NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE. Centre for Clinical Practice

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1 NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE Centre for Clinical Practice Review consultation document Review of Clinical Guideline (CG) CG 114: Anaemia management in Chronic Kidney Disease. Background information Guideline issue date: CG year review: CG (first review) 5 year rapid update: CG114 Feb 2011 (superseded CG39) 5 year review: CG114 Nov 2011 (second review) National Collaborating Centre: National Collaborating Centre for Chronic Conditions 1. Consideration of the evidence Literature search From a high-level randomised control trial (RCT) search, new evidence was identified related to the following clinical areas within the guideline: Management of anaemia o Nutritional supplements o Androgens o Patient centred care Assessment and optimisation of erythropoiesis o Benefits of treatment with erythropoiesis-stimulating agents (ESAs ) CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 1 of 41

2 o Comparison of ESAs o Early or deferred ESA therapy o ESA route of administration o ESA dose and frequency o Optimal Haemoglobin levels o Treating Iron deficiency- correction and maintenance Monitoring treatment of anaemia of CKD Through this stage of the process, a sufficient number of 78 studies relevant to the above clinical areas were identified from the high level RCT to allow an assessment for a proposed review decision and are summarised in table 1 below. From initial intelligence gathering, qualitative feedback from other NICE departments, the views expressed by the Guideline Development Group, as well as the high-level RCT search, an additional focused literature search was also conducted for the following clinical area: The risk and benefits of correcting anaemia in patients with CKD and a malignancy. The results of the focused searches are also summarised in table 2 below. All references identified through the high-level RCT search, initial intelligence gathering and the focused search can be viewed in Appendix 1. CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 2 of 41

3 Table 1. Summary of articles from the high level RCT search Clinical area 1: Management of anaemia Clinical question Summary of evidence Relevance to guideline recommendations Related clinical questions from the guideline What is the benefit of vitamin C, vitamin E, folic acid, carnitine or glutathione supplementation in the treatment of anaemia due to chronic kidney disease? What is the benefit of androgens in the treatment of anaemia Through an assessment of the abstracts from the high level RCT search nine studies relevant to the clinical question were identified. Nutritional supplements Two systematic reviews and one RCT were identified. The systematic reviews concluded that although the studies in this area are limited by small numbers of subjects, short durations of follow-up, and variable quality, these results suggest that compared with standard care, ascorbic acid use may result in an increase in haemoglobin concentration and transferrin saturation and decrease in ESA requirements in haemodialysis patients 1, 2. One RCT in haemodialysis patients with refractory anaemia and hyperferritinemia found that vitamin C in comparison to standard care improved responsiveness to epoetin alfa, either by augmenting iron New evidence was identified which may change current guideline recommendations. CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 3 of 41

4 due to chronic kidney disease? What are the patient preferences and experiences when receiving ESAs for the treatment of ACKD? Relevant section of guideline 5.5, 5.7 Recommendations R15, R16, R21 mobilization from its tissue stores or through antioxidant effects 3. Androgens Three RCTS published just after the final evidence search for the original guideline in 2005 were identified 4,5,6. Two studies indicated that adjunctive androgen therapy did not show any clinical benefit whereas one RCT indicated some efficacy in a subgroup of male patients who were over 50 years old. Patient centred care Three studies 7,8,9, one in paediatric patients 7, were identified that had specifically addressed the issue of injection site pain with regards to ESA treatment. All three RCTs found that subcutaneous epoetin-beta caused statistically significant less immediate pain sensation compared to subcutaneous darbepoetin-alpha. CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 4 of 41

5 Summary The guideline recommends that supplements of vitamin C should not be prescribed as adjutants specifically for the treatment of anaemia of CKD. There is limited new evidence that indicates that vitamin supplementation may be beneficial in this patient population. The use of androgens to treat anaemia in people CKD was not recommended in the guideline. Nandrolone decanoate is no longer used in clinical practice and concern over side effects had resulted in the treatment with this agent (as an adjunct to ESAs) being considered outdated despite some limited efficacy. The new evidence identified supported the current recommendations. The guideline recommends that when prescribing ESA therapy patient preferences including pain on injection should be taken into account. Clinical area 2: Assessment and optimisation of erythropoiesis Clinical question Summary of evidence Relevance to guideline CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 5 of 41

6 Related clinical Through an assessment of the abstracts from the high level RCT search questions from the 68 studies relevant to the clinical question were identified. guideline In patients with ACKD The majority of studies identified focused on ESA therapy or iron what are the benefits supplementation. One limitation of research conducted within this field is and risks of correcting that it does not clearly state the population in the abstract (i.e. non-dialysis, anaemia with ESAs haemodialysis or peritoneal dialysis) and many earlier studies targeting compared to placebo or haemoglobin levels for therapy are now not currently thought to be optimal no treatment in reducing (rapid update of the haemoglobin target thresholds in 2011) due to safety morbidity and mortality concerns on the level of haemoglobin in this population. The abstracts are and improving quality of summarised below: life? In patients with ACKD Benefits of treatment with ESAs what are the benefits Five studies, two systematic reviews and three RCTs, were identified. One and risks of correcting systematic review and meta-analysis indicated that ESA treatment has a anaemia with epoetin consistent and positive impact on exercise tolerance and physical alfa compared to functioning in ACKD adult dialysis patients 10. The second systematic epoetin beta in reducing review indicated that ESAs for CKD anaemia improve energy and physical CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 6 of 41 recommendations New evidence was identified which may invalidate current guideline recommendations.

