HEALTH TECHNOLOGY ASSESSMENT

HEALTH TECHNOLOGY ASSESSMENT VOLUME 19 ISSUE 75 SEPTEMBER 2015 ISSN 1366-5278 Does home oxygen therapy (HOT) in addition to standard care reduce disease severity and improve symptoms in peope with chronic heart faiure? A randomised tria of home oxygen therapy for patients with chronic heart faiure Andrew L Cark, Miriam Johnson, Caroine Fairhurst, David Torgerson, Sarah Cockayne, Sara Rodgers, Susan Griffin, Victoria Agar, Lesey Jones, Samantha Nabb, Ian Harvey, Iain Squire, Jerry Murphy and Michae Greenstone DOI 10.3310/hta19750

Does home oxygen therapy (HOT) in addition to standard care reduce disease severity and improve symptoms in peope with chronic heart faiure? A randomised tria of home oxygen therapy for patients with chronic heart faiure Andrew L Cark, 1 * Miriam Johnson, 2 Caroine Fairhurst, 3 David Torgerson, 3 Sarah Cockayne, 3 Sara Rodgers, 3 Susan Griffin, 4 Victoria Agar, 5 Lesey Jones, 6 Samantha Nabb, 7 Ian Harvey, 8 Iain Squire, 9 Jerry Murphy 10 and Michae Greenstone 11 1 Hu York Medica Schoo, Caste Hi Hospita, Cottingham, UK 2 Hu York Medica Schoo, University of Hu, Hu, UK 3 Department of Heath Sciences, York Trias Unit, University of York, York, UK 4 Centre for Heath Economics, University of York, York, UK 5 Hu York Medica Schoo, University of York, York, UK 6 Schoo of Socia Sciences, University of Hu, Hu, UK 7 Department of Sport, Heath and Exercise Science, University of Hu, Hu, UK 8 Department of Academic Cardioogy, Caste Hi Hospita, Cottingham, UK 9 Leicester Cardiovascuar Biomedica Research Unit, Genfied Hospita, Leicester, UK 10 Department of Cardioogy, Darington Memoria Hospita, Darington, UK 11 Medica Chest Unit, Caste Hi Hospita, Cottingham, UK *Corresponding author Decared competing interests of authors: Caroine Fairhurst, Sarah Cockayne, Sara Rodgers and David Torgerson a report other grants from the Nationa Institute for Heath Research Heath Technoogy Assessment programme. Pubished September 2015 DOI: 10.3310/hta19750

This report shoud be referenced as foows: Cark AL, Johnson M, Fairhurst C, Torgerson D, Cockayne S, Rodgers S, et a. Does home oxygen therapy (HOT) in addition to standard care reduce disease severity and improve symptoms in peope with chronic heart faiure? A randomised tria of home oxygen therapy for patients with chronic heart faiure. Heath Techno Assess 2015;19(75). Heath Technoogy Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch ) and Current Contents / Cinica Medicine.

Heath Technoogy Assessment HTA/HTA TAR ISSN 1366-5278 (Print) ISSN 2046-4924 (Onine) Impact factor: 5.116 Heath Technoogy Assessment is indexed in MEDLINE, CINAHL, EMBASE, The Cochrane Library and the ISI Science Citation Index. This journa is a member of and subscribes to the principes of the Committee on Pubication Ethics (COPE) (www.pubicationethics.org/). Editoria contact: nihredit@southampton.ac.uk The fu HTA archive is freey avaiabe to view onine at www.journasibrary.nihr.ac.uk/hta. Print-on-demand copies can be purchased from the report pages of the NIHR Journas Library website: www.journasibrary.nihr.ac.uk Criteria for incusion in the Heath Technoogy Assessment journa Reports are pubished in Heath Technoogy Assessment (HTA) if (1) they have resuted from work for the HTA programme, and (2) they are of a sufficienty high scientific quaity as assessed by the reviewers and editors. Reviews in Heath Technoogy Assessment are termed systematic when the account of the search appraisa and synthesis methods (to minimise biases and random errors) woud, in theory, permit the repication of the review by others. HTA programme The HTA programme, part of the Nationa Institute for Heath Research (NIHR), was set up in 1993. It produces high-quaity research information on the effectiveness, costs and broader impact of heath technoogies for those who use, manage and provide care in the NHS. Heath technoogies are broady defined as a interventions used to promote heath, prevent and treat disease, and improve rehabiitation and ong-term care. The journa is indexed in NHS Evidence via its abstracts incuded in MEDLINE and its Technoogy Assessment Reports inform Nationa Institute for Heath and Care Exceence (NICE) guidance. HTA research is aso an important source of evidence for Nationa Screening Committee (NSC) poicy decisions. For more information about the HTA programme pease visit the website: http://www.nets.nihr.ac.uk/programmes/hta This report The research reported in this issue of the journa was funded by the HTA programme as project number 06/80/01. The contractua start date was in January 2010. The draft report began editoria review in November 2014 and was accepted for pubication in May 2015. The authors have been whoy responsibe for a data coection, anaysis and interpretation, and for writing up their work. The HTA editors and pubisher have tried to ensure the accuracy of the authors report and woud ike to thank the reviewers for their constructive comments on the draft document. However, they do not accept iabiity for damages or osses arising from materia pubished in this report. This report presents independent research funded by the Nationa Institute for Heath Research (NIHR). The views and opinions expressed by authors in this pubication are those of the authors and do not necessariy refect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Heath. If there are verbatim quotations incuded in this pubication the views and opinions expressed by the interviewees are those of the interviewees and do not necessariy refect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Heath. Queen s Printer and Controer of HMSO 2015. This work was produced by Cark et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Pubished by the NIHR Journas Library (www.journasibrary.nihr.ac.uk), produced by Prepress Projects Ltd, Perth, Scotand (www.prepress-projects.co.uk).

