62 Independent economic assessment 62 Methods 62 Assessment of cost-effectiveness 67 Estimate of base-case mode parameters 67 Data for interventions 76 Resuts 78 Chapter 5 Discussion 91 Chapter 6 Concusions 95 Impications for practice 95 Recommendations for future research 95 Acknowedgements 97 References 99 Appendix 1 Search strategy 111 Appendix 2 Excuded studies 117 Appendix 3 Data extraction of incuded studies 119 Appendix 4 Quaity assessment of incuded studies 217 Appendix 5 Summary 229 Appendix 6 Quaity assessment forms (cost-effectiveness systematic review) 231 Appendix 7 Additiona detais for the base-case mode parameters 233 Appendix 8 Protoco 245 viii NIHR Journas Library

11 DOI: /hta18100 HEALTH TECHNOLOGY ASSESSMENT 2014 VOL. 18 NO. 10 List of tabes TABLE 1 Summary of incuded trias 12 TABLE 2 Absorbabe-meta-stent and restenosis 16 TABLE 3 Absorbabe-meta-stent and ate umen oss 17 TABLE 4 Absorbabe-meta-stent and compications 17 TABLE 5 Sef-expanding-stent and restenosis 17 TABLE 6 Sef-expanding stent and need for reintervention 21 TABLE 7 Sef-expanding stent and Rutherford cassification 22 TABLE 8 Sef-expanding stent and waking capacity 22 TABLE 9 Sef-expanding stent and QoL 23 TABLE 10 Sef-expanding stent and compications 24 TABLE 11 Baoon-expandabe stent and restenosis 25 TABLE 12 Baoon-expandabe stent and need for reintervention 27 TABLE 13 Baoon-expandabe stent and waking capacity 28 TABLE 14 Baoon-expandabe stent and compications 28 TABLE 15 Pacitaxe-euting stent and restenosis 30 TABLE 16 Pacitaxe-euting stent and surviva from adverse events 30 TABLE 17 Siroimus-euting stent and restenosis 31 TABLE 18 Siroimus-euting stent and need for reintervention 31 TABLE 19 Siroimus-euting stent and Rutherford cassification 32 TABLE 20 Siroimus-euting stent and compications 32 TABLE 21 Stent-graft and restenosis 33 TABLE 22 Stent-graft and cinica success 33 TABLE 23 Stent-graft and Rutherford cassification 34 TABLE 24 Stent-graft compications 34 TABLE 25 Atherectomy and restenosis 35 TABLE 26 Atherectomy and improvement of cinica category 35 Queen s Printer and Controer of HMSO This work was produced by Simpson 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

12 LIST OF TABLES TABLE 27 Atherectomy and compications 36 TABLE 28 Cutting baoon and restenosis 36 TABLE 29 Cutting baoon and need for reintervention 36 TABLE 30 Cutting baoon and cinica symptoms 37 TABLE 31 Cutting baoon and waking capacity 37 TABLE 32 Cutting baoon compications 37 TABLE 33 Cryopasty and restenosis 38 TABLE 34 Cryopasty and need for reintervention 38 TABLE 35 Cryopasty and improvement 39 TABLE 36 Cryopasty and compications 39 TABLE 37 Endovascuar brachytherapy and restenosis 40 TABLE 38 Endovascuar brachytherapy and ate umen oss 41 TABLE 39 Endovascuar brachytherapy and need for reintervention 43 TABLE 40 Endovascuar brachytherapy and cinica improvement 44 TABLE 41 Endovascuar brachytherapy and waking capacity 44 TABLE 42 Endovascuar brachytherapy and compications 45 TABLE 43 Externa beam radiation and restenosis 45 TABLE 44 Externa beam radiation and need for reintervention 46 TABLE 45 Externa beam radiation and cinica change 46 TABLE 46 Drug-coated baoon and restenosis 47 TABLE 47 Drug-coated baoon and ate umen oss 47 TABLE 48 Drug-coated baoon and need for reintervention 48 TABLE 49 Drug-coated baoon and cinica change 50 TABLE 50 Drug-coated baoon and compications 51 TABLE 51 Laser and restenosis 51 TABLE 52 Laser and cinica success 52 TABLE 53 Laser and compications 52 x NIHR Journas Library

