appendix 1: literature search strategies

A-1

APPENDIX 1: LITERATURE SEARCH STRATEGIES

Table 1: Literature search strategies Database and Platform Search Strategies Date of

Search Coverage of Search

MEDLINE (OVID)

1 11096 26 7 erythropoietin.rn. 13140 2 Aranesp.tw. 58 3 Biosynthetic Erythropoietin.tw. 2 4 (Darbe and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or epoietin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis)).tw. 1 5 Darbepoietin.tw. 15 6 Darbopoetin.tw. 1 7 (e-alpha or e-alfa).tw. 1080 8 epo alfa.mp. 2 9 Epo alpha.tw. 11 10 Epo beta.tw. 8 11 Epoch.tw. 1266 12 Epoconn.tw. 1 13 Epoietin.tw. 34 14 Epoetin alfa/ or epoetin alfa.tw. 982 15 Epoetin alpha.mp. 97 16 (Epoietin alpha or Epoietin alfa).tw. 18 17 Epoetinum alfa.mp. 1 18 Epogen.tw. 53 19 Epogin.tw. 1 20 Eprex.tw. 105 21 Erantin.tw. 0 22 Erypo.tw. 11 23 Erythropoietin/ or Erythropoietin.tw. 18616 24 erythropoetin$.tw. 80 25 erythropoiten-alpha.tw. 0 26 Espo.tw. 4 27 Exprex.tw. 1 28 Gal-GlcNAc-Epo.rn. 1 29 Heberitro.rn. 1 30 Hematopoieti$.mp. 70882 31 Hemax.tw. 1 32 Hemopoietin.tw. 82 33 huepo.tw. 423 34 (Krn 321 or Krn321).tw. 2 35 (Krn 5702 or Krn5702).tw. 2 36 Marogen.tw. 3 37 Neorecormon.tw. 24 38 Nesp.tw. 55 39 Nespo.tw. 2 40 Procrit.tw. 25 41 r-HuEPO.tw. 408 42 (r adj HuEPO).tw. 408 43 rHuEPO.tw. 1309 44 R-Hu Epo.tw. 46 45 Erythropoietin, Recombinant/ 2357 46 Recombinant.mp. and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis).tw. [mp=title, original title, abstract, name of substance word, subject heading word] 6972 47 Recombinant Proteins/ and (e-beta or e-alfa or e-alpha or Epo or Epoetin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis).tw. 2994 48 Recormon.tw. 25 49 Renal Erythropoietic Factor.tw. 33 50 Repotin.tw. 1 51 (Snb 5001 or Snb5001).tw. 5 52 or/1-51 90039 53 Chronic kidney disease.tw. 2062 54 Chronic Kidney Disorder.tw. 2 55 Kidney Failure, Chronic/ or chronic kidney failure.tw. 58114

12 Dec 2006 1966 to November Week 3 2006

A-2

Database and Platform Search Strategies Date of Search

Coverage of Search

56 Chronic Kidney Insufficiency.tw. 172 57 Chronic Nephropathy.tw. 251 58 Chronic Renal Disease.tw. 1711 59 Chronic renal failure.tw. 16952 60 Renal Insufficiency, Chronic/ or Chronic Renal Insufficien$.tw. 3543 61 End-stage renal disease.tw. 10937 62 End-stage renal failure.tw. 3722 63 End-stage kidney disease.tw. 222 64 End-stage kidney failure.tw. 46 65 Esrd.tw. 5323 66 ESRF.tw. 534 67 Kidney Chronic Failure.tw. 2 68 Kidney Insufficien$.tw. 498 69 Kidney failure/ or kidney failure.tw. 8136 70 ((kidney$ or renal) adj2 (diseases$ or failure$ or insufficien$)).tw. 74649 71 ((kidney$ or renal) adj2 (diseases$ or failure$ or insufficien$)).tw. 74649 72 Terminal Kidney Failure.tw. 82 73 or/53-72 114020 74 52 and 73 4061 75 clinical trial.pt. 470405 76 randomized.ab. 156592 77 placebo.ab. 100962 78 clinical trials.sh. 140293 79 randomly.ab. 112290 80 trial.ti. 70021 81 or/75-80 682173 82 animals.sh. 4172974 83 humans.sh. 10026435 84 82 not (82 and 83) 3152830 85 81 not 84 643915 86 74 and 85 804

MEDLINE economic (OVID) 1 economics/ or value of life/ or economics, medical/ or economics, hospital/ or budgets/ or models, economic/ or markov chains/ or monte carlo method/ or decision trees/ or quality of life/ or patient satisfaction/ or quality-adjusted life years/ or economics.fs. 354821 2 ((econom$ or cost or costly or costing or costed or price or prices or pricing or priced or discount or discounts or discounted or discounting or expenditure$ or budget$ or afford$ or pharmacoeconomic$ or pharmaco) adj1 economic$).tw. 72689 3 (cost$ adj1 (util$ or effective$ or efficac$ or benefit$ or consequence$ or analy$ or minimi$ or saving$ or breakdown or lowering or estimate$ or variable$ or allocation or control or illness or sharing or life or lives or affordabl$ or instrument$ or technolog$ or day$ or fee or fees or charge or charges)).tw. 53726 4 ((unit or drug or hospital or health care or medical) adj1 (cost or costs)).tw. 12747 5 (markov or markow or monte carlo).tw. 12755 6 (decision adj1 (tree$ or analy$ or model$)).tw. 5009 7 ((value or values or valuation) adj2 (money or monetary or life or lives)).tw. 1746 8 (QOL or QOLY or QOLYs or HRQOL or QALY or QALYs).tw. 9667 9 ((quality adj1 life) or (willingness adj1 pay) or (quality adj1 adjusted life year$)).tw. 3537 10 or/1-9 434846 11 11096 26 7 erythropoietin.rn. 12600 12 Aranesp.tw. 59 13 Biosynthetic Erythropoietin.tw. 2 14 (Darbe and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or epoietin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis)).tw. 1 15 Darbepoietin.tw. 16 16 Darbopoetin.tw. 1

