kdoqi clinical practice guideline and clinical practice recommendations for anemia in chronic

KDOQI CLINICAL PRACTICE GUIDELINE AND CLINICAL PRACTICE RECOMMENDATIONS FOR

ANEMIA IN CHRONIC KIDNEY DISEASE

2007 UPDATE OF HEMOGLOBIN TARGET

NOTICE

SECTION I USE OF THE CLINICAL PRACTICE GUIDELINE AND CLINICAL PRACTICE RECOMMENDATIONS

The Clinical Practice Guideline (CPG) and Clinical Practice Recommendations (CPRs) are designed to provide information and assist decision-making They are not intended to define a standard of care and should not be construed as one Neither should they be interpreted as prescribing an exclusive course of management

Variations in practice will inevitably and appropriately occur when clinicians take into account the needs of individual patients available resources and limitations unique to an institution or type of practice Every health-care professional making use of the CPG and CPRs is responsible for evaluating the appropriateness of applying them in the setting of any particular clinical situation

SECTION II CONFLICTS OF INTEREST DISCLOSURE

The National Kidney Foundation (NKF) makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal professional or business interest of a member of the Work Group

Specifically all members of the Work Group are required to complete sign and submit a Conflict of Interest Disclosure and Attestation form showing all such relationships that might be perceived as real or potential conflicts of interest All affiliations are published in their entirety at the end of this document in the Work Group membersrsquo biographical sketch and are on file at the NKF

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WORK GROUP MEMBERSHIP

Work Group Co-Chairs David B Van Wyck MD Kai-Uwe Eckardt MD

University of Arizona College of Medicine University of Erlangen-Nuremberg Tucson AZ Erlangen Germany

Work Group John W Adamson MD Patricia Bargo McCarley RN MSN NP Blood Center of SE Wisconsin Diablo Nephrology Medical Group Blood Research Institute Walnut Creek CA Milwaukee WI

Allen R Nissenson MD Jeffrey S Berns MD UCLA Medical Center University of Pennsylvania School of Medicine Los Angeles CA Philadelphia PA

Gregorio T Obrador MD Steven Fishbane MD Universidad Panamericana School of Medicine Winthrop University Hospital Mexico City Mexico Mineloa NY

John C Stivelman MD Robert N Foley MD Northwest Kidney Center Nephrology Analytical Services Seattle WA Minneapolis MN

Colin T White MD Sana Ghaddar RD PhD British Columbia Childrenrsquos Hospital American University of Beirut Vancouver Canada Faculty of Agriculture and Food Sciences Beirut Lebanon

John S Gill MD MS Liaison Members University of British Columbia Francesco Locatelli MD St Pauls Hospital Azienda Ospedaliera DI Lecco Vancouver Canada Lecco Italy

Kathy Jabs MD Iain C Macdougall MD Vanderbilt University Medical Center Kingrsquos College Hospital Nashville TN London England

Evidence Review Team

National Kidney Foundation Center for Guideline Development and Implementation at Tufts-New England Medical Center Boston MA

Katrin Uhlig MD MS Program Director Nephrology Joseph Lau MD Program Director Evidence Based Medicine

Amy Earley BS Research Assistant

3

KDOQItrade ADVISORY BOARD MEMBERS

Adeera Levin MD FACP KDOQItrade Chair

Michael Rocco MD MSCE

Garabed Eknoyan MD KDOQItrade Co-Chair Emeritus

Bryan Becker MD Peter G Blake MD FRCPC MBBCh Allan J Collins MD FACP Peter W Crooks MD William E Haley MD Bertrand L Jaber MD Cynda Ann Johnson MD MBA Karren King MSW ACSW LCSW Michael J Klag MD MPH Craig B Langman MD Derrick Latos MD Linda McCann RD LD CSR Ravindra L Mehta MD FACP Maureen Michael BSN MBA William Mitch MD

KDOQItrade Vice-Chair

Nathan Levin MD FACP KDOQItrade Co-Chair Emeritus

Gregorio Obrador MD MPH Rulan S Parekh MD MS Brian JG Pereira MD DM Neil R Powe MD Claudio Ronco MD Raymond Vanholder MD PhD Nanette Kass Wenger MD MACP David Wheeler MD MRCP Winfred W Williams Jr MD Shuin-Lin Yang MD

Ex-Officio Josephine Briggs MD David Warnock MD

NKF-KDOQItrade Guideline Development Staff

Kerry Willis PhD Donna Fingerhut Michael Cheung Dekeya Slaughter-Larkem

4

TABLE OF CONTENTS

Work Group Membershiphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 3KDOQItrade Advisory Board Membershelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 4List of Tables and Figureshelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 6Clinical Practice Recommendation 211helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 8Clinical Practice Recommendation 212helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 10Clinical Practice Guideline 213helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 12Appendix 1 Anemia Update Methodshelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 19Appendix 2 Comparison of FDA-Approved Prescribing Information for Epoetin Alfa and

KDOQI Anemia Guidelineshelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 27Referenceshelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 30Summary and Evidence Profile Tableshelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 33Work Group Membersrsquo Biographical and Disclosure Informationhelliphelliphelliphelliphelliphelliphelliphelliphellip 57

5

TABLES

Table 1 Ongoing Randomized Controlled Trials on Hemoglobin Targets in Adult Patients with CKD Identified from Clinicaltrialsgovhelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 33

Table 2 Summary Table of RCTs Comparing Different Hb TargetsESA Doses on Key Clinical Outcomes in the HD-CKD and PD-CKD Populationshelliphelliphelliphelliphelliphelliphelliphellip 34

Table 3 Summary Table of RCTs Comparing Different Hb TargetsESA Doses on Quality of Life in the HD-CKD and PD-CKD Populationshelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 36

Table 4 Summary Table of RCTs Comparing Hb TargetsESA Doses in Non-CVD Mortality Adverse Event Rates in the HD-CKD and PD-CKD Populationshelliphellip 39

Table 5 Summary Table of RCTs Comparing Hb TargetsESA Doses on Exercise Capacity in the HD-CKD and PD-CKD Populationshelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 42

Table 6 Evidence Matrix of Study Quality by Outcome for RCTs Comparing Different Hb TargetsESA Doses in the HD-CKD and PD-CKD Populationshelliphelliphelliphelliphelliphelliphelliphellip 43

Table 7 Evidence Profile of RCTs Comparing Different Hb TargetsESA Doses in the HDshyCKD and PD-CKD Populationshelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 44

Table 8 Summary Table of RCTs Comparing Different Hb TargetsESA Doses on Key Clinical Outcomes in the ND-CKD Populationhelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 47

Table 9 Summary Table of RCTs Comparing Different Hb TargetsESA Doses on Quality of Life in the ND-CKD Populationhelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 50

Table 10 Summary Table of RCTs Comparing Hb TargetsESA Doses in Non-CVDMortality Adverse Event Rates in the ND-CKD Populationhelliphelliphelliphelliphelliphelliphellip 52

Table 11 Evidence Matrix of Study Quality by Outcome for RCTs Comparing Different Hb TargetsESA Doses in the ND-CKD Populationhelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 54

Table 12 Evidence Profile of RCTs Comparing Different Hb TargetsESA Doses in the NDshy CKD Populationshelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 55

FIGURES

Figure 1 Randomized controlled trials comparing lower with higher Hb target levelshelliphelliphellip 11 Figure 2 Relative mortality risk for assignment to higher Hb treatment targets in patients

with non-dialysis CKD (Stages 1-5)helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 13 Figure 3 Relative risk of adverse cardiovascular events for assignment to higher Hb

treatment target in patients with non-dialysis CKD (Stage 1-5)helliphelliphelliphelliphelliphelliphelliphellip 13 Figure 4 Relative mortality risk for assignment to higher Hb treatment target in CKD

patients undergoing dialysishelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 14 Figure 5 Relative risk of adverse cardiovascular events for assignment to higher Hb

treatment target in CKD patients undergoing dialysishelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 14

6

1 CPG and CPR 21 HEMOGLOBIN TARGET

2

3 The Hb target is the intended aim of ESA therapy for the individual CKD patient In clinical 4 practice achieved Hb results vary considerably from the Hb target 5

6

7 211 In the opinion of the work group selection of the Hb target and selection of the Hb 8 level at which ESA therapy is initiated in the individual patient should include 9 consideration of potential benefits (including improvement in quality of life and

10 avoidance of transfusion) and potential harms (including the risk of life-threatening 11 adverse events) (Clinical Practice RECOMMENDATION) 12

13 212 In the opinion of the work group in dialysis and non-dialysis CKD patients receiving 14 ESA therapy the selected Hb target should generally be in the range of 110 to 120 15 gdL (Clinical Practice RECOMMENDATION) 16

17 213 In dialysis and non-dialysis CKD patients receiving ESA therapy the Hb target should 18 not be above 130 gdL (Clinical Practice GUIDELINE - MODERATELY STRONG 19 EVIDENCE)

20 Background 21 KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in 22 Chronic Kidney Disease published in May 2006 included recommendations for Hb targets that 23 were based on a systematic review and structured appraisal of Randomized Controlled Trials 24 (RCTs) comparing treatment to different Hb targets Following publication of these guidelines 25 five additional RCTs were published1-5 An additional small trial published in 2005 was 26 unintentionally not included in the evidence review6 The new studies expanded the evidence on 27 clinically important outcomes doubled the number of all CKD patients examined and increased 28 the number of ND-CKD patients studied in RCTs from 575 to 3432 In keeping with criteria for 29 updating a systematic review and guidelines prior to a scheduled revision the Work Group 30 undertook a reexamination of the available evidence on Hb treatment targets The re-examination 31 included both the new studies the study not included in the previous review and those appraised 32 previously 33

34 The resulting clinical practice recommendations (211 and 212) and clinical practice guideline 35 (213) are intended to assist the practitioner caring for patients in selecting Hb targets appropriate 36 for individual patients receiving or about to receive ESA therapy Recommended Hb targets apply 37 exclusively to patients receiving ESA Hb targets are not intended to apply to the treatment of iron 38 deficiency in patients receiving iron therapy without the use of ESA 39

40 Warnings indications precautions and instructions for dosing and administration of ESAs are 41 available from national regulatory agencies including the United States Food and Drug 42 Administration (FDA) and product package inserts7-9 The Work Group directed considerable 43 thought and attention in particular to the most recent FDA-approved prescribing information 44 Appendix 2 provides a detailed comparison of KDOQI CPGs and CPRs (May 2006 and update

7

45 2007) with FDA-approved prescribing information current as of 307 46

47 Ongoing and future trials in CKD patients are expected to provide more information on ESA use 48 and Hb targets including treatment with ESA as compared to placebo and higher compared to 49 lower Hb targets (Table 1)

50 Rationale 51 Selection of the Hb target and selection of the Hb level at which ESA therapy is initiated in 52 the individual patient should include consideration of potential benefits (including 53 improvement in quality of life and avoidance of transfusion) and potential harms (including 54 the risk of life-threatening adverse events) 55

56 The Work Group chose the wording order and placement of this statement to guide 57 practitioners in selecting a Hb target for ESA therapy and a Hb level at which ESA therapy is 58 initiated in the individual CKD patient with anemia The statement reflects the conclusion that 59 improvement in quality of life and avoidance of transfusion are the most likely treatment benefits 60 and that there is potential for harm when aiming for high Hb targets 61

62 The statement selection of the Hb target and selection of the Hb level at which ESA 63 therapy is initiated in the individual patient captures the conclusion of the Work Group that the 64 selection of the Hb target for ESA therapy and the selection of the Hb level at which ESA therapy 65 is initiated in the individual patient are separate but related steps in medical decision making for 66 the individual patient In available RCTs when the baseline Hb falls within at or below the 67 assigned Hb target treatment assignment and initiation of treatment have generally been 68 simultaneous 69

70 The statement should include consideration reflects the limitations of our current evidence 71 base which does not allow precise recommendations for each individual patient (see below 72 Limitations of Evidence) The statement also acknowledges that judgments about benefits 73 and harm may vary from patient to patient and for the same patient under different conditions 74 Limitations of the current evidence base differences in individual judgments and variable 75 responsiveness between patients argue for engaging the patient and for maintaining flexibility 76 when setting Hb targets for ESA therapy 77

78 Reference to quality of life benefit reflects the appraisal that when selecting the Hb target an 79 improvement in quality of life should be an expected treatment benefit Quality of life is an 80 outcome of direct importance to patients and should be valued accordingly10 Measurement of 81 health-related quality of life (HRQoL) is performed using standardized instruments that have been 82 validated in a range of target populations including patients with CKD requiring or not requiring 83 dialysis Results yielded by these instruments achieve levels of reliability and precision that are 84 comparable to those seen with other commonly-used clinical tests11 HRQoL has been examined 85 in several RCTs comparing lower and higher hemoglobin targets in CKD patients receiving ESA 86 for anemia Although it is difficult to aggregate HRQoL effects across studies because different 87 HRQoL instruments were used and some reports lack detail evidence supports the following 88 conclusions 89 bull There is potential benefit for HRQoL with most studies showing improvement of HRQoL 90 in patients assigned to higher Hb targets when compared to those assigned to lower Hb

8

91 targets Although there is inconsistency among studies all studies determined to be level A 92 in quality showed evidence of HRQoL benefit (Table 3 and Table 9) 93 bull The number and class of HRQoL domains showing benefit in the higher Hb treatment 94 group varies by instrument and by report 95 bull Several studies reported robust HRQoL benefits spanning multiple domains with general 96 (SF-36)1 and disease-specific (KDQ)1213 instruments 97 bull Higher Hb targets lead to improvements in both physical114 and mental health 98 domains11213

99 bull The improvement in HRQoL with higher Hb targets has been seen in the earliest 100 assessment performed even in studies where treatment assignment was masked to 101 participating patients1315

102 bull HRQoL scores deteriorate over time in dialysis patients15

103 bull HRQoL benefits of higher Hb targets diminish over time115

104 bull However HRQoL effects have been seen in some domains to persist for at least 2 years1

105 bull Over the range of Hb targets tested there is no apparent Hb threshold above which there 106 definitely is or is not any quality of life improvement in the higher Hb treatment arms 107 (Table 3 and Table 9) 108

109 Reference to avoidance of transfusions reflects the appraisal that higher compared to lower Hb 110 targets are associated with a reduction in red blood cell transfusion rates in hemodialysis patients 111 (Table 2) Assignment to Hb targets above 13 gdL reduces but does not eliminate transfusions in 112 hemodialysis patients14 Transfusion-related risks are discussed in detail elsewhere (KDOQI 113 Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic 114 Kidney Disease CPR 34 AJKD 47(5) Suppl 4S79-S80 2006) 115

116 Potential harms refers to evidence from RCTs suggesting that assignment to Hb targets gt 130 117 gdL may increase risk of life-threatening adverse events This evidence is discussed in detail in 118 the rationale to statement 213 119

120 The Work Group concluded that although there is some inconsistency in the evidence 121 assignment to higher compared to lower Hb treatment targets confers neither harm nor benefit in 122 preserving renal function in patients with anemia and ND-CKD (Table 8) 123

124 The distinction between Hb targets and achieved Hb levels is fundamental to the 125 development of this guideline In considering information available to guide selection of Hb 126 targets we specifically excluded evidence from Hb levels achieved in RCTs or reported in 127 observational studies Patients achieving higher Hb levels in RCTs within assigned treatment arms 128 (including arms with targets ge 13 gdL)14 longitudinal cohort studies16 and cross-sectional studies 129 of large medical databases1718 consistently show lower mortality less frequent hospitalization and 130 less severe LVH than their within-group counterparts achieving lower Hb levels By contrast 131 treating a patient to a higher compared to a lower hemoglobin target in RCTs (Table 2 and Table 132 8) has failed to demonstrate benefits in mortality cardiovascular events hospitalization or LVH 133 The apparent benefit of higher achieved Hb levels is explained by targeting bias described 134 previously for dialysis dose19 patients with a high disease burden are likely to suffer adverse 135 events and unlikely to achieve higher Hb whereas patients with a low disease burden are unlikely 136 to suffer adverse events but likely to achieve higher Hb This phenomenon is seen in patients

9

137 assigned to either lower or higher treatment targets and occurs regardless of the absolute target 138 level1214

139

140 The consensus opinion of the Work Group that HRQoL avoidance of transfusion and 141 potential harm must each be considered coupled with an absence of specific quantitative 142 information to assist the practitioner in weighing each component renders statement 211 a 143 clinical practice recommendation 144

145 Rationale 146 In dialysis and non-dialysis CKD patients receiving ESA therapy the selected Hb target 147 should generally be in the range of 110 to 120 gdL 148

149 Evidence supporting the statement that in dialysis and non-dialysis CKD patients receiving 150 ESA therapy the selected Hb target should generally be in the range of 110 to 120 gdL includes 151 results from 12 RCTs in dialysis patients and 15 RCTs in non-dialysis patients and is presented in 152 detail for each trial (Tables 2-5 Tables 8-10) and in summary for each outcome (Table 6 and 7 153 Table 11 and 12) 154

155 The evidence considered by the Work Group to support the statement is confined to results 156 of between-group comparisons generated by intention to treat trials that randomized patients to 157 distinct Hb targets including trials that used ESA in both treatment arms and trials that used ESA 158 in one treatment arm and either placebo or no treatment in the control arm (Figure 1) 159

160 The practitioner approaches the decision to select a Hb treatment goal with the intent to 161 treat the individual patient and should expect that the achieved Hb level will vary considerably 162 from the intended Hb target To develop these guidelines and recommendations therefore we 163 appraised only evidence that was generated from intent-to-treat analyses of trials in patients 164 randomly assigned to either higher or lower Hb targets 165

166 The evidence base for the statement the selected Hb target should generally be in the range 167 of 110 to 120 gdL includes results from trials that examined Hb targets between 6 to 16 gdL 168 (Tables 2-5 Tables 8-10 Fig 1) Early RCTs differ substantially from later RCTs in both size and 169 Hb targets RCTs conducted before 1998 are characterized by smaller study size upper Hb targets 170 in the range of 10 to 13 gdL and lower Hb targets that reflect assignment to placebo or noshy171 treatment control Trials published in 1998 and thereafter are characterized by larger study size 172 higher Hb targets in the range of 12 to 16 gdL and lower Hb targets between 9 and 12 gdL In 173 more recent trials by comparison Hb baseline values are higher than those seen in early trials 174 Moreover recent RCTs set lower targets at Hb levels well above those seen in patients assigned in 175 earlier trials to placebo or no treatment control groups Both effects combine to render differences 176 between Hb targets smaller in more recent trials 177