13 DOI: /hta18100 HEALTH TECHNOLOGY ASSESSMENT 2014 VOL. 18 NO. 10 TABLE 54 Incusion criteria for the systematic review of economic evauations 56 TABLE 55 Cost-effectiveness resuts from the BASIL tria 60 TABLE 56 Cost-effectiveness resuts from the NICE CEA 62 TABLE 57 Cinica cassifications of PAD used in this assessment 63 TABLE 58 Effectiveness data, specific to patients with IC, used in the economic anaysis 68 TABLE 59 Effectiveness data, specific to patients with CLI, used in the economic anaysis 69 TABLE 60 Effectiveness data, appicabe to a patients, used in the economic anaysis 70 TABLE 61 Data on heath-reated QoL (as measured by EQ-5D) and costs (2009/10 UK pounds) used in the economic anaysis 70 TABLE 62 Detais of the two studies used for compication rates 72 TABLE 63 Costs and effects for interventions: femoropopitea arteries 76 TABLE 64 Costs and effects for interventions: infrapopitea arteries 77 TABLE 65 Evidence sources for the cinica effectiveness of each intervention 78 TABLE 66 Fu incrementa anaysis of PTA and a the potentia interventions 79 TABLE 67 Incrementa probabiity (%) of being cost-effective for specified eves of wiingness to pay 80 TABLE 68 Breakdown of costs 81 TABLE 69 Breakdown of utiities and ife-years 81 TABLE 70 Fu incrementa anaysis of PTA and a the potentia interventions 82 TABLE 71 Incrementa probabiity (%) of being cost-effective for specified eves of wiingness to pay 83 TABLE 72 Breakdown of costs 84 TABLE 73 Breakdown of utiities and ife-years 84 TABLE 74 Incrementa costs (vs. comparator) for each intervention against age in patients with IC 85 TABLE 75 Incrementa QALYs (vs. comparator) for each intervention against age in patients with IC 86 TABLE 76 Incrementa costs (vs. comparator) for each intervention against age in patients with CLI 86 Queen s Printer and Controer of HMSO This work was produced by Simpson 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

14 LIST OF TABLES TABLE 77 Incrementa QALYs (vs. comparator) for each intervention against age in patients with CLI 86 TABLE 78 Costs and QALYs when amputation costs are removed 87 TABLE 79 Costs and QALYs when ipsiatera disease progression is not affected by the intervention 88 TABLE 80 Costs and QALYs for interventions appied to infrapopitea arteries in patients with CLI 89 TABLE 81 Life tabe of patency for patients with IC and stenosis of the femoropopitea arteries 234 TABLE 82 Detais of the studies used in Hunink et a TABLE 83 Overview of studies reporting QoL that were considered for this economic evauation 238 TABLE 84 Overview of studies reporting procedura costs that were considered for this economic evauation 241 TABLE 85 Overview of studies reporting ong-term costs that were considered for this economic evauation 242 xii NIHR Journas Library

15 DOI: /hta18100 HEALTH TECHNOLOGY ASSESSMENT 2014 VOL. 18 NO. 10 List of figures FIGURE 1 Fow diagram of study seection (based on a revised version of the PRISMA diagram) FIGURE 2 Forest pot of comparison: 1 SES vs. PTA, restenosis 6 months fixed two studies. 19 FIGURE 3 Forest pot of comparison: 1 SES vs. PTA, restenosis 6 months random two studies. 19 FIGURE 4 Forest pot of comparison: 1 SES vs. PTA, restenosis 12 months fixed three studies. 19 FIGURE 5 Forest pot of comparison: 1 SES vs. PTA, restenosis 12 months random three studies. 19 FIGURE 6 Forest pot of comparison: 1 SES vs. PTA, restenosis 12 months fixed two studies. 20 FIGURE 7 Forest pot of comparison: 1 SES vs. PTA, restenosis 12 months random two studies. 20 FIGURE 8 Forest pot of comparison: 2 BES vs. PTA, restenosis at 12 months fixed. 26 FIGURE 9 Forest pot of comparison: 2 BES vs. PTA, restenosis at 12 months random. 26 FIGURE 10 Forest pot of comparison: 2 BES vs. PTA, restenosis at 24 months fixed. 27 FIGURE 11 Forest pot of comparison: 2 BES vs. PTA, restenosis at 24 months random. 27 FIGURE 12 Forest pot of comparison: 4 EVBT vs. PTA, restenosis at 6 months fixed two studies. 41 FIGURE 13 Forest pot of comparison: 4 EVBT vs. PTA, restenosis at 6 months random two studies. 42 FIGURE 14 Forest pot of comparison: 4 EVBT vs. PTA, restenosis at 12 months fixed three studies. 42 FIGURE 15 Forest pot of comparison: 4 EVBT vs. PTA, restenosis at 12 months random three studies. 42 FIGURE 16 Forest pot of comparison: 5 DCB vs. PTA, restenosis at 6 months fixed. 48 FIGURE 17 Forest pot of comparison: 5 DCB vs. PTA, restenosis at 6 months random. 48 FIGURE 18 Forest pot of comparison: 5 DCB vs. PTA, TLR at 6 months fixed. 49 FIGURE 19 Forest pot of comparison: 5 DCB vs. PTA, TLR at 6 months random. 49 FIGURE 20 Forest pot of comparison: 5 DCB vs. PTA, TLR at 24 months fixed. 49 Queen s Printer and Controer of HMSO This work was produced by Simpson 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