7 morbidity and mortality and improving quality of life? In patients with chronic kidney disease what are the risks and benefits of early vs deferred correction of anaemia? In patients with ACKD, what factors determine the route of administration of ESAs? In patients with ACKD, what factors (including patient factors) determine the dose and frequency of ESA required to correct anaemia? functioning in non dialysis patients 11. One placebo controlled RCT post hoc analysis reported that treating haemodialysis patients with epoetin alfa improved HRQOL 12. In addition one large RCT which assessed the effectiveness of darbepoetin alfa in comparison to placebo for patients with diabetes and ACKD not on dialysis was identified and analysed in two reports 13,14. The use of darbepoetin alfa conferred a small improvement in fatigue and overall quality of life but did not reduce the risk of either death or a cardiovascular event or death or a renal event but was associated with an increased risk of stroke. Comparison of ESAs Three ESAs (epoetin alfa, epoetin beta, darbepoetin alfa) were assessed and compared, where evidence permitted, in the original guideline. 14 studies relating to newer agents which have been licensed since the 2006 guideline was published have been identified. This includes; Methoxy polyethylene glycol-epoetin beta. Six active comparator RCTS were identified assessing the long-acting erythropoietin CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 7 of 41

8 What haemoglobin range should be maintained during anaemia treatment in CKD? What is the most effective and safest dose, frequency, preparation and route of administration of iron in ACKD patients with functional iron deficiency prior to ESA treatment? What is the most effective and safest dose, frequency, preparation and route of receptor activator methoxy polyethylene glycol-epoetin beta (C.E.R.A). Fortnightly subcutaneous C.E.R.A was found to be as effective as darbepoetin alfa in patients not on dialysis 15. For the same population of patients that had responded to fortnightly subcutaneous C.E.R.A. treatment every four weeks was also found to be effective and safe in maintaining stable haemoglobin levels 16. Once monthly C.E.R.A. treatment was found to be more effective maintaining stable haemoglobin levels than darbepoetin alfa every two weeks in haemodialysis patients 17. C.E.R.A has also been assessed in three Phase III studies against epoetin for correcting anaemia in CKD in dialysis patients either every two weeks 18,19,20 or once a month 20. In addition a pooled analysis of all completed phase II and III for patients either on dialysis or not on dialysis indicated that CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 8 of 41

9 administration of iron in ACKD patients with functional iron deficiency receiving ESA treatment? Relevant section of guideline 6.1, 6.3, 6.4, 6.7, 6.8, 6.9, 6.11, 6.12, 6.13 Recommendations R24, R27, R30, R31, R32, R41, R42, R43 C.E.R.A. has a comparable safety profile to other ESAs 21. Recombinant human erythropoietin (type not stated). Two RCTs were identified that have assessed the efficacy of recombinant human erythropoietin (r-huepo) in comparison to darbepoetin alfa 22,23. Darbepoetin alfa was found to be non-inferior to r-huepo in a paediatric population 22 and both agents maintained haemoglobin levels within the target range in peritoneal dialysis patients 23. Epoetin zeta. Epoetin zeta was found to have equivalent efficacy to epoetin alfa when administered either subcutaneously 24 or intravenously 25. In addition, post hoc analysis of three studies indicates that epoetin zeta and epoetin alfa therapy are interchangeable with no clinical alteration with regards to efficacy, safety or dose in patients on dialysis 26. Epoetin theta. One RCT in haemodialysis patients indicated that CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 9 of 41

10 intravenous epoetin theta had a similar efficacy compared to epoetin beta in haemodialysis patients based on haemoglobin changes from baseline to end of treatment (non-inferiority). The safety profile was similar in both groups 27. HX575. One RCT for HX575 (human recombinant epoetin alfa) the first biosimilar ESA with marketing authorization in Europe demonstrated therapeutic equivalence and a comparable safety profile to epoetin-a, together with a comparable safety profile in anaemia CKD patients on haemodialysis following 28. Two RCTsthat have directly compared agents addressed in the guideline were identified. One RCT was identified that compared intravenous epoetin alpha and subcutaneous epoetin beta. These agents showed an equivalent degree of efficacy in renal anaemia treatment of haemodialysis patients. The route of erythropoietin administration did not significantly affect the level of haemoglobin 29. A further RCT comparing epoetin alfa and darbepoetin alfa showed equivalent efficacy with regard to left ventricular parameters 30. CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 10 of 41

11 In addition studies relating to the following unlicensed agents have also been identified: Epoetin omega. One RCT found that subcutaneous epoetin omega provides greater bioavailability and anti-anaemic effect per administered dose than epoetin alpha in haemodialysis patients 31. Epoetin delta. Two RCTs have shown that epoetin delta has equivalent efficacy to epoetin alfa in dialysis patients with anaemia. This agent has since been withdrawn by the manufacturers 32,33. Early or late therapy One RCT assessed the efficacy of subcutaneous epoetin-alpha administered in early anaemia compared to in late anaemia in pre-dialysis CKD patients 34. The study was prematurely terminated due to contraindication of the subcutaneous administration route. However, the authors concluded that the early intervention to correct anaemia in CKD patients did not have a significant impact on left ventricular mass and time to dialysis/death was not significantly different between the treatment CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 11 of 41