21 Feb 2007 1950 to February Week 2 2007

A-3


Coverage of Search

17 (e-alpha or e-alfa).tw. 1031 18 epo alfa.mp. 3 19 Epo alpha.tw. 12 20 Epo beta.tw. 8 21 Epoch.tw. 1218 22 Epoconn.tw. 1 23 Epoietin.tw. 32 24 Epoetin alfa/ or epoetin alfa.tw. 930 25 Epoetin alpha.mp. 92 26 (Epoietin alpha or Epoietin alfa).tw. 17 27 Epoetinum alfa.mp. 1 28 Epogen.tw. 51 29 Epogin.tw. 1 30 Eprex.tw. 101 31 Erantin.tw. 0 32 Erypo.tw. 9 33 Erythropoietin/ or Erythropoietin.tw. 17782 34 erythropoetin$.tw. 82 35 erythropoiten-alpha.tw. 0 36 Espo.tw. 4 37 Exprex.tw. 1 38 Gal-GlcNAc-Epo.rn. 1 39 Heberitro.rn. 1 40 Hematopoieti$.mp. 63079 41 Hemax.tw. 1 42 Hemopoietin.tw. 82 43 huepo.tw. 401 44 (Krn 321 or Krn321).tw. 2 45 (Krn 5702 or Krn5702).tw. 2 46 Marogen.tw. 3 47 Neorecormon.tw. 22 48 Nesp.tw. 52 49 Nespo.tw. 2 50 Procrit.tw. 29 51 r-HuEPO.tw. 387 52 (r adj HuEPO).tw. 387 53 rHuEPO.tw. 1246 54 R-Hu Epo.tw. 45 55 Erythropoietin, Recombinant/ 2248 56 Recombinant.mp. and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis).tw. [mp=title, original title, abstract, name of substance word, subject heading word] 6568 57 Recombinant Proteins/ and (e-beta or e-alfa or e-alpha or Epo or Epoetin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis).tw. 2873 58 Recormon.tw. 24 59 Renal Erythropoietic Factor.tw. 34 60 Repotin.tw. 1 61 (Snb 5001 or Snb5001).tw. 5 62 or/11-61 81451 63 Chronic kidney disease.tw. 2167 64 Chronic Kidney Disorder.tw. 2 65 Kidney Failure, Chronic/ or chronic kidney failure.tw. 55865 66 Chronic Kidney Insufficien$.tw. 170 67 Chronic Nephropathy.tw. 243 68 Chronic Renal Disease.tw. 1717 69 Chronic renal failure.tw. 16409 70 Renal Insufficiency, Chronic/ or Chronic Renal Insufficien$.tw. 3550 71 End-stage renal disease.tw. 10588 72 End-stage renal failure.tw. 3628 73 End-stage kidney disease.tw. 221 74 End-stage kidney failure.tw. 48 75 Esrd.tw. 5168 76 ESRF.tw. 516 77 Kidney Chronic Failure.tw. 1 78 Kidney Insufficien$.tw. 488

A-4


Coverage of Search

79 Kidney failure/ or kidney failure.tw. 7865 80 ((kidney$ or renal) adj2 (diseases$ or failure$ or insufficien$)).tw. 73272 81 ((kidney$ or renal) adj2 (diseases$ or failure$ or insufficien$)).tw. 73272 82 Terminal Kidney Failure.tw. 83 83 or/63-82 111182 84 62 and 83 3919 85 10 and 84 373 86 from 85 keep 1-373 373

EMBASE (OVID)

1 Aranesp.tw. 383 2 Biosynthetic Erythropoietin.tw. 1 3 Darbe.mp. 3 4 Darbepoietin.tw. 21 5 Darbopoetin.tw. 4 6 Dynepo.tw. 12 7 e-beta.tw. 545 8 (e-alpha or e-alfa).tw. 442 9 Epo.tw. 5047 10 Epo alfa.tw. 2 11 Epo alpha.tw. 4 12 Epo beta.tw. 7 13 Epoch.tw. 941 14 Epoconn.tw. 1 15 Epoietin.tw. 93 16 Epoietin beta.tw. 9 17 Epoetin alfa.tw. 601 18 Epoetin alpha.tw. 50 19 Epoietin alpha.tw. 13 20 Epogen.tw. 475 21 Epogin.tw. 36 22 Eprex.tw. 858 23 Erantin.tw. 13 24 Erypo.tw. 137 25 exp Erythropoietin/ or Erythropoietin.tw. 16541 26 Erythropoetin.tw. 98 27 Espo.tw. 21 28 Exprex.tw. 11 29 Globuren.tw. 17 30 Hematopoietin.tw. 122 31 Hemopoietin.tw. 59 32 Heberitro.tw. 1 33 Hemax.tw. 9 34 Huepo.tw. 422 35 (Krn 321 or Krn321).tw. 2 36 (Krn 5702 or Krn5702).tw. 8 37 Marogen.tw. 20 38 Neorecormon.tw. 232 39 Nesp.tw. 62 40 Nespo.tw. 9 41 Novel Erythropoiesis Stimulating Protein/ or Novel Erythropoiesis Stimulating Protein.tw. 905 42 Procrit.tw. 404 43 r-HuEPO.tw. 406 44 (r adj HuEPO).tw. 406 45 rHuEPO.tw. 1203 46 R-Hu Epo.tw. 39 47 Recombinant human erythropoietin.tw. 2940 48 recombinant EPO.tw. 107 49 recombinant erythropoietin/ 8097 50 Recombinant Protein/ and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis).tw. 122 51 Recormon.tw. 198 52 Recormone.tw. 2 53 Repotin.tw. 1

