ANAEMIA MANAGEMENT IN CHRONIC KIDNEY DISEASE

Transcription

1 The National Collaborating Centre for Chronic Condition Funded to produce guideline for the NHS by NICE ANAEMIA MANAGEMENT IN CHRONIC KIDNEY DISEASE National clinical guideline for management in adult and children Publihed by

2 Anaemia management in chronic kidney dieae Miion tatement The Royal College of Phyician play a leading role in the delivery of high quality patient care by etting tandard of medical practice and promoting clinical excellence. We provide phyician in the United Kingdom and overea with education, training and upport throughout their career. A an independent body repreenting over 20,000 Fellow and Member worldwide, we advie and work with government, the public, patient and other profeion to improve health and healthcare. The National Collaborating Centre for Chronic Condition The National Collaborating Centre for Chronic Condition (NCC-CC) i a collaborative, multi-profeional centre undertaking commiion to develop clinical guidance for the NHS. The NCC-CC wa etablihed in It i an independent body, houed within the Clinical Standard Department at the Royal College of Phyician of London. The NCC-CC i funded by the National Intitute for Health and Clinical Excellence (NICE) to undertake commiion for national clinical guideline on an annual rolling programme. Citation for thi document National Collaborating Centre for Chronic Condition. Anaemia management in chronic kidney dieae: national clinical guideline for management in adult and children. London: Royal College of Phyician, ISBN-13: ISBN-10: ROYAL COLLEGE OF PHYSICIANS 11 St Andrew Place, London NW1 4LE Regitered charity No Copyright 2006 Royal College of Phyician of London All right reerved. No part of thi publication may be reproduced in any form (including photocopying or toring it in any medium by electronic mean and whether or not traniently or incidentally to ome other ue of thi publication) without the written permiion of the copyright owner. Application for the copyright owner written permiion to reproduce any part of thi publication hould be addreed to the publiher. Typeet by Dan-Set Graphic, Telford, Shrophire Printed in Great Britain by The Lavenham Pre Ltd, Suffolk

3 Content Member of the Guideline Development Group Acknowledgement Preface v vi vii DEVELOPMENT OF THE GUIDELINE 1 Introduction 1.1 Definition of anaemia Chronic kidney dieae: definition and prevalence How to ue thi guideline Recommendation for children with anaemia of CKD 9 2 Methodology 2.1 Aim Scope Audience Involvement of people with anaemia of CKD Guideline limitation Other work relevant to the guideline Background The proce of guideline development Diclaimer Funding 17 3 Key meage of the guideline 3.1 Key prioritie for implementation Algorithm Audit criteria 27 THE GUIDELINE 4 Diagnotic evaluation and aement of anaemia 4.1 Diagnotic role of Hb level Diagnotic role of glomerular filtration rate Diagnotic tet to determine iron tatu Meaurement of erythropoietin 47 5 Management of anaemia 5.1 Initiation of ESA therapy in iron-deficient patient Maximum iron level in patient with anaemia of CKD Clinical utility of ESA therapy in iron-replete patient Nutritional upplement 55 iii

4 Anaemia management in chronic kidney dieae 5.5 Androgen Hyperparathyroidim Patient-centred care: ESA Patient education programme 67 6 Aement and optimiation of erythropoiei 6.1 Benefit of treatment with ESA Blood tranfuion Comparion of ESA Early or deferred ESA therapy Coordinating care Providing ESA ESA: optimal route of adminitration ESA: doe and frequency Optimal Hb level Optimum haemoglobin level in children with anaemia of CKD Adjuting ESA therapy Treating iron deficiency: correction Treating iron deficiency: maintenance ESA: monitoring iron tatu during treatment Monitoring treatment of anaemia of CKD 7.1 Monitoring iron tatu Monitoring haemoglobin level Detecting ESA reitance Managing ESA reitance Reearch recommendation 129 APPENDICES Appendix A: Evidence-baed clinical quetion and literature earche 131 Appendix B: Scope 135 Appendix C: Health economic model: target haemoglobin in Appendix C: haemodialyi patient 139 Appendix D: Health economic calculation: route of adminitration of ESA 149 Appendix E: Gloary 153 REFERENCES 159 iv

5 Member of the Guideline Development Group Dr David Halpin (Chair) Conultant Thoracic Phyician, Royal Devon and Exeter NHS Foundation Trut Dr Penny Ackland, Royal College of General Practitioner General Practitioner, London Dr Samir Agrawal, Royal College of Pathologit Senior Lecturer, Queen Mary, Univerity of London Honorary Conultant in Haematology, Bart and The London NHS Trut M Carol Anderon, Anaemia Nure Specialit Aociation Anaemia Nure Specialit, Eat Kent Hopital NHS Trut Mr Robert Bradley, UK Renal Pharmacy Group Pharmacit, Cardiff and Vale NHS Trut Mr Robert Dunn, National Kidney Federation Patient and Carer Repreentative, Devon Dr Jonathan Evan, Britih Aociation for Paediatric Nephrology Conultant Paediatrician, Nottingham City Hopital NHS Trut Mr Bernadette Ford, NCC-CC Information Scientit Dr Jane Fiher, NCC-CC Project Manager (until July 2005) Mr Rob Grant, NCC-CC Senior Project Manager (from Augut 2005) M Chritine Howard, National Kidney Reearch Fund Patient and Carer Repreentative, Devon M Karen Jenkin, Royal College of Nuring Anaemia Nure Specialit, Eat Kent Hopital NHS Trut Dr Mick Kumwenda, Britih Renal Society Conultant Renal Phyician, Conwy and Denbighhire NHS Trut Profeor Alion MacLeod, Cochrane Renal Group Conultant Nephrologit, Aberdeen Royal Infirmary Profeor of Medicine, Univerity of Aberdeen Dr Nyokabi Muila, NCC-CC Health Service Reearch Fellow in Guideline Development (until February 2006) M Debbie Nicholl, NCC-CC Health Economit (until November 2005) v

6 Anaemia management in chronic kidney dieae Dr Shelagh O Riordan, Britih Geriatric Society Conultant Phyician in Healthcare of Older People, Eat Kent Hopital NHS Trut Mr Alion Richard, NCC-CC Information Scientit M Alion Roche, Anaemia Nure Specialit Aociation Nure Conultant, King College Hopital NHS Trut Dr Paul Roderick, Faculty of Public Health Senior Lecturer in Public Health, Univerity of Southampton and Southampton Univerity Hopital NHS Trut Dr Paul Steven (Clinical Advier) Conultant Renal Phyician, Eat Kent Hopital NHS Trut Dr Stephen Thoma, Royal College of Phyician Conultant in Diabete Medicine, Guy and St Thoma NHS Foundation Trut Dr Eric Will, Britih Renal Society Conultant Renal Phyician, Leed Teaching Hopital NHS Trut M Jane Alderdice wa invited to contribute at a pecific meeting a an expert repreenting the Britih Dietetic Aociation, but wa not a full member of the GDG Dr Luigi Gnudi acted a a deputy for Dr Stephen Thoma at a GDG meeting, repreenting the Royal College of Phyician Acknowledgement The Guideline Development Group i grateful to the following for their valuable contribution to the development of thi guideline: Dr Bernard Higgin, Director, NCC-CC M Jane Ingham, Director of Clinical Standard, Royal College of Phyician of London M Eter Klaeijen, Adminitrator, NCC-CC Mr Derek Lowe, Medical Statitician, Atraglobe Ltd M Jill Parnham, Manager, NCC-CC Mr Suan Varney, Reearch Fellow, NCC-CC Colleague working on the Health Technology Aement of erythropoiei-timulating agent for cancer treatment-induced anaemia. vi

7 Preface Chronic kidney dieae (CKD) i not the mot common caue of anaemia in the UK, but data from different ource ugget that nationally there are around 100,000 people with the combination of CKD and a low haemoglobin level. Anaemia in thi context i important becaue it contribute ignificantly to the heavy ymptom burden of CKD, and becaue it i potentially reverible with appropriate treatment, including erythropoietin. Erythropoietin i naturally produced by the kidney and ha been available in ynthetic form for the treatment of anaemia of CKD ince 1989, but it remain a fairly expenive product and it uage i not traightforward. Moreover, it will not necearily be the only therapy required for optimal treatment. Againt thi background, the preent guideline ha been commiioned to addre the appropriate management of anaemia of CKD for patient in the NHS. The guideline ha been produced uing tandard NICE methodology, 1 and i therefore explicitly evidence-linked. Following a comprehenive literature earch and evaluation of reearch paper, a Guideline Development Group (GDG) compriing clinical expert and patient and carer repreentative aeed the evidence and ued it to produce a detailed et of recommendation. Thi wa no eay tak, but one which the GDG have carried out diligently, thoroughly and with patient good humour. They have been a pleaure to work with and all at the National Collaborating Centre for Chronic Condition are grateful to them. The guideline recommendation cover many apect of anaemia management in CKD, but ome deerve emphai. The threhold at which treatment hould be conidered receive deerved attention, a do target value for haemoglobin. The GDG were clear that treatment, including adminitration of erythropoiei timulating agent, hould be conidered for all age when there i the propect of improving phyical function and quality of life. The importance of correctly managing iron tatu i emphaied a well a the role of erythropoiei timulating agent. The GDG alo treed the importance of agreeing a detailed plan with patient regarding all apect of delivery of treatment. There i no doubt that ymptom would be improved in many patient with CKD if anaemia were to be managed optimally. We hope and expect that thi guideline will make a ignificant contribution to improving the live of the patient who uffer from thi debilitating condition. Dr Bernard Higgin MD FRCP Director, National Collaborating Centre for Chronic Condition vii

8 DEVELOPMENT OF THE GUIDELINE

9 1 Introduction 1.1 Definition of anaemia Internationally anaemia i defined a a tate in which the quality and/or quantity of circulating red blood cell are below normal. Blood haemoglobin (Hb) concentration erve a the key indicator for anaemia becaue it can be meaured directly, ha an international tandard, and i not influenced by difference in technology. However, becaue haemoglobin value in healthy individual within a population how a normal ditribution, a certain number of healthy individual will fall below a given cut-off point. Conventionally anaemia i defined a a haemoglobin concentration lower than the etablihed cut off defined by the World Health Organization (WHO), 2 and different biological group have different cut-off haemoglobin value below which anaemia i aid to be preent. Thi cutoff figure range from 11 gram per decilitre (g/dl) for pregnant women and for children between 6 month and 5 year of age, to 12 g/dl for non-pregnant women, and to 13 g/dl for men (Table 1.1). No downward adjutment for the elderly i made for age. Although there i a theoretical bai for a fall in male haemoglobin level with age, becaue of reduced tetoterone production, thi i clearly not the cae for women. Furthermore there i accumulating evidence that anaemia reflect illne and i aociated with advere outcome in the elderly. 3 In the Cardiovacular Health Study 8.5% of participant were anaemic by WHO criteria. Thoe who were anaemic had a greater prevalence of aociated comorbidity and ignificantly higher 11-year death rate than thoe without anaemia (57% and 39% repectively, p 0.001). The tronget correlate of anaemia were low body ma index, low activity level, fair or poor elfreported health, frailty, congetive heart failure, and troke or tranient ichemic attack. Anaemia wa alo aociated with higher concentration of creatinine, C-reactive protein, and fibrinogen, and lower level of albumin and white blood cell count. 4 Table 1.1 Haemoglobin cut off to define anaemia in people living at ea level 2 Age or gender group Haemoglobin below: (g/dl) Children 6 month to 5 year to 11 year to 14 year 12.0 Non-pregnant female >15 year 12.0 Men >15 year 13.0 In addition to gender, age, and pregnancy tatu, other factor influence the cut-off value for haemoglobin concentration. Thee include altitude, race, and whether the individual moke. Although altitude i not a factor in patient in England, ethnicity may influence the cut-off value for haemoglobin concentration. 3

10 Anaemia management in chronic kidney dieae Data from the USA how that healthy people of African extraction of all age group at all time, except during the perinatal period, have haemoglobin concentration g/dl below thoe of white people, a difference independent of iron-deficiency and ocioeconomic factor. 5 9 Haemoglobin concentration increae in moker becaue of the formation of carboxyhaemoglobin, which ha no oxygen tranport capacity. 10 The US Center for Dieae Control and Prevention have developed a moking-pecific haemoglobin adjutment to define anaemia in moker (Table 1.2) and ugget that thee value hould be ubtracted from oberved haemoglobin value. 11 Table 1.2 Haemoglobin adjutment for moker Amount moked Haemoglobin adjutment (g/dl) pack/day pack/day 0.5 >2 pack/day 0.7 All moker Chronic kidney dieae: definition and prevalence The Renal National Service Framework 12,13 ha adopted the US National Kidney Foundation Kidney Dieae Outcome Quality Initiative (NKF-KDOQI) claification of chronic kidney dieae (CKD). 14 Thi claification divide CKD into five tage (Table 1.3) defined by evidence of kidney damage and level of renal function a meaured by glomerular filtration rate (GFR). Table 1.3 Stage of chronic kidney dieae Stage GFR (ml/min/1.73m 2 ) Decription 1 >90 Normal or increaed GFR, with other evidence of kidney damage Slight decreae in GFR, with other evidence of kidney damage Moderate decreae in GFR, with or without other evidence of kidney damage Severe decreae in GFR, with or without other evidence of kidney damage 5 <15 Etablihed renal failure Stage 5 CKD may be decribed a etablihed renal failure (alo called end tage renal failure), and i CKD which ha progreed o far that renal replacement therapy (regular dialyi treatment or kidney tranplantation) will be required to maintain life. Etablihed renal failure i an irreverible, long-term condition. A mall number of people with etablihed renal failure may chooe conervative management only. 4

11 1 Introduction Conventionally, the total number of people receiving renal replacement therapy ha been taken a a proxy meaure for the prevalence of etablihed renal failure. The National Service Framework (NSF) for renal ervice etimate that more than 27,000 people were receiving renal replacement therapy in England in Approximately one-half of thee had a functioning tranplant and the remainder were on dialyi. It i predicted that number will rie to around 45,000 over the next 10 year. However, the mot recently publihed Renal Regitry Report (2004) highlight that in the UK there were over 37,000 patient receiving renal replacement therapy during 2003, a prevalence of 632 per million population. Of thee, 46% had a functioning tranplant and the remainder were receiving dialyi treatment. 15 Data from the third US National Health and Nutrition Examination Survey (NHANES III) ugget that overall 11% of the population have ome degree of kidney dieae: 3.3% of the population are in tage 1 CKD, 3.0% in tage 2 CKD, 4.3% in tage 3 CKD, 0.2% in tage 4 CKD and 0.2% in tage 5 CKD. 10 A imilar population prevalence of tage 3 5 CKD ha recently been decribed for England from data derived from primary care record. 16 It i etimated that 4.9% of the population are in tage 3 5 CKD (etimated GFR le than 60 ml/min/1.73m 2 ), although for methodological reaon thi i probably an underetimate I chronic kidney dieae a natural conequence of ageing? For many year glomerular filtration rate ha been hown to decline with age. However, i i unclear to what extent thee change are a reult of normal ageing or a reult of dieae procee. The cumulative expoure of the kidney to common caue of chronic kidney dieae (atherocleroi, hypertenion, diabete, heart failure, infection and nephrotoxin) increae with age and it i difficult to eparate thee from the ageing proce. Only one ignificant longitudinal tudy to date ha addreed the iue of decreaing GFR with increaing age. In the Baltimore Longitudinal Study of Ageing, community-dwelling participant were followed over a period of up to 24 year. Their data ugget that the decline in GFR with increaing age i largely attributable to hypertenion, poibly a a conequence of microvacular dieae. 17 In the abence of hypertenion or other identifiable caue of renal dieae, one-third of older participant were noted to have table GFR over a period of 20 year. In a mall percentage of participant, GFR actually increaed with ageing. Similarly, Flier et al 18 in a cro-ectional tudy uing inulin clearance found heart failure to be a ignificant factor in the decline of GFR with increaing age. Additionally, both heart failure and hypertenion contributed to reduction in renal plama flow and increae in the filtration fraction and renal vacular reitance. In a pot-mortem tudy, Kaike 19 ha demontrated a relationhip between the prevalence of clerotic glomeruli and atheroclerotic vacular dieae. Although twice a many patient with ignificant atherocleroi had a hitory of hypertenion a thoe with milder atherocleroi, hypertenion wa not found to be independently predictive of glomerulocleroi. Further evidence 20 ugget that cumulative dietary protein intake i an important determinant of the fall in GFR. Studie uch a the Antihypertenive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) have hown that the prevalence of reduced GFR i high in older hypertenive patient. Patient with moderate or evere reduction in GFR in the ALLHAT trial were more likely to have a hitory of cardiovacular dieae and left ventricular 5

12 Anaemia management in chronic kidney dieae hypertrophy compared with thoe with higher level of GFR. Even modet reduction in GFR were independently aociated with a higher prevalence of cardiovacular dieae and left ventricular hypertrophy. 21 The implication are that dieae procee for renal dieae in older people are imilar to thoe of younger people and that a decline in renal function i not an inevitable conequence of ageing Prevalence of anaemia in patient with chronic kidney dieae The importance of anaemia in CKD ha become increaingly apparent ince the introduction of erythropoietin treatment into clinical practice in the late However, until recently it ha not been fully appreciated that anaemia begin to develop early in the coure of CKD. NHANES III found lower level of kidney function to be aociated with lower haemoglobin level and a higher prevalence and everity of anaemia. 22 Table 1.4 NHANES III data Median Hb in men Median Hb in women Prevalence of egfr (ml/min/1.73m 2 ) (g/dl) (g/dl) anaemia* % % % * Hb <12.0 g/dl in men, Hb <11.0 g/dl in women. The UK information concerning the prevalence of anaemia in patient with CKD come from two tudie. The prevalence of diagnoed CKD, predicated by erum creatinine level of 130 µmol/l in women and 180 µmol/l in men, wa 5,554 per million population (pmp), median age wa 82 year (range, 18 to 103 year), and median calculated GFR wa 28.0 ml/min/1.73m 2 (range, 3.6 to 42.8 ml/min/1.73 m 2 ). 23 Data for haemoglobin level were available for 85.6% of patient. Mean haemoglobin concentration wa 12.1±1.9 g/dl: 49.6% of men had haemoglobin level le than 12 g/dl and 51.2% of women had level le than 11 g/dl. Furthermore, in 27.5% of patient identified, the haemoglobin level wa le than 11 g/dl, equivalent to nearly 90,000 of the population baed on 2001 Cenu population figure. In a larger cro-ectional tudy abtracting data from 112,215 unelected patient with an age and ex profile repreentative of the general population, haemoglobin level wa weakly correlated with egfr (r=0.057, p <0.001). 16 The population prevalence of tage 3 5 CKD in thi tudy wa etimated to be 4.9%. In thoe patient with tage 3 5 CKD the prevalence of anaemia, defined a a haemoglobin level le than 12 g/dl in men and pot-menopaual women and le than 11 g/dl in pre-menopaual women, wa 12.0%, haemoglobin level wa le than 11 g/dl in 3.8%, equivalent to over 108,000 of the population baed on 2001 Cenu population figure. 6

13 1 Introduction Diabete, CKD and anaemia It ha been known for ome year that anaemia exit in patient with diabete and CKD, and that thi anaemia occur early in the coure of diabetic kidney dieae and i aociated with inappropriately low erythropoietin concentration. 24,25 Ihimura et al 25 demontrated that when thoe with Type 2 diabete and CKD are compared with thoe with non-diabetic CKD, depite imilarly advanced CKD and imilar erum erythropoietin level, thoe with Type 2 diabete were ignificantly more anaemic. Similar finding have alo been demontrated in people with Type 1 diabete and CKD compared with thoe without diabete. 26 More recently, in a erie of article baed on croectional urvey of patient with diabete, Thoma and colleague demontrated that at all level of GFR, anaemia wa more prevalent in thoe with diabete compared with the general population, 27 that with increaing albuminuria the prevalence of anaemia wa higher at each level of renal function, 28 and that level of erythropoietin were inappropriately low in thoe with anaemia. 29 Finally, in a report from the Kidney Early Evaluation Programme (KEEP), 30 the prevalence of anaemia in thoe with diabete wa ignificantly higher than in thoe without diabete in tage 2 and 3 CKD (7.5% v 5%, p=0.015 and 22.2% v 7.9%, p<0.001 repectively). Although the prevalence of anaemia wa alo higher in thoe with diabete in tage 1 and 4 CKD the difference were not ignificant (8.7% v 6.9% and 52.4% v 50% repectively) Caue of anaemia other than chronic kidney dieae Not all anaemia in patient with CKD will be renal anaemia and caue of anaemia other than CKD hould be actively looked for and excluded before a diagnoi of anaemia aociated with CKD can be made (Table 1.5) Table 1.5 Other caue of anaemia in CKD Chronic blood lo Iron deficiency Vitamin B 12 or folate deficiency Hypothyroidim Chronic infection or inflammation Hyperparathyroidim Aluminium toxicity Malignancy Haemolyi Bone marrow infiltration Pure red cell aplaia 7

14 Anaemia management in chronic kidney dieae Iron deficiency anaemia i the mot common caue of anaemia worldwide, either due to negative iron balance through blood lo (commonly gatrointetinal or mentrual), or to inadequate intake which may be nutritional or related to poor gatrointetinal aborption. Studie in elderly patient (aged over 65 year) how that the anaemia of chronic diorder predominate, accounting for 34% to 44% of caue Iron-deficiency i the caue in 15% to 36% of cae and recent bleeding in 7.3%. Vitamin B 12 or folate deficiency i the caue in 5.6% to 8.1%, myelodyplatic yndrome and acute leukaemia in 5.6% and chronic leukaemia and lymphoma-related diorder in 5.1%. Other haematological diorder (myelofibroi, aplatic anaemia, haemolytic anaemia) are the caue in 2.8%, and multiple myeloma in 1.5% Pathogenei of anaemia aociated with chronic kidney dieae Although anaemia in patient with CKD may develop in repone to a wide variety of caue, erythropoietin deficiency i the primary caue of anaemia aociated with CKD. Erythropoietin i predominantly produced by peritubular cell in the kidney and i the hormone reponible for maintaining the proliferation and differentiation of erythroid progenitor cell in the bone marrow. Lo of peritubular cell lead to an inappropriately low level of circulating erythropoietin in the face of anaemia. Other factor in the genei of renal anaemia include functional or abolute iron deficiency, blood lo (either occult or overt), the preence of uraemic inhibitor (for example, parathyroid hormone, inflammatory cytokine), reduced half-life of circulating blood cell, and deficiencie of folate or Vitamin B How to ue thi guideline The purpoe of thi guideline i to upport clinical judgement, not to replace it. Thi mean the treating clinician hould: take into conideration any contraindication in deciding whether or not to adminiter any treatment recommended by thi guideline conider the appropriatene of any recommended treatment for a particular patient in term of the patient relevant clinical and non-clinical characteritic. Wherever poible, before adminitering any treatment the treating clinician hould follow good practice in term of: dicuing with the patient why the treatment i being offered and what health outcome are anticipated highlighting any poible advere event or ide-effect that have been aociated with the treatment obtaining explicit conent to adminiter the treatment. 8

15 1 Introduction For thoe recommendation involving pharmacological treatment, the mot recent Summary of Product Characteritic hould be followed for the determination of: indication drug doage method and route of adminitration contraindication uperviion and monitoring product characteritic except in thoe cae where guidance i provided within the recommendation itelf. 1.4 Recommendation for children with anaemia of CKD Thi guideline give recommendation for both adult and children. Where the recommendation are different for children, detail are given eparately, ee: recommendation R33 35 in ection recommendation R40 in ection

16 2 Methodology 2.1 Aim The aim of the National Collaborating Centre for Chronic Condition (NCC-CC) i to provide a uer-friendly, clinical, evidence-baed guideline for the National Health Service (NHS) that: offer bet clinical advice for anaemia management in chronic kidney dieae (AMCKD) i baed on bet publihed evidence and expert conenu take into account patient choice and informed deciion-making define the major component of NHS care proviion for anaemia of CKD indicate area uitable for clinical audit detail area of uncertainty or controvery requiring further reearch provide a choice of guideline verion for differing audience. 2.2 Scope The guideline wa developed in accordance with a cope, which detailed the remit of the guideline originating from the Department of Health and pecified thoe apect of anaemia of CKD to be included and excluded. Prior to the commencement of the guideline development, the cope wa ubjected to takeholder conultation in accordance with procee etablihed by the National Intitute for Health and Clinical Excellence (NICE). 1,34 The full cope i hown in Appendix B. 2.3 Audience The guideline i intended for ue by the following people or organiation: all healthcare profeional people with anaemia of CKD and their parent and carer patient upport group commiioning organiation ervice provider. 2.4 Involvement of people with anaemia of CKD The NCC-CC wa keen to enure the view and preference of people with anaemia of CKD and their parent and carer informed all tage of the guideline. Thi wa achieved by: having a peron with anaemia of CKD and a uer organiation repreentative on the Guideline Development Group (GDG) conulting the Patient and Public Involvement Programme (PPIP) houed within NICE during the pre-development (coping) and final validation tage of the guideline. 11

17 Anaemia management in chronic kidney dieae 2.5 Guideline limitation Thee include: Clinical guideline uually do not cover iue of ervice delivery, organiation or proviion (unle pecified in the remit from the Department of Health). NICE i primarily concerned with health ervice and o recommendation are not provided for ocial ervice and the voluntary ector. However, the guideline may addre important iue in how NHS clinician interface with thee other ector. Generally, the guideline doe not cover rare, complex, complicated or unuual condition. 2.6 Other work relevant to the guideline The NCC-CC and NICE are developing a clinical guideline on chronic kidney dieae (publication i expected in 2008). NICE ha publihed technology appraial guidance on erythropoietin for anaemia induced by cancer treatment. Thi i available from Background The development of thi evidence-baed clinical guideline draw on the method decribed by the NICE Guideline development method manual 1 and the methodology pack 35 pecifically developed by the NCC-CC for each chronic condition guideline (ee The developer role and remit i ummaried in Table 2.1. Table 2.1 Role and remit of the developer National Collaborating Centre for Chronic Condition (NCC-CC) NCC-CC Technical Team Guideline Development Group The NCC-CC wa et up in 2001 and i houed within the Royal College of Phyician (RCP). The NCC-CC undertake commiion received from the National Intitute for Clinical Excellence (NICE). A multiprofeional partner board incluive of patient group and NHS management govern the NCC-CC. The technical team met approximately two week before each Guideline Development Group (GDG) meeting and compried the following member: GDG Chair GDG Clinical Advior Information Scientit Reearch Fellow Health Economit Project Manager. The GDG met monthly for 12 month (January to December 2005) and compried a multidiciplinary team of profeional, ervice uer (a peron with anaemia of CKD), carer, and uer organiation repreentative who were upported by the technical team. The GDG memberhip detail including patient repreentation and profeional group are detailed in the GDG memberhip table at the front of thi guideline. continued 12

18 2 Methodology Table 2.1 Role and remit of the developer continued Guideline Project Executive (PE) The PE wa involved in overeeing all phae of the guideline. It alo reviewed the quality of the guideline and compliance with the DH remit and NICE cope. The PE compried: NCC-CC Director NCC-CC Aitant Director NCC-CC Manager NICE Commiioning Manager Technical Team. Sign-off workhop At the end of the guideline development proce the GDG met to review and agree the guideline recommendation. Member of the GDG declared any interet in accordance with the NICE technical manual. 1 A regiter i available from the NCC-CC for inpection upon requet: ncc-cc@rcplondon.ac.uk 2.8 The proce of guideline development The baic tep in the proce of producing a guideline are: developing clinical evidence-baed quetion ytematically earching for the evidence critically appraiing the evidence incorporating health economic evidence ditilling and yntheiing the evidence and writing recommendation grading the evidence tatement and recommendation agreeing the recommendation tructuring and writing the guideline updating the guideline. Developing evidence-baed quetion The technical team drafted a erie of clinical quetion that covered the guideline cope. The GDG and Project Executive refined and approved thee quetion, which are hown in Appendix A. Searching for the evidence The information cientit developed a earch trategy for each quetion. Key word for the earch were identified by the GDG. In addition, the health economit earched for upplemental paper to inform detailed health economic work (for example modelling). Paper that were publihed or accepted for publication in peer-reviewed journal were conidered a evidence by the GDG. Conference paper abtract and non-englih language paper were excluded from the earche. Each clinical quetion dictated the appropriate tudy deign that wa prioritied in the earch trategy but the trategy wa not limited olely to thee tudy type. The reearch fellow or health economit identified title and abtract from the earch reult that appeared to be 13

19 Anaemia management in chronic kidney dieae relevant to the quetion. Excluion lit were generated for each quetion together with the rationale for the excluion. The excluion lit were preented to the GDG. Full paper were obtained where relevant. See Appendix A for literature earch detail. Appraiing the evidence The reearch fellow or health economit, a appropriate, critically appraied the full paper. In general, no formal contact wa made with author, however, there were ad hoc occaion when thi wa required in order to clarify pecific detail. Critical appraial checklit were compiled for each full paper. One reearch fellow undertook the critical appraial and data extraction. The evidence wa conidered carefully by the GDG for accuracy and completene. All procedure are fully compliant with: NICE methodology a detailed in the Guideline development method information for National Collaborating Centre and guideline developer manual. 1 NCC-CC quality aurance document and ytematic review chart, available at: Health economic evidence Area for health economic modelling were agreed by the GDG after the formation of the clinical quetion. The health economit reviewed the clinical quetion to conider the potential application of health economic modelling, and thee prioritie were agreed with the GDG. The health economit performed upplemental literature earche to obtain additional data for modelling. Aumption and deign of the model were explained to and agreed by the GDG member during meeting, and they commented on ubequent reviion. Ditilling and yntheiing the evidence and developing recommendation The evidence from each full paper wa ditilled into an evidence table and yntheied into evidence tatement before being preented to the GDG. Thi evidence wa then reviewed by the GDG and ued a a bai on which to formulate recommendation. 2 The criteria for grading evidence and claifying recommendation are hown in Table 2.2. Evidence table are available online at Agreeing the recommendation The ign-off workhop employed formal conenu technique 36 to: enure that the recommendation reflected the evidence bae approve recommendation baed on leer evidence or extrapolation from other ituation reach conenu recommendation where the evidence wa inadequate debate area of diagreement and finalie recommendation. 14

20 2 Methodology Table 2.2 Grading the evidence tatement and recommendation 2 Level of evidence Claification of recommendation Level Type of evidence Cla Evidence 1++ High-quality meta-analyi (MA), ytematic A Level 1++ and directly applicable to the target review (SR) of randomied controlled trial population (RCT), or RCT with a very low rik of bia. or 1+ Well-conducted MA, SR or RCT, or RCT with a low rik of bia. Level 1+ and directly applicable to the target population AND conitency of reult. Evidence from NICE technology appraial. 1 MA, SR of RCT, or RCT with a high rik of bia. Not ued a a bai for making a recommendation. 2++ High-quality SR of cae-control or cohort tudie. B Level 2++, directly applicable to the target population High-quality cae-control or cohort tudie with and demontrating overall conitency of reult. a very low rik of confounding, bia or chance and a high probability that the relationhip i or caual. Extrapolated evidence from 1++ or Well-conducted cae-control or cohort tudie with a low rik of confounding, bia or chance and a moderate probability that the relationhip i caual. 2 Cae-control or cohort tudie with a high rik Not ued a a bai for making a recommendation. of confounding, bia or chance and a ignificant rik that the relationhip i not caual 3 Non-analytic tudie (for example cae report, C Level 2+, directly applicable to the target population cae erie). and demontrating overall conitency of reult 4 Expert opinion, formal conenu. D Level 3 or 4 or Extrapolated evidence from 2++. or Extrapolated from 2+ or Formal conenu. GPP A good practice point (GPP) i a recommendation baed on the experience of the GDG. Diagnotic tudy level of evidence and claification of recommendation wa alo included. 1 The ign-off workhop alo reached agreement on the following: five to ten key prioritie for implementation five key reearch recommendation algorithm. 15

21 Anaemia management in chronic kidney dieae In prioritiing key recommendation for implementation, the ign-off workhop alo took into account the following criteria: high clinical impact high impact on reducing variation more efficient ue of NHS reource allowing the patient to reach critical point in the care pathway more quickly. The audit criteria provide uggetion of area for audit in line with the key recommendation for implementation. 1 Structuring and writing the guideline The guideline i divided into ection for eae of reading. For each ection the layout i imilar and contain: Clinical introduction et a uccinct background and decribe the current clinical context. Methodological introduction decribe any iue or limitation that were apparent when reading the evidence bae. Evidence tatement provide a ynthei of the evidence bae and uually decribe what the evidence howed in relation to the outcome of interet. Health economic preent, where appropriate, an overview of the cot-effectivene evidence bae. From evidence to recommendation et out the GDG deciion-making rationale providing a clear and explicit audit trail from the evidence to the evolution of the recommendation. Recommendation provide tand alone, action-orientated recommendation. Evidence table are not publihed a part of the full guideline but are available online at Thee decribe comprehenive detail of the primary evidence that wa conidered during the writing of each ection. Writing the guideline The firt draft verion of the guideline wa drawn up by the technical team in accord with the deciion of the GDG. The guideline wa then ubmitted for two formal round of public and takeholder conultation prior to publication. 1 The regitered takeholder for thi guideline are detailed on the NICE webite, ee Editorial reponibility for the full guideline ret with the GDG. The following verion of the guideline are available: Table 2.3 Verion of thi guideline Full verion NICE verion Quick reference guide Information for the public Detail the recommendation. The upporting evidence bae and the expert conideration of the GDG. Available at Document the recommendation without any upporting evidence. Available at An abridged verion. Available at A lay verion of the guideline recommendation. Available at 16

22 2 Methodology Updating the guideline Literature earche were repeated for all of the evidence-baed quetion at the end of the GDG development proce, allowing any relevant paper publihed by 28 September 2005 to be conidered. Future guideline update will conider evidence publihed after thi cut-off date. Two year after publication of the guideline, NICE will commiion a National Collaborating Centre to determine whether the evidence bae ha progreed ignificantly to alter the guideline recommendation and warrant an early update. If not, the guideline will be updated approximately 4 year after publication Diclaimer Healthcare provider need to ue clinical judgement, knowledge and expertie when deciding whether it i appropriate to apply guideline. The recommendation cited here are a guide and may not be appropriate for ue in all ituation. The deciion to adopt any of the recommendation cited here mut be made by the practitioner in light of individual patient circumtance, the wihe of the patient, clinical expertie and reource. The NCC-CC diclaim any reponibility for damage ariing out of the ue or non-ue of thee guideline and the literature ued in upport of thee guideline Funding The National Collaborating Centre for Chronic Condition wa commiioned by the National Intitute for Health and Clinical Excellence to undertake the work on thi guideline. 17