16 LIST OF FIGURES FIGURE 21 Forest pot of comparison: 5 DCB vs. PTA, TLR at 24 months random. 49 FIGURE 22 Summary of economic evauation seection and excusion. 56 FIGURE 23 Diagram of the structure of the decision mode. 64 FIGURE 24 Diagram of the heath states modeed. 65 FIGURE 25 Percutaneous transumina baoon angiopasty; cumuative faiure rates over time for the two patient popuations. Based on the meta-anaysis of Hunink et a FIGURE 26 Bypass surgery; cumuative faiure rates over time for the two patient popuations. Based on the meta-anaysis of Hunink et a FIGURE 27 Incrementa cost-effectiveness acceptabiity curve for the base-case mode resuts (a but two of the interventions have probabiities 0 for a wiingness-to-pay threshods) 79 FIGURE 28 Cost-effectiveness pane showing incrementa cinica effectiveness and costs of seected interventions vs. the comparator (base case). 80 FIGURE 29 Resuts of EVPI. 81 FIGURE 30 Incrementa cost-effectiveness acceptabiity curve for the base-case mode resuts (a but two of the interventions have probabiities 0 for a wiingness-to-pay threshods) 83 FIGURE 31 Cost-effectiveness pane showing incrementa cinica effectiveness and costs of seected interventions vs. the comparator (base case). 83 FIGURE 32 Resuts of EVPI anaysis. 85 FIGURE 33 Funne pot of studies reporting restenosis. 228 FIGURE 34 Regression anaysis of the association between the proportion of patients with an occusion and the proportion with CLI. (a) With possibe outiers [weighted by sampe size (see tabe for numbers)]; and (b) without (excuding study 4) 235 FIGURE 35 Weibu modes used to predict faiure. Conditiona faiure rates are conditiona on surviving beyond year 1. Soid ine=observed; dashed ine= modeed (Weibu). 236 FIGURE 36 Average cost by run number for patients with IC. 243 FIGURE 37 Average QALY by run number for patients with IC. 243 FIGURE 38 Average cost by run number for patients with CLI. 243 FIGURE 39 Average QALY by run number for patients with CLI. 243 xiv NIHR Journas Library

17 DOI: /hta18100 HEALTH TECHNOLOGY ASSESSMENT 2014 VOL. 18 NO. 10 Gossary Dominated (simpe) When an intervention is ess effective and more expensive than its comparator. Meta-anaysis A statistica method whereby the resuts of a number of studies are pooed to give a combined summary statistic. Posterior distribution A representation of the knowedge associated with the true vaue of a popuation parameter after combining the prior distribution with sampe data. Prior distribution A representation of the knowedge associated with the true vaue of a popuation parameter in addition to any sampe data. Reative risk The ratio of the probabiity of an event occurring in an exposed group reative to a non-exposed or contro group. Queen s Printer and Controer of HMSO This work was produced by Simpson 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