12 groups. ESAs: optimal route of administration Four RCTs were identified that have examined the route of ESA administration 35,36,37,38. As the review process only considers abstracts it is not possible to determine if these studies met the inclusion criteria detailed in the guideline. Three RCTs compared intravenous to subcutaneous administration of darbepoetin alfa. Two RCTS showed equivalent efficacy and no significant difference in required doses for either route of administration for maintenance of a stable haemoglobin level in haemodialysis patients 35,36. Whereas, one RCT indicated that lower doses during intravenous treatment with darbepoetin alfa were needed in comparison to the subcutaneous route 37. A further RCT assessed the effect of route of administration of erythropoietin on vascular access outcomes in haemodialysis patients 38. The risk of vascular access failure was found to be greater with subcutaneous compared with intravenous administration of EPO two to three times weekly, however efficacy and dosage was not affected by route of administration. CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 12 of 41

13 ESAs: dose and frequency One meta-analysis evaluated the potential dose savings when comparing epoetin alfa or beta to darbepoetin alfa when using an initial 200:1 conversion ratio, as indicated on the European label 39. The overall percentage dose savings attained when dialysis patients were converted from epoetin to darbepoetin alfa was 30 with greater dose savings noted with i.v. administration compared with subcutaneous. In addition, one RCT on haemodialysis patients evaluated erythropoietin doses on the basis of the computer recommendations or using standard anaemia management protocol. The Model predictive resulted in better anaemia management with fewer patients not maintaining target haemoglobin levels 40. C.E.R.A. Five RCTs assessing dose and/or frequency of the long lasting C.E.R.A. treatment were identified 41,42,43,44,45. o Three Phase II studies were identified, one concluded that 0.60 u/kg subcutaneous C.E.R.A. given twice monthly is a suitable starting dose for patients not on dialysis 41. Whereas two studies CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 13 of 41

14 study indicated that subcutaneous C.E.R.A. or intravenous C.E.R.A. at up to once monthly intervals provides stable maintenance of Hb levels in dialysis patients 44, 45. o A Phase III study found that intravenous C.E.R.A. administered once every two weeks (Q2W) for Hb maintenance following direct conversion from darbepoetin alfa (DA) was safe and effective in dialysis patients 42. A further study reported that C.E.R.A. was effective in maintaining Haemoglobin concentrations in patients receiving dialysis treatment at weekly or Q2W 43. Epoetin alfa. Two RCTs in stage 3 and 4 CKD patients with CKD anaemia were identified. o One showed that administration of epoetin alfa at weekly and biweekly intervals are potential alternatives to twice weekly dosing 46.The second study showed that Q2W and Q4W dosing with epoetin alfa maintained haemoglobin levels and were non inferior to weekly dosing schedules 47. o Four RCTs in haemodialysis CKD patients were identified. One study demonstrates that once-weekly subcutaneous CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 14 of 41

15 administration of high dose epoetin alfa was as effective and safe as two or three times weekly administration in maintaining haemoglobin levels 48. A second dosing and scheduling study indicated that epoetin alfa can be initiated Q4W in anaemic CKD subjects 49. Likewise a third RCT found that the mean final haemoglobin levels of the Q2W and Q4W groups were statistically non-inferior to the weekly dosing 50. A post hoc analysis from this RCT demonstrated that patients with diabetes responded in a similar manner as patients without diabetes to extended dosing of epoetin alfa up to Q4W with and without diabetes as the primary cause of chronic kidney disease 51. One RCT did not show therapeutic equivalence of once-weekly intravenous epoetin alfa with conventional dosing regimens in haemodialysis patients 52. Darbepoetin alfa. One RCT found that administration of darbepoetin alfa biweekly could maintain haemoglobin level similarly to that obtained with weekly dosing in haemodialysis patients 53. CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 15 of 41

16 Epoetin beta. One RCT showed that biweekly and once-weekly subcutaneous epoetin beta regimens were equivalent in the maintenance phase of anaemia treatment in long-term stable haemodialysis patients without diabetes 54. Optimal haemoglobin levels Since the systematic review undertaken for the 2011 rapid update two studies were identified that related to the optimal haemoglobin levels. The first was a health economic cost-utility analysis to determine the costeffectiveness of treating anaemic patients with chronic kidney disease (CKD) with ESAs to a low ( g/dl), intermediate (11-12 g/dl), or high (> 12 g/dl) haemoglobin level target compared with a strategy of managing anaemia without ESAs 55. This analysis based on a publicly funded health care system indicated that using ESAs to target high haemoglobin levels has additional costs and worst clinical outcomes compared with using ESAs to target lower haemoglobin levels. The second study was a RCT which assessed the correction of anaemia in type 2 diabetes patients with CKD stages 3-4 to a target haemoglobin CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 16 of 41