23 3 Key meage of the guideline 3.1 Key prioritie for implementation Management of anaemia hould be conidered in people with anaemia of chronic kidney dieae (CKD) when the haemoglobin level i le than or equal to 11g/dl (or 10 g/dl if under 2 year of age). Treatment with erythropoiei timulating agent (ESA) hould be offered to patient with anaemia of CKD who are likely to benefit in term of quality of life and phyical function. ESA therapy hould be clinically effective, conitent and afe in people with anaemia of CKD. To achieve thi, the precriber and patient hould agree a plan which i patient-centred and include: continuity of drug upply flexibility of where the drug i delivered and adminitered the lifetyle and preference of the patient cot of drug upply deire for elf-care where appropriate regular review of the plan in light of changing need. In people with anaemia of CKD, treatment hould maintain table haemoglobin (Hb) level between 10.5 and 12.5 g/dl for adult and children aged over 2 year, and between 10 and 12 g/dl in children aged under 2 year, reflecting the lower normal range in that age group. Thi hould be achieved by: conidering adjutment to treatment, typically when Hb rie above 12.0 or fall below 11.0 g/dl taking patient preference, ymptom and comorbidity into account and reviing the apirational range and action threhold accordingly. Age alone hould not be a determinant for treatment of anaemia of CKD. People receiving ESA maintenance therapy hould be given iron upplement to keep their: erum ferritin between 200 and 500 µg/l in both haemodialyi patient and nonhaemodialyi patient, and either the tranferrin aturation level above 20% (unle ferritin >800 ug/l) or percentage hypochromic red cell (%HRC) le than 6% (unle ferritin >800ug/l). In practice it i likely thi will require intravenou iron. 3.2 Algorithm An algorithm i any et of detailed intruction which reult in a predictable end-tate from a known beginning, ideally preented in an eay-to-follow deciion tree format. Algorithm are only a good a the intruction given, however, and the reult will be incorrect if the algorithm 19

24 Anaemia management in chronic kidney dieae i not properly defined. The algorithm preented in thi ection are uggeted management algorithm baed on the known literature but importantly they have not been teted and hould be ued a guide to aid development of local practice Algorithm for diagnoi of anaemia of CKD in adult egfr <60 ml/min/1.73m 2 AND Hb 11 g/dl? Ye No Conider other caue Treat and repeat Hb No Non-renal caue and haematinic deficiency excluded? Ye Patient on haemodialyi? No Ye See ection 5 and 6 See the initial management algorithm (Figure 3.2) Figure 3.1 Diagnoi of anaemia of CKD in adult Table 3.1 Tet for functional iron deficiency with ferritin and TSAT or ferritin and %HRC Ferritin TSAT % MCV HRC % Functional iron deficiency >100 µg/l <20 Normal range >6 Abolute iron deficiency <100 µg/l <20 Low >6 TSAT = tranferrin aturation; MCV = mean corpucular volume; HRC = hypochromic red cell. 20

25 3 Key meage of the guideline Initial management algorithm for adult patient (aume Hb <11g/dl) Thi algorithm i an example trategy for adult haemodialyi patient. Treatment hould be tailored to individual patient according to the guideline recommendation. Patient with anaemia of CKD Ferritin <500 µg/l? Additional iron therapy i not normally recommended if ferritin >500 µg/l becaue of the rik of iron overload Ye No Ye Ferritin <200 µg/l? No TSAT <20% OR %HRC >6%? Ye functional iron deficiency No ESA (.c. or i.v.) Ae Hb Hb >9 g/dl Hb <9 g/dl i.v. iron ee doe chedule Hb >11 g/dl Ae Hb level at 6 week Hb <11 g/dl ESA (.c. or i.v.) and iron (i.v.). See ection 6.12 and 6.13 If Hb increae <1 g/dl after 4 week, increae ESA ee doe chedule Continue monitoring Hb and iron tatu. Reduce/top i.v. iron Figure 3.2 Initial management for adult patient (aume Hb <11g/dl) Once Hb >11 g/dl, enter the Hb maintenance algorithm (Figure 3.3) and adjut ESA doe according to chedule 21

26 Anaemia management in chronic kidney dieae Iron doage chedule Thi i an example trategy for adult haemodialyi patient weighing over 50 kg. Treatment hould be tailored to individual patient according to the guideline recommendation. Table 3.2 Iron doage chedule Haemodialyi patient Induction/loading doe Maintenance doe Either iron ucroe Iron ucroe 50 mg/week or 200 mg/week for 5 week or 100 mg/fortnight low molecular weight iron dextran 1g Non-haemodialyi patient Iron ucroe 200 mg/fortnight x 3 doe or low molecular weight iron dextran 1g Throughout ESA induction: In people with anaemia of chronic kidney dieae, haemoglobin hould be monitored: every 2 4 week in the induction phae of ESA therapy every 1 3 month in the maintenance phae of ESA therapy more actively after an ESA doe adjutment in a clinical etting choen in dicuion with the patient, taking into conideration their convenience and local healthcare ytem. Be aware of ide effect and comorbiditie 22

27 3 Key meage of the guideline Haemoglobin maintenance algorithm (aume patient i receiving ESA and maintenance i.v. iron) Thi i an example trategy for adult patient. Treatment hould be tailored to individual patient according to the guideline recommendation. Ye Ferritin <200 µg/l? No Ye Ferritin <500 µg/l? No Additional iron therapy i not normally recommended if ferritin >500 µg/l becaue of the rik of iron overload TSAT <20% OR %HRC >6%? Ye functional iron deficiency No Hb >11 g/dl? Ye No Meaure Hb Enter initial management algorithm (Figure 3.2) Hb <11 g/dl Hb g/dl Hb g/dl Hb >15 g/dl If Hb i peritently low, ee poor repone algorithm (Figure 3.4) Increae ESA doe/frequency according to chedule unle Hb riing by >1 g/dl/month. Check Hb according to chedule No change, unle Hb riing by more than 1 g/dl/month, in which cae conider ESA doe adjutment Conider topping i.v. iron. Decreae ESA doe/ frequency according to chedule, unle Hb falling by more than 1 g/dl/month. Check Hb according to chedule Stop i.v. iron, conider topping ESA or halve doe/frequency, check Hb in 2 week Figure 3.3 Haemoglobin maintenance algorithm (aume patient i receiving ESA and maintenance i.v. iron) 23

28 Anaemia management in chronic kidney dieae ESA adjutment chedule for adult patient make adjutment baed on abolute Hb level and/or rate of change of Hb >1g/dl/month Table 3.3 Erythropoietin Current doe Increaed doe (if ingle doe Decreaed doe (conider reducing (unit/week) conider increaing doe frequency) doe frequency, minimum weekly) 1,000 2,000 Supend 2,000 3,000 1,000 3,000 4,000 2,000 4,000 6,000 3,000 6,000 9,000 4,000 9,000 12,000 6,000 12,000 Seek advice 9,000 >12,000 Seek advice Seek advice Table 3.4 Darbepoetin Current doe Increaed doe (conider Decreaed doe (conider reducing (µg/week) increaing doe frequency) doe frequency, minimum monthly) Supend Seek advice 60 >80 Seek advice Seek advice 24

29 3 Key meage of the guideline Frequency of haemoglobin monitoring in adult Table 3.5 Haemodialyi patient Haemoglobin level and rate of change Monitoring frequency <11 g/dl, rate of change 1 g/dl/month 4 week <11 g/dl, rate of change >1 g/dl/month 2 week g/dl, rate of change 1 g/dl/month 4 week g/dl, rate of change >1 g/dl/month 2 week >12 15 g/dl, rate of change 1 g/dl/month 4 week >12 15 g/dl, rate of change >1 g/dl/month 2 week >15 g/dl 2 week Table Table Peritoneal Peritoneal dialyi dialyi and and predialyi predialyi (including tranplant) patient <11 g/dl, rate of change 1 g/dl/month 4 week <11 g/dl, rate of change >1 g/dl/month 2 week g/dl, rate of change 1 g/dl/month 4 12 week g/dl, rate of change >1 g/dl/month 2 week >12 15 g/dl, rate of change 1 g/dl/month 4 12 week >12 15 g/dl, rate of change >1 g/dl/month 2 week >15 g/dl 2 week 25

30 Anaemia management in chronic kidney dieae Algorithm for adult patient with poor repone to ESA Ae concordance Ye I reticulocytoi preent? No Invetigate poible blood lo/haemolyi Ferritin <500 µg/l? Ye No Ferritin <200 µg/l? Ye No See initial management algorithm (Figure 3.2) Ye functional iron deficiency TSAT <20% OR %HRC >6%? Ye No I dialyi adequate? Haemodialyi: Kt/V >1.2 or URR >65% Peritoneal dialyi: Kt/V >1.7 No Ye I there evidence of the following: B12/folate deficiency? Myelodyplaia? Drug-induced bone marrow uppreion? Haemoglobinopathie? Infection or inflammation? Hyperparathyroidim? Aluminiumn or chloramine toxicity? Correct dialyi and re-ae No Invetigate and treat appropriately. Conider referral to haematologit Trial of high doe ESA Figure 3.4 Algorithm for adult patient with poor repone to ESA 26

31 3 Key meage of the guideline 3.3 Audit criteria Table 3.7 Audit criteria Key priority for implementation Criterion Exception Management of anaemia hould be 1. % of patient with CKD with Documented refual, conidered in people with anaemia of recorded Hb 11 g/dl (or 10 g/dl if contraindication. chronic kidney dieae (CKD) when under 2 year of age) who were the haemoglobin level i le than or tarted on iron/esa at the time, or equal to 11 g/dl (or 10 g/dl if under at the following appointment. 2 year of age). Treatment with ESA hould be offered to patient with anaemia of CKD who are likely to benefit in term of quality of life and phyical function. ESA therapy hould be clinically effective, conitent and afe in people with anaemia of CKD. To achieve thi, the precriber and patient hould agree a plan which i patient-centred and include: proviion of a ecure drug upply flexibility of where the drug i delivered and adminitered lifetyle and preference cot of drug upply deire for elf-care where appropriate regular review of the plan in light of changing need. 2. % of patient with ACKD with recorded Hb 11 g/dl not on anaemia treatment, with a breakdown of the reaon for it not being offered. 3. % of patient with ACKD receiving anaemia treatment who are receiving ESA, with a plan recorded a pecified. In people with anaemia of chronic 4. % of patient with diagnoed ACKD Patient who have kidney dieae, treatment hould who have received treatment for underlying caue for maintain table haemoglobin (Hb) level 3 month or longer and, at the time of poor repone (ee between 10.5 and 12.5 g/dl for adult a cro-ectional audit, have Hb level ection 1.2.4), and children aged over 2 year, and between 10.5 and 12.5 g/dl for adult patient who are in between 10 and 12 g/dl in children aged and children aged over 2 year, or the induction phae under 2 year, reflecting the lower between 10 and 12 g/dl in children of their treatment. normal range in that age group. Thi aged under 2 year. hould be achieved by: Conidering adjutment to treatment, typically when Hb rie above 12.0 or fall below 11.0 g/dl. Taking patient preference, ymptom and comorbidity into account and reviing the apirational range and action threhold accordingly. continued 27

32 Anaemia management in chronic kidney dieae Table 3.7 Audit criteria continued Key priority for implementation Criterion Exception Patient receiving ESA maintenance 5. % of patient with diagnoed ACKD therapy hould be given iron and on maintenance therapy with ESA upplement to keep their: who, at the time of a cro-ectional erum ferritin between 200 and audit, have: 500 µg/l in both haemodialyi erum ferritin between 200 and patient and non-haemodialyi 500 µg/l in both haemodialyi patient, and either patient and non-haemodialyi the tranferrin aturation level patient and either above 20% (unle ferritin The tranferrin aturation level above > 800 ug/l) or 20% (unle ferritin >800 ug/l) or percentage hypochromic red cell percentage hypochromic red cell (%HRC) le than 6% (unle (%HRC) le than 6% (unle ferritin ferritin > 800ug/l). >800ug/l). In practice it i likely thi will require i.v. iron. 28

33 THE GUIDELINE

34 4 Diagnotic evaluation and aement of anaemia 4.1 Diagnotic role of Hb level Clinical introduction Poible advere effect of anaemia in patient with CKD include reduced oxygen utiliation, increaed cardiac output and left ventricular hypertrophy (cardiac dilatation ± increaed wall thickne). The relationhip between thee are et out in Figure 4.1. Renal dieae Anaemia Volume overload Hypertenion Stroke volume Heart rate Sympathetic activity LVH Figure 4.1 Left ventricular hypertrophy (LVH) in CKD patient (Mann JF, Nephrol Dial Tranplant 1999;14(Suppl 2):29 36) It i alo uggeted that anaemia i aociated with increaed progreion of CKD, reduced cognition and concentration, reduced libido and reduced immune reponivene. How much thee advere effect tranlate into advere outcome uch a impaired quality of life, increaed hopitaliation, increaed cardiovacular event and increaed cardiovacular and all-caue mortality ha been the ubject of debate for everal year. Large obervational tudie how an invere aociation between haemoglobin level and advere outcome but randomied controlled trial (RCT) evidence of an improvement in thee outcome with correction of anaemia i lacking. Part of the problem i that the available tudie do not compare no treatment of anaemia with treatment, but rather partial correction of anaemia to better correction. I it likely that advere outcome aociated with anaemia are influenced by age, gender or ethnicity? The implication of thi quetion are that we might adopt a differing trategy when correcting anaemia if there i evidence to dictate uch an approach. 31

35 Anaemia management in chronic kidney dieae Methodological introduction A literature earch identified longitudinal, before and after and cohort tudie, conducted predominantly in haemodialyi patient. Four tudie had methodological limitation and were excluded from evidence tatement. Notable apect of the evidence bae were: No tudie were found which pecifically addreed the iue of gender and ethnicity and only one tudy wa identified which tratified the tudy population according to age. 44 Only two tudie included population over 80 year old. 38,47 Not all tudie reported gender and ethnicity of the participant. Some tudie included predominantly male 42,43 or predominantly white participant 46,47 or predominantly male and white participant. 48,50 One tudy included a population that wa 67% African American. 38 The number of tudy participant varied greatly, ranging between 7 and over 60,000. A comprehenive literature earch did not identify any tudie that were uitable to addre the economic apect, therefore no health economic evidence tatement are given Evidence tatement Thee evidence tatement are grouped by outcome meaure per ub-population of anaemia patient. Left ventricular hypertrophy Predialyi patient In a 1-year tudy (n=318), 48 a mean decreae in Hb of 0.5 g/dl from baeline of 12.8 ± 1.9 g/dl wa found to be one of three factor (including ytolic blood preure and left ventricular (LV) ma index) that wa aociated with left ventricular hypertrophy (LVH) (OR 1.32, 95% CI 1.1 to 1.59, p=0.004). (Level 2+) A decreae in LV ma index (p<0.01) wa oberved after raiing haematocrit (Hct) from 23.6 ± 0.5% (Hb ~ 7.8 g/dl) to 39.1 ± 0.8% (Hb ~ 13 g/dl) with epoetin over a time period of 12 month in a mall ample (n=9). 41 Similarly, in another tudy (n=11) 37 treatment with epoetin increaed Hct level from 26.3 ± 0.6% (Hb ~ 8.7 g/dl) to 34.4 ± 1.1% (Hb ~ 11.4 g/dl) at 3 month and 34.7 ± 1.3% (Hb ~ 11.5 g/dl) at 6 month. A reduction in LV ma index at month 6 (p<0.05), cardiac output (p<0.05), cardiac index (p<0.05), and an increae in total peripheral reitance (p<0.05) at month 3 and 6 of the tudy were oberved. (Level 3) In two tudie, 37,41 increaed Hct level with epoetin from 26.3 ± 0.6% (Hb ~ 8.7 g/dl) to 34.7 ± 1.3% (Hb ~ 11.5 g/dl) at 6 month 37 and from 23.6 ± 0.5% (Hb ~ 7.8 g/dl) to 39.1 ± 0.8% (Hb ~ 13 g/dl) at 12 month 41 found no change in LV end-diatolic/ytolic diameter, interventricular eptum thickne, LV poterior wall thickne over 6 month 37 or over 12 month. 41 (Level 3) 32

36 4 Diagnotic evaluation and aement of anaemia Haemodialyi patient In a 12 month tudy 42 where Hb wa increaed from a baeline level of 6.3 ± 0.8 g/dl to 11.4 ± 1.5 g/dl by epoetin adminitration, a reduction in LV ma (p <0.001), LV end-diatolic volume (p=0.005) and LV end diatole (p=0.003) wa found in patient with baeline LV ma above 210 g. In the ame tudy, 42 no ignificant change were oberved in echocardiography meaurement of LV poterior wall, interventricular eptum or mean wall thickne. (Level 3) In a mall tudy (n=7), 43 an increae in Hb from 9.8 ± 1.3 g/dl to 14.2 ± 0.6 g/dl uing epoetin over a period of approximately 6 month found a ignificant reduction in cardiac output (p<0.01) and troke volume (p<0.01), which wa accompanied with a ignificant increae in total peripheral reitance (p<0.05). However, there wa no change in mean arterial preure. (Level 3) Hopitaliation Haemodialyi patient A cohort (n=66,761), with data tratified into increaing Hct level and compared with an Hct level of 33 to 35% over a 1-year follow-up period 46 found the following: Table 4.1 Summary data from tudy 46 (Level 2+) Hct (%) <30 30 to to 35 (Ref) 36 to Hb (g/dl) < to 11.7 (Ref) 12 to RR of all-caue hopitaliation RR of hopitaliation from NS cardiac caue RR of hopitaliation from infection RR = relative rik; NS = not ignificant. In a 2.5-year follow-up tudy, 47 participant (n=50,579) were tratified into increaing Hct level and compared with patient with the arbitrary reference of Hct 34 to 36% (n=22,192), ee Table 4.2 to 4.5. Table 4.2 Adjuted relative rik of firt hopitaliation due to any cardiac dieae 47 (Level 2+) Hct (%) to to 36 (Ref) 37 to Hb (g/dl) to to 12 (Ref) 12.3 to RR % CI Not reported Not reported N/A 0.88 to to 0.87 RR = relative rik. 33

37 Anaemia management in chronic kidney dieae Table 4.3 Adjuted relative rik of firt hopitaliation due to pecific cardiac dieae 47 (Level 2+) Hct (%) 34 to 36 (Ref) 37 to Hb (g/dl) 11.3 to 12 (Ref) 12.3 to RR due to congetive heart failure, fluid overload or (95% CI 0.77 to 0.95) (95% CI 0.65 to 0.97) cardiomyopathy RR due to ichemic heart 1.00 NS 0.81 dieae, cerebrovacular (95% CI 0.70 to 0.93) dieae or circulatory ytem dieae RR due to other cardiac 1.00 NS 0.76 dieae (95% CI 0.62 to 0.92) RR = relative rik; NS = not ignificant. Table 4.4 Adjuted relative rik of firt hopitaliation for patient with cardiac comorbid condition (n=45,166) 47 (Level 2+) Hct (%) 34 to to Hb (g/dl) 11.3 to to Relative rik % CI N/A 0.89 to to 0.87 Table 4.5 Adjuted relative rik of hopitaliation for patient with Hct 37 to 39% without pre-exiting cardiac dieae (3-year follow-up) 47 (Level 2+) RR p value All-caue hopitaliation 0.78 < Any cardiac hopitaliation

38 4 Diagnotic evaluation and aement of anaemia Mortality Haemodialyi patient Data from a cohort (n=66,761) were tratified into increaing Hct level and compared with an arbitrary Hct level of 33 to 35% over a 1-year follow-up period: 46 Table 4.6 Adjuted relative rik (Level 2+) Hct (%) <30 30 to to 35 (Ref) 36 to Hb (g/dl) < to 11.7 (Ref) 12 to RR of all-caue NS NS mortality RR of mortality NS NS from cardiac caue RR of mortality NS NS from infection NS = not ignificant. In a 3-year follow-up tudy 47 participant (n=50,579) were tratified into Hct level and compared with patient with the arbitrary reference of Hct 34 to 36% (n=22,192): Table 4.7 Adjuted relative rik of mortality due to cardiac dieae 47 Hct (%) 34 to 36 (Ref) 37 to Hb (g/dl) 11.3 to 12 (Ref) 12.3 to Relative rik % CI N/A 0.87 to to 0.93 Table 4.8 Adjuted relative rik of all-caue mortality 47 Hct (%) 34 to 36 (Ref) 37 to Hb (g/dl) 11.3 to 12 (Ref) 12.3 to Relative rik % CI N/A 0.88 to to 0.93 Table 4.9 Adjuted relative rik of mortality for patient with Hct 37 to 39% without preexiting cardiac dieae 47 RR p value All-caue death Any cardiac death

39 Anaemia management in chronic kidney dieae In one tudy (n=309), 38 no aociation wa found between any Hct quartile (<33.4%, 33.4 to 35.73%, 35.74% to 38.55%, and >38.55%) and urvival over 18 month. (Level 3) In a 4-year tudy, 39 renal unit with more than 87% of patient achieving target Hct 33% (Hb 11 g/dl) had a lower mortality rate than thoe with le than 64% of patient achieving target Hct (p<0.0001). A 10% point increae in the fraction of patient with Hct of more than or equal to 33% (Hb 11 g/dl) wa found to be aociated with a 1.5% decreae in mortality (p=0.003). (Level 3) A retropective cohort tudy with 1-year follow-up (n=75,283) 45 found an increae in the age group aociated with higher all-caue and caue-pecific mortality. Female patient had better outcome. When compared with white patient, black patient and other ethnic minority patient had lower all-caue and caue-pecific mortality. In the ame tudy, 45 mortality data were compared with Hct 30 to <33% (Hb 10 to <11 g/dl), 45 ee Table Table 4.10 Adjuted relative rik 47 (Level 2+) Hct (%) <27 27 to <30 30 to <33 (REF) 33 to < and 1993 data (n=9,130) (n=22,217) (n=33,122) (n=10,129) 33 to <36 (n=61,797) 1992 & 1993 data Hb <9 g/dl 9 to <10 g/dl 10 to <11 g/dl 11 to <12 g/dl 11 to <12 g/dl (n=9,130) (n=22,217) (REF) (n=33,122) (n=10,129) (n=61,797) RR of all NS 0.96 caue death 95% CI 95% CI 95% CI RR of cardiac NS Not reported death 95% CI 95% CI RR of NS Not reported infectiou 95% CI 95% CI death NS = not ignificant. MI, troke and all-caue mortality Predialyi patient In one tudy (n=2,333), 40 the hazard ratio for the compoite outcome (MI, troke and all-caue mortality) wa ignificantly increaed in individual with anaemia (defined a Hb <12 g/dl or Hct <36% in women and Hb <13 g/dl or Hct <39% in men) when compared with thoe without anaemia (hazard ratio 1.51; 95% CI 1.27 to 1.81). (Level 3) 36

40 4 Diagnotic evaluation and aement of anaemia Quality of life Haemodialyi patient When evaluated in epoetin-treated patient (n=57) 44 whoe Hct increaed from 21 ± 0.3% (Hb ~ 7 g/dl) at baeline to 28 ± 0.4% (Hb ~ 9.3 g/dl) at month 3 and 29 ± 0.4% (Hb ~ 9.7 g/dl) at month 6, quality of life wa hown to improve by mean of the Karnofky cale (p=0.0001) and the global (p=0.0001), phyical (p=0.0001) and pychoocial (p=0.0001) dimenion of the Sickne Impact Profile (SIP) quetionnaire. Thi wa further reinforced by linear regreion between improvement of the SIP global core and final achieved Hct (29 ± 0.4%) (b coefficient 0.57, p<0.05, R ). (Level 2+) Effect of age on quality of life Haemodialyi patient In a ubgroup analyi of epoetin-treated patient divided into age group of more than or equal to 60 year (n=23) and le than 60 year (n=34), Hct level were higher in the younger age group (p<0.05). 44 No difference were oberved in improvement of quality of life core uing the Karnofky cale or SIP core when thee age group were compared. 44 The ame wa true when patient were tratified into age group of more than 60 year (n=34) and more than or equal to 65 year (n=15). 44 (Level 2+) From evidence to recommendation Data about the outcome of LVH were preented to the GDG. 48 Two tudie which demontrated an aociation between decreaing left ventricular ma and increaing haematocrit level 37,41 were baed on mall ample ize (n=9 and n=11) and the GDG weighed thee tudie accordingly in their deliberation. Two tudie were appraied that examined the rate of progreion of renal failure but thee were excluded a underpowered by the GDG 37,41 and hence, no evidence tatement were preented for thi outcome. The GDG noted that the greater hopitaliation rate een in a tudy baed on regitry data 46 could be a reflection of a icker population and thi may be another reaon for the lower Hb level. It wa alo noted that the lowet haematocrit group required double the amount of EPO to reach thi level, and a uch, thee participant may have a reduced health tatu. The tudy by Moreno et al 49 wa excluded by the GDG becaue of a highly elected population (excluding both elderly and ill patient) and a lack of intention to treat analyi. The group agreed to increae the grade of one other tudy 47 from 3 to 2+ a the tudy participant had been ubdivided according to Hct level and a multivariate analyi of rik had been performed. The GDG agreed that the evidence upported an aociation between decreaed haematocrit and increaed rik of hopitaliation. The group felt that the evidence preented on mortality from one tudy 46 uggeted that there wa an increae in mortality between Hct <30 to <33% (Hb level ~ 1 11g/dl) when compared with Hct 33 to 36% (Hb ~ 11 12g/dl). It wa noted that thi range pan the tandard level quoted in 37

41 Anaemia management in chronic kidney dieae many guideline. The data preented by two tudie 39,45 ugget that a Hb of <11g/dl wa the threhold below which there wa an increaed rik of mortality. However, the GDG noted that thee tudie may not have accounted for confounding factor uch a intercurrent illne. The iue wa alo raied that there might be a revere cauality and that patient requiring high amount of epoetin may be icker and hence more likely to require hopitaliation. One tudy 38 concluded that the haematocrit level wa not a predictor of urvival and that other marker of morbidity were more important. The data alo uggeted that confounding factor may be preent that were not taken into account, eg infection. Thi poibility wa reflected in the tudy a the haematocrit level were corrected for albumin. Thi tudy alo uggeted that men and women require different doe of ESA: women appear to need more ESA than men. Only one tudy wa appraied that evaluated haemodynamic parameter but thi wa excluded for thi outcome by the GDG a it wa felt to be underpowered (n=7). 43 Concerning quality of life in haemodialyi patient(n=57), 44 a ubgroup analyi of thoe over and under 60 year of age found a ignificant increae in quality of life core aociated with higher Hb level in both age group. RECOMMENDATION R1 Management of anaemia hould be conidered in people with anaemia of chronic kidney dieae (CKD) when their haemoglobin level i le than or equal to 11 g/dl (C) (or 10 g/dl if younger than 2 year of age). (D) See for the aociated algorithm. 4.2 Diagnotic role of glomerular filtration rate Clinical introduction Data from population tudie uch a NHANES III in the USA and the NEOERICA tudy in the UK ugget an increaing prevalence of anaemia with decreaing GFR level. A imilar relationhip between glomerular filtration rate (GFR) and anaemia ha alo been demontrated in population cohort of people with diabete. 27 Although anaemia i common in people with diabete it i alo commonly unrecognied and undetected. 53 The prevalence of anaemia in people with diabete i increaed at all level of renal function in thoe with increaed proteinuria/albuminuria, 54 and it ha been uggeted that in people with diabete, anaemia aociated with CKD may occur earlier in the evolution of CKD when compared with people without diabete. In invetigating the evidence bae, thi ection eek to decribe the relationhip between GFR and haemoglobin level and provide guidance for clinician about the threhold level of GFR below which they hould upect that anaemia i aociated with CKD Methodological introduction A literature earch identified five tudie invetigating the aociation between GFR or creatinine clearance (CCr) with Hb/Hct level in non-diabetic patient and four tudie in diabetic patient. 16,27,28,30 38

42 4 Diagnotic evaluation and aement of anaemia Notable apect of the evidence bae were: Two tudie were not limited to patient with CKD. 55,56 Two tudie were conducted in elected patient population and one tudy 59 wa conducted in children. Patient population in ome tudie were not tratified to diabetic and non-diabetic patient and where reported, the percentage of diabetic varied from 5% 55 to 28% 58 and to 64.4%. 57 All patient with CKD were in the untreated predialyi tage, except for one tudy where ome patient received oral iron (26%) and epoetin (12.8%) to treat their anaemia. 59 One tudy wa conducted in people with Type 2 diabete, 28 and one in people with Type 1 and people with Type 2 diabete. 27 A comprehenive literature earch did not identify any tudie that were uitable to addre the economic apect, therefore no health economic evidence tatement are given Evidence tatement Hb/Hct level aociated with different GFR or CCr level in non-diabetic patient Table 4.11 GFR v Hb 55 (Level 3) Median Hb level in women (g/dl) Median Hb level in men (g/dl) egfr (ml/min/1.73 m 2 ) Table 4.12 GFR v Hb uing >80 ml/min/1.73 m 2 a the reference value 56 (Level 2+) Women (n=8,495) Men (n=3,560) GFR (ml/min/1.73 m 2 ) Difference Difference >80=ref in Hb (g/dl) p value in Hb (g/dl) p value >70 to < NS % CI >60 to NS % CI >50 to % CI % CI >40 to < % CI 0.4, % CI 1.1, 0.5 >30 to < < % CI 0.8, % CI 1.8, 1.0 >20 to < < % CI 1.8, % CI 2.3, < < % CI 2.3, % CI 3.9,

43 Anaemia management in chronic kidney dieae Table 4.13 GFR v Hb 57 (Level 3) GFR % of n with % of n with % of n with (ml/min/1.73m 2 ) n Hb 10 g/dl Hb >10 to 12 g/dl Hb 12 g/dl to <60 2, to <30 1, < Table 4.14 GFR v Hct 58 (Level 2+) Hct (%) Etimated Hb (g/dl) GFR (ml/min/1.73 m 2 ) <28 < ± < ± < ± < ± ± 7.9 Table 4.15 GFR v Hct in children (<21 year old) 59 % of patient with Hct 30 % % >33 % % of patient with etimated Hb (g/dl) 10 >10 <11 >11 All patient 30.9 % 13.0 % 56.1 % GFR (ml/min/1.73 m 2 ) < % 11.3 % 25.8 % % 16.8 % 35.1 % % 13.3 % 61.0 % % 8.1 % 78.7 % 2.4% of the tudy participant were treated with RBC tranfuion after tudy entry. In addition, 26% of tudy participant received oral iron and 12.8% received epoetin during the coure of the tudy. (Level 2+) 40

44 4 Diagnotic evaluation and aement of anaemia Hb level aociated with different GFR level in diabetic patient In a retropective cro-ectional tudy (n=28,862), 16 diabete wa recorded in 15.4% of patient with GFR of more than 60 (tage 3 5 CKD). Of thee, 15.3% were anaemic when defined a Hb <12 g/dl for women and <13 g/dl for men) and 3.8% were anaemic when defined a Hb <11 g/dl. (Level 3) In a retropective cro-ectional tudy in people with Type 1 and 2 diabete (n=820), 27 GFR wa found to be an independent predictor of Hb (p<0.0001). Aociation between Hb and GFR were continuouly ignificant (p<0.05) at lower level of GFR <70 v GFR Hb wa ignificantly lower in all male and female patient with GFR <70 (both p<0.0001). GFR of more than 80 ml/min/1.73 m 2 wa not ignificantly aociated with anaemia defined a Hb 11 g/dl (irrepective of ex) and Hb <13 g/dl in men and Hb <12 g/dl in women. (Level 3) Diabete tatu and etimated GFR (egfr) (ml/min/1.73m 2 ) categorie <30, 30 59, and were ignificantly aociated with an increaed likelihood of anaemia, defined a Hb <12.0 g/dl for men and pot-menopaual women (older than 50 year old) and Hb <11.0 for premenopaual women (50 year old or younger) uing egfr 90 a the reference. 30 (Level 3) In the ame tudy, 30 when egfr wa divided into 10 ml/min/1.73m 2 trata, the prevalence of anaemia by diabete tatu wa tatitically ignificant at each of the categorie between 31 and 60 ml/min/1.73m 2, but did not differ for any other categorie. In addition, in men with diabete, ignificantly lower Hb level were oberved at all egfr categorie <60 ml/min/1.73m 2, wherea among women with diabete and all tudy participant without diabete (both men and women), ignificantly lower Hb level were not apparent until more advanced level of kidney impairment were oberved (egfr <31 ml/min/1.73m 2 ). (Level 3) Hb level aociated with different CCr level in diabetic patient Type 2 diabetic patient with mild renal impairment (CCr ml/min/1.73 m 2 ) 28 were approximately twice a likely to have anaemia a diabetic patient with normal renal function, defined a Hb <130 g/l in men and Hb <120 g/l in women (CCr >90 ml/min/1.73 m 2 ) (p value not reported by the author). (Level 3) From evidence to recommendation The comparion of diabetic and non-diabetic population wa baed on a clinical perception that the diabetic population wa at rik of developing anaemia of CKD at an earlier tage. The GDG felt that thi perception had arien partly becaue of the elected patient population in many of the tudie, the cro-ectional nature of the tudie, and the lack of tandardiation of etimate of renal function ued in the variou tudie. The current clinical perception of the GDG i that although there wa a correlation between diabete and the anaemia of CKD, the prevalence of anaemia in thoe with diabete appeared greater than thoe without at higher level of GFR. Within whole population tudie there were imilar mean haemoglobin level between thoe with diabete and thoe without diabete acro a range of GFR. 41

45 Anaemia management in chronic kidney dieae It wa agreed that etting a threhold value of egfr of 60 ml/min/1.73m 2 (the boundary between tage 2 and tage 3 CKD) would be of ue in helping clinician decide whether to conider anaemia of CKD a a caue of the anaemia, although there were ome concern about whether the error around a ingle meaurement would make thi a uitable recommendation. It wa felt there wa ome merit in an empirical tatement that upported etting an egfr of <60 ml/min/1.73m 2 which hould alert a clinician to conider anaemia of CKD a the caue, and that other caue were likely in patient with a egfr > 60. RECOMMENDATION R2 An etimated glomerular filtration rate (egfr) of <60 ml/min/1.73m 2 hould trigger invetigation into whether anaemia i due to CKD. When the egfr i 60 ml/min/1.73m 2 the anaemia i more likely to be related to other caue. (D) See for the aociated algorithm. 4.3 Diagnotic tet to determine iron tatu Clinical introduction The purpoe of the evidence review in thi ection wa to identify the bet combination of tet to determine iron tatu in patient with CKD. The aim of determining iron tatu i to identify which patient need iron upplementation, a well a thoe who do not. Although abolute iron deficiency may occur in patient with chronic kidney dieae we more frequently identify what i termed functional iron deficiency. Although iron tore may eem adequate when meaured by conventional indice of iron tatu, there may be a lack of freely available iron for effective erythropoiei in the bone marrow. There i a lack of well-accepted gold tandard tet for determining iron deficiency in the etting of CKD. While bone marrow iron tore are often regarded a the bet indicator of iron tatu, thi i not univerally accepted and taking a bone marrow ample i invaive, relatively time conuming and expenive. The frequent coexiting inflammatory or infective problem in patient with CKD can complicate the interpretation of iron tatu parameter. For example, erum ferritin i a good marker of torage iron and decreae in iron deficiency tate. However, it i alo an acute phae reactant, which mean it i frequently raied in inflammatory condition, uch a CKD, regardle of the iron tatu. All the available tet of iron tatu are ubject to imilar limitation and detailed dicuion i beyond the cope of thi guideline. The Britih Committee for Standard in Haematology i producing a document Evaluation of iron tatu, which will deal comprehenively with thee iue (although not pecifically in the etting of CKD). It i accepted that no ingle parameter can determine iron tatu. In patient without CKD normal erum ferritin level are over 20 µg/l, but in thoe with CKD a value of 100 µg/l i conidered to be the lower limit of normal to allow for the aociated mild inflammatory tate. The percentage of hypochromic red cell (HRC) directly reflect the number of red blood cell with uboptimal level of haemoglobin content (<28 g/dl) and may be determined uing certain analyer. HRC <2.5% i normal and HRC >10% indicate definite 42