178 In the statement the selected Hb target should generally be in the range of 110 to 120 179 gdL the Work Group used the word target to distinguish between a Hb target and an achieved Hb 180 level Among hemodialysis patients receiving ESA therapy with a Hb target in the range of 110 181 and 120 gdL the proportion of patients who achieve Hb levels between 110-120 gdL in a single 182 month is as low as 302021 Moreover achievement of a Hb level within the 110-120 target in 183 hemodialysis patients is transitory Over 90 of patients experience cyclical Hb excursions

10

184 averaging 103 weeks in duration and 25 gdL in amplitude22 In part due to these fluctuations 185 approximately 50 of patients who achieve a Hb level in a 110-120 target range in one month 186 will show Hb results above or below that range in the subsequent month2021 Given the variability 187 of Hb observed in clinical practice the width of a Hb interval that would encompass 95 of Hb 188 results in a population of dialysis patients undergoing ESA therapy is 56 gL23 Accordingly to 189 assure that no more than 25 of patients exceed a Hb target of 120 gdL a target range designed 190 to include 95 of patients would have a lower Hb limit of 64 (that is 120 ndash 56) gdL 191

192 In the statement the selected Hb target should generally be in the range of 110 to 120 193 gdL the word generally emphasizes the need to maintain flexibility in medical decision-making 194 given the breadth of variability between patients in individual needs values functional status 195 disease burden prognosis and responsiveness to ESA therapy (CPR 211 on page 7) 196

197 In the statement the selected Hb target should generally be in the range of 110 to 120 198 gdL the two specific values 110 gdL and 120 gdL define inclusively either a single Hb target 199 range (110-120 gdL) or a range of possible single-point Hb targets between 110 and 120 gdL 200 entail unavoidable subjectivity in selecting Hb cutoffs explicitly exclude reference to achieved Hb 201 levels and together reflect the efforts of the Work Group to balance the potential quality of life 202 benefits and avoidance of transfusions gained by ESA therapy against the potential harm suffered 203 by patients whose Hb targets are above 13 gdL 204

205 206 Figure 1 Randomized controlled trials comparing lower with higher Hb target levels Data are represented as 207 target Hb (whiskers) achieved mean Hb for patients assigned to lower (closed circles) or upper (open circles) 208 Hb targets and placebo or untreated control (filled triangles) Study size (N) is indicated by the bars on the 209 right In 12 trials published since 1998 achieved mean Hb levels frequently did not match intended target 210 levels 211

212 Available RCTs illustrate the distinction between a Hb target range1352425 and a discrete 213 Hb target (Figure 1)214

11

214

215 The lack of information to support specific Hb cutoff values in defining an optimum Hb 216 target renders statement 212 a clinical practice recommendation

217 Rationale 218 In dialysis and non-dialysis CKD patients receiving ESA therapy the Hb target should not 219 be above 130 gdL 220

221 The conclusion that the hemoglobin target should not be above 130 gdL is based on 222 analysis of all-cause mortality and adverse cardiovascular events in CKD patients assigned to Hb 223 targets gt 130 gdL compared to lower Hb targets for ESA therapy (Table 2 Table 4 Table 8 224 Table 10 Tables 6 and 7 Tables 11 and 12) These trials evaluated whether a Hb target above 225 130 gdL would prevent adverse cardiovascular events or mortality testing the specific hypothesis 226 that rates of fatal and non-fatal cardiovascular events or all-cause mortality in patients assigned to 227 Hb targets above 13 gdl differed from those seen in patients assigned to lower targets None of 228 the trials showed a benefit of higher Hb targets for these outcomes Similarly there is no evidence 229 from the trials performed to date that hemoglobin targets have an effect on left ventricular 230 dimensions With the exception of one small trial6 RCTs also failed to show a benefit of higher 231 Hb targets in terms of reducing the progression of kidney disease 232

233 In developing the statement that in dialysis and non-dialysis CKD patients receiving ESA 234 therapy the Hb target should not be above 130 gdL the Work Group considered a meta-analysis 235 performed by the Evidence Review Team The meta-analysis included published trials that 236 reported results of all-cause mortality and adverse cardiovascular events in patients assigned to 237 higher compared to lower Hb targets 238

239 In patients with non-dialysis CKD (predominantly stages 3 and 4) combining mortality 240 outcomes from 8 studies with 3038 individuals yields a risk ratio of 101 (95 CI 063 161) 241 (Figure 2-left panel) Most deaths derive from the CHOIR (Singh et al)2 and CREATE (Drueke et 242 al)1 studies which together contribute 87 of the weight of the total Ordering studies 243 chronologically in cumulative meta-analysis (Figure 2 ndashright panel) shows that an earlier (1994shy244 2005) non-significant trend favoring higher hemoglobin targets resolves to a point estimate of 1 245 after addition of the two later largest studies 246

247

12

248 249 Figure 2 Relative mortality risk for assignment to higher Hb treatment targets in patients with non-dialysis 250 CKD Standard (left) and cumulative (right) meta-analysis plots according to random effects model 251

252 In patients with non-dialysis CKD (predominantly stage 3-4) combining adverse 253 cardiovascular events from 6 studies in 2850 individuals yields a risk ratio of 124 (102 to 151) 254 (Figure 3-left panel) Again most events derive from the primary composite outcomes of the 255 CHOIR (Singh et al)2 and CREATE (Drueke et al)1 studies which include deaths from any cause 256 as a first event Together these two studies contribute 94 of the weight in this meta-analysis The 257 cumulative meta-analysis (Figure 3-right panel) shows that with the addition of these 2 studies the 258 point estimate moves from favoring higher Hb targets to favoring control treatment a finding that

becomes statistically significant 259

260 261 Figure 3 Relative risk of adverse cardiovascular events for assignment to higher Hb treatment target in 262 patients with non-dialysis CKD shown as standard (left) and cumulative (right) meta-analysis plots according 263 to random effects model 264

265

13

266 In dialysis CKD patients combining mortality outcomes from 4 studies with 2391 267 individuals yields a risk ratio of 112 (95 CI 091 137) (Figure 4-left panel) Most deaths derive 268 from the study by Besarab et al14 which contributes 81 of the weight 269

270 271 Figure 4 Relative mortality risk for assignment to higher Hb treatment target in CKD patients undergoing 272 dialysis shown as standard (left) and cumulative (right) meta-analysis plots according to random effects model 273

274 In dialysis CKD patients combining adverse cardiovascular events from 3 studies in 1975 275 individuals yields a risk ratio of 114 (079 164) (Figure 5-left panel) Again most events derive 276 from the study by Besarab et al14 which contributes 88 of the weight 277

278 279 Figure 5 Relative risk of adverse cardiovascular events for assignment to higher Hb treatment target in CKD 280 patients undergoing dialysis shown as standard (left) and cumulative (right) meta-analysis plots according to 281 random effects model 282

283 We compared both our methods and our results to those reported in another recent metashy284 analysis26 We included RCTs with ge 6 months of follow-up without restriction on study size 285 whereas the previous meta-analysis included RCTs with ge 12 weeks of follow-up and gt than 100 286 subjects our statistical model was more conservative (random effects model vs fixed effects 287 model) and unlike the previous report we did not pool studies in dialysis patients with those from 288 non-dialysis patients given the dissimilarity between these two target populations in ESA 289 administration Hb monitoring and the presence or absence of dialysis Finally for cardiovascular 290 outcomes the previous meta-analysis included only myocardial infarctions whereas we combined 291 all cardiovascular disease events including all events from the primary composite outcome in both

14

292 CHOIR and CREATE Thus our definition of cardiovascular disease as an outcome was less 293 precise but more inclusive than that of the other meta-analysis 294

295 For mortality our meta-analysis like the recently published meta-analysis showed no 296 statistically significant difference for assignment to higher versus lower Hb in either dialysis or 297 non-dialysis patients Among non-dialysis CKD patients we showed a risk ratio closer to 10 and 298 a wider confidence interval (RR 101 CI 063 to 161 versus 133 CI 098-181) than that 299 previously reported because our analysis included results from 4 studies627-29 not included in the 300 other meta-analysis These 4 studies added 441 patients and 18 deaths (5 in the upper Hb arms and 301 13 in the lower Hb arms) Among patients with dialysis CKD the two meta-analyses included the 302 same studies and yielded essentially identical results (RR 112 CI 091-137 vs 111 CI 094-131 303 current vs previous meta-analysis) 304

305 In appraising the overall evidence the Work Group considered mortality cardiovascular 306 events and HRQoL as outcomes of high importance The Work Group rated the evidence showing 307 a trend toward greater cardiovascular events in dialysis and non-dialysis patients assigned to Hb 308 targets gt 130 gdL to be of moderately high quality for showing harm and of high quality for 309 showing lack of benefit The Work Group considered the HRQoL benefits in patients assigned to 310 higher Hb targets as low quality evidence based on the limitations of reported HRQoL evidence 311 (see below Limitations of Evidence) The conclusion that in dialysis and non-dialysis CKD 312 patients receiving ESA therapy the Hb target should not be above 130 gdL reflects the Work 313 Grouprsquos judgment that the possibility to cause harm weighs more heavily than the potential to 314 improve quality of life and reduce the likelihood of transfusions 315

316 The appraisal of the Work Group that the evidence for harm is moderately high renders 317 statement 213 a moderately strong evidence-based clinical practice guideline As discussed in 318 more detail elsewhere (Methods) the designation moderately strong acknowledges the possibility 319 that further research may alter either the guideline itself or the confidence in the guideline The 320 designation moderately strong therefore allows for continued investigation

321 Limitations of Evidence

322 Patient Outcomes 323 Most reports provide incomplete information with respect to HRQoL findings Complete reporting 324 should ideally include point estimates and assessments of dispersion of HRQoL scores for each 325 domain at each interval measured by Hb target assignment Furthermore the fact that all studies 326 published to date are open label may have particular implications for the HRQoL outcome 327 measurements 328

329 Meta-analysis of cardiovascular events in dialysis patients is dominated by the results of the study 330 by Besarab et al (1998) 14 and in non-dialysis CKD patients by the results of the study by Singh et 331 al (2006)2 Although all RCTs have limitations major limitations of those trials dominating metashy332 analysis-results are of particular importance The Work Group identified no major limitations to 333 the results of the study by Besarab et al but identified several major limitations of the study by 334 Singh et al Compared to the group assigned to the lower Hb treatment target the group assigned 335 to the higher Hb target in that trial showed at baseline a statistically greater proportion of patients 336 with a history of hypertension and coronary artery bypass graft2 A report posted by the study 337 sponsor (PROCRITreg Clinical Study Report PR00-06-014 (CHOIR) SYNOPSIS 12 September

15

338 2006 wwwclinicaltrialsgov last accessed 11207) indicates that patients assigned to the higher 339 Hb treatment arm also had a significantly greater severity of CHF at baseline The results of a 340 multivariate analysis included in this report indicate that after adjustment for baseline conditions 341 (CHF by NHANES CHF score atrial fibrillationflutter serum albumin reticulocyte count and 342 age) the relationship between treatment assignment and primary composite outcome events is no 343 longer statistically significant (Hazard Ratio 124 95 CI 095 to 162 p=011 as compared to the 344 unadjusted Hazard Ratio of 134 95 CI 103 to 174 p=003 reported in the publication 2) Thus 345 although a trend toward higher risk of events in the higher Hb arm remains after adjustment for 346 baseline imbalances the null hypothesis of no treatment effect cannot be safely rejected 347 Generalizability of the CHOIR results is further limited by unexpectedly high rates of premature 348 study termination leading to censoring of the observation time and by lack of information on when 349 HRQoL was measured 350

351 One of the limitations of the CREATE trial is that the event rate was much lower than predicted so 352 that the study was not sufficiently powered to detect safety differences 353

354 Several studies are characterized by a failure to achieve the higher Hb target in the majority of 355 patients at any time (Figure 1) and no study provided description of the hemoglobin cycling 356 around the achieved mean for either the higher or lower target treatment 357

358 A further limitation of the currently available evidence is that important subgroups have not been 359 specifically studied or are not well represented in the existing studies including children and 360 young adults patients with ischemic vascular disease or chronic lung disease 361

362 Finally trials published to date have not been designed to distinguish between the potentials 363 effects of Hb targets ESA doses and other anemia therapy including iron

364 Implementation issues 365 Aiming for a Hb target within narrow boundaries in ESA treated patients requires frequent 366 dose adjustments in many patients Over 60 of patients receiving ESA therapy with Hb targets 367 between 110 and 120 gdL require between 6 and 9 dose changes per year22 No comparative 368 information is available to support evidence-based guidelines for the dosing and administration of 369 ESA therapy in order to achieve a target Hb However descriptive information from quality 370 improvement interventions and RCT treatment protocols may be helpful to practitioners in 371 weighing options that may best fit patient needs and practice settings 372

373 In a 24-month study examining the effectiveness of a computer-assisted decision support 374 algorithm for anemia management in hemodialysis patients epoetin therapy (administered 375 subcutaneously thrice weekly) was adjusted monthly in response to monthly Hb determinations30

376 Epoetin doses were adjusted upward by 1000 units per dose to achieve Hb levels gt 110 gdL and 377 downward by 1000 units per dose once a month when Hb results exceeded predetermined 378 ceilings (120 130 then 120 gdL at intervals during the study) or by 50 if the Hb exceeded 379 155 gdL Since mean epoetin doses ranged from 9800 IUwk to 6400 IUwk during the course 380 of the study an increase or decrease of 1000 IU per dose represented on average a 10 to 16 381 change in epoetin dose Although the ceiling Hb alternated in 3 periods between 120 gdL and 382 130 gdL median achieved Hb remained stable as did Hb variability around the median with 383 approximately 50 of achieved Hb results falling within 10 gdL above and below the median at

16

384 each monthly interval30 A similar algorithm was used to adjust epoetin and darbepoetin doses 385 given SC weekly31

386

387 In hemodialysis patients holding ESA doses for Hb above target range is associated with 388 subsequent downward Hb excursions22 often below target range consistent with the biology of 389 erythropoietin as a cell-salvage agent (KDOQI Clnical Practice Guidelines and Clinical Practice 390 Recommendations for Anemia in Chronic Kidney Disease Executive Summary AJKD 47 (5) 391 Suppl 3S11-S115 2006) The time between holding ESA doses and return of Hb to target range 392 is variable and unpredictable Among hemodialysis patients with Hb values above 140 gdL the 393 median time for Hb to return to le 120 gdL after holding of SC-administered ESA is 7 weeks for 394 long-acting ESA (range 2 to 13 weeks) and 9 weeks for short-acting ESA (range 6 to 13 weeks 395 difference between long and short-acting ESA not significant)32

396

397 The effect of initiating a fixed monthly downward epoetin dose adjustment in response to 398 achieved Hb levels gt 130 gdL was recently examined using the database of a large US dialysis 399 provider21 At baseline approximately 35 of 95000 patients receiving epoetin therapy showed 400 average 3-month Hb results within the target range of 11-12 gdL and 15 percent showed 401 average 3-month Hb results gt 130 gdL When a computer-mandated 25 monthly dose decrease 402 was initiated for end-of-month Hb results gt 130 gdL the percentage of patients with Hb values lt 403 110 and gt 130 gdL both increased Mean Hb however did not change 404

405 The necessary ESA dose adjustment frequency may differ between initiation and 406 maintenance of ESA therapy In a randomized double-blind trial comparing a short-acting ESA to 407 a long-acting ESA in hemodialysis patients previously receiving epoetin alfa dose adjustments 408 were made in 25 increments or decrements of the baseline dose aiming to maintain individual Hb 409 concentrations within -10 and +15 gdL of their baseline values and within a range of 90 to 130 410 gdL33 Approximately 70 of patients required dose adjustment in the 20-week titration period 411 and 50 required dose adjustment during the 8-week maintenance period Both dose increases 412 and dose decreases were required No between-group differences were seen in frequency or 413 direction of ESA dose change 414

415 Taken together these reports suggest that when the target Hb is 110-120 gdL variability 416 of achieved Hb around the target is high the fraction of prevalent patients with achieved Hb within 417 the target range is low ESA dose titration is required frequently during maintenance therapy and 418 that either 25 ESA dose changes33 or 10-16 dose changes can be an effective maintenance dose 419 titration strategy31 Clinical evidence is lacking about how to respond to achieved Hb levels above 420 target range Holding ESA doses may lead to to steep downward Hb excursions and high 421 amplitude Hb cycling22 On the other hand flexibility in determining the size of the dose 422 adjustment may be needed imposing a fixed 25 dose reduction in response to above-target Hb 423 appears to promote greater Hb variability and more above-target Hb values in patients undergoing 424 maintenance therapy21

17

425 Measuring performance 426 In general a Hb target range suggests that ESA dose adjustment decisions are made by comparing 427 the patientrsquos achieved Hb to the selected Hb target Performance in achieving a Hb target range 428 can be expressed as the proportion of patients with Hb levels within the target range In practice 429 only 30 of patients at any one time point have an actual Hb level in the Hb target range of 110 430 and 120 gdl when targeted to that range In practice the result of a single sampling in a single 431 patient can not be expected to lie within a narrow Hb target range (eg Hb 110 ndash 120 gdL) or to 432 equal a discrete point Hb target (eg Hb 110 115 or 120 gdL) However the mean or median 433 Hb levels of a group of patients or the mean Hb levels of a single patient repeated over time would 434 be expected to lie within a Hb target range or to approximate a discrete Hb target In short 435 measures of clinical performance to be clinically useful must account for a high degree of withinshy436 patient and between-patient variability 437

438 Although available RCTs have employed either a range or a discrete target Hb value 439 (Figure 1) published reports include little practical information on how ESA and iron therapy were 440 actually adjusted based on achieved levels or how closely adjustments adhered to study protocol 441 There is no information to determine how to best quantify Hb variability or to examine the effect 442 of Hb variability on outcomes Comparative information is similarly lacking to determine 443 optimum frequency for monitoring Hb the number of Hb results needed to reliably measure 444 clinical performance or the expected day-to-day within-patient variability of Hb in different 445 patient populations (ND-CKD HD-CKD and PD-CKD) 446