12 Dec 2006 1988 to 2006 Week 49

A-5


Coverage of Search

54 (Snb 5001 or Snb5001).tw. 5 55 (Tyb 5220 or Tyb5220).tw. 20 56 or/1-55 22404 57 Chronic kidney disease/ or chronic kidney disease.tw. 4084 58 Chronic Kidney Disorder.tw. 1 59 Chronic kidney failure/ or Chronic kidney failure.tw. 12454 60 Chronic Kidney Insufficien$.tw. 23 61 Chronic Nephropathy.tw. 154 62 Chronic Renal Disease.tw. 1082 63 Chronic renal failure.tw. 10383 64 Chronic Renal Insufficien$.tw. 1548 65 End-stage renal disease.tw. 8816 66 End-stage renal failure.tw. 3028 67 End stage kidney disease.tw. 164 68 End-stage kidney failure.tw. 30 69 Esrd.tw. 4196 70 ESRF.tw. 427 71 Kidney Insufficien$.tw. 72 72 Kidney failure/ or kidney failure.tw. 42260 73 Renal Failure.tw. 35010 74 Renal Insufficien$.tw. 7492 75 Terminal Kidney Failure.tw. 35 76 or/57-75 75033 77 56 and 76 4079 78 exp clinical trial/ 411836 79 randomi?ed.ti,ab. 162962 80 placebo.ti,ab. 81073 81 (ae or dt or to).fs. 1520460 82 randomly.ti,ab. 84045 83 trial.ti,ab. 143569 84 groups.ti,ab. 565538 85 78 or 79 or 80 or 82 or 83 or 84 1039327 86 animal/ 7202 87 human/ 4759997 88 86 not (86 and 87) 5790 89 85 not 88 1038936 90 77 and 89 1224

EMBASE economic (OVID) 1 Health economics/ or economic evaluation/ or pharmacoeconomics/ or pharmacoeconomics.fs. or economic aspect/ or quality adjusted life year/ or quality of life/ 119911 2 Aranesp.tw. 391 3 Biosynthetic Erythropoietin.tw. 1 4 Darbe.mp. 3 5 Darbepoietin.tw. 22 6 Darbopoetin.tw. 4 7 Dynepo.tw. 12 8 e-beta.tw. 556 9 (e-alpha or e-alfa).tw. 443 10 Epo.tw. 5093 11 Epo alfa.tw. 2 12 Epo alpha.tw. 4 13 Epo beta.tw. 7 14 Epoch.tw. 957 15 Epoconn.tw. 1 16 Epoietin.tw. 94 17 Epoietin beta.tw. 9 18 Epoetin alfa.tw. 608 19 Epoetin alpha.tw. 51 20 Epoietin alpha.tw. 14 21 Epogen.tw. 480 22 Epogin.tw. 36 23 Eprex.tw. 871 24 Erantin.tw. 13 25 Erypo.tw. 140 26 exp Erythropoietin/ or Erythropoietin.tw. 16742 27 Erythropoetin.tw. 99

21 Feb 2007 1988 to 2007 Week 7

A-6


Coverage of Search

28 Espo.tw. 21 29 Exprex.tw. 11 30 Globuren.tw. 17 31 Hematopoietin.tw. 122 32 Hemopoietin.tw. 59 33 Heberitro.tw. 1 34 Hemax.tw. 9 35 Huepo.tw. 426 36 (Krn 321 or Krn321).tw. 3 37 (Krn 5702 or Krn5702).tw. 8 38 Marogen.tw. 20 39 Neorecormon.tw. 241 40 Nesp.tw. 64 41 Nespo.tw. 9 42 Novel Erythropoiesis Stimulating Protein/ or Novel Erythropoiesis Stimulating Protein.tw. 951 43 Procrit.tw. 412 44 r-HuEPO.tw. 408 45 (r adj HuEPO).tw. 408 46 rHuEPO.tw. 1213 47 R-Hu Epo.tw. 39 48 Recombinant human erythropoietin.tw. 2960 49 recombinant EPO.tw. 109 50 recombinant erythropoietin/ 8217 51 Recombinant Protein/ and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis).tw. 125 52 Recormon.tw. 198 53 Recormone.tw. 2 54 Repotin.tw. 1 55 (Snb 5001 or Snb5001).tw. 5 56 (Tyb 5220 or Tyb5220).tw. 20 57 or/2-56 22712 58 Chronic kidney disease/ or chronic kidney disease.tw. 4347 59 Chronic Kidney Disorder.tw. 1 60 Chronic kidney failure/ or Chronic kidney failure.tw. 12596 61 Chronic Kidney Insufficien$.tw. 23 62 Chronic Nephropathy.tw. 156 63 Chronic Renal Disease.tw. 1095 64 Chronic renal failure.tw. 10475 65 Chronic Renal Insufficien$.tw. 1571 66 End-stage renal disease.tw. 8946 67 End-stage renal failure.tw. 3059 68 End stage kidney disease.tw. 168 69 End-stage kidney failure.tw. 33 70 Esrd.tw. 4272 71 ESRF.tw. 433 72 Kidney Insufficien$.tw. 78 73 Kidney failure/ or kidney failure.tw. 42939 74 Renal Failure.tw. 35391 75 Renal Insufficien$.tw. 7597 76 Terminal Kidney Failure.tw. 36 77 or/58-76 76194 78 57 and 77 4148 79 1 and 78 421 80 from 79 keep 1-421 421

All EBM Reviews (OVID)

1 11096 26 7 erythropoietin.mp. [mp=ti, ab, tx, kw, ct, ot, sh, hw] 1 2 Aranesp.tw. 14 3 Darbepoitin.tw. 1 4 Darbepoietin.tw. 3 5 Darbopoetin.tw. 4 6 (e-alpha or e-alfa).tw. 67 7 e-beta.mp. [mp=ti, ab, tx, kw, ct, ot, sh, hw] 121 8 epo alfa.mp. 3 9 Epo alpha.tw. 3 10 Epo beta.tw. 3