46 4 Diagnotic evaluation and aement of anaemia iron deficiency. Meaurement mut be on a freh ample (<4 hour after the blood i withdrawn) becaue of torage artefact. Reticulocyte haemoglobin content (CHr) may alo be meaured by certain analyer and i derived from the imultaneou meaurement of volume and haemoglobin concentration in reticulocyte. Level indicating functional iron deficiency depend on the analyer ued. Tranferrin aturation (TSAT) i a derived value and may be calculated from erum iron 100 total iron binding capacity; or erum iron (mg /dl) 70.9 erum tranferrin (mg/dl). Tranferrin level are alo influenced by inflammation and nutrition (correlating with erum albumin level). A TSAT of <20% ugget iron deficiency Methodological introduction A literature earch identified tudie which addreed the ability of tet to detect iron deficiency and the ability of tet to predict the repone to intravenou iron upplementation in patient with predefined iron parameter receiving epoetin Of the ix tudie looking at the repone to intravenou iron, five tudie predefined the patient population to whom iron wa given a being iron deficient (ee Table 4.16). In one tudy 66 the repone to intravenou iron wa ued to define the prior iron tatu. No tudy addreed the iue of loading with iron prior to epoetin adminitration. Table 4.16 Definition of detection of iron deficiency Definition of poitive repone to iron adminitration, Reference Iron doing regimen ie iron-deficient 64 1g infuion (over 2 hour) Erythropoietic repone to the iron treatment; a utained increae in corrected reticulocyte index of one bae point (ie from 1.7% to 2.7%) within 2 week mg to 1g infuion >5% increae in Hct, 4 week after adminitration (over 1 hour) 66 ~1g over 8 week Hb repone 15% of baeline value mg iron colloid over Not reported 2 week g over 41.7 week Reduction in weekly epoetin doe of at leat 30 U/kg/week in the ubequent 12 week while maintaining a target Hct of 30 to 33% Reduction in weekly epoetin doe of at leat 60 U/kg/week in the ubequent 12 week while maintaining a target Hct of 30 to 33% 63 1g over 10 HD treatment 5% increae in Hct or a decreae in epoetin doe if the Hct HD = Haemodialyi. increaed to more than 38% 43

47 Anaemia management in chronic kidney dieae Evidence tatement Studie where iron wa adminitered A variety of tudie looked at the utility of a number of marker of iron tatu a indicator of iron deficiency following iron adminitration. Repone to iron adminitration wa variably defined by an increae in haemoglobin level and/or reduction in erythropoietin doe. Table 4.17 Studie where iron wa given Iron tet (cut- Tet Tet off range in cut-off cut-off Evidence Reference N (range) tudie) value Senitivity value Specificity hierarchy 64 66, Serum ferritin <50 µg/l 19.6% <100 µg/l % DSII (50 to 400 µg/l) DSIII 68 <100 µg/l % <50 µg/l 94.6% 64,66 32 and 51 %HRC >4% 86.3% >4% 78.4% DSII 64,66 (>4% to >10%) >10% 42.8 and >10% 80 and 100% 45.1% TSAT <20% % <20% 36 80% DSII (<12% to <28%) DSIII 68 65,66 17 and 51 Serum ferritin Serum 33% and Serum ferritin 67% and DSII 65,66 (<100µg/l) and ferritin 68.6% (<100µg/l) 60.8% TSAT (<20%) <100µg/l and %TSAT and TSAT (<20%) <20% 64,66, Ret Hb (<26 pg <26 pg 100% <26 pg 80% DSII 64,66,67 to <32.5 pg) <32.5 pg 23.1% <32.5 pg 66.7% ZPP (>52 and >52 µmol/ 80.6% >52 µmol/mol 68.7% DSII >90 µmol/mol mol haem haem haem) >90 µmol/ 13.9% >90 µmol/mol 96.9% mol haem haem continued 44

48 4 Diagnotic evaluation and aement of anaemia Table 4.17 Studie where iron wa given continued Iron tet (cut- Tet Tet off range in cut-off cut-off Evidence Reference N (range) tudie) value Senitivity value Specificity hierarchy %HRC (>6%) %HRC 86.3% %HRC >6% 93.2% DSII and other tet >6% and and Ret Hb Ret Hb 29 pg 29 pg %HRC 82.4% %HRC >6% 89.2% >6% and and erum erum ferritin ferritin <50 ng/ml <50 ng/ml %HRC 96.1% %HRC >6% 74.3% >6% and and TSAT TSAT <19% <19% %HRC 94.9% %HRC >6% 71.9% >6% and and ZPP ZPP >52 mmol/ >52 mmol/ mol haem mol haem %HRC 85.7% %HRC >6% 73.2% >6% and and STR STR >1.5 mg/100 ml >1.5 mg/ 100 ml HRC = hypochromic red cell; TSAT = tranferrin aturation; Ret Hb = reticulocyte haemoglobin content; ZPP = erythrocyte zinc protoporphyrin; STR = erum tranferrin receptor; PPV = poitive predictive value; NPV = negative predictive value. 45

49 Anaemia management in chronic kidney dieae No iron adminitration Table 4.18 Studie where iron wa not given Iron tet Tet Tet cut-off range cut-off cut-off Evidence Reference N (range) in tudie) value Senitivity value Specificity hierarchy STR (1.39 µg/ml STR 84% STR 30% DSIb to 3.5 µg/ml) 1.39 µg/ml 1.39 µg/ml STR 38% STR 3.5 µg/ml 90% 3.5 µg/ml Bone marrow BME v 41% BME v 100% DSIb examination Serum Serum ferritin (BME) v other ferritin <200 µg/l tet <200 µg/l BME v 88% BME v 63% TSAT TSAT <20% <20% TSAT v other TSAT 73 TSAT <15% 100 DSII tet <15% v v Ret Hb Ret Hb <26 pg <26 pg TSAT 91 TSAT <15% 54 <15% v v %HRC %HRC >2.5% >2.5% TSAT 91 TSAT <15% 62 <15% v v %HRC %HRC >5% >5% From evidence to recommendation The group compared the tet baed on the enitivity, pecificity and receiver operator characteritic. The group did not ue the negative or poitive predictive value a they were conidered enitive to demographic and epidemiology and therefore not generaliable. Thee iron upplementation tudie have dealt with iron deficiency or functional iron deficiency (where torage iron may be adequate, but iron utiliation in red cell production i defective). The tudie have not addreed the iue of whether iron upplementation could be beneficial in patient having erythropoietin even with apparently normal iron tatu, or when iron upplementation hould be topped becaue of a rik of iron overload. Recticulocyte Hb content and the percentage of hypochromic red cell were alo dicued. Neither of thee tet are widely available and both are currently under a commercial patent. With repect to recticulocyte Hb content, the GDG felt that although thi looked like a enitive tet, the cut-off for thi tet wa a Hb content of le than 26pg. Thi wa conidered very low a the normal range i reported to be 31 33pg. The GDG noted that the percentage of hypochromic red cell provided the bet enitivity and pecificity from a ingle tet. 46

50 4 Diagnotic evaluation and aement of anaemia In general, the GDG noted that tet for erum ferritin and tranferrin aturation were the mot widely ued but that they had poor enitivity and pecificity. The GDG took note, however, that thee tet were both cheap and widely available. It wa noted that erum ferritin wa the only tet addreing iron torage while the other tet reviewed in the evidence aeed iron utiliation. The GDG agreed that no ingle tet wa adequate to determine iron tatu. Serum ferritin howed the bet correlation with bone marrow iron core. Iron deficiency hould be acertained by a combination of erum ferritin (torage iron) and tet of iron utiliation (reticulocyte haemoglobin content, percentage of hypochromic red cell, tranferrin aturation, ZPP). RECOMMENDATIONS R3 Serum ferritin level may be ued to ae iron deficiency in people with CKD. Becaue erum ferritin i an acute phae reactant and frequently raied in CKD, the diagnotic cut-off value hould be interpreted differently to non-ckd patient. (A(DS)) R4 Iron deficiency anaemia hould be: diagnoed in people with tage 5 CKD with a ferritin level of le than 100 µg/l conidered in people with tage 3 and 4 CKD if the ferritin level i le than 100 µg/l. (D(GPP)) R5 In people with CKD who have erum ferritin level greater than 100 µg/l, functional iron deficiency (and hence thoe patient who are mot likely to benefit from intravenou iron therapy) hould be defined by: percentage of hypochromic red cell >6%, where the tet i available or tranferrin aturation <20%, when the meaurement of the percentage of hypochromic red cell i unavailable. See for the aociated algorithm. (B(DS)) 4.4 Meaurement of erythropoietin Clinical introduction Although anaemia in CKD may develop in repone to a wide variety of caue, erythropoeitin (EPO) deficiency i the primary caue of renal anaemia. Predominantly produced by peritubular cell in the kidney, EPO i the hormone reponible for maintaining the proliferation and differentiation of erythroid progenitor cell in the bone marrow. Lo of peritubular cell lead to an inappropriately low level of circulating EPO in the face of anaemia (Figure 4.2). We know that anaemia develop early in the coure of chronic kidney dieae. NHANES III found lower level of kidney function to be aociated with lower haemoglobin level and a higher prevalence and everity of anaemia. 55 The prevalence of anaemia, defined a haemoglobin level of le than 12 g/dl in men and le than 11 g/dl in women, increaed from 1% at an etimated GFR of 60 ml/min per 1.73 m 2, to 9 and 33% at etimated GFR of 30 and 15 ml/min per 1.73 m 2 repectively. Uing the ame definition of anaemia, it i uggeted that in people with diabete and CKD the prevalence of anaemia in tage 2 and 3 CKD i greater than in thoe without diabete. 30 In a tudy of 5,380 participant from the Kidney Early Evaluation 47

51 Anaemia management in chronic kidney dieae Haemoglobin (g/dl) Expected EPO level Oberved EPO level (mu/ml) Haemoglobin (g/dl) WHO cut-off 6 n= <10 Percent of normal kidney function Figure 4.2 Evolution of anaemia in CKD (reproduced with kind permiion of Dr Anatole Bearab). EPO = erythropoietin; WHO = World Health Organization EPO level (mu/ml) Program, 22% of thoe with CKD tage 3 and diabete had anaemia, compared with 7.9% of thoe with tage 3 CKD alone (p<0.001). In tage 2 CKD 7.5% of thoe with diabete were anaemic compared with 5.0% of thoe without diabete (p=0.015). In people with diabete the prevalence of anaemia at all level of GFR i greater with increaing level of albuminuria. 28 When patient with diabete and CKD are tratified into thoe more likely to be iron-replete (TSAT>16%) and thoe le likely to be iron-replete (TSAT<16%) anaemia i aociated with a relative lack of EPO repone in thoe with TSAT>16%. 29 In patient with le advanced CKD there may be ome uncertainty about whether or not the anaemia i aociated with lack of EPO, and thi may be particularly o in tranplanted patient in whom immunouppreion may alo play a role in uppreing the bone marrow repone. In thee patient, knowledge of erum EPO level may be beneficial and the evidence review in thi ection eek to addre thi Methodological introduction One cohort tudy, 70 ix cro-ectional tudie 26,29,71 74 and two longitudinal tudie, propective 75 and retropective, 76 which examined the aociation between erum erythropoeitin with Hb level or renal function, were identified in a literature earch. Notable apect of the evidence bae were: The tudie compried elected and unelected participant. Of the three tudie conducted in people with diabete, the tudy population conited of people with Type 2 diabete without nephropathy, 76 elected people with Type 1 diabete with diabetic nephropathy in the abence of advanced renal failure, 26 people with Type 1 and 2 diabete. 29 Other caue of anaemia were explicitly ruled out in ome tudie. 26,70,72,75,76 48

52 4 Diagnotic evaluation and aement of anaemia Where reported, anaemia wa defined a <13 g/l for men and <11.5 g/l for women, 76 Hb 11.5 g/dl for women and 12.0 g/dl for men, 26 Hb <11 g/dl, 72 Hb <12 g/dl for women and Hb <13 g/dl for men. 29 A comprehenive literature earch did not identify any tudie that were uitable to addre the economic apect, therefore no health economic evidence tatement are given Evidence tatement Adult with diabete In people with Type 2 diabete without nephropathy (n=62) a ignificant negative correlation between erum EPO and Hb level wa found (r 2 =0.612, p=0.01). 76 (Level 3) In contrat to the above finding, a tudy in people with Type 1 diabete with diabetic nephropathy (in the abence of advanced renal failure) (n=27), found no ignificant EPO repone to lower Hb level. 26 (Level 3) A cro-ectional tudy conducted in people with diabete 29 found no ignificant EPO repone in anaemic patient (defined a Hb <12 g/dl for women and Hb <13 g/dl for men) with GFR >60 ml/min/1.73m 2 or >90 ml/min/1.73m 2. (Level 3) In a ubgroup of iron replete diabetic patient (tranferrin aturation level >16%), from the above tudy, 29 erum EPO level did not change ignificantly with Hb level a hown below. Table 4.19 Characteritic in anaemia and raied or normal erum EPO (Level 3) Anaemia + normal EPO, Anaemia + raied EPO, No anaemia, n=554 n=131 n=37 Erythropoietin (IU/l) 15 ± 8 16 ± 7 74 ± 112* # Haemoglobin (g/dl) 14.1 ± ± 1.0* 11.0 ± 1.1* # GFR (ml/min/1.73m 2 ) 79 ± ± 28* 66 ± 28* # TSAT <16% 15% 31%* 73%* # * V no anaemia p<0.05. # V anaemia with normal level of EPO. Children with chronic renal failure No ignificant correlation wa found between erum EPO and Hb/Hct level in three tudie conducted in children with chronic renal failure (n=7; 71 n=10; 74 n=37 75 ). (Level 3) Likewie, no ignificant correlation wa found between erum EPO level and renal function aeed by mean of egfr (n=37) 75 or erum creatinine (SCr) (n=30) 73 in children with chronic renal failure. (Level 3) The reult of a tudy which invetigated Hb and erum EPO level in children with chronic renal failure and healthy children are hown in Table

53 Anaemia management in chronic kidney dieae Table 4.20 Hb and erum EPO in children (Level 3) N Hb (g/dl) Mean erum EPO (U/l) Predialyi ± (range 7 to 235) Pot-tranplant ± (range 10 to 125) Healthy children ± (range 18 to 64) Adult with chronic renal failure on conervative therapy In patient with CKD of varying renal function (CCr 2 to 90 ml/min/1.73m 2 (n=117)), mean erum EPO level were ignificantly elevated in all patient when compared with healthy control (n=59) (p<0.01). In a ubgroup analyi of patient with CCr 2 40 ml/min/1.73m 2 (n=88), CCr and erum EPO howed a poitive correlation (r=0.27, p<0.015). 70 (Level 2+) Unelected population of adult In a random ample of patient invetigated by coronary angiography (n=395) tratified by renal function, a ignificant invere relationhip wa found between erum EPO and Hb level in participant with CCr >40 ml/min (r=-0.35, p<0.0001). No ignificant correlation wa found, however, in participant with CCr <40 ml/min. 72 (Level 3) From evidence to recommendation Anaemia i aociated with increaed EPO level in individual without evidence of CKD but the anaemia aociated with CKD i characteried by a relative lack of EPO repone. However, in the clinical ituation routine meaurement of EPO level i of limited value in aeing anaemia. The GDG reached conenu on a threhold GFR of 40 ml/min, below which anaemia i mot likely to be of renal aetiology and meaurement of erythropoietin level will not be required except in exceptional circumtance. At GFR level between 40 and 60 ml/min, the utility of teting i uncertain from the exiting evidence, and a reearch recommendation i given. RECOMMENDATION R6 Meaurement of erythropoietin level for the diagnoi or management of anaemia hould not be routinely conidered for people with anaemia of CKD. (D(GPP)) 50

54 5 Management of anaemia 5.1 Initiation of ESA therapy in iron-deficient patient Clinical introduction Iron management form an eential part of the treatment of anaemia aociated with CKD and availability of iron i of key importance for iron optimal erythropoiei. Before erythropoietin treatment wa available, patient with anaemia aociated with CKD frequently received blood tranfuion. One of the conequence of thi wa the progreive accumulation of iron, manifeted by extremely high ferritin level in exce of 1,500 to 5,000 µg/l. With the advent of ESA therapy thi accumulated iron wa rapidly mobilied, and erum ferritin level fell accordingly. We now recognie that in order to manage the anaemia optimally, there need to be an appropriate balance between timulation of erythropoiei and proviion of iron a a key ubtrate in the manufacture of haemoglobin. In health, iron i almot completely recycled and loe are of the order of 1 mg/day, requiring minimal replacement. Iron deficiency i the mot common caue of anaemia worldwide. Thi i due to either negative iron balance through blood lo (commonly gatrointetinal or mentrual), or to inadequate intake (which may be nutritional or related to poor gatrointetinal aborption). Patient with CKD are particularly uceptible to gatrointetinal blood lo and additional ource of ignificant blood lo include routine (and non-routine) blood ampling, and blood lo on haemodialyi which may repreent the need for up to an extra 3,000 mg iron per year. In the firt 3 month of ESA therapy it i etimated that a haemodialyi patient need an extra 1,000 mg of upplemental iron, underlining the importance of adequate availability of iron for optimal erythropoiei Clinical methodological introduction A comprehenive literature earch did not identify any tudie that were uitable to addre the clinical apect of thi ection, therefore no evidence tatement are given Health economic methodological introduction One tudy met methodological criteria. 78 Thi Canadian tudy etimated annual cot aving of intravenou iron dextran from reduction in EPO and oral iron in patient who did not tolerate or did not repond adequately to oral iron in a 6-month propective tudy with an initial goal erum ferritin of µg/l. If an increae in haemoglobin wa not achieved, tranferrin aturation wa meaured and when le than 20%, the goal erum ferritin wa increaed to µg/l. EPO wa ued to maintain haemoglobin level of g/l only if ferritin target were met Health economic evidence tatement The tudy found that intravenou iron dextran aved approximately Canadian $63 per patient ($3,016 total) from EPO aving and oral iron aving in 50 patient. However, the initial cot 51

55 Anaemia management in chronic kidney dieae of i.v. iron dextran loading wa $3,426 in the firt year. Therefore, the loading doe of i.v. iron dextran offet the cot reduction in EPO and oral iron in the firt year but would not apply in ubequent year. Intravenou iron dextran cot were $29,692 (Canadian $, 1996) per year in the 50 patient in the tudy with $30,120 of EPO aving per year and $2,738 from oral iron aving per year From evidence to recommendation There i little evidence in thi area but the GDG agreed that ESA alone hould not be adminitered to patient with iron deficiency (ferritin level <100 µg/l). The GDG debated whether ESA hould be adminitered together with iron upplement. It wa noted that ome patient with higher GFR had a good repone to iron treatment alone but that there wa no evidence to upport a threhold for iron tore required prior to commencing ESA, except in patient with iron deficiency. RECOMMENDATIONS R7 ESA therapy hould not be initiated in the preence of abolute iron deficiency without alo managing the iron deficiency. (D(GPP)) R8 In people with functional iron deficiency, iron upplement hould be given concurrently when initiating ESA therapy. Alo ee recommendation R40 in ection (D(GPP)) 5.2 Maximum iron level in patient with anaemia of CKD Clinical introduction Iron i crucial for urvival and i neceary for erythropoiei and the production of uable energy through oxidative phophorylation. However, iron-overload tate are harmful and the potent oxidiing ability of non-tranferrin bound iron make it potentially toxic. The majority of iron not actively circulating a haemoglobin i afely equetered in the form of ferritin and hemoiderin in macrophage of the reticuloendothelial ytem. Molecule that hold iron tend to be very large, containing a central core of iron with a proteinaceou envelope that inulate the body from the iron atom. We know that in iron-overload tate, uch a haemochromatoi, in which erum ferritin level can increae to more than 10,000 µg/l, the body i preented with unmanageable level of free iron leading to iron-related toxicity. The focu of debate about potential iron toxicity in patient with anaemia aociated with CKD revolve around the poible increaed uceptibility to infectiou complication and increaed cardiovacular morbidity and mortality engendered by iron adminitration. In vitro, iron preparation enhance bacterial growth, induce leukocyte dyfunction, inhibit phagocytoi, produce reactive oxygen pecie, increae oxidative tre, conume antioxidant and, at very high doe, promote lipid peroxidation and cell death. Thee obervation have led to concern that too much iron might tranlate thee in vitro phenomena into advere infectiou and cardiovacular in vivo effect. 52

56 5 Management of anaemia Methodological introduction A comprehenive literature earch did not identify any tudie that were uitable to addre the clinical or economic apect of thi ection, therefore no evidence tatement are given From evidence to recommendation Becaue of the lack of evidence, it wa agreed that an upper limit of 800 µg/l of ferritin hould be ued in line with the current European Bet Practice Guideline.* Thi level i drawn from data on iron toxicity tudie performed in the pre-esa era that demontrated that high ferritin level >1,000 µg/l led to the depoition of iron in tiue. However, in practice, in order to prevent erum ferritin from riing above 800 µg/l a patient iron doe hould be reviewed if their erum ferritin level exceed 500 µg/l. It wa noted that it wa not known whether there are any long-term conequence related to the adminitration of intravenou iron a thi route bypaed normal aborption route and homeotatic mechanim. It hould be noted that ferritin i an acute phae protein that i increaed during inflammatory event, thi affect the interpretation of ome of the tudie reviewed. RECOMMENDATION R9 In people treated with iron, erum ferritin level hould not rie above 800 µg/l. In order to prevent thi, the doe of iron hould be reviewed when erum ferritin level reach 500 µg/l. (D (GPP)) 5.3 Clinical utility of ESA therapy in iron-replete patient Clinical introduction Patient who are iron replete (ferritin >100 µg/l and %HRC <6% or TSAT 20%) yet till have anaemia aociated with CKD will not achieve target haemoglobin level without adminitration of ESA. Should all patient regardle of the clinical ituation and their functional tatu receive ESA? Etimate of the number of people in England and Wale with ignificant CKD (egfr <60 ml/min) and a haemoglobin level below 11 g/dl not currently receiving ESA ugget that the potential number requiring anaemia management i 108,000. However, thi etimate wa made from an unelected population that will have included thoe with caue of anaemia other than CKD. A ignificant number may not have been iron replete, and the mean age of the cohort wa 75.1 ± year. The National Service Framework for Older People tate that NHS ervice will be provided, regardle of age, on the bai of clinical need alone. For many older patient improvement in quality of life i their paramount need, and older people hould not necearily be excluded from thee treatment. Becoming able to move around your houe independently and therefore not needing admiion to a care home would clearly be a ucceful outcome in treating anaemia. * At the time of writing the current European guideline were: European bet practice guideline for the management of anemia in patient with chronic renal failure. Nephrology Dialyi Tranplantation 1999;14(Suppl 5):

57 Anaemia management in chronic kidney dieae The key goal in the management of anaemia are increaed exercie capacity, improved quality of life, improved cognitive function, improved exual function, reduced tranfuion requirement, regreion/prevention of left ventricular hypertrophy, improved morbidity, prevention of progreion of renal dieae, reduced rik of hopitaliation, and reduced mortality. We do not yet have the evidence that all of thee goal are achievable and there may be certain patient whoe phyical and mental tatu render thee goal unachievable from the outet. Clearly thee patient will not therefore benefit from adminitration of ESA Methodological introduction A comprehenive literature earch did not identify any tudie that were uitable to addre the clinical or economic apect of thi ection, therefore no evidence tatement are given From evidence to recommendation The GDG expected there to be a paucity of literature in thi area. The reaon for invetigating the evidence bae in thi ection wa to determine whether there were any ubgroup of patient in whom the adminitration of ESA may be of little clinical benefit. The GDG dicued whether they conidered there were any patient ubgroup with a Hb level below 11 g/dl and with tage 3 5 CKD who hould not be conidered for treatment with ESA. The GDG felt that it wa a matter of clinical judgement, baed on a patient individual circumtance (eg preence of comorbiditie), a to whether a patient would benefit from the adminitration of ESA. The GDG conidered it important to note that antibody mediated pure red cell aplaia (PRCA) doe occur poradically and thi wa one group of patient where epoetin adminitration hould be very carefully conidered. The GDG felt the mot relevant iue wa how to bet focu reource in the wider CKD population to provide the mot benefit. The lack of evidence would ugget thi i an area where reearch i required. The GDG dicued that where there i uncertainty over the benefit a patient may gain from ESA therapy, a trial of ESA therapy and aement of repone may be indicated prior to continuing long-term treatment. The GDG felt that the patient wa a good judge of whether the treatment had any noticeable improvement on their quality of life and did not feel there wa any need to recommend any formal tet. The GDG felt trongly that the deciion to actively manage an individual patient anaemia hould be made by an experienced clinician, but that thi did not necearily have to be a renal phyician. RECOMMENDATIONS R10 The pro and con of a trial of anaemia management hould be dicued between the clinician, the peron with anaemia of CKD and their familie and carer if applicable. (D (GPP)) R11 ESA need not be adminitered where the preence of comorbiditie, or the prognoi, i likely to negate the benefit of correcting the anaemia. (D (GPP)) 54

58 5 Management of anaemia R12 R13 R14 A trial of anaemia correction hould be initiated when there i uncertainty over whether the preence of comorbiditie, or the prognoi, would negate benefit from correcting the anaemia with ESA. (D (GPP)) Where a trial of ESA therapy ha been performed, the effectivene of the trial hould be aeed after an agreed interval. Where appropriate, a mutual deciion hould be agreed between the clinician, the peron with anaemia of CKD and their familie and carer on whether or not to continue ESA therapy. (D (GPP)) All people tarted on ESA therapy hould be reviewed after an agreed interval in order to decide whether or not to continue uing ESA. (D(GPP)) 5.4 Nutritional upplement Clinical introduction Vitamin are eential cofactor that regulate the metabolic pathway from which lipid, protein and carbohydrate are generated and proceed. The uraemic environment i reponible for the development of ignificant alteration in erum level, body tore and function of many vitamin. In patient with more advanced CKD (tage 4 and 5) the dietary retriction impoed for potaium and phophate inevitably limit the intake of ome vitamin from natural ource. More recently dietary counelling ha focued more on nutritional upport than dietary retriction, with people eating more liberal diet to try and optimie nutritional tatu. Currently there are no recommendation or guidance a to which population would benefit from vitamin upplementation and in what quantity. Much of our information about upplementation of vitamin come from tudie with mall ubject number, over hort period of time. Many of the tudie only addre vitamin requirement in the dialyidependent population, excluding predialyi patient. Reaon to upport vitamin upplementation include dietary retriction, uraemic toxin, drug nutrient interaction and the dialyi proce itelf. Water oluble vitamin are lot during both haemodialyi (HD) and continuou ambulatory peritoneal dialyi (CAPD). However, thi may be offet by the altered kinetic caued by renal failure which may reult in reduced urinary loe or renal catabolim. The fact that CKD affect the normal aborption, retention and activity of the neceary micronutrient which upport all apect of carbohydrate, protein and lipid metabolim, further trengthen the evidence in favour of upplementation. Le i known about the nutritional requirement of fat oluble vitamin in patient with CKD. Studie report anything from ubnormal through normal to enhanced level. In practice upplementation with fat oluble vitamin i not recommended. Data remain incomplete on individual requirement of vitamin, the handling of vitamin in uraemia, the vitamin tatu of uraemic patient and the effect of vitamin adminitration. Carnitine i yntheied in the body from two eential amino acid, lyine and methionine, wherea glutathione i a peptide containing the amino acid glutamic acid, cyteine and glycine. Carnitine and glutathione have both been implicated in enhancing reponivene to EPO in CKD patient but there are few tudie to date. In practice, thi i not done routinely. 55

59 Anaemia management in chronic kidney dieae Although much i known about the prevalence of macronutrient deficiency in renal patient, nutritional tatu in CKD i beyond the cope of thi guideline. Thi ection focue on micronutrient upplementation and it effect on the treatment of anaemia due to CKD Methodological introduction A comprehenive literature earch identified eight tudie. Of thee, two tudie addreed vitamin C: a cro-over RCT 79 and a non-randomied controlled trial. 80 One RCT addreed folic acid. 81 Five tudie addreed carnitine upplementation, which conited of three RCT, a cro-over RCT 85 and a before and after tudy. 86 Eleven tudie had methodological limitation and were thu excluded from the evidence tatement. Thee include four which addreed vitamin C, one which addreed vitamin E, 91 one which addreed folate, 92 and five which addreed carnitine upplementation Notable apect of the evidence bae were: No tudie addreing vitamin E or glutathione were found. The meta-analyi invetigating carnitine upplementation 93 did not meet quality criteria, hence the tudie within it were individually appraied. One tudy wa conducted in children. 86 One tudy 79 wa conducted in a pre-elected patient population. A comprehenive literature earch did not identify any tudie that were uitable to addre the economic apect of thi ection Evidence tatement Vitamin C Haemodialyi patient A non-randomied trial (n=52) 80 where 100 mg acorbic acid wa adminitered i.v. three time weekly in one group (n=23) and a an adjunct to ESA and i.v. iron in another, found no ignificant change in Hb level from baeline in either group after 6 month. In addition, no change were identified in either group in any of the eight domain of quality of life aeed uing the Short-Form 36 (SF 36) cale. (Level 2+) In a randomied controlled trial (RCT) of cro-over deign (n=27), 79 where acorbic acid 1,500 mg/week wa adminitered i.v. for 3 month, Hb increaed (p<0.01 in group I and p<0.005 in group II) and TSAT increaed (both group I and group II p<0.001), wherea ferritin decreaed (p<0.004 in group I and p<0.001 in group II) when compared with baeline level. Epoetin doe, however, remained unchanged in both group. (Level 1+) Folic acid Haemodialyi patient Reticulocyte count (both p<0.05) and Hct level (both p<0.01) increaed from baeline level in both et of patient receiving folic acid 5 mg three time a week over 12 month (n=10) and patient whoe folic acid upplementation had been topped over thi time period (n=10). Hct 56

60 5 Management of anaemia level increaed further (both p<0.01) in the 6-month follow-up period after folic acid upplementation had been topped in both group of patient. There were no difference, however, in repone to epoetin between the two group. 81 (Level 1+) Carnitine Haemodialyi patient No difference were oberved in any of the five domain of quality of life a aeed by the Kidney Dieae Quetionnaire or in overall quality of life, in a RCT of cro-over deign (n=16) in which placebo or 20 mg/kg L-carnitine were adminitered i.v. over a 12-week period. Similarly, no difference were oberved in epoetin doe or Hb level. 85 (Level 1+) No difference were oberved in epoetin doe requirement or Hct and reticulocyte count in a 6-month tudy invetigating the effect of upplementation with 1 g L-carnitine three time a week in elderly patient (n=28), after which patient were followed up for 3 month. 82 (Level 1+) No difference were found when patient treated with epoetin were upplemented with 1 g carnitine three time a week or placebo (n=24) for 6 month and compared in term of epoetin doe, endogenou epoetin level or Hct and iron level. 83 (Level 1+) No ignificant change in epoetin doe requirement were oberved between patient upplemented with either 5 mg/kg (n=15) or 25 mg/kg (n=5) L-carnitine v placebo (n=20) over 8 month. However, a greater reduction in change in epoetin doe wa oberved in the carnitine treated group (p<0.05) and a higher epoetin reitance index (epoetin doe:hb ratio) (p<0.02). Additionally, after 4 month, there were ignificant negative correlation between plama free carnitine, plama total carnitine and plama free carnitine:plama total carnitine to EPO doe and ERI in both treatment group. 84 (Level 1+) Paediatric haemodialyi and peritoneal dialyi patient Total carnitine and free carnitine increaed ignificantly from baeline (both p <0.05) after 26 week treatment with orally adminitered L-carnitine 20 mg/kg daily in both haemodialyi (n=8) and peritoneal dialyi patient (n=4), with a mean age of 10.2 year. Acylcarnitine increaed only in haemodialyi patient (n=8) after 26 week. Depite thi, no change were oberved in Hb level or epoetin doe from baeline in both et of patient. In addition, no correlation wa found between epoetin doe or Hb level with total carnitine, free carnitine and acylcarnitine level. 86 (Level 3) From evidence to recommendation It wa concluded that there wa no evidence to upport the adjunctive ue of vitamin C, folic acid or carnitine upplement in the treatment of anaemia of CKD. There wa very little evidence available for the CKD population and no evidence in the predialyi population. It wa conidered acceptable to extrapolate the concluion to the predialyi population. With regard to vitamin C, the appraied tudie adminitered very high doe (1,500 mg/wk, 1,000 mg/wk and 100 mg/wk). A doe of 50 mg/week wa conidered to be a more appropriate upplement given in clinical practice to renal patient. The biological bai for the adminitration of vitamin C wa related to aiding the mobiliation of iron and promoting effective erythropoiei. The evidence bae wa mall. 57

61 Anaemia management in chronic kidney dieae In clinical practice, when patient are given folate upplement thi i generally for other reaon than the correction of anaemia. The tudie appraied on carnitine upplementation gave negative reult. RECOMMENDATION R15 Supplement of vitamin C, folic acid or carnitine hould not be precribed a adjuvant pecifically for the treatment of anaemia of CKD. (A) 5.5 Androgen Clinical introduction Interet in the ue of androgen a adjunctive treatment in the management of anaemia aociated with CKD tem from their ue prior to the availability of ESA. A number of early tudie uggeted a beneficial effect on renal anaemia by treatment with androgen, although notably one double blind cro-over trial of nandrolone decanoate failed to how a utained ignificant effect on haemoglobin level or red cell ma. 103 However, their regular ue wa abandoned becaue of the requirement for parenteral adminitration and a number of advere effect uch a acne, fluhing of kin, hirutim, change in voice, maculiniation, amenorrhoea and increaing libido, together with advere effect related to liver function uch a pelioi a well a hepatocellular adenoma and carcinoma. The mechanim of action of androgen on erythropoiei i till not completely undertood and mechanim propoed include increaed production of endogenou erythropoietin, ynergim with ESA, enhanced enitivity of erythroid precuror to erythropoietin, increaed red cell urvival, and a direct effect on erythroid precuror. There i thu a potential role for androgen in enhancing the effectivene and reducing the doe requirement of available ESA Methodological introduction A literature earch identified eight tudie, including two RCT, 104,105 three cohort tudie and one before and after tudy. 109 Two tudie 110,111 had methodological limitation and were therefore excluded from the evidence tatement. The GDG agreed that the following outcome were prioritie: mortality and morbidity improved repone to ESA quality of life Hb/Hct level ESA doe advere effect. Notable apect of the evidence bae were: The tudie were invetigating: epoetin v nandrolone 104,107 epoetin v epoetin and nandrolone 105,106 58

