Scientific summary. Health Economics Research Unit, University of Aberdeen, Aberdeen, UK 2

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1 Mutipe-frequency bioimpedance devices for fuid management in peope with chronic kidney disease receiving diaysis: a systematic review and economic evauation Graham Scotand, 1 Moira Cruickshank, 2 Eisabet Jacobsen, 1 David Cooper, 2 Cynthia Fraser, 2 Micha Shimonovich, 2 Angharad Marks 3 and Miriam Brazzei 2 * 1 Heath Economics Research Unit, University of Aberdeen, Aberdeen, UK 2 Heath Services Research Unit, University of Aberdeen, Aberdeen, UK 3 NHS Grampian, Aberdeen Roya Infirmary, Aberdeen, UK *Corresponding author m.brazzei@abdn.ac.uk Decared competing interests of authors: none Pubished January 2018 DOI: /hta22010 Scientific summary Mutipe-frequency bioimpedance devices in chronic kidney disease Heath Technoogy Assessment 2018; Vo. 22: No. 1 DOI: /hta22010 NIHR Journas Library

2 SCIENTIFIC SUMMARY: MULTIPLE-FREQUENCY BIOIMPEDANCE DEVICES IN CHRONIC KIDNEY DISEASE Scientific summary Background Chronic kidney disease (CKD) is a ong-term condition in which the kidneys do not function effectivey. In the most severe stage of CKD, the kidneys operate at 15% of their norma function, and treatment in the form of conservative management, kidney transpantation or diaysis wi be required. Diaysis invoves removing waste products and excess fuid from the boodstream, and there are two main types: 1. Haemodiaysis (HD), in which the person is connected to a diaysis machine that uses a semipermeabe membrane to fiter out excess sats and water in the bood; HD is commony prescribed for 4 hours, three times per week, administered either in hospita, in a sateite unit or at home. 2. Peritonea diaysis (PD), in which diaysis fuid is passed into the peritonea cavity through a permanent catheter and waste products and excess fuid are drawn from the bood into the diaysis fuid by the bood vesses ining the cavity. The process of fuid exchange can either be carried out overnight by a machine (automated PD) or conducted manuay, four times daiy, taking minutes for each fuid exchange (continuous ambuatory PD). To optimise the voume of fuid to be removed during diaysis (to avoid underhydration or overhydration, both of which are associated with potentiay serious compications), peope are assigned a target weight, which is commony assessed using cinica methods, such as weight gain between diaysis sessions, preand post-diaysis bood pressure and patient-reported symptoms. However, these methods are not precise, and measurement devices based on bioimpedance technoogy, which are non-invasive, simpe and inexpensive, are increasingy used in diaysis centres. There is currenty imited evidence on the cinica effectiveness and cost-effectiveness of bioimpedance devices compared with standard cinica assessment for fuid management in peope with CKD receiving diaysis. Objectives The specific objectives of this assessment were to: systematicay review the evidence on the cinica effectiveness of mutipe-frequency bioimpedance devices [i.e. Body Composition Monitor (BCM; Fresenius Medica Care, Bad Homburg vor der Höhe, Germany), MutiScan 5000 (Bodystat, Dougas, Ise of Man), BioScan 920-II (Matron Internationa, Essex, UK), BioScan touch i8 (Matron Internationa, Essex, UK) and InBody S10 (InBody, Seou, South Korea)] compared with that of standard cinica assessment for fuid management in peope with CKD receiving diaysis treatment systematicay review existing economic evauations on mutipe-frequency bioimpedance devices for peope with CKD receiving diaysis treatment deveop a de novo economic mode to assess the cost-effectiveness of mutipe-frequency bioimpedance technoogies (using BCM, MutiScan 5000, BioScan 920-II, BioScan touch i8 or InBody S10) for fuid management in peope with CKD receiving diaysis treatment versus standard cinica assessment. ii NIHR Journas Library