17 value in the subnormal range ( g/l,) or normal range ( g/l) 56. Blood pressure, 24-h proteinuria and egfr did not differ significantly during two year follow-up. There was no significant difference regarding Medical Outcomes Study 36-item Short-Form Health Survey score change or adverse event occurrence. Treating iron deficiency 24 studies were retrieved that have investigated treating iron deficiency in CKD anaemia. From the abstracts the population studied was not always clearly defined in terms of dialysis status. A systematic review and meta-analysis concluded that compared with oral iron, there was a significantly greater haemoglobin level in dialysis patients treated with i.v. (intravenous) iron however for patients with CKD, and the effect was small. Data for all-cause mortality were sparse, and there was no difference in adverse events between the i.v. and oral-treated patients. 57 Haemodialysis patients. Eleven studies assessing iron supplementation in patients with anaemia and CKD on dialysis CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 17 of 41

18 (haemodialysis or peritoneal) were identified. The following active comparator trials were identified: o In anaemic patients with CKD stage 5D on haemodialysis on ESA, rapid i.v. injection of ferumoxytol showed superior efficacy to oral iron at increasing haemoglobin levels with comparable tolerability 58. o Iron sucrose and Fe chloride were found to be safe and work equally well for haemodialysis patients in one RCT 59. o One RCT found both iron saccharate complex and sodium ferric gluconate complex effective and safe for adequate repletion of iron stores 60. o I.v. iron sucrose was more effective that oral iron at increasing haemoglobin levels and serum iron parameters. It was well tolerated and permitted reductions in the required dose of erythropoietin peritoneal dialysis 61. o I.v. iron sucrose was found to be safe and more effective than oral iron gluconate at increasing serum iron serum ferritin, and transferrin saturation in paediatric replete patients on CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 18 of 41

19 haemodialysis 62. o One RCT found investigating potential side effects of iron supplementation indicated that that the incidence of side effects associated with i.v. iron-dextran was not different than that of i.v. iron-sucrose in end stage renal disease 63. o I.v. iron sucrose was well tolerated and more effective at increasing serum iron parameters and haemoglobin levels and allowed more reductions in the required dose of EPO in patients on haemodialysis than oral iron sucrose in one RCT 64. o One RCT indicated that oral iron (ferrous Fumarate) showed equivalent efficacy to i.v. iron at increasing haemoglobin, haematocrit and dry weight and reducing ESA dose requirement in anaemic patients using ultrapure dialysate 65. In addition the following three placebo controlled trials were identified: o I.v. iron sucrose was shown to have a vasodilatory effect, but did not impair vascular reactivity in peritoneal dialysis (PD) patients in one RCT 66. o I.v. iron sucrose was an effective adjunct to ESA therapy in CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 19 of 41

20 anaemic patients with PD-dependent CKD and was administered safely at 300 mg over 1.5 h or 400 mg over 2.5 h in one RCT 67. o Administration of intravenous ferric gluconate was superior to no iron therapy in anaemic dialysis patients receiving adequate ESA in one RCT 68. Non-dialysis (ND-CKD). Four studies in non-dialysis patient assessing iron supplementation in ND-CKD were identified: o One RCT compared i.v. sodium ferric gluconate complex with oral ferrous sulphate in anaemic, iron-deficient ND-CKD not receiving ESAs. 69 I.v. iron was more effective in increasing haemoglobin levels and caused greater improvements in quality of life, whereas oral iron achieved greater improvements in ferritin and TSAT. o One RCT found that i.v. ferric carboxymaltose was more effective and better tolerated than oral ferrous sulphate for treatment of iron deficiency in ND-CKD patients 70. CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 20 of 41

21 o I.V. iron sucrose administration was superior to oral ferrous sulphate therapy in the management of ND-CKD patients with anaemia in one RCT 71. o One RCT indicated that bimonthly i.v. iron sucrose and oral iron sulphate had equivalent effects on haemoglobin levels and were equally safe. The supplementation elevated iron indices but did not increase haemoglobin synthesis in the study population of ESA-naive, iron replete, non-dialysis patients with Hb >110 g/l CKD Stages CKD-not stated/mixed. Five studies were identified in a population that was stated as mixed or CKD. o Ferumoxytol (newly licensed agent) was assessed in three studies; One placebo controlled RCT found ferumoxytol to be well tolerated in anaemic patients CKD stages 1 to 5 and 5D and have a similar safely profile to placebo 73. A report from the FDA summarised three clinical trials. Two evaluated patients with ND- CKD and a third trial assessed patients undergoing CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 21 of 41

22 haemodialysis. All three clinical trials showed that ferumoxytol administration increased the mean blood haemoglobin concentrations in comparison to oral iron 74. A Phase III trial found that ferumoxytol was more effective than oral iron in increasing haemoglobin in patients were not receiving ESA and in those who were receiving ESAs 75. o One RCT assessed side effects of i.v. iron dextran, i.v. sodium ferric gluconate complex and i.v. iron sucrose. Iron dextran had comparable adverse drug events to sodium ferric gluconate complex but more adverse drug events than iron sucrose and drug discontinuation occurred more often with iron dextran 76 o One study examined differences in proteinuria between i.v. iron sucrose and i.v. ferric gluconate after multiple doses. Although multiple doses of either i.v. iron did not increase basal levels of proteinuria, post-dose proteinuria was greater with iron sucrose than with ferric gluconate 77. CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 22 of 41