62 5 Management of anaemia epoetin and nandrolone (no control group) 109 Nandrolone alone (no control group). 108 Although ide effect were noted in ome tudie, 105,108,109 the author did not attempt to quantify all of thee. The tudie were conducted in both male and female patient except for two tudie, 104,106 which were conducted olely in male patient Evidence tatement Hb/Hct level Haemodialyi patient In a before and after tudy conducted in male (n=9) and female (n=8) patient, 109 Hb (p=0.001) and Hct (p=0.003) level increaed following adjuvant therapy with epoetin (3,000 U/week.c.) and nandrolone decanoate (100 mg i.m. weekly) for 6 month. When tratified into ex of patient, Hb and Hct level (both p=0.01) were higher only in female patient. (Level 3) In a cohort tudy conducted in male (n=67) and female (n=17) patient, 108 Hb and Hct level roe (both p<0.01) following 6 month therapy with nandrolone decanoate 200 mg i.m. weekly. Although baeline Hb level were higher in the male patient (p<0.05), the increae with repect to baeline level wa imilar in both exe throughout the tudy. In order to evaluate the influence of other factor, patient were divided into the following: non-reponder (Hb increae <1 g/dl with repect to baeline; n=28) mild reponder (Hb increae g/dl with repect to baeline; n=18) good reponder (Hb increae g/dl with repect to baeline; n=25) excellent reponder (Hb increae >2.9 g/dl with repect to baeline; n=13). Only age wa ignificantly aociated with repone to androgen therapy (p<0.01). When the cohort wa tratified into age le than 46 year (n=29), year (n=28) and more than 55 year (n=27), only the latter two group howed improvement in Hb level (both p<0.01) following androgen therapy. (Level 2+) A 6-month cohort tudy conducted to compare the effect of 200 mg nandrolone decanoate i.m. once weekly in male patient aged over 50 year (n=18) v epoetin 6,000 IU a week in male and female patient aged le than 50 year (n=22) found an increae in Hb level in both group (both p<0.01), depite a drop in erum ferritin level in the epoetin treatment group (p<0.01). 107 (Level 2+) In a cohort tudy 106 conducted over 12 week in male patient treated with epoetin 6,000 U i.v. 3 time a week (n=7) v epoetin 6,000 U i.v. 3 time a week and 100 mg nandrolone decanoate i.m. once a week (n=8), Hct value increaed in the group receiving adjuvant therapy (p<0.001) after 12 week and no tranfuion were required in either group. (Level 2+) A RCT conducted in predominantly black male and female patient adminitered with epoetin 4,500 U per week v epoetin 4,500 U per week (n=10; 4 men and 6 women) and nandrolone 100 mg i.m. once a week (n=9; 7 men and 2 women) over 26 week found a ignificant increae in Hct in both treatment group when compared with baeline value (p=0.003 and p=0.001 repectively). However, the rie in Hct wa greater in the epoetin plu androgen group (p=0.012) when compared with epoetin alone. 105 (Level 1+) 59

63 Anaemia management in chronic kidney dieae CAPD patient Hb and Hct level increaed in both treatment group in a RCT 104 invetigating influence of epoetin initiated at 50 U/kg/week and tailored to target Hb of g/dl v nandrolone 200 mg i.m. once weekly (both p<0.001) when compared with baeline value. However, thee increae in Hb and Hct level were not ignificantly different when the treatment group were compared with each other. (Level 1+) Epoetin doe Haemodialyi patient In a before and after tudy conducted in male (n=9) and female (n=8) patient, 109 weekly epoetin doe following adjuvant therapy with nandrolone decanoate (100 mg i.m. weekly for 6 month) did not change ignificantly, either in the overall cohort or when tratified into male and female patient. (Level 3) In a cohort tudy conducted over 12 week in male patient treated with epoetin (6,000 U i.v. three time a week) (n=7) v epoetin (6,000 U i.v. three time a week) and nandrolone decanoate 100 mg i.m. once a week (n=8), no difference wa oberved in epoetin doe between the two treatment group. 106 (Level 2+) Advere event erum triglyceride Haemodialyi patient In a cohort tudy conducted in male (n=67) and female (n=17) patient, erum triglyceride increaed (p<0.01) after therapy with nandrolone decanoate 200 mg i.m. weekly for 6month. 108 (Level 2+) A 6-month cohort tudy conducted to compare the effect of nandrolone decanoate (200 mg i.m. once weekly) in male patient aged over 50 year (n=18) v epoetin (6,000 IU a week) in male and female patient aged le than 50 year (n=22) found an increae in erum triglyceride in the androgen group (p<0.001). 107 (Level 2+) From evidence to recommendation The rationale for the adminitration of androgen to patient with anaemia of CKD wa hitorical in that androgen were adminitered in the pre-esa era. The tudie had adminitered nandrolone decanoate but thi androgen i no longer ued in clinical practice. The doe of nandrolone adminitered in the tudie were conidered to be upraphyiological. The group agreed that there wa ome evidence of efficacy in that the adminitration of androgen could reduce the doe of ESA required but were concerned about the potential ide effect and conidered thi an outdated approach to anaemia management. RECOMMENDATION R16 In people with anaemia of CKD, androgen hould not be ued to treat the anaemia. (C) 60

64 5 Management of anaemia 5.6 Hyperparathyroidim Clinical introduction Elevation in erum parathyroid hormone (PTH) concentration (econdary hyperparathyroidim) are een early in CKD and are common when the etimated GFR i <60 ml/min (tage 3 CKD onward) Elevation of PTH in the tage 3 and 4 CKD population predict the development of more evere hyperparathyroidim, which in turn i clearly aociated with increaed keletal and cardiovacular morbidity and mortality. 115 Whether hyperparathyroidim caue anaemia and reitance to treatment of anaemia, and if it doe, what degree of hyperparathyroidim i clinically important, remain controverial. Potential mechanim include a direct effect of PTH on endogenou erythropoietin ynthei, on bone marrow erythroid progenitor, and on red cell urvival through accelerated haemolyi, and an indirect effect through induction of bone marrow fibroi. Thi ection look at whether treatment of hyperparathyroidim in people with anaemia aociated with CKD improve the management of anaemia in term of haemoglobin level achieved and doe of ESA required, and alo attempt to determine when treatment hould be conidered Methodological introduction A literature earch identified even tudie. Thee conited of a cohort tudy, 116 a two-part tudy compriing a cohort tudy and propective before and after tudy, 117 a two-part tudy compriing a propective longitudinal tudy and cohort tudy, 118 a propective before and after tudy and cohort tudy, 119 a propective longitudinal tudy, 120 and two retropective before and after tudie. 121,122 Six tudie had methodological limitation and were therefore excluded from the evidence tatement. The GDG agreed that the following outcome were prioritie: parathyroid hormone level mortality and morbidity quality of life ESA doe improved repone to ESA plama erythropoietin level reduction in ESA reitance Hb/Hct level. Notable apect of the evidence bae were: Treatment for parathyroidim wa tratified into drug-baed with calcitriol, 117,118 alfacalcidol, 120 or urgery. 116,117,121,122 A comprehenive literature earch did not identify any tudie that were uitable to addre the economic apect of thi ection, therefore no health economic evidence tatement are given. 61

65 Anaemia management in chronic kidney dieae Evidence tatement Table 5.1 Summary of evidence for appraied tudie Baeline Sample ipth level Treatment Level of Reference Drug-baed therapy ize (pg/ml) duration Outcome Effect evidence 117 Calcitriol 2 µg n= ± month n=7 Level 2+ reponder ipth Hct Epoetin doe 120 Alfacalcidol n=12 ~ month ipth Level 3 6 mg Hb 118 Calcitriol i.v. 2 µg n= ± month Hb/Hct Level 3 IPTH 118 Calcitriol i.v. 2 µg n= ± month Epoetin ue No change Level 2+ (n=21) v No Epoetin (n=7) Epoetin doe 118 Calcitriol i.v. 2 µg n= ± month Reponder Level 2+ (n=19) v nonreponder (n=9) Hct Epoetin doe No change Length of Author/ Baal follow-up Study ID Surgical procedure Sample ipth level after Level of ize (pg/ml) urgery Outcome Effect evidence 122 Subtotal parathyroidectomy n=10 Not reported 6 month ipth Level 3 (n=9) and total Hct parathyroidectomy with Epoetin doe forearm autotranplantation (n=1) 117 Total parathyroidectomy n=3 976 ± month ipth Level 3+ with forearm Hct autotranplantation Epoetin doe 121 Subtotal parathyroidectomy n=19 1,726 ± 1, year Hb No change Level 3 (n=44) Total parathyroidectomy n= ± year Hb and autotranplantation (n=24) Total parathyroidectomy n=10 1,006 ± 668 Partial parathyroidectomy n=6 1,176 ± 3346 (removal of 2 3 parathyroid gland) continued 62

66 5 Management of anaemia Table 5.1 Summary of evidence for appraied tudie continued Length of Author/ Baal follow-up Study ID Surgical procedure Sample ipth level after Level of ize (pg/ml) urgery Outcome Effect evidence 119 Total parathyroidectomy n= ± month ipth Level 3 and forearm Note n=7 Hb autotranplantation underwent Plama reoperation erythropoietin for recurrence 12 month Epoetin ue No change Level 2+ in neck and (n=23) v forearm No Epoetin (n=6) Epoetin doe 116 Total parathyroidectomy n=32 Reponder 3 month n=17 No change Level 2+ and forearm 1,338 ± reponder autotranplantation ( 10% Hb Non- increae No change reponder pot-ptx) 1,228 ± v n=15 non- No difference reponder Hb Serum erythropoietin ipth but no difference between the 2 group = ignificant increae; = ignificant decreae; PTX = parathyroidectomy From evidence to recommendation Treatment of hyperparathyroidim econdary to CKD i part of good clinical practice a i routine monitoring of PTH level in patient with CKD. Early control of hyperparathyroidim i crucial for preventing metabolic bone dieae and treating hyperparathyroidim i beneficial to anaemia management. The trategie ued do not differ in patient with CKD whether they are anaemic or not. On the evidence available, it wa not felt to be appropriate to recommend pecific intervention and the Britih, 129 American 130 and European 131 treatment guideline in the management of renal oteodytrophy which are aimed at attainment of target PTH, calcium and phophate concentration hould be followed. RECOMMENDATION R17 In people with anaemia of CKD, clinically relevant hyperparathyroidim hould be treated to improve the management of the anaemia. (C) 63

67 Anaemia management in chronic kidney dieae 5.7 Patient-centred care: ESA Clinical introduction The ESA currently available in clinical practice differ in term of frequency of adminitration and route of adminitration. The ESA currently available in clinical practice may be adminitered either ubcutaneouly or intravenouly. Darbepoetin i likely to require le frequent adminitration than the erythropoietin, while the erythropoietin are likely to require le frequent adminitration and a lower doe when adminitered ubcutaneouly v intravenouly. Logitically it i eaier for patient not on haemodialyi to receive ESA ubcutaneouly by elf-adminitration or adminitration by their carer/practice nure at home; patient on haemodialyi may alo elect to receive their ESA either through elf-adminitration or from dialyi taff at the end of haemodialyi. Key conideration for patient with anaemia aociated with kidney dieae are that: ESA are precribed when clinically indicated. The ESA upply, route of upply and torage arrangement are clearly defined, ecure and convenient. The adminitration and monitoring of anaemia treatment i a efficient, comfortable and leat diruptive a poible Methodological introduction Seven tudie were identified, including two RCT, 132,133 one of which wa of cro-over deign, 133 one retropective longitudinal tudy, 134 one retropective cae erie, 135 and three cro-ectional tudie One tudy 139 had methodological limitation and wa thu excluded from the evidence tatement. The buffer ued in the preparation in the cro-over tudy 133 i no longer ued, and the paper wa therefore not conidered further. Notable apect of the evidence bae were: The tudie conducted uing quetionnaire were limited by the ue of cloed quetion in their deign, 134,136,138 with the exception of one tudy, 137 which reported the ue of both cloed and open quetion. All the tudie uing quetionnaire were cro-ectional, with the exception of one tudy, 134 which wa of longitudinal deign. A comprehenive literature earch did not identify any tudie that were uitable to addre the economic apect of thi ection, therefore no evidence tatement are given. 64

68 5 Management of anaemia Evidence tatement Route of adminitration effect on quality of life Haemodialyi patient In a 24-week cro-over tudy 132 where.c. wa compared with i.v. adminitration, quality of life aeed by mean of the Kidney Dieae Quetionnaire (KDQ), which conit of five domain, found improvement from epoetin adminitration (both intravenou and ubcutaneou) in the phyical (p<0.05) and fatigue (p<0.05) domain, but no ignificant difference between the two mode of adminitration in any other domain. 133 (Level 1+) Adherence and ESA adminitration Peritoneal dialyi patient In a retropective longitudinal tudy, of 54 (35%) patient adminitering.c. epoetin in the home etting were non-concordant (defined a le than 90% of the precribed doe ued), with the mot commonly reported reaon being forgetfulne. Miing dialyi exchange, completion of econdary education and younger age were found to be independent predictor of non-adherence (r 2 =0.36). (Level 3) In a retropective tudy, of 55 (55%) patient adminitering epoetin.c. in the home etting were non-concordant (defined a le than 90% of the precribed doe ued). Whether another peron adminitered the ESA on behalf of the patient wa the only ignificant correlation with concordance (r=0.46, p=0.005). (Level 3) Haemodialyi and continuou ambulatory and automated peritoneal dialyi patient In a cro-ectional tudy, 136 concordance ranged from 24 33%, with the over-60 age group leat likely to mi an epoetin doe and reduced frequency of adminitration aociated with le mied doe. The majority of patient were likely to elf-adminiter. Fewer injection were preferred by 72.5%, with the under-60 age group preferring once-weekly becaue of convenience, pain on injection and epoetin torage. (Level 3) Predialyi, hopital and home haemodialyi and continuou ambulatory peritoneal dialyi patient In a cro-ectional tudy, of 86 (66%) patient reported they never mied doe, while 31% admitted to occaionally miing doe and 3% admitted to frequently miing doe. Following a mied doe, the majority (39%) informed the renal unit, 27% carried on a uual after the mied doe, 19% adminitered the mied doe a oon a they remembered. The majority (55%) of patient preferred elf-adminitration of epoetin, with 17% reporting difficultie with injection preparation and 17% reporting pain at the injection ite. (Level 3) 65

69 Anaemia management in chronic kidney dieae Communication and obtaining of ESA Predialyi, hopital and home haemodialyi and continuou ambulatory peritoneal dialyi patient In a cro-ectional tudy, 137 the majority of patient (89%) reported the renal unit anaemia nure to be the preferred ource of information. However, mot patient (59%) reported they did not need more information. Mot requet for information were found to be about how epoetin work (31%), poible ide effect (29%) and what epoetin i for (26%). Epoetin upply wa found to be motly by GP (71%), although 20 patient (23%) reported that their GP had refued to upply epoetin. Mot patient preferred obtaining epoetin upplie from a community pharmacy (n=63). (Level 3) Predialyi, dialyi and tranplant patient In a cro-ectional tudy, 138 mot (91%) anaemic patient received epoetin therapy. Of the 4% that were refued epoetin, the reaon given were that the GP could not pay for it (50%) and that the hopital could not pay for it (20%). (Level 3) EPO adminitration effect on quality of life Predialyi, dialyi and tranplant patient In a cro-ectional tudy, 138 leep diturbance, tiredne and ability to attend a 9am to 5pm job were found to be aociated with baeline Hb and pot-treatment level. Patient whoe pottreatment Hb level had increaed from below 11 g/dl to above 11 g/dl were 1.8 time more likely to report an improvement in QoL. Patient with pot-treatment Hb level >11 g/dl were 1.9 time more likely to agree with the tatement I can attend a 9am 5pm job. (Level 3) From evidence to recommendation The evidence from even tudie contained outcome data on quality of life, pain, concordance, obtaining ESA and communication with patient. The data upported the view that patient preference and experience hould be taken into account, where poible, when deciion are reached about treatment with ESA. The patient hould be given acce to ufficient information about their condition and it treatment to allow them to make informed choice about the management of their condition (for example, whether to have upervied- or elf-adminitration of ESA). It wa noted that ome tudie had hown an increaed lack of concordance in ome group who had choen elfadminitration. 134,135 Patient need to be aware of the conequence of poor concordance and one tudy highlighted that a reduced frequency of adminitration of ESA reulted in increaed concordance. 136 Currently many patient have difficultie ecuring a upply of ESA. Many patient are unable to obtain ESA from their local hopital or GP practice and have the ESA delivered to them at home. Thi can caue problem in finding the capacity to refrigerate large quantitie of drug. Thi area need to be addreed by healthcare provider to enure adequate drug upply and torage facilitie for patient. 66

70 5 Management of anaemia RECOMMENDATIONS R18 People offered ESA therapy, and their GP, hould be given information about why ESA therapy i required, how it work, and what benefit and ide effect may be experienced. (D) R19 When managing the treatment of people with anaemia of CKD, there hould be agreed protocol defining role and reponibilitie of healthcare profeional in primary and econdary care. (D(GPP)) R20 People receiving ESA therapy hould be informed about the importance of concordance with therapy and the conequence of poor concordance. (D) R21 When precribing ESA therapy, healthcare profeional hould take into account patient preference about upervied- or elf-adminitration, doe frequency, pain on injection, method of upplying ESA and torage. (D(GPP)) R22 In order for people to elf-adminiter their ESA in a way that i clinically effective and afe, arrangement hould be made to provide ready, reaonable and uninterrupted acce to upplie. (D) 5.8 Patient education programme Clinical introduction Patient elf-management i one of the cornertone of chronic dieae management, enabling patient ome degree of control of their own dieae proce. The level of independence each individual achieve depend a much on the quality of the information and elf-management tool provided a it doe on the ability of the individual patient. Patient education programme are therefore of paramount importance in achieving effective patient elf-management. Structured patient education involve planned education that cover all apect of anaemia management and i flexible in content, i relevant to a peron clinical and pychological need, and i adaptable to their educational and cultural background. A well-planned education coure will provide a written outline, be delivered by trained educator (preferably omeone who i both well vered in the principle of patient education and i competent to teach the programme), be quality aured, and provide the opportunity for feedback Methodological introduction A comprehenive literature earch did not identify any clinical or health economic tudie that were uitable to addre thi ection From evidence to recommendation Patient education wa conidered to be hugely important and information hould be available at different level. Adequate information help patient to make deciion about their treatment and illne, although it wa noted that there might be ome patient who will wih to remain paive about their condition. 67

71 Anaemia management in chronic kidney dieae Patient education hould meet the individual need of each patient and five theme drawn from recent work in the area 140 were conidered to be important: practical management of anaemia knowledge (about ymptom, iron and ESA management and product delivery and torage) profeional upport (contact information, community ervice, continuity of care, monitoring, feedback on progre of reult) lifetyle (diet, phyical exercie, maintaining normality, meeting other patient) adaptation (caue of anaemia, aociated medication, phae of treatment, previou information and expectation, reolution of ymptom). RECOMMENDATION R23 Culturally and age-appropriate patient education programme hould be offered to all people diagnoed with anaemia of CKD and their familie and carer. Thee hould be repeated a requeted, and according to the changing circumtance of the patient. They hould include the following key area: practical information about how anaemia of CKD i managed knowledge (eg about ymptom, iron management, caue of anaemia, aociated medication, phae of treatment) profeional upport (eg contact information, community ervice, continuity of care, monitoring, feedback on progre of reult) lifetyle (eg diet, phyical exercie, maintaining normality, meeting other patient) adaptation to chronic dieae (eg previou information and expectation, reolution of ymptom). (D(GPP)) 68

72 6 Aement and optimiation of erythropoiei 6.1 Benefit of treatment with ESA Clinical introduction The introduction of ESA into clinical practice nearly 20 year ago dramatically changed the management of anaemia aociated with chronic kidney dieae. Prior to ESA therapy, dialyidependent patient were profoundly anaemic, frequently manifeting haemoglobin level of between 6 and 7 g/dl, the only treatment available being blood tranfuion, iron or androgen therapy. The potential benefit aociated with anaemia treatment are numerou. Thee include avoidance of blood tranfuion with their attendant rik of enitiation againt future tranplantation, iron overload, blood-borne dieae and tranfuion reaction; improved quality of life and phyical functioning; improved cognitive and exual function; cardiovacular benefit in term of tructure, function, incidence and prevalence of dieae; and reduced hopitaliation, morbidity and mortality Clinical methodological introduction Four tudie were identified. A meta-analyi (epoetin v placebo or no treatment), 141 two multiite RCT (epoetin v placebo), 142,143 one cohort tudy (epoetin v no treatment) 144 and a retropective longitudinal tudy. 145 Two tudie 145,146 had methodological limitation and were therefore excluded. The outcome to ae the efficacy of the ESA preparation in comparion with placebo or no treatment were morbidity, left ventricular hypertrophy, left ventricular function, mortality, hopitaliation and dialyi adequacy. Notable apect of the evidence bae: All tudie except for two included in the meta-analyi 141 did not explicitly tate if they ued epoetin-alfa or epoetin-beta. The tudy duration ranged from 12 week to 3.5 year. Studie included in the meta-analyi 141 achieved a lower Hb level and excluded patient with ignificant comorbiditie. In one tudy 143 red cell tranfuion were given to placebo or treatment arm when required Clinical evidence tatement Quality of life Predialyi patient Of the tudie in the meta-analyi, 141 Kleinman (1989), by mean of a viual analogue cale rating of three quetion, found an improvement in quality of life after 12 week with a mean difference of 35 (95% CI to 57.53). Roth (1994), by mean of the Sickne Impact Profile 69

73 Anaemia management in chronic kidney dieae and other validated tet, found an improvement at 48 week, with the control group having decreaed phyical function (p=0.03) and the epoetin group having increaed phyical function (p=0.015) a well a increaed energy (p=0.045). However, the number of domain aeed in thi tudy wa not provided by the author. (Level 1+) Haemodialyi patient In one tudy 142 an improvement in four out of five categorie of the Kidney Dieae Quetionnaire were found (phyical p<0.001; fatigue p<0.001; relationhip p=0.001; depreion p=0.018). In addition, the Sickne Impact Profile quetionnaire found an improvement in quality of life a reflected by the reduction of the global core (p=0.024) and the phyical core (p=0.005). Pychoocial core did not change ignificantly. (Level 1+) Mortality There were inufficient mortality data available from the meta-analyi 141 and the RCT 143 to write evidence tatement. Hopitaliation Study participant new haemodialyi patient No tatitically ignificant difference in hopitaliation between epoetin and placebo treatment group wa found, including when tratified and analyed into admiion type, age group and hitory of cardiovacular dieae. 144 (Level 2+) Health economic methodological introduction Three tudie were identified. 14,147,148 One tudy 149 did not meet met quality criteria and therefore no evidence tatement were made. One tudy contained a cot-effectivene analyi before and during epoetin therapy. 14 It wa predominantly a cot-aving analyi with 1990 to 1991 UK and earlier cot. However, the 1990 to 1991 or earlier cot data meant that there wa inufficient data from which to derive evidence tatement for application to the current NHS context. One tudy compared cot per QALY reult in five European countrie including the UK. 147 Thi tudy ued QALY a the effectivene meaure. Neverthele, cot were derived from 1988 value, which indicate there are inufficient data from which to derive evidence tatement for the current NHS context. An additional tudy 148 evaluated the cot per QALY of epoetin uing the ame framework a the Leee tudy 147 (1988 value), but updated data with value from the year 2000 in the UK Health economic evidence tatement The cot per QALY of ESA therapy in the UK uing data from the year 2000 wa 17,067. The model wa mot enitive to change in the QALY gain. The baeline QALY gain ued to derive the cot per QALY wa per year. However, if a 0.17 QALY gain occur, the cot per QALY 70

74 6 Aement and optimiation of erythropoiei drop to 8,809, converely if a 0.02 QALY gain occurred, the cot per QALY would increae to 74, From evidence to recommendation One tudy 141 wa appraied that aeed mortality but the GDG conidered the tudy to be underpowered to determine whether there wa a clinically important difference in mortality rate. The GDG felt that the evidence wa not ufficient to make a ound evidence tatement. The GDG concluded that the tudy of people receiving peritoneal dialyi 143 did not contribute meaningful data a the tudy duration wa too hort (12 week) to ae mortality. Of the outcome aeed, the GDG felt there wa only good evidence upporting improvement in quality of life through ESA therapy. The GDG noted that the tudie had mall ample ize and had concern over the tatitical validity of the evidence. The tudie in the meta-analyi 141 achieved a low target haemoglobin and the patient that may have hown the greatet benefit were excluded from the tudie. The GDG noted that becaue highly elected population were included in thee tudie, the effect reported were not a large a thoe oberved in the unelected patient population oberved in clinical practice. The GDG concluded on the bai of qualitative data and clinical experience that ESA are of value. Health economic evidence wa preented to the group. The GDG agreed that one tudy wa preented that wa ufficiently robut to be included and gave ueful cot per QALY information in the UK context. 148 However, a the model wa enitive to the gain in QALY, the GDG felt further economic evidence i required before definitive tatement about the cot effectivene are made. The GDG felt the other tudie: etimated the price but underetimated the benefit of the treatment (n=24) 147 were baed on a tudy deign that could introduce bia, 149 or were baed on hitorical cot data that no longer had relevance to the current NHS context. 14 RECOMMENDATION R24 Treatment with ESA hould be offered to people with anaemia of CKD who are likely to benefit in term of quality of life and phyical function. See for the aociated algorithm. (A) 6.2 Blood tranfuion Clinical introduction The potential rik of blood tranfuion include tranfuion reaction, immunomodulation, iron overload and tranfuion tranmitted infection. 71

75 Anaemia management in chronic kidney dieae Data concerning advere tranfuion event in the UK are collected by the Seriou Hazard of Tranfuion (SHOT) group. Their 2003 report included data from 351/415 UK hopital (ee Since the inception of SHOT in 1996 there ha been an increae in the number of advere tranfuion incident reported with now over 2,000 recorded in the SHOT databae (Table 6.1). Although the number of tranfuion-tranmitted infection reported are low, the lit of infection that may be potentially tranmitted i growing rapidly and include hepatiti B, C and G, human immunodeficiency viru (HIV), human t-lymphocytotrophic viru (HTLV-1), tranfuion tranmitted viru (TTV), cytomegaloviru (CMV), Creutzfeld- Jakob dieae (CJD), human herpe viru (HHV-8), leihmaniai, Lyme dieae, malaria, babeioi and toxoplamoi. Table 6.1 Seriou Hazard of Tranfuion (SHOT) Report 2003 Reported cae SHOT category , n (%) Rik category Etimated rik Incorrect blood component 1393 (66.7) Rik of incorrect blood 1 in 16,500 tranfued component tranfued Acute tranfuion reaction 233 (11.2) Rik of ABO incompatibility 1 in 102,200 Delayed tranfuion reaction 213 (10.2) Tranfuion-related acute 139 (6.7) Rik of tranfuion-related 1 in 165,000 lung injury acute lung injury Tranfuion-tranmitted 45 (2.2) infection Pot-tranfuion purpura 44 (2.1) Rik of eriou hazard 1 in 11,000 Tranfuion-aociated GVHD 13 (0.6) Rik of major morbidity 1 in 92,000 Unclaified 7 (0.3) Rik of death 1 in 255,500 Prior to the introduction of ESA, in addition to the immediate rik of tranfuion reaction and infection, the two bigget concern for patient with CKD were enitiation againt future tranplantation and iron overload. Thi wa complicated by the evidence uggeting that tranfuion prior to tranplantation may actually be beneficial in term of future tranplant outcome. Thi had been firt uggeted in However, a ubequent aement following the introduction of cicloporin failed to confirm a benefit 151 and thi ubject remain controverial. Donor-pecific tranfuion prior to living-related tranplantation appear favourable 152 but in cadaveric tranplantation the picture i le clear. A multicentre randomied controlled trial of tranfuion of three unit of packed cell demontrated improved graft urvival at 1 and 5 year. 153 However, approximately 5% of the patient in thi tudy became enitied, and had not been tranplanted by the end of the tudy period. In children, a retropective tudy hinted at a beneficial effect from tranfuion of 1 5 unit of blood, but thi beneficial effect wa lot with greater number of unit tranfued. 154 A recent tudy looking at the caue of enitiation of potential renal allograft recipient in Ireland in the pot-epo era demontrated that the level of enitiation clearly increaed with the number of unit tranfued. 155 Non-enitied participant (PRA <10%) received a mean of 5.65 unit 72

76 6 Aement and optimiation of erythropoiei (SEM 1.38), enitied participant (PRA 11 59%) a mean of 9.8 unit (SEM 3.17), ignificantly enitied (PRA 60 79%) a mean of 18.2 unit (SEM 6.51), while highly enitied participant (PRA 80%) received a mean of 37.8 unit (SEM 8.4). There wa a direct relationhip between the waiting time for tranplantation and the degree of enitiation. Although blood tranfuion i not the only factor related to recipient enitiation, ince ESA have become more freely available and the ue of routine blood tranfuion for correction of anaemia ha diappeared, enitiation ha markedly reduced (Figure 6.1) % tranplant Senitiation poitive negative Figure 6.1 Recipient pre-tranplant HLA-pecific enitiation: adult recipient of cadaver donor kidney (Mancheter Kidney Tranplant, NWKTA Audit Project, January 2003) Methodological introduction A comprehenive literature earch identified two tudie, a cae-control tudy 156 and a before and after tudy. 157 Five tudie 155, had methodological limitation and were therefore excluded from the evidence tatement. A comprehenive literature earch did not identify any tudie that were uitable to addre the economic apect of thi ection, therefore no health economic evidence tatement are given Evidence tatement Immunological parameter / enitiation Haemodialyi patient No ignificant difference were oberved in the analye of lymphocyte, monocyte, T8, T4, T11, T13, Ia and B1 cell or T4/T8 ratio in patient who had previouly received five or more tranfuion over 6 month (n=30) when compared with a matched lightly tranfued group (n=30). 156 (Level 2+) 73

77 Anaemia management in chronic kidney dieae Dialyi patient More patient in the lightly tranfued group developed narrowly reactive antibodie (reacting with 10 29% panel cell) in comparion with the more heavily tranfued group who developed antibodie againt 30% panel cell. Senitiation increaed waiting time for tranplant both in ubequently tranplanted patient (p<0.003) and the entire patient population regardle of tranplantation (p<0.03). 157 (Level 3) From evidence to recommendation The GDG noted the lack of evidence on important factor that would impact on the rik of correcting anaemia with regular blood tranfuion, uch a blood borne virue and iron overload. In the late 1970 and early 1980 there wa evidence that giving blood tranfuion before tranplantation improved tranplant outcome and mot unit had a deliberate tranfuion policy; mot reearch focued on the rik of enitiation which meant that certain donor would be excluded if the antibodie were directed to their lymphocyte (detected in the cro match tet ). Around the mid-1980 tranmiion of blood borne virue by tranfuion (in particular HIV) became a major public health iue. At the ame time cicloporin came into regular ue. Cicloporin improved urvival, and taken together with the rik of the tranmiion of blood borne virue and the availability of erythropoietin for treating anaemia, deliberate tranfuion wa dicontinued. The GDG conidered the evidence on the immunological rik of correcting anaemia with regular blood tranfuion. They agreed that the evidence relating to the development of cytotoxic antibodie to lymphocyte 157 wa more clinically relevant than the data on the level of different ubtype of lymphocyte induced by tranfuion. 156 It wa noted that blood tranfuion increaed the percentage of cytotoxic antibodie in dialyi patient reulting in not only an increaed waiting time for a tranplant but alo increaed difficulty in finding a cro match negative donor. The GDG felt it wa important to tre the benefit of tranfuion when clinically indicated for blood lo or in ome cae the correction of anaemia (eg in ome elderly patient). The GDG agreed that there were general clinical reaon to avoid blood tranfuion and the relevant haematology guideline hould be followed (eg the Britih Committee for Standard in Haematology (BCSH) guideline RECOMMENDATIONS R25 R26 In people with anaemia of CKD, in whom kidney tranplant i a treatment option, blood tranfuion hould be avoided where poible. In people with anaemia of CKD there may be ituation where a tranfuion i indicated clinically. In thee cae, the relevant haematology guideline 162 hould be followed. (D) (D (GPP)) 74

78 6 Aement and optimiation of erythropoiei 6.3 Comparion of ESA Clinical introduction Erythropoiei timulating agent (ESA) are agent timulating production of red blood cell through a direct or indirect action on erythropoietin receptor of erythroid progenitor cell in the bone marrow. There are three licened form of ESA currently available in England and Wale, * two hort-acting (epoetin alfa and epoetin beta) and one long-acting (Darbepoetin alfa). Epoetin alfa i a glycoprotein manufactured by recombinant DNA technology and ha the ame biological effect a endogenou erythropoietin. It ha an apparent molecular weight of 32,000 to 40,000 dalton and i produced by mammalian cell into which the human erythropoietin gene ha been introduced. The protein fraction of the molecule contribute about 58% and conit of 165 amino acid. Four carbohydrate chain are attached via three N-glycoidic bond and one O-glycoidic bond to the protein moiety. Epoetin alfa obtained by gene technology i identical in it amino acid and carbohydrate compoition to endogenou human erythropoietin that ha been iolated from the urine of anaemic patient. In both patient and normal volunteer, after intravenou adminitration of epoetin alfa, erum level decline in a monoexponential manner and the volume of ditribution i imilar to that of the plama volume. The half-life in normal volunteer i approximately 5 hour, but in patient with renal failure it i prolonged to approximately 9 hour. With multiple injection of epoetin alfa, half-life and clearance decreae. Meaurement of epoetin alfa following multiple doe intravenou adminitration revealed a half-life of approximately 4 hour in normal volunteer and approximately 5 hour in renal failure patient. A half-life of approximately 6 hour ha been reported in children. After.c. adminitration of epoetin alfa, peak erum level occur between 12 and 18 hour later. The peak i alway well below the peak achieved uing the i.v. route (approximately 1/20th of the value). The bioavailability of ubcutaneou injectable epoetin alfa i approximately 20% lower than that of the intravenou drug. Elevated level of epoetin alfa are found in the erum 48 hour after a ubcutaneou doe, but not after an intravenou doe. Epoetin beta i alo identical in it amino acid and carbohydrate compoition to erythropoietin that ha been iolated from the urine of anaemic patient. Pharmacokinetic invetigation in healthy volunteer and uraemic patient how that the half-life of intravenouly adminitered epoetin beta i between 4 and 12 hour and that the ditribution volume correpond to one to two time the plama volume. After ubcutaneou adminitration of epoetin beta to uraemic patient, the protracted aborption reult in a erum concentration plateau, whereby the maximum concentration i reached after an average of 12 to 28 hour. The terminal half-life i higher than after intravenou adminitration, with an average of 13 to 28 hour. The bioavailability of epoetin beta after ubcutaneou adminitration i between 23 and 42% when compared with intravenou adminitration. The biological efficacy of epoetin alfa and epoetin beta ha been demontrated in variou animal model in vivo (normal and anaemic rat, polycythaemic mice). After adminitration of * Epoetin delta wa granted marketing approval in March 2002 by EMEA and introduction into the UK market i pending. Precriber hould be aware of development in the available product and hould check the mot recent Summarie of Product Characteritic. 75