3 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 1 (SCIENTIFIC SUMMARY) Methods Cinica effectiveness Comprehensive eectronic searches were undertaken between June and October 2016 to identify reevant reports of pubished studies. There were no date restrictions. Databases searched incuded MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Science Citation Index and Cochrane Centra Register of Controed Trias (CENTRAL). Evidence was considered from randomised controed trias (RCTs) assessing mutipe-frequency bioimpedance devices versus standard cinica assessment, and non-randomised cohort studies. The popuation was peope with CKD being treated with HD or PD. The comparator was standard cinica assessment, consisting of bood pressure, presence of oedema, changes in weight, residua rena function, pre-existing cardiovascuar (CV) conditions and/or patient-reported symptoms of overhydration or underhydration. Data on cinica outcomes, intermediate outcomes and patient-reported outcomes were extracted from the incuded studies. Binary and continuous data were meta-anaysed (when appropriate) as pooed summary effect sizes using standard inverse variance methods. Cost-effectiveness A Markov mode was deveoped to simuate the progression of the prevaent diaysis cohort through a set of mutuay excusive heath states capturing mortaity, CV events and other causes of hospitaisation, transpantation (for those isted) and graft faiure post transpant. The mode incuded costs to the heath service of providing diaysis treatment, costs of inpatient hospitaisation, costs of outpatient attendance, costs of kidney transpantation, post-transpant foow-up and immunosuppressant costs and costs of diaysis foowing transpant graft faiure. Heath state utiity mutipiers were identified and incorporated for the diaysis and post-transpant states in the mode, aowing cumuative quaity-adjusted ife-years (QALYs) to be estimated. Further proportiona reductions in heath state utiity were modeed in the short term for a hospitaisation events and in the ong term foowing incident CV hospitaisation events. The added costs and pausibe effects of bioimpedance-guided fuid management (based on four tests per year) were added to the baseine mode, and the cumuative costs and QALYs were simuated over the ifetime of the cohort in the aternative arms of the mode. In the base-case cinica effectiveness scenarios, proportiona reductions in a-cause mortaity and CV event-reated or a-cause hospitaisation were appied in the bioimpedance-guided arm of the mode. Given the imited direct evidence from the cinica effectiveness review, these effects [incorporated as hazard ratios (HRs)] were primariy estimated by inking effects on surrogate end points [arteria stiffness (puse wave veocity; PWV) and hydration status] to possibe effects on the fina outcomes using secondary pubished sources. Resuts Cinica effectiveness A tota of five RCTs (pubished in six papers) anaysing a tota of 904 participants, and eight non-randomised studies (pubished in nine papers) anaysing a tota of 4915 participants were incuded in the review of cinica effectiveness. A incuded studies investigated the use of the BCM in the reevant popuation, a of which were aduts. Of the RCTs, one tria was rated as having a high risk of bias, and four trias did not provide sufficient information to make a robust judgement. We further identified four ongoing trias. The resuts of the meta-anayses conducted for this assessment showed that both absoute overhydration and reative overhydration were significanty ower in the BCM group than in the standard cinica assessment group [weighted mean difference 0.44, 95% confidence interva (CI) 0.72 to 0.15, p = 0.003, I 2 = 49%; and weighted mean difference 1.84, 95% CI 3.65 to 0.03, p = 0.05, I 2 = 52%, respectivey]. The pooed effects of bioimpedance monitoring on bood pressure (mean difference 2.46, 95% CI 5.07 to 0.15; p = 0.06, I 2 = 0%), arteria stiffness (mean difference 1.18, 95% CI 3.14 to 0.78; p = 0.24, I 2 = 92%) and mortaity (HR 0.689, 95% CI 0.23 to 2.08; p = 0.51, I 2 = 54%) were not statisticay significant. Queen s Printer and Controer of HMSO This work was produced by Scotand 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. iii