18

Appendix 1 Anemia Update Methods

Criteria for updating a guideline and updating a systematic review

An update of a systematic review of a guideline topic denotes an event with the aim to search for and identify new evidence to incorporate into a previously completed systematic review34

Changes to guidelines can be undertaken for correction of typographical or content errors Such changes do not constitute an update because they do not allow for the possibility of new evidence being identified

In general guidelines and the systematic reviews they are based on should be updated as scheduled An earlier update of the systematic review on a particular guideline topic can be prompted if all of the following conditions are met

bullThere is new evidence on important clinical outcomes

bullThe evidence is from a studystudies that was adequately powered for the clinical outcome(s)

bullThe new evidence has the potential to raise the grade for the quality of the evidence or change the assessment of the balance of benefits and harms

Evidence from surrogate end point trials can prompt an update of a systematic review if the criteria outlined by the ldquoUsersrsquo Guide for a Surrogate End Point Trialrdquo are met35

Adapted from Bucher et al JAMA 1999 282 (8) 771-778

19

Methods used for this guideline update

Process For this guideline update we updated the systematic review of randomized controlled trials (RCTs) that compared the effect of targeting different hemoglobin levels with ESA treatment A detailed description of the methods can be found in the methods chapter in the Anemia guidelines 200636 The inclusion criteria were RCTs in patients with CKD stages 1-5 with a minimum of 2 months follow-up duration Outcomes of interest were all-cause mortality cardioshy cerebro- and peripheral vascular disease left ventricular hypertrophy quality of life hospitalizations progression of kidney disease dialysis adequacy hypertension transfusions and seizures

An updated search conducted on December 7 2006 with the previously used key words of KIDNEY and ANEMIA identified 639 citations of English language studies indexed in Medline after November 2004 Furthermore the ERT searched the clinical trialsgov registration website to identify additional studies that might be completed The search update resulted in the addition of 6 RCTs to the systematic review on this topic1-6 All were in patients not on dialysis mostly with CKD stage 3-4 The ERT also updated a table (table 1) of ldquoongoing studiesrdquo to show what trials will be completed in the future

The new studies were critically appraised by the NKF Evidence Review Team (ERT) at Tufts-New England Medical Center in Boston The ERT extracted the data from these studies and added them to the summary tables published in the 2006 Anemia guidelines Each study was graded with regards to its methodological quality mainly for its primary outcome and also for the QOL outcome if it was not the primary outcome The workgroup experts reviewed and confirmed data and quality grades in the summary tables The ERT and the workgroup members updated the evidence profiles for non-dialysis patients following the modified GRADE approach37 The ERT tabulated an evidence matrix that provides an overview over the quality of the reviewed evidence It tabulates all studies included in the review by type of outcome and quality

A meeting of the original 2006 KDOQI Anemia guidelines workgroup members the ERT and NKF support staff was held in Dallas on February 2-3 2007 The meeting was chaired by a KDQOI co-chair (MR) who reported no conflicts of interest with regards to this topic The workgroup reviewed the summary tables evidence profiles a list of currently FDA recommended hemoglobin targets for prescribers of Procrit Epogen or Aranesp and a list of ongoing studies It then deliberated on what guideline recommendation the expanded evidence base would support and if and how the prior guidelines and clinical practice recommendations would have to be modified The workgroup then drafted recommendations and graded the strength of the recommendations The strength of a guideline recommendation is shown in parentheses following the guideline statement as ldquostrongrdquo ldquomoderately strongrdquo A clinical practice recommendationrdquo is followed by a ldquoCPRrdquo in parentheses Issues considered in the grading of the quality of the evidence and the strength of the recommendations were detailed in the rationale section corresponding to each statement Each rationale section was graded according to the quality of the overall evidence on which it is based

20

The draft of the updated guidelines underwent refinement and internal review by all workgroup members via emails and conference calls and subsequent review by the KDOQI Advisory Board and the public

Grading of the quality of a study

A detailed description can be found in the methods section of the prior anemia guideline Each study was graded with regards to its methodological quality mainly for its primary outcome and also for the QOL outcome if it was not the primary outcome Table A shows the grades for the quality of a study

Table A Grading of Study Quality

Least bias results are valid A study that mostly adheres to the commonly held concepts of high quality including the following a formal study clear description of the population and

A setting clear description of an appropriate reference standard proper measurement techniques appropriate statistical and analytic methods no reporting errors and no obvious bias Not retrospective studies or case series Susceptible to some bias but not sufficient to invalidate the results A study that does not

B meet all the criteria in category above It has some deficiencies but none likely to cause major bias Significant bias that may invalidate the results A study with serious errors in design or

C reporting These studies may have large amounts of missing information or discrepancies in reporting

Grading of the quality of evidence

The evidence profile recorded the assessment of the quality of evidence the summary of the effect for each outcome the judgment about the overall quality of the evidence and a summary assessment of the balance of benefits and harms37

The quality of a body of evidence pertaining to a particular outcome of interest was initially categorized based on study design For questions of interventions the initial quality grade was ldquohighrdquo if the body of evidence consisted of randomized controlled trials ldquolowrdquo if it consisted of observational studies or ldquovery Lowrdquo if it consisted of studies of other study designs The grade for the quality of evidence for each interventionoutcome pair was then decreased if there were serious limitations to the methodological quality of the aggregate of studies if there were important inconsistencies in the results across studies if there was uncertainty about the directness of evidence including limitations to the applicability of the findings to the population of interest if the data were imprecise or sparse or if there was thought to be a high likelihood of reporting bias (See table B) The final grade for the quality of the evidence for an interventionoutcome pair could be one of the following four grades ldquohighrdquo ldquomoderaterdquo ldquolowrdquo or ldquovery lowrdquo (Table B)

The quality of the overall body of evidence was then determined based on the quality grades for all outcomes of interest taking into account explicit judgments about the relative importance of each of the outcomes To judge the balance between benefits and harms the summaries for the

21

actual results for each outcome were reviewed Four final categories for the quality of overall evidence were used as defined in Table B

22

Table B GRADE System for Grading Quality of Evidence

Step 1 Starting Step 2 Reduce grade Step 3 Raise grade Final grade for grade for quality of quality of evidence evidence based on and definition study design

Randomized trials = High

Observational studies = Low

Any other evidence = Very Low

Study quality -1 level if serious limitations

-2 levels if very serious limitations

Consistency -1 level is important inconsistency

Directness -1 level if some uncertainty

-2 levels if major uncertainty

Other Considerations -1 level if sparse or imprecise data

-1 level is high probability of reporting bias

Strength of association +1 level is strong no plausible confounders

+2 levels if very strong no major threats to validity

+1 level if evidence of a dose response gradient

+1 level if all residual plausible confounders would have reduced the observed effect

High = Further research is unlikely to change confidence in the estimate of the effect

Moderate = Further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate

Low = Further research is very likely to have an important impact on confidence in the estimate and may change the estimate

Very Low = Any estimate of effect is very uncertain

Strong evidence of association is defined as lsquosignificant relative risk of gt2 (lt05)rsquo based on consistent evidencefrom two or more observational studies with no plausible confoundersVery strong evidence of association is defined as rsquosignificant relative risk of gt5 (lt02)rsquo based on direct evidence with no major threats to validity GRADE Grades of Recommendation Assessment Development and Evaluation Ref Uhlig et al modified from (GRADE) and Kunz and Farquhar

23

Grading or guideline recommendations

Overall the strength of a guideline is based on the extent to which the Workgroup could be confident that adherence will do more good than harm The strength of a recommendation was based on the quality of the overall supporting evidence as well as additional considerations The strength of a guideline recommendation could be rated by as either ldquostrongrdquo or ldquomoderately strongrdquo A ldquostrongrdquo guideline requires support by evidence of ldquohighrdquo quality A ldquomoderately strongrdquo guideline requires support by evidence of at least ldquomoderaterdquo quality Incorporation of additional considerations can modify the linkage between quality of evidence and strength of a guideline usually resulting in a lower strength of the recommendation than would be supportable based on the quality of evidence alone

A ldquostrongrdquo rating indicates the expectation that that the guideline recommendation will be followed unless there are compelling reasons to deviate from the recommendation in an individual This is based on ldquohighrdquo quality evidence that the practice results in net medical benefit to the patient and the assumption that most well-informed individuals will make the same choice A ldquomoderately strongrdquo rating indicates the expectation that consideration will be given to follow the guideline recommendation This is based on at least ldquomoderaterdquo quality evidence that the practice results in net medical benefit to the patient and the assumption that a majority of well informed individuals will make this choice but a substantial minority may not

Clinical Practice Recommendations

In the absence of ldquohighrdquo or ldquomoderaterdquo quality evidence or when additional considerations did not support ldquostrongrdquo or ldquomoderately strongrdquo evidence-based guideline recommendations the Workgroup was able to draft ldquoclinical practice recommendationsrdquo based on overall consensus of the opinions of the workgroup members As such the Workgroup recommends that clinicians give consideration to following these ldquoclinical practice recommendationsrdquo for eligible patients

24

Table C Strength of Guideline Recommendations Consensus-Based Statements and Linkage to Quality of Evidence Recommendation Description Prerequisite Assumption Implication or statement in GRADE

approach Strong guideline We recommendation recommend

(should)

The quality of the evidence is lsquohighrsquo and other considerations support a strong recommendation

Most well-informed individuals will make the same choice

The expectation is that the recommendation will be followed unless there are compelling reasons to deviate from the recommendation in an individual A strong recommendation may for the basis for a clinical performance measure

Weak guideline We suggest recommendation1 (might)

The quality of A majority The expectation is that the evidence is of well- consideration should be lsquohighrsquo or informed given to follow the lsquomoderatersquo but individuals recommendation additional will make considerations this choice support a lsquoweakrsquo but a recommendation substantial

minority may not

Consensus-based Not statement2 applicable

The quality of the evidence is lsquolowrsquo lsquovery lowrsquo or absent This a consensus based on expert opinion supported in the public review of the statement

The expectation is that consideration should be given to follow the statement

Reference 37 GRADE Grades of Recommendation Assessment Development and Evaluation 1 Anemia workgroup chose to designate as ldquoModerately strongrdquo 2 Anemia workgroup chose to denote as Clinical Practice Recommendation

25

Meta-analyses

Meta-analyses were performed on a subset of RCTs in our systematic review that had 6 or more months of mean follow-up Risk ratios (RR) with 95 confidence intervals (CI) were calculated for each study for mortality and for cardiovascular disease For the cardiovascular disease endpoint we combined events for coronary cerebrovascular peripheral vascular disease and heart failure as defined in each study For CHOIR and CREATE we included all events from the primary composite outcomes even though they also included deaths from any cause or from cardiac arrhythmias We grouped studies according to whether they were conducted in non-dialysis patients or in dialysis patients We included the Furuland study with the dialysis studies even though it contained a subgroup of non-dialysis patients

Calculations were performed using Meta-Analyst (Version 099 1997 Joseph Lau Tufts-New England Medical Center Boston USA) Because of the clinical heterogeneity of the studies in terms of populations interventional protocols duration of follow-up and outcome definitions we used a random effects model according to DerSimonian and Laird for dichotomous outcomes The random effects model incorporates both within study and between studies variability in assigning weights to each study It gives a wider confidence interval when heterogeneity is present and thus is more conservative compared to a fixed effect model

26

Appendix 2 Comparison of FDA-Approved Prescribing Information for Epoetin Alfa and KDOQI Anemia Guidelines Epogenreg amp Procritreg Prescribing Information

(March 2007 product labeling) KDOQI Anemia Guidelines

(May 2006 CPRs and CPGs amp update 2007) Section Recommendation

Black Box Warning 1 Goal of Treatment Avoid transfusion or Hb gt 12 CPR 211 Selection of the Hb target and selection of the Hb level at which ESA therapy

is initiated in the individual patient should include consideration of potential benefits (including improvement in quality of life and avoidance of transfusion) and potential harms (including the risk of life-threatening adverse events) CPR 212 The selected Hb target should generally be in the range of 110 to 120 gdL CPG 213 Hb target should not be above 130 gdL CPR 34 No single Hb concentration justifies or requires transfusion The target Hb should not serve as a transfusion trigger

Indications and Usage 2 Indications Elevate Hb decrease transfusion need CPR 211 Rationale Identifies both HRQoL improvement and lower transfusion need as

potential benefits of ESA therapy describes relationship of benefit to Hb target and achieved Hb in RCTs by target population

3 Starting Hb in CKD Hb lt 10 gdL CPR 211 Rationale Selection of Hb target and selection of Hb level to initiate therapy are separate but related steps in medical decision-making Makes no specific recommendation but notes that target Hb assignment and initiation of therapy has generally been simultaneous in available RCTs

4 Starting Hb in HD no specific recommendation CPR 211 Rationale As above Iron status TSAT gt 20 Ferritin gt 100 ngmL prior

to Epogen CPR 3231 TSAT gt 20 or CHr gt 29 pg ferritin gt 200 ngmL in HD-CKD CPR 3232 TSAT gt 20 or CHr gt 29 pg ferritin gt 100 ngmL in ND-CKD PD-CKD CPR 324 Upper level of ferritin insufficient evidence to recommend IV iron if ferritin gt 500 ngmL

5 Physicians Role Under guidance of physician Executive Summary Guidelines are intended to assist practitioners caring for individual patients with CKD

Contraindications Hypertension Hypersensitivity

Uncontrolled hypertension Hypersensitivity to mammalian cell-derived products and albumin

CPR 3125 Hypertension is not a contraindication to ESA therapy Rationale If hypertension is Control hypertension with usual measures

Warnings 6 Target Hb When administered to target a Hb gt 12

gdL CPR 212 The selected Hb target should generally be in the range of 110 to 120 gdL

7 Rate of Hb Rise A Hb rate of rise gt 1 gdL over 2 weeks CPR 3121 The initial ESA dose and dose adjustments should be determined by the patientrsquos Hb level the target Hb level the observed rate of increase in Hb level and clinical circumstances Rationale 31 In general the objective of initial ESA therapy is a rate of Hb increase of 10 to 20 gdL per month

8 Achieved Hb The Hb concentration should not exceed 12 gdL

CPR 21 Background Statements amp Rationale Distinguishes achieved Hb from target Hb Achieved Hb varies considerably from target Hb To avoid achieved Hb gt 12 gdL would require a Hb target of 92 gdL

27

9 Rate of Hb Rise The Hb rate of rise should not exceed 1 gdL in any 2 week period

CPR 31 Rationale In general the objective of initial ESA therapy is a rate of Hb increase of 10 to 20 gdL per month

10 Hypertension If hypertension is difficult to control by appropriate measures decrease epoetin dose

CPR 3125 Hypertension is not a contraindication to ESA therapy Rationale If hypertension arises in the course of anemia treatment it should be treated appropriately with antihypertensive measures

11 Cardiovascular Disease Patients with pre-existing cardiovascular disease should be monitored closely

Guideline statements do not distinguish between patients with and without cardiovascular disease

Precautions 12 Lack or Loss of Response

Consider iron deficiency and 8 other categories of conditions

CPR 32 Gives explicit guidance on evaluating and maintaining optimum iron status CPR 35 Gives specific information on evaluating and correcting persistent failure to reach or maintain intended Hb defines hyporesponse features lists associated disorders Specifies when to consider and how to evaluate PRCA

13 Iron Evaluation TSAT should be gt 20 and ferritin gt 100 ngmL before starting epoetin

CPRs specify recommended iron status for patients undergoing ESA therapy including ferritin upper limit CPR 3231 TSAT gt 20 or CHr gt 29 pg ferritin gt 200 ngmL in HD-CKD CPR 3232 TSAT gt 20 or CHr gt 29 pg ferritin gt 100 ngmL in ND-CKD PD-CKD CPR 324 Upper level of ferritin insufficient evidence to recommend IV iron if ferritin gt 500 ngmL

Monitor TSAT and ferritin regularly provide iron

CPR 321 Specifies frequency of iron status tests as monthly during initial ESA treatment at least every 3 months during stable ESA treatment

14 Informing Patients Patients should be informed of increased risks when epoetin used in off-label dose regimens or populations

Guidelines do not apply to either non-renal population or off-label use

15 Hematology and Laboratory Monitoring

Monitor Hb twice weekly for 2-6 weeks adjust dose no more frequently than 2 week intervals CBC with platelets and differential should be performed regularly chemistries (list) should be performed regularly diet may need to be adjusted hyperkalemia should be monitored dialysis prescription may need to be adjusted no change in renal function expected in ND-CKD

CPR 121 Recommends CBC with platelets differential WBC absolute reticulocyte count and iron status tests on first evaluation of anemia in CKD

CPR 311 Specifies frequency of Hb monitoring as at least monthly in patients treated with ESA therapy Rationale reviews published experience describes twice-monthly and monthly Hb determination no reports of twice-weekly Hb monitoring in CKD

No specific recommendations for monitoring non-hematological laboratory tests or monitoring non-Hb elements of CBC Table 2 includes evidence that dialysis adequacy is statistically lower in patients higher compared to lower Hb target but difference is small No evidence from Hb target trials that diet modification or potassium monitoring should be included in anemia management Table 8 presents evidence from 10 Hb target trials in ND-CKD showing no between-group effect (benefit or harm) on renal function

Dosing amp Administration 16 Starting Dose 50-100 ukgtiw CPR 3121 The initial ESA dose and dose adjustments should be determined by the

patientrsquos Hb level the target Hb level the observed rate of increase in Hb level and clinical circumstances CPR 3121 Rationale In general the objective of initial ESA therapy is a rate of Hb increase of 10 to 20 gdL per month

17 Route IV recommended in HD CPR 3131 Route of administration should be determined by the CKD stage treatment setting efficacy safety and class of ESA used CPR 3122 Convenience favors SC administration in non-HD-CKD patients CPR 3123 Convenience favors IV administration in HD-CKD patients

18 Reduce Dose When Hb approaches 12 gdL or Hb rise exceeds 1 gdL over 2 weeks

CPR 21 Rationale Review of literature on dose adjustment options and dose titration in response to Hb above and below Hb target CPR 31 Rationale In general the objective of initial ESA therapy is a rate of Hb increase of 10 to 20 gdL per month

28

19 Increase Dose If Hb does not increase by 2 gdL over 8 weeks of therapy and Hb remains at a level not sufficient to avoid the need for transfusion

CPR 21 31 No specific recommendations on timing of 1st dose adjustment after ESA initiating therapy

20 Maintenance Dose Individually titrate to achieve and maintain the lowest Hb level sufficient to avoid the need for RBC transfusion and not to exceed 12 gdL

