HEALTH TECHNOLOGY ASSESSMENT

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1 HEALTH TECHNOLOGY ASSESSMENT VOLUME 17 ISSUE 33 AUGUST 2013 ISSN Cost-effectiveness of transcatheter aortic vave impantation (TAVI) for aortic stenosis in patients who are high risk or contraindicated for surgery: a mode-based economic evauation R Orando, M Pennant, S Rooney, S Khogai, S Bayiss, A Hassan, D Moore and P Barton DOI /hta17330

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3 Cost-effectiveness of transcatheter aortic vave impantation (TAVI) for aortic stenosis in patients who are high risk or contraindicated for surgery: a mode-based economic evauation R Orando, 1 M Pennant, 2 S Rooney, 3 S Khogai, 4 S Bayiss, 2 A Hassan, 2 D Moore 2 and P Barton 1 * 1 Unit of Heath Economics, University of Birmingham, Birmingham, UK 2 Unit of Pubic Heath, Epidemioogy and Biostatistics, University of Birmingham, Birmingham, UK 3 Department of Cardiac Surgery, Queen Eizabeth Hospita, Birmingham, UK 4 Heart and Lung Centre, New Cross Hospita, Woverhampton, UK *Corresponding author Decared competing interests of authors: The foowing authors have no conficts of interest: RO, MP, SB, AH, DM and PB. SR has received training support for TAVI from Edwards Life Sciences. SK has received training support from both Edwards Life Sciences and Medtronic and is a TAVI proctor (Medtronic CoreVave). Pubished August 2013 DOI: /hta17330 This report shoud be referenced as foows: Orando R, Pennant M, Rooney S, Khogai S, Bayiss S, Hassan A, et a. Cost-effectiveness of transcatheter aortic vave impantation (TAVI) for aortic stenosis in patients who are high risk or contraindicated for surgery: a mode-based economic evauation. Heath Techno Assess 2013; 17(33). 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 10/110/01. The contractua start date was in January The draft report began editoria review in Apri 2011 and was accepted for pubication in August 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 Orando 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 Dr Tom Marsha Reader in Primary Care, Schoo of Heath and Popuation Sciences, University of Birmingham, 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, 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: /hta17330 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 33 Abstract Cost-effectiveness of transcatheter aortic vave impantation (TAVI) for aortic stenosis in patients who are high risk or contraindicated for surgery: a mode-based economic evauation R Orando, 1 M Pennant, 2 S Rooney, 3 S Khogai, 4 S Bayiss, 2 A Hassan, 2 D Moore 2 and P Barton 1 * 1 Unit of Heath Economics, University of Birmingham, Birmingham, UK 2 Unit of Pubic Heath, Epidemioogy and Biostatistics, University of Birmingham, Birmingham, UK 3 Department of Cardiac Surgery, Queen Eizabeth Hospita, Birmingham, UK 4 Heart and Lung Centre, New Cross Hospita, Woverhampton, UK *Corresponding author Background: Cacific aortic stenosis (AS) is a common vavuar heart disease. Patients with severe symptomatic AS typicay survive ess than 3 years. In such patients, intervention with surgica aortic vave repacement (SAVR) may increase surviva. However, in some patients SAVR is associated with a high operative risk and medica management is considered appropriate. Transcatheter aortic vave impantation (TAVI) is a reativey recent technique to avoid the invasiveness of open surgery. This procedure has been used for the treatment of patients with severe AS who are unsuitabe for SAVR (because it is too high risk and/or for other reasons such as suffering from porceain aorta) and is increasingy being considered for other patients. Objectives: To determine the cost-effectiveness of TAVI being made avaiabe for patients who are high risk or contraindicated for SAVR through a review of existing economic evauations and deveopment of a mode. Data sources and review methods: Bibiographic databases [MEDLINE, EMBASE, The Cochrane Library, Heath Technoogy Assessment (HTA), Database of Abstracts of Reviews of Effects (DARE) and NHS Economic Evauation Database (EED), Centre for Reviews and Dissemination HTA, DARE and NHS EED], guideine resources, current trias registers, websites/grey iterature and manufacturers' websites, and consutation with cinica experts were used to identify studies for the review and information for the mode. Databases were searched from 2007 to November A mode was buit to assess the cost-effectiveness of TAVI separatey in patients suitabe and unsuitabe for SAVR, together with overa resuts for the effect of making TAVI avaiabe. Substantia deterministic sensitivity anaysis was carried out together with probabiistic sensitivity anaysis. Resuts: No fuy pubished cost-effectiveness studies were found. Modeing patients not suitabe for SAVR, the base-case resuts show TAVI as more costy but more effective than medica management, with an incrementa cost-effectiveness ratio (ICER) of 12,900 per quaity-adjusted ife-year (QALY). The ICER was beow 20,000 per QALY for over 99% of mode runs in the probabiistic sensitivity anaysis. For patients suitabe for SAVR, the comparator with TAVI is