12 Dec 2006

4th Quarter 2006

A-7


Coverage of Search

11 Epoch.tw. 62 12 Epoietin.tw. 17 13 Epoetin alfa/ or epoetin alfa.tw. 228 14 Epoetin alpha.mp. 30 15 (Epoietin alpha or Epoietin alfa).tw. 9 16 Epogen.tw. 10 17 Eprex.tw. 23 18 Erantin.tw. 3 19 Erypo.tw. 7 20 Erythropoietic.tw. 101 21 Erythropoietin/ or Erythropoietin.tw. 1384 22 erythropoetin$.tw. 27 23 Espo.tw. 19 24 Heberitro.tw. 1 25 Hematopoieti$.mp. 1137 26 huepo.tw. 122 27 (Krn 5702 or Krn5702).tw. 3 28 Marogen.tw. 5 29 Neorecormon.tw. 20 30 Nesp.tw. 19 31 Procrit.tw. 15 32 r-HuEPO.tw. 119 33 (r adj HuEPO).tw. 119 34 rHuEPO.tw. 259 35 R-Hu Epo.tw. 13 36 Erythropoietin, Recombinant/ 242 37 Recombinant.mp. and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis).tw. [mp=ti, ab, tx, kw, ct, ot, sh, hw] 883 38 Recombinant Proteins/ and (e-beta or e-alfa or e-alpha or Epo or Epoetin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis).tw. 261 39 Recormon.tw. 11 40 (Snb 5001 or Snb5001).tw. 6 41 (Tyb 5220 or Tyb5220).tw. 2 42 or/1-41 3032 43 Chronic kidney disease.tw. 134 44 Kidney Failure, Chronic/ or chronic kidney failure.tw. 1876 45 Chronic Kidney Insufficien$.tw. 5 46 Chronic Nephropathy.tw. 13 47 Chronic Renal Disease.tw. 114 48 Chronic renal failure.tw. 901 49 Renal Insufficiency, Chronic/ or Chronic Renal Insufficien$.tw. 248 50 End-stage renal disease.tw. 644 51 End-stage renal failure.tw. 231 52 End-stage kidney disease.tw. 48 53 End-stage kidney failure.tw. 5 54 Esrd.tw. 384 55 ESRF.tw. 55 56 Kidney Insufficien$.tw. 66 57 Kidney failure/ or kidney failure.tw. 406 58 Renal failure.tw. 2590 59 Renal Insufficiency/ or renal insufficien$.tw. 842 60 Terminal Kidney Failure.tw. 2 61 or/43-60 4825 62 42 and 61 392

EconLit (EBSCO)

Econom* and erythropo* 1 Econom* and Aranesp 0 Econom* and Darbe* 2 Econom* and darbo* 0 Econom* and e-alpha or e-alfa 0 Econom* and epo alfa 0 Econom* and Epo alpha 0 Econom* and Epo beta 0 Econom* and Epoch in abstract 95

7 Mar 2007 1969 to Feb 2007

A-8


Coverage of Search

Econom* and Epoconn 0 Econom* and Epoietin 0 Econom* and Epoetin 0 Econom* and Epoetinum 0 Econom* and Epogen or epogin 0 Econom* and Eprex 0 Econom* and Erantin 0 Econom* and Erypo or Espo or Exprex 0 Econom* and Heberitro or Hematopoieti* or Hemax or Hemopoietin 0 Econom* and huepo 0 Econom* and Krn 321 or Krn321 or Krn 5702 or Krn5702 0 Econom* and Marogen 0 Econom* and Neorecormon 0 Econom* and Nesp 0 Econom* and nespo 0 Econom* and Procrit 0 Econom* and R-Hu Epo 0 Econom* and Recormon 0 Econom* and Repotin 0 Econom* and Snb 5001 or Snb5001 0 (decision tree* or quality of life or patient satisfaction or quality-adjusted life year*) and (erythropo* or Aranesp or Darbe* or darbo*) 2 (decision tree* or quality of life or patient satisfaction or quality-adjusted life year*) and (e-alpha or e-alfa or epo alfa or Epo alpha or Epo beta) 0 (decision tree* or quality of life or patient satisfaction or quality-adjusted life year*) and (epoch in abstract) 0 (decision tree* or quality of life or patient satisfaction or quality-adjusted life year*) and (Epoconn or Epoietin or Epoetin or Epoetinum or Epogen or epogin) 1 (decision tree* or quality of life or patient satisfaction or quality-adjusted life year*) and (Eprex or Erantin or Erypo or Espo or Exprex) 0 (decision tree* or quality of life or patient satisfaction or quality-adjusted life year*) and (Heberitro or Hematopoieti* or Hemax or Hemopoietin or huepo ) 0 (decision tree* or quality of life or patient satisfaction or quality-adjusted life year*) and (Krn 321 or Krn321 or Krn 572 or Krn572 or Marogen) 0 (decision tree* or quality of life or patient satisfaction or quality-adjusted life year*) and (Neorecormon or Nesp or nespo or Procrit or R-Hu Epo) 0 (decision tree* or quality of life or patient satisfaction or quality-adjusted life year*) and (Recormon or Repotin or Snb 51 or Snb51 ) 0 (cost* or price* or pricing or discount* or expenditure* or budget* or afford* or pharmacoeconomic*) and (erythropo* or Aranesp or Darbe* or darbo*) 2 (cost* or price* or pricing or discount* or expenditure* or budget* or afford* or pharmacoeconomic*) and (e-alpha or e-alfa or epo alfa or Epo alpha or Epo beta) 0 (cost* or price* or pricing or discount* or expenditure* or budget* or afford* or pharmacoeconomic*) and (epoch in abstract) 0 (cost* or price* or pricing or discount* or expenditure* or budget* or afford* or pharmacoeconomic*) and (Epoconn or Epoietin or Epoetin or Epoetinum or Epogen or epogin) 2