CPR 212 Specifies that the selected Hb target should generally be in the range of 110 to 120 gdL on basis of balance of HRQoL benefit transfusion benefit potential harm at Hb targets gt 13 gdL

21 Individualize Dose Doses must be individualized to ensure that Hgb is maintained at an appropriate level for each patient

CPR 211 Selection of the Hb target and selection of the Hb level at which ESA therapy is initiated in the individual patient should include consideration of potential benefits (including improvement in quality of life and avoidance of transfusion) and potential harms (including the risk of life-threatening adverse events)

22 Dose Adjustment Frequency

Increases should not be made more often than once a month

No specific recommendations on frequency of dose adjustment CPR 212 Rationale includes literature review of approaches to dose adjustment

23 Dose Adjustment Hb level

Hb increasing and approaching 12 gdL No specific recommendations on the level of Hb that requires dose adjustment in relation to Hb 12 gdL or lower Hb targets CPR 212 Rationale includes literature review of approaches to dose adjustment

24 Dose Adjustment Dose Decrease For Hb Level

1st dose decrease 25 If Hb continues to increase and approaches 12 gdL doses should be temporarily held until the Hb begins to decrease at which point therapy should be reintroduced at a dose approximately 25 below the previous dose

No specific recommendations on the level of Hb that requires dose adjustment in relation to Hb 12 gdL or lower Hb targets CPR 212 Rationale includes literature review of approaches to dose adjustment Review includes evidence that holding ESA doses is associated with Hb cycling above and below the Hb target range Report of impact of fixed 25 dose adjustment for Hb gt 13 gdL is reviewed

25 Dose Adjustment Slow Hb Rise

If the increase in Hgb is lt 1 gdL over 4 weeks and iron stores are adequate dose of Epogen may be increased by 25 of the previous dose Further increases may be made at 4-week intervals until the specified Hgb is obtained

No specific recommendations on the rate of Hb increase that requires dose adjustment in relation to Hb 12 gdL or lower Hb targets No specific recommendations on frequency of dose adjustment CPR 212 Rationale No specific recommendations on percent dose increments or decrements but literature on available information is reviewed

26 Dose Adjustment Maintenance Iron Status

If TSAT is gt 20 dose may be increased

CPRs specify recommended iron status for patients undergoing ESA therapy including ferritin upper limit CPR 3231 TSAT gt 20 or CHr gt 29 pg ferritin gt 200 ngmL in HD-CKD CPR 3232 TSAT gt 20 or CHr gt 29 pg ferritin gt 100 ngmL in ND-CKD PD-CKD CPR 324 Upper level of ferritin - insufficient evidence to recommend IV iron if ferritin gt 500 ngmL

27 Dose Adjustment Maintenance Hb Monitoring

Hb should be monitored twice weekly for 2 to 6 weeks following dose increases

CPR 3111 Recommends Hb monitoring no less frequently than monthly

28 Lack or Loss of Response

If TSAT is lt 20 supplemental iron should be administered

Specifies that iron should be given to maintain TSAT gt 20 but adds caution that safety of IV iron administration when ferritin gt 500 ngmL has not been established CPR 324 Upper level of ferritin - insufficient evidence to recommend IV iron if ferritin gt 500 ngmL

29

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2 Singh AK Szczech L Tang KL et al Correction of anemia with epoetin alfa in chronic kidney disease N Engl J Med 3552085-2098 2006

3 Rossert J Levin A Roger SD et al Effect of early correction of anemia on the progression of CKD Am J Kidney Dis 47738-750 2006

4 Macdougall IC Temple RM Kwan JT 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 Nephrol Dial Transplant 22784shy793 2007

5 Ritz E Laville M Bilous RW et al Target level for hemoglobin correction in patients with diabetes and CKD primary results of the Anemia Correction in Diabetes (ACORD) Study Am J Kidney Dis 49194-207 2007

6 Gouva C Nikolopoulos P Ioannidis JP et al Treating anemia early in renal failure patients slows the decline of renal function A randomized controlled trial Kidney Int 66753shy760 2004

7 Epogen (Epoetin alfa) for injection Prescribing information 1-30 5-12-2006 Silver Spring MD United States Food and Drug Administration (USFDA) Ref Type Report

8 Procrit (Epoetin alfa) for injection Prescribing information 1-22 2007 Silver Spring MD United States Food and Drug Administration (USFDA) Ref Type Report

9 Aranesp (darbepoetin alfa) for injection Prescribing information 1-22 2007 Silver Spring MD United States Food and Drug Administration (USFDA) Ref Type Report

10 World Health Organization WHOQOL Measuring Quality of Life The World Health Organization Quality of Life Instruments WHOMSAMNHPSF974 1997 Geneva Switzerland Ref Type Serial (BookMonograph)

11 Hahn E A Cella D Chassany O Fairclough D L Wong G Y and Hays R D A Comparison of the Precision of Health-Related Quality of Life Data Relative to Other Clinical Measures Mayo Clinic Proceedings 2007 Ref Type In Press

12 Furuland H Linde T Ahlmen J et al A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients Nephrol Dial Transplant 18353-361 2003

30

13 Foley RN Parfrey PS Morgan J et al Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy Kidney Int 581325-1335 2000

14 Besarab A Bolton WK Browne JK et al The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and Epoetin N Engl J Med 339584-590 1998

15 Parfrey PS Foley RN Wittreich BH et al Double-Blind Comparison of Full and Partial Anemia Correction in Incident Hemodialysis Patients without Symptomatic Heart Disease J Am Soc Nephrol 162180-2189 2005

16 Levin A Djurdjev O Duncan J et al Haemoglobin at time of referral prior to dialysis predicts survival an association of haemoglobin with long-term outcomes Nephrol Dial Transplant 2005

17 Ofsthun N Labrecque J Lacson E et al The effects of higher hemoglobin levels on mortality and hospitalization in hemodialysis patients Kidney Int 631908-1914 2003

18 Roberts TL Foley RN Weinhandl ED et al Anaemia and mortality in haemodialysis patients interaction of propensity score for predicted anaemia and actual haemoglobin levels Nephrol Dial Transplant 211652-1662 2006

19 Greene T Daugirdas J Depner T et al Association of achieved dialysis dose with mortality in the hemodialysis study an example of dose-targeting bias J Am Soc Nephrol 163371-3380 2005

20 Lacson E Ofsthun N Lazarus JM Effect of variability in anemia management on hemoglobin outcomes in ESRD Am J Kidney Dis 41111-124 2003

21 Ofsthun NJ Lazarus JM Impact of the Change in CMS Billing Rules for Erythropoietin on Hemoglobin Outcomes in Dialysis Patients Blood Purif 2531-35 2007

22 Fishbane S Berns JS Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin Kidney Int 681337-1343 2005

23 Berns JS Elzein H Lynn RI et al Hemoglobin variability in epoetin-treated hemodialysis patients Kidney Int 641514-1521 2003

24 Levin A Djurdjev O Thompson C et al Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD Am J Kidney Dis 46799-811 2005

25 Roger SD McMahon LP Clarkson A et al Effects of early and late intervention with epoetin alpha on left ventricular mass among patients with chronic kidney disease (stage 3 or 4) results of a randomized clinical trial J Am Soc Nephrol 15148-156 2004

26 Phrommintikul A Haas SJ Elsik M et al Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin a metashyanalysis Lancet 369381-388 2007

31


28 Kuriyama S Tomonari H Yoshida H et al Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure especially in nondiabetic patients Nephron 77176-185 1997

29 Roth D Smith RD Schulman G et al Effects of recombinant human erythropoietin on renal function in chronic renal failure predialysis patients Am J Kidney Dis 24777-784 1994

30 Richardson D Bartlett C Will EJ Optimizing erythropoietin therapy in hemodialysis patients Am J Kidney Dis 38109-117 2001

31 Tolman C Richardson D Bartlett C et al Structured Conversion from Thrice Weekly to Weekly Erythropoietic Regimens Using a Computerized Decision-Support System A Randomized Clinical Study J Am Soc Nephrol 161463-1470 2005

32 Locatelli F Olivares J Walker R et al Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency Kidney Int 60741-747 2001

33 Nissenson AR Swan SK Lindberg JS et al Randomized controlled trial of darbepoetin alfa for the treatment of anemia in hemodialysis patients Am J Kidney Dis 40110-118 2002

34 Moher D Tsertsvadze A Systematic reviews when is an update an update Lancet 367 (9514) 881-3 2006

35 Bucher HC Guyatt GH Cook DJ Holbrook A McAlister FAUsers guides to the medical literature XIX Applying clinical trial results A How to use an article measuring the effect of an intervention on surrogate end points Evidence-Based Medicine Working Group JAMA 282(8) 771-8 1999

36 National Kidney Foundation KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease Am J Kidney Dis 47 S1shyS145 2006 (suppl 3)

37 Uhlig K Macleod A Craig J Lau J Levey AS Levin A Moist L Steinberg E Walker R Wanner C Lameire N Eknoyan G Grading evidence and recommendations for clinical practice guidelines in nephrology A position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney Int 70(12) 2058-65 2006

38 Conlon PJ Kovalik E Schumm D Minda S Schwab SJ Normalization of hematocrit in hemodialysis patients with cardiac disease does not increased blood pressure Ren Fail 22 432-444 2000

32

Table 1 Ongoing Randomized Controlled Trials on Hemoglobin Targets in Adult Patients with CKD Identified from Clinicaltrialsgov

Name of Study Reference Patient

PopulationInclusion Criteria

Follow-up

N of Patients

InterventionTreatment Targets Experimental

Group Control Group

Outcomes Start Date

Projected End Date

ND- or D-CKD Population TREAT Trial to Reduce Cardiovascular Events with Aranesp Therapy

PI nd (Amgen)

STIMULATE Study Anemia Correction and HRQoL Outcomes in Elderly CKD Patients

PI nd (Amgen) NEPHRODIAB2 Prospective Randomized Controlled Open-Labeled Trial Comparing Effect of Two Haemoglobin Levels

PI Villar E Lyon France Transplant Population Correction of Anemia and Progression of Renal Failure on Transplanted Patients

PI Choukroun G (Hoffmann-La Roche)

CKD Stage 2-4 DM type 2 Hb lt 110 TSAT gt15

CKD Stage 3-5 (ND-CKD) age ge70 yrs Hblt11gdl TSAT ge15

CKD stage 3-4 (CG clearance 25-60mlmin) Type 2 DM age 18-80 yrs Hb 10-13gdl

CKD Tx stage 3-4 (GFR 20-50 mlmin173m2) Transplanted 1-20 yrs age 18-70 yrs Hb lt115 no iron deficiency

25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130

Darbepoetin alfa Induction Phase once every 2 weeks Maintenance phase once a month

Hb target 13-149

Hb target 13-15

Hb target gt90

Placebo or Darbepoetin alfa started when Hb fell below 9 gdl

Hb target 11-129

Hb target 105-115

Primary All-cause mortality and CVD

Secondary All-cause mortality CVD mortality MI CVA CHF RRT eGFR decline QoL (fatigue) Primary QoL (vitality by the SF-36 vitality subscale score)

Secondary Hb ge11gdl mean Hb QoL Primary kidney function decline

Secondary mortality serious AEs thrombosis RRT QoL

Primary kidney function decline (Ccr) at 24 mos

Secondary iohexol GFR SCr QoL at 6 mos proteinuria and albuminuria rejection graft and patient survival AEs BP transfusions EPO dose

806

104

404

Enrollment

period 15yrs

Study Duration 4 yrs 109 (but in 806 not yet open for enrollment)

(1208)

References httpwwwclinicaltrialsgovctshowNCT00093015 amp httpwwwikidneycomiKidneyInfoCenterNephrologyInciteArchiveTreat16htm ClinicalTrialsgov Identifier NCT00093015 Phase III httpclinicaltrialsgovctshowNCT00364845order=26 httpclinicaltrialsgovctshowNCT00279084order=32 httpclinicaltrialsgovctshowNCT00396435order=12

Abbreviations AE Adverse event BP Blood pressure Ccr Creatinine clearance CG Cockcroft-Gault CHF Chronic heart failure CVA Cardiovascular accident CVD Cardiovascular disease DM Diabetes eGFR Estimated GFR GFR Glomerular filtration rate Hb Hemoglobin MI Myocardial infarction nd no data QoL Quality of life RRT Renal replacement therapy SCr Serum creatinine TSAT Transferrin saturation Tx Transplant wk week yr year

33

Table 2 Summary Table of RCTs Comparing Different Hb TargetsESA Doses on Key Clinical Outcomes in the HD-CKD and PD-CKD Populations

Arm 1 Mean Hb Clinical Outcomes (Arm 1 vs Arm 2 vs Arm 3 )

Arm 2 (gdL)

Quali

ty

Author Year N CVD event LVH Mortality Hospitali- Dialysis Adequacy Transfusion QoLbTarget

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity

Arm 3 (Achieved) () () zations ()

ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)

Non Fatal MI 31 vs 23

NSc mdash 296 vs 244

NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005

mdash See QoL Table A

Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash

3 vs 3 vs 72 ESA vs Placebo

Plt005f

See QoL Table

See QoL Table

A

A

Furuland 2003 [1942]

Suzuki 1989 [1934]

Furuland 2005 [7] Substudy of Furuland 2003

McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity Arm 1 Mean Hb Clinical Outcomes (Arm 1 vs Arm 2 vs Arm 3 )

Quali

ty

Arm 2 (gdL) Target CVD event LVH Mortality Hospitali- Dialysis Adequacy Transfusion QoLb


ESA v Placebo

Nissenson ESA 107-127 ∆ Upt4 wk 1995 [2078] 152 PD-CKD 8 6-9 (112) mdash mdash NS mdash mdash -021 vs +042 mdash B

Placebo (80) Plt005

Bahlmann ESA 10-117 9 vs 60129 HD-CKD 77 6 (106-109) NS mdash NS mdash mdash mdash B1991 [1935] Placebo (78) Plt005

10-117 LVEDd Sikole 1993 ESAe

(113) (mm) [1878] 38 HD-CKD 67 12 mdash 48 vs 53 mdash mdash mdash mdash mdash B

Control (83)g P=0002

ESA v Placebo in Pediatric Patients

ESA 105 -12 SeeMorris 1993 11 PD-CKD 73 6 (112) mdash mdash mdash mdash mdash mdash QoL C[1873] HD-CKD Placebo (7) Table

Annotations Primary Outcome a All baseline data given for arm 1 unless otherwise specified b Global Scores if documented are provided here Refer to Hb Targets Quality of Life Table for details of quality of life measurements c The pri mary outcome was a composite of non-fatal MI or death RR 13 95 CI 09-18 Pgt 005 d 294 HD-CKD 51 PD-CKD 72 ND-CKD patients e Iron co-intervention not documented f Data at 8 weeks g Median h estimated from graph during maintenance phase i The data and safety monitoring board recommended that the study be terminated at the time of the third interim analysis because of concern about safety even though the futility boundary corresponding to an overall 5 level of significance had not been crossed

Abbreviations CVA Cerebrovascular accident CVD Cardiovascular disease LVD Left ventricular dilation LVEDd Left ventricular end diastolic diameter LVH Left ventricular hypertrophy MR Mitral regurgitation MI Myocardial infarction SCD Sudeen cardiac death URR Urea reduction ratio Upt4 wk Units per patient per 4 weeks

Coding of Outcomes Mortality all cause mortality CVD event Includes CHF exacerbation MI arrythmias angina interventional procedure such as CABG or angioplasty sudden death CVA LVH as identified by ECHO with minimum of 6 month follow-up NS Not significant nd Not documented

35

Table 3 Summary Table of RCTs Comparing Different Hb TargetsESA Doses on Quality of Life in the HD-CKD and PD-CKD Populations

Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up

months Applic-ability

Arm 1 Arm 2

Arm 3

Mean Hb (gdL) Target

(achieved)

Primary Outcome of

Study ScaleTest

Quality of Life (Arm 1 vs Arm 2 vs Arm 3 )

Global QoL VitalityFatigue Other Measures of QoL

Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)

Left Ventricular Volume Index

SF36 Vitality and Quality of Social

Interaction (at mean follow-up)

FACIT Fatigue Scale (at mean follow-up)

SF-36 Vitality+

Fatigue NS

KDQOL Quality of Social Interaction NS A

Physical NS

ESA High 115-13 (117)

KDQ (at 6 months) Fatigue NS Relationships NS

Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low

ESA High plus ESA Low

Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)

QoL and Functional Capacityc

SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +

Frustration NS Physical NS

Psychosocial NS

NS

Physical + Relationships+ Depression + Frustration NS

Physical + Psychosocial NS

NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)

Mortality and Non-fatal MI

SF-36 (at 12 months) Physical +d A

Physical Symptoms NS

Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)

∆ LV mass index in individuals with concentric LVH ∆

cavity volume index in

individuals with LVD

KDQf

(at 12 months)

SF-36 (at 12 months)

Fatigue +

Vital

ity NS

Depression + Relationships + Frustration NS

Physical Function NS General Health NS

Bodily Pain NS Social Functioning nd

Emotional Role nd Mental Health nd

A

HUI Mean HUI = 081 (at 12 months) (CI 078 085)

36

CKD Arm 1 Mean Hb Quality of Life (Arm 1 vs Arm 2 vs Arm 3 ) Stage Follow- PrimaryAuthor N Up Applic- Arm 2 (gdL) Outcome of QualityYear ability Target ScaleTest Global VitalityFatigue Other Measures of QoLBaseline months Study QoL

Hb (gdL) Arm 3 (achieved)

4-5 135ndash160 Physical +Furuland (PDHD) ESA High (136) KDQ Relationship NS2003 253 12 [1942] 9-12

QoL and Safety (at 12 months)

Fatig

ue NSg Depression + B

109 ESA Low (114) Frustration NSg

5 (HD) ESA High 14 Several primary Physical NS

McMahon (~14) 19992000 outcomes

14 15 including QoL and SIP +[1647] Exercise (at target Hb) B [1986] 83 ESA Low 10

(~10) Performance Psychosocial+

Pediatric Patients

5 105 -12 QoL Diet 25-part Parental Physical Sleep NS

Morris (PDHD)

ESA (112) Exercise Questionnaireh Performance Diet NS 1993 10 8 Tolerance and (after 6 months of NS General Health B [1873] PD Efficiency ESA treatment)