a mixture of SAVR and medica management. TAVI is both more costy and ess effective than this comparator assuming that most patients woud receive SAVR in the absence of TAVI. This is robust to a number of assumption changes about the effects of treatment, but sensitive to assumptions about the proportion of patients receiving SAVR in the comparator. If the use of Queen's Printer and Controer of HMSO This work was produced by Orando 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 TAVI is extended to incude more patients suitabe for SAVR, the overa resuts from the mode become ess favourabe for TAVI. Limitations: The modeing invoves extrapoation of short-term data and the comparison between TAVI and SAVR is not based on randomised data. More tria data on the atter have been pubished since the modeing was undertaken. Concusions: The resuts for TAVI compared with medica management in patients unsuitabe for surgery are reasonaby robust and suggest that TAVI is ikey to be cost-effective. For patients suitabe for SAVR, TAVI coud be both more costy and ess effective than SAVR. The overa resuts suggest that, if a very substantia majority of TAVI patients are those unsuitabe for SAVR, the cost-effectiveness of a broad poicy of introducing TAVI may fa beow 20,000 per QALY. Future work required incudes the incorporation of new data made avaiabe after competion of this work. Funding: The Nationa Institute for Heath Research Heath Technoogy Assessment programme. vi NIHR Journas Library

9 DOI: /hta17330 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 33 Contents List of abbreviations.... Scientific summary... Chapter 1 Introduction Aortic stenosis Treatment of severe aortic stenosis Chapter 2 Rationae and objectives Chapter 3 Cost-effectiveness review Searches Study seection, data extraction and quaity assessment Resuts Chapter 4 Cost-effectiveness mode Mode description Identifying studies for mode parameters Transcatheter aortic vave impantation mode data and inputs Base-case anaysis Deterministic sensitivity anaysis Probabiistic sensitivity anaysis Summary of mode resuts Chapter 5 Discussion and concusions Comparison with other pubished resuts Strengths Limitations Impications for heath care Research recommendations Acknowedgements References Appendix 1 Risk-scoring systems Appendix 2 Transcatheter aortic vave impantation search strategies Appendix 3 Fitting surviva curves for surgica aortic vave repacement and medica management Appendix 4 Detais of costing Appendix 5 Protoco ix xi Queen's Printer and Controer of HMSO This work was produced by Orando 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

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11 DOI: /hta17330 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 33 List of abbreviations ACE AS AVA BCIS CABG CI CRD DARE ESC angiotensin-converting enzyme aortic stenosis aortic vave area British Cardiovascuar Intervention Society coronary artery bypass grafting confidence interva Centre for Reviews and Dissemination Database of Abstracts of Reviews of Effects European Society of Cardioogy EuroSCORE European System for Cardiac Operative Risk Evauation GP genera practitioner HTA Heath Technoogy Assessment ICER incrementa cost-effectiveness ratio ICU intensive care unit IEOA indexed effective orifice area ISRCTN Internationa Standard Randomised Controed Tria Number LES ogisitic EuroSCORE MDT mutidiscipinary team MESH medica subject heading NHS EED NHS Economic Evauation Database NICE NYHA OR PARTNER PPM QALY QoL ROC SAVR SD STS-PROM TAVI TA TF UKCRN UHSM WHO Zetoc Nationa Institute for Heath and Care Exceence New York Heart Association odds ratio European Pacement of AoRtic TraNscathetER vaves tria prosthesis patient mismatch quaity-adjusted ife-year quaity of ife receiver operating characteristic surgica aortic vave repacement standard deviation Society of Thoracic Surgeons Predicted Risk Of Mortaity transcatheter aortic vave impantation transapica transfemora UK Cinica Research Network University Hospita of South Manchester Word Heath Organization British Library's Eectronic Tabe of Contents A abbreviations that have been used in this report are isted here uness the abbreviation is we known (e.g. NHS), or it has been used ony once, or it is a non-standard abbreviation used ony in figures/tabes/appendices, in which case the abbreviation is defined in the figure egend or in the notes at the end of the tabe. Queen's Printer and Controer of HMSO This work was produced by Orando 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