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19 DOI: /hta18100 HEALTH TECHNOLOGY ASSESSMENT 2014 VOL. 18 NO. 10 List of abbreviations ABPI anke brachia pressure index ICER incrementa costeffectiveness ratio ABSOLUTE AMS AMS INSIGHT BES BMS BS CB CEA CEAC CI CLI DCB DES DESM EBRT EQ-5D randomized baoon angiopasty versus stenting with nitino stents in the superficia ankfemora artery absorbabe meta stent bio-absorbabe meta stent investigation in chronic imb ischaemia treatment baoon-expandabe stent bare-meta stent bypass surgery cutting baoon cost-effectiveness anaysis cost-effectiveness acceptabiity curve confidence interva critica imb ischaemia drug-coated baoon drug-euting stent discrete-event simuation mode externa beam radiotherapy European Quaity of Life-5 Dimensions ITT LEVANT I MACE NICE PAD PRISMA PTA QALY QoL QVA RCT intention to treat the Lutonix pacitaxecoated baoon for the prevention of femoropopitea restenosis tria composite outcome for adverse events incuding death, stroke, myocardia infarction, revascuarisation, emboisation in treated imb, worsening of 1+ Rutherford category Nationa Institute for Heath and Care Exceence periphera arteria occusive disease Preferred Reporting Items for Systematic Reviews and Meta-Anayses percutaneous transumina baoon angiopasty quaity-adjusted ife-year quaity of ife quantitative vesse anaysis randomised controed tria EQ-VAS ESC EVBT EVPI EuroQo visua anaogue scae European Society of Cardioogy endovascuar brachytherapy expected vaue of perfect information RESILIENT randomised study comparing the Edwards sef-expanding LifeStent with angiopasty aone in esions invoving the superficia femora artery and/or proxima popitea artery FAST FemPac IC Femora Artery Stenting Tria Femora Pacitaxe tria intermittent caudication RR SES SF-36 reative risk sef-expanding stent Short Form questionnaire-36 items Queen s Printer and Controer of HMSO This work was produced by Simpson 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

20 LIST OF ABBREVIATIONS SF-8 SIROCCO TASC THUNDER Short Form questionnaire-8 items SIROimus-Coated COrdis sef-expandabe stent tria Trans-Atantic Inter-Society Consensus oca taxane with short exposure for reduction of restenosis in dista arteries TLR TTO TVR VARA VascuCoi VSGBI target esion revascuarisation time trade-off target vesse revascuarisation VAscuar RAdiotherapy tria intracoi femoropopitea stent tria The Vascuar Society of Great Britain and Ireand xviii NIHR Journas Library

21 DOI: /hta18100 HEALTH TECHNOLOGY ASSESSMENT 2014 VOL. 18 NO. 10 Scientific summary Background Periphera arteria occusive disease (PAD) is a cause of major morbidity in the UK. There have been rapid technoogica deveopments aimed at improving the short- and ong-term resuts of percutaneous transumina baoon angiopasty (PTA). Objectives This report aimed to assess current evidence on the cinica effectiveness and cost-effectiveness of additiona techniques designed to improve the resuts of standard transumina baoon angiopasty for PAD, to deveop a heath economic mode to assess cost-effectiveness and to identify areas where further primary research is needed. Data sources The foowing eectronic databases were searched from inception to 2011: MEDLINE; MEDLINE In-Process & Other Non-Indexed Citations (Ovid); EMBASE (Ovid); The Cochrane Library; Cumuative Index to Nursing and Aied Heath Literature (CINAHL); Science Citation Index (via ISI Web of Science); Socia Science Citation Index (via ISI Web of Science); Conference Proceedings Citation Index Science (CPCI-S) (via ISI Web of Science); UK Cinica Research Network Portfoio Database; Current Controed Trias; and CinicaTrias.gov. Searches were conducted between May and October Methods Systematic reviews were conducted of cinica effectiveness and cost-effectiveness of enhancement to angiopasty. Additiona focused searches were conducted on the natura history and quaity of ife (QoL) for PAD. The popuation was participants with symptomatic PAD undergoing endovascuar treatment for disease dista to the inguina igament. Interventions were techniques used as an adjunct to, or as a repacement for, baoon angiopasty in the periphera circuation. Conventiona PTA was the main comparator. An expert group of cinicians assisted in the identification of reevant technoogies, known trias and important outcome measures. Outcomes incuded measures of cinica effectiveness, restenosis and the need for reintervention, and costs. Data were extracted from randomised controed trias (RCTs), which were quaity assessed using standard criteria. A discrete-event simuation mode was deveoped to assess the reative cost-effectiveness of the interventions from a NHS perspective over a ifetime. The patient popuations of intermittent caudication (IC) and critica imb ischaemia (CLI) were modeed separatey. Univariate and probabiistic sensitivity anayses were undertaken. Queen s Printer and Controer of HMSO This work was produced by Simpson 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