(includes school School Performance NS70 Placebo (~65) attendance) + Psychosocial NS

Annotations a No CVD or LVD b All individuals had LVD or LVH at baseline no CVD c Data shown for ESA arms vs Placebo All statistical comparisons for ESA High vs ESA Low were not significant d Increased by 06 point for each percentage point increase in hematocrit e Free of marked comorbidity f Results given are from repeated measures analysis of variance g P= 005 h 25-Part Parental Questionnaire modified from a previously used questionnaire [1873-appendix] Questions covered various aspects of the childrsquos wellbeing and behavior including mood and psychological behavior social interaction somatic complaints and general health sleep diet school functioning and physical performance

Abbreviations LV Left ventricular LVD Left ventricular dilation LVH Left ventricular hypertrophy QoL Quality of Life Coding of Outcomes Coding of comparison of study arm 1 versus study arm 2 ldquo+rdquo better ldquondash ldquo worse (with reference to benefit for patient) NS Not statistically significant nd Not documented

KEY to Quality of Life Measurement ScalesTests 36-item Medical Outcomes Study Short-Form Health Survey (SF-36) evaluates eight health-related aspects physical function social function physical role emotional role mental health energy painand general health perceptions Each portion of the test is scored on a scale that ranges from 0 (severe limitation) to 100 (no limitation) Functional Assessment of Chronic Illness Therapy (FACIT) is a 27-item compilation of general questions divided into four primary QOL domains Physical Well-Being SocialFamily Well-Being Emotional Well-Being and Functional Well-Being (wwwfacitorg)Health Utilities Index (HUI) provides an overall index of health derived from scores in seven aspects sensation mobility emotion cognition self-care pain and fertility This is an interval scale that can varyin theory between 0 (death) and 1 (perfect health) Kidney Disease Quality of Life (KDQOL) is validated in dialysis patients The Short Form (SF) version was used for assessment of vitality Kidney Diseases Questionnaire (KDQ) is validated in dialysis patients Contains 26 questions divided into five sections patient-specific physical symptoms fatigue depression relationships and frustration All questions are scored on a 7-point Likert scale (7=no problem 1=severe problem)

37

Sickness Impact Profile (SIP) is a behavior-related questionnaire that evaluates non-disease-specific sickness-related behavioral dysfunction It is widely used for end-stage renal disease patients and in studies evaluating quality-of-life improvement with ESA treatment for end-stage renal disease-related anemia The SIP includes 136 items grouped into 12 categories of activity in physical and psychologic dimensions Scores range from 0 (no behavioral dysfunction) to 100 (100 dysfunction in a category or group) Unlike the KPS and the KDQ lower scores for the SIP indicate better quality of life Time Trade-off (TTO) is a unidimensional measure of quality of life that gives a value to a patientrsquos quality of life ranging from 10 (full health) to 0 (patient is indifferent between life and death) This is a utility measure using the time trade-off hypothesis

38

Table 4 Summary Table of RCTs Comparing Hb TargetsESA Doses in Non-CVDMortality Adverse Event Rates in the HD-CKD and PD-CKD Populations

Arm 1 Adverse Events (Arm 1 vs Arm 2 vs Arm 3)

Author Year N

Dialy

sis

Moda

lity

Description of Intervention

Follo

w-up

mon

ths

Arm 2 BP change or Hypertension Access Thrombosis () Seizures Other Reported AEa Mean Hb

Description and Arm 3 (gdL) Definition Outcome Definition Outcome Tota

l DC

of

Drug

Target ESA vs ESA (achieved)

Results

IV or SC ESA ESA 140 Besarab

618 15X pre-trial dose High (127-133) Mean SBP and Both synthetic 39 vs 29 0

HDb adjusted after 2 weeks 14 DBP during the NS grafts and NS mdash 1998 [2002] studyc natural fistulae (P= 0001) 615 IV or SC ESA adjusted ESA 100 0Low (100)

ESA 135-145 AV fistulae 284 IV or SC ESA for 24 wks permanent Overall Treatment

Parfrey High (133) Hypertension not 23 vs 19 Emergent AE in gt10 2005 [303] HD to reach target then 24

ESA 95-115 specified NS catheter non (NS) mdash of patients nd 281 maintained for 72 wks site specific 96 vs 94d

Low (109) embolism

ESA 135ndash160 Individuals with at 216 SC ESA TIW High (134-143) 90 vs 83 Complication in 5 vs 2 in HD least 1 SAE NOS 34

Furuland HD ∆ mean DBP from synthetic graft 51 vs 385 (NS) 2003 [1942] PDe 12 baseline mmHg fistulae catheter patients only mdash Thromboembolic

200 SC ESA TIW or no ESA 9-12 (P= 002) during study (NS) Event 56 vs 47 per 15treatment Low (113-117) arm (NS)f

59 ESA High

lt11 (87)

58 ESA Low (82)Suzuki

1989 [1934] HD IV ESA 3000 IU TIW 2 AE NOSIncreased dose of 5 vs 4 vs 1 mdash mdash mdash 67 vs 83 ndh

Anti-HTN meds individuals vs 17 per armg

57 Placebo (61) SC ESA ESA 13-14 For LVH

73 ESA high arm had a 24 Mean SBP DBP significant Foley High (13) during between 8 vs 142000 [1865] HD wk ldquorampingrdquo phase 11

ESA 95-105 groups and use of SBP and AV access (NS)i mdash mdash nd

73 24 wk maintenance was uarrAnti-HTN similar in both arms Low (105) Anti-HTN meds For LVD NS

39 ESA (116) of individuals 200 Ukg 56 vs Abraham IV ESA TIW with increases in 1991 40 HD after HD session 25- ESA (110) DBP ge10 mm Hg 52 vs mdash mdash mdash mdash nd [1966] 25 100 or 200 IUkg 45 100 Ukg andor Anti-HTN 45

42 ESA (88) meds (NS) 25 Ukg

ESA 115-13 CanEPO 38

IV ESA High (117) 5 vs 5 of Events 0 vs 5 Non-Specific AEs 2

1990 HD 100 IUkg initial dose 6 ESA 95-11 Severe HTN vs 0 Access clotting 7 vs 4 vs 1 vs 25 63 vs 61 vs 65 per [1606 40 titrated to achieve targets Low (102) required withdrawalj (P=001) (P=001) (NS) armk

2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths


Description and ResultsArm 3 (gdL) Definition Outcome Definition Outcome To

tal D

C o

fDr

ug

Target (achieved) ESA 14 HTN Slightly more

Berns 14 HD ESA to maintain target 12 High (140) SBP gt140 mm Hg prevalent in mdash mdash mdash mdash nd1999 [1714] DBP gt90 mm Hg or Low vs High ESA 1014 Low (101) ∆ Anti-HTN meds (NS)

ESA 14McMahon SC ESA 2xwk Mean ABP for peak 8 High (140)1999 [1647] HD if total dose lt20000 IUwk day and nocturnal15 NS mdash mdash mdash mdash 2000 [1986] IV ESA TIW ESA 10 readings taken pre 6[Crossover] if total dose gt20000 IUwk and post HD Low (10)

ESA vs Placebo 125-135 No correlationl

151 IV ESA TIW ESA (108) Correlation ESA armAbraham HD after HD session 2-3 between BP and 1 individual mdash mdash 3 vs 0 mdash nd1991 [1966] change in Hb or individuals 78 100 IUkg Placebo (75) rate of Hb rise withdrawn for

severe high BP Self-admin SC ESA TIW 106-126 Nissenson 78 Blinded phase 4000 IUmL ESA (112) Increased DBP and Mild and SAE

1995 [2078] PD Maintenance phase 6-9 Anti-HTN 55 vs 20 mdash mdash mdash 407 AE in 74 patients vs nd [Crossover] 74 2000 4000 or 10000 Placebo (80) Regimen 325 AE in 63 patientsm

IUmL IV ESA each HD session 10-117 HTN

Bahlmann 53 Blinded Phase (4 wk) ESA (106) SBP ge 160 mm Hg Infection events 0 HD 80 IUkgwk to target 6 or DBP ge 95 mm Hg or 28 vs 11 Clot of AV fistula 9 vs 9 0 vs 0 20 vs 10n1991 [1935]

46 Maintenance phase Placebo (78) Anti-HTN therapy 0 40 IUkgwk initiated or intensified Annotations a For Other Reported AErdquo column outcomes may be recorded in or of events per arm or or of events per patient or given heterogeneity in reporting b All individuals had evidence of congestive heart failure and ischemic heart disease c Pre-study ABP had to be below 160100 for 4 weeks prior to study Subgroup analysis [ref 38] 31 patients Mean day amp nocturnal BP readings for 24 hr were NS at baseline or at follow-up d Of these Pgt005 for all comparisons except headache was greater in the ESA high arm and skeletal pain and surgery were greater in ESA low arm e Includes some pre-dialysis patients stages 4-5 f Thromboembolic events were defined by WHO classification g 7 of 10 continued treatment h Not documented per arm 3 individuals receiving ESA discontinued treatment i Patients with ongoing access problems were specifically excluded The event rates small and study did not have enough statistical power to detect a moderate impact on access thrombosis the proportion using natural fistulae in the Besarab study was 23 compared to 76 in this study j Diastolic BP was increased in patients on ESA compared to placebo P=0001 No statistical difference between High ESA to Low ESA k Nonspecific events include clotting of tubing in dialysis machine flu-like symptoms headache red eye epistaxis or hemorrhage pain in chest abnormal sense of taste aches in bone and muscle l No significant correlation but clinically important increases in BP appeared dose-related with earlier time to peak and peak BP achieved m Mild and severe reactions not otherwise specified Of 408 events such in ESA group 37 (N=149) considered mild severity but possibly related to study medication 1 (N=5) were considered severe or life threatening possibly or definitely related to study medication In the placebo group 26 (N=85) were considered mild severity but possibly related to study medication lt1 (N=2) were considered severe or life threatening possibly or definitely related to study medication n More infections in ESA group but only with URTIviral only pneumonias seen in placebo arm

40

0

0

Coding of Outcomes (Variable per Column Description) Hypertension includes mean changes in SBP DBP MAP increase in use of anti-HTN medications difficult to control hypertension Access Thrombosis synthetic grafts and fistulae

Abbreviations ABP Ambulatory blood pressure AE Adverse events Anti-HTN Anti-hypertension BP Blood pressure (systolicdiastolic blood pressure) DC Discontinuation DBP Diastolic blood pressure HTN Hypertension LVD Left ventricular dilation LVH Left ventricular hypertrophy MAP Mean arterial blood pressure NOS Not otherwise specified SAE Severe adverse effect SBP Systolic blood pressure URTI Upper respiratory tract infection

41

Table 5 Summary Table of RCTs Comparing Hb TargetsESA Doses on Exercise Capacity in the HD-CKD and PD-CKD Populations CKD Arm1 Mean Hb Quality of Life (Arm 1 vs Arm 2 vs Arm 3 )

Author Stage Follow-Applic- Arm 2 (gdL) Primary Outcome ofN Up ability Target Study Quality

Hb (gdL) Arm 3 (achieved) Year Baseline months Scale Test Description Results

135-145 Parfrey 5 (HD) ESA High (131) Left Ventricular Volume Patients are asked to cover as much 2005 324

95-115 Index 6-min Walk Test distance in an enclosed corridor as they NS A24 a [303] 110 ESA Low can in 6 minutes

(108)

CanEPO 5 (HD) ESA High 115 -13 Naughton Stress

NS

1990-1991 (117) Test QoL and Functional[1606 118 6 b 95-11 Capacityc Patients are asked to cover as much A

1837 ESA Low (102) 6-min Walk Test distance in an enclosed corridor as they NS701937] Placebo (74) can in 6 minutes

14 Peak Heart Rate NS McMahon 5 (HD) ESA High (~14) Several primary 19992000 outcomes including [1647] 14 15 QoL and Exercise Exercise Testd Peak O2 consumption + [1986] 83 ESA Low 10 Performance

(~10) Work Done + Pediatric Patients

5 105 -12Morris (PDHD) ESA (112) QoL Diet Exercise Exercise 2-min walking NSe

1993 10 8 Tolerance and PD Tolerance Test C [1873] 70 Placebo (~65) Efficiency Treadmill NSf

Annotations a No CVD or LVD b All individuals had LVD or LVH at baseline no CVD c Data shown for ESA arms vs Placebo All statistical comparisons for ESA High vs ESA Low were not significant d With cycle ergometer e Not a significant improvement but did improve over study time f Only 3 children completed the treadmill test

Coding of Outcomes Coding of comparison of study arm 1 versus study arm 2 ldquo+ rdquo betterldquondashldquo worse (with reference to benefit for patient) NS Not statistically significant nd Not documented

42

C

Table 6 Evidence Matrix of Study Quality by Outcome for RCTs Comparing Different Hb TargetsESA Doses in the HD-CKD and PD-CKD Populations

Methodological Quality Outcome A B C

Author Year N FU(mo) Author Year N FU

(mo) Author Year N FU(mo)

All Cause Mortality

Besarab 1998 Parfrey 2005 Foley 2000 CanEPO 1990-1991

1233 596 146 118

14 24 11 6

Nissenson 1995 Bahlman 1991

152 129

6-9 6

Furuland 2003 416 12

Non-Fatal CV Events Besarab 1998 Parfrey 2005 Foley 2000

1233 596 146

14 24 11

Bahlman 1991 129 6

LVH Parfrey 2005 Foley 2000

596 146

24 11

Sikole 1993 38 12

Hospitalizations Besarab 1998 1233 14 Furuland 2003 416 12 QoL-Global Score Generic Instrument

Parfrey 2005 CanEPO 1990-1991

596 118

24 6

McMahon 1999 2000 Morris 1993

14 11

15 8

QoL-With Kidney-Specific Instruments

Parfrey 2005 CanEPO 1990-1991 Foley 2000

596 118 146

24 6

11


Transfusion Requirement Besarab 1998 CanEPO 1990-1991

1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6

Bahlman 1991 129 6 Furuland 2003 416 12

Other Thrombotic Events Furuland 2003 416 12 Seizures Besarab 1998

CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45

Blood Pressure Change


1233 596 146 118

14 24 11 6


152 129

6-9 6

Furuland 2003 McMahon 1999 2000 Suzuki 1989 Berns 1999 [Quality nd] Abraham 1991 ESA vs ESA amp ESA vs Placebo

416 14 179 28

229

12 15 2

12

25-45

Dialysis Adequacy Besarab 1998 Parfrey 2005 Foley 2000

1233 596 146

14 24 11

Furuland 2005 24 55

Other Adverse Events Parfrey 2005 CanEPO 1990-1991

596 24 Nissenson 1995 Bahlman 1991

152 129

6-9 6

Furuland 2003 Suzuki 1989

416 179

12 2118 6

43

Table 7 Evidence Profile of RCTs Comparing Different Hb TargetsESA Doses in the HD-CKD and PD-CKD Populations

of Studies Total N of Methodologic Directness of Outcome amp Study Patients Quality of Consistency the Evidence Other Quality ofacross Studies including Considerations Design Randomized Studies Applicability Evidence for

Outcome

High for patients with CVDImportant SomeAll-Cause Mortality 7 RCTs 2790 No limitationsa

inconsistenciesb uncertaintyc None Moderate for

others

Non-fatal Some No important Moderate CV Events 5 RCTs 2104 limitationsd inconsistencies Direct Not sparsee

LVH 3 RCTs 780 No limitations Important Direct None Highinconsistenciesf

Hospitalizations 2 RCTs 1649 Some No important Major Sparse data Lowlimitations inconsistencies uncertainityg

QOL ndashGlobal Score Generic 4 RCTs limitationsh inconsistenciesi

739

Some Important Direct None Moderate Instrument

QOL ndash With Kidney Some Important Specific 4 RCTs 1276 limitations inconsistenciesi Direct None Moderate Instruments

Transfusion Some No important Some Moderate Requirement 5 RCTs 1811 limitationsj inconsistencies uncertaintyk None

Access Some No important Some Moderate Thrombosis 6 RCTs 2638 limitationsl inconsistencies uncertaintym None

Other thrombo- Serious Some Lowembolic events 1 RCT 416 limitationsn NA uncertainityo Sparse Data

No important Seizures 4 RCTs 1709 No limitationsp inconsistencies Direct Sparse Data Low

44

Summary of Findings

Qualitative Description of Effect of high versus low hemoglobin target2

No benefit and possible harm The Besarab study had a composite outcome of time to death or fatal MI with 183 deaths and 19 MIs vs 150 and 14 (Hazards ratio [95 CI] 13 [09-19]) Other studies (without large number of CVD patients) show no difference between arms No benefit and possible harm The Parfrey study reported higher CVA rates in the high Hb group 4 vs 1 (P=0045) but did not show differences in other CV event rates No consistent or statistically significant benefit Partial correction of anemia leads to partial regression of LVH full correction has no incremental benefit over partial correction of anemia No benefit The Besarab study and Furuland study showed NS Benefit 2 of 2 studies showed improved Sickness Impact Profile with higher target Trials using SF-36 Facit Fatigue and Health Utilities Index showed no differences Besarab study did not report global score but showed increase in physical function Likely some benefit All studies based on KDQ or derivative 3 of 4 showed fatigue better (with higher Hb) 1 study approached statistical significance P=005 3 of 3 showed depression better 2 of 4 showed physical symptoms better 2 of 3 showed relationships better 0 of 3 showed frustration better 1 study approached statistical significance P=005 Benefit Transfusion rates reduced by as little as 13 to essentially 0 in all studies in higher Hb arms Differences were statistically significant Harm Increased risk of clotting with approximately 10 higher rate of thrombosis Rates of thrombosis were 39 vs 29 in the Besarab study 21 vs 12 in CanEPO Other studies showed no significant differences No benefit No statistically significant difference OR of total Vascular Events was 124 (56 events) vs 10 (47 events) (p=037) Likely no harm No statistically significant difference in the two large studies CanEPO provides breakdown of 3 seizures in ESA vs 0 in Placebo arms the Besarab study does not provide actual data but reports NS

Importance of Outcome

High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate

Directness of of Studies Total N of Methodologic Consistency the Evidence OtherOutcome amp Study Patients Quality of across Studies including Considerations Design Randomized Studies Applicability

Blood Pressure 12 RCTsq 3469 Some Important Major No dose effectu Change Limitationsr inconsistenciess uncertainityt

No important Dialysis Adequacy 4 RCTs 1999 No limitationsw inconsistencies Directx None