A-9


Coverage of Search

(cost* or price* or pricing or discount* or expenditure* or budget* or afford* or pharmacoeconomic*) and (Eprex or Erantin or Erypo or Espo or Exprex) 0 (cost* or price* or pricing or discount* or expenditure* or budget* or afford* or pharmacoeconomic*) and (Heberitro or Hematopoieti* or Hemax or Hemopoietin or huepo) 0 (cost* or price* or pricing or discount* or expenditure* or budget* or afford* or pharmacoeconomic*) and (Krn 321 or Krn321 or Krn 572 or Krn572 or Marogen) 0 (cost* or price* or pricing or discount* or expenditure* or budget* or afford* or pharmacoeconomic*) and (Neorecormon or Nesp or nespo or Procrit or R-Hu Epo) 0 (cost* or price* or pricing or discount* or expenditure* or budget* or afford* or pharmacoeconomic*) and (Recormon or Repotin or Snb 51 or Snb51 ) 0 (markov or markow or monte carlo or decision analy* or decision model*) and (erythropo* or Aranesp or Darbe* or darbo*) 1 (markov or markow or monte carlo or decision analy* or decision model*) and (e-alpha or e-alfa or epo alfa or Epo alpha or Epo beta) 0 (markov or markow or monte carlo or decision analy* or decision model*) and (epoch in abstract) 4 (markov or markow or monte carlo or decision analy* or decision model*) and (Epoconn or Epoietin or Epoetin or Epoetinum or Epogen or epogin) 0 (markov or markow or monte carlo or decision analy* or decision model*) and (Eprex or Erantin or Erypo or Espo or Exprex) 0 (markov or markow or monte carlo or decision analy* or decision model*) and (Heberitro or Hematopoieti* or Hemax or Hemopoietin or huepo) 0 (markov or markow or monte carlo or decision analy* or decision model*) and (Krn 321 or Krn321 or Krn 572 or Krn572 or Marogen) 0 (markov or markow or monte carlo or decision analy* or decision model*) and (Neorecormon or Nesp or nespo or Procrit or R-Hu Epo) 0 (markov or markow or monte carlo or decision analy* or decision model*) and (Recormon or Repotin or Snb 51 or Snb51) 0 (value* or valuation or money or monetary or QOL or QOLY or QOLYs or HRQOL or QALY or QALYs) and (erythropo* or Aranesp or Darbe* or darbo*) 1 (value* or valuation or money or monetary or QOL or QOLY or QOLYs or HRQOL or QALY or QALYs) and (e-alpha or e-alfa or epo alfa or Epo alpha or Epo beta) 0 (value* or valuation or money or monetary or QOL or QOLY or QOLYs or HRQOL or QALY or QALYs) and (e-alpha or e-alfa or epo alfa or Epo alpha or Epo beta) 0 (value* or valuation or money or monetary or QOL or QOLY or QOLYs or HRQOL or QALY or QALYs) and (epoch in abstract) 26 (value* or valuation or money or monetary or QOL or QOLY or QOLYs or HRQOL or QALY or QALYs) and (Epoconn or Epoietin or Epoetin or Epoetinum or Epogen or epogin) 1

A-10


Coverage of Search

(value* or valuation or money or monetary or QOL or QOLY or QOLYs or HRQOL or QALY or QALYs) and (Eprex or Erantin or Erypo or Espo or Exprex) 0 (value* or valuation or money or monetary or QOL or QOLY or QOLYs or HRQOL or QALY or QALYs) and (Heberitro or Hematopoieti* or Hemax or Hemopoietin or huepo) 0 (value* or valuation or money or monetary or QOL or QOLY or QOLYs or HRQOL or QALY or QALYs) and (Krn 321 or Krn321 or Krn 572 or Krn572 or Marogen) 0 (value* or valuation or money or monetary or QOL or QOLY or QOLYs or HRQOL or QALY or QALYs) and (Neorecormon or Nesp or nespo or Procrit or R-Hu Epo) 0 (value* or valuation or money or monetary or QOL or QOLY or QOLYs or HRQOL or QALY or QALYs) and (Recormon or Repotin or Snb 51 or Snb51) 0

Agency for Healthcare Research and Quality (AHRQ) (Technology Assessments)

Aranesp (3) (Darbe and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or epoietin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis)) (0) Darbepoietin (0) Darbopoetin (0) Dynepo (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoconn (0) Epoietin (0) Epoetin alfa or epoetin alfa (41) Epoetin alpha (0) Epoietin alpha or Epoietin alfa (0) Epoetinum alfa (0) Epogen (30) Epogin (0) Eprex (9) Erantin (0) Erypo (0) Erythropoietin (151) Erythropoietic or erythropoetin or Erythropoiesis (26) erythropoetin* (18) erythropoiten-alpha (0) Espo (0) Exprex (0) Globuren (0) Heberitro (0) Heberitrorn (0) Hematopoietin (0) Hemax (0) Hemopoietin (0) huepo (1) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (9) Neorecormon (0) Nesp (0) Nespo (0) Procrit (22) r-HuEPO (1) rHuEPO (3) R-Hu Epo (2) recombinant EPO (8) Recormon (9) Recormone (0) Renal Erythropoietic Factor (2) Repotin (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

10 Jan 2007

Canadian Agency for Drugs and Technologies in Health


10 Jan 2007

Centre for Evaluation of Medicines Aranesp (0) (Darbe and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or epoietin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis)) (0) Darbepoietin (0) Darbopoetin (0) Dynepo (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoconn (0) Epoietin (0) Epoetin alfa or epoetin alfa (0) Epoetin alpha (0) Epoietin alpha or Epoietin alfa (0) Epoetinum alfa (0) Epogen (0) Epogin (0) Eprex (0) Erantin (0) Erypo (0) Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) Espo (0) Exprex (0) Globuren (0) Heberitro (0) Heberitrorn (0) Hematopoietin (0) Hemax (0) Hemopoietin (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or

10 Jan 2007

A-11


Coverage of Search

Krn5702 (0) Marogen (0) Neorecormon (0) Nesp (0) Nespo (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Recormone (0) Renal Erythropoietic Factor (0) Repotin (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

Centre for Health Services and Policy Research, University of British Columbia (Reports from 1991 to 2002 of the former British Columbia Office of Health Technology Assessment (BCOHTA)