23 Summary CG114 makes many recommendations relating to ESA therapy and iron supplementation. The recommendations that relate to the new evidence identified above are summarised below along with a brief summation of the new evidence. The guideline recommends that ESAs should be offered to people with ACKD who are likely to benefit in terms of quality of life and physical function. The majority of evidence supports this recommendation; however there is new evidence on a sub group of patients who may potentially be at increased risk of stroke due to ESA treatment. The guideline recommends that the choice of ESA should be discussed with the patient on initiation of treatment and at subsequent reviews. The patient s dialysis status, route of administration and availability should be considered. However at the time of the guidance there was no evidence to distinguish between ESAs in terms of efficacy. There is now new evidence relating to both new therapies and head to head comparisons of ESAs. However in terms of efficacy there is no evidence that would change CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 23 of 41

24 recommendations as the majority of studies report equivalent efficacy for these agents. The GDG were unable to make any recommendations relating to the Early or deferred ESA therapy due to a lack of evidence in the orginal guideline development process. The new evidence is unlikely to change the current guideline. The current recommendations state the prescriber and patient should agree the route of administration of ESA taking into account patient characteristics and preferences as well as drug costs. The frequency and dose of the ESA should determined by the duration and action and route of administration of the ESA. The guideline also states that for short-acting ESAs subcutaneous injection allows lower drug doses than intravenous injection. There is new evidence on the scheduling and dosing of ESAs to maintain target haemoglobin levels. There are also new ESAs available which are longer lasting agents. In addition, there is new and conflicting evidence CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 24 of 41

25 around the differing efficacy of the route of administration for longer lasting ESAs (frequency doses > weekly). Furthermore, there is evidence that contradicts the current recommendation for short acting ESAs and indicates an increased risk of vascular access failure with this recommendation. The guideline recommends that people with anaemia of CKD who are receiving ESAs should be given iron therapy, with patients with functional iron deficiency to be treated with i.v. iron. PD and ND-CKD who do not respond to oral iron will require i.v. iron. There are new agents and new evidence that assesses the relative efficacy and safety of iron supplementations that may alter guideline recommendations. Clinical area 3: Monitoring treatment of anaemia of CKD. Clinical question Summary of evidence Relevance to guideline recommendations Related clinical Through an assessment of the abstracts from the high level search one No new evidence was questions from the study relevant to the clinical question were identified. identified which would CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 25 of 41

26 guideline In patients with ACKD treated with ESAs, how frequently should iron status be checked? How should ESA resistance be managed? Relevant section of guideline 7.1, 7.2 A post hoc analysis of a study which investigated the impact of European Best Practice Guideline prompting on patient outcomes was identified 78. The availability of a computerised clinical decision support did not affect anaemia management compared to centres that had a non- computerised clinical decision support. However the study showed adherence to a European Best Practice Guideline improved attainment of anaemia indices. The guideline makes recommendations related to the frequency of monitoring patients with ACKD. The study supported monitoring patients. invalidate current guideline recommendations. Recommendations R46, R47 CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 26 of 41

27 Table 2. Summary of articles from the focused search Clinical area 1: Benefits of treatment with ESAs Clinical question Summary of evidence Relevance to guideline In patients with CKD and a malignancy what are the benefits and risks of correcting anaemia with ESAs? Relevant section of guideline 6.1, 7.3 Recommendations R24, R48 Through an assessment of the abstracts from the focus search one study relevant to the clinical question were identified. A large prospective observational study analyzed the factors that can modify the response to epoetin in patients on hemodialysis and its influence on early mortality over a follow-up of 12 months. The erythropoietin resistance index (the weekly weight-adjusted dose of EPO divided by the haemoglobin level) showed that patients with malignant neoplasm had significantly higher erythropoietin resistance index than those without. The resistance to ESA was directly related with incident co-morbidity and early mortality in these patients on hemodialysis 79. recommendations No new evidence was identified which would invalidate current guideline recommendations Whilst the guideline recommends that treatment with ESAs should be offered to people with anaemia of CKD who are likely to benefit in terms of CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 27 of 41

28 quality of life and physical function patients with anaemia, CKD and malignancy are not specifically addressed within the guideline. With regards to resistance to ESAs the guideline provides a clinical definition that excludes other causes of anaemia such as intercurrent illness or chronic blood loss. Very limited evidence (one study) was found for the sub group of patients with ACKD and malignancy and ESA treatment, however there is some indication that this group of patients may have differing clinical outcomes relating to ESA therapy. CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 28 of 41

29 Numerous recent or ongoing clinical trials (publication dates unknown) were identified focusing on ESA therapy (C.E.R.A (33 placebo trials and 19 active comparators trials registered), 11 trials on epoetin alfa, 5 trials on epoetin beta, 2 trials on epoetin delta, 3 trials on hematide (peginesatide), two trials on HX575 and 24 trials on darbepoetin alfa (23 placebo trials and 1 active comparator trial)). There were also 25 trials registered that were investigating iron supplements (ferumoxytol, ferrous sulphate, ferric carboxymaltose and iron sucrose). No evidence was identified that was relevant to research recommendations in the original guideline. Guideline Development Group and National Collaborating Centre perspective A questionnaire was distributed to GDG members and the National Collaborating Centre to consult them on the need for an update of the guideline. Seven responses were received with respondents highlighting that there is no variation in the practice of the recommendations. However, two respondents reported substantial modifications in practice relating to the new haemoglobin targets which were noted to have had improved clinical practice and changes relating to the ESA therapy and iron management. In addition, one respondent highlighted that since publication of the guideline more literature has become available on treatment response, variability in haemoglobin levels, ESA therapy and iron management. GDG members were also asked whether they were aware of evidence or practice which would demonstrate better value for money. A GDG member reported that the national contract for ESA therapy in Wales has allowed for cost savings for renal units only and one respondent stated that all ESAs had come off patent. However, whilst no audits of practice or implementation were CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 29 of 41