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13 DOI: /hta17330 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 33 Scientific summary Background Cacific aortic stenosis (AS) is a degenerative disease in which narrowing of the aortic vave causes obstruction of eft ventricuar outfow. AS is the most common vavuar heart disease in Western countries, affecting approximatey 2% of peope over the age of 65 years. In patients with severe symptomatic AS, the risk of death is approximatey 2% per month, and typica surviva is <2 to 3 years. Intervention in the form of surgica aortic vave repacement (SAVR) in such patients can effectivey improve rates of surviva, often reaching rates simiar to those of an age-matched popuation without AS. However, in some patients with severe AS, age or comorbidities mean that SAVR is associated with a high risk of operative mortaity or morbidity. For these patients, athough medica management is considered to be argey ineffective, it has been considered appropriate because the risks associated with SAVR in these patients are too high. Transcatheter aortic vave impantation (TAVI) is a reativey recent technique (first used in 2002) used for the impantation of repacement aortic vaves without the invasiveness of open surgery. TAVI invoves catheter-guided transport of a new aortic vave that dispaces the od diseased vave and is expanded in pace. This procedure has been used for the treatment of patients with severe AS who are unsuitabe for SAVR (because the risk is too high and/or for other reasons such as they suffer from porceain aorta) and, in such patients, TAVI is associated with better outcomes than medica management. TAVI is aso increasingy being considered for patients in whom the risk associated with SAVR woud be high but not high enough for it to be competey contraindicated. Guideines recommend that TAVI may be used in patients in whom SAVR is contraindicated or associated with high risk. Patients are to be assessed by mutidiscipinary teams comprising cardiac surgeons, cardioogists and anaesthesioogists, and subsequenty referred for SAVR, TAVI or medica management. There are a number of factors that infuence the treatment decision, incuding the assessed patient risk score, pre-existing comorbidities, associated procedures, age, patient preference and the referra process itsef. There is no cear distinction of the exact group of patients in whom TAVI is ikey to be beneficia, and no fuy pubished cost-effectiveness anaysis to evauate the vaue of TAVI in practice has been found. Objective The objective of this work was to determine the cost-effectiveness of TAVI being avaiabe compared with not being avaiabe for patients who are high risk or in whom SAVR is contraindicated. The work aimed to conduct a iterature review of cost-effectiveness studies and to buid a mode to anayse the cost-effectiveness of the use of TAVI in practice. Methods Comprehensive searches of bibiographic databases [MEDLINE, EMBASE, The Cochrane Library, Heath Technoogy Assessment (HTA), Database of Abstracts of Reviews of Effects (DARE) and NHS Eectronic Evauation Database (EED), Centre for Reviews and Dissemination HTA, DARE and NHS EED], guideine resources, current trias registers, websites/grey iterature and manufacturers' websites, and consutation with cinica experts were used to identify studies for the review of cost-effectiveness and studies containing information reevant to the cost-effectiveness mode [costs, quaity of ife (QoL), ong-term outcomes and other parameters]. As a recent systematic review (Bazian. Percutaneous aortic vave repacement for severe aortic stenosis. Part A: Technoogy assessment and impact mode for East Midands Speciaist Commissioning Queen's Printer and Controer of HMSO This work was produced by Orando 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 SCIENTIFIC SUMMARY Group. Bazian Ltd; 2008) has examined the iterature to 2007, searches were conducted to cover the period 2007 to November 2010, and were combined with previous findings. No fuy pubished cost-effectiveness studies were found. Parameters for the cost-effectiveness mode were seected on the basis of their appicabiity to the patient group under consideration and their representativeness in terms of the wider body of evidence. Cost-effectiveness mode A mode was buit to assess the cost-effectiveness of TAVI separatey in patients suitabe and unsuitabe for SAVR, together with overa resuts for the effect of making TAVI avaiabe. Substantia deterministic sensitivity anaysis was carried out together with probabiistic sensitivity anaysis. Deaing first with the patients not suitabe for SAVR, the comparison in this case is simpy between TAVI and medica management. The base-case resuts show that TAVI is more costy but more effective than the comparator, with an incrementa cost-effectiveness ratio (ICER) of 12,900 per quaity-adjusted ife-year (QALY). This resut was robust to a number of changes in the mode. In the deterministic sensitivity anaysis, the ony case in which the ICER exceeded 20,000 per QALY was when the QoL scores were taken to an extremey ow vaue. The ICER was beow 20,000 per QALY for over 99% of mode runs in the probabiistic sensitivity anaysis. On the other hand, for patients suitabe for SAVR, the comparator with TAVI is a mixture of SAVR and medica management. In this case, TAVI is both more costy and ess effective (in terms of QALYs) than the comparator in the base-case anaysis, which assumes that the vast majority of patients in this group woud receive SAVR in the absence of TAVI. The base-case resut is robust to a number of changes in the assumptions about the effects of treatment, but highy sensitive to assumptions about the proportion of patients receiving