79 Anaemia management in chronic kidney dieae epoetin alfa and epoetin beta, the number of erythrocyte, the Hb value and reticulocyte count increae a well a the Fe-incorporation rate. It ha been hown in cell culture of human bone marrow cell that epoetin alfa and epoetin beta timulate erythropoiei pecifically and do not affect leucopoiei. Darbepoetin alfa i an erythropoiei timulating protein, cloely related to erythropoietin, that i produced by recombinant DNA technology. It i a 165-amino acid protein that differ from recombinant human erythropoietin in containing five N-linked oligoaccharide chain. The two additional N-glycoylation ite reult from amino acid ubtitution in the erythropoietin peptide backbone. Darbepoetin timulate erythropoiei by the ame mechanim a endogenou erythropoietin and epoetin alfa and beta. Following ubcutaneou adminitration, aborption i low and rate limiting. The oberved half-life in patient with renal failure wa 49 hour (range: 27 to 89 hour) and reflect the rate of aborption. Following intravenou adminitration to patient with renal failure, erum concentration-time profile are biphaic, with a ditribution half-life of approximately 1.4 hour and a mean terminal half-life of 21 hour. Following ubcutaneou adminitration in patient with renal failure peak concentration occur at 34 hour (range: 24 to 72 hour). Following intravenou adminitration, the terminal half-life of darbepoetin i approximately three time longer than epoetin alfa. The bioavailability of darbepoetin in patient with renal failure after ubcutaneou adminitration i 37% (range: 30% to 50%) Clinical methodological introduction Epoetin alfa v epoetin beta There were no tudie comparing epoetin alfa and epoetin beta. Darbepoetin v epoetin alfa One multiite RCT 163 comparing darbepoetin and epoetin alfa wa identified. One tudy 164 wa excluded becaue of methodological limitation. Notable apect of the evidence bae were: Of the 28-week tudy duration, 163 the firt 20 week were a doe titration and tabiliation period. Darbepoetin v epoetin beta A comprehenive literature earch identified one open-label RCT comparing darbepoetin and epoetin beta. 165 Notable apect of the evidence bae were: Darbepoetin doe wa converted at 200 IU:1 µg according to the manufacturer doe converion. 76

80 6 Aement and optimiation of erythropoiei The GDG agreed that the following outcome were prioritie in aeing the efficacy of the ESA preparation: haemoglobin level ESA doe morbidity mortality quality of life left ventricular hypertrophy and left ventricular function Clinical evidence tatement Darbepoetin v epoetin alfa Haemodialyi patient Efficacy A mean change in Hb level between baeline and evaluation period of 0.13 g/dl (95% CI 0.08 to 0.33) wa above the pre-defined margin of 1.0 g/dl and therefore implied that no ignificant difference wa oberved between the two treatment group. 163 (Level 1+) No ignificant difference wa oberved for: haemoglobin variability aeed a variance in haemoglobin percentage value within the Hb target range percentage value within the therapeutic range and intability of Hb level requiring a doe change within the two treatment group. 163 (Level 1+) Doe change from baeline to evaluation wa imilar for both treatment group. 163 (Level 1+) The number of patient with doe change during the titration and evaluation period wa imilar for both treatment group. 163 (Level 1+) Safety The type and frequency of advere event wa imilar in both treatment group, with no antibody formation to either treatment detected. 163 (Level 2+) Darbepoetin v epoetin beta Haemodialyi patient Efficacy There wa no ignificant difference in maintaining Hb at g/dl between darbepoetin (n=81) and epoetin beta (n=81), both adminitered.c. weekly over 9 month. 165 (Level 1+) Doe Over the 9-month tudy duration, median doe fell in the darbepoetin arm (p=0.006), but increaed in the epoetin beta arm (p=0.002). When converted into the ame unit (IU/kg/week) 77

81 Anaemia management in chronic kidney dieae uing the manufacturer doe converion, darbepoetin doe required to achieve the ame Hb outcome wa ignificantly lower than epoetin beta doe at 9 month (95%CI IU/kg/week, p<0.001). 165 (Level 1+) Blood preure Blood preure did not change ignificantly in the coure of the tudy in either treatment arm. 165 (Level 1+) Health economic methodological introduction Only one economic evaluation 166 wa found that compared darbepoetin and epoetin alfa. However, thi tudy had methodological limitation and therefore no evidence tatement were made. * From evidence to recommendation The GDG agreed that the evidence tatement from the multiite RCT upport the ummary that there i no difference between darbepoetin and epoetin alfa for the outcome meaured, in a elected group of patient who were table. 163 Evidence tatement on efficacy ugget that both darbepoetin and epoetin beta effectively maintain target haemoglobin level. ESA are made available to NHS trut through a ytem of tendering for local upply contract. Cot therefore vary between location and over time. The recommendation below outline the conideration in agreeing on a firt choice ESA rather than pecifying a particular agent for all patient. Thi i intended to allow flexibility for local unit over the lifetime of the guideline while providing ueful advice in electing the bet treatment for the patient. RECOMMENDATION R27 The choice of ESA hould be dicued with the peron with anaemia of CKD when initiating treatment and at ubequent review, taking into conideration the patient dialyi tatu, the route of adminitration and the local availability of ESA. There i no evidence to ditinguih between ESA in term of efficacy. (A) 6.4 Early or deferred ESA therapy Clinical introduction The patient mot likely to derive the greatet long-term benefit from correction of anaemia are thoe with chronic kidney dieae who are predialyi. Early intervention to correct anaemia ha the potential to impact on the progreion of chronic kidney dieae and affect patient morbidity, * In interpreting economic evaluation of ESA, it hould be borne in mind that different unit will have developed their own pricing tructure which may differ coniderably from BNF lit price. 78

82 6 Aement and optimiation of erythropoiei hopitaliation rate, quality of life, and mortality. The key goal in the management of anaemia are increaed exercie capacity, improved quality of life, improved cognitive function, improved exual function, reduced tranfuion requirement, regreion/prevention of left ventricular hypertrophy, improved morbidity, prevention of progreion of renal dieae, reduced rik of hopitaliation, and reduced mortality Methodological introduction A comprehenive literature earch identified two tudie. 167,168 Notable apect of the evidence bae were: One tudy 167 wa conducted in a elected patient population, recruiting only patient without diabete. Target Hb level in both tudie were not met. The target Hb level for one tudy 167 wa 13 g/dl, however, the mean Hb level achieved wa 12.9 g/dl (tandard deviation 0.4) in the early treatment group and 10.3 g/dl (tandard deviation 1.0) in the deferred treatment group. The target Hb level for the other tudy 168 were g/dl in the early treatment group and 9 10 g/dl in the deferred treatment group, while mean level achieved were 12.1 g/dl (tandard deviation 1.4) and 10.8 g/dl (tandard deviation 1.3) repectively. A comprehenive literature earch did not identify any tudie that were uitable to addre the economic apect of thi ection, therefore no health economic evidence tatement are given Evidence tatement Left ventricular ma index Predialyi patient No ignificant difference were oberved in left ventricular ma index meaurement in a 2-year tudy 168 conducted to maintain Hb g/dl (n=75) v 9 10 g/dl (n=80) uing epoetin. Treatment wa initiated in the latter group when Hb wa <9 g/dl at two conecutive aement 2 month apart or <8 g/dl at any one time. (Level 1++) Renal function Predialyi patient No ignificant difference were oberved in renal function (egfr) in a 2-year tudy 168 conducted to maintain Hb g/dl (n=75) v 9 10 g/dl (n=80) uing epoetin. However, egfr progreively decreaed in the two treatment arm (p<0.001). Treatment wa initiated in the latter group when Hb wa <9 g/dl at two conecutive aement 2 month apart or <8 g/dl at any one time. (Level 1++) In a tudy conducted over 22.5 month in patient without diabete with imilar baeline creatinine clearance level, where initiation of epoetin treatment wa early (n=45) v deferred (n=43, Hb <9 g/dl) and adminitered to achieve a target Hb 13 g/dl, the adjuted relative hazard for doubling of erum creatinine, renal replacement or death wa 0.37 (95% CI 0.18 to 79

83 Anaemia management in chronic kidney dieae 0.73, p=0.004) in the early epoetin treatment arm. Additionally, the rik of an event increaed 2.23-fold (95% CI 1.56 to 3.18, p<0.01) per 1 mg/dl higher erum creatinine at baeline. Similarly, the adjuted relative hazard for renal replacement or death wa 0.38 (95% CI 0.19 to 0.76, p=0.006) in the early epoetin treatment arm and the rik of an event increaed 2.25-fold (95% CI 1.57 to 3.23, p<0.001) per 1 mg/dl higher erum creatinine at baeline. 167 (Level 1+) Hypertenion Predialyi patient In a 2-year tudy conducted to maintain Hb g/dl (n=75) v 9 10 g/dl (n=80), uing epoetin and initiated in the latter group when Hb wa <9 g/dl at two conecutive aement 2 month apart or <8 g/dl at any one time, no ignificant difference were oberved in ytolic and diatolic blood preure. 168 (Level 1++) In a tudy conducted over 22.5 month in non-diabetic patient with imilar baeline creatinine clearance level, whereby initiation of epoetin treatment wa early (n=45) v deferred (n=43, Hb <9 g/dl) and adminitered to achieve a target Hb 13 g/dl, no ignificant difference were oberved in ytolic and diatolic blood preure between the 2 treatment arm. 167 (Level 1+) Quality of life Predialyi patient In a 2-year tudy conducted to maintain Hb g/dl (n=75) v 9 10 g/dl (n=80), uing epoetin and initiated in the latter group when Hb wa <9 g/dl at two conecutive aement 2 month apart or <8 g/dl at any one time, no ignificant difference were oberved in quality of life domain, a aeed by the Renal Quality of Life Profile and Short Form 36 (SF 36) quetionnaire. 168 (Level 1++) From evidence to recommendation Both tudie preented in the evidence were conidered to be methodologically ound. The GDG felt that the tudy by Gouva et al 167 had achieved the tudy aim (in term of level of Hb achieved) and howed a ignificant reduction in rate of renal progreion. The tudy by Roger et al 168 did not achieve the tudy aim and howed no ignificant difference in any outcome. It wa not conidered poible to reach any ound concluion on the bai of thee paper. The GDG felt they could not make any recommendation on thi area baed on thee tudie alone. The evidence howed no contraindication to early correction of anaemia. 6.5 Coordinating care Clinical introduction During the pat decade in the UK, the management of anaemia aociated with CKD ha evolved into a nure-led programme in many renal unit. The introduction of pecialit nure dedicated to managing anaemia in CKD i in repone to an increaed number of patient 80

84 6 Aement and optimiation of erythropoiei receiving treatment for renal anaemia. Thi role may alo be undertaken by other health profeional, uch a pharmacit, the goal being to deliver an effective, efficient, patientcentred anaemia ervice. The inefficient ue of ESA, the increae in the ue of intravenou iron therapy, the requirement for patient monitoring and for regular audit have alo highlighted the need to have a dedicated peron reponible for anaemia management. Specialit nure are able to work within protocol, become upplementary and extended nure precriber, and therefore can manage thi group of patient with a high degree of independence. The exact role of thee health profeional will depend on how the anaemia management programme i et up and run, and thi will vary from unit to unit. For example, they may be reponible for a mall cae load uch a haemodialyi patient and the management may be lead by a computer algorithm or clinician, or they may be reponible for managing the entire anaemia programme acro all modalitie Methodological introduction A comprehenive literature earch identified a before and after tudy. 169 However, becaue of methodological limitation, it wa excluded from the evidence tatement. A comprehenive literature earch did not identify any health economic tudie that were uitable to addre thi iue From evidence to recommendation The GDG felt that there i a benefit to having a healthcare worker identified a having reponibility for the proviion of care of pecific patient. There are core ocial and profeional kill that will be needed which can be delivered by people from different clinical background, for example nure or pharmacit. The cot effectivene varie according to the activity of the anaemia coordinator and improve with increaingly independent activity. RECOMMENDATION R28 People with anaemia of CKD hould have acce to a deignated contact peron or peron who have principal reponibility for their anaemia management and who have kill in the following activitie: monitoring and managing a caeload of patient in line with locally agreed protocol providing information, education and upport to empower patient and their familie and carer to participate in their care coordinating an anaemia ervice for people with CKD, working between econdary and primary care and providing a ingle point of contact, to enure patient receive a eamle ervice of the highet tandard precribing medicine related to anaemia management and monitoring their effectivene. (D(GPP)) 81

85 Anaemia management in chronic kidney dieae 6.6 Providing ESA Clinical introduction Patient with anaemia aociated with CKD do not necearily need to receive their treatment within a hopital etting. One of the core principle involved in improving health outcome for people with long-term condition i improved care in primary care and community etting, emphaiing the patient role in elf-care and thu promoting independence and empowering patient to allow them to take control of their live. Proviion of ESA therapy i no different and can only be achieved with an appropriate infratructure and an effective delivery ytem enabling the right patient to get the right ESA at the right time and in the right place Methodological introduction A comprehenive literature earch identified one cro-ectional tudy. 137 A comprehenive literature earch did not identify any health economic tudie that were uitable to addre thi iue Evidence tatement Predialyi, hopital and home haemodialyi and continuou ambulatory peritoneal dialyi patient In a cro-ectional tudy 137 of 87 patient, ESA upply wa found to be motly by GP (71%), followed by hopital pharmacie (29%), although 20 patient (23%) reported that their GP had refued to upply an ESA. Of 124 patient, 51% preferred obtaining their ESA upplie from a community pharmacy, while 19% preferred a hopital pharmacy. The reaon for both community and hopital pharmacy were primarily convenience (55%), followed by eaier acce (16%), upply alway available (13%), horter waiting time (10%) and proviion of a larger upply (6%) From evidence to recommendation One cro-ectional tudy howed that there were iue for patient in obtaining ESA upplie from GP and that many patient obtained their drug from community pharmacit or the hopital pharmacy. Thi tudy wa completed prior to the introduction of home delivery cheme run by pharmaceutical companie. However, there wa often little flexibility in the day/time that companie could provide a home delivery ervice to patient. Hopital ource the cheapet upply of ESA from the drug companie and cot wa alo an important factor in the proviion of ESA. However, every patient hould have a ecure upply of ESA obtained from a ource that took the patient choice and lifetyle into conideration. It wa noted that maintaining choice for patient in how ESA are upplied and adminitered wa vital a ome patient were dependant on hopital to adminiter drug or did not have the facilitie to tore large quantitie of drug. 82

86 6 Aement and optimiation of erythropoiei RECOMMENDATION R29 ESA therapy hould be clinically effective, conitent and afe in people with anaemia of CKD. To achieve thi, the precriber and patient hould agree a plan that i patient-centred and include: (D (GPP)) continuity of drug upply flexibility of where the drug i delivered and adminitered the lifetyle and preference of the patient cot of drug upply deire for elf-care where appropriate regular review of the plan in light of changing need. 6.7 ESA: optimal route of adminitration Clinical introduction Three ESA are currently available in the UK, two hort-acting (epoetin alfa and epoetin beta) and one long-acting (darbepoetin). Short-acting ESA are more uited to hort doe interval and long-acting ESA are more uited to doing interval of at leat a week or more. Intravenou adminitration of ESA obviouly require intravenou acce and i therefore logitically difficult in predialyi, peritoneal dialyi, and tranplant patient. Patient on haemodialyi treatment may therefore eaily receive ESA therapy by any route, and at varying doe interval, wherea other patient with anaemia aociated with CKD will normally require ubcutaneou adminitration with doing interval largely determined by the ESA ued Methodological introduction A literature earch identified 58 tudie. Becaue of the high number of retrieved tudie, tudie were grouped into the variou identified factor and only the tudie decribing clinically relevant factor of the highet level of evidence and thoe which ued regreion analyi were included in the evidence tatement. Thee are detailed below: Table 6.2 Studie included in the evidence tatement Route of adminitration Study type 170 RCT 171 RCT, cro-over 172 RCT 173 RCT 174 RCT, cro-over 132 RCT 175 RCT continued 83

87 Anaemia management in chronic kidney dieae Table 6.2 Studie included in the evidence tatement continued Frequency of adminitration Study type 176 RCT 177 RCT 178 RCT Patient population Study type 179 Non-randomied tudy 180 Cohort tudy 181 Cohort tudy Hypertenion Study type 182 Propective longitudinal tudy Patient preference Study type 183 Propective cro-ectional cro-over tudy Four tudie were excluded from the evidence tatement becaue of methodological limitation. The buffer ued in the preparation in the patient preference tudy i no longer ued, and the paper wa therefore not conidered further. The GDG agreed the following outcome were prioritie: mortality morbidity quality of life pain Hb/Hct level complication patient atifaction patient concordance patient compliance ESA doe required. A comprehenive literature earch found no uitable health economic tudie to addre thi iue Evidence tatement Haematocrit and arterial preure Haemodialyi patient A 6-month tudy 182 conducted in hypertenive patient (n=13) found no ignificant change in Hct after converion of epoetin adminitration from the intravenou route to the ubcutaneou 84

88 6 Aement and optimiation of erythropoiei route. However, a ignificant decreae in predialyi mean arterial preure from the firt month wa oberved (p<0.05). (Level 3) Antihypertenive doe requirement Continuou ambulatory peritoneal dialyi patient In a 16-week RCT, 173 a mean epoetin doe of 84 ± 9 U/kg/week adminitered ubcutaneouly v a mean doe of 133 ± 7 U/kg/week adminitered intraperitonealy increaed antihypertenive therapy in both group, but no ignificant difference wa found between the two group. (Level 1+) Pain Haemodialyi patient In an RCT tudy 183 (n=208) comparing intravenou and ubcutaneou route for three time weekly treatment, 172 level of dicomfort aeed uing the Viual Analogue Scale found imilar core between the two mode of adminitration. (Level 1++) ESA doe requirement Haemodialyi (HD) and continuou ambulatory peritoneal dialyi (CAPD) patient In a 130-day non-randomied tudy invetigating epoetin adminitration by ubcutaneou v intravenou route (n=29), 179 the time and cumulative doe required to achieve a target Hb of 11.3 g/dl wa lower in the.c. treated HD (n=9) and CAPD group (n=9) (both p<0.05) when compared with the i.v. treated HD group (n=11). In addition, once target Hb wa achieved, a lower epoetin doe wa required in the HD and CAPD ubcutaneou group (p<0.05) when compared with the intravenouly treated HD group. There were no difference in epoetin doe requirement between the ubcutaneouly treated HD and CAPD group. In agreement with thi finding, no difference were oberved in both Hb/Hct level and epoetin requirement over 6 month in a cohort tudy 181 comparing epoetin adminitration by the ubcutaneou route in CAPD (n=8) v HD (n=7) patient. (Level 2+) In contrat to the above finding, a 24-week cohort tudy 180 comparing HD (n=10) v CAPD (n=11) when epoetin wa adminitered by the ubcutaneou route found that the epoetin requirement, both to achieve and to maintain a target Hct of 30%, were higher in the HD group (both p<0.05). (Level 2+) Frequency of adminitration Haemodialyi patient Three RCT of week duration invetigating ubcutaneou epoetin adminitration once weekly v twice weekly 177 and once weekly v three time weekly, 176,178 found no ignificant difference in epoetin requirement or rie in Hb level or ytolic blood preure in both group. 176 (Level 1+) 85

89 Anaemia management in chronic kidney dieae Efficacy Haemodialyi patient Four RCT of the following duration: 12 month to 24-week active treatment duration with 24-week follow-up period week duration coniting of a 26-week maintenance phae month 175 compared ubcutaneou v intravenou epoetin adminitration three time weekly and found no ignificant difference in Hb/Hct level between the two group, 132,170,172,175 although time to reach the target Hb wa higher in the intravenouly treated group (p=0.037) of one tudy. 132 One tudy 170 found no ignificant difference between the two mode of adminitration of epoetin in term of the weight-tandardied epoetin doe at monthly interval or the cumulative epoetin doe to achieve target Hct 28 36%. One other tudy 132 found greater epoetin requirement in the intravenou group (p=0.019) during the Hb tabiliation (correction) phae of the tudy, but once target Hb wa achieved in both group, no difference wa oberved. Two other tudie 172,175 found that the epoetin requirement wa le for the ubcutaneouly treated group (p=0.02). In addition, one tudy 132 aeed quality of life uing the Kidney Dieae Quetionnaire and howed improvement in the phyical and fatigue domain of both the intravenou and ubcutaneou group. Thee improvement, however, did not differ between the two route of adminitration at any time. (Level 1+ and 1++) In contrat to the above finding, in a randomied cro-over tudy 174 patient received imilar doe of ubcutaneou epoetin once (A1), twice (A2) or three time (A3) weekly (n=43), and croed over to receiving intravenou epoetin once (B1), twice (B2) or three time (B3) weekly (n=38) over 3 month (or vice vera). A ignificant rie (p<0.001) in Hb wa noted during the ubcutaneou phae, wherea the intravenou phae wa aociated with a fall in Hb (p<0.001). (Level 1++) Continuou ambulatory peritoneal dialyi (CAPD) patient In a 16-week RCT (n=19), ubcutaneouly adminitered epoetin produced a rie in Hb level (p<0.01), wherea intraperitonealy adminitered epoetin did not, depite a higher mean. 173 (Level 1+) Peritoneal dialyi patient Similarly to the CAPD patient, in a 32-week randomied cro-over tudy (n=13) 171 Hb level in patient receiving intraperitoneal epoetin fell (p=0.03) when compared with the ubcutaneou route. In upport of thi finding, the 16-week area under the Hct repone curve (p=0.001) and the mean lope of the 16-week Hct repone curve (p=0.05) were greater for ubcutaneou doing. Converely, epoetin requirement per week wa greater with intraperitoneal treatment in term of the 16-week doe-requirement area under the curve (p=0.0029) and the lope of the 16-week doe requirement curve (p=0.017). In addition, the 86

90 6 Aement and optimiation of erythropoiei mean total doe per week over the entire tudy wa greater for the intraperitoneal route (p<0.01). (Level 1+) Health economic: cot-minimiation analyi A meta-analyi of trial data wa conducted to compare cot for ubcutaneou and intravenou adminitration of ESA. Only epoetin beta had ufficient data to allow a valid comparion. Subcutaneou adminitration appear to ave 1,100 ± 727 per patient per year, compared with intravenou adminitration. Full detail are given in Appendix D From evidence to recommendation Of the factor addreed, hypertenion wa not hown to be affected by the route of adminitration of ESA. The patient population, pain of injection, frequency of adminitration, efficacy and cot were all important factor in determining the route of adminitration. The following point were alo relevant: It wa not practicable to adminiter ESA by the intravenou route in patient not on haemodialyi. Equally, patient on haemodialyi may prefer to receive their ESA via the intravenou route. Frequency of adminitration wa alo conidered important for nuring compliance. In ome unit it wa conidered better to give ESA routinely at all dialyi viit rather than at every third. The half-life of the drug alo determine the frequency of adminitration. With regard to efficacy, adminitration via the ubcutaneou route uing hort-acting ESA required up to 30% le drug to be adminitered to achieve the ame Hb/Hct. RECOMMENDATIONS R30 The patient with anaemia of CKD and the precriber hould agree (and revie a appropriate) the route of adminitration of ESA, taking into account the following factor: patient population (eg haemodialyi patient) pain of injection frequency of adminitration the lifetyle and preference of the patient efficacy (eg ubcutaneou v intravenou adminitration, or long-acting v hort-acting preparation) cot of drug upply. (C) R31 The precriber hould take into account that when uing hort-acting ESA, ubcutaneou injection allow the ue of lower doe of drug than intravenou adminitration. (A) 87

91 Anaemia management in chronic kidney dieae 6.8 ESA: doe and frequency Clinical introduction Currently, the available ESA fall into two broad clae, hort- and long-acting. The characteritic of long-acting ESA are uch that when uing thee agent the hortet doe interval i weekly, with no appreciable difference between ubcutaneou and intravenou route of adminitration. With hort-acting ESA, doe interval of a week or more are le cot effective than horter doe interval, and the ubcutaneou route of adminitration i more cot effective than the intravenou route. In patient without renal dieae, tudie looking at erythropoietin repone to anaemia how an exponential rie in erum EPO level with falling haemoglobin, uggeting that with increaing everity of anaemia the natural endogenou EPO doe i initially high and ubequently tail off a the anaemia correct. Although it would be logical to attempt to mimic thi, the early day of ESA therapy howed that very rapid correction of anaemia wa aociated with ignificant advere effect. The doe and frequency of adminitration of ESA i therefore likely to depend on haemoglobin level and rate of change of haemoglobin, the cla of ESA ued and (in the cae of hort-acting ESA) the route of adminitration, the CKD population under treatment, and variou patient factor and patient preference Methodological introduction A literature earch identified nine tudie Two tudie 197,198 had methodological limitation and were therefore excluded from the evidence tatement. A the meta-analyi 198 addreing route of adminitration had methodological limitation, the 10 tudie within it were individually appraied and five met quality criteria. 132,170,172,175,199 The clinically relevant factor and repective tudy type are detailed in Table 6.3. Table 6.3 Summary of included tudie Route of adminitration Study deign Studie included in the meta-analyi 132 RCT 170 RCT 172 RCT 175 RCT 199 Cohort tudy Study publihed after the meta-analyi literature earch cut-off date 188 Cohort tudy continued 88

92 6 Aement and optimiation of erythropoiei Table 6.3 Summary of included tudie continued Starting Hb level Study deign 189 Propective longitudinal tudy Hypertenion Study deign 190 Before and after tudy 191 RCT (open-label) Rate of Hb correction Study deign 192 Propective longitudinal tudy 193 Retropective longitudinal tudy 194 Cohort tudy 195 Propective longitudinal tudy 196 RCT(open-label) The GDG agreed that the outcome of priority were Hb level, rate of Hb correction and complication. Notable apect of the evidence bae were: Due to methodological limitation, one RCT 191 wa downgraded to Level 2 in the evidence hierarchy. Adjuvant red blood cell tranfuion were adminitered in addition to epoetin during the tudy period in four tudie. 172,189,195,196 Two tudie addreing rate of Hb correction 193,195 were conducted in children Evidence tatement Route of adminitration Table 6.4 Haemodialyi patient Study Evidence reference hierarchy ESA therapy arm Outcome 188 Level 2++ Once weekly.c. The number of patient who maintained a v table Hb level (defined a a decreae of once weekly i.v. 1 g/dl) wa imilar in both group. Decreae (p<0.05) in Hb concentration in the i.v. treated group when the evaluation phae of the tudy wa compared with the doing phae. Increaed (p<0.05) mean weekly doe of epoetin alfa needed to maintain individual target Hb level in the i.v. group. continued 89

93 Anaemia management in chronic kidney dieae Table 6.4 Haemodialyi patient continued Study Evidence reference hierarchy ESA therapy arm Outcome 172 Level 1++ Three time weekly i.v. Hb and Hct were imilar in both group. v Average weekly epoetin doe wa lower three time weekly.c. (p=0.002) in the.c. group. 175 Level 1++.c. Mean Hb level were table and remained v equivalent in both group at the end of i.v. the tudy. Epoetin requirement wa found to be le (p=0.02) when adminitered by the.c. route. When the different doing trata were tudied (ie >150 U/kg/week v U/kg/week v <100 U/kg/week), it wa evident that thi difference wa only in patient with the highet epoetin need (>150 U/kg/wk). 199 Level 2+.c. Hct level were imilar over the entire v tudy period. i.v. 170 Level 1+ Three time weekly.c. Weight-tandardied epoetin doe at v monthly interval and cumulative epoetin three time weekly i.v. doe were imilar in both group. Hct level were imilar in both group. 132 Level 1+ Three time weekly.c. Although time to reach the target Hb wa v longer (p=0.037) in the i.v. treated group, three time weekly i.v. mean Hb and Hct level were imilar in both group. Epoetin requirement wa greater (p=0.019) in the i.v. group during the Hb tabiliation phae of the tudy, but once target Hb wa achieved in both group, no difference wa oberved between the two group. A meta-analyi of the four Level 1 tudie addreing epoetin doe when adminitered.c. v i.v. 132,170,172,175 found a lower epoetin requirement when adminitered.c. (weighted mean difference (WMD) (95% CI to 16.14) I 2 =7%). Thi wa in upport of the finding of the excluded heterogeneou meta-analyi. 198 A enitivity analyi excluding the tudy with ample ize n < wa alo in agreement with thi finding and ruled out heterogeneity (WMD (95% CI to 22.55) I 2 =0%). 90

94 6 Aement and optimiation of erythropoiei Table 6.5 Starting Hb level Study Evidence Hb level reference Patient population hierarchy at baeline Outcome 189 Continuou Level g/dl Time to achieve Hb target wa ambulatory v longer (p<0.001) in the lower peritoneal dialyi >7.5 g/dl Hb group at 6 month depite (CAPD) imilar rate of Hb increae and epoetin doe in both group. 195 Children on Level 3 <6.8 g/dl A imilar proportion of each haemodialyi v group (81% v 80%) reached 6.8 g/dl the target Hb of g/dl. The median time to achieve target Hb wa higher in the lower Hb group (median 13 week v 9 week; p-value not reported by the author). Table 6.6 Hypertenion: haemodialyi patient Evidence ESA therapy Study reference hierarchy arm Outcome 190 Level 3 i.v. three time weekly No change in mean ytolic and diatolic blood preure wa found, and only three of 24 patient who had required treatment for hypertenion before epoetin therapy required an increaed doe of antihypertenive medication. 191 Level 2+ Hct 40.8 ± 5.2% No difference were found in mean v daytime ytolic or diatolic BP and Hct 30 ± 4.3% mean night time ytolic or diatolic BP between the two group. Table 6.7 Rate of Hb correction Study Patient Evidence reference population hierarchy ESA therapy Outcome 192 Predialyi Level 3.c. twice weekly There wa a rie in Hb and Hct when compared with baeline level after 3 month, which wa utained after 6 month and 12 month (all p<0.001). Target Hb wa achieved g/dl after 6 month. continued 91

95 Anaemia management in chronic kidney dieae Table 6.7 Rate of Hb correction Study Patient Evidence reference population hierarchy ESA therapy Outcome 195 Children on Level 3 i.v. two to three A median time to target of 11 week haemodialyi time weekly with wa achieved with a median doe of an aim to achieve 150 U/kg/week in 81% of patient. a rie in Hb of The mean rate of Hb rie wa 1 g/dl per 0.5 g/dl per 4 week in patient 4 week in order receiving the tarting doe of to attain target 75 U/kg/week and 0.8 g/dl per Hb g/dl 4 week in thoe whoe doe had been increaed to 150 U/kg/week (p value not reported by the author). 194 Haemodialyi Level 2+ Same weekly Patient who received 4,000 U epoetin alfa doe epoetin a a bolu injection did not in varying doe require increaed epoetin doe, interval but doing interval ignificantly increaed (p=0.01), unlike patient who received 10,000 U epoetin at interval who required higher epoetin doe (p=0.002) with reduced doing interval (p=0.0001) to maintain Hb >11 g/dl throughout the 24-week tudy period. 196 Peritoneal Level 1+ 5, 10 and 20 U/kg The difference in the mean weekly dialyi epoetin daily.c., change in Hct were ignificant patient to target Hct (p<0.05) over the 8 week contant % doe phae, between all three group, in acending order. During the correction phae, the time to achieve the target Hct in 50% of the patient (total n=72) who received 5, 10 and 20 U/kg daily.c. wa 154, 119 and 92 day repectively and the median cumulative epoetin doe to reach target Hct were calculated a 1,494, 1,523 and 1,678 U/kg repectively. 193 Pot- Level 3 Thrice weekly.c. There wa an increaed Hct in 84% tranplant v twice weekly.c. of the children from 23.2% ± 3.1% paediatric v once weekly.c. to 33% ± 3.1% (p value not patient with reported by the author) within chronic 7.2 ± 4.9 week at a mean rate of allograft 1.98% per week. dyfunction Hct increae and epoetin tarting doe were linearly related (r=0.44, p<0.05). 92

96 6 Aement and optimiation of erythropoiei Health economic methodological introduction One tudy 200 wa identified in a literature earch. Three tudie 149,198,201 did not meet quality criteria. The included tudy 200 etimated the increaed cot of changing from.c. epoetin to i.v. epoetin in a retropective analyi of 99 haemodialyi patient over 7 month. A cot-minimiation analyi wa conducted at the requet of the GDG to compare ubcutaneou and intravenou epoetin adminitration. Full detail are given in Appendix D. * Evidence tatement The mean doe in the.c. witched to i.v. patient increaed ignificantly ( IU/kg/week, +34.9%, p=0.001) over 7 month and wa etimated to increae cot by 1, (Euro, 2002) per patient per year (+26.3%). 200 The cot-minimiation analyi preented to the GDG tated in concluion: The ubcutaneou route of adminitration of epoetin v intravenou route reult in cot aving of approximately 1, per patient per year From evidence to recommendation Of the factor addreed, hypertenion wa not hown to have an effect in determining the doe and frequency of ESA required to correct anaemia. But the route of adminitration and the rate of correction were important factor. An acceptable rate of rie of haemoglobin wa conidered to be ~1 2g/dl/month. In general, it wa thought that a patient pre-treatment tarting level of Hb would not influence the tarting doe of ESA, but that their ubequent haemoglobin repone would influence the doe thereafter. Hypertenion hould be treated prior to the adminitration of ESA. It wa tated that epiode of evere hypertenion would temporarily alter the doe of ESA, but that generally hypertenion would not affect thi iue. The included health economic tudy upported the excluded meta-analyi 198 that intravenou adminitration of hort-acting ESA wa more cotly than ubcutaneou adminitration. The group concluded that in general.c. adminitration lead to a reduced doe of hort acting ESA. One tudy indicated that thi wa only relevant during the tabiliation phae but not during the maintenance phae of treatment. RECOMMENDATION R32 When correcting anaemia of CKD, the doe and frequency of ESA hould be: determined by the duration of action and route of adminitration of the ESA (B) adjuted to keep the rate of Hb increae between 1 and 2g/dl/month. (D(GPP)) * In interpreting economic evaluation of ESA, it hould be borne in mind that different unit will have developed their own pricing tructure which may differ coniderably from BNF lit price. 93