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

DOI: 10.3310/hta19750 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 75 Abstract Does home oxygen therapy (HOT) in addition to standard care reduce disease severity and improve symptoms in peope with chronic heart faiure? A randomised tria of home oxygen therapy for patients with chronic heart faiure Andrew L Cark, 1* Miriam Johnson, 2 Caroine Fairhurst, 3 David Torgerson, 3 Sarah Cockayne, 3 Sara Rodgers, 3 Susan Griffin, 4 Victoria Agar, 5 Lesey Jones, 6 Samantha Nabb, 7 Ian Harvey, 8 Iain Squire, 9 Jerry Murphy 10 and Michae Greenstone 11 1 Hu York Medica Schoo, Caste Hi Hospita, Cottingham, UK 2 Hu York Medica Schoo, University of Hu, Hu, UK 3 Department of Heath Sciences, York Trias Unit, University of York, York, UK 4 Centre for Heath Economics, University of York, York, UK 5 Hu York Medica Schoo, University of York, York, UK 6 Schoo of Socia Sciences, University of Hu, Hu, UK 7 Department of Sport, Heath and Exercise Science, University of Hu, Hu, UK 8 Department of Academic Cardioogy, Caste Hi Hospita, Cottingham, UK 9 Leicester Cardiovascuar Biomedica Research Unit, Genfied Hospita, Leicester, UK 10 Department of Cardioogy, Darington Memoria Hospita, Darington, UK 11 Medica Chest Unit, Caste Hi Hospita, Cottingham, UK *Corresponding author a..cark@hu.ac.uk Background: Home oxygen therapy (HOT) is commony used for patients with severe chronic heart faiure (CHF) who have intractabe breathessness. There is no tria evidence to support its use. Objectives: To detect whether or not there was a quaity-of-ife benefit from HOT given as ong-term oxygen therapy (LTOT) for at east 15 hours per day in the home, incuding overnight hours, compared with best medica therapy (BMT) in patients with severey symptomatic CHF. Design: A pragmatic, two-arm, randomised controed tria recruiting patients with severe CHF. It incuded a inked quaitative substudy to assess the views of patients using home oxygen, and a free-standing substudy to assess the haemodynamic effects of acute oxygen administration. Setting: Heart faiure outpatient cinics in hospita or the community, in a range of urban and rura settings. Participants: Patients had to have heart faiure from any aetioogy, New York Heart Association (NYHA) cass III/IV symptoms, at east moderate eft ventricuar systoic dysfunction, and be receiving maximay toerated medica management. Patients were excuded if they had had a cardiac resynchronisation therapy device impanted within the past 3 months, chronic obstructive pumonary disease fufiing the criteria for LTOT or maignant disease that woud impair surviva or were using a device or medication that woud impede their abiity to use LTOT. Queen s Printer and Controer of HMSO 2015. This work was produced by Cark 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