Aranesp (0) (Darbe and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or epoietin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis)) (0) Darbepoietin (0) Darbopoetin (0) Dynepo (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoconn (0) Epoietin (0) Epoetin alfa or epoetin alfa (0) Epoetin alpha (0) Epoietin alpha or Epoietin alfa (0) Epoetinum alfa (0) Epogen (0) Epogin (0) Eprex (0) Erantin (0) Erypo (0) Erythropoietin or Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) Espo (0) Exprex (0) Globuren (0) Heberitro (0) Heberitrorn (0) Hematopoietin (0) Hemax (0) Hemopoietin (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Neorecormon (0) Nesp (0) Nespo (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Recormone (0) Renal Erythropoietic Factor (0) Repotin (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

10 Jan 2007

Institute for Clinical Evaluative Sciences (ICES), Ontario

Aranesp (0) (Darbe and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or epoietin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis)) (0) Darbepoietin (0) Darbopoetin (0) Dynepo (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoconn (0) Epoietin (0) Epoetin alfa or epoetin alfa (0) Epoetin alpha (0) Epoietin alpha or Epoietin alfa (0) Epoetinum alfa (0) Epogen (0) Epogin (0) Eprex (0) Erantin (0) Erypo (0) Erythropoietin or Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) Espo (0) Exprex (0) Globuren (0) Heberitro (0) Heberitrorn (0) Hematopoietin (0) Hemax (0) Hemopoietin (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Neorecormon (0) Nesp (0) Nespo (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Recormone (0) Renal Erythropoietic Factor (0) Repotin (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

10 Jan 2007

Manitoba Centre for Health Policy (MCHP)

Aranesp (0) (Darbe and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or epoietin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis)) (0) Darbepoietin(0) Darbopoetin (0) Dynepo (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoconn (0) Epoietin (0) Epoetin alfa or epoetin alfa (0) Epoetin alpha (0) Epoietin alpha or Epoietin alfa (0) Epoetinum alfa (0) Epogen (0) Epogin (0) Eprex (0) Erantin (0) Erypo (0) Erythropoietin or Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) Espo (0) Exprex (0) Globuren (0) Heberitro (0) Heberitrorn (0) Hematopoietin (0) Hemax (0) Hemopoietin (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Neorecormon (0) Nesp (0) Nespo (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Recormone (0) Renal Erythropoietic Factor (0) Repotin (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

10 Jan 2007

Ontario Ministry of Health and Long Term Care, Health Technology Reviews

Aranesp (4) (Darbe and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or epoietin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis)) (0) Darbepoietin (2) Darbopoetin (0) Dynepo (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (2) Epo beta (1) Epoch (1) Epoconn (0) Epoietin (0) Epoetin alfa or epoetin alfa (1) Epoetin alpha (0) Epoietin alpha or Epoietin alfa (0) Epoetinum alfa (0) Epogen (0) Epogin (0) Eprex (10) Erantin (0) Erypo (0) Erythropoietin (10) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) Espo (0) Exprex (0) Globuren (0) Heberitro (0) Heberitrorn (0) Hematopoietin (0) Hemax (0) Hemopoietin (0) huepo (1) Krn 321 or Krn321 (0) Krn

10 Jan 2007

A-12


Coverage of Search

5702 or Krn5702 (0) Marogen (0) Neorecormon (0) Nesp (0) Nespo (0) Procrit (0) r-HuEPO (1) rHuEPO (0) R-Hu Epo (0) recombinant EPO (1) Recormon (0) Recormone (0) Renal Erythropoietic Factor (0) Repotin (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

The Technology Assessment Unit of the McGill University Health Centre


10 Jan 2007

The Therapeutics Initiative. Evidence-Based Drug Therapy, University of British Columbia

Aranesp (0) (Darbe and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or epoietin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis)) (0) Darbepoietin (0) Darbopoetin (0) Dynepo (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoconn (0) Epoietin (0) Epoetin alfa or epoetin alfa (0) Epoetin alpha (0) Epoietin alpha or Epoietin alfa (0) Epoetinum alfa (0) Epogen (0) Epogin (0) Eprex (0) Erantin (0) Erypo (0) Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) Espo (0) Exprex (0) Globuren (0) Heberitro (0) Heberitrorn (0) Hematopoietin (0) Hemax (0) Hemopoietin (0) huepo (0) rn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Neorecormon (0) Nesp (0) Nespo (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Recormone (0) Renal Erythropoietic Factor (0) Repotin (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

10 Jan 2007

Health Technology Assessment International (HTAi)

Aranesp (0) (Darbe and (e-beta or e-alpha or e-alfa or Epo or Epoetin$ or epoietin$ or Epogen or erythropoietic or Erythropoietin$ or erythropoetin$ or Erythropoiesis)) (0) Darbepoietin (0) Darbopoetin (0) Dynepo (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoconn (0) Epoietin (0) poetin alfa or epoetin alfa (0) Epoetin alpha (0) Epoietin alpha or Epoietin alfa (0) Epoetinum alfa (0) Epogen (0) Epogin (0) Eprex (0) Erantin (0) Erypo (0) Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) Espo (0) Exprex (0) Globuren (0) Heberitro (0) Heberitrorn (0) Hematopoietin (0) Hemax (0) Hemopoietin (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Neorecormon (0) Nesp (0) Nespo (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Recormone (0) Renal Erythropoietic Factor (0) Repotin (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

10 Jan 2007

International Network for Agencies for Health Technology Assessment (INAHTA)

Aranesp (0) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoetin alfa or epoetin alfa (0) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (3) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

11 Jan 2007

A-13


Coverage of Search

Centre for Clinical Effectiveness (Monash University)

Aranesp (0) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0)Epo alpha (0) Epo beta (0) Epoch (0) Epoetin alfa or epoetin alfa (0) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

11 Jan 2007

NPS RADAR st. Aranesp (0) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoetin alfa or epoetin alfa (0) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

11 Jan 2007

ITA - Institute of Technology Assessment


11 Jan 2007

Finnish Office for Health Care Technology and Assessment (FinOHTA), National Research and Development Centre for Welfare and Health


11 Jan 2007

Health Council of the Netherlands


11 Jan 2007

New Zealand Health Technology Assessment Clearing House for Health Outcomes and Health Technology Assessment (NZHTA)


11 Jan 2007

Norwegian Centre for Health Technology Assessment (SMM)