22 SCIENTIFIC SUMMARY Resuts In tota, 40 RCTs were incuded, athough many had sma sampe sizes. Significanty reduced restenosis rates were shown in meta-anayses of sef-expanding stents (SES) {reative risk (RR) 0.67 [95% confidence interva (CI) 0.52 to 0.87]}, endovascuar brachytherapy (EVBT) [RR 0.63 (95% CI 0.48 to 0.83)] at 12 months and drug-coated baoons (DCBs) at 6 months [RR 0.40 (95% CI 0.23 to 0.69)], and singe studies of stent-graft or drug-euting stent (DES), compared with PTA; a singe study showed improvement of DES versus bare-meta stents (BMSs). Compared with PTA, waking capacity was not significanty affected by cutting baoon, baoon-expandabe stents or EVBT; in SES, there was evidence of improvement in waking capacity after up to 12 months. The use of DCBs dominated both the assumed standard practice of PTA with bai-out BMSs and a other interventions because it owered ifetime costs and improved QoL. These resuts were seen for both patient popuations (IC and CLI). Sensitivity anayses showed that the resuts were robust to different assumptions about the cinica benefits attributabe to the interventions, suggesting that the use of DCBs is cost-saving. Discussion Despite many studies being identified, there remains uncertainty in the resuts of the report. Cinicay, there was evidence of a significant benefit to reducing restenosis rates for SES, stent-graft, EVBT and DCB compared with PTA and for DES compared with BMS. If it is assumed that patency transates into beneficia ong-term cinica outcomes, then DCB and bai-out DES are most ikey to be the cost-effective enhancements to PTA. A RCT comparing current recommended practice (PTA with bai-out BMS) with DCB and bai-out DES coud assess ong-term foow-up and cost-effectiveness. Data reating patency status to the need for reintervention and to the probabiity of symptoms returning shoud be coected, as shoud heath-reated QoL measures [European Quaity of Life-5 Dimensions (EQ-5D) and maximum waking distance]. Study registration This study is registered as PROSPERO CRD Funding Funding for this study was provided by the Heath Technoogy Assessment programme of the Nationa Institute for Heath Research. xx NIHR Journas Library