ABSTRACT Interventions: Patients received BMT and were randomised (unbinded) to open-abe LTOT, prescribed for 15 hours per day incuding overnight hours, or no oxygen therapy. Main outcome measures: The primary end point was quaity of ife as measured by the Minnesota Living with Heart Faiure (MLwHF) questionnaire score at 6 months. Secondary outcomes incuded assessing the effect of LTOT on patient symptoms and disease severity, and assessing its acceptabiity to patients and carers. Resuts: Between Apri 2012 and February 2014, 114 patients were randomised to receive either LTOT or BMT. The mean age was 72.3 years [standard deviation (SD) 11.3 years] and 70% were mae. Ischaemic heart disease was the cause of heart faiure in 84%; 95% were in NYHA cass III; the mean eft ventricuar ejection fraction was 27.8%; and the median N-termina pro-b-type natriuretic hormone was 2203 ng/. The primary anaysis used a covariance pattern mixed mode which incuded patients ony if they provided data for a baseine covariates adjusted for in the mode and outcome data for at east one post-randomisation time point (n = 102: intervention, n = 51; contro, n = 51). There was no difference in the MLwHF questionnaire score at 6 months between the two arms [at baseine the mean score was 54.0 (SD 18.4) for LTOT and 54.0 (SD 17.9) for BMT; at 6 months the mean score was 48.1 (SD 18.5) for LTOT and 49.0 (SD 20.2) for BMT; adjusted mean difference 0.10, 95% confidence interva (CI) 6.88 to 6.69; p = 0.98]. At 3 months, the adjusted mean MLwHF questionnaire score was ower in the LTOT group ( 5.47, 95% CI 10.54 to 0.41; p = 0.03) and breathessness scores improved, athough the effect did not persist to 6 months. There was no effect of LTOT on any secondary measure. There was a greater number of deaths in the BMT arm (n = 12 vs. n = 6). Adherence was poor, with ony 11% of patients reporting using the oxygen as prescribed. Concusions: Athough the study was significanty underpowered, HOT prescribed for 15 hours per day and subsequenty used for a mean of 5.4 hours per day has no impact on quaity of ife as measured by the MLwHF questionnaire score at 6 months. Suggestions for future research incude (1) a tria of patients with severe heart faiure randomised to have emergency oxygen suppy in the house, suppied by cyinders rather than an oxygen concentrator, powered to detect a reduction in admissions to hospita, and (2) a study of bed-bound patients with heart faiure who are in the ast few weeks of ife, powered to detect changes in symptom severity. Tria registration: Current Controed Trias ISRCTN60260702. Funding: This project was funded by the NIHR Heath Technoogy Assessment programme and wi be pubished in fu in Heath Technoogy Assessment; Vo. 19, No. 75. See the NIHR Journas Library website for further project information. viii NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19750 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 75 Contents List of tabes List of figures List of abbreviations Pain Engish summary Scientific summary xiii xv xvii xix xxi Chapter 1 Introduction 1 Heart faiure 1 Pumonary disease and oxygen 2 Heart disease and oxygen 3 Seep apnoea 3 Home oxygen therapy for breathessness 4 The home oxygen therapy tria rationae 5 Chapter 2 Synopsis of tria evoution 7 Tria structure and protoco 7 Stage 1: the North East Oxygen Network tria 7 Stage 2: the three-arm home oxygen therapy tria 9 Stage 3: the two-arm home oxygen therapy tria 10 Chapter 3 The home oxygen therapy tria: methods 11 Approvas obtained 11 Patient study group 12 Incusion criteria 12 Excusion criteria 12 Randomisation 12 Primary outcome 12 Power cacuation 13 Secondary outcomes 13 Measures of quaity of ife 13 Severity of heart faiure 14 Exercise capacity 14 Performance 14 Comorbidity 14 Prevaence of hypoxia 14 Safety and adherence 15 Other measurements 15 Cost-effectiveness 15 Adverse events 16 Queen s Printer and Controer of HMSO 2015. This work was produced by Cark 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

CONTENTS Chapter 4 Statistica anaysis 17 Tria competion 17 Baseine data 17 Primary anaysis 17 Sensitivity anayses 18 Secondary anaysis 18 Comparisons with the nocturna oxygen therapy subgroup 18 Secondary outcomes 18 Mortaity 18 Number of days aive and out of hospita 19 Heath-reated quaity of ife as measured by the European Quaity of Life-5 Dimensions 19 Prevaence of hypoxia 19 Patient-reported adherence 19 Number of hours of oxygen used measured by concentrator meter 19 Adverse events 19 Chapter 5 Study procedures 21 Baseine and foow-up assessments 21 Home oxygen therapy 21 Best medica therapy 22 Foow-up 22 Tria competion 23 Chapter 6 Resuts 25 Tria recruitment 25 Withdrawas 28 Baseine participant characteristics 28 Primary outcome 31 Predictors of Minnesota Living with Heart Faiure questionnaire score at 6 months 34 Minnesota Living with Heart Faiure questionnaire score at 3 and 12 months 35 Minnesota Living with Heart Faiure questionnaire score at 6 months adjusting for centre 35 The nocturna oxygen therapy subgroup 35 Secondary outcomes 38 Epworth Seepiness Scae 38 Numerica Rating Scae for breathessness 38 Hospita Anxiety and Depression Scae 40 Karnofsky Performance Status scae of physica activity 41 Charson Comorbidity Index 41 The 6-minute wak test 41 Prevaence of hypoxia 44 N-termina pro-b-type natriuretic hormone 44 Left ventricuar ejection fraction 47 Mortaity 47 Number of days aive and out of hospita 50 European Quaity of Life-5 Dimensions 50 Adverse events 51 Serious adverse events 51 Foow-up for serious adverse events 53 Non-serious adverse events 53 Adherence 54 Patient-reported adherence 55 Oxygen suppiers meter readings 56 Overnight Embetta seep study 57 x NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19750 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 75 Chapter 7 Acute oxygen substudy 61 Background 61 Methods 61 Incusion criteria 61 Excusion criteria 62 Procedures 62 Sampe size 62 Cacuations 62 Resuts 63 Chapter 8 The home oxygen therapy tria quaitative substudy 67 Background and rationae 67 Aims and objectives 67 Methods 67 Design 67 Samping strategy 68 Data coection 68 Data anaysis 68 Resuts 69 Participants 69 Findings 70 Chapter 9 Discussion 81 Cinica effectiveness 81 Quaity of ife measures 82 Safety 82 Why was the home oxygen therapy tria neutra? 82 Patient seection 83 Prevaence of hypoxia 83 Adherence 83 Substudies 85 Acute oxygen substudy (see Chapter 7) 85 Quaitative substudy (see Chapter 8) 85 Limitations 86 Concusions 88 Recommendations for future research 88 Acknowedgements 89 References 93 Appendix 1 Origina Heath Technoogy Assessment commissioning brief 101 Appendix 2 Reguatory approvas and detais of study sites 105 Appendix 3 Home oxygen therapy patient information sheet version 7 107 Appendix 4 Patient consent form 117 \ Appendix 5 Graphica checks of the assumptions for the primary anaysis mode 119 Queen s Printer and Controer of HMSO 2015. This work was produced by Cark 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