Aranesp (0) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (1) Epo alpha (0) Epo beta (0) Epoch (1) Epoetin alfa or epoetin alfa (1) Epoietin alpha or Epoietin alfa (0) Epogen (1) Eprex (0) Erythropoietin (1) Erythropoietic or erythropoetin or Erythropoiesis (1) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (1)

11 Jan 2007

A-14


Coverage of Search

Recormon (0) Renal Erythropoietic Factor (1) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

Centre for Medical Technology Assessment (CMT)

Aranesp (0) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoetin alfa or epoetin alfa (0) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (0)erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

11 Jan 2007

Swedish Council on Technology Assessment in Health Care (SBU)

Aranesp (0) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) E poch (0) Epoetin alfa or epoetin alfa (0) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

11 Jan 2007

Swiss Network for Health Technology Assessment


11 Jan 2007

The European Information Network on New and Changing Health Technologies (EUROSCAN)


11 Jan 2007

The National Horizon Scanning Centre (NHSC)

Aranesp (1) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (1) Epoetin alfa or epoetin alfa (1) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (5) Erythropoietic or erythropoetin or Erythropoiesis(1)erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

11 Jan 2007

NHS Health Technology Assessment /National Coordinating Centre for Health Technology Assessment (NCCHTA), Department of Health R&D Division


11 Jan 2007

NHS National Institute for Clinical Excellence (NICE)

Aranesp (10) Darbepoietin (7) Darbopoetin (2) e-alpha or e-alfa (0) epo alfa (1) Epo alpha (0) Epo beta (1) Epoch (9) Epoetin alfa or epoetin alfa (65) Epoietin alpha or Epoietin alfa (3) Epogen (4) Eprex (7) Erythropoietin (95) Erythropoietic or erythropoetin or

11 Jan 2007

A-15


Coverage of Search

Erythropoiesis (2) erythropoetin* (37) erythropoiten-alpha (0) huepo (4) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (2) Procrit (3) r-HuEPO (4) rHuEPO (8) R-Hu Epo (0) Recombinant EPO (13) Recormon (0) Renal Erythropoietic Factor (10) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

The Wessex Institute for Health Research and Development, Succinct and Timely Evaluated Evidence Review (STEER)

Aranesp (0) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoetin alfa or epoetin alfa (0) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) Recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

12 Jan 2007

West Midlands Health Technology Assessment Collaboration (WMHTAC)

Aranesp (1) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (1) Epoetin alfa or epoetin alfa (1) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (5) Erythropoietic or erythropoetin or Erythropoiesis (1)erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) Recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

12 Jan 2007

Agency for Healthcare Research and Quality (AHR) (Evidence-Based Practice Centers Evidence reports and technology assessments)


12 Jan 2007

Evidence Based Information on Prescription Drugs for Consumers and Health Care Providers

Aranesp (1) Darbepoietin (0) Darbopoetin (0 e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch [search came up with geological sites, so Ilimited it to must not contain ‘geo*’ or ‘earth’] (0) Epoetin alfa or epoetin alfa (2) Epoietin alpha or Epoietin alfa (0) Epogen (9) Eprex (0) Erythropoietin (45) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (1) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (15) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

12 Jan 2007

CenterWatch Clinical Trials Listing Service™

Aranesp (21) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (2) Epoetin alfa or epoetin alfa (139) Epoietin alpha or Epoietin alfa (0) Epogen (1) Eprex (0) Erythropoietin (364) Erythropoietic or erythropoetin or Erythropoiesis (1003) [ search engine only displayed the first 1000 results, so I did each term separately (799+54+150) and added them all to the same document] erythropoetin* (54) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (9) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (3) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

12 Jan 2007

Clinical Trials Database (US National Institutes of Health)

Aranesp (35) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (1) Epo alpha (1) Epo beta (0) Epoch (95) Epoetin alfa or

12 Jan 2007

A-16


Coverage of Search

epoetin alfa (70) Epoietin alpha or Epoietin alfa (0) Epogen (70) Eprex [ for the rest of the searches in this website, to not have duplicates and spend so much time cutting and pasting duplicates, my searches are “term” NOT Epogen, as I’ve already pasted all the hits for Epogen] (0) Erythropoietin (2) [72 before limiting it to NOT Epogen] Erythropoietic or erythropoetin or Erythropoiesis (2) erythropoetin* (0) [70 before limiting it to NOT Epogen] erythropoiten-alpha (0) huepo (1) Krn 321 or Krn321 (2) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (23) [35 before limiting to NOT Epogen] Procrit (0) [70 before limiting it to NOT Epogen] r-HuEPO (2) [47 before limiting it to NOT Epogen] rHuEPO (2) [47 before limiting it to NOT Epogen] R-Hu Epo (2) [47 before limiting it to NOT Epogen] recombinant EPO (2) [48 before limiting it to NOT Epogen] Recormon (1) [11 before limiting it to NOT Epogen] Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

Current Controlled Trials

Aranesp (13) Darbepoietin (4) Darbopoetin (3) e-alpha or e-alfa (483) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoetin alfa or epoetin alfa (3) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (1) Erythropoietin (27) Erythropoietic or erythropoetin or Erythropoiesis(10) erythropoetin* (4) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (10) rHuEPO (0) R-Hu Epo (0) Recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

12 Jan 2007

National Research Register, UK Department of Health

Aranesp (5) Darbepoietin (0) Darbopoetin (1) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (1) Epo beta (1) Epoch (7) Epoetin alfa or epoetin alfa (67) Epoietin alpha or Epoietin alfa (4) Epogen (0) Eprex (13) Erythropoietin (88) Erythropoietic or erythropoetin or Erythropoiesis (58) erythropoetin* (0) [erythropoetin* NOT ((Erythropoietic or erythropoetin or Erythropoiesis) or Erythropoietin or Aranesp or (Epoetin alfa or epoetin alfa) or (Epoietin alpha or Epoietin alfa) or Eprex or Epoch)] erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (3) Procrit (1) r-HuEPO (8) rHuEPO (0) R-Hu Epo (0) recombinant EPO (1) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