30 indicated as having been published since the guideline, the National Audit for Wales has been planned and the Renal Registry data for 2012 will be available in the New Year. With regard for potential to improve important health outcomes the GDG feedback indicated that cycling haemoglobin levels are of a clinical concern and that there is still some uncertainty on the impact of leaving lower haemoglobin in resistant anaemia patients. In addition, two anecdotal efficacy or safety concerns about the recommended practice that may not be reported in the literature were reported by GDG members. These related to uncertainty around the toxic levels of iron and the target haemoglobin levels in the very elderly. The potential for inequalities in access to services by patients who are pregnant or have intercurrent illness as well as age related inequalities were highlighted by two GDG members. The respondents were also asked if they were aware of any important or relevant areas not covered by the guideline; the classification and definition of kidney disease and ESA therapy for CKD patients with a malignancy were indicated. This feedback contributed towards the development of the clinical questions for the focused searches. The majority of respondents felt that there is adequate evidence at this time to warrant an update of the current guideline. Implementation and post publication feedback In total 14 enquiries were received from post-publication feedback, most of which were routine. Information was obtained from the NHS Information Centre for health and social care from a sample of anonymised GPs patient records data using the IMS Disease Analyzer. There were low numbers of patients diagnosed with CKD and anaemia who had been prescribed an ESA or an ESA plus an iron CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 30 of 41

31 supplement in each of the 5 study years, (<1% in all years linked data and <2% not linked data). These numbers are very low and should be treated with caution as it may reflect poor recording by GPs. No new evidence was identified through post publication enquiries or implementation feedback that would indicate a need to update the guideline. Relationship to other NICE guidance The following NICE guidance is related to CG114: Guidance CG73: Chronic kidney disease National clinical guideline for early identification and management in adults and secondary care (2008) Review date Update review December 2011 TA142 Anaemia (cancertreatment induced) - erythropoietin (alpha and beta) and darbepoetin (2008) Related NICE guidance in progress Reviewed for update July 2011 To be updated Acute Kidney Injury August 2013 TA Kidney disease (anaemia, chronic) peginesatide Due to delays in licensing timetable this will be subject to scoping in 2013 Anti-discrimination and equalities considerations No evidence was identified to indicate that the guideline scope does not comply with anti-discrimination and equalities legislation. The original scope is inclusive of all adults and children who have a clinical diagnosis of anaemia CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 31 of 41

32 associated with CKD. This includes people with non-dialysis CKD, people with established renal failure receiving renal replacement therapy, people with established renal failure receiving conservative management, and people after renal transplant surgery. The following groups were specifically outside of the scope as CKD is not the principal cause of the anaemia: haematological disease, acute and chronic inflammatory disease states, malignancy, acquired immunodeficiency syndrome and acute renal failure. The guideline covers the diagnostic assessment, management and monitoring of anaemia in primary, secondary and tertiary NHS care settings. Conclusion From the evidence and intelligence identified through the process, it suggests that some areas of the guideline may need updating at this stage, particularly in relation to: Management of anaemia o Nutritional supplements Assessment and optimisation of erythropoiesis o Benefits of treatment with erythropoiesis-stimulating agents (ESAs ) o Comparison of ESAs o ESA route of administration o ESA dose and frequency o Treating Iron deficiency- correction and maintenance Wording and definitions relating to non-dialysis and classification of CKD stages are in line with CG73 CKD. Review recommendation The guideline should be considered for an update at this time. CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 32 of 41