97 Anaemia management in chronic kidney dieae 6.9 Optimal Hb level Clinical introduction The optimal haemoglobin range to be maintained following correction of anaemia aociated with CKD i that which confer the mot benefit and leat advere effect in the mot coteffective way. The key quetion are: Do patient with higher haemoglobin level do well becaue they are le ick, and i it becaue they are le ick that they attain higher haemoglobin level? Or i there a caual relationhip between higher haemoglobin level and lower rik of morbidity and mortality, and if o what i the optimal haemoglobin range to be maintained? Clinical methodological introduction A literature earch identified one meta-analyi 202 containing 19 RCT, which aeed the effect of lower v higher haemoglobin collectively in predialyi, peritoneal dialyi and haemodialyi patient attained by mean of ESA therapy or blood tranfuion. The finding were tratified into two categorie, namely tudie that compared treatment to two haemoglobin range, higher ( g/dl) v lower ( g/dl) (even tudie) and thoe which aeed the effect of epoetin (Hb g/dl) v no treatment (Hb g/dl) (12 tudie). An additional three RCT and a propective longitudinal tudy 206 were found which addreed the effect of lower v higher Hb level. The different Hb level examined and tudy duration need to be accounted for when evaluating the evidence and are ummaried in Table 6.8. Table 6.8 Study duration and Hb level for the included tudie Reference Study duration Low Hb (g/dl) High Hb (g/dl) to 29 month to 12 month month month 10.9 ± ± month 10.5 ± ± 3.1 Notable apect of the evidence bae were: Although the meta-analyi 202 wa of rigorou methodology leading to a ytematic review of a high tandard, the trial within it were of variable quality. The meta-analyi 202 wa heavily weighted by a ingle tudy 207 conducted in haemodialyi patient with evere cardiovacular dieae, which may imply unuitability for extrapolation to the entire CKD patient population. 94

98 6 Aement and optimiation of erythropoiei Although two tudie in the meta-analyi 202 enrolled children, the finding were not tratified on the bai of age. Due to methodology limitation, one RCT 204 wa downgraded to Level 2+ of the evidence hierarchy. The mean of achieving target Hb in the tudie included the ue of ESA and/or blood tranfuion Clinical evidence tatement Table 6.9 Summary of appraied tudie Patient Aiming for Aiming for a Evidence Reference Outcome population (n) a high Hb low Hb grading 202 All-caue mortality Predialyi, peritoneal g/dl g/dl Level 1++ dialyi and haemodialyi (n=1949) 202 All-caue mortality Predialyi, peritoneal g/dl g/dl Level 1++ dialyi and haemodialyi No difference (n=255) 202 Hypertenion Predialyi, peritoneal g/dl g/dl Level 1++ dialyi and haemodialyi No difference (n=1277) 203 Hypertenion Haemodialyi (n=12) 12.0 g/dl 9.0 g/dl Level Quality of life Predialyi, peritoneal g/dl g/dl Level 1++ dialyi and haemodialyi No difference (n=unknown) 202 Quality of life Predialyi, peritoneal g/dl g/dl Level 1++ dialyi and haemodialyi No difference (n=unknown) 204 Quality of life Haemodialyi (n=12) 12.0 g/dl 9.0 g/dl Level 2+ No difference 203 Phyical performance- Haemodialyi (n=12) 12.0 g/dl 9.0 g/dl Level 2+ exercie radionuclide No difference ventriculogram 203 Phyical performance- Haemodialyi (n=12) 12.0 g/dl 9.0 g/dl Level 2+ maximal incremental exercie teting minute walking ditance Haemodialyi (n=596) 12.6 ± 1.0 g/dl 10.9 ± 0.7 g/dl Level 1++ No difference 203 Left ventricular ma and Haemodialyi (n=12) 12.0 g/dl 9.0 g/dl Level 2+ ma index No difference (note: hort tudy duration) continued 95

99 Anaemia management in chronic kidney dieae Table 6.9 Summary of appraied tudie continued Patient Aiming for Aiming for a Evidence Reference Outcome population (n) a high Hb low Hb grading 205 Left ventricular Haemodialyi (n=596) 12.6 ± 1.0 g/dl 10.9 ± 0.7 Level 1++ volume index, No difference left ventricular ma index in either cardiovacular parameter 206 Left ventricular eptal, Haemodialyi patient 13.4 ± 3.1 g/dl 10.5 ± 0.9 g/dl Level 3 poterior wall thickne with LVH and enhanced and left ventricular ma LVMI at baeline (n=23) All index Left ventricular ESD No difference and EDD RWT parameter for left ventricular geometry = ignificant increae; = ignificant decreae Health economic methodological introduction A cot-utility analyi tudy wa appraied, which etimated the incremental cot per QALY of treating haemodialyi patient with epoetin doe adjuted to attain haemoglobin target range of 9.5 to 10.5 g/dl, 11.0 to 12.0 g/dl, 12.0 to 12.5 g/dl and 14.0 g/dl. 208 An economic model wa contructed to evaluate the cot effectivene of variou haemoglobin range in haemodialyi patient. Full detail are given in Appendix C. * Health economic evidence tatement An additional $55,295 per additional QALY gained (95% CI: $51,404 $59,822) wa required to achieve the target haemoglobin range of g/dl v a g/dl haemoglobin target range. 208 An additional $613,015 per additional QALY gained (95% CI: $569,884 $663,210) wa required to achieve the target haemoglobin range of g/dl v a g/dl haemoglobin target range. 208 An additional $828,215 per additional QALY gained (95% CI: $769,942 $896,030) wa required to achieve the target haemoglobin of 14.0 g/dl v a g/dl haemoglobin target range. 208 The doe of epoetin and the etimate of health-related quality of life had the larget effect on reult in the enitivity analyi, auming 32% (bae-cae aume 14%) lower doe requirement for ubcutaneou epoetin than intravenou epoetin: * In interpreting economic evaluation of ESA, it hould be borne in mind that different unit will have developed their own pricing tructure which may differ coniderably from BNF lit price. 96

100 6 Aement and optimiation of erythropoiei Table 6.10 Target Hb level and incremental cot per QALY Target Hb Incremental cot per QALY g/dl v g/dl $38, g/dl v g/dl $423, g/dl v g/dl $569,500 Health economic modelling The economic model preented to the GDG tated in concluion: The reult ugget that treating anaemia with a target Hb g/dl i cot effective in haemodialyi patient baed on a 30,000 (incremental cot-effectivene ratio) threhold. However, there i uncertainty in the reult of the model from lack of certainty in the input parameter. Neverthele, the reult are relatively robut baed on one-way enitivity analye and threhold analye. Thi analyi i a implified model of the cot and benefit of treating anaemia in the haemodialyi population and a variety of aumption have been ued in the baeline analyi. See Appendix C for detail From evidence to recommendation The GDG noted that the larget meta-analyi conidered wa heavily kewed by one tudy that influenced the data on mortality. 202 Thi tudy of patient with cardiovacular dieae wa terminated early becaue of a trend toward increaed mortality in the high target haemoglobin group. Thu tatitical ignificance between the two group could not be achieved. The GDG accepted that mot of the tudie it contained did not tate their method of randomiation and were not adequately blinded; only two were carried out on an intention to treat bai. 202 It wa noted that a target Hb level of 14 ± 1 g/dl (converted from Hct) wa aociated with higher mortality in a tudy of patient with congetive heart failure and ichaemic heart dieae. The GDG thought thi may have related to the large doe of iron and epoetin that had to be adminitered in order for a icker patient to achieve a haemoglobin in thi range. 202 It wa conidered unhelpful both clinically and economically to adminiter increaing doe of epoetin and iron to a patient who wa not reponding adequately to the treatment. The GDG agreed with the author of the meta-analyi that it would be prudent to enure that patient with cardiovacular impairment maintain a Hb below 12.0 g/dl. The GDG did not feel that increaing age hould be a pecific factor in etting a haemoglobin target but felt that low level of phyical activity in ome individual hould be conidered before etting the haemoglobin range for that individual. The GDG highlighted that two tudie within the meta-analyi 202 included children but that no outcome data were pecifically reported from thi population. The GDG noted that depite a lack of direct evidence relating to children, they could in general be expected to benefit from a imilar Hb level to adult. The GDG noted that the kinetic of a patient repone to epoetin vary. Thi mean that whatever range of haemoglobin i pecified a being optimal, it i inevitable that ome patient will have a haemoglobin outide thi range ome of the time. Thi i becaue action to maintain 97

101 Anaemia management in chronic kidney dieae the haemoglobin within the pecified range may only be taken when a haemoglobin meaurement fall outide the range and it will take time for any action to produce an effect. The GDG therefore agreed that they would pecify a target range in the knowledge that thi would reult in mot patient maintaining a haemoglobin concentration within 0.5g/dl either ide of that pecified range. The GDG felt that etting a Hb range of g/dl would in effect allow the majority of patient to reach a level between 10.5 and 12.5 g/dl. It wa noted from anecdotal evidence that maintaining a Hb of 12g/dl could make a large difference to a patient quality of life, exercie capacity and cognitive function; the increae in phyical performance wa further upported by the evidence. 203 The GDG alo conidered a health economic model that uggeted haemoglobin range above 12 g/dl were not cot effective becaue of the high cot of epoetin and low incremental QALY gained from higher haemoglobin range. 208 The conenu among the GDG wa that a range of g/dl wa conitent with both the clinical and health economic evidence. RECOMMENDATIONS R33 In people with anaemia of CKD, treatment hould maintain table haemoglobin (Hb) level between 10.5 and 12.5 g/dl for adult and children older than 2 year of age, and between 10 and 12 g/dl in children younger than 2 year of age, reflecting the lower normal range in that age group. Thi hould be achieved by: Adjuting treatment, typically when Hb rie above 12.0 or fall below 11.0 g/dl. Taking patient preference, ymptom and comorbiditie into account and reviing the apirational range and action threhold accordingly. (C) R34 In people who do not achieve a haemoglobin level above 10.5g/dl (or 10.0 g/dl in children younger than 2 year of age) depite correction of iron deficiency and excluion of the known caue of reitance to ESA therapy (defined a treatment with 300 IU/kg/week of ubcutaneou epoetin or 450IU/kg/week of intravenou epoetin or 1.5µg/kg/week of darbepoetin), lower level of haemoglobin may have to be accepted. (D(GPP)) R35 Age alone hould not be a determinant for treatment of anaemia of CKD. (D(GPP)) See for the aociated algorithm Optimum haemoglobin level in children with anaemia of CKD Methodological introduction The two RCT reported in the meta-analyi 202 conducted in children 209,210 one of cro-over deign 210 were ued to addre the effect of lower v higher haemoglobin and were individually appraied. An additional cro-over RCT 211 that wa conducted in the ame paediatric population wa alo appraied. 98

102 6 Aement and optimiation of erythropoiei Iue for conideration were a follow: The two cro-over RCT 211,210 were downgraded to Level 2+ becaue of methodological limitation. One tudy 209 had et out to invetigate doing requirement. Study duration to ae cardiovacular benefit of epoetin adminitration 211 may not have been ufficiently long at 48 week. Table 6.11 Summary characteritic of appraied tudie Study N Target Hb Study type Study duration Between mean and RCT of low doe v high 12 week 2 tandard deviation doe epoetin below mean for age g/dl Cro-over RCT of 24 week in each limb, epoetin v placebo 48 week total g/dl Cro-over RCT of epoetin 24 week in each limb, v placebo 48 week total Evidence tatement Table 6.12 Evidence tatement for optimum Hb level in children Hypertenion and cardiovacular Patient Achieved Achieved Evidence Study parameter population (n) high Hb low Hb grading 209 Sytolic and diatolic BP Children on haemodialyi, 12.9 ± 0.7; 8.4 ± 1.0; Level 1+ No difference peritoneal dialyi and 11.9 ± 1.6; 10 ± 2.04; predialyi (n=44) 12.7 ± 2.0 g/dl 11.9 ± 1.8 g/dl 211 Cardiac index (p=0.01), Children on peritoneal 11.5 g/dl 6.9 g/dl Level 2+ ventricular troke index dialyi (n=7) (target (p=0.03),heart rate g/dl) (p=0.002), aortic troke ditance (p=0.01), minute ditance (p=0.03) and left ventricular end diatolic diameter (p=0.04) all decreaed. There wa no change in hortening fraction, interventricular eptum and left ventricular poterior wall thickne. No change wa found in ytolic, diatolic or mean BP. continued 99

103 Anaemia management in chronic kidney dieae Table 6.12 Evidence tatement for optimum Hb level in children continued Exercie teting and Achieved Achieved Evidence Study quality of life Patient population (n) high Hb low Hb grading 210 No change were found Children on peritoneal Median Median Level 2+ in the 2-minute walking dialyi (n=7) 11.2 g/dl 7.3 g/l ditance (n=7) and (range (range treadmill exercie g/dl) g/l) teting workload (n=3). A reduction in heart rate at ret wa found after epoetin adminitration (p=0.02) and at each ucceive tage of the exercie tet. No arrhythmia or ichaemic change were found. 210 Quality of life (25-part Children on peritoneal Median Median Level 2+ parental quetionnaire, dialyi (n=7) 11.2 g/dl 7.3 g/l uing a viual analogue (range (range cale) found an g/dl) g/l) improvement in phyical performance and general health (p<0.02), but the global core did not find an improvement in quality of life From evidence to recommendation The ue of exercie teting for outcome i not meaningful in very young children, which exacerbate the problem of the mall ample ize in the evidence. RECOMMENDATIONS Recommendation pertaining to children with anaemia of chronic kidney dieae are preented in relevant ection throughout the guideline Adjuting ESA therapy Clinical introduction ESA doe adjutment are made to encourage haemoglobin level into the recommended range. The detail of uch targeting varie unit by unit, but mut alway involve deciion on when to make the doe change (ie at what haemoglobin level), and by how much to change the ESA doe and/or frequency. ESA therapy (even with the currently available long-acting agent) involve delivery of hort, intermittent, pharmacological burt of bioavailable EPO which bear no relation, either temporally or in magnitude, to normal phyiological control of erythropoiei. Under 100

104 6 Aement and optimiation of erythropoiei normal condition, the body oxygen ening, EPO-producing, and erythropoietic ytem are cloely regulated and coordinated to maintain haemoglobin level within a narrow range. During ESA therapy, haemoglobin level fluctuate widely and the pattern of fluctuation varie from patient to patient. 212 Thi haemoglobin cycling may complicate the management of anaemia aociated with CKD. Factor likely to be aociated with fluctuation in haemoglobin level include change in ESA doe, intravenou iron treatment, intercurrent illne (epecially infection) and hopitaliation. Thoe patient experiencing more frequent fluctuation, and thoe with the greatet amplitude of fluctuation, have been characteried a being more reponive to ESA. 213 Experimental and clinical tudie have defined a deirable outcome range of haemoglobin and have ued the limit of the range to trigger a doe change when the haemoglobin level fall above or below thee limit. The extent of the doe change, whether an abolute amount or a proportion of the exiting doe, ha to fit the available ESA formulation or deciion are required about the doage interval. However, becaue of logitical delay in reponding to any current laboratory value and becaue of difference in the momentum of haemoglobin change, it may be neceary to alter ESA therapy pre-emptively prior to the haemoglobin level breaching the limit of the deirable range. There are alo individual variation in the repone to ESA that may be taken into account from hitorical data. The cae mix and treatment hitory of any patient cohort will alo influence the outcome and while tailoring of the timing and doe change may be attempted there i inevitable unpredictability of outcome. So how then do we adjut ESA doe and doe frequency to keep haemoglobin level within the maintenance range, and what factor determine how we do thi? Clinical methodological introduction A literature earch found 13 tudie: an RCT, 214 propective cohort tudie, 215,216 retropective cohort tudie, cro-over tudie, 220,221 retropective longitudinal tudie, 222,223 and cro-ectional tudie One tudy 187 had methodological limitation and wa therefore excluded from the evidence tatement Clinical evidence tatement Factor affecting epoetin doe: route of epoetin adminitration Haemodialyi patient One tudy 222 found patient adminitered with epoetin by the i.v. route received ignificantly higher doe than thoe precribed epoetin by the.c. route (p=0.0001). (Level 3) Iron tatu Haemodialyi patient Three tudie found epoetin doe to be inverely correlated with iron tatu when meaured by mean of erum tranferrin aturation (p=0.0001), 222 erum aturation ratio (r=-0.16, p=0.003) 224 and total iron binding capacity level (r=0.27, p<0.01). 219 (Level 3 and Level 2+) 101

105 Anaemia management in chronic kidney dieae In contrat, one tudy 219 did not find an aociation with erum tranferrin aturation. Alo, no aociation between epoetin doe and erum ferritin level wa found in two tudie. 219,222 (Level 3 and Level 2+) Dialyi adequacy Haemodialyi patient One tudy 222 found an invere correlation between urea reduction ratio and adminitered epoetin doe (p<0.0001). (Level 3) Caue of end tage renal failure Haemodialyi patient One tudy 222 found diabete mellitu a the caue of end tage renal failure to be aociated with lower epoetin doe (p=0.003). (Level 3) Inflammation Haemodialyi patient One tudy 224 found a direct correlation between adminitered epoetin doe and malnutritioninflammation core (ie increaing degree of everity) (r=0.13, p=0.03). Thi wa reflected in the direct correlation between weekly epoetin doe and logarithmic inflammatory cytokine, IL-6 (r=0.31, p<0.001) and TNF-α (r=0.18, 0.001) a well a C-reactive protein (CRP) (r=0.18, p<0.001) and lactae (p<0.001) level. Similarly, there wa an invere correlation oberved between epoetin doe and nutritional marker (r=-0.19, p<0.001). In another tudy, 225 albumin (r=-0.359, p<0.001), log CRP (r=0.337, p=0.001), log ferritin (r=0.240, p=0.021) and tranferrin (r= 0.264, p=0.011) all howed correlation with epoetin:hct ratio. When patient in the lowet and highet epoetin:hct quartile were compared, only median CRP howed tatitical ignificance (p=0.009). (Level 3) Contrary to the above finding, in one tudy 226 C-reactive protein level did not how any aociation with epoetin doe. (Level 3) Peritoneal dialyi patient In one tudy, 225 albumin (r=-0.453, p=0.006) and CRP (r=0.375, p=0.024) howed correlation with epoetin/hct ratio, but not ferritin. (Level 3) Haemodialyi v peritoneal dialyi patient When compared with one another in the ame tudy, 225 haemodialyi patient had a greater epoetin/hct ratio than peritoneal dialyi patient (p<0.001), which wa matched with a higher epoetin doe (p<0.001) and lower Hct level (p=0.002). Alo lower CRP (p<0.001), ferritin (p<0.001), tranferrin (p<0.001) and aluminium (p<0.001) level were found in the haemodialyi patient. However, no difference wa oberved for albumin, tranferrin aturation, intact parathyroid hormone and PCRn. (Level 3) 102

106 6 Aement and optimiation of erythropoiei Adjunctive medical treatment Haemodialyi patient Higher epoetin doe were adminitered to patient receiving ACE-inhibitor therapy when compared with thoe not treated with ACE-inhibitor (p<0.05) in one tudy. 219 In a 12-month tudy, 216 patient receiving high doe enalapril (ACE-inhibitor) required a higher epoetin doe at the end of the tudy period (p<0.0001) and alo when compared with thoe receiving nifedipine (calcium-channel blocker) (p<0.0001) or control (epoetin only) (p<0.0001) to maintain a Hb >10 g/dl. Similarly, in a 12-month tudy aimed to maintain Hb >10 g/dl, 215 high doe loartan (angiotenin-ii receptor blocker) required a higher epoetin doe at the end of the tudy period (p<0.0001) and alo when compared with thoe receiving amlodipine (calciumchannel blocker) (p<0.0001) or control (epoetin only) (p<0.0001). (Level 2+) In contrat to the above finding, two tudie with patient receiving ACE-inhibitor 217,220 aimed to maintain Hct level at 30 36% (Hb ~ g/dl) did not find any aociation between ACE-inhibitor adminitration and epoetin reitance. (Level 2+) Peritoneal dialyi patient Weekly epoetin doe given to maintain Hct >30% (Hb ~ 10 g/dl) at the end of a 12-week tudy 214 wa greater in patient receiving ACE-inhibitor (p<0.01) and in patient receiving angiotenin-ii receptor blocker treatment (p<0.05), but not in thoe receiving calcium-channel blocker when compared with individual weekly doe at the beginning of the tudy. In addition, plama epoetin level were higher in the ACE-inhibitor treated group (p<0.05) but not in the angiotenin-ii receptor blocker and control group. (Level 1+) Parathyroid hormone Haemodialyi patient In a tudy conducted in patient over the age of 65 year, whereby patient were divided into PTH >250 pg/ml and <250 pg/ml, depite imilar epoetin doe and erum iron and ferritin level, patient in the hyperparathyroid group had lower Hb and Hct level (p=0.009 and p=0.008 repectively) a well a higher level of alkaline phophatae (p=0.023), phophoru (p=0.001) and calcium x phophoru product (p=0.009). 221 (Level 2+) Hopitaliation Haemodialyi patient In one tudy, 223 higher epoetin doe were required in patient who were tranfued during hopitaliation up to 2 month following dicharge (p<0.05). (Level 3) The ame tudy 223 found no aociation between dicharge diagnoi, (inflammatory v noninflammatory) or urgical procedure during hopitaliation and epoetin requirement up to 2 month following dicharge. (Level 3) 103

107 Anaemia management in chronic kidney dieae Dialyate chloramine level Haemodialyi patient One before and after tudy (n=72) 227 found an aociation between higher achieved Hb level (p<0.001) and decreaed epoetin doe (p<0.001) with intallation of new carbon filter, which decreaed the chloramine level from to 0.25 part per million (ppm) to <0.1 ppm. Thi wa upported by finding in a ubgroup analyi (n=15) that howed low-grade haemolyi by a pot-dialyi rie in methaemoglobin (p<0.01) and a drop in haptoglobin (p<0.01), which wa not detected after the ue of the carbon filter. Additionally, the water board confirmed the utained two fold increae in chloramine level and acceptable level of nitrate, aluminium, bacterial count and endotoxin in the main water upply during the tudy time period. In agreement, one atellite dialyi unit, 218 found decreaing Hb level at month 10 (p<0.01) and 11 (p<0.01) of the tudy depite higher epoetin doe (p=0.04) when compared with other local dialyi unit. Thee finding were aociated with a high chlorine water content relative to the deirable limit (p value not given), which coincided with evidence of haemolyi a hown by higher ferritin (p<0.01) and low haptoglobin (p value not given). Furthermore, intallation of an activated charcoal filter decreaed chlorine concentration to <0.02, which wa accompanied by an increae in Hb and a reduction in epoetin requirement. (Level 2+ and Level 3) Health economic methodological introduction The appraied tudy 228 performed a deciion analyi comparing three doage regimen: epoetin-6 trategy, 6,000 U (107 U/kg), epoetin-9 trategy, 9,000 U (167 U/kg) and epoetin-12 trategy, 12,000 U (211 U/kg) of ubcutaneou epoetin in continuou ambulatory peritoneal dialyi to maintain the target Hct level of 0.33 (equivalent to 11 g/dl). 228 Epoetin wa given weekly for the firt 2 month until a target Hct of 0.33 wa reached. Thi wa maintained for an additional 3 month with the adminitration frequency reduced to fortnightly or 4-weekly. Non-reponder in 6,000 U and 9,000 U after 2 month entered 12,000 U regimen Health economic evidence tatement Of the three ubcutaneou epoetin trategie compared, it wa mot cot effective in peritoneal dialyi patient to give 6,000 unit weekly for 2 month, followed by a weekly or 2-weekly epoetin 6,000 unit doe for the next 3 month while maintaining the target Hct level of 0.33 and to retart non-reponder after 2 month on the 12,000 unit epoetin trategy. 228 The aving from the lower adminitration frequency of the 9,000 unit doage regime were offet by the higher cumulative acquiition cot. 228 Varying the parameter over the 20-week treatment period: Epoetin-6 trategy i alway the leat cotly over the $0 60 range for drug adminitration cot. Drug adminitration cot mut be $137 for epoetin-6 to become more cotly than epoetin-12. Epoetin-6 i leat cotly over the 95% CI range for repone probabilitie. Epoetin-12 trategy become le cotly than the Epoetin-9 a drug adminitration cot increae over $

108 6 Aement and optimiation of erythropoiei Varying the parameter over a 1-year treatment period: Epoetin-6 wa le cotly than both epoetin-9 and epoetin-12 over the range of cot ($0 60). Epoetin-6 become more cotly than epoetin-12 at $95. Epoetin-6 wa le cotly over whole range of 95% CI. Epoetin-9 wa more cotly than epoetin-12 at lower 95%CI limit. Epoetin-12 become le cotly than epoetin-9 at drug adminitration cot of $8 per injection and above From evidence to recommendation Of all of the outcome conidered in the evidence, the GDG felt that the route of ESA adminitration, the patient iron tatu, adminitration of adjunctive medical treatment, and the preence or abence of inflammation were of mot relevance to determine the doe and frequency of ESA required to keep haemoglobin level within the maintenance range in all CKD patient. Doe adjutment were alo likely to be influenced by: the patient haemoglobin level the oberved rate of change in haemoglobin level an individual patient repone to ESA therapy. In patient on haemodialyi, chloramine level in dialyi water were alo of relevance. The outcome of dialyi adequacy, adjunctive medical treatment, race, and parathyroid hormone level were dicued but the evidence wa either limited or would be more fully covered in eparate guideline ection, the GDG therefore did not wih to make any recommendation regarding thee. The outcome of end-tage renal failure and hopitaliation were included but the GDG did not feel that they were helpful in determining the doe and frequency of ESA required to keep haemoglobin level within the maintenance range for individual patient. With regard to the route of adminitration, two tudie reported that doe of hort-acting ESA could be reduced when adminitered ubcutaneouly a oppoed to intravenouly. 187,222 It wa noted that the deciion of whether to adminiter ESA.c. or i.v. wa alo a matter of patient choice. Several tudie upported the view that the amount of ESA required i inverely correlated with iron tatu. 187,222,224 The GDG felt thi wa an important factor to take into account when determining the doe and frequency of ESA required to keep haemoglobin level within the maintenance range and alo Unit policy in view of the need for uniform and convenient clinical procedure. The GDG noted that there wa evidence to upport a correlation between the weekly doe adminitration of ESA and inflammatory cytokine (IL-6, TNF-alfa). 224 The GDG noted that the evidence upported the intuitive notion that icker patient generally require higher doe of ESA. 225 The GDG dicued that intercurrent illne may be a caue of temporary reitance that hould be aeed, and it wa noted that in patient with a chronic illne, reitance to ESA may be prolonged. 105

109 Anaemia management in chronic kidney dieae The GDG dicued the evidence with repect to adjunctive medical treatment, that patient receiving either ACE inhibitor therapy or angiotenin-ii receptor antagonit required an increaed doe of ESA in comparion with thoe patient adminitered a calcium-channel blocker or to control group. 215,219 Two further tudie reported no aociation between ACEinhibitor adminitration and reitance to ESA. 217,220 The GDG conidered one tudy to have methodological limitation due to the non-randomied tudy deign. 220 The GDG noted that the treatment range in thee tudie were appropriate and the doe being adminitered would not lead the GDG to conider that ESA reitance hould be upected. The GDG concluded that there wa no evidence that ACE-inhibitor caued ESA reitance and that uch treatment hould not be topped, although the doe of ESA may require adjutment. The GDG dicued the implication of dialyi water purity on ESA adminitration, in particular the GDG noted that increaed chloramine level (formed by the combination of free chlorine and ammonia ga) were aociated with a need for higher doe of ESA in haemodialyi patient. 218,227 The GDG dicued that the addition of activated charcoal filter reduced the level of chlorine in the dialyi water. However, it wa noted that thee filter can be prone to infection uggeting that a rik benefit analyi would be ueful. It wa noted that neither tudy had performed uch an analyi. The GDG noted that NHS Etate have produced a document covering facilitie for renal ervice. Thi outline that the required tandard for water purity mut be monitored and achieved (point 2.19), and pecifically note that carbon filter hould be elected to achieve ufficient contact time to remove all chlorine and chloramine (point 6.78). 229 Thi iue wa conidered an iue for a dialyi unit rather than the individual patient but the information may be of ue to unit manager. The GDG concluded that dialyi unit hould conider the ue of carbon filter but that a rik benefit analyi hould be ued to ae the benefit of reducing chloramine level againt the rik of infection of the carbon filter. The GDG dicued monitoring iue around how frequently patient hould be monitored and when to intervene to correct the Hb level. It wa felt that there wa a need to follow the trend of a patient repone to Hb but that in general, if two conecutive tet taken a month apart fell outide the target range, or if the rate of rie or fall of haemoglobin exceeded 1g/dl/month, then intervention would be neceary to correct the Hb level. With regard to the health economic evidence, the GDG felt that there were ome iue with the tranferability of the cot from a tudy conducted in the USA to the UK healthcare etting. However, the GDG did agree with the principal meage that giving a low doe of ESA more frequently wa more cot effective at the unit level. RECOMMENDATIONS R36 R37 Iron tatu hould be optimied before or coincident with the initiation of ESA adminitration. Ue of angiotenin-converting enzyme (ACE) inhibitor or angiotenin-ii receptor antagonit i not precluded, but if they are ued, an increae in ESA therapy hould be conidered. (C) (D) 106

110 6 Aement and optimiation of erythropoiei R38 Haemoglobin meaurement hould be taken into account when determining the doe and frequency of ESA adminitration: The caue of an unexpected change in Hb level hould be invetigated (ie intercurrent illne, bleeding) to enable intervention. ESA doe and/or frequency hould be increaed or decreaed when Hb meaurement fall outide action threhold (uually below 11.0g/dl or above 12.0g/dl), or for example when the rate of change of haemoglobin ugget an etablihed trend (eg >1g/dl/month). (D(GPP)) See for the aociated algorithm Treating iron deficiency: correction Clinical introduction While there are many different preparation of oral iron available (ee Table 6.13), there are currently only two form of parenteral iron licened in the UK, iron ucroe and iron dextran. The key iue are iron afety and efficacy. Table 6.13 Iron content of different oral iron preparation Iron alt Doe Content of ferrou iron Ferrou fumarate 200 mg 65 mg Ferrou gluconate 300 mg 35 mg Ferrou uccinate 100 mg 35 mg Ferrou ulphate 300 mg 60 mg Ferrou ulphate, dried 200 mg 65 mg Oral iron preparation contain varying amount of ferrou iron, and the frequency of gatrointetinal ide effect related to each different preparation tend to be directly related to the content of ferrou iron. Common advere effect from oral preparation include contipation, diarrhoea, nauea, vomiting, and dypepia. Iron ucroe i a complex of ferric hydroxide with ucroe containing 2% (20 mg/ml) of iron and iron dextran i a complex of ferric hydroxide with dextran containing 5% (50 mg/ml) of iron. Advere effect from intravenou iron are mainly related to the ize of doe and rate of infuion. Potential advere effect include nauea, vomiting, abdominal pain, fluhing, anaphylactoid reaction, dypnoea, numbne, fever, urticaria, rah, arthralgia, myalgia, blurred viion, injection-ite reaction including phlebiti, rarely diarrhoea, arrhythmia, hypotenion, chet pain, eizure, tremor, dizzine, fatigue and weating. Intetinal iron aborption decline a erum ferritin increae 230,231 and ESA adminitration boot iron aborption in erythropoietin deficient haemodialyi patient. 232 Patient with CKD who have anaemia, a GFR below 40 ml/min, and are not receiving ESA therapy are likely 107

111 Anaemia management in chronic kidney dieae to be erythropoietin deficient. 72 The relative lack of oral iron efficacy in each of thee condition may be due to a lack of erythropoietin-timulated iron aborption. Thi lack of oral iron efficacy led to the ue of i.v. iron and early ue of i.v. iron employed low doe given relatively frequently and adminitered a an infuion. Frequent adminitration of i.v. iron in haemodialyi patient i made feaible through ue of dialyi vacular acce but in peritoneal dialyi and predialyi patient venou acce i required for each doe. Adminitration of higher doe in CKD patient not on haemodialyi offer the potential to pare venou acce, but at the poible expene of increaed advere effect. Relative to other CKD patient group there i a wealth of information concerning iron tatu and repone to iron adminitration in patient on haemodialyi. In CKD patient not on dialyi low iron indice are common. TSAT level below 20% and ferritin level below 100 µg/l may occur in up to 20 70% of patient, depending on CKD tage and gender 233 However, little i known about the relationhip between baeline iron tatu, the likelihood of a repone to an iron challenge, and the relative efficacy and afety of oral v intravenou iron. Iron therapy in haemodialyi patient i an eential adjuvant to ESA therapy and adequate iron tore are required prior to treatment with ESA to enure effective erythropoiei. Virtually all haemodialyi patient will require ESA therapy to achieve target haemoglobin level. By contrat, a ignificant proportion of predialyi CKD patient, and ome peritoneal dialyi patient, may not require ESA therapy to achieve target haemoglobin level. Iron therapy in thee patient may be undertaken a primary treatment of anaemia Methodological introduction A comprehenive literature earch identified one RCT 234 invetigating the efficacy of oral v i.v. iron in predialyi patient without concurrent ESA therapy and two before and after tudie invetigating the efficacy of i.v. iron over 6 month 235 or a a ingle doe 236 in iron-deficient predialyi patient who had not previouly received ESA therapy. A further before and after tudy wa identified invetigating the efficacy of i.v. iron over 12 month. 237 One tudy 238 did not meet quality criteria and wa therefore excluded from the evidence tatement Evidence tatement Iron dextran: predialyi patient Following adminitration of 1g iron dextran in 500 ml normal aline i.v. a a total doe infuion over 6 hour (n=56), Hb (p<0.001) and erum ferritin (p<0.0001) level increaed after 12 week. However, thi increae in Hb wa not apparent after one year (n=21); ferritin wa till increaed compared with baeline, although to a leer extent than at 12 week (p<0.001). In addition, no major advere event were found and ytolic and diatolic blood preure did not change after 12 week. 236 (Level 3) 108