23 DOI: /hta18100 HEALTH TECHNOLOGY ASSESSMENT 2014 VOL. 18 NO. 10 Chapter 1 Background Periphera arteria occusive disease (PAD) is a cause of major morbidity in the UK. Disease in the arteries to the egs causes a reduction in the circuation and can present cinicay as intermittent caudication (IC; pain on waking), which can severey impair ifestye. More severe disease may present as critica ischaemia with rest pain, uceration or gangrene in the ower extremities. In recent years, there has been a rapid increase in the use of endovascuar treatment, particuary percutaneous transumina baoon angiopasty (PTA). In this procedure, a device is inserted through a sma puncture under oca anaesthetic and a narrowed or bocked area of artery is opened up by the infation of baoons. There is a high demand for PTA for PAD, with in excess of 20,000 procedures per annum in Engand (based on data for ). 1 Revascuarisation strategy is individua to the patient, and treatment by vascuar speciaists, or within speciaised vascuar centres, is recommended by the European Society of Cardioogy (ESC) guideines 2 and the Vascuar Society of Great Britain and Ireand (VSGBI). 3 There have aso been rapid technoogica deveopments aimed at improving the short- and ong-term resuts of this treatment. Such deveopments incude the use of stents, drug-euting stents (DESs), drug-euting baoons, cryotherapy, atherectomy and drug treatments. Many of these techniques have been deveoped for use in the coronary circuation and extended to the periphera circuation or may be evauated in the periphera circuation with a view to using simiar methods in the coronary circuation. The purpose of this report was to evauate the range of additiona technoogies that are avaiabe and identify the cinica situations in which they are most ikey to be of benefit, or those technoogies for which further research studies are justified. When considering the introduction of new technoogies, there are a number of considerations regarding the cinica situation that may be reevant to the appicabiity and outcome of particuar techniques and may therefore be important in defining subgroups that are important in the consideration of the new technoogies. These are particuary the cinica stage or symptomatic presentation of the condition being treated, the anatomica distribution of disease and the pace of the endovascuar procedure in the treatment pathway. Cinica presentation The majority of patients with PAD wi present with symptoms of IC (pain in the musce of the eg brought about by waking). This may vary in severity from mid pain that occurs ony after considerabe exercise or when going uphi, to severe pains that stop activity after ony a few paces. It may aso affect one or both egs. More severe PAD may resut in insufficient bood suppy to the egs, even at rest. In these circumstances, the patient may deveop rest pain, particuary nocturna pain when the egs are eevated in bed and, in the more advanced stages, tissue oss, uceration and gangrene. The severity of the symptoms of PAD may be cassified using a variety of scaes, the most common being the Fontaine or Rutherford cassifications. These may be used in research settings, athough they are consistenty used in routine cinica practice. The cassifications divide up patients depending upon the severity of the condition based upon IC and critica imb ischaemia (CLI) and then further subdivide them. The Fontaine cassification uses subdivisions based upon pain-free waking distance, whereas the Rutherford cassification uses the resuts of the treadmi exercise test and anke brachia pressure index (ABPI) measurements. In addition, PAD is associated with other forms of arteria disease, particuary ischaemic heart disease and cerebrovascuar disease. In many patients with generaised atheroscerosis, there is some degree of Queen s Printer and Controer of HMSO This work was produced by Simpson 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. 1

24 BACKGROUND asymptomatic PAD, and mid degrees of IC are quite common in the genera popuation: the Edinburgh Artery Study reported a prevaence of 4.5% [95% confidence interva (CI) 3.5% to 5.5%] in peope aged years. 4 Those with IC may go on to deveop worsening symptoms, athough it is quite common for symptoms to remain static for many years and ony a sma proportion, probaby around 5 10% over 5 years, 5 wi go on to deveop critica ischaemia, about a quarter of whom may eventuay require amputation. As the cinica presentation has a significant bearing on outcome and particuary the risk of reoccusion foowing an endovascuar procedure, this is an important aspect to be taken into consideration when evauating new technoogies. Anatomica distribution Both IC and CLI may be the resut of a reduction in bood fow due to narrowing or occusion of the arteries to the ower imb at any eve. From the point of view of management, the eves of arteria disease are often divided into aortoiiac, that is affecting anywhere in the aorta or common and externa iiac arteries, and infrainguina, those arteries beow the inguina igament. Disease beow the inguina igament is aso often further subdivided into femoropopitea disease, that is disease in the femora arteries and popitea artery above or beow the knee and infragenicuate or dista disease, referring to those vesses beow the popitea artery (anterior and posterior tibia and peronea arteries). Owing to the differences in arteria caibre and bood fow, the natura history and outcomes of treatments may be expected to differ among the different anatomica sites. The position, size and accessibiity of different vesses may aso give rise to particuar technica chaenges. There are many other ways in which the anatomica distribution of disease may be important in determining treatment; these incude: whether there is a partia or compete occusion of a vesse the ength of any area of disease that requires treatment the accessibiity of the diseased area of artery the eccentricity of any residua umen the presence or absence of cacification. The presence or absence of disease either proxima or dista to the area being treated is aso a major determinant of the potentia success of any procedure. It is therefore important to consider a these issues when evauating a new technoogy, particuary as some technoogies may be especiay usefu for deaing with a specific cinica situation, such as when there is cacification or a very eccentric umen. Treatment pathway Many of the new technoogies that are considered in this report have been evauated primariy in reativey simpe, short stenotic or occuded areas of a singe vesse. However, in practice, PAD is a chronic condition in which there are often mutipe areas of disease, and the patient may undergo a series of different treatments over many years. Endovascuar treatments may be used for mutipe areas of disease as an adjunct to other interventions. This may be either simutaneous or as part of a panned series of procedures for disease at different sites. They may aso be used for the retreatment of areas that have previousy been treated by endovascuar means or in the treatment of stenosis in arteria bypass grafts. Athough these are reevant areas in which some of the technoogies considered in this report may be used, these situations are often specificay excuded or simpy not represented in the cinica trias. 2 NIHR Journas Library