33 Centre for Clinical Practice 14 th November 2011 CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 33 of 41

34 Appendix I 1. Deved V, Poyah P, James MT et al. (2009) Ascorbic acid for anemia management in hemodialysis patients: a systematic review and metaanalysis. [Review] [42 refs]. American Journal of Kidney Diseases 54: Einerson B, Nathorn C, Kitiyakara C et al. (2011) The efficacy ofascorbic acid in suboptimal responsive anemic hemodialysis patients receiving erythropoietin: a meta-analysis. Journal of the Medical Association of Thailand 94:Suppl Attallah N, Osman-Malik Y, Frinak S et al. (2006) Effect of intravenous ascorbic acid in hemodialysis patients with EPO-hyporesponsive anemia and hyperferritinemia. American Journal of Kidney Diseases 47: Sheashaa H, Abdel-Razek W, El-Husseini A et al. (2005) Use of nandrolone decanoate as an adjuvant for erythropoietin dose reduction in treating anemia in patients on hemodialysis. Nephron 99:c102-c Brockenbrough AT, Dittrich MO, Page ST et al. (2006) Transdermal androgen therapy to augment EPO in the treatment of anemia of chronic renal disease. American Journal of Kidney Diseases 47: Aggarwal HK, Sehgal R, Singh S et al. (2005) Evaluation of efficacy of low dose recombinant human erythropoietin in combination with androgen therapy in anaemia of chronic renal failure. Journal Indian Academy of Clinical Medicine 6: Schmitt CP, Nau B, Brummer C et al. (2006) Increased injection pain with darbepoetin-alpha compared to epoetin-beta in paediatric dialysis patients. Nephrology Dialysis Transplantation 21: Roger SD, Suranyi MG, Walker RG et al. (2008) A randomised, cross-over study comparing injection site pain with subcutaneous epoetin beta and subcutaneous darbepoetin alfa in patients with chronic kidney disease. Current Medical Research and Opinion 24: Ter Wee PM, de KY, van d, V et al. (2009) Immediate pain sensation is less with subcutaneous epoietin-beta compared to subcutaneous darbepoietinalpha. Clinical Nephrology 72: Johansen KL, Finkelstein FO, Revicki DA et al. (2010) Systematic review and meta-analysis of exercise tolerance and physical functioning in dialysis patients treated with erythropoiesis-stimulating agents. [Review] [70 refs]. American Journal of Kidney Diseases 55: CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 34 of 41

35 11. Gandra SR, Finkelstein FO, Bennett AV et al. (2010) Impact of erythropoiesis-stimulating agents on energy and physical function in nondialysis CKD patients with anemia: a systematic review. [Review] [44 refs]. American Journal of Kidney Diseases 55: Keown PA, Churchill DN, Poulin-Costello M et al. (2010) Dialysis patients treated with Epoetin alfa show improved anemia symptoms: A new analysis of the Canadian Erythropoietin Study Group trial. Hemodialysis International 14: Lewis EF, Pfeffer MA, Feng A et al. (2011) Darbepoetin Alfa impact on health status in diabetes patients with kidney disease: A randomized trial. Clinical Journal of the American Society of Nephrology 6: Pfeffer MA, Burdmann EA, Chen CY et al. ( ) A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. New England Journal of Medicine 361: Macdougall IC, Walker R, Provenzano R et al. (2008) C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. Clinical Journal of The American Society of Nephrology: CJASN 3: Kessler M, Martinez-Castelao A, Siamopoulos KC et al. (2010) C.E.R.A. once every 4 weeks in patients with chronic kidney disease not on dialysis: The ARCTOS extension study. Hemodialysis International 14: Carrera F, Lok CE, de FA et al. (2010) Maintenance treatment of renal anaemia in haemodialysis patients with methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa administered monthly: a randomized comparative trial. Nephrology Dialysis Transplantation 25: Spinowitz B, Coyne DW, Lok CE et al. (2008) C.E.R.A. maintains stable control of hemoglobin in patients with chronic kidney disease on dialysis when administered once every two weeks. American Journal of Nephrology 28: Klinger M, Arias M, Vargemezis V et al. (2007) Efficacy of intravenous methoxy polyethylene glycol-epoetin beta administered every 2 weeks compared with epoetin administered 3 times weekly in patients treated by hemodialysis or peritoneal dialysis: a randomized trial. American Journal of Kidney Diseases 50: Sulowicz W, Locatelli F, Ryckelynck JP et al. (2007) Once-monthly subcutaneous C.E.R.A. maintains stable hemoglobin control in patients with chronic kidney disease on dialysis and converted directly from epoetin one to three times weekly. Clinical Journal of The American Society of Nephrology: CJASN 2: CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 35 of 41

36 21. Locatelli F, Mann JF, Aldigier JC et al. (2010) C.E.R.A. safety profile: a pooled analysis in patients with chronic kidney disease. Clinical Nephrology 73: Warady BA, Arar MY, Lerner G et al. (2006) Darbepoetin alfa for the treatment of anemia in pediatric patients with chronic kidney disease. Pediatric Nephrology 21: Li WY, Chu TS, Huang JW et al. (2008) Randomized study of darbepoetin alfa and recombinant human erythropoietin for treatment of renal anemia in chronic renal failure patients receiving peritoneal dialysis. Journal of the Formosan Medical Association 107: Krivoshiev S, Wizemann V, Czekalski S et al. (2010) Therapeutic equivalence of epoetin zeta and alfa, administered subcutaneously, for maintenance treatment of renal anemia. Advances in Therapy 27: Krivoshiev S, Todorov VV, Manitius J et al. (2008) Comparison of the therapeutic effects of epoetin zeta and epoetin alpha in the correction of renal anaemia. Current Medical Research & Opinion 24: Wiecek A, Ahmed I, Scigalla P et al. (2010) Switching epoetin alfa and epoetin zeta in patients with renal anemia on dialysis: Posthoc analysis. Advances in Therapy 27: Gertz B, Kohler E, Kes P et al. (2010) Epoetin theta: Efficacy and safety of IV administration in anaemic haemodialysis patients in the maintenance phase in comparison to epoetin beta. Current Medical Research and Opinion 26: Haag-Weber M, Vetter A, Thyroff-Friesinger U et al. (2009) Therapeutic equivalence, long-term efficacy and safety of HX575 in the treatment of anemia in chronic renal failure patients receiving hemodialysis. Clinical Nephrology 72: Ostrvica E, Mesic E, Ostrvica D et al. (2010) Effectiveness of treating the renal anemia in chronic hemodialyzed patients by epoietin alpha and beta. Medicinski Arhiv 64: Chen HH, Tarng DC, Lee KF et al. (2008) Epoetin alfa and darbepoetin alfa: effects on ventricular hypertrophy in patients with chronic kidney disease. Journal of Nephrology 21: Milutinovic S, Plavljanic E, and Trkulja V. (2006) Comparison of two epoetin brands in anemic hemodialysis patients: results of two efficacy trials and a single-dose pharmacokinetic study. Fundamental & Clinical Pharmacology 20: CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 36 of 41