4 SCIENTIFIC SUMMARY: MULTIPLE-FREQUENCY BIOIMPEDANCE DEVICES IN CHRONIC KIDNEY DISEASE Evidence from non-randomised studies suggested that there were no statisticay significant differences in bood pressure between the foowing subgroups: patients in whom overhydration was reduced within 6 months compared with those whose overhydration was not reduced within 6 months, patients receiving short-term versus ong-term diaysis and patients who were normohydrated compared with those who were overhydrated. Cost-effectiveness Six main cinica effectiveness scenarios were expored in the cost-effectiveness modeing, with HRs of varying magnitude appied to a-cause mortaity and CV event-reated or a-cause hospitaisation rates. One of the scenarios aso expored the impact of modeing a reduction in the use (cost) of bood pressure medication with bioimpedance-guided fuid management. There was insufficient evidence to justify the incusion of effects on diaysis requirements (number and duration of sessions), residua rena function and the heath-reated quaity of ife of patients receiving diaysis (independent of effects on hospitaisation). When diaysis costs were incuded in the mode, the incrementa cost-effectiveness ratios (ICERs) for bioimpedance-guided fuid management ranged from 58,723 to 66,007 per QALY gained. These ICERs reated to mean incrementa costs that varied between 4518 and 35,676, and corresponding ifetime incrementa QALY gains that varied from 0.07 to The costs of diaysis in added years made up the vast majority of the incrementa costs. When diaysis costs were excuded from the mode, the base-case ICERs ranged from 15,215 to 21,201. Sensitivity anayses Beyond the incusion/excusion of diaysis costs, the cost-effectiveness resuts were found to be most sensitive to the effect of bioimpedance-guided fuid management on a-cause mortaity. When diaysis costs were incuded in the mode, the ICER was most favourabe ( 40,300) when the HR for a-cause mortaity was set equa to one, that is, no reduction in mortaity eading to no extra diaysis costs, but retained benefits on non-fata hospitaisation events. With diaysis costs and an effect on mortaity incuded in the mode, there woud need to be an accompanying effect of bioimpedance monitoring on the cost of diaysis and/or heath state utiity over the ifetime of patients receiving diaysis. There is currenty imited avaiabe evidence to justify such scenarios. When diaysis costs were excuded from the mode, the ICER for bioimpedance-guided fuid management remained beow 20,000 in most scenarios assessed. Given the reativey ow cost of adding bioimpedance testing four times a year, the ICERs remained favourabe with modest effects on mortaity and hospitaisation rates. With diaysis costs excuded, probabiities of cost-effectiveness ranged from 61% to 67% at a wiingness-to-pay threshod of 20,000 per QALY gained. Discussion Strengths, imitations of the anayses and uncertainties The methods used to conduct this assessment were detaied and thorough. The main imitation was the ack of evidence on any of the specified devices, with the exception of the BCM, and on chidren receiving diaysis. In ight of the imited avaiabe cinica effectiveness evidence, the economic modeing reied on estimated effects on surrogate end points (hydration status, arteria stiffness and bood pressure) to mode pausibe reductions in a-cause mortaity and CV event-reated/a-cause hospitaisation. Criticay, there were no idea sources of evidence to ink intervention-induced changes in the reevant surrogates to effects on mortaity and hospitaisation rates. Therefore, the possibe effects were informed by reference to cross-sectiona prognostic studies, eading to great uncertainty in the robustness of the cost-effectiveness findings. iv NIHR Journas Library

5 HEALTH TECHNOLOGY ASSESSMENT 2018 VOL. 22 NO. 1 (SCIENTIFIC SUMMARY) Generaisabiity of the findings The incuded trias invoved ony the BCM, and it is not known if the effects of this device generaise across the other mutipe-frequency bioimpedance devices specified for this appraisa. None of the incuded studies was conducted in the UK or invoved paediatric popuations, so the appicabiity of our findings in those contexts is uncear. The generaisabiity of the modeed cost-effectiveness scenarios is aso dependent on the generaisabiity of the estimated pooed effects of bioimpedance-guided management on arteria stiffness (PWV) or inferred effects on hydration status. As a the incuded RCTs were conducted outside the UK, this remains uncertain. Concusions Our findings indicate that both absoute overhydration and reative overhydration