SAVR in the comparator arm of the mode. Overa resuts in the base-case anaysis are cose to the resuts for patients not suitabe for SAVR, as woud be expected given that these patients are assumed to form the majority of the modeed popuation. When the use of TAVI is extended to incude a arger number of patients suitabe for SAVR, the overa resuts from the mode become ess favourabe for TAVI. Concusions The resuts given here for TAVI compared with medica management in patients unsuitabe for surgery are reasonaby robust and suggest that TAVI is ikey to be cost-effective in these patients. On the other hand, for patients who coud have surgery as an aternative, the mode resuts suggest that TAVI coud be both more costy and ess effective than SAVR. However, these resuts are not based on randomised data and coud easiy be upset by the resuts of trias reporting after this work was carried out. The overa resuts suggest that the tota effect of introducing TAVI fas within conventiona standards of cost-effectiveness. It shoud be stressed that this depends on the assumption that a very substantia majority of TAVI patients wi be those who are unsuitabe for surgery. From a decision-theoretic point of view, the overa resuts shoud not be used to guide any decision, but the decision to aow TAVI for different patient groups shoud be taken separatey for each group based on the resuts for that patient group aone. However, in practice a decision to aow TAVI for patients deemed unsuitabe for surgery is ikey to ead to TAVI being offered to some higher-risk patients who woud have received surgery in the absence of TAVI. It is hepfu to quantify the importance of this possibiity. xii NIHR Journas Library

15 DOI: /hta17330 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 33 Impications for heath care The resuts in this report suggest that TAVI is a cost-effective treatment when the comparator is medica management. However, the modeing in this report does not suggest that TAVI shoud be widey used as an aternative to SAVR. Recommendations for future research The various initia modes, incuding those produced for manufacturers and the Scottish Heath Technoogies Group, need to be reconcied with each other and with the mode introduced in this report. The sensitivity anaysis from each of these modes shoud give an indication of the importance of the various features of an agreed mode. The data being generated whie this report was under construction shoud be incuded where appropriate in any revised anaysis based on an agreed mode structure. Future data coection, incuding any future trias, shoud be designed with economic evauation in mind. In particuar, once a set of reevant heath states for future modeing is agreed, every effort shoud be made to obtain reaistic and reasonabe QoL scores for those heath states. Funding The Nationa Institute for Heath Research Heath Technoogy Assessment programme. Queen's Printer and Controer of HMSO This work was produced by Orando 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

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17 DOI: /hta17330 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 33 Chapter 1 Introduction Aortic stenosis Aetioogy Aortic stenosis (AS) is a condition in which the aortic vave becomes progressivey narrowed, eading to gradua obstruction of eft ventricuar outfow. The most common form, occurring in about 80% of cases, is degenerative. 1 This primariy presents as cacific AS 2 and shares a simiar deveopmenta process and risk factors to atheroscerosis. 2 4 Risk factors for the deveopment of AS incude mae sex, hypertension, eevated ow-density ipoproteins, diabetes, choestero, smoking and a famiy history of heart disease. 1,5 Patients with chronic AS may remain asymptomatic for many years but, in most patients, symptoms of disease eventuay deveop. AS is usuay considered in terms of its haemodynamic and symptomatic disease severity. Haemodynamic diagnosis and severity measurement can be conducted using echocardiography, Dopper studies and cardiac catheterisation. 2,5 Severity can be assessed in terms of the aortic vave area (AVA), peak aortic jet veocity (V max ) and transaortic vave gradient, severe AS being defined as AVA <1cm 2, V max >4m/second and mean transaortic vave gradient >40mmHg. 6 Cinica symptoms of AS incude chest pain or breathessness on exertion, angina, dizziness and syncope, and patients may suffer sudden death. 2,5 The New York Heart Association (NYHA) heart faiure cassification is used to cassify the severity of symptoms, ranging from cass I, in which the patient has no imitation in daiy physica activity, to cass IV, in which the patient is breathess at rest. Of patients with vavuar heart disease, 30% are in each of the casses I, II and III and 10% are in cass IV. 1 Most patients with severe AS dispay symptoms of disease. However, this is not aways the case and some patients with haemodynamicay severe AS are asymptomatic. 7 Epidemioogy Aortic stenosis is the most common vavuar heart disease in Western countries. 2,3,5 The majority of peope treated for AS are >60 years of age 1 and the prevaence of AS has been found to be 2% in those 65 years, 3% in those 75 years 8 and 4% in those 85 years. 