37 32. Spinowitz BS, Pratt RD, and Epoetin D. (2006) Epoetin delta is effective for the management of anaemia associated with chronic kidney disease. Current Medical Research & Opinion 22: Martin KJ. (2007) The first human cell line-derived erythropoietin, epoetindelta (Dynepo), in the management of anemia in patients with chronic kidney disease. Clinical Nephrology 68: Macdougall IC, Temple RM, and Kwan JT. (2007) Is early treatment of anaemia with epoetin-alpha beneficial to pre-dialysis chronic kidney disease patients? Results of a multicentre, open-label, prospective, randomized, comparative group trial. Nephrology Dialysis Transplantation 22: Bommer J, Asmus G, Wenning M et al. (2008) A comparison of haemoglobin levels and doses in haemodialysis patients treated with subcutaneous or intravenous darbepoetin alfa: a German prospective, randomized, multicentre study. Nephrology Dialysis Transplantation 23: Kim CD, Park SH, Kim DJ et al. (2009) Randomized trial to compare the dosage of darbepoetin alfa by administration route in haemodialysis patients. Nephrology 14: Aarup M, Bryndum J, Dieperink H et al. (2006) Clinical implications of converting stable haemodialysis patients from subcutaneous to intravenous administration of darbepoetin alfa. Nephrology Dialysis Transplantation 21: Lee Y-K, Koo J-R, Kim J-K et al. (2009) Effect of Route of EPO Administration on Hemodialysis Arteriovenous Vascular Access Failure: A Randomized Controlled Trial. American Journal of Kidney Diseases 53: Bonafont X, Bock A, Carter D et al. (2009) A meta-analysis of the relative doses of erythropoiesis-stimulating agents in patients undergoing dialysis. NDT Plus 2: Brier ME, Gaweda AE, Dailey A et al. (2010) Randomized trial of model predictive control for improved anemia management. Clinical Journal of The American Society of Nephrology: CJASN 5: Provenzano R, Besarab A, Macdougall IC et al. (2007) The continuous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis: results of a phase II study. Clinical Nephrology 67: Canaud B, Mingardi G, Braun J et al. (2008) Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 37 of 41

38 with darbepoetin alfa: results from STRIATA, a randomized phase III study. Nephrology Dialysis Transplantation 23: Besarab A, Salifu MO, Lunde NM et al. (2007) Efficacy and tolerability of intravenous continuous erythropoietin receptor activator: a 19-week, phase II, multicenter, randomized, open-label, dose-finding study with a 12-month extension phase in patients with chronic renal disease. Clinical Therapeutics 29: Locatelli F, Villa G, de Francisco AL et al. (2007) Effect of a continuous erythropoietin receptor activator (C.E.R.A.) on stable haemoglobin in patients with CKD on dialysis: once monthly administration. Current Medical Research & Opinion 23: Levin NW, Fishbane S, Canedo FV et al. ( ) Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA).[Erratum appears in Lancet Feb 2;371(9610):386]. Lancet 370: Pergola PE, Gartenberg G, Fu M et al. (2009) A randomized controlled study of weekly and biweekly dosing of epoetin alfa in CKD Patients with anemia. Clinical Journal of The American Society of Nephrology: CJASN 4: Pergola PE, Gartenberg G, Fu M et al. (2010) A randomized controlled study comparing once-weekly to every-2-week and every-4-week dosing of epoetin alfa in CKD patients with anemia. Clinical Journal of The American Society of Nephrology: CJASN 5: Lee YK, Kim SG, Seo JW et al. (2008) A comparison between onceweekly and twice- or thrice-weekly subcutaneous injection of epoetin alfa: results from a randomized controlled multicentre study. Nephrology Dialysis Transplantation 23: Spinowitz B, Germain M, Benz R et al. (2008) A randomized study of extended dosing regimens for initiation of epoetin alfa treatment for anemia of chronic kidney disease. Clinical Journal of The American Society of Nephrology: CJASN 3: Provenzano R, Bhaduri S, Singh AK et al. (2005) Extended epoetin alfa dosing as maintenance treatment for the anemia of chronic kidney disease: the PROMPT study. Clinical Nephrology 64: Provenzano R and Singh AK. (2007) Hemoglobin maintenance with use of extended dosing of epoetin alfa in patients with diabetes and anemia of chronic kidney disease. Endocrine Practice 13: CG 114: Anaemia management in CKD, review proposal consultation document 14 th Nov-28 th Nov 38 of 41