are significanty ower among peope with CKD receiving diaysis who are managed using the BCM instead of standard cinica methods. The use of bioimpedance monitoring may reduce systoic bood pressure (SBP), athough the pooed estimates of effects show a certain degree of heterogeneity and a non-significant effect. The current evidence does not demonstrate a significant effect on arteria stiffness and on mortaity. There is currenty no evidence to indicate that these findings are generaisabe to paediatric popuations or across other mutifrequency bioimpedance devices. With possibe effects on mortaity and hospitaisation rates modeed indirecty through estimated pooed reductions in surrogate end points (PWV or overhydration), it appears unikey that the ICER for bioimpedance-guided fuid management wi fa beow standard threshods for cost-effectiveness with diaysis costs incuded. If diaysis costs are excuded from the mode, the ICER may feasiby fa beow 20,000, with modest effects on mortaity and/or hospitaisation rates. The economic modeing is subject to substantia uncertainty, given the imitations in the cinica evidence base. Impications for service provision The current evidence suggests that BCM use, in addition to routine cinica assessment, may reduce overhydration and potentiay improve intermediate outcomes such as SBP, but significant effects on mortaity have not been demonstrated. It woud be usefu if services that are currenty, or subsequenty, routiney using the BCM to augment routine cinica assessment coud provide information on ong-term outcomes before and after introduction of the bioimpedance device to extend the current evidence base. Services that pan to introduce the routine use of the BCM to augment routine cinica assessment may consider adopting a protoco that is transparent and reproducibe. Suggested research priorities The utimate aim of introducing mutipe-frequency bioimpedance device measurement in addition to standard cinica assessment into cinica practice is to reduce cinicay important events such as mortaity, CV events and hospita admissions, whether this is through a reduction in overhydration- or underhydrationreated events. However, cinica effectiveness has not been demonstrated yet for these important heath outcomes. The effects of introducing mutipe-frequency bioimpedance device measurement on intermediate outcomes, such as SBP contro and hydration status, have been documented. The timeine from these intermediate end points to those end points that are cinicay reevant, however, may not be captured within the identified cinica trias. The studies were generay short-ived and the sustainabiity of introducing a change in routine practice has yet to be estabished. Those centres that have introduced routine mutipe-frequency bioimpedance device measurement to augment cinica assessment of diaysis patients may consider conducting adjusted retrospective anayses to estimate effects on cinicay reevant and intermediate outcomes both before and after the introduction of the device. It woud aso be usefu to obtain further information on the sustainabiity of the measurement and its use in cinica practice over a sustained period. Queen s Printer and Controer of HMSO This work was produced by Scotand 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

6 SCIENTIFIC SUMMARY: MULTIPLE-FREQUENCY BIOIMPEDANCE DEVICES IN CHRONIC KIDNEY DISEASE It is important that currenty ongoing and future cinica trias are adequatey powered to identify any cinica benefit (not just intermediate benefits) and the ikey timeine of how any benefit (e.g. through better bood pressure contro) is factored in to aow such studies to truy demonstrate whether or not an important cinica effect exists. Future trias shoud adopt protocos that are ikey to be cinicay appicabe in mutipe areas (e.g. 3-monthy testing to aow use at routine review appointments). Future trias shoud aso carefuy match their incuded popuation to the outcomes of interest. For exampe, if the primary outcome is a reduction in bood pressure, an appropriate cinica popuation woud be patients who had high bood pressure and were fuid overoaded post HD, as they woud be ikey to have overhydration-reated hypertension. Removing fuid from patients with hypertension who are