Other Adverse 6 RCTs 1590 Serious NAaa Major Sparse and Events limitationsz uncertaintyab imprecise Dataz

Total N of Patients 14 RCTs 3205

Balance of Benefit and Harms Likely benefit for Qol at Hb ge 11 gdL

No benefit and possible harm for mortality and cardiovascular diseaseUncertain trade-offs at each Hb target but likely increasingly unfavorable risk-benefit

ratio with increasing Hb targets

Summary of Findings Quality of Qualitative Description of Effect of high versus Evidence for Outcome low hemoglobin target2

Potential harm In studies looking at high vs low Hb 2 studies showed significant increase in SBPDBP and number of antihypertensive medications In Foley study this was only true for subgroup with LVH not in subgroup with LVD 2 low quality studies suggest increase in DBP with higher ESA or ∆ Hb gt22 gdL In studies comparing ESA vs Placebo (6 RCTs) the majority showed significant increases in SBPDBP or number of antihypertensive medications needed in patients treated with ESAv

Potential harm Lower KtV in HD-CKD patients assigned to target Hb gt 13 in 4 of 4 trials Likely no harm There seemed to be no pattern of higher rates of additional AEs in the higher Hb arms


Moderate

Moderatey

NA

Moderate

High

Very low

Quality of Overall Evidence Moderate

45

Directness of Summary of Findings of Studies Total N of Methodologic Consistency the Evidence OtherOutcome amp Study Patients Quality of Design Randomized Studies across Studies including Considerations Quality of Qualitative Description of Effect of high versus Importance Evidence for Applicability Outcome low hemoglobin target2 of Outcome

Annotations a 4 Grade A 2 Grade B and 1 Grade C trial b The largest study (the Besarab study) showed significantly higher mortality in the higher Hb group This study was composed of the highest risk patients for CVD (ie possible confounder) The remaining studies showed no statistically significant difference c The duration of 3 of 7 trials was lt1 year unclear if this is long enough to measure mortality outcome d 3 Grade A 1 Grade B and 1 Grade C However the 3 A studies comprise 93 of patients Most studies were inadequately powered to study non-fatal CVD events (ie possible confounder) The Besarab study was adequately powered to assess CHF but was stopped early e 55 studies report outcomes of angina 45 non-fatal MI 35 pulmonary edema or heart failure f Foley study shows a trend towards smaller LVMI and less progression in LV dilation in high vs low Hb g Not primary outcome unclear if reason for admission can be solely related to the Hb level h 2 Grade A and 2 Grade C studies some studies not blinded heterogeneity of timing and follow-up i Different instruments j Transfusions were not primary outcome k No trial specified indications for transfusions l 4 Grade A studies 1 Grade B and 1 Grade C the Besarab study had 76 grafts (Other studies not powered to show difference in access clotting) m Most studies do not mention prior history of graft or fistula ie its inherent risk of clotting n Primary outcome had been physical activity study stopped retooled further enrollment then another round of enrollment before recruitment complete o Multiple sites across many countries Only 1 coordinator recorded and classified events centrally and likely did not do site visits Strength was the consistent use of scoring system from the World Health Organization p 2 Grade A studies with ~1300 patients and 1 Grade B study and 1 Grade C study

q These 12 RCTs are 11 adult 1 Peds (n=21) 3 of the 11 are based on ABPM (n=87) Only 6 involve placebo arms others are ESA vs ESA r 4 Grade A 2 Grade B 4 Grade C and 1 grade was not documented s Majority of problems are linked to the wide variation in definitions and measurements with respect tocasual vs ABPM mean of SBP vs DBP different definitions of being hypertensive (being on medications vs specific cut-off) defining worsening BP as both increase in BP and or medication amountdose t Reason Unclear how this translates into clinical outcomes u Restricted to looking at 6 studies involving high vs low dose ESA v In the Furuland study a number of patients were not on ESA in low Hb arm but data not available to extract and only the Abraham study which reported on only blood pressure outcomes from 3 other multi-site trials did not show a difference in BP between ESA vs placebo groupsq 3 Grade A studies and 1 Grade C study x Only issue here is use of URR as lsquosurrogatersquo for KtV in the Foley study y From the HEMO study it is relatively clear that even a statistically significant decrease in KtV isunlikely to affect mortality (presume spKtV gt ~13 URR 66) z Ascertainment of additional AEs was not consistently or prospectively performed Reporting was not standardized Only AEs that occurred during duration of RCTs were captured aa Numbers too small ab Reported events included sick leave infection events hyperkalemia gastrointestinal symptoms or were unspecifiedAbbreviations ABPM Ambulatory blood pressure monitoring BP Blood pressure CHF Congestiveheart failure CV Cardiovascular CVA Cerebrovascular accident DBP Diastolic blood pressure LVH Left ventricular hypertrophy LVMI Left ventricular mass index LVVI Left ventricular volume index KDQ Kidney disease questionnaire MI Myocardial infarction OR Odds ratio SBP Systolic blood pressure SF-36 36-item Medical Outcomes Study Short-Form Health Survey URR Urea reduction ratio

46

Table 8 Summary Table of RCTs Comparing Different Hb TargetsESA Doses on Key Clinical Outcomes in the ND-CKD Population Clinical Outcomes (Arm 1 vs Arm 2 )

Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity Arm 1 Arm 2 Kidney Disease Progression

Mean Hb Mean Hb (gdL) (gdL) CVD

CreatCreat-Trans-

Target Target LVH Mortality Based QoLb event Measurement Events Fusions

(Achiev ed) (Achiev ed) or ∆Creat of ∆eGFR

Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS

∆eGFR darr68 mlmin vs darr50 mlmin

NS

RRT 127 vs 111

Shorter Time to Dialysis

P=003

26 vs 33 See QoL Table A

Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) 6 vs 6h ∆LVMi NS nd


RRT 2 vs 3 mdash See QoL

Table A

Levin 2005 226 ESA High ESA Low 1 vs 1 1 vs 3 RRT [479] 172 3-4 118 (median) 12-14 9-105 NS ∆LVMi NS NSi ∆eGFR NS 8 vs 11 mdash mdash A

(128) (115) NS

Roger 2004 ESA High ESA Low j See QoL

[154 ] 155 3-4 112 24 12-13 9-10 nd ∆LVMi NS nd ∆GFRNS nd mdash Table A (121) (108)

Roth 1994 [2041] ESA Control 0 vs 1 0 vs 1 RRT See QoL Revicki 1995 83 4-5 89 11 117 NS mdash NS ∆eGFR NS 16 vs 13 4 vs 9 Table A [1663] (112) (87)

Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)

nd mdash 3 vs 4 mdash Composite End Point 13 vs 23n

P=00078 mdash mdash B

Doubling CreatinineKuriyama ESA Control 1 vs 2 22 vs 261997 73 3-5 9 14-36 110-117 nd mdash mdash mdash mdash B

[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity

Clinical Outcomes (Arm 1 vs Arm 2 ) Arm 1


(Achiev ed)

Arm 2 Mean Hb (gdL) Target

(Achiev ed)

CVD event LVH Mortality

Kidney Disease Progression CreatCreat-

Based Measurement or ∆Creat of

Events Trans-

Fusions QoLb

∆eGFR

Quali

ty

Kleinman ESA Placebo 1989 14 1-3 94 3 127-133 1 vs 0 mdash 0 1creatinine mdash mdash mdash B [1868] (119) (94) NS

Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12

(120dr) 3 vs 4 mdash 1 vs 6

NS Rate of GFR decline NS mdash mdash See QoL

Table C

Macdougall 2006 [8]s

197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63

Mea n Time to Dialysis or Death NS

mdash mdash C

Clyne 1992 ESA Control [2102] 20 4-5 86 3 100 nd mdash nd ∆GFR NS nd mdash mdash

(117) (94)

ESA ESA ESA Placebo Lim1989 150 IUkg 100 IUkg 50 IUkg ∆Creatine [1666] 14 4-5 91 2 TIW TIW TIW nd mdash 0 clearance NS nd mdash mdash

(137) (120) (117) (8)

Accelerated Watson 1990 ESA Placebo renal failure [1956] 11 5 97 3 126 nd mdash nd mdash 0 vs 2 mdash mdash C

(117) (87) NS

Abraham ESA Placebo 1990 8 3-5 100 2-3 123-133 nd mdash nd ∆SCr NS mdash mdash mdash C [1664] (123) (96)

Annotations Primary outcome a All baseline data given for arm 1 unless otherwise specified b Global Scores if documented are provided here Refer to Hb Targets Quality of Life Table for details of quality of life measurements

48

C

C

c The data and safety monitoring board recommended that the study be terminated in May 2005 at the time of the second interim analysis even though neither the efficacy nor the futility boundaries had been crossed because the conditional power for demonstrating a benefit for the high-Hb group by the scheduled end of study was less than 5 for all plausible values of the true effect for the remaining data Other factors that the board considered included an examination of differences between the treatment groups in adverse events biochemical data and QoL data d From graph Averaged over all measurements e End point was a composite of death myocardial infarction hospitalization for congestive heart failure (excluding renal replacement therapy) and stroke There was statistically significant imbalance at baseline with more individuals with CABG and HTN in higher Hb target arm Statistical significance of the primary outcome is lost after multivariate adjustment for CHF atrial fibrillationflutter serum albumin reticulocyte count and age [HR 124 (95 CI 095162) P=0111] f Follow-up in Arm 1 was 35 months Arm 2 was 36 months g End point was a composite of a first cardiovascular event including sudden death myocardial infarction acute heart failure stroke transient ischemic attack angina pectoris resulting in hospitalization for 24 hours or more or prolongation of hospitalization complication of peripheral vascular disease (amputation or necrosis) or cardiac arrhythmia resulting in hospitalization for 24 hours or more h 6 vs 5 patients for cardiac adverse events and 0 vs 1 patient for ischemic stroke i All adverse events leading to death were determined to be unrelated to the study drug j Pre-power calculation sample size of 75 patientstreatment arm needed to detect difference in LVMi of 15 gm2 at α =005 (2-sidedCI) with 80 power Number actually analyzed at 2 year follow-up was less in each arm k In February 2002 case series of PRCA were reported in patients receiving mainly SC EPO alpha Although no such adverse events had been recorded in any of the enrolled patients in our study enrollment of new patients was suspended with 88 of the target enrollment being achieved In November 2002 the indication of SC EPO alpha administration in chronic renal failure patients was withdrawn because PRCA had been documented in a further number of patients receiving EPO in Europe Australia and Canada At this point all study patients were informed of this modification and SC EPO alpha was discontinued l Results at 12-month measurement m Because no patient in the deferred arm group had their Hb fall to lt9gdl they were not treated with EPO and are considered to be a control group n End point was a composite of doubling of creatinine initiation of renal replacement therapy or death Adjusted analysis for baseline serum creatinine resulted in a trend toward a higher risk in patients in the ESA High group [hazard ratio of 037 (95 CI 018-073 P=0004) o Because of safety concerns in late 2002 related to the risk for EPO-induced pure red cell aplasia and subsequent labeling changes for SC administration of Eprex the study was terminated prematurely by the sponsor Thus GFR decline over 1 year could only be assessed in 163 patients (75 in Arm 1 and 88 in Arm 2) p Intended 36 months but study stopped early Therefore study duration was 4 months of stabilization phase and a median of 7 months in the High Hb and 86 months in the Low Hb group of maintenance phase q Hemoglobin target was 14-15 gdl for men and 13-14 gdl in women r In the High Hb group the achieved Hb for men was 142 gdl and for women was 136 gdl In the low Hb group the achieved Hb for men was 121 gdl and for women was 115 gdl s The study which began in 1997 was stopped early (December 2002) by the sponsor due to contraindication of the SC route of administration for EPO Patients were followed-up for reasons of safety after their discontinuation and were subsequently continued on a different EPO preparation to maintain their well-being The results presented here provide some of the final available trial data in CKD patients administered EPO by the SC route before discontinuation of the study t Follow-up in Arm 1 was 24 months Arm 2 was 21 months u Group B results include one death that occurred after dialysis started v For HR inverse was taken of those reported in the article to convert to HR of higher versus lower Hb target

Abbreviations CV Cardiovascular CVD Cardiovascular disease LVH Left ventricular hypertrophy LVMi Left ventricular mass index eGFR Estimated glomerular filtration rate RRT Renal replacement therapy Dialysis or Transplantation

Coding of Outcomes NA Not applicable nd Not documented NS Not significant

49

Table 9 Summary Table of RCTs Comparing Different Hb TargetsESA Doses on Quality of Life in the ND-CKD Population CKD Arm 1 Arm 2

Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)

Primary Outcome of Study

Scale Test

Quality of Life (Arm 1 vs Arm 2)

Global QoL VitalityFatigue Other Measures of QoL Quality

3-4 SF-36 (at year 1) Vitality +

General health + Mental health +

Physical function + Physical Role + Social function +

Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event

SF-36 (at year 2) Vitality + General Health +

Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36

(at 15 months) Vitality nd General Health + A

SF-36 Physical Health NS Roger 2004 3-4 ESA High ESA Low Change in LV (at 24 months) Mental Health NS [154] 155a 24 a 12-13 9-10 Mass RQoLP A

112 (121) (108) (at 24 months) NS

LASA (nd when assessed) NS

3-4 KDQ (nd when assessed) Fati gue NS NSSingh 2006

[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event

SF-36 (nd when assessed) Vitality NS Emotional Role -

Others NS

B

Selected SIP Scales (at 12 months

4-5 Selected SF-36 Scales

Revicki1995 ESA Control (at 12 months) [1663] 83 Health-Related Roth1994 12 117 Quality of Lifeb QoAL [2041] (112) (90) (at 12 months)

CESDS 89 (at 12 months)

Sexual Dysfunction Interview

(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36

(after 4 months of stabilization)

Vitality + Others NS C

Vitality +

Home Management NS Alertness Behavior NS Social Interaction NS Physical Function +Role Function NS

Health Distress NS B

Life

Satisfaction NS

Depres

sion NS

NS 50

Annotations a Excluded patients with unstable or poorly controlled angina severe congestive heart failure (grade III-IV) severe chronic respiratory disease symptomatic peripheral vascular disease or a created arteriovenous fistula b The interview incorporated dimensions of HRQL identified to cover the expected effects ESA therapy and anemia in pre-dialysis CKD patients based on review of medical literature and discussions with nephrologists and nurses The intent was to comprehensively measure broad areas of functioning and well-being

Abbreviations CVD Cardiovascular disease GFR Glomerular filtration rate LV Left ventricular Coding of Outcomes Coding of comparison of study arm 1 versus study arm 2 ldquo+rdquo better ldquondash ldquo worse (with reference to benefit for patient) NS Not statistically significant nd Not documented

Key for QOL Scales 36-item Medical Outcomes Study Short-Form Health Survey (SF-36) evaluates eight health-related aspects physical function social function physical role emotional role mental health energy pain and general health perceptions Each portion of the test is scored on a scale that ranges from 0 (severe limitation) to 100 (no limitation) Center for Epidemiologic Studies Depression Scale (CESDS) has been used extensively in epidemiologic studies of the general community and chronic disease populations It is scored from 0 to 60 with higher scores indicating a greater number of depression symptoms Kidney Diseases Questionnaire (KDQ) is validated in dialysis patients Contains 26 questions divided into five sections patient-specific physical symptoms fatigue depression relationships and frustration All questions are scored on a 7-point Likert scale (7=no problem 1=severe problem) Linear Analogue Self-Assessment (LASA) questionnaire is a brief measurement tool consisting of 3 questions that evaluate energy level daily activity and overall QOL[38] It uses a 100-mm linear analogue scale for responses the opposite ends represent the negative and positive extremes for each measured variable with 0 being the lowest score and 100 being the highest (best HRQOL) This tool is easy to use and takes 1 to 2 minutes to complete Patients draw a line on the 100-point scale to reflect their perceived QOL with the score being measured as the number of millimeters from the zero reference point [Coates A et al On the receiving end--II Linear analogue self-assessment (LASA) in evaluation of aspects of the quality of life of cancer patients receiving therapy European Journal of Cancer amp Clinical Oncology 1983 19(11)1633-7] Quality of American Life Survey (QoAL) is a life satisfaction scale from Campbell et al The Quality of American Life New York NY Russell Sage Foundation 1976 Renal Quality of Life Profile (RQoLP) although renal-specific is comprehensive in its own right (the construct coming from the patients themselves) Its perspective is social psychological consisting of five dimensions namely eating and drinking physical activity leisure psychosocial aspects and treatment effects with each representing several QOL indicators [Salak S Quality-of-Life Assessment in Patients on Peritoneal Dialysis Proceedings of the ISOD rsquo95-The VIIth Congress of the ISPD Peritoneal Dialysis International 1996 Vol 16 Supplement 1] Sickness Impact Profile (SIP) established generic health status measure of disability associated with chronic illness

51

Table 10 Summary Table of RCTs Comparing Hb TargetsESA Doses in Non-CVDMortality Adverse Event Rates in the ND-CKD Population

Arm 1 Arm 2 Adverse Events (Arm 1 vs Arm 2 )Mean Hb Mean Hb BP change or Hypertension Any non-CVD mortality AEa

Author Year RefID N

CKD

Stag

e


Follo

w-up

(mo) (gdL) (gdL) DC of Drug or

WithdrawTarget Target Definition Outcome Reason for DC or Withdraw(Achieved) (Achieved) (N arm)

715 Singh 2006 [1] 717

3-4

Initially received10000 U ESA SC weekly for 3 weeks Subsequent ESA permitted every other week if Hb level

was stable

16 ESA High

135 (127)

ESA Low 113

(114) Mean systolic BP from baseline

to the end of the study darr23 mm Hg vs darr26 mm Hg

(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302

3-4 Initial dose of ESA 2000 IU

SC weekly dose Dose adjustments to achieve target

were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb

88c SC ESA 2000 IU once weekly Ritz 2007

[3] 82c 1-3 SC ESA 2000 IU once

weekly if Hb lt105 gdL

15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---

SC ESA 2000 IU once Levin 2005

85 weekly ESA High ESA Low Individuals with at least 1 [479] 3-4 SC ESA 2000 IU once 24 12-14 9-105 recorded BP gt 14090d 51 vs 54 nd ---

87 weekly if Hb lt90 gdL (128) (115)