112 6 Aement and optimiation of erythropoiei Ferric accharate (alo known a ferric hydroxide ucroe or iron ucroe): predialyi patient In one tudy 200 mg elemental iron (Ferric accharate) wa adminitered in 150 ml aline over 2 hour, once monthly for 5 month, to give a total i.v. iron doe of 1,000 mg per patient (n=33). After 3 month of i.v. iron treatment, the mean Hct and Hb value were not ignificantly increaed, depite raied erum ferritin level compared with baeline (p<0.05). At 6 month, however (ie 1 month after the lat iron doe), the mean Hct (p=0.035) and Hb (p=0.008) had ignificantly increaed. Additionally, there were no difference in thoe reponding to i.v. iron treatment with an increae in mean Hct and Hb compared with thoe not reponding in any of the other parameter (erum creatinine, creatinine clearance, ytolic and diatolic blood preure) either before or after onet of i.v. iron therapy. None of the patient reported ide effect during the tudy period. Alo, no correlation wa found between Hb/Hct and any other of the tudy parameter in the reponder and non-reponder. 235 (Level 3) In a tudy of pre-dialyed chronic renal failure patient with haemoglobin level le than 11g/dl who were not receiving erythropoietin (n=60), 237 monthly intravenou adminitration of 200mg of iron ucroe for a period of 12 month wa aociated with a ignificant increae in haemoglobin from 9.7 ± 1.1 at baeline to 11.3 ± 2.5g/dl after 12 month (p<0.05): a mean increae of 1.6g/dl. No worening of renal function, no increae in blood preure and no other ide effect were noted. (Level 3) Oral v i.v. iron ucroe: predialyi patient In a RCT 234 invetigating i.v. iron ucroe 1,000mg in divided doe over 14 day adminitered either a an injection or infuion v oral ferrou ulphate 325 mg three time daily ( 195 mg ferrou iron per day) for 56 day, in patient with and without ESA ue, mean adherence of 97.3 (95% CI ) in the i.v. treatment group wa greater than in the oral treatment group mean 88.5 (95% CI ). In addition, both the proportion of patient who achieved the primary end point (ie rie in Hb 1.0 g/dl) (p=0.0344) and the mean increae in Hb were higher in the i.v. group by day 42 (p=0.0298). Notably, the difference in ESA ue in achieving primary end point in the i.v. and oral group wa not found to be ignificant. Three patient in the i.v. group dicontinued treatment due to advere event attributed to the tudy drug (hypotenion, n=2 and nauea, n=1). Tranient tate diturbance (dygeuia) wa the mot prominent GI complaint aociated with i.v. iron adminitration. Contipation, diarrhoea, nauea, vomiting and dypepia were aociated prominently with oral iron therapy, while headache, myalgia and hypotenion were excluively aociated with i.v. iron adminitration. (Level 1++) Health economic methodological introduction One tudy wa found but did not meet quality criteria. 239 The patient population contained three patient receiving epoetin, methodology of analyi wa not tated, cot analyi wa inufficiently reported and there wa no etimation of uncertainty From evidence to recommendation The available publihed evidence doe not ugget the mot effective and afet doe, frequency, preparation or route of adminitration of iron in ACKD patient with functional iron deficiency prior to ESA therapy. GDG conenu wa that patient with anaemia aociated with 109

113 Anaemia management in chronic kidney dieae CKD and functional iron deficiency will require intravenou iron treatment. The publihed evidence did not allow the GDG to recommend a preparation. Two preparation are available in the UK and the doe and frequency will be dictated by the preparation ued and by meaurement and monitoring of iron indice (erum ferritin and %HRC or %TSAT). RECOMMENDATIONS R39 People with anaemia of CKD who are receiving ESA hould be given iron therapy to maintain: (D(GPP)) erum ferritin >200 µg/l tranferrin aturation >20% (unle ferritin >800 µg/l) hypochromic red blood cell <6% (unle ferritin >800 µg/l) Mot patient will require 600 1,000 mg of iron for adult or equivalent doe for children, in a ingle or divided doe depending on the preparation. Patient with functional iron deficiency hould be treated with intravenou iron. Peritoneal dialyi and non-dialyi patient who do not repond to oral iron will require intravenou iron. In appropriate circumtance, iron treatment can alo be adminitered in the community. R40 In non-dialyi patient with anaemia of CKD in whom there i evidence of abolute or functional iron deficiency, thi hould be corrected before deciding whether ESA therapy i neceary. (D(GPP)) See for the aociated algorithm Treating iron deficiency: maintenance Clinical introduction See Methodological introduction Becaue of the high number of retrieved tudie in the literature earch, thee were grouped into: induction iron therapy for iron deficiency (both abolute and functional iron deficiency) and maintenance iron therapy for iron replete patient on epoetin and thereafter further ubgrouped into the variou iron route and frequencie of adminitration invetigated. The eventeen tudie included in the evidence tatement were elected on the bai of evidence level hierarchy. Two tudie 240,241 did not meet quality criteria and were therefore excluded from the evidence tatement. 110

114 6 Aement and optimiation of erythropoiei Notable apect of the evidence bae were: Three tudie were conducted in children Study duration ranged from 12 week to 18 month, which ha implication on the time required to meaure tability of treatment outcome. The GDG agreed that the following outcome were prioritie: epoetin doe efficacy/hb repone compliance patient preference ide effect afety. Following the firt conultation on the guideline draft, the GDG alo conidered additional retropective tudie on the incidence of advere event with intravenou iron. Thee paper did not report whether patient had previouly had ESA therapy or not and becaue of potential confounding were not added a evidence tatement but are dicued below under from evidence to recommendation (ee ection ) Evidence tatement Oral iron v intravenou iron Two RCT 251,252 in adult dialyi patient with erum ferritin level >100 µg/l compared i.v. and oral iron. One tudy 251 (n=52, all haemodialyi) adminitered 100 mg i.v. iron dextran twice a week and the other 252 (n=37, 15 haemodialyi and 19 peritoneal dialyi) adminitered 250 mg iron dextran fortnightly. Oral comparator were ferrou ulphate ( mg td) and iron polyaccharide (150 mg bd). Both tudie found i.v. iron to be uperior. In one tudy 251 haematocrit increaed (p<0.05) and ESA doe fell (p<0.05); in the econd tudy 252 haemoglobin increaed (p<0.05) compared with thoe treated with oral iron. (Level 1+) A tudy in predialyi patient 253 randomied patient with baeline ferritin level of µg/l to either oral ferrou ulphate 200 mg td (n=23) or 300 mg intravenou iron ucroe. Over a follow-up period of 5.2 month, no ignificant difference in haemoglobin level or ESA requirement wa oberved. (Level 1++) In a 29-day tudy with follow-up after 14 day 254 patient were randomied to epoetin and intermittent i.v. iron ucroe 200 mg bolu weekly (n=48) v epoetin and ferrou ulphate (65 mg elemental iron) orally 3 time daily (n=48). Although the i.v. iron group had a greater increae in erum ferritin level (p<0.0001), the rie in Hb from baeline wa not tatitically different between the two treatment group. However, when patient were tratified by a baeline erum ferritin < or 100 µg/l, the i.v. iron group had a greater increae in Hb at followup compared with oral iron patient (p<0.05). Alo, more patient in the i.v. iron group attained Hb >11.0 g/dl compared with the oral iron group (p=0.028) and the percentage change from baeline to follow-up for both Hb and ferritin wa ignificantly greater for the i.v. iron group (p<0.0001). Mean treatment concordance aeed by tablet count wa lower in the oral iron group (85.5%) compared with the i.v. iron group (95.0%); no p-value wa reported. GI ide effect were more common in the oral iron group and tate diturbance in the i.v. iron group. No patient required dicontinuation of iron treatment in either group. (Level 1+) 111

115 Anaemia management in chronic kidney dieae In a tudy conducted in peritoneal dialyi patient 255 comparing oral and intravenou iron uing a croover deign, higher haematocrit level (p=0.02) and lower ESA doe (p=0.008) were found with intravenou iron. Nine patient received oral ferrou ulphate 325 mg td for 4 month followed by a ingle bolu infuion of 1 g iron dextran after a wahout period of 1month. (Level 2+) One tudy conducted in children with TSAT>20% 242 randomied them to intravenou iron dextran or oral ferrou fumarate (n=35, all haemodialyi). Doe were baed on weight; ferrou fumarate varied between 4 and 6 mg/kg/day, children <20 kg received 25 mg/week iron dextran, thoe weighing kg received 50 mg/week and thoe >40 kg received 100 mg/week. After 16 week, no difference in ESA requirement or haemoglobin level were found. (Level 1+) Intravenou iron tudie in adult Three obervational tudie in haemodialyi patient noted a reduction in ESA requirement with regular maintenance intravenou iron: p<0.0005, 256 p<0.05, 257 p< One tudy 256 (n=116) ued iron ucroe 100 mg pot-haemodialyi. Another tudy 257 (n=24) ued either a loading doe of 1g iron dextran given in divided doe over 10 conecutive dialye followed by further bolue when TSAT fell below 20% or erum ferritin fell below 200 µg/l, or an initial pule of iron dextran mg followed by mg every 1 2 week to maintain TSAT 30 50%. The third tudy 258 (n=396) maintained haemoglobin at a median level of 11.3 to 11.8 g/dl over a 24-month period. Patient with erum ferritin <500 µg/l were treated with concomitant i.v. iron ucroe regimen a follow: month 1 3, for ferritin <100 µg/l, 50 mg iron ucroe twice weekly, for ferritin µg/l, 50 mg iron ucroe once weekly, month 4 9, for ferritin <100 µg/l, 50 mg iron ucroe twice weekly, for ferritin ng/ml, iron ucroe doe depended on functional iron deficiency. Thoe with %HRC <5% were given 50 mg iron ucroe once weekly and thoe with %HRC >5%, 50 mg iron ucroe twice weekly. During month thoe with ferritin <100 µg/l received 50 mg iron ucroe thrice weekly. Thoe with ferritin µg/l received 50 mg iron ucroe once weekly if %HRC <2% (iron replete), or 50 mg iron ucroe twice weekly if %HRC 2 5%, or 50 mg iron ucroe thrice weekly if %HRC >5%. (Level 2+ and Level 3) Another obervational tudy in haemodialyi patient 259 tratified patient repone to 20 mg intravenou iron accharate given 3 time a week over a 6-month period by ferritin <100 µg/l (n=17) v 100 <400 µg/l (n=16). Haemoglobin level (p<0.0001) increaed and ESA level decreaed (p<0.003) in all patient compared with baeline but there wa no difference between group. Four patient reported a metallic tate in aociation with iron but no other advere event were reported. (Level 2+) A further obervational tudy 260 adminitered 100 mg intravenou ferric accharate twice a month to 41 haemodialyi patient and 4 peritoneal dialyi patient who had been receiving ESA for at leat 6 month, and 11 haemodialyi patient who tarted ESA and intravenou iron imultaneouly. In thoe previouly on ESA, haematocrit level were higher (p<0.05) and ESA doe lower (p<0.05) after 12 month. Thoe who tarted ESA and intravenou iron imultaneouly had higher haematocrit level (p<0.05) after 6 month of treatment. (Level 2+) Four tudie compared different intravenou iron doing regimen In three tudie conducted in haemodialyi patient the ame total doe of iron wa adminitered. One tudy

116 6 Aement and optimiation of erythropoiei gave 400 mg accharated ferric oxide in 10 divided doe either following 10 conecutive dialyi eion (n=12) or weekly for 10 week (n=12). Thi tudy alo included 11 ubject to whom iron wa not adminitered. Thee patient had lower haemoglobin level and greater ESA requirement compared with the iron treated group. The only difference in the iron treated group wa a lower ESA requirement compared with baeline (p<0.01) in thoe given equential treatment after each dialyi. One tudy 262 gave a total of 600 mg iron dextran (n=43). Patient received either a ingle bolu doe, ix divided doe of 100 mg following conecutive dialye, or 100 mg/week for 6 week. No difference wa oberved in haemoglobin or ESA requirement with the different doing regimen. (Level 1+ and Level 2+) A further tudy in haemodialyi patient aiming for a target haemoglobin level of 11.8 g/dl compared three different iron dextran regimen. 263 A total doe infuion of mg wa ued in 14 patient, 12 patient received 500 mg/week a a bolu doe to a total of mg and 17 patient were given 100 mg/dialyi eion to a total doe of mg. No difference in peak haematocrit or time to peak haematocrit were oberved between group. (Level 1+) In peritoneal dialyi patient, one tudy 264 gave a total doe of intravenou ferric accharate of 600 mg in divided doe with two different regimen uing a croover deign (n=17). There wa a greater increae in haematocrit level in patient given 50 mg twice a week (p<0.05) compared with thoe given 100 mg/week. (Level 1+) Intravenou iron tudie in children In a 6-month tudy 243 (n=40) children below 16 year of age received epoetin to target Hct 30% and i.v. iron dextran adminitered a a maintenance doe of 1 mg/kg/week following a weightbaed loading doe. Thi wa compared with an a required intermittent weight-baed coure of 10 doe of iron dextran if Hct wa <33%, ferritin <100 µg/l and/or TSAT <20%. Depite the higher cumulative doe in the intermittent group (p<0.001) the average epoetin doe wa imilar in both group and Hb increaed to 10 g/dl, with no difference between the 2 treatment group. (Level 1+) A double-blind RCT in children <16 year old receiving epoetin 244 randomied patient to concomitant treatment with eight conecutive intravenou infuion of either 1.5 mg/kg (n=24) or 3.0 mg/kg (n=32) of odium ferric gluconate complex. Mean cumulative doe in the 1.5 mg/kg group wa 431 ± 168 mg and 725 ± 202 mg in the 3.0 mg/kg group (p<0.0001). Although increae from baeline were found in both group at 2- and 4-week evaluation time point after the lat iron doe, no difference wa found in Hb level between the two group. Reponder were defined by Hb increae 1.0 g/dl. No difference wa found between number of reponder in either group. Epoetin doe remained unchanged in both treatment group. (Level 1+) Intravenou iron afety tudie In a afety tudy, n=657 patient received 200 mg bolu injection of iron ucroe. 265 A total of 2,297 injection were adminitered, with ome patient receiving multiple injection with a minimum of 1 week between injection. Mild and tranient metallic tate wa found for 412 injection and other advere event for 57 injection. Thee were anaphylactoid reaction in even patient, pain during injection in 31 patient, pain after injection in nine patient, 113

117 Anaemia management in chronic kidney dieae with/without bruiing, nauea/gi ymptom in three patient, lethargy in four patient, and light-headedne in three patient. (Level 3) A cohort tudy 266 (n=32,566) ought to invetigate if an apparent relationhip between iron doing and mortality wa confounded by incomplete repreentation of iron doing and morbidity over time. The tudy found doe of iron >1,000 mg over 6 month to be aociated with increaed rik of mortality compared with ubject not receiving iron uing an adjuted proportional hazard analyi relating baeline iron doe to urvival with a hazard ratio (HR) of 1.09 (95% CI ). Thoe receiving >1800 mg of iron had HR 1.18 (95% CI ). However, the aociation diappeared when the adjuted probability of dying in a particular month a a function of cumulative iron doe received during the previou 0 to 6 month, 6 to 12 month and 12 to 18 month wa etimated. No ignificant aociation wa found between mortality and any level of iron doing >0 to >1,800 mg over 6 month. (Level 2+) Oral iron tudie One tudy 267 randomied iron replete patient to polyaccharide-iron complex 150 mg elemental iron twice daily (n=12) v placebo (n=13) over 3 month with 2 month follow-up. No difference wa found in Hct level between the two group. The ame tudy alo randomied iron deficient patient to either polyaccharide-iron complex 150 mg elemental iron twice daily (n=14) or placebo (n=10) over 3 month and 2 month follow-up. Thoe receiving iron had an increae in Hct level (p<0.01) (Level 1+) Another tudy 268 randomied patient to a number of different oral iron preparation containing a daily doe of 200 mg elemental iron, ferrou fumarate (Chromagen, n=12 and Tabron, n=11), ferrou ulphate (n=11) and iron-polyaccharide complex (n=12). Patient were alo given variou doe of daily acorbic acid (750, 1,000, 0, 100 mg repectively) over 6month. Hct level increaed with all preparation (Chromagen and ferrou ulphate, p<0.01; Tabron p<0.05), except for the iron-polyaccharide complex. In addition, Hct/epoetin ratio decreaed (p<0.05) in the Tabron (ferrou fumarate) treatment group only. No difference were noted in compliance. (Level 1+) Health economic methodological introduction Six tudie were appraied and one tudy met quality criteria. 269 Three of the tudie did not report unit cot, total cot or doe adequately 270,271,273 One tudy wa excluded becaue of potential bia by phyician adjutment of the epoetin doe in a before and after deign. 272 One tudy 274 wa excluded a cot-aving were not baed on evidence Health economic evidence tatement One tudy found iron dextran did not reduce the average doe of ESA in 33 patient but improved the number of patient with ucceful treatment (10 v 27). Succeful treatment wa defined a Hct 33 36%, TSAT >20%, ferritin concentration of >100ng/ml and no blood adminitered except for acute blood lo. The tudy etimated the incremental cot effectivene of iron dextran to be $41.61 (US$, 1998) per ucceful treatment. 269 No enitivity analyi wa performed. 114

118 6 Aement and optimiation of erythropoiei From evidence to recommendation The publihed evidence wa very limited in peritoneal dialyi and predialyi patient. It did not provide data to allow the GDG to pecify a tet doe of iron in the recommendation, nor a route or frequency of adminitration. Caution i required becaue of the potential ide-effect profile (particularly anaphylaxi) when adminitering both tet and maintenance doe of iron. The GDG conidered additional retropective tudie of advere event in patient receiving intravenou iron to inform the recommendation: Baillie et al 245 invetigated ten of million of 100mg doe equivalent (the exact ample ize i not given in the paper) from the American Food and Drug Adminitration (FDA) freedom of information urveillance databae. They conidered all advere event between January 1997 and September 2002 and found rate per million 100mg doe equivalent of 29.2 for iron dextran, 10.5 for odium ferric gluconate and 4.2 for iron ucroe (which had the lowet rate for all clinical categorie of advere event). Chertow et al 246,247 invetigated 30,063,800 doe in FDA data from 2001 to 2003 and found ignificantly lower rate among people who received odium ferric gluconate or iron ucroe, compared with thoe who received higher molecular weight iron dextran. Rate of life-threatening event per million doe were 11.3 for higher molecular weight iron dextran, 3.3 for lower molecular weight iron dextran, 0.9 for odium ferric gluconate, and 0.6 for iron ucroe. Fihbane et al 248 invetigated all patient (n=573) receiving intravenou iron dextran at any of four USA haemodialyi centre between July 1993 and June 1995 and found 27 patient (4.7%) had related advere event. Hitory of drug allergy (OR 2.4, p=0.03) and multiple drug allergy (OR 5.5, p<0.001) were found to be ignificant rik factor for advere event. Flete et al 249 invetigated the Freeniu Medical Care North America (FMCNA) clinical variance report from October 1998 to March 1999 for iron dextran only and found an advere event rate of per million doe. The tudy reported higher rate in patient receiving higher molecular weight iron dextran, but thi wa not tatitically ignificant. Walter and van Wyck 250 invetigated 1,066,099 doe of intravenou iron dextran from the Gambro Healthcare US databae between January 1999 and April They found a rate of advere event per million doe for all everitie, and reported in detail on even patient who had advere event requiring reucitation, all of whom were receiving tet doe or firt therapeutic doe. Significance teting to compare molecular weight of iron dextran wa only reported for thee even patient. Advere event rate for intravenou iron are very low for both preparation in ue in the UK (circa 3.3 event per million doe for low molecular weight iron dextran, and 0.6 per million doe for iron ucroe), and the GDG therefore did not ditinguih between them in the recommendation. The GDG acknowledged the cot-effectivene evidence of predialyi anaemia treatment i limited a there i little data to make comparion to alternative treatment and inufficient effectivene data of patient benefit uch a quality of life. The GDG noted that collecting quality of life data that could be converted into utility core and reource data in all future randomied controlled trial would be ueful, epecially in predialyi patient. 115

119 Anaemia management in chronic kidney dieae RECOMMENDATION R41 Once ferritin >200 µg/l and HRC <6% or TSAT >20%, people with anaemia of CKD who are receiving ESA hould be given maintenance iron. The doing regimen will depend on modality, for example haemodialyi patient will require the equivalent of mg intravenou iron per week (or an equivalent doe in children of 1 mg/kg/week). Peritoneal dialyi and non-dialyi patient who do not repond to oral iron will require intravenou iron. (D(GPP)) See for the aociated algorithm ESA: monitoring iron tatu during treatment Clinical introduction Meaurement of ferritin together with %HRC or %TSAT provide an indication of iron tore and availability of iron for erythropoiei. We know that in patient with anaemia aociated with CKD who are under treatment with ESA, an adequate upply of iron i eential for effective erythropoiei and cot-efficient ue of ESA. We alo know that too much iron may expoe patient to rik of infectiou complication and may alo increae cardiovacular rik through oxidative tre. What then are the mot deirable level of thee parameter of iron tatu to be maintained during treatment with ESA? Clinical methodological introduction A literature earch identified four tudie coniting of a RCT, 77 a cohort tudy, 275 a propective longitudinal tudy 258 and a propective longitudinal tudy in children. 276 One tudy 277 did not meet quality criteria and wa therefore excluded from the evidence tatement. Notable apect of the evidence bae were: In the tudy comparing TSAT 20 30% and 30 50%, 77 achieved TSAT level were 27.6% and 32.6% in the repective group at the end of the 6-month tudy period Clinical evidence tatement Serum ferritin Haemodialyi patient Intravenou iron upplementation which led to an increae in mean ferritin to 395 ± 206 mg/ 100 ml (p-value not given) in children aged year (n=8) lead to an increae in the Hb (p=0.0117) and Hct (p=0.0024), depite a fall in epoetin doe from 6,500 U to 6,150 U with no ide effect noted, particularly hypertenion. 276 (Level 3) In a 24-month tudy (n=396) 258 Hb wa maintained at a median level of 11.3 to 11.8 g/dl and median epoetin doe decreaed to 72 (inter-quartile range ) (p<0.001) when compared with baeline, when patient with erum ferritin <500 ng/ml were treated with concomitant i.v. iron ucroe regimen. (Level 3+) 116

120 6 Aement and optimiation of erythropoiei Tranferrin aturation (TSAT) Haemodialyi patient In a tudy comparing the effect of TSAT 20 30% v 30 50% on epoetin doe required to maintain Hb g/dl, epoetin doe progreively decreaed in the TSAT 30 50% group, with ~40% doe reduction in month 4, 5 and 6 when compared with the 20 30% group (p=0.0038). Thi change in epoetin doe wa independent of baeline doe in both the TSAT 30 50% group and TSAT 20 30% group. 77 (Level 1+) Percentage of hypochromic red cell (%HRC) Haemodialyi patient In an 8-week tudy whereby patient tratified by baeline %HRC 0 3%, 4 9% and 10% received a fixed epoetin doe and i.v. iron accharate 200 mg once weekly up to erum ferritin 250 µg/l, although mean Hb and ferritin level ignificantly increaed in all 3 group (P for all), mean Hb increae wa greater with increaing %HRC at baeline (p=0.02). In addition the proportion of patient with >1 g/dl increae in Hb wa greater a %HRC at baeline increaed (p=0.02). 275 (Level 2+) Health economic methodological introduction Three tudie were appraied 77,273,278 and two met quality criteria. 77,278 The tudy that did not meet quality criteria etimated cot-aving baed on average reduced EPO doage. 273 However, with no incluion of the price ued, the coting wa not ufficiently tranparent to warrant incluion. An American tudy etimated the cot-aving per patient per year over a 6-month period while maintaining TSAT between 30 and 50% v 20 to 30% uing maintenance intravenou iron dextran. 77 One American tudy wa a cot analyi of ESA uing percent reduction of urea (PRU) a an index of dialyi adequacy and tranferrin aturation a a meaure of iron tore. The tudy invetigated two comparion: the total doe of ESA received during the 4-week tudy by the 20 participant with the highet tranferrin aturation to the 20 participant with the lowet tranferrin aturation, and the total doe of ESA adminitered during the 4-week tudy to the 20 patient with the highet PRU to the 20 participant with the lowet PRU Health economic evidence tatement The tudy etimated intravenou iron dextran ave approximately $109 per month or $1,308 per year per patient when maintaining the TSAT between 30 and 50% (n=23) (v 20 to 30% in control group; n=19). 77 Cot difference between the intervention and control group wa tatitically ignificant by the third month of tudy and remained ignificant until the end of the tudy at 6 month (p<0.02). 77 At $10 per 1,000 unit of ESA, it cot $45 (10.2%) more per month per patient in the 20 patient with the lowet tranferrin aturation compared with the 20 patient with the highet tranferrin aturation

121 Anaemia management in chronic kidney dieae From evidence to recommendation The GDG agreed that there wa very little long-term effectivene data to determine the mot appropriate maintenance level. The GDG baed their recommendation on the European Bet Practice Guideline. 279 RECOMMENDATIONS R42 Patient receiving ESA maintenance therapy hould be given iron upplement to keep their: erum ferritin between 200 and 500 µg/l in both haemodialyi patient and (D) non-haemodialyi patient, and either the tranferrin aturation level above 20% (unle ferritin > 800 µg/l) or (B) percentage hypochromic red cell (%HRC) le than 6% (unle ferritin > 800 µg/l). (D(GPP)) In practice it i likely thi will require intravenou iron. 118

122 7 Monitoring treatment of anaemia of CKD 7.1 Monitoring iron tatu Clinical introduction Monitoring of iron tatu hould be aimed at enuring that patient undergoing treatment with ESA maintain level of iron that enure maximally effective erythropoiei. The frequency of monitoring mut take account of the tage of anaemia treatment, ie initial correction of anaemia or maintenance of target range of haemoglobin, the frequency and mode of iron upplementation, CKD tatu (haemodialyi patient have an unavoidable lo of iron through the dialyi proce), clinical ituation likely to reult in depletion of iron tore uch a bleeding and urgery, clinical ituation likely to reult in miinterpretation of iron parameter (for example, co-exitent infection lead to falely elevated ferritin level and depreed %TSAT), and preexiting iron-overload tate. The frequency of monitoring may alo be dictated by the availability of the patient and by trend analyi of change in iron tatu over time Methodological introduction A comprehenive literature earch identified a cohort tudy. 257 A comprehenive literature earch did not identify any tudie that were uitable to addre the economic apect of thi ection, therefore no health economic evidence tatement are given Evidence tatement Monitoring after intermittent iron doing Haemodialyi patient Table 7.1 Time profile of intermittent i.v. iron dextran doing regimen (n=14) (Level 2) Treatment with Time averaged value over 1,000 mg iron dextran 4 month after completion over 10 doe T=0 T=3 day (trapezoid method) TSAT (%) 20.6 ± ± (range 15 37) (range ) T=0 T=2 month (peak value) Ferritin (ng/ml) 197 ± (range ) T=0 T=3 month T=4 month TIBC (µg/ml) 210 ± ± ± 11 ( ) 119

123 Anaemia management in chronic kidney dieae Monitoring after ingle iron doe Haemodialyi patient Table 7.2 Time profile of ingle doe i.v. iron dextran 50 mg or 100 mg (n=16) (Level 2+) T=0 Time averaged over 2 week TSAT (%) Mean 34.6 ± 3.1 (n=16) 35.5 for 50 mg group (n=8) 36.7 for 100 mg group (n=8) T=0 Ferritin (ng/ml) 231 ± 29 (n=16) T=1 week, 297 ± 44 (n=16) T=2 week, 276 ± 35 (n=16) T=0 Time averaged over 2 week TIBC (µg/ml) Not reported No change (data not reported) From evidence to recommendation The GDG agreed on a range of poible interval for iron tore monitoring, which will allow practice to be tailored to the individual patient and to local ytem. It i clear from the evidence that monitoring oon after intravenou iron i not helpful, and the GDG felt that a minimum time elaped of 1 week would be appropriate. RECOMMENDATIONS R43 People with anaemia of CKD hould not have iron level checked earlier than 1 week after receiving intravenou iron. The length of time to monitoring of iron tatu i dependant on the product ued and the amount of iron given. (C) R44 Routine monitoring of iron tore hould be at interval of 4 week to 3 month. (D(GPP)) 7.2 Monitoring haemoglobin level Clinical introduction The initial tep in clinical management of the CKD patient maintained in an anaemia programme mut be the acquiition of laboratory and treatment data at pecified interval. The frequency of acquiition of data ha been driven by anaemia treatment algorithm and deciion matrice deigned to achieve the required rate of rie of haemoglobin during the correction phae, and the deired haemoglobin level during the maintenance phae. However, the effectivene of uch algorithm and deciion matrice i difficult to evaluate becaue there i a lack of publihed clinical outcome related to their ue. Furthermore, there i inherent variability in haemoglobin level within a given population, and there are everal component of thi variability. One component i population or interpatient variability. Biological variability i found with nearly all laboratory meaurement and in the cae of haemoglobin 120

124 7 Monitoring treatment of anaemia of CKD level in patient with CKD multiple factor contribute including gender and race, environmental factor, aay or ampling difference, the patient tate of hydration and other related phyiological determinant. Another component of haemoglobin level variability i individual or intraindividual variability. Here there i variation with repeated meaurement over time in the ame individual. Again there are multiple factor contributing to thi variability including eaonal variation, ampling method, comorbid condition uch a nutritional tatu, inflammation, gatrointetinal bleeding, and bone marrow fibroi. Two major factor are under control of the anaemia management team: ESA and iron therapy, and thee are alo determinant of haemoglobin level and factor in population variability. The phyiological characteritic of erythropoiei are uch that there i a time required for the bone marrow to react to changing ESA timulu and that reaction time varie widely among patient with CKD, ranging from a few week to a few month. It require 1 to 2 month to induce red blood cell production and 1 to 3 month after removal of ESA timulu for patient to experience turnover of red blood cell to ceae production. Data from a 1-year tudy demontrate that haemoglobin level may change from le than 11 g/dl to greater than 12 g/dl (or vice vera) in more than 28% of patient. 212 Haemoglobin ynthei, red blood cell production and detruction are not procee that can be controlled intantaneouly and haemoglobin level underhooting or overhooting hould be expected when health profeional react to ingle haemoglobin value. We hould therefore react to trend in haemoglobin level but how frequently hould the haemoglobin level be monitored to determine the trend? Methodological introduction A comprehenive literature earch did not identify any tudie that were uitable to addre the clinical or economic apect of thi ection, therefore no evidence tatement are given From evidence to recommendation Monitoring i part of care in ESA induction and maintenance, including conideration of the rate of haemoglobin change. The GDG felt that a range of interval would allow monitoring to be tailored to the patient and the local ytem, and agreed on 2 4 week in induction and 1 3 month in maintenance. RECOMMENDATION R45 In people with anaemia of CKD, haemoglobin hould be monitored: every 2 4 week in the induction phae of ESA therapy every 1 3 month in the maintenance phae of ESA therapy more actively after an ESA doe adjutment in a clinical etting choen in dicuion with the patient, taking into conideration their convenience and local healthcare ytem. (D(GPP)) 121

125 Anaemia management in chronic kidney dieae 7.3 Detecting ESA reitance Clinical introduction The phyiological characteritic of erythropoiei are uch that there i a time required for the bone marrow to react to ESA timulu and that reaction time varie widely among patient with CKD, ranging from a few week to a few month. The magnitude of reaction to ESA timulu i alo variable. In determining reitance to ESA therapy it i important to ditinguih between true reitance, a lack of bone marrow repone to ESA therapy, and apparent reitance where increaed red cell detruction or red cell lo offet ESA timulated red cell production. It i alo important to determine a doe threhold of ESA above which reitance to therapy i defined and a duration of therapy beyond which reitance to therapy hould be upected Methodological introduction A literature earch identified a cae erie 280 and a cohort tudy. 281 Five tudie did not meet quality criteria and were therefore excluded from the evidence tatement. A comprehenive literature earch did not identify any tudie that were uitable to addre the economic apect of thi ection, therefore no evidence tatement are given Evidence tatement Pure red cell aplaia (PRCA) Haemodialyi patient In a tudy of patient predominantly receiving ubcutaneou epoetin alfa, erum from all epoetintreated patient (n=13) inhibited growth of erythroid cell and addition of epoetin to their erum ample revered inhibitory effect. Alo erum from all patient wa hown to bind to epoetin and Scatchard analyi uggeted preence of homogeneou binding ite. 280 (Level 3) Aluminium toxicity Haemodialyi patient In a tudy conducted to maintain Hct 30% (Hb ~10 g/dl), where patient were divided into 2group on the bai of repone to epoetin treatment, the poor reponder received a higher epoetin doe (p<0.05), yet had lower Hb and Hct level (both p<0.001). Of the haematological parameter invetigated, baal aluminium and aluminium level following challenge with deferrioxamine were higher in the poor reponder (both p<0.01). In addition, mean corpucular volume howed invere correlation with baal aluminium (data not provided), pot-deferrioxamine aluminium (r= 0.617, p=0.005) and change in aluminium level (r= 0.711, p<0.001) in the poor reponder. In the good reponder, mean corpucular volume only howed correlation with change in aluminium level (r= 0.476, p=0.03). 281 (Level 2+) 122

126 7 Monitoring treatment of anaemia of CKD From evidence to recommendation In conidering when reitance to ESA hould be upected and what condition lead to ESA reitance, the GDG reviewed evidence on two outcome, PRCA and aluminium toxicity. The GDG conidered the definition of reitance and agreed on the definition uggeted by the Revied European bet practice guideline for the management of anaemia in patient with chronic renal failure. 287 It wa agreed to upect reitance when a patient doe not achieve the target Hb level after receiving an epoetin doe more than 300 U/kg/week.c. (approximately 20,000 unit/week) or equivalent or 1.5 mg/kg darbepoetin alfa.c. or i.v. (approximately 100 mg/week) or ha a continued need for the adminitration of high doe of ESA to maintain the target Hb level. 287 It wa noted that 300 U/kg/week i ued a thi value i two tandard deviation above the mean value ued. The GDG conidered that reitance hould be upected after 3 month of failure to repond to ESA, after excluion of other caue of a temporary lack of repone (eg intercurrent illne or other caue of chronic bleeding). With regard to condition that lead to ESA reitance the GDG reviewed evidence on PRCA. The GDG agreed their working definition of PRCA to be the preence of a low reticulocyte count, together with anaemia and the preence of neutraliing antibodie. The GDG conidered PRCA to be confirmed where anti-erythropoietin antibodie are preent (a hown by an appropriate laboratory aay) and there wa a lack of pro-erythroid progenitor cell in the bone marrow. The GDG noted that PRCA can be induced by other caue aide from enitiation to erythropoietin. Thi ha ince been addreed by uing a fluoro-rein coating, which form a barrier between the rubber topper and erythropoietin in ome pre-filled yringe. The evidence preented pecifically addreed PRCA induced by enitiation to erythropoietin and demontrated that the inhibition of the erythroid cell wa correlated with the preence of antierythropoietin antibodie. 280 The GDG noted that the iue of aluminium toxicity wa of clinical importance but the incidence i now very rare. The GDG noted that there wa a current ource of aluminium from the reponible ue of aluminium hydroxide capule (Alu-cap, ued a phophate binder to reduce the aborption of dietary phophate). However, it wa conidered unlikely that the ue of Alu-cap would lead to aluminium toxicity. The iue of toxicity originally temmed from a lack of water purity which ha improved. It wa noted that the trial 281 did not report either the ue of aluminium-baed phophate binder or whether any water purification ytem wa being ued. The GDG noted that aluminium level are routinely meaured in their haemodialyi patient but that the need to continue doing o wa under quetion. RECOMMENDATIONS R46 After other caue of anaemia, uch a intercurrent illne or chronic blood lo have been excluded, people with anaemia of CKD hould be conidered reitant to ESA when: an apirational Hb range i not achieved depite treatment with 300 IU/kg/week of ubcutaneou epoetin or 450 IU/kg/week of intravenou epoetin or 1.5 µg/kg/week of darbepoetin, or there i a continued need for the adminitration of high doe of ESA to maintain the apirational Hb range. (D(GPP)) 123