9 The prevaence of vave disease is strongy inked to popuation ageing 10 and the prevaence of AS is therefore ikey to increase in deveoped countries such as the UK because of the increasing proportion of edery peope in those popuations. Natura history The progression of AS is very variabe, with some patients iving a ong time with stabe, asymptomatic disease. However, once symptoms deveop, risk of death is high. 2,11 Symptoms may deveop in patients of any age but most commony present in patients in their 60s. 11 In patients with severe symptomatic AS, in the absence of treatment, surviva rates have been shown to dispay a sharp decrease, independent of age at symptom onset. 11 Mortaity risk is about 2% per month 4 and typica surviva is <2 to 3 years. 5,12 Two-year mortaity is approximatey 50% 13 and 3-year mortaity approximatey 75%. 4 In a tria which enroed patients unsuitabe for surgica intervention, the 1-year mortaity under standard therapy was approximatey 50%. 14 This higher mortaity is not unexpected given the patient group invoved. In asymptomatic patients, sudden death is rare 2 but there is a sma risk that symptoms wi deveop very rapidy and the patient wi die suddeny or even that death wi occur suddeny without the onset of cinica symptoms. The risk of sudden death in asymptomatic patients has been estimated to be around 1% per year. 2,7 Queen's Printer and Controer of HMSO This work was produced by Orando 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

18 INTRODUCTION Treatment of severe aortic stenosis Surgica aortic vave repacement Patients Surgica aortic vave repacement (SAVR) is considered the treatment of choice for patients with severe symptomatic AS and is recommended in a patients who are candidates for surgery. 2 Some researchers argue that asymptomatic patients shoud aso be considered for surgica intervention. 4,7 However, the disease-reated risk of sudden death ( 1% 7 ) may be ow compared with the risks associated with surgery 4 and, as it is often difficut to accuratey standardise haemodynamic measures of severity, 4 it may be difficut to identify particuary severe asymptomatic patients in whom surgery woud be indicated. In the UK, SAVR has increased from 1900 cases per annum in 1999 to 4250 cases in The mean age of patients undergoing SAVR has risen from 68 years in 1994 to 73.5 years in Since 1999, the percentage of patients >80 years of age undergoing SAVR has more than doubed from 6% to 13%. 15 Procedure Surgica aortic vave repacement is a major surgica procedure. It invoves division of the sternum to achieve adequate exposure of the heart and aorta for the procedure. During SAVR, cardiopumonary bypass is used to maintain the circuation and bood oxygenation. The approach to the diseased vave is via the ascending aorta and the vave is repaced with a prosthetic vave. Foowing cosure of the aorta, coronary artery perfusion is re-estabished. Cardiopumonary bypass support is then graduay withdrawn and the patient's heart resumes contro of the circuation. Mechanica or bioogica prosthesis can be used for SAVR. Historicay, approximatey haf of patients undergoing SAVR for AS received mechanica and haf received bioogica vaves. 1 However, there has been an increasing trend towards the use of bioogica vaves. In 2004, 60% of SAVRs used bioogica vaves; in 2008 this had risen to 73%. 15 This refects not ony an increase in mean age of this group of patients, but aso that data have shown better ongevity for the modern generation of bioogica vaves. 15 Mechanica vaves may be more durabe, but they require ifeong anticoaguation therapy with monitoring and are usuay more appropriate for younger patients, whereas bioogica vaves may be more appropriate in oder patients with shorter anticipated ifespans. Some guideines have suggested a threshod of 65 years of age for choosing a bioogica rather than mechanica vave, but in the UK and mainand Europe the trend has been towards a threshod of 70 or 75 years of age. 1 Outcomes Eary studies (pre 1966) of patients undergoing SAVR give rates of procedura mortaity of around 4 20%. 11 However, the risks associated with surgica intervention have decreased and, more recenty, operative mortaity of isoated SAVR is typicay around 2 5%. 1,5,13,15 Operative mortaity may be around 5 15% in oder patients. 2,16 With surgica intervention, overa patient surviva is proonged. In a meta-anaysis of SAVR studies, postprocedura mortaity risk was estimated as 4.3% per year. 17 Postsurgica projections have been shown to track heathy ife expectancy 11 and, where SAVR is successfu, rates of ong-term surviva may be simiar to those of age-matched popuations without AS. 2,4,5 The success of SAVR in edery patients may be anticipated to be ower than in younger patients as age-associated comorbidities have a arge impact on procedura and ong-term risks. 18 However, studies restricted to edery patients ( 80 years) undergoing SAVR have aso shown positive outcomes. Rates of 5-year surviva have been estimated to be around 50 70% and these may compare we with rates of ife expectancy of the same-aged genera popuation. 15,18 In many studies, around 50% of patients undergoing SAVR are aso undergoing additiona procedures [usuay coronary artery bypass grafting (CABG)] In a arge cohort of patients undergoing SAVR 2 NIHR Journas Library