DOI: 10.3310/hta19750 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 75 List of tabes TABLE 1 The NYHA cassification of symptoms in heart faiure 1 TABLE 2 Schedue of patient assessments: study structure 22 TABLE 3 Number of participants randomised by group and site, n (%) 26 TABLE 4 Reasons (where given) for participant change of circumstances 28 TABLE 5 Baseine participant characteristics by treatment group 29 TABLE 6 Baseine characteristics by treatment group 30 TABLE 7 Raw and adjusted primary outcome data 32 TABLE 8 Baseine characteristics of participants as incuded in the primary anaysis by treatment group 33 TABLE 9 Coefficients from the primary anaysis mode 34 TABLE 10 Baseine participant characteristics of a patients randomised up to 30 Apri 2013 by treatment group 36 TABLE 11 Observed and adjusted summaries for the primary outcome measure by treatment group at each time point 37 TABLE 12 Observed summaries of the ESS by treatment group at each time point 38 TABLE 13 The NRS for breathessness score by treatment group at each time point 38 TABLE 14 Observed summaries of the HADS anxiety subscae by treatment group at each time point 40 TABLE 15 Observed summaries of the HADS depression subscae by treatment group at each time point 41 TABLE 16 Distribution of KPS scores at baseine 42 TABLE 17 Distribution of KPS scores at baseine for patients recruited by 1 May 2013 42 TABLE 18 Karnofsky Performance Status scae summaries by treatment group at each time point 43 TABLE 19 Charson Comorbidity Index scores by treatment group at each time point 44 TABLE 20 Six-minute wak test distance by treatment group at each time point 44 TABLE 21 Arteria oxygen saturation in the 6MWT 45 Queen s Printer and Controer of HMSO 2015. This work was produced by Cark et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xiii

LIST OF TABLES TABLE 22 Oxygen saturation measured before the 6MWT, by treatment group at each time point 45 TABLE 23 Oxygen saturation measured at peak (maximum saturation observed during 6MWT), by treatment group at each time point 46 TABLE 24 Oxygen saturation measured at 5 minutes post 6MWT, by treatment group at each time point 46 TABLE 25 Leve of NT-proBNP by treatment group at each time point 46 TABLE 26 Left ventricuar ejection fraction and severity of LV dysfunction by treatment group at each time point 48 TABLE 27 Days aive and out of hospita 50 TABLE 28 Summary of EQ-5D-3L scores for each treatment group by time point 51 TABLE 29 Serious adverse events 52 TABLE 30 Foow-up SAEs 53 TABLE 31 Non-SAEs 54 TABLE 32 Patient-reported adherence to HOT 55 TABLE 33 Oxygen machine usage data 56 TABLE 34 Resuts from the Embetta seep test by treatment group at each time point 58 TABLE 35 Baseine data for patients in the oxygen substudy 63 TABLE 36 Pressure measurements during right heart catheterisation 64 TABLE 37 Oxygen saturation and derived measures from cardiac catheterisation 64 TABLE 38 Patients in the quaitative substudy 69 TABLE 39 Major themes and subthemes 70 TABLE 40 Studies of adherence in patients receiving LTOT for chronic airways disease 84 TABLE 41 Timing of MREC approvas 105 TABLE 42 Timings of approvas for sites 105 xiv NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19750 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 75 List of figures FIGURE 1 The origina design for the NEON tria 7 FIGURE 2 The origina design for the three-arm HOT tria 9 FIGURE 3 The fina design for the two-arm HOT tria 10 FIGURE 4 The overa rate of recruitment in the HOT tria 25 FIGURE 5 Participant recruitment by site (two sites did not recruit any patients) 26 FIGURE 6 The CONSORT fow diagram 27 FIGURE 7 Adjusted means for MLwHF questionnaire score by treatment group over time from the primary anaysis mode 34 FIGURE 8 Kapan Meier surviva curve 49 FIGURE 9 Kapan Meier surviva curve for BMT vs. LTOT pus NOT 49 FIGURE 10 Reations between haemodynamic variabes 65 FIGURE 11 Histogram of the standardised residuas 119 FIGURE 12 Q Q pot of the standardised residuas 120 FIGURE 13 Scatterpot of residuas vs. predicted vaues 120 Queen s Printer and Controer of HMSO 2015. This work was produced by Cark 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