not overhydrated may resut in harm to some participants. Reated to further key uncertainties identified in the economic modeing, we recommend that future studies: assess the impact of hydration status and bioimpedance-guided fuid management on heath-reated quaity of ife, preferaby using a generic preference-based instrument suitabe for the estimation of QALYs assess the impact of bioimpedance testing on the frequency and duration of diaysis, and associated costs further deveop and strengthen the evidence base for inking changes in surrogate end points (e.g. fuid management-induced changes in bood pressure and PWV) to changes in heath outcomes (mortaity, CV events, hospitaisation rates). Ideay, data from reevant randomised studies shoud be used to quantify reationships between intervention-induced changes in the surrogate end points and onger-term changes in heath outcomes quantify the risks and cost burdens of different types of hospitaisation event in peope receiving diaysis, and better characterise the impact of hydration status on these risks. Study registration This study is registered as PROSPERO CRD Funding Funding for this study was provided by the Heath Technoogy Assessment programme of the Nationa Institute for Heath Research. vi NIHR Journas Library

7 Heath Technoogy Assessment NICE TAR and DAR ISSN (Print) ISSN (Onine) Impact factor: Heath Technoogy Assessment is indexed in MEDLINE, CINAHL, EMBASE, The Cochrane Library and the Carivate Anaytics Science Citation Index. This journa is a member of and subscribes to the principes of the Committee on Pubication Ethics (COPE) ( Editoria contact: journas.ibrary@nihr.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 commissioned and funded by the HTA programme on behaf of NICE as project number 15/17/07. The protoco was agreed in June The assessment report began editoria review in December 2016 and was accepted for pubication in May 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 Scotand 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 (

8 Heath Technoogy Assessment Editor-in-Chief Professor Hywe Wiiams Director, HTA Programme, UK and Foundation Professor and Co-Director of the Centre of Evidence-Based Dermatoogy, University of Nottingham, UK NIHR Journas Library Editor-in-Chief Professor Tom Waey Director, NIHR Evauation, Trias and Studies and Director of the EME Programme, UK NIHR Journas Library Editors Professor Ken Stein Chair of HTA and EME Editoria Board and Professor of Pubic Heath, University of Exeter Medica Schoo, UK Professor Andrée Le May Chair of NIHR Journas Library Editoria Group (HS&DR, PGfAR, PHR journas) Dr Martin Ashton-Key Consutant in Pubic Heath Medicine/Consutant Advisor, NETSCC, UK Professor Matthias Beck Professor of Management, Cork University Business Schoo, Department of Management and Marketing, University Coege Cork, Ireand Dr Tessa Criy Director, Crysta Bue Consuting Ltd, UK Dr Eugenia Cronin Senior Scientific Advisor, Wessex Institute, UK Dr Peter Davidson Director of the NIHR Dissemination Centre, University of Southampton, UK Ms Tara Lamont Scientific Advisor, NETSCC, UK Dr Catriona McDaid Senior Research Feow, York Trias Unit, Department of Heath Sciences, University of York, UK Professor Wiiam McGuire Professor of Chid Heath, Hu York Medica Schoo, University of York, UK Professor Geoffrey Meads Professor of Webeing Research, University of Winchester, UK Professor John Norrie Chair in Medica Statistics, University of Edinburgh, UK Professor John Powe Consutant Cinica Adviser, Nationa Institute for Heath and Care Exceence (NICE), UK Professor James Raftery Professor of Heath Technoogy Assessment, Wessex Institute, Facuty of Medicine, University of Southampton, UK Dr Rob Riemsma Reviews Manager, Keijnen Systematic Reviews Ltd, UK Professor Heen Roberts Professor of Chid Heath Research, UCL Institute of Chid Heath, UK Professor Jonathan Ross Professor of Sexua Heath and HIV, University Hospita Birmingham, 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 Professor Martin Underwood Director, Warwick Cinica Trias Unit, Warwick Medica Schoo, University of Warwick, UK Pease visit the website for a ist of members of the NIHR Journas Library Board: Editoria contact: journas.ibrary@nihr.ac.uk