19 DOI: /hta17330 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 33 (n=4131), the presence of additiona procedures was shown to be an independent predictor of adverse outcome [odds ratio (OR) 1.81, 95% confidence interva (CI) 1.4 to 2.3]. 21 Mortaity is approximatey doubed in patients receiving SAVR combined with CABG compared with those receiving SAVR aone. 15,19 As operative and ong-term risk is ikey to be substantiay higher for patients undergoing concomitant procedures, data from retrospective surgica series, that are not restricted to isoated SAVR, may tend to underestimate the effectiveness of SAVR. Medica management Patients Patients with severe symptomatic AS deemed ineigibe for surgery are treated with medica therapy. 2 In some cases, patients may be potentiay eigibe for invasive intervention but choose to be treated medicay. Treatments Since ipids are invoved in fibrosis, cacification and subsequent stenosis, ipid-owering agents, such as hydroxymethygutary-coenzyme A reductase inhibitors or statins, may be used to potentiay sow the progression of AS. 5 Other medications, such as angiotensin-converting enzyme (ACE) inhibitors and bisphosphonates, have aso been identified as potentiay usefu for the treatment of AS. 5 Outcomes In patients with severe AS, medica management is considered to bring itte benefit. 4 Studies have shown variabe resuts and medica therapy has not been demonstrated to ater the natura history of AS. 2,5 In a study of severe symptomatic AS patients who, as a resut of ineigibiity for transcatheter aortic vave impantation (TAVI) or SAVR or patient preference, underwent medica treatment, 1- and 1.5-year overa surviva rates were 63% and 58% respectivey. 22 These patients were od [mean age 81.7 years, standard deviation (SD) 8.7 years] and at particuary high risk [mean ogistic European System for Cardiac Operative Risk Evauation (EuroSCORE) 35.1%, SD 22.3%] and there was a high prevaence of comorbidities. Athough overa surviva was ow, as the prognosis of this patient group was poor, it may be that medica treatment brought some benefit. However, in the absence of controed data, it is difficut to judge whether or not medica management contributes additiona surviva for patients with severe AS. Baoon aortic vavuopasty Patients Baoon aortic vavuopasty has been used as an aternative approach in patients who are not fit for surgery, but this is usuay taiored to the patient. Baoon aortic vavuopasty can be associated with poor outcomes, but in specific patients who are haemodynamicay unstabe it may serve as a bridge to surgery or TAVI, or as a paiative measure where surgery is contraindicated. 2,3,23 Procedure Baoon aortic vavuopasty is the use of a baoon catheter to attempt to increase the size of the vave opening and improve bood fow. The catheter is passed into the narrowed aortic vave and then infated to diate the vave. 24 Outcomes Historica cohort data show that baoon vavuopasty resuts in compications in around 10% of cases 2 and is associated with high rates of mortaity and morbidity. 3,23 Restenosis is common, with recurrence of symptoms within a few months, 3,23 and baoon vavuopasty is thought to have itte impact on the natura history of AS. 2,18 Queen's Printer and Controer of HMSO This work was produced by Orando 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

20 INTRODUCTION Transcatheter aortic vave impantation Patients Transcatheter aortic vave impantation is a reativey new technique for the treatment of AS and, at the time of this report, it was considered for use in patients who are deemed ineigibe or too high risk for surgery. Where possibe, it is often used in preference to medica treatment or baoon vavuopasty. Since the work reported here has been competed, new Nationa Institute for Heath and Care Exceence (NICE) guidance 25 has been issued aowing TAVI in the foowing circumstances: For patients with aortic stenosis who are considered to be unsuitabe for surgica aortic vave repacement...tavi may be used with norma arrangements for cinica governance, consent and audit. For patients with aortic stenosis for whom SAVR is considered suitabe but to pose a high risk...tavi shoud ony be used with specia arrangements for cinica governance, consent and data coection or research. For patients with aortic stenosis for whom SAVR is considered suitabe and not to pose a high risk... TAVI shoud ony be used in the context of research. Procedure Vave impantation is achieved by keyhoe catheter technique (without bypass and open-heart surgery) in which the new vave, oaded within a catheter, is deivered with radiographic guidance into the native vave. In the process, the od, diseased vave is dispaced and the new TAVI vave is impanted within it. The first percutaneous aortic vave impantation was conducted in and, since then, more sophisticated deivery systems have been deveoped. 27 Based on data from 2007, the TAVI procedure takes around 2 to 2.5 hours. 