DOI: 10.3310/hta19750 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 75 List of abbreviations 6MWT 6-minute wak test HRQoL heath-reated quaity of ife AHI apnoea hypopnoea index HTA Heath Technoogy Assessment AMD adjusted mean difference KPS Karnofsky Performance Status scae ANCOVA anaysis of covariance LTOT ong-term oxygen therapy BMT best medica therapy LV eft ventricuar CCI Charson Comorbidity Index LVEF eft ventricuar ejection fraction CHF chronic heart faiure MLwHF Minnesota Living with Heart Faiure CI confidence interva MRC Medica Research Counci CONSORT Consoidated Standards of Reporting Trias MREC Medica Research and Ethics Committee COPD DAOH df ECG chronic obstructive pumonary disease days aive and out of hospita degree of freedom eectrocardiography NEON NOT NRS NT-proBNP North East Oxygen Network nocturna oxygen therapy Numerica Rating Scae N-termina pro-b-type natriuretic hormone EQ-5D EQ-5D-3L ESS FEV 1 European Quaity of Life-5 Dimensions European Quaity of Life-5 Dimensions-3 Leves Epworth Seepiness Scae forced expiratory voume in 1 second NYHA PaO 2 QoL RCT SAE SD New York Heart Association partia pressure of arteria oxygen quaity of ife randomised controed tria serious adverse event standard deviation FVC forced vita capacity SDB seep-disordered breathing HADS HOT Hospita Anxiety and Depression Scae home oxygen therapy SE SVR standard error systemic vascuar resistance HR hazard ratio Queen s Printer and Controer of HMSO 2015. This work was produced by Cark et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xvii

DOI: 10.3310/hta19750 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 75 Pain Engish summary Oxygen therapy is the administration of additiona oxygen for medica reasons. Patients with severe chronic heart faiure suffer from breathessness that may ruin their quaity of ife (QoL). Party because patients with severe ung disease benefit from home oxygen therapy (HOT), patients with severe heart faiure are often prescribed home oxygen. However, oxygen therapy can be burdensome. It imits mobiity, it can cause soreness around the nose and the equipment is noisy. There is no evidence to support its use in patients with heart faiure. The HOT tria was designed to measure any beneficia effects on QoL measured with the Minnesota Living with Heart Faiure questionnaire. We aocated, at random, 114 patients with severey symptomatic heart faiure either to receive home oxygen for 15 hours a day or not to receive oxygen therapy. A participants continued to receive the best medica therapy for their condition. The average age of patients was 70 years, and 70% of patients were men. None of the patients had a ow eve of oxygen in their bood. As ony 11% of patients reported that they used the oxygen for the fu 15 hours a day, the tria was stopped eary. We found no evidence that home oxygen improved patients QoL, symptoms or any other measurement of severity of heart faiure. There was a sma improvement in surviva with oxygen, but the difference was not statisticay significant. Further study might identify whether or not having emergency oxygen avaiabe at home woud reduce the need for admission to hospita. Queen s Printer and Controer of HMSO 2015. This work was produced by Cark et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xix

DOI: 10.3310/hta19750 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 75 Scientific summary Background Chronic heart faiure (CHF) affects at east 1% of the popuation and is responsibe for around 4% of a admissions to hospita in the UK. The prognosis of heart faiure if it is not we treated is beak. The cinica course for most patients with heart faiure tends to be one of gradua decine, often punctuated with episodes of severe deterioration resuting in hospitaisation. Towards the end of their ives, many patients with CHF become very symptomatic, with imiting breathessness on minima exertion and even at rest. Athough standard treatment may reieve symptoms, for many the ast few months and even years of ife can be miserabe, with persisting severe breathessness on minima exertion and episodic hospitaisation. Home oxygen therapy (HOT) is commony prescribed to patients with severey symptomatic CHF in order to aeviate suffering. However, unike the situation for patients with chronic obstructive airways disease and severe hypoxia, in whom oxygen proongs surviva, there is no evidence to support the use of HOT in patients with CHF. Objectives The HOT tria was designed to address the question of whether or not there is any effect of HOT on quaity of ife (QoL) in patients with severey symptomatic heart faiure. Secondary end points were to assess the effects of HOT on breathessness, 6-minute wak test distance, severity of eft ventricuar (LV) systoic dysfunction, N-termina B-type natriuretic hormone (NT-proBNP) eve and prognosis. The study consisted of three parts. The main study was a randomised controed tria (RCT) designed to measure the impact of HOT on QoL in severey symptomatic patients. A quaitative substudy assessed the burden on patients and their carers, and an acute oxygen substudy assessed whether or not there was any effect of oxygen given in the same concentration as used by concentrators at home on haemodynamics. Methods The main study was a pragmatic, two-arm RCT, recruiting patients with severe CHF. Patients were recruited from heart faiure outpatient cinics in hospita or the community, in a range of urban and rura settings. Patients had to have heart faiure of any aetioogy, severe symptoms (breathessness either at rest or on minima exertion) and at east moderate LV systoic dysfunction, and be receiving maximay toerated medica management. Patients were excuded if they had had a cardiac resynchronisation therapy device impanted in the past 3 months, chronic obstructive pumonary disease fufiing the criteria for ong-term oxygen therapy (LTOT), interstitia ung disease or maignant disease that woud impair surviva or were using a device or medication that woud impede their abiity to use LTOT. Patients received best medica therapy (BMT) and were randomised to open-abe LTOT, prescribed for 15 hours per day incuding overnight hours, or no oxygen therapy. Home oxygen was deivered by concentrators in the patients homes. The inspired oxygen was increased from 20.9% (norma room air) to approximatey 28%. There were two substudies: a inked quaitative substudy to assess the view of 25 patients and a free-standing oxygen substudy to assess the haemodynamic effects of acute oxygen administration. Queen s Printer and Controer of HMSO 2015. This work was produced by Cark et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxi

SCIENTIFIC SUMMARY Resuts The HOT tria was stopped eary by the funders, the Heath Technoogy Assessment programme, because of poor patient adherence to the oxygen prescription. Between Apri 2012 and February 2014, 114 patients were randomised to receive either LTOT or BMT. The mean age was 72.3 years [standard deviation (SD) 11.3 years] and 70% of patients were mae. Ischaemic heart disease was the cause of heart faiure in 84% of patients; 95% were in New York Heart Association cass III; mean eft ventricuar ejection fraction (LVEF) was 27.8%; and median NT-proBNP was 2203 ng/. Arteria oxygen saturation was norma at rest and there was no significant change in arteria oxygen saturation during exercise or during recovery from exercise. There was a ow prevaence of seep-disordered breathing. The primary anaysis used a covariance pattern mixed mode which incuded patients ony if they provided data for a baseine covariates adjusted for in the mode and outcome data for at east one post-randomisation time point (n = 102: intervention, n = 51; contro, n = 51). There was no difference in Minnesota Living with Heart Faiure (MLwHF) questionnaire score at 6 months between the two arms [at baseine the mean score was 54.0 (SD 18.4) for LTOT and 54.0 (SD 17.9) for BMT; at 6 months the mean score was 48.1 (SD 18.5) for LTOT and 49.0 (SD 20.2) for BMT; adjusted mean difference 0.10, 95% confidence interva (CI) 6.88 to 6.69; p = 0.98]. At 3 months, the adjusted mean MLwHF questionnaire score was ower in the LTOT group (adjusted mean difference 5.47, 95% CI 10.54 to 0.41; p = 0.03), coinciding with improvements in breathessness scores which did not persist to 6 months. There was no effect of LTOT on any secondary measure incuding 6-minute wak test distance, NT-proBNP eve and LVEF. There was sighty greater surviva in the oxygen-treated group (unadjusted hazard ratio 2.03, 95% CI 0.76 to 5.40, for BMT reative to LTOT), but the difference was not statisticay significant (p = 0.16). In the haemodynamic substudy there were no deeterious effects of 28% oxygen. There was a sma increase in cardiac output and a sma fa in pumonary vascuar resistance. Adherence to HOT was poor, with ony 11% of patients reporting using the oxygen as prescribed. Findings from the quaitative substudy suggested that participants viewed study participation in the tria both as an atruistic act and as a way of accessing optima cinica care. Adherence was reated not specificay to the context of a cinica tria but to a deep-seated beief that oxygen was a therapy for acute deterioration or for those with end-stage disease. Thus, participants fet that the use of LTOT was counterintuitive, despite cear expanation of the tria s aim. This misunderstanding formed a poor basis for subsequent weighing up by the participants of the benefit burden baance of the LTOT. Concusions The prevaence of hypoxia in patients with severe heart faiure at rest, foowing exercise and during an overnight seep test is ow. There is no evidence that LTOT, athough safe, improves the symptoms, prognosis or severity of heart faiure in patients with severe CHF at 6 months. There is no evidence to support the use of HOT in patients with heart faiure. xxii NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19750 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 75 Recommendations for future research The tria was stopped eary because of poor adherence to the prescription of 15 hours per day. However, the prescription was based on extrapoation from studies of patients with a different pathoogy, chronic airways disease, and who had severe hypoxia. It may be that shorter periods of exposure might have been effective, either in terms of symptom reief or in terms of preventing hospitaisation. We suggest that two further studies might be appropriate: 1. a tria of patients with severe heart faiure randomised to have emergency oxygen suppy in the house, suppied by cyinders rather than oxygen concentrator, powered to detect a reduction in admissions to hospita 2. a study of bed-bound patients with heart faiure who are in the ast few weeks of ife, powered to detect changes in symptom severity. Tria registration This tria is registered as ISRCTN60260702. Funding Funding for this study was provided by the Heath Technoogy Assessment programme of the Nationa Institute for Heath Research. Queen s Printer and Controer of HMSO 2015. This work was produced by Cark et a. under the terms of a commissioning contract issued by the Secretary of State for Heath. This issue may be freey reproduced for the purposes of private research and study and extracts (or indeed, the fu report) may be incuded in professiona journas provided that suitabe acknowedgement is made and the reproduction is not associated with any form of advertising. Appications for commercia reproduction shoud be addressed to: NIHR Journas Library, Nationa Institute for Heath Research, Evauation, Trias and Studies Coordinating Centre, Apha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxiii

DOI: 10.3310/hta19750 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 75 Chapter 1 Introduction Heart faiure Heart faiure is a cinica syndrome that arises when the heart fais to pump in a manner adequate to meet the body s needs. It is increasingy common and affects between 1% and 2% of the UK popuation. Its incidence and prevaence rise markedy with age. 1 The most common cause of heart faiure is myocardia infarction and, as more peope survive acute myocardia infarction with modern therapy, so the popuation of patients with damaged heart musces grows. 2 Heart faiure is the singe most common cause for admission to hospita in Engand and Waes and, foowing admission to hospita, there is a 25% chance of readmission or death within 12 weeks. By 1 month after an index admission, 15% of patients have died, either as an inpatient or during the days foowing discharge. 3 The prognosis of heart faiure is beak if it is not we treated. However, one of the greatest success stories of modern medicine is the dramatic improvement in prognosis for patients with chronic heart faiure (CHF). Good medica management argey consists of medicines designed to bock the adverse consequences of neuroendocrine activation such as beta-bockers, angiotensin-converting enzyme inhibitors and mineraocorticoid receptor antagonists. In seected patients, treatment with cardiac resynchronisation therapy aso improves prognosis and, taken together, these treatments approximatey doube ife expectancy. 4 Chronic heart faiure has been recognised for many years as having the greatest symptomatic burden of any chronic medica condition. 5 The cardina symptoms of heart faiure are breathessness and fatigue, particuary on exertion. Worsening breathessness is part of the cause of most admissions to hospita with heart faiure, athough many patients aso compain of anke sweing due to fuid retention. Drug therapy is very successfu in controing symptoms, and can induce remission in a number of patients; that is, their symptoms can remit amost entirey. However, the cinica course for most patients with heart faiure tends to be one of gradua decine, often punctuated with episodes of severe deterioration resuting in hospitaisation. Symptom severity is most commony measured using the New York Heart Association (NYHA) cassification of symptoms (Tabe 1). Towards the end of their ives, many patients with CHF become very symptomatic, with imiting breathessness on minima exertion (cass III) and even at rest (cass IV). Once they have reached this stage, athough patients need continued treatment with drugs known to improve prognosis, the emphasis of treatment becomes the reief of symptoms, that is, paiative care. However, athough drug treatment with diuretics (which reieve fuid congestion), other drugs and pacing devices may reieve symptoms, for many the ast few months and even years of ife can be miserabe, with persisting severe breathessness on minima exertion and episodic hospitaisation. TABLE 1 The NYHA cassification of symptoms in heart faiure NYHA cass I II III IV Symptoms Breathess on severe exertion (norma) Breathess and/or fatigue on moderate exertion Breathess and/or fatigue on mid exertion Breathess and/or fatigue at rest Queen s Printer and Controer of HMSO 2015. This work was produced by Cark 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

INTRODUCTION Athough there is some evidence that opioids may reieve breathessness in patients with chronic airways disease and cancer, 6 8 the evidence is mixed in heart faiure, 9 11 and there is no specific intervention for the intractabe breathessness of severe CHF. Another frequenty encountered group with severe breathessness is those patients with chronic airways disease. In patients with chronic airways disease who aso have hypoxia, there is reasonaby robust evidence that ong-term oxygen therapy (LTOT) can improve prognosis as we as symptoms (see Pumonary disease and oxygen). By extension from these data, physicians often use home oxygen therapy (HOT) for patients with severey symptomatic heart faiure. There is, however, no evidence that LTOT is hepfu in CHF, either for the reief of symptoms or to improve prognosis. Pumonary disease and oxygen For many years, patients with chronic airways disease or chronic obstructive pumonary disease (COPD) have been treated with LTOT, particuary if they have evidence of hypoxia at rest. Treatment is given for at east 15 hours a day (incuding overnight). The evidence for the benefit of oxygen therapy comes from randomised cinica trias; the Medica Research Counci s (MRC s) oxygen tria 12 and the Nocturna Oxygen Therapy (NOT) tria 13 are perhaps the best known. A Cochrane review of oxygen therapy for patients with chronic airways disease suggests that ong[-]term home oxygen therapy improved surviva in... COPD patients with severe hypoxaemia (PaO 2 [partia pressure of arteria oxygen] ess than 55 mmhg (8.0 kpa)). 14 In the MRC s oxygen tria, 12 treating five patients with severe hypoxaemic COPD with LTOT saved one ife over the 5-year study period. 14 The prognostic benefits were not apparent unti after more than 1 year of therapy. Athough it does not affect prognosis in peope with more modest hypoxaemia, LTOT does appear to hep by reducing the severity of breathessness. 15 There is no evidence that NOT aone (in other words, giving oxygen ony at night) improves prognosis. 14 The authors of the systematic review and meta-anaysis observed significant heterogeneity in most of their anayses and pointed out that most studies were either singe binded or not binded at a. They therefore recommended an individua approach to care unti data from arge randomised controed trias (RCTs) are avaiabe. Data on the effects of oxygen therapy on quaity of ife (QoL) in patients with chronic airways disease are not cear-cut. Athough the MRC reported that symptoms improved, few data were given. In patients with moderate hypoxaemia, the Cochrane meta-anaysis reported a reasonaby robust improvement in breathessness equivaent to a reduction of 0.78 cm on a 10-cm visua anaogue scae. 15 It is difficut to estimate adherence to LTOT in peope with airways disease. Using the oxygen deivery system for 15 hours per day is ceary burdensome, and most studies suggest that adherence to this demand is ess than 50%. 16 The summary figure of 45 70% is commony quoted, 17 but the studies from which the figures are derived are now quite od (see Chapter 9 for discussion). The ony recent study suggests that adherence remains poor. 18 Athough the origina studies demonstrated a positive reationship between benefit and duration of oxygen, the mechanism is not cear. Peope who used oxygen for a onger period of time woud have been more ikey to have prevented worse desaturations during seep or exertion, and the same benefit coud have been achieved by suppementa oxygen at night ony, or during exertion. Furthermore, if the prevention of exertion-induced desaturation heped exercise toerance, then increased physica activity and reconditioning over time coud have been the mechanism of improved symptoms and prognosis. 19 However, given that the ony studies to show an improvement in prognosis had a target of oxygen use for ong periods of time during the 24 hours, 15 hours per day remains the recommended prescription for prognostic benefit. 2 NIHR Journas Library www.journasibrary.nihr.ac.uk