Roger 2004 75 SC ESA ESA High ESA Low 2 yr adjusted mean systolic and Systolic NS [154] 3-4 24e 12-13 9-10 diastolic BP between high and Diastolic 81 vs 78 0 vs 3 nd

80 SC ESA if Hb lt9 gdL (121) (108) low ESA arms P=0009

Roth1994 [2041]

43

40

1-3

SC ESA 50 IUkgwk which could be increased by 75 IUkgwk adjusted

monthly Placebo

12 ESA 117

(112)

Placebo

(87) Reported Hypertension Not otherwise specified 26 vs 10 1 vs 0

Individual with nausea vomiting

GI bleed

45 SC ESA 50 Ukg once weekly HTN 1 vs 1

Gouva 2004 [4]

43 3-5

SC ESA 50 Ukg once weekly if Hb lt90 gdL

225 ESA Early

13 (129)

ESA Latef

13 (103) BP Change NS

--- ---

7 SC ESA 100 IUkg TIW

Kleinman 1989 [1868]

1-3 3 ESA

127-133 (119)

Placebo

(94)

∆Anti-hypertensive medication over the 3-month amp ∆Mean

SBP DBP during study NS 0 ---

7 Placebo

52

195

Rossert 2006 [5]

195

3-4

Initial dose of ESA was 25-100 IUkg Therapy was

given in weekly SC doses Dose adjustments were

permitted in steps of 4 weeks as needed to achieve target

Hb level with a permitted increase in weekly dose of

25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS

6 vs6 PRCA (N=2 in ESA high group) angina

pruritus

65 SC ESA 1000U twice weekly Macdougall 2006 [8]

132

2-5

SC ESA 2000 U thrice weekly if Hb lt90 gdL

36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5

ESA dose of 300 IUkg maintained until Hct uarr10 of initial value or stabilized at

Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)

uarr in SBP by 10 mmHg or more or uarr in DBP by 5 mmHg or

made adjustments anti-hypertension medications

67 vs 38 4 vs 0 ESA stopped until BP controlled

Lim 1989 [1666]

4 4 3 3

4-5

IV ESA 50 100 or 150 IUkg TIW

Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)

ndash ndash 0 vs 0 vs 0 vs 1 Seizure

Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo

(87) Mean Blood Pressure during

trial No increase with ESA treatment 2 vs 0

Patients withdrew because of suspicion

of acceleration of renal failure

IV or SC ESAAbraham 4 50 -150 IUkg TIW ESA Placebo Increase in antihypertensive 1990 3-5 19 123-133 50 vs 50 nd ---

[1664] 4 Placebo (123) (96) medications

Annotations a Any non-CVDmortality related adverse event that required discontinue of drug or resulted in withdraw from study b 12 of the 127 (9) renal replacement therapy patients in the high ESA group and 8 of the 111 (7) renal replacement therapy patients in the Low ESA group experienced a thrombotic event c Two patients from a single center were randomly assigned but were excluded from all analysis because the center was closed due to major violation of Good Clinical Practice guidelines d Statistically significant difference in ∆ DBP between arms (P=0027) However baseline DBP was higher in Late ESA group There were 4 episodes of hypertension as an adverse event None were attributed to the study drug and all were resolved e Or until RRT f Because no patient in the deferred arm group had their Hb fall to lt9gdl they were not treated with EPO and are considered to be a control group Abbreviations AE Adverse events BP Blood pressure DC Discontinuation DBP Diastolic blood pressure GI Gastrointestinal HTN Hypertension MAP Mean arterial blood pressure PRCA Pure red cell aplasia RRT Renal replacement therapy SBP Systolic blood pressure Coding of Outcomes NA Not applicable nd Not documented NS Not significant

53

Table 11 Evidence Matrix of Study Quality by Outcome for RCTs Comparing Different Hb TargetsESA Doses in the ND-CKD Population

Methodological Quality A B COutcome

FU FU FUAuthor Year N Author Year N Author Year N(mo) (mo) (mo) Singh 2006 1432 16 Gouva 2004 88 225 Rossert 2006 390 78 Drueke 2006 603 36 Kuriyama 1997 73 14-36 Macdougall2007 197 22All Cause Mortality Levin 2005 172 24 Kleinman 1989 14 3 Lim 1989 14 2 Roth 1994 Revicki 1995 83 11 Singh 2006 1432 16 Rossert 2006 390 78Kleinman 1989 14 3 Drueke 2006 603 36

Non-Fatal CV Events Ritz 2007 172 15 Levin 2005 172 24 Roth 1994 Revicki 1995 83 11 Drueke 2006 603 36 Macdougall 2007 197 22 Ritz 2007 172 15LVH Levin 2005 172 24 Roger 2004 155 24 Drueke 2006 603 36 Singh 2006 1432 16 Rossert 2006 390 78

QoL Ritz 2007 172 15 Roth 1994 Revicki 1995 83 11 Roger 2004 155 24

Drueke 2006 603 36Transfusion Requirement Roth 1994 Revicki 1995 83 11

Singh 2006 1432 16 Gouva 2004 88 225 Rossert 2006 390 78 Drueke 2006 603 36 Kuriyama 1997 73 14-36 Macdougall 2007 197 22 Ritz 2007 172 15 Kleinman 1989 14 3 Clyne 1992 20 3Kidney Disease

Progression Levin 2005 172 24 Lim 1989 14 2 Roger 2004 155 24 Watson 1990 11 3 Roth 1994 Revicki 1995 83 11 Abraham 1990 8 2-3

Lim 1989 14 2Seizures Watson 1990 11 3

Singh 2006 1432 16 Gouva 2004 88 225 Rossert 2004 390 78 Drueke 2006 603 36 Kleinman 1989 14 3 Macdougall 2007 197 22 Ritz 2007 172 15 Clyne 1992 20 3Blood Pressure

Change Levin 2005 172 24 Watson 1990 11 3 Roger 2004 155 24 Abraham 1990 8 2-3 Roth 1994 Revicki 1995 83 11

54

Table 12 Evidence Profile of RCTs Comparing Different Hb TargetsESA Doses in the ND-CKD Populations Directness of the Summary of Findings of Studies Total N of Methodologic Consistency Evidence Other Quality ofOutcome amp Patients Quality of across Studies including Considerations Evidence for Qualitative Description of Effect Size Importance of

Study Design Randomized Studiesa Applicability Outcome

No major High All Cause Mortality 10 RCTs 3066 No limitations No important uncertainty

Noneinconsistencies Some uncertaintyc Moderate

No major HighCVD No important uncertainty (including mortality) 7 RCTs 2866 No limitations inconsistencies Some

None Moderate uncertaintyd

LVH 5 RCTs 1299 No limitations No important No major None Highinconsistencies uncertainty

Some QoL 6 RCTs 2835 No limitations inconsistencye Some uncertainyf None Low

Transfusion Some No important Some LowRequirement 2 RCTs 686 limitationsb inconsistencies uncertaintyg None

No important Kidney Disease inconsistencies Some

Moderate Progression 15 RCTs 3432 No limitations among large high uncertaintyh None quality studies

Seizures 2 RCTs 25 Major NA Some uncertaintyi Sparse data Very lowlimitations

Blood Pressure Change No important Moderate (Hypertension) 13 RCTs 3345 No limitations inconsistencies Some uncertaintyj None

Total N of patients 15 RCTs 3432

Balance of Benefit and Harm Likely benefit for QoL in particular vitality with higher Hb targets

Harm for mortality and cardiovascular disease with Hb targets gt 13 compared to lt 115Uncertain trade-offs at each Hb target but likely increasingly unfavorable risk-benefit-

ratio with increasing Hb targetsAbbreviations BP Blood pressure LVH Left ventricular hypertrophy QoL Quality of Life

(Higher versus Lower Hb Targets)

No benefit

Harm Singh HR 148 (097227) Drueke HR 151 (087263)

No benefit

Harm Singh HR 134 (103174) Drueke HR128 (069189)

No benefit

Potential benefit but inconsistent findings with four studies showing some benefit for QoL and two showing no benefit There was inconsistency across studies regarding which subscales showed statistically significant benefit In one study that showed benefit for QoL in 66 subscales at 1 yr 4 subscales lost statistical significance at 2 years Three out of four studies showing some benefit for QoL tested vitality and found benefit in this subscale In contrast one of the two studies which showed no benefit for any QoL scale also assessed vitality

Potential benefit

No benefit based on large high quality studies

No harm potential benefit 0 vs 2 individuals in all studies noting seizures

Potential harm requiring increased intensity of monitoring and treatment

Quality of Overall Evidence Low for QoL

Moderate for other important outcomes

Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55

Annotations a See Evidence Matrix for quality grades of individual studies assessed for this outcome b Quality for the evidence for this particular outcome is lower than the quality of the studies for their primary outcome c Outcome not statistically significant in primary studies d In Singh study statistical significance of the primary outcome is lost after multivariate adjustment for CHF atrial fibrillationflutter serum albumin reticulocyte count and age [HR 124 (95 CI 095162) P=0111] e See qualitative description of effect size f Unable to assess the comparability of baseline QoL or compare the magnitude of the changes across different studies because of incomplete reporting g Indications for transfusions were not per protocol h Different degrees of blood pressure control and dietary modifications as concomitant therapies i Seizures were not primary or secondary outcomes of the studies j Inconsistent reporting and use of different definitions for HTN Some uncertainty about clinical relevance of reported changes in BP

56

BIOGRAPHICAL AND DISCLOSURE INFORMATION

John W Adamson MD has served as Executive Vice President for Research and Director of the Blood Research Institute of the Blood Center of Southeastern Wisconsin in Milwaukee since 1998 He holds the position of Professor of Medicine (Hematology) at the Medical College of Wisconsin Before moving to Milwaukee he was Director of the Lindsley F Kimball Research Institute of the New York Blood Center since 1989 and President of the Center from 1989 to 1997 Dr Adamson received his MD from the University of California Los Angeles after which he trained at the University of Washington in Seattle and at the National Institutes of Health in Bethesda MD in the fields of internal medicine and hematology Before assuming his position in New York Dr Adamson was professor of medicine and head of the Division of Hematology at the University of Washington Dr Adamson is a past-President of the American Society of Hematology and past chairman of its committees on scientific affairs and transfusion medicine Dr Adamson served as a member of the Advisory Council of the National Institute of Diabetes Digestive and Kidney Diseases of the National Institutes of Health In 1988 he was designated clinical research professor by the American Cancer Society and elected a Fellow of the American Association for the Advancement of Science Dr Adamson is past editor-in-chief of Blood past editor of the Journal of Cellular Physiology and founding editor of Current Opinion in Hematology Altogether he has authored or co-authored more than 400 scientific publications Dr Adamson reported no relevant financial relationships

Jeffrey S Berns MD earned his MD at Case Western Reserve University then went on to complete his internship and residency in Internal Medicine at University Hospitals of Cleveland He did a fellowship in Nephrology and was an Associate Research Scientist in the Department of Physiology at Yale University Dr Berns recently was promoted to Professor of Medicine at the University of Pennsylvania School of Medicine where he is Director of Clinical Nephrology and Director of the Renal Fellowship Program for the Renal Electrolyte and Hypertension Division Dr Berns was a member of the NKF DOQI and KDOQI Anemia Workgroup He has published and lectured on topics related to chronic kidney disease anemia management in patients with CKD and other areas in clinical nephrology He is co-editor of Drug Prescribing in Renal Failure-Dosing Guidelines for Adults He also serves on the editorial board of Seminars in Dialysis American Journal of Kidney Diseases and Clinical Journal of the American Society of Nephrology He is an active investigator in clinical trials related to anemia treatment in patients with CKD Advanced Magnetics Inc GrantResearch Support (no personal income) Hoffman LaRocheGrantResearch Support (no personal income)

Kai-Uwe Eckardt MD (Work Group Co-Chair) is Professor of Medicine and Chief of Nephrology and Hypertension at the University of ErlangenndashNuremberg Germany He received his MD from the Westfaumllische Wilhelms-Universitaumlt Muumlnster Germany In 1993 following post-graduate training in internal medicine pathology and physiology he was appointed Assistant Professor of Physiology at the University of Regensburg Germany Subsequently he continued his training in internal medicine and nephrology at the Chariteacute Humboldt University in Berlin where he was appointed Associate Professor of Nephrology in 2000 His major scientific interests are in the molecular mechanisms and physiologicalpathophysiological relevance of oxygen sensing and the management of anemia Professor Eckardt is Subject Editor

57

of Nephrology Dialysis and Transplantation and serves on the editorial board of several other journals He contributed to the development of the EBPGs for Anemia Management and is a member of the executive committee of KDIGO Dr Eckardt is associated with CREATE and TREAT studies Amgen Consultant Speaker Biotech GrantResearch Support (no personal income)Jansen Cilag GrantResearch Support (no personal income) Johnson amp Johnson GrantResearch Support (no personal income)Ortho GrantResearch Support (no personal income)Roche Consultant Speaker GrantResearch Support (no personal income)

Steven Fishbane MD currently is Chief of Nephrology and Associate Chair of the Department of Medicine at Winthrop-University Hospital (WUH) in Mineola NY as well as Professor of Medicine at SUNY Stony Brook School of Medicine He is the Medical Director of WUH Dialysis Network which includes 4 outpatient dialysis units and 3 hospital units Dr Fishbane serves as the Chairman of the Long Island Health Network Quality Council Chairman of the Department of Medicine Quality Improvement Program WUH Chairman of Clinical Guidelines Committee WUH Co-Chairman of WUH Patient Care Committee and Associate Chairman of the Department of Medicine WUH Dr Fishbane is a member of the Network 2 Medical Review Board Amgen GrantResearch Support (no personal income) Consultant Speaker Honoraria Roche GrantResearch Support (no personal income) Consultant Speaker Honoraria Watson GrantResearch Support (no personal income) Consultant Speaker Honoraria

Robert N Foley MD was born in Ireland and received his undergraduate MD from University College Cork He completed Internal Medicine training in Cork later moving to Saint Johnrsquos Newfoundland Canada where he completed a residency in nephrology as well as a Masters in Clinical Epidemiology From 1999 to 2002 Dr Foley worked at Hope Hospital Salford UK and has been Director Nephrology Analytical Services Minneapolis Medical Research Foundation since September of 2002 Dr Foley also is a Co-Editor of the American Journal of Kidney Diseases His major interest is in outcomes research especially the interplay of cardiovascular and renal disease Dr Foley is active in anemia correction trials as well as in the USRDS Cardiovascular Special Study Center Amgen GrantResearch Support (no personal income) Roche GrantResearch Support (no personal income)

Sana Ghaddar PhD RD is an Assistant Professor at the American University of Beirut Lebanon She has over 10 years experience in the renal and clinical dietetics field She was one of the renal dietitians at the Peninsula Nephrology Inc in San Mateo CA currently a division of Satellite Healthcare and has served as a Principle Investigator for two research studies that examined the ability of heme-iron-polypeptide to sustain response to Recombinant Erythropoietin in both hemo and peritoneal dialysis patients She has presented these and other studies she has been involved in at many national conferences including National Kidney Foundation American Dietetics Association and Gerontological Society of America Dr Ghaddar has received research funds grants or contracts from the American University of Beirut Research Board Additionally Dr Ghaddar is associated with the Kidney Nutrition Education amp Life Improvement (KNELI) study funded by the American University of Beirut Dr Ghaddar reported no relevant financial relationships

58

John S Gill MD MS obtained his MD from the University of British Columbia (UBC) in 1995 He completed his internal medicine training at the University of Western Ontario in 1998 and his nephrology training in 2000 at UBC He then completed his transplantation training at TuftsndashNew England Medical Center in Boston and obtained in Masters in Clinical Care Research from Tufts in 2002 Dr Gill currently is assistant professor of medicine in the division of Nephrology at UBC and has a cross appointment at TuftndashNew England Medical Center Dr Gillrsquos research interests focus on clinical outcomes in kidney transplant recipients He is the principal investigator and co-investigator on current Canadian Institutes of Health Research (CIHR) Kidney Foundation and Michael Smith Funded studies Dr Gill is chair of the Canadian Society of Transplantation Work Group for Pan-Canadian database development member of the Canadian Organ Replacement Register Advisory Board and member of a number of NKF Committees Dr Gill reported no relevant financial relationships

Kathy Jabs MD is a Pediatric Nephrologist who trained at Babies Hospital NY and Childrenrsquos Hospital Boston She has been a faculty member at Childrenrsquos in Boston (1988 to 1996) and was the Director of Dialysis and Renal Transplantation at Childrenrsquos Hospital of Philadelphia (1996 to 2000) She currently is the Director of Pediatric Nephrology at Vanderbilt Childrenrsquos Hospital and an Associate Professor of Pediatrics at Vanderbilt University School of Medicine Nashville TN Dr Jabs has had a long-standing interest in the care of children with CKD Dr Jabs is associated with the CKid and FSGS studies sponsored by the NIH Dr Jabs reported no relevant financial relationships

Francesco Locatelli MD is Scientific Director and Head of the Department of Nephrology and Dialysis of A Manzoni Hospital Lecco and Postgraduate Professor of Nephrology at Brescia and Milan Universities in Italy He is past-President of the European Renal Associationndash European Dialysis and Transplantation Association Italian Society of Nephrology and International Society of Blood Purification and was Chairman of the EBPGs Amgen Advisory Board Roche Advisory Board Speaker

Iain C Macdougall MD is a combined medical and science graduate of Glasgow University Scotland from which he was awarded a First Class Honours BSc in Pharmacology in 1980 For the last 10 years Dr Macdougall has been Consultant Nephrologist and Honorary Senior Lecturer at Kingrsquos College Hospital in London He has developed both a clinical and a basic science research interest in factors affecting responsiveness to erythropoietic agents He has served on the Working Parties responsible for both (1999 and 2004) EBPGs on Renal Anaemia Management and he currently is a member of the US Anemia Guidelines Working Group the KDIGO Board of Directors the Global Scientific Advisory Board for PRCA and the Council of the European Renal Association He is frequently invited to lecture both nationally and internationally on this topic and he has co-authored the section on renal anaemia for the last 2 editions of the Oxford Textbook of Clinical Nephrology and the current edition of Comprehensive Clinical Nephrology He also is Subject Editor for Nephrology Dialysis Transplantation Amgen GrantResearch Support Advisory Board Roche GrantResearch Support Advisory Board Speaker