25 DOI: /hta18100 HEALTH TECHNOLOGY ASSESSMENT 2014 VOL. 18 NO. 10 Limitations of current techniques Percutaneous transumina angiopasty has been widey adopted and is a common and usefu procedure in the management of periphera arteria disease; however, it has certain imitations and potentia risks that may be addressed by some of the new technoogies considered in this report. The site and extent of disease may determine whether or not endovascuar treatments are possibe. Longer occusions of sma dista arteries are increasingy difficut to treat and have poor outcomes. However, there is no absoute criterion to determine suitabiity, as is demonstrated by the variabiity of cinicians readiness to randomise patients in some trias. 6 When endovascuar treatment is attempted, there may be faiure or compications at any stage of the procedure: There may be faiure to gain access to the site of the disease. It may prove impossibe to cross the occuded segment with the device used for treatment. It may prove impossibe to reopen the vesse sufficienty to obtain a suitabe umen. Procedura compications may occur, incuding beeding at the puncture site, emboisation of materia from the diseased segment of artery, dissection, perforation or immediate reoccusion. After a successfu initia procedure, there is a risk of ate restenosis and reoccusion causing recurrence of symptoms. New techniques associated with angiopasty may address any of these potentia difficuties in carrying out the procedure. The technoogies that are considered in this report are primariy concerned with either increasing the effectiveness of the initia recanaisation or preventing ate restenosis. For exampe, stents, aser and atherectomy devices are intended to improve the immediate resut, whereas DESs, drug-coated baoons (DCBs) and radiotherapy are unikey to affect the immediate anatomica resut but are aimed at reducing the rate of subsequent restenosis and reoccusion. In addition to these there are other technoogies that have not been considered in this report, such as deveopments in catheters and guide-wire technoogy, which may improve access and cosure devices, which may reduce the risk of the compication of postprocedure beeding. Queen s Printer and Controer of HMSO This work was produced by Simpson 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. 3

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27 DOI: /hta18100 HEALTH TECHNOLOGY ASSESSMENT 2014 VOL. 18 NO. 10 Chapter 2 Definition of decision probem Purpose of assessment This report aimed to answer the foowing research questions: What are the cinica effectiveness and cost-effectiveness of additiona techniques designed to improve the resuts of endovascuar treatment (standard transumina baoon angiopasty) for PAD? For which of these techniques is further primary research ikey to ead to information that wi improve the cinica effectiveness and cost-effectiveness of care for this condition? Pace of the intervention in the treatment pathway The techniques under consideration in this assessment were those that are used either as a repacement for or in conjunction with conventiona baoon angiopasty. In genera, treatments were considered that occupy the same pace as baoon angiopasty in the treatment pathway for PAD. Incuded interventions This assessment is of new endovascuar techniques that may be used to either suppement or repace existing endovascuar procedures to improve the circuation of the ower imb in cases of PAD. The foowing interventions were incuded. Absorbabe stents This is a type of stent that is bio-absorbabe. 7 Sef-expanding stents This is a type of bare-meta stent (BMS) that expands when impanted. Baoon-expandabe stents This is a type of BMS that requires expansion with a baoon. Drug-euting stents There are a number of designs of meta stents that are coated with drugs that are graduay reeased and may reduce the rate of restenosis. These incude stents that reease cytotoxic or immunosuppressant drugs. These have been quite widey used in the coronary circuation and various configurations are now avaiabe that are suitabe for use in the periphera circuation. Stent-graft Stents may be covered with graft materia, usuay eptfe (expanded poytetrafuoroethyene), to produce stent-grafts. Large stent-grafts are now commony used for treating aneurysms and smaer-diameter versions are avaiabe for use in the periphera arteries. Such devices may be inserted by a percutaneous route or may be used as a part of surgica procedures. Atherectomy Whereas conventiona baoon angiopasty or stenting does not remove the occuding materia but opens up and stretches the umen of the vesse, atherectomy is a technique that attempts to remove some of the Queen s Printer and Controer of HMSO This work was produced by Simpson 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. 5