28 Cinica advice is that procedure time may have reduced sighty since then in some cases, as a resut of equipment deveopment and increased famiiarity with the procedure. TAVI may be undertaken in a number of ways. Access routes A number of approaches to percutaneous heart vave repacements have been deveoped. The femora artery [retrograde transfemora (TF)], subcavian artery, and transapica (TA; antegrade transapica) and direct aortic approaches are the most commony used. 13 More recenty, there has been increased uptake of the direct aortic route in TAVI cases with a concomitant reduction in the TA approach. For the TF approach, a catheter, introduced through the groin, is passed up through the femora and iiac arteries to the aorta and aortic vave. 13 There may be difficuty with this approach, especiay where there is a high degree of atheroscerosis, because the catheter that must be passed through the iiac artery and aorta is arge. However, good cinica outcomes have resuted in the TF approach being favoured by some cardioogists. 27 TA aortic vave repacement has been deveoped for patients who are unsuited to the femora approach (unsuitabe aortic or iiac artery anatomy), athough it may be used more widey. 13 TA is conducted by a eft thoracotomy incision without cardiopumonary bypass but requires a genera anaesthetic. 13 Aternative vascuar access routes more commony used for TAVI incude the eft subcavian and direct aortic routes. The atter is used in patients in whom there is no suitabe TF or subcavian access. TAVI is normay performed under genera anaesthesia athough, for the TF approach, sedation and oca anaesthesia are used in suitabe patients. 10 The basis for seection of a route for TAVI is compex and invoves consideration of many factors reating to access to the vesse site, the extent of disease in the periphera vascuature and other factors such as respiratory status. 28 There aso appears to be a certain degree of subjective infuence. For exampe, in the European Pacement of AoRtic TraNscathetER Vaves (PARTNER) tria, rates of TF versus TA varied widey between centres, with TF being used in % of patients in different centres NIHR Journas Library

21 DOI: /hta17330 HEALTH TECHNOLOGY ASSESSMENT 2013 VOL. 17 NO. 33 Athough it is ikey that patient characteristics wi determine which approach is more appropriate, currenty there is no evidence to suggest whether or not one approach is better. From a systematic review of the iterature, 13 rates of impantation success for femora and TA approaches (93% and 94% respectivey) and 30-day surviva (90% and 88% respectivey) appear simiar. It is recommended that decisions are based on the expertise of those conducting procedures and the condition of the patient. 10 Transcatheter aortic vave impantation vaves Currenty, there are two vaves in cinica use for TAVI: the Edwards SAPIEN Transcatheter Heart Vave (Edwards Lifesciences, Irvine, CA, USA) and the Medtronic CoreVave ReVaving System (Medtronic, Minneapois, MN, USA). 13 These vaves are impanted in different ways. The baoon-expandabe (SAPIEN) vave is deivered retrogradey through a steerabe guiding catheter through the aorta to the aortic annuus. The CoreVave is a sef-expanding device oaded within a specia deivery catheter. The vave is deivered using standard transcatheter technique and advanced into the aortic annuus and depoyed by controed sef-expansion. 27 Both vave types may be impanted using the TF approach. The CoreVave device can aso be inserted via the eft subcavian and direct aortic routes. The Edwards SAPIEN vave can be inserted via the TA route and in some cases via the direct aortic route. 27 There is no consensus as to the comparative effectiveness of these types of vaves. In a systematic review of TAVI studies, rates of impantation success and 30-day surviva appeared simiar for both and no definitive concusions coud be drawn. 13 As the number of procedures increases, further investigation wi be possibe. The ony rea difference so far apparent between the vaves is a higher proportion of patients requiring pacemaker impantation after receiving CoreVave. 29 Repacement aortic vaves used for transcatheter impantation vary in size and an appropriate size is seected to match the size of the patient. Prosthesis patient mismatch (PPM) describes the condition when the prosthetic vave that has been fitted is too sma in reation to the size of the aortic annuus. 30 The degree of mismatch may be severe or moderate depending on the size of the indexed effective orifice area (IEOA); an IEOA of 0.85cm 2 /m 2 represents a moderate mismatch and an IEOA of <0.65cm 2 /m 2 represents a severe mismatch. 15,30 A study of patients undergoing TAVI successfuy found that 16% of patients had severe and 23% had moderate PPM foowing the procedure. 