DOI: 10.3310/hta19750 HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. 75 Heart disease and oxygen Oxygen is commony prescribed for patients with heart disease. There is a widespread perception that oxygen therapy can do no harm and may possiby be hepfu and, thus, patients are often given high concentrations of inspired oxygen immediatey foowing acute myocardia infarction or when they are admitted with acute pumonary oedema. It is aso commony used during an admission for CHF. Patients with severe (or even end-stage) CHF can appear very simiar to patients with severe chronic airways disease. They are breathess at rest or on minima exertion despite maxima medica therapy. A consequence is that HOT is often prescribed for severey breathess patients with heart faiure, even in the absence of hypoxia, particuary towards the end of ife. There is ony very imited evidence for the use of oxygen in heart disease, and much of the evidence suggests that oxygen might be harmfu. In a study of patients with acute myocardia infarction, oxygen was given at as near to 100% as possibe. Oxygen therapy was associated with a fa in cardiac output and stroke voume, together with a rise in heart rate. 20 The faiing heart requires a higher fiing pressure. The higher the fiing pressure, the worse the cardiac function; hence an intervention causing a rise in fiing pressure is deeterious. In a study of 10 patients with CHF, 21 100% oxygen caused a rise in cardiac fiing pressure, a fa in cardiac output and an increase in systemic vascuar resistance (SVR). The SVR represents the oad against which the heart has to work: the higher the SVR, the greater the work required of the heart. In another study of 12 patients with CHF, 22 high-dose oxygen was associated with an increase in eft ventricuar (LV) fiing pressure. In contrast, in a study of patients with CHF given ower doses of oxygen (50%), exercise capacity increased and patients were ess breathess and had a ower eve of ventiation during exercise than during exercise with room air. 23 Findings from studies are inconsistent; another study has suggested that suppementary oxygen has itte effect on exercise performance. 24 There is itte evidence of the effect of oxygen when given to patients with heart faiure at the much more modest eves used for treating chronic airways disease. There is no evidence on whether or not the ow-dose oxygen deivered by home oxygen concentrators is safe in patients with heart faiure. There is no evidence about the effects of ow-dose oxygen on haemodynamics in patients with severe heart faiure. The equivoca findings are perhaps not surprising. Oxygen is perhaps ikey to be hepfu ony to peope who are hypoxic (i.e. have ow eves of arteria oxygen). Where it has been measured, oxygen has been found to be norma, or even high, during exercise in patients with CHF. 25 When patients with CHF are found to be hypoxic, there is usuay an aternative expanation, such as coincident ung disease or congenita heart disease. 26 Thus, athough patients with CHF may resembe patients with chronic airways disease cinicay, they are much ess ikey to be hypoxic, and so might be thought, a priori, to be ess ikey to gain benefit from oxygen treatment. Seep apnoea One compicating issue in patients with heart faiure is the possibe contribution of seep-disordered breathing (SDB). Depending on the popuation studied, approximatey one-third of patients with heart faiure have SDB. 27 SDB happens when breathing stops during seep. There are two kinds of SDB: obstructive and centra seep apnoea. In obstructive seep apnoea, there is upper airways obstruction from soft tissues; respiratory efforts continue but there is no movement of air into the ungs. The patient usuay wakes and breathing restarts. In centra seep apnoea, the centra drive to breathe stops, usuay in a cycica manner aternating with periods of hyperventiation. Queen s Printer and Controer of HMSO 2015. This work was produced by Cark 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