127 Anaemia management in chronic kidney dieae R47 R48 In people with CKD, pure red cell aplaia (PRCA) i indicated by a low reticulocyte count, together with anaemia and the preence of neutraliing antibodie. The GDG conidered that PRCA hould be confirmed when anti-erythropoietin antibodie are preent and there i a lack of pro-erythroid progenitor cell in the bone marrow. In people with anaemia of CKD, aluminium toxicity hould be conidered a a potential caue of a reduced repone to ESA after other caue uch a intercurrent illne and chronic blood lo have been excluded. See for the aociated algorithm. (D) (C) 7.4 Managing ESA reitance Clinical introduction Management of ESA reitance will clearly depend on the underlying caue. The Netherland Cooperative Study on Adequacy of Dialyi (NECOSAD-2) identified an incidence of inadequate ESA repone of 16.7 per 1,000 patient year on ESA while on dialyi. 288 Fifty-even of 1,677 patient with incident end tage renal dieae in the NECOSAD-2 tudy had an inadequate ESA repone. Table 7.3 how the variou caue identified. Table 7.3 Poible caue for ESA reitance from the NECOSAD-2 tudy (n=57) Caue for inadequate ESA repone Number* Caue for inadequate ESA repone Number* Infection/inflammation 41 Blood lo 16 Hyperparathyroidim/aluminium 10 toxicity Haemoglobinopathy 2 Folate/vitamin B12 deficiency 1 Multiple myeloma/myelofibroi/ 6 myelodyplatic yndrome Malnutrition 5 Haemolyi 0 Pure red cell aplaia 1 Malignancy 7 Graft/hunt problem 14 Operation 8 Supected noncompliance 9 Medication ( bone marrow uppre) 4 Unknown 2 Inadequate dialyi 2 *Some patient fell into more than one category (ie there wa more than one poible caue for their inadequate ESA repone) Methodological introduction The literature earch identified three tudie: a 2-part tudy with a propective cohort group and a ubequent before and after tudy in a ubgroup, 289 a retropective cae erie 290 and a before and after tudy

128 7 Monitoring treatment of anaemia of CKD A comprehenive literature earch did not identify any tudie that were uitable to addre the economic apect of thi ection, therefore no evidence tatement are given Evidence tatement Treatment of aluminium toxicity with deferrioxamine Dialyi patient Patient receiving epoetin with no concurrent or prior treatment for aluminium toxicity (n=5) had a low mean rie of Hb above baeline and did not achieve target Hb 9 g/dl over 20 week, unlike the control group with treatment prior to the tudy (n=4) (p<0.05) and no aluminium toxicity (n=8) (p<0.05), which reached target Hb within 12 week of the tudy. 289 Thi wa upported by the correlation between baeline erum aluminium level and the mean rie of Hb (r= 0.51, p=0.03) and between Hb rie during epoetin therapy and aluminium increment following challenge with deferrioxamine. (Level 2+) In addition, concurrent treatment with deferrioxamine in thi group led to a mean Hb rie when compared with previou treatment with epoetin only (p<0.01). 289 (Level 3) Reduced T-cell production of inflammatory marker TNF-α and IFN-γ with low doe pentoxifylline Patient population not pecified Hb level in poor reponder to epoetin (n=12) ignificantly improved after 4 month treatment with low doe pentoxifylline (p=0.0001). Thi wa aociated with a decreae in TNF-α (p=0.0007) and IFN-γ (p=0.0002) production 6 8 week following pentoxifylline therapy, and no change in white blood cell production after 4 month. Thi uggetive evidence wa upported by a correlation between change in Hb and TNF-α production (r =0.7145, p=0.0118), however, no correlation wa found between change in Hb and IFN-γ (r =0.4406, p=0.1542). 291 (Level 3) Treatment of ESA-induced pure red cell aplaia (PRCA) with immunouppreant/immunoglobulin/kidney tranplant Not on dialyi, haemodialyi and peritoneal dialyi patient In a group of patient with epoetin-induced PRCA (n=43 epoetin alfa ± epoetin beta or darbepoetin and n=4 epoetin beta excluively), 37 patient received treatment which conited of one treatment (n=26), two conecutive treatment regimen (n=10) or five different regimen (n=1). Of thee, 29 patient recovered (ie reticulocyte count >20,000/µl and not requiring red cell tranfuion), however, no patient wa challenged with ESA. A the treatment are not comparable for uperiority, the data from the tudy i preented in the Table

129 Anaemia management in chronic kidney dieae Table 7.4 Summary data from Verhelt (2004) 290 (Level 3) Number of patient Time before recovery PRCA treatment n who recovered (month) Follow-up (month) Corticoteroid alone (n=14) (56%) 1, 2, 2, 3, 3, 3, 3, 3, 3, 3, 5, 13, ± high doe i.v. 3, 3, 6, 18 20, 30 immunoglobulin High doe i.v. 9 1 (11%) 3 3, 3, 4, 4, 4, 9, 10, 19 immunoglobulin alone Corticoteroid (87%) 1, 2, 2, 3, 4, 5, 7 3 cyclophophamide Cicloporin 6 4 (67%) 1, 1, 1, 1 3, 9 Kidney tranplant * 6 6 (100%) <1, <1, <1, <1, <1, <1 Antibodie to CD , 3 Corticoteroid + high 1 1 (100%) 3 doe i.v. immunoglobulin + plama exchange Mycophenolate motefil Note: for patient who did not recover, follow-up wa length of time between tart of treatment and lat viit or tart of new treatment. Received only 1 kind of treatment. * Received induction treatment followed by triple immunouppreive therapy From evidence to recommendation When conidering how ESA reitance hould be managed the GDG reviewed evidence on three outcome, aluminium toxicity, marker of inflammation and the treatment of PRCA. The GDG noted that with regard to treating aluminium toxicity that deferrioxamine wa conidered the treatment of choice. If aluminium toxicity wa upected, a patient hould be adminitered a bolu of deferrioxamine and the amount of aluminium fluhed into the blood tream determined. Treatment with deferrioxamine hould be adminitered until aluminium toxicity i no longer preent. The GDG noted that it wa rare to find patient with toxic level of aluminium and that thi hould be conidered a pecial circumtance that would be mot likely to occur in haemodialyi patient managed by renal phyician. With regard to inflammatory marker, the GDG reviewed one tudy that uggeted that in poor reponder to ESA, treatment with low-doe pentoxifylline reduced the production of inflammatory marker (TNF-α and IFN-γ) by T-cell. 291 However, the GDG cautioned that thi wa an academic cientific tudy that, although intereting, did not reflect current clinical practice and noted that pentoxifylline wa not licened for thi ue. The GDG felt that clinical trial were needed to upport thi data. The GDG reviewed evidence on the treatment of ESA-mediated PRCA. The GDG felt thi wa a pecialied area with few annual cae. Becaue of thi, the GDG acknowledged that the 126

130 7 Monitoring treatment of anaemia of CKD treatment of thi condition wa not fully etablihed and that the mot up-to-date information wa available online and wa written by the PRCA Global Scientific Adviory Board (GSAB: and thi hould be acceed to determine the current bet practice to treat thi condition. The GDG noted that immunouppreive therapie have been hown to revere antibody-mediated PRCA. However, it wa noted that the total number of patient with thi condition wa o mall that they felt unable to recommend thi treatment. The GDG noted that the GSAB uggeted cicloporin a the treatment of choice. RECOMMENDATIONS R49 R50 In haemodialyi patient with anaemia of CKD in whom aluminium toxicity i upected, a deferrioxamine tet hould be performed and the patient management reviewed accordingly. (C) ESA-induced PRCA hould be managed in accordance with current bet practice. Specialit referral hould be conidered. Note: current bet practice for thi rare condition i available from the PRCA Global Scientific Adviory Board (GSAB: See ection for the aociated algorithm. 127

131 8 Reearch recommendation The Guideline Development Group ha made the following recommendation for reearch, on the bai of it review of the evidence. The Group regard thee recommendation a the mot important reearch area to improve NICE guidance and patient care in the future. Intravenou iron in children A propective tudy of adequate duration of i.v. iron preparation in children with anaemia of CKD, including afety, doing and efficacy outcome. Why thi i important There i very little evidence relating to anaemia of CKD in children. It i known that there i a range of iron level for adult outide which advere outcome become more likely and thi help guide monitoring and treatment adjutment over anaemia correction and maintenance. In children, there i likely to be much greater variation between individual. Trial of ESA in children Trial of ESA in children with anaemia of CKD (including darbepoetin, which i currently unlicened in children younger than 12 year), including afety, doing and efficacy outcome. Why thi i important A above, there i very little evidence relating to anaemia of CKD in children. ESA are a key therapy and therefore more data are needed in order to define uitable treatment regimen. Haemoglobin level in older people An obervational tudy of Hb level and advere outcome in older people. Why thi i important Evidence ugget that anaemia due to reduced erythropoiei occur even in early tage of CKD. Thi may be undetected, and i aociated with advere outcome in older people. A better undertanding of the haemoglobin level aociated with advere outcome in older people would enable improved detection of anaemia of CKD and reduction of rik. ESA tolerance tet A trial of an ESA tolerance tet including collection of data on ESA regimen and Hb level achieved. 129

132 Anaemia management in chronic kidney dieae Why thi i important A better undertanding of the practical impact of ESA tolerance teting on treatment and outcome would clarify whether uch tet are ueful, particularly in term of tailoring ESA and optimal Hb level for individual patient depending on their repone. Iron level in predialyi patient An RCT to ae Hb level a an outcome in predialyi patient treated to erum ferritin level <200 µg/l v thoe treated to µg/l. Why thi i important The ferritin level up to which predialyi patient hould be treated to achieve acceptable Hb (and at which ESA are conidered if Hb i till inadequate) i not well addreed in the evidence bae. Implementation of management algorithm An obervational tudy of patient management in line with the initial management and maintenance algorithm given in thi guideline, with the aim of formally piloting and validating them, or providing evidence for amendment when the guideline i updated. Why thi i important Protocol and precribing algorithm for ESA are in ue, including computeried deciion upport ytem. Some of thee have been piloted and validated, and it i important that the NICE guideline algorithm match thi tandard to provide additional upport at the broader cale of management trategie. Other potential reearch topic Optimal Hb level to be achieved with ESA in children with ACKD. Are the ame level of erum ferritin, %HRC and %TSAT that define functional iron deficiency in dialyi patient applicable to the predialyi population? The value of endogenou erythropoietin teting in the diagnoi of anaemia aociated with CKD. Which patient would mot benefit from ESA therapy in the wider CKD population? Doe the co-adminitration of ESA with phyiological doe of androgen reduce the doe of ESA adminitered? 130

133 Appendix A: Evidence-baed clinical quetion and literature earche Evidence-baed clinical quetion and literature earche Quetion ID Quetion wording Study type filter ued Databae and year PROG1 In patient with chronic kidney dieae, what All tudy type Medline haemoglobin (Hb) / haematocrit level are aociated with Embae advere outcome and what are the effect of a) age Cochrane b) gender c) ethnicity? Cinahl DIAG1 In patient with chronic kidney dieae, what i the All tudy type Medline aociation between glomerular filtration rate (GFR) and Embae haemoglobin level in a) diabetic and b) non-diabetic Cochrane patient? Cinahl DTEST2 What are the bet tet, or combination of tet, to Diagnoi Medline determine iron tatu in patient with chronic kidney Embae dieae? Cochrane Cinahl DTEST1 What i the role of erythropoietin teting in the All tudy type Medline aement of anaemia in patient with chronic kidney Embae dieae? Cochrane Cinahl MGTFE1 Up to what level of erum ferritin, percentage tranferrin Sytematic review, Medline aturation and percentage hypochromic red cell hould RCT and comparative Embae patient with ACKD be treated with iron without advere tudie Cochrane event? Cinahl MGTFE2 In patient with ACKD what, if any, are the erum ferritin, Sytematic review, Medline tranferrin aturation and percentage hypochromic red RCT and comparative Embae cell threhold for commencing treatment with ESA? tudie Cochrane Cinahl MGTFE3 In patient with ACKD what, if any, are the optimal erum Sytematic review, Medline ferritin, tranferrin aturation and percentage hypochromic RCT and comparative Embae red cell level to be maintained during treatment with tudie Cochrane ESA? Cinahl MGTN1 What i the benefit of vitamin C, vitamin E, folic acid, Sytematic review and Medline carnitine or glutathione upplementation in the treatment RCT Embae of anaemia due to chronic kidney dieae? Cochrane Cinahl MGTN2 What i the benefit of androgen in the treatment of Sytematic review and Medline anaemia due to chronic kidney dieae? RCT Embae Cochrane Cinahl continued 131

134 Anaemia management in chronic kidney dieae Evidence-baed clinical quetion and literature earche continued Quetion ID Quetion wording Study type filter ued Databae and year HYP1 When doe treating hyperparathyroidim improve the All tudy type Medline management of anaemia caued by chronic kidney Embae dieae? Cochrane Cinahl PAT1 What are the patient preference and experience when All tudy type Medline receiving ESA for the treatment of ACKD? Embae Cochrane Cinahl BNI PAT2 I the effectivene of anaemia management of CKD All tudy type Medline improved by patient education programme? Embae Cochrane Cinahl BNI PycInfo MGTHB1 What haemoglobin range hould be maintained during Sytematic review, Medline anaemia treatment in CKD? RCT and comparative Embae tudie Cochrane Cinahl MGTHB2 In patient with chronic kidney dieae what are the rik Sytematic review and Medline and benefit of early v deferred correction of anaemia? RCT Embae Cochrane Cinahl TXFE1 What i the mot effective and afet doe, frequency, Sytematic review and Medline preparation and route of adminitration of iron in ACKD RCT Embae patient with functional iron deficiency prior to ESA Cochrane treatment? Cinahl TXFE2 What i the mot effective and afet doe, frequency, Sytematic review and Medline preparation and route of adminitration of iron in ACKD RCT Embae patient with functional iron deficiency receiving ESA Cochrane treatment? Cinahl TXEF1 In patient with ACKD what are the benefit and rik of Sytematic review, Medline correcting anaemia with epoetin alfa compared to RCT and comparative Embae epoetin beta in reducing morbidity and mortality and tudie Cochrane improving quality of life? Cinahl TXEF2 In patient with ACKD what are the benefit and rik of Sytematic review, Medline correcting anaemia with epoetin alfa compared to RCT and comparative Embae darbepoetin in reducing morbidity and mortality and tudie Cochrane improving quality of life? Cinahl TXEF3 In patient with ACKD what are the benefit and rik of Sytematic review, Medline correcting anaemia with epoetin beta compared to RCT and comparative Embae darbepoetin in reducing morbidity and mortality and tudie Cochrane improving quality of life? Cinahl TXEF4 In patient with ACKD what are the benefit and rik of Sytematic review, Medline correcting anaemia with ESA compared to placebo or RCT and comparative Embae no treatment in reducing morbidity and mortality and tudie Cochrane improving quality of life? Cinahl continued 132

135 Appendix A: Evidence-baed clinical quetion and literature earche Evidence-baed clinical quetion and literature earche continued Quetion ID Quetion wording Study type filter ued Databae and year MGTE1 Which iron replete patient with ACKD hould receive Sytematic review, Medline ESA? RCT and comparative Embae tudie Cochrane Cinahl TXEF5 In patient with ACKD what are the benefit and rik of Sytematic review, Medline correcting anaemia with blood tranfuion in reducing RCT and comparative Embae morbidity and mortality and improving quality of life? tudie Cochrane Cinahl TXDF1 In patient with ACKD, what factor (including patient Sytematic review, Medline factor) determine the doe and frequency of ESA RCT and comparative Embae required to correct anaemia? tudie Cochrane Cinahl TXDF2 In patient with ACKD, what factor determine the doe Sytematic review, Medline and frequency of ESA required to keep the haemoglobin RCT and comparative Embae level within the maintenance range? tudie Cochrane Cinahl ESAD1 In patient with ACKD, what factor determine the All tudy type Medline proviion of ESA? Embae Cochrane Cinahl ESAD2 In patient with ACKD, what factor determine the route Sytematic review, Medline of adminitration of ESA? RCT and comparative Embae tudie Cochrane Cinahl NURS1 I the effectivene of anaemia management in chronic All tudy type Medline kidney dieae improved by the involvement of anaemia including qualitative Embae nure pecialit/ coordinator? Cochrane Cinahl MON1 In patient with ACKD treated with ESA, how frequently All tudy type Medline hould iron tatu be checked? Embae Cochrane Cinahl MON2 In patient with ACKD treated with ESA, how frequently All tudy type Medline hould haemoglobin level be checked a) during Hb Embae correction and b) during Hb maintenance? Cochrane Cinahl ESAR1 When hould reitance to ESA be upected and what All tudy type Medline condition lead to ESA reitance? Embae Cochrane Cinahl ESAR2 How hould ESA reitance be managed? All tudy type Medline Embae Cochrane Cinahl NOTE: The final cut-off date for all earche wa 28 September

136 Appendix B: Scope Guideline title Anaemia management in people with chronic kidney dieae (CKD) Short title Anaemia in chronic kidney dieae Background The National Intitute for Clinical Excellence ( NICE or the Intitute ) ha commiioned the National Collaborating Centre for Chronic Condition to develop a clinical guideline on the management of anaemia in chronic kidney dieae (CKD) for ue in the NHS in England and Wale. Thi follow referral of the topic by the Department of Health and Welh Aembly Government (ee below). The guideline will provide recommendation for good practice that are baed on the bet available evidence of clinical and cot effectivene. The Intitute clinical guideline will upport the implementation of National Service Framework (NSF) in thoe apect of care where a Framework ha been publihed. The tatement in each NSF reflect the evidence that wa ued at the time the Framework wa prepared. The clinical guideline and technology appraial publihed by the Intitute after an NSF ha been iued will have the effect of updating the Framework. The NSF for Renal Service (2004) i of particular relevance to thi guideline. Clinical need for the guideline The NSF for Renal Service (2004) define chronic kidney dieae (CKD) a kidney (renal) dieae that i irreverible and progreive. Etablihed renal failure (alo called end tage renal failure) i CKD that ha progreed o far that renal replacement therapy (regular dialyi treatment or kidney tranplantation) i needed to maintain life. Etablihed renal failure i an irreverible, long-term condition. A mall number of people with etablihed renal failure may chooe conervative management only. Conventionally the total number of people receiving renal replacement therapy ha been taken a a proxy meaure for the prevalence of etablihed renal failure. The NSF for Renal Service etimate that more than 27,000 people received renal replacement therapy in England in Approximately one-half of thee had a functioning tranplant and the remainder were on dialyi. It i predicted that number will rie to around 45,000 over the next 10 year. However, the mot recent Renal Regitry Report (2003) tate that 32,500 patient received renal replacement therapy with 46% having a renal tranplant. The UK Renal Regitry Report (2003) highlight that 43% of patient newly receiving dialyi had a haemoglobin level of <10 g/dl in Thi i depite the fact that patient receiving dialyi treatment during 2002 had haemoglobin concentration that continued to improve. 135

137 Anaemia management in chronic kidney dieae The Regitry demontrated that 82% of haemodialyi patient and 88% of peritoneal dialyi patient had a haemoglobin concentration >10 g/dl. The clinical need for the guideline i upported by the wide variation in practice and lack of agreement on the optimal management of renal anaemia. The UK Renal Regitry Report (2003) draw attention to the fact that it wa not poible to provide accurate information about erythropoietin becaue of variation in the recording of erythropoietin data and alo the proviion of erythropoietin from primary care in ome part of the UK. An evidence-baed guideline hould improve the tandard of care acro renal unit and aid appropriate commiioning of cot-effective treatment. The guideline The guideline development proce i decribed in detail in two publication which are available from the NICE webite (ee further information below). Guideline development proce an overview for takeholder, the public and the NHS decribe how organiation can become involved in the development of a guideline. The Guideline development method information for national collaborating centre and guideline developer provide advice on the technical apect of guideline development. Thi document i the cope. It define exactly what thi guideline will (and will not) examine, and what the guideline developer will conider. The cope i baed on the referral from the Department of Health and Welh Aembly Government (ee below). The area that will be addreed by the guideline are decribed in the following ection. Population Group that will be covered (a) The guideline will offer bet practice advice on the care of people who have a clinical diagnoi of anaemia aociated with CKD. (b) The guideline will encompa the care of people with predialyi CKD, people with etablihed renal failure receiving renal replacement therapy, people with etablihed renal failure receiving conervative management, and people after renal tranplant urgery. (c) The guideline will cover children (aged <16 year). Group that will not be covered Where CKD i not the principal caue of the anaemia it will be excluded, for example: anaemia caued by haematological dieae anaemia caued by acute and chronic inflammatory dieae tate anaemia caued by malignancy anaemia caued by acquired immunodeficiency yndrome anaemia caued by acute renal failure. 136

138 Appendix B: Scope Healthcare etting The guideline will cover the care provided by healthcare profeional in direct contact with patient with anaemia aociated with CKD and make deciion about their care. Thi will include healthcare profeional in primary, econdary and tertiary NHS care etting. Clinical management The guideline will include recommendation in the following area. (a) Detection and diagnoi of anaemia in people with CKD: excluion of other caue of anaemia diagnotic evaluation of anaemia in CKD aement of anaemia. (b) Criteria for the threhold level of haemoglobin concentration for initiating the treatment of anaemia. (c) Factor which have an impact on anaemia in renal dieae and their management including: nutritional tatu including haematinic dialyi adequacy (peritoneal and haemodialyi) hyperparathyroidim aement and optimiation of erythropoiei to include iron tore, iron upplement and erythropoiei timulating agent monitoring of treatment of anaemia aociated with people with CKD. Guideline recommendation will normally fall within licened indication; exceptionally, and only where clearly upported by evidence, ue outide a licened indication may be recommended. The guideline will aume that precriber will ue the Summary of product characteritic to inform their deciion for individual patient. Statu Scope Thi i the final verion of the cope. Guideline The development of the guideline recommendation will begin in October Further information Information on the guideline development proce i provided in: Guideline development proce an overview for takeholder, the public and the NHS Guideline development method information for national collaborating centre and guideline developer Thee booklet are available a PDF file from the NICE webite ( Information on the progre of the guideline will alo be available from the webite. 137

139 Anaemia management in chronic kidney dieae Referral from the Department of Health and Welh Aembly Government The Department of Health and Welh Aembly Government aked the Intitute: To develop a guideline for the NHS in England and Wale for the management of anaemia in people with poor renal function, including chronic kidney dieae and etablihed renal failure, baed on evidence of clinical and cot effectivene of intervention available for treating anaemia in uch people. The intervention hould be all thoe factor that have an impact on anaemia including nutritional tatu, dialyi effectivene, iron tore and the ue of recombinant human erythropoietin. The purpoe of the guideline will be to take renal taff and patient through the mot cot-effective et of invetigation and procedure which will optimie haemoglobin and if poible keep it above the accepted international tandard, for example European and K-DOQI of 11 g/dl. 138

140 Appendix C: Health economic model: target haemoglobin in haemodialyi patient Background The treatment of anaemia in CKD help increae the health-related quality of life of patient. However, the optimal haemoglobin target continue to be debated. While there i an economic evaluation on the cot effectivene of different target baed on US data, the lack of coteffectivene data in the UK warranted further invetigation. Aim The aim of the model i to compare three alternative haemoglobin (Hb) target in the anaemia management of haemodialyi patient over a 2-year period. The haemoglobin target evaluated were: <11 g/dl, g/dl and >12 g/dl. The cot per quality-adjuted life year gained wa calculated. Method A cot-effectivene model wa contructed from the perpective of the NHS. The effectivene outcome meaure ued wa quality-adjuted life year (QALY) and the incremental cot per QALY wa calculated. Point etimate are derived from probabilitic reult. Incremental cot per QALY = (C 1 C 2 ) / (Q 1 Q 2 ) Where: C 1 = Etimated cot of anaemia treatment to reach Hb target C 2 = Etimated cot of anaemia treatment to reach higher Hb target Q 1 = Etimated quality-adjuted life year from Hb target Q 2 = Etimated quality-adjuted life year from higher Hb target The data ource of the cot and benefit are decribed in further detail in Table C.1 C.4. All cot and benefit were dicounted at an annual rate of 3.5% in accordance with current NICE recommendation in their Guideline development method Cot and benefit were accrued monthly over the 2-year period. A 1-month cycle wa choen a blood tet are routinely taken monthly in haemodialyi patient. A 2-year time horizon wa choen a it wa conidered a clinically relevant time period of treatment conidering tranplantation rate and urvival on dialyi. The g/dl haemoglobin target wa elected baed on the GDG interpretation of the clinical data. Thi alternative wa compared with below 11 g/dl and above 12 g/dl to ae the cot effectivene of thee alternative trategie. All cot are in pound terling with bae-year One-way enitivity analyi and a cot-effectivene acceptability curve were contructed to ae the impact of uncertainty on the incremental cot-effectivene ratio (ICER). Threhold analye were performed to invetigate the value of the utility of Hb target g/dl for which the ICER become 30,

141 Anaemia management in chronic kidney dieae Data ource and aumption Table C.1 C.4 lit the baeline cot and effectivene outcome along with the ource of data. Aumption and method of calculating etimate are decribed in further detail below. Table C.1 Doe of ESA for each Hb target range Model target Hb Hb target in ource (g/dl) tudy (g/dl) Type of ESA IU/wk Source < Epoetin-alfa 10, (SD 7,236, n=18) >11.0 Epoetin-alfa/beta 10,831 (n=189)* 294.c. and i.v. > Epoetin-alfa 236 (U/kg/wk) 295.c. (SD 148, n=157) 15,340** (Etimate) (SD 148.3, n=157) * No tandard deviation given in tudy. Aumed ame %SD of IU/wk a <11. (67.8%, etimated SD 7,344). ** Auming kg average weight. Mean epoetin value in Table C.1 were derived from RCT data where poible and elected baed on the target haemoglobin in the tudie being the cloet to <11, and >12 g/dl. The cot of epoetin wa calculated uing a unit cot of 7.96 for 1,000 unit of epoetin alfa and pre-filled yringe from the Britih national formulary (BNF) 49. Table C.2 Calculation per month IU/month of ESA Cot per month ( ) 46, , , Table C.3 All-caue mortality 46 RR (adjuted) per month Death/1,000 Death/1,000 cycle: (mortality rate, tandard treatment-yr Hb (g/dl) treatment-yr (adjuted)* error) (unadjuted) < (.021,.0045) (.016,.0040) > (.016,.0040) *Calculated uing unadjuted rate and RR. 140

142 Appendix C: Health economic model Table C.4 Utility core Model target Hb target in ource Meaurement Hb (g/dl) tudy (g/dl) Value technique n Source < Time trade off ( ) (etimate)* > Time trade off ( ) * Etimated the utility core of the Hb target g/dl a the midpoint between the value for target Hb<11 and Hb>12. (.545). Note: no tandard deviation given in tudy. Standard error of.02 (~10%SD) for each utility value. Explanation of aumption and data ued Cot Only cot pecific to anaemia treatment rather than haemodialyi care and thoe that are different between the treatment trategie were included. Hb target <11 g/dl The monthly cot of reaching the Hb target wa derived from the mean doe of ESA per week ued in a randomied open-label trial comparing target Hb of g/dl and g/dl in 35 dialyi patient 293 and the unit cot of epoetin alfa in a pre-filled yringe. The total cot of care per patient wa conidered table for the 2-year period. Hb target g/dl The monthly cot of Hb target g/dl wa derived from the mean epoetin doe from the Reult of the European Survey on Anaemia Management in 2003 (ESAM) 294 baed on 189 haemodialyi, haemofiltration and haemofiltration patient in the UK and the unit cot of epoetin alfa in a pre-filled yringe. Hb target >12 g/dl The monthly cot of Hb target >12 g/dl wa derived from the mean U/kg/week of epoetin from a randomied controlled trial of 157 haemodialyi patient treated to a target Hb range of g/dl and the unit cot of epoetin alfa in a pre-filled yringe. It wa aumed an average patient would be kg in order to calculate the mean unit/week. Other cot driver that were aumed to be the ame regardle of the Hb target range were: conultation time and type of health profeional reponible for anaemia management iron trategy haemodialyi treatment (conidered part of tandard care). 141

143 Anaemia management in chronic kidney dieae Quality-adjuted life year Hb target <11 g/dl, Hb target >12 g/dl The quality of life in Hb target <11 g/dl and Hb target >12 g/dl were derived from a randomied tudy comparing placebo, g/dl and g/dl achieved Hb range in 118 haemodialyi. The reult from the time trade off technique were ued a the QALY weight in the etimation of QALY. Although thee were achieved Hb range, it wa aumed that a target of >12 g/dl or <11 g/dl would have achieved haemoglobin level imilar to thee range. Total QALY gain in each month cycle wa added with a 3.5% annual dicount rate. Hb target g/dl The quality of life in target Hb g/dl wa etimated a the midpoint between the value for target Hb <11 and Hb >12. (.545) Thi method of etimation wa choen on the following reaoning from the clinical evidence: In quality of life tudie > 6 month in duration there i tatitically ignificant quality of life improvement in certain dimenion uch a phyical functioning. There i ignificant improvement between and g/dl, and 14 g/dl 207 and 10.2 and 12.5 g/dl. 49 There i improvement (but not ignificant) between and Thi ugget that the quality of life between 11 and 12 i probably not the ame a >12, and probably i lightly le than it i in Hb >12 and more than <11, uggeting a linear etimation i reaonable. Additional aumption There i no increaed rik of acce failure or hypertenion with higher haemoglobin target. Concordance. Rate of tranplantation i equivalent in each treatment trategy. Dialyi adequacy i equivalent in each treatment trategy. Mean epoetin doe remain repreentative of cot over a 2-year period. There i no difference in hopitaliation rate with different haemoglobin target. Obervational tudie ugget a difference in the number of hopitaliation and reduction in duration of tay, 46,49 however, it i very poible thee value were not adjuted ufficiently for confounder. Two RCT 207,295 and the meta-analyi 202 indicate there i no ignificant difference in rate and day of hopitaliation. Therefore, the rate of hopitaliation wa not ued in the model to differentiate between Hb target. Mortality rate The mortality rate ued in the model were derived from the adjuted relative rik of death and all-caue mortality rate in patient in an obervational tudy of 66,761 patient. 46 The GDG felt the evidence on mortality in the meta-analyi 202 may be more biaed by the weight given to one tudy on patient with cardiovacular dieae 207 than the obervational tudy. 142

144 Appendix C: Health economic model Reult Table C.5 Probabilitic model reult: 2-year time horizon Hb range (g/dl) Cot ( ) QALY <11 7, , >12 10, Table C.6 Probabilitic incremental reult of baeline value Hb range (g/dl) Incremental cot ( ) Incremental QALY ICER ( per QALY) v < ,985 >12 v , ,458 Note: difference due to rounding. Senitivity analyi The etimate ued in the model are ubject to uncertainty. Therefore, a one-way enitivity analyi wa carried out to ae the impact of key variable ued in the model. A one-way enitivity analyi varie one parameter while maintaining the other parameter at baeline value. The variable included reflect the mortality rate, cot, utilitie and hopitaliation rate ued in the determinitic model. Reult for the upper and lower etimate are given in Table C.7 and C.8. Table C.7 One-way enitivity analyi Baeline Range ICER range etimate Variable value evaluated Hb comparion (dominant trategy) RR death v <11 4,369 Hb < ,999 RR death >12 v ,906 Hb > ,224 Cot per month v <11 55,808 cycle Hb <11 ( ) Hb11 12 Cot per month v <11 Hb11 12 cycle Hb ( ) ,007 >12 v ,557 Hb>12 Cot per month >12 v ,026 cycle Hb >12 ( ) ,617 continued 143

145 Anaemia management in chronic kidney dieae Table C.7 One-way enitivity analyi continued Baeline Range ICER range etimate Variable value evaluated Hb comparion (dominant trategy) Utility Hb < v <11 2, ,632 Utility Hb v <11 61, ,454 >12 v ,856 Hb11 12 Utility Hb> >12 v Hb ,018 Table C.8 Senitivity analyi of hopitaliation rik and cot Baeline Etimate Obervational Study Cot of (No difference) Etimate hopitaliation ( ) RR of hopitaliation ,190 Hb <11 RR of hopitaliation Hb RR of hopitaliation Hb >12 ICER Hb11 12 v Hb<11 4,719 1,444 ICER 54,822 41,481 Hb>12 v Hb11 12 ICER Hb11 12 v Hb<11 3, (lower etimate) ICER 46,750 Hb>12 v Hb11 12 ICER Hb11 12 v Hb< ,983 (upper etimate) ICER 38,333 Hb>12 v Hb11 12 The extent of uncertainty in the probabilitic model i diplayed in Figure C.1. Figure C.2 ummarie into probabilitie the uncertainty that an alternative i cot effective for a range of willingne-to-pay threhold. 144

146 Appendix C: Health economic model 6,000 Hb g/dl Hb >12 g/dl 4,000 Incremental cot ( ) 2, ,000 4,000 6,000 Incremental QALY Figure C.1 Probabilitic enitivity analyi reult: incremental cot-effectivene plane Probability cot-effective Hb >12 g/dl ,000 20,000 30,000 40,000 50,000 60,000 Willingne to pay Figure C.2 Cot-effectivene acceptability curve ( ) Hb 11 g/dl Hb g/dl Dicuion Point etimate ugget Hb target g/dl i the optimal trategy with a 20,000 30,000 threhold. Uncertainty wa aeed in the determinitic reult in a one-way and two-way enitivity analye (Table C.7 and C.8). At the upper etimate of the monthly cot of Hb ( ), target Hb i dominated by Hb >12: the total cot in Hb are higher than Hb >12 but reult in le QALY. While the upper etimate i a plauible etimate of Hb 11 12, it would mean the unlikely ituation, in the abence of hopitaliation cot aved, where the monthly cot to reach Hb >12 i le than the monthly cot to reach Hb ( ). At the lower etimate of Hb utility, the Hb v Hb<11 ICER increaed to 61,140 and the Hb >12 v Hb ICER increaed to 21,856. The lower etimate of Hb (0.49) i le than the baeline etimate of Hb <11 (0.51), contrary to clinical evidence. Rather than make an aumption about the utility of Hb target g/dl per month, if we allow the utility to vary, the value at which the ICER of g/dl v <11 g/dl target i 30,000 i Thi 145