30 PPM may be encountered foowing TAVI or SAVR. Based on haemodynamic data, it is generay beieved that PPM is ess of a probem in TAVI than in SAVR. From their systematic review of SAVR PPM studies, Urso et a. 15 concuded that severe PPM coud be a predictor of short- and mid-term mortaity among patients undergoing SAVR and that a moderate PPM was ony ikey to be a predictor of eary- and mid-term mortaity in patients with poor ejection fraction. As severe mismatch appears to affect a reasonabe proportion of TAVI patients, and there is reasonabe evidence that it affects risk of mortaity, the seection of the most appropriate sized vave for TAVI is important. This is aso important to minimise the incidence of paravavuar eakage and aortic root rupture. As this is a reativey new procedure, the ong-term durabiity of TAVI vaves is aso currenty unknown. 10 However, with the potentia use of TAVI in a wider range of patients and the increasing ength of postprocedura ife expectancy, vave durabiity may become an important factor for consideration. Outcomes In centres experienced in conducting TAVIs, procedura success may be around 90% or more and cosey inked to experience, with greater earning resuting in better patient seection and outcomes. 10 Some studies have shown high rates of success and, in a systematic review of TAVI, more recent studies showed procedura mortaity rates of 0 10%. 13 Thirty-day mortaity may range from 5% to 18%. 10,13,29,31,32 Studies of ong-term mortaity show 2-year surviva rates of 70 80%. 10,29 In most TAVI studies, the majority of patients are >80 years of age and rates of comorbidities are high. 10,29 Thus, ong-term mortaity rates cannot be directy compared with those from SAVR series. 31 It is aso uncear to what extent rates of observed ong-term surviva depart from the natura rate of surviva in patients of this age and heath status. Queen's Printer and Controer of HMSO This work was produced by Orando 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

22 INTRODUCTION Other important outcomes incude paravavuar regurgitation, pacemaker requirement, effects on quaity of ife (QoL) and adverse events. Moderate to severe paravavuar regurgitation is higher in TAVI than in SAVR patients at 30 days, 1 year and 2 years. 33 Rates of pacemaker requirement appear to be somewhat higher in TAVI than in SAVR patients. 33 Furthermore, resuts from the UK TAVI registry showed pacemaker requirement of 24% for CoreVave and 7% for Edwards SAPIEN. 29 Transcatheter aortic vave impantation is thought to give important improvements in QoL. Studies have shown significant improvements in QoL from baseine foowing TAVI 34 and significant improvements compared with contro patients receiving medica therapy (additiona data provided by US PARTNER study investigators on request 14 ). Evidence suggests that intervention with TAVI improves QoL. However, the degree to which improvements are reated to an intervention being conducted [some medica patients aso showed sustained improvement in QoL (additiona data 14 )] and the degree to which improvements woud bring patients' QoL in ine with that of peope who had not suffered from AS are uncertain. Athough TAVI has shown good outcomes in terms of overa surviva and QoL, some associated adverse outcomes have been highighted: 10,29 major vascuar compications with the TF approach compared with other routes ong-term consequences of paravavuar eaks, even if mid to moderate regurgitation is considered not to have significant consequences in the short term atrioventricuar bock, the incidence, timing and predictors of which need to be identified more precisey. Current treatment guideines In 2008, NICE pubished its initia guidance for the use of TAVI in patients with AS; this was updated in As we as defining the reevant patient groups (see Transcatheter aortic vave impantation, Patients), the foowing guidance was given: 25 Cinicians wishing to undertake TAVI for patients with aortic stenosis for whom SAVR is considered suitabe but to pose a high risk...shoud take the foowing actions. n n Inform the cinica governance eads in their Trusts. Ensure that patients understand the risk of stroke and death, and the uncertainty about the procedure's efficacy in the ong term. Provide them with cear written information. In addition, the use of NICE's information for patients ( Understanding NICE guidance ) is recommended. Patient seection shoud be carried out by a mutidiscipinary team incuding interventiona cardioogists, cardiac surgeons, a cardiac anaesthetist and an expert in cardiac imaging. The mutidiscipinary team shoud determine the risk eve for each patient. TAVI is a technicay chaenging procedure that shoud be performed ony by cinicians and teams with specia training and experience in compex endovascuar cardiac interventions. Units undertaking this procedure shoud have both cardiac and vascuar surgica support for emergency treatment of compications. NICE encourages further research into TAVI for aortic stenosis. In particuar, NICE encourages cinicians to enter a suitabe patients into the UK TAVI tria. Information from research trias that wi be usefu for future guidance incudes patient seection criteria and comparisons between TAVI and SAVR in patients who woud be suitabe for either procedure. Outcomes shoud incude incidence of stroke and other adverse events, symptom reief, quaity of ife, occurrence of aortic regurgitation, and vave durabiity in the short and ong term. 6 NIHR Journas Library