59

Patricia Bargo McCarley RN MSN NP is a nephrology nurse practitioner at Diablo Nephrology Medical Group in Walnut Creek California Ms McCarley received her BSN and MSN from Vanderbilt University She is active in ANNA having served on local regional and national committees She is currently a member of the Nephrology Nursing Journal Board Ms McCarley has authored many publications including most recently chapters in the 2005 ANNA Nephrology Nursing Standards of Practice and Guidelines for Care and the Contemporary Nephrology Nursing Principles and Practice (2nd Ed) Amgen Speaker

Allen R Nissenson MD FACP is Professor of Medicine and Director of the Dialysis Program at the David Geffen School of Medicine at UCLA where he has developed a comprehensive dialysis program He is President of the National Anemia Action Council (NAAC) and recently chaired a Chancellorrsquos committee at UCLA on Financial Conflicts of Interest in Clinical Research He currently is serving on a University of California Task Force on Institutional Conflicts of Interest in Research Dr Nissenson is Chair of the Faculty Executive Council for the David Geffen School of Medicine at UCLA He has served as Chair of the Southern California ESRD Network during its organizational years in the early 1980s and recently was elected as President-elect He is Chair of the Medical Review Board Dr Nissenson currently is consulting for RMS Disease Management Inc and for Philtre Ltd an organization developing new renal replacement therapies based on the application of nanotechnology to this field Dr Nissenson served as a Robert Wood Johnson Health Policy Fellow of the Institute of Medicine in 1994 to 1995 He is Immediate Past President of the Renal Physicians Association and has served as a member of the Advisory Group overseeing the entire NKF-DOQI as well as serving as a member of the anemia Work Group Dr Nissensonrsquos major research interests focus on the quality of care for patients with CKD His research has included extensive clinical trials of new devices and drugs related to renal disease Dr Nissenson is co-principal investigator on a recently obtained National Institutes of Health Center Grant looking at issues of disparities in health care delivery for patients with CKD He is the author of 2 dialysis textbooks both in their fourth editions and was the founding Editor-in-Chief of Advances in Renal Replacement Therapy an official journal of the NKF He currently is Editor-in-Chief of Hemodialysis International the official journal of the International Society for Hemodialysis He has more than 340 publications in the field of nephrology dialysis anemia management and health care delivery and policy Among his numerous honors is the Presidentrsquos Award of the NKF He delivers more than 25 invited lectures each year and developed and chairs an annual second-year nephrology fellows preceptorship program serving more than 65 Fellows from throughout the United States Affymax Consultant Amgen Consultant DaVita Consultant Fibrogen Consultant Medgenics Consultant OBI Researcher Roche Consultant

Gregorio T Obrador MD MPH is Professor of Medicine and Dean at the Universidad Panamericana School of Medicine in Mexico City He also serves as Adjunct Staff at the Division of Nephrology of the TuftsndashNew England Medical Center and Assistant Professor of Medicine at the Tufts University School of Medicine in Boston While doing a clinical research fellowship at the TuftsndashNew England Medical Center and a Master of Public Health at Harvard

60

University he began a line of investigation in the area of CKD Through several publications he and others showed that the prendashESRD management of patients with CKD is suboptimal and that this is an important factor for the high morbidity and mortality observed in these patients A particular area of interest has been anemia management before the initiation of dialysis therapy By using population registry data he and his colleagues have reported trends in anemia and iron management Dr Obrador has served as reviewer for several journals including Kidney International the Journal of the American Society of Nephrology and the American Journal of Kidney Diseases He also has been a member of the Advisory Board of the NKF-KDOQI Dr Obrador reported no relevant financial relationships

John C Stivelman MD is Chief Medical Officer of the Northwest Kidney Centers and Associate Professor of Medicine in the Division of Nephrology Department of Medicine at the University of Washington School of Medicine in Seattle Dr Stivelman obtained his MD degree from the University of Pennsylvania completed his residency in Internal Medicine at Harbor- UCLA Medical Center and nephrology training at Brigham and Womenrsquos Hospital Dr Stivelman has been involved in investigative efforts to optimize hematopoietic therapy for dialysis patients since the phase III recombinant erythropoietin trials in 1986 His major interests and literature contributions center on iron utilization mechanisms of resistance of erythropoietin therapy improved dialytic survival in disadvantaged populations and the interaction of regulatory issues with optimization of care Dr Stivelman has served as the Chair of the Network 6 Medical Review Board and a member of the Forum of ESRD Networks Board of Directors He currently serves as medical director of one of Northwest Kidney Centersrsquo free-standing facilities and as a member of the Boards of Directors of the Renal Physiciansrsquo Association and the Northwest Renal Network (Network 16) Amgen GrantResearch Support Auxilium GrantResearch Support Shire Inc GrantResearch Support Watson GrantResearch Support Speaker Advisory Board

David B Van Wyck MD (Work Group Co-Chair) is Professor of Medicine and Surgery at the University of Arizona College of Medicine in Tucson After completing his undergraduate studies at Washington University St Louis Dr Van Wyck earned his MD at the University of Arizona College of Medicine There he undertook a research fellowship in Surgical Biology and completed his residency in Internal Medicine and fellowship in Nephrology Dr Van Wyck has written or contributed to books book chapters articles and abstracts on basic iron metabolism and reticuloendothelial function and on clinical aspects of iron and anemia in patients with CKD On the subject of anemia and kidney disease he pursues research provides consultation to industry including American Regent Amgen and Gambro Healthcare and reviews manuscripts for the major nephrology journals Dr Van Wyck served on the original KDOQI Anemia Work Group He assumed Chair responsibilities in 2002 Frequently invited to speak Dr Van Wyck has lectured on the molecular and cellular control of erythropoiesis and iron homeostasis diagnostic and treatment issues in anemia and iron management protocol development in the treatment of dialysis-associated anemia and new approaches to iron and erythropoietin replacement therapy American Regent GrantResearch Support Consultant Speaker Amgen Consultant Speaker DaVita Part-time employee DaVita (Gambro) Advisory Board Speaker Consultant

61

Ortho BiotechJohnson amp Johnson Consultant Speaker Vifor Consultant Speaker

Colin T White MD is a pediatric nephrologists at BC Childrenrsquos Hospital in Vancouver and clinical assistant professor at the University of British Columbia in Canada He completed medical school in Ottawa and Pediatrics in London Ontario There he did 3 years of pediatric nephrology training before moving to Vancouver to complete 3 more years He has been on staff as a Pediatric Nephrologist since 2003 and currently is the Director of Dialysis at BC Childrenrsquos Hospital He has a number of research interests including medical education optimizing dialysis care in children estimation of GFR and CKD and its complications Dr Whitersquos interest in anemia management is geared toward children He is presently completing a Masters degree in Medical Education Dr White is associated with the CKid study and various NAPRTC protocols Dr White reported no relevant financial relationships

62

NOTICE

SECTION I USE OF THE CLINICAL PRACTICE GUIDELINE AND CLINICAL PRACTICE RECOMMENDATIONS

The Clinical Practice Guideline (CPG) and Clinical Practice Recommendations (CPRs) are designed to provide information and assist decision-making They are not intended to define a standard of care and should not be construed as one Neither should they be interpreted as prescribing an exclusive course of management

Variations in practice will inevitably and appropriately occur when clinicians take into account the needs of individual patients available resources and limitations unique to an institution or type of practice Every health-care professional making use of the CPG and CPRs is responsible for evaluating the appropriateness of applying them in the setting of any particular clinical situation

SECTION II CONFLICTS OF INTEREST DISCLOSURE

The National Kidney Foundation (NKF) makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal professional or business interest of a member of the Work Group

Specifically all members of the Work Group are required to complete sign and submit a Conflict of Interest Disclosure and Attestation form showing all such relationships that might be perceived as real or potential conflicts of interest All affiliations are published in their entirety at the end of this document in the Work Group membersrsquo biographical sketch and are on file at the NKF

2















3












4

TABLE OF CONTENTS



5

TABLES













FIGURES






6


2


6








7








8











9


139








10






11

214






247

12





265

13






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62















3












4

TABLE OF CONTENTS



5

TABLES













FIGURES






6


2


6








7








8











9


139








10






11

214






247

12





265

13






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62












4

TABLE OF CONTENTS



5

TABLES













FIGURES






6


2


6








7








8











9


139








10






11

214






247

12





265

13






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62

TABLE OF CONTENTS



5

TABLES













FIGURES






6


2


6








7








8











9


139








10






11

214






247

12





265

13






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62

TABLES













FIGURES






6


2


6








7








8











9


139








10






11

214






247

12





265

13






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62


2


6








7








8











9


139








10






11

214






247

12





265

13






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62








8











9


139








10






11

214






247

12





265

13






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62











9


139








10






11

214






247

12





265

13






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62


139








10






11

214






247

12





265

13






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62






11

214






247

12





265

13






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62

214






247

12





265

13






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62





265

13






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62






14








15









16


386


396




17



18











19






20













21


22






















23






24



(should)






minority may not





25

Meta-analyses



26




















27


























28



























29

REFERENCES













30















31













32




Follow-up

N of Patients


Group Control Group

Outcomes Start Date

Projected End Date


PI nd (Amgen)









25yr

36 wks

2 yrs

2 yrs

~4000

260

204

140

Hb target 130


Hb target 13-149

Hb target 13-15

Hb target gt90


Hb target 11-129

Hb target 105-115







806

104

404

Enrollment

period 15yrs


(1208)



33



Arm 2 (gdL)

Quali

ty


CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi

lity


ESA v ESA

Besarab 1998 [2002]i 1233 HD-CKD 102 14

(median) ESA High

ESA Low

140 (127-133)

100 (100)



NSc NS ∆KtV

-003 vs +006 Plt0001

21 vs 31 P=0001

See QoL Table A

Parfrey 2005 [303] 596 HD-CKD 110 185

ESA High

ESA Low

135 - 145 (131)

95 - 115 (108)

CVA 4 vs 1

P=0045 Other CVD

NS

NS NS mdash ∆URR

0 vs +2 Plt005


Foley 2000 [1865]

CanEPO 1990-1991 [16061837 1937]

146

118

HD-CKD

HD-CKD

104

70

12

6

ESA High

ESA Low

ESA High

ESA Low

Placebo

13 ndash 14 (13)h

95 - 105 (105)h

115 - 13 (117)

95 ndash 11 (102)

(74)

NS

mdash

NS

mdash

NS

NS

mdash

mdash

KtV LVD 141 vs 150

P=0025

mdash

mdash


Plt005f

See QoL Table

See QoL Table

A

A


Suzuki 1989 [1934]


McMahon 19992000 [1647] [1986]

416

179

24

14

4-5 PD-CKD HD-CKDd

HD-CKD

HD-CKD

HD-CKD

109

63

111

85

12

2

55

15

ESA High

ESA Low

ESA Highe

ESA Low Placebo

ESA High

ESA Low

ESA Highj

ESA Low

135ndash160 (136) 9-12

(113-117) lt11 (87) (82) (61)

135ndash160 (143) 9-12

(109) 14

(14) 10

(10)

mdash

mdash

mdash

---

mdash

mdash

mdash

mdash

NS

mdash

mdash

mdash

NS

mdash

mdash

mdash

mdash

mdash

∆KtV -01 vs 0

nd

mdash

mdash


Plt005

mdash

mdash

See QoL Table

mdash

See QoL Table

C

C

C

C

34

Author Year N

CKD

Stag

e

Base

linea

Hb (g

dL)

Mean

Fol

low-

up

mon

ths

Appl

icabi


Quali

ty



ESA v Placebo


Placebo (80) Plt005










35


Author Year N

CKD Stage

Baseline Hb (gdL)

Follow-Up


Arm 1 Arm 2

Arm 3


(achieved)

Primary Outcome of

Study ScaleTest



Quality

KDQOL subscales

Parfrey 2005 [303]

324 5 (HD)

110

24 a ESA High

ESA Low

135-145 (131)

95-115 (108)





SF-36 Vitality+

Fatigue NS


Physical NS

ESA High 115-13 (117)


Depression NS

CanEPO 1990-1991 [1606 1837 1937]

118

5 (HD)

70

6

ESA Low


Placebo

95-11 (102)

115-13 (117) plus

95-11 (102)

(74)


SIP (at 6 months)

TTO (at 6 months)

KDQ (at 6 months

SIP (at 6 months)

TTO (at 6 months

NS

+

Fatigue +


Psychosocial NS

NS



NS

A

Besarab 1998 [2002]

1233 5 (HD)

102

14 ESA High

ESA Low

140 (127-133)

100 (100)




Foley 2000 [1865]

94

5 (HD)

101

12 e

ESA High

ESA Low

13-14 (13)

95-105 (105)




KDQf

(at 12 months)


Fatigue +

Vital

ity NS





A


36





Fatig







Pediatric Patients


Morris (PDHD)






37


38



Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



l DC

of

Drug


Results







Low (109) embolism




59 ESA High

lt11 (87)













2 1837] 40 Placebo (74) 0

39


Author Year N

Dialy

sis

Moda

lity


Follo

w-up

mon

ths



tal D

C o

fDr

ug











40

0

0



41






(108)


NS









42

C





All Cause Mortality


1233 596 146 118

14 24 11 6


152 129

6-9 6



1233 596 146

14 24 11

Bahlman 1991 129 6


596 146

24 11

Sikole 1993 38 12



596 118

24 6


14 11

15 8



596 118 146

24 6

11



1233 118

14 6


152 129

6-9 6

Suzuki 1989 179 2

Access Thrombosis


1233 596 146 118

14 24 11 6



CanEPO 1990-1991 1233 118

14 6

Bahlman 1991 129 6 Abraham 1991 229 25-45



1233 596 146 118

14 24 11 6


152 129

6-9 6


416 14 179 28

229

12 15 2

12

25-45


1233 596 146

14 24 11

Furuland 2005 24 55



152 129

6-9 6


416 179

12 2118 6

43



Outcome



others





739







44

Summary of Findings




High

High

Moderate

Moderate

High

High

High

High

Moderate or High

Moderate













Moderate

Moderatey

NA

Moderate

High

Very low


45




46


Quali

ty

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi



CreatCreat-Trans-



Singh 2006 [1]c 1432 3-4 101 16

ESA High 135

(127d)

ESA Low 113

(114d)

125 vs 97e

HR 134 (103174)

P=003 mdash

52 vs 36 HR 148

(097227) NS

mdash

RRT 155 vs 134

HR 119 (094149)

P=015


Drueke 2006 [2] 603 3-4 116 36f

ESA High 13-15 (134d)

ESA Low 105-115

(116d)

58 vs 47g

HR 128 (069189)

NS ∆LVMi NS

31 vs 21 HR151

(087263)v

NS


NS

RRT 127 vs 111


P=003


Ritz 2007 [3] 172 1-3 119 15

ESA High 13-15 (135)

ESA Low 105-115




Table A


(128) (115) NS




Gouva 2004 [4]k 88 3-5 101 225

ESA Early 13

(129l)

ESA Latem

13 (103l)




[1869] (118) (84) NS P=00003 RRT 14 vs 20

P=0008

47

Auth

or Y

ear

RefID

N of

Pat

ients

Ra

ndom

ized

CKD

Stag

e

Base

linea

Hb

(gd

L)

Mean

Fol

low-

up

(mo)

Appl

icabi

lity



(Achiev ed)


(Achiev ed)




Events Trans-

Fusions QoLb

∆eGFR

Quali

ty


Rossert 2006 [5] 390o 3-4 116 118p

ESA High13-15q

(140dr)

ESA Low 11-12



Table C


197 2-5 109 22t ESA Early

11 (11)

ESA Late 11

(105) nd Worst LVM

NS 1 vs 6u mdash

RRT 30 vs 63


mdash mdash C


(117) (94)


(137) (120) (117) (8)


(117) (87) NS



48

C

C




49


Author Year N

Stage

Baseline Hb (gdL)

Follow-Up



(achieved)


(achieved)


Scale Test






Drueke 2006 [2] 603

116

36 ESA High

13-15 (134)

ESA Low 105-115

(116) CVD event


Others NS

A

1-3Ritz 2007 [3] 172

119 15

ESA High 13-15 (135)

ESA Low 105-115

(121) Change in LV

Mass SF-36



112 (121) (108) (at 24 months) NS



[1] 1432

101

16 ESA High

135 (127)

ESA Low 113

(114) CVD event


Others NS

B






(at 12 months)

3-4Rossert 2006 [5]

390 116

78 ESA High

13-15 (140)

ESA Low 11-12 (120)

GFR decline SF-36



Vitality +



Life

Satisfaction NS

Depres

sion NS

NS 50




51



Author Year RefID N

CKD

Stag

e


Follo

w-up



715 Singh 2006 [1] 717

3-4


was stable

16 ESA High

135 (127)

ESA Low 113



(NS) 147 vs 160 nd

(not for RRT)

301Drueke 2006 [2] 302



were permitted 36

ESA High 13-15 (134)

ESA Low 105-115

(116) HTN

89 vs 59 (30 vs 20)

P=0005 17 vs10

NS ndb


[3] 82c 1-3 SC ESA 2000 IU once


15 ESA High

13-15 (135)

ESA Low 105-115

(121) HTN 15 vs 9

(17 vs 11) 0 ---






Roth1994 [2041]

43

40

1-3


monthly Placebo

12 ESA 117

(112)

Placebo



GI bleed


Gouva 2004 [4]

43 3-5


225 ESA Early

13 (129)

ESA Latef


--- ---



1-3 3 ESA

127-133 (119)

Placebo

(94)



7 Placebo

52

195

Rossert 2006 [5]

195

3-4





25 IUkg

36 ESA High

13-15 (130)

ESA Low 11-12 (118)

HTN 26 vs 22

(13 vs 11) NS


pruritus


132

2-5


36 ESA High

11 (11)

ESA Low 9-11

(105) HTN 14 vs 9

(22 vs 7)

Clyne 1992 [2102]

12

8

4-5


Hct gt30

Placebo

3 ESA 100

(117)

Placebo

(94)




Lim 1989 [1666]

4 4 3 3

4-5


Placebo 2

ESA 150

(137)

ESA 100

(120)

ESA 50

(117)

Plac ebo (8)


Watson 1990 [1956]

5

6 5

SC ESA 100 IUkg TIW

Placebo 3

ESA 126

(117)

Placebo








53












54



















No benefit


No benefit


No benefit


Potential benefit






Outcome

High

High

Moderate

High

Moderate

High

Moderate

Moderate

55


56





57





58





59




60




61



62

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kdoqi clinical practice guideline and clinical practice recommendations for anemia in chronic