12 Jan 2007

Pharmaceutical Research and Manufacturers of America, the industry's


12 Jan 2007

TrialsCentral™


12 Jan 2007

HEED (Available online) Health Economic Evaluations Database

Aranesp (0) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoetin alfa or epoetin alfa (1) Epoietin alpha or Epoietin alfa (0) Epogen (1) Eprex (0) Erythropoietin (8) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0)Marogen (0)

12 Jan 2007

A-17


Coverage of Search

Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (1 R-Hu Epo (0) recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

Australian Drug Evaluation Committee


12 Jan 2007

Australian Pharmaceutical Benefits Scheme

Aranesp (0) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0 Epoetin alfa or epoetin alfa (42) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (14) Erythropoietin (22) Erythropoietic or erythropoetin or Erythropoiesis(13) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (1) Procrit (0) r-HuEPO (1) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

12 Jan 2007

European Agency for the Evaluation of Medicinal Products (EMEA)

Aranesp (14) Darbepoietin (2) Darbopoetin (0) e-alpha or e-alfa (4) epo alfa (1) Epo alpha (0) Epo beta (0) Epoch (0) Epoetin alfa or epoetin alfa (35) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (18) Erythropoietic or erythropoetin orErythropoiesis(25) erythropoetin* (0) erythropoiten-alpha (0) huepo (28) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (4) Procrit (0) r-HuEPO (0) rHuEPO (10) R-Hu Epo (0) recombinant EPO (0) Recormon (2) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

13 Jan 2007

European Pharmaceutical Regulatory Sector


13 Jan 2007

Food and Drug Administration (FDA), US Department of Health and Human Services

Aranesp (205) Darbepoietin (3) Darbopoetin (0) e-alpha or e-alfa (20) epo alfa (4) Epo alpha (0) Epo beta (0) Epoch (64) Epoetin alfa or epoetin alfa (161) Epoietin alpha or Epoietin alfa (0) Epogen (47) Eprex (33) Erythropoietin (340) Erythropoietic or erythropoetin or Erythropoiesis (137) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (57) r-HuEPO (0) rHuEPO (0) R- Hu Epo (1) Recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

13 Jan 2007

Medicines and Healthcare Products Regulatory Agency, Department of Health, UK

Aranesp (6) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0 Epo beta (0) Epoch (0) Epoetin alfa or epoetin alfa (13) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (2) erythropoetin* (2) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) Recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

13 Jan 2007

Pharmac (Pharmaceutical Management Agency, NZ)

Aranesp (1) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (1) epo alfa (0) Epo alpha (0) Epo beta (1) Epoch (0) Epoetin alfa or epoetin alfa (0) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex

13 Jan 2007

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Coverage of Search

(2) Erythropoietin (14) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) Recombinant EPO (0) Recormon (6) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

Centre for Health Economics and Policy Analysis (CHEPA), Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Canada

Aranesp (0) Aranesp (0) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoetin alfa or epoetin alfa (2) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (2) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (2) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0) Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

13 Jan 2007

Health Economics Research Group (HERG), Brunel University, UK

Aranesp (0) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (0) Epoetin alfa or epoetin alfa (0) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (0) Erythropoietic or erythropoetin or Erythropoiesis (0) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (0) Recormon (0)Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

13 Jan 2007

Health Economics Research Unit (HERU), University of Aberdeen


13 Jan 2007

University of Connecticut, Department of Economics, RePEc database

Aranesp (1) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (0) epo alfa (0) Epo alpha (0) Epo beta (0) Epoch (35) Epoetin alfa or epoetin alfa (0) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (0) Erythropoietin (2) Erythropoietic or erythropoetin or Erythropoiesis (2) erythropoetin* (0) erythropoiten-alpha (0) huepo (0) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (1) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (0) recombinant EPO (1) Recormon (0) Renal Erythropoietic Factor (0)Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

13 Jan 2007

Directory of Open Access Journals

Aranesp (0) Darbepoietin (0) Darbopoetin (0) e-alpha or e-alfa (13) epo alfa (0)Epo alpha (0) Epo beta (0) Epoch (20) Epoetin alfa or epoetin alfa (1) Epoietin alpha or Epoietin alfa (0) Epogen (0) Eprex (1) Erythropoietin (38) Erythropoietic or erythropoetin or Erythropoiesis (7) erythropoetin* (0) erythropoiten-alpha (0) huepo (1) Krn 321 or Krn321 (0) Krn 5702 or Krn5702 (0) Marogen (0) Nesp (0) Procrit (0) r-HuEPO (0) [r-HuEPO NOT Huepo] rHuEPO (0) [rHuEPO NOT Huepo] R-Hu Epo (0) recombinant EPO (1) Recormon (0)Renal Erythropoietic Factor (0) Snb 5001 or Snb5001 (0) Tyb 5220 or Tyb5220 (0)

13 Jan 2007

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APPENDIX 2: FLOWCHARTS OF SELECTED STUDIES Figure 1A: Flowchart of selected clinical studies for systematic review

2289 citations identified from electronic search and

broad screened

4 citations identified from other sources

2062 citations excluded

231 potentially relevant reports retrieved for further scrutiny

(full text, if available)

194 reports excluded: • Not original human

research (n=36) • Not a RCT (n=51) • Crossover (n=12) • Children (n=1) • No CKD (n=3) • No relevant comparison

(n=11) • No relevant outcome or

usable data (n=17) • Sample size <30 (n=38) • Multiple publications

(n=25)

37 relevant reports describing 38 unique trials

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Figure 1B: Flowchart of selected studies for economic review

2289 citations identified from electronic search and

broad screened

2230 citations excluded

60 potentially relevant reports retrieved for further scrutiny

(full text, if available)

54 reports excluded: • Not a cost-effectiveness

evaluation (n=51) • No CKD (n=1) • No relevant comparator

(n=1) • Multiple publication (n=1)

6 relevant reports describing 6 unique studies

1 citation identified from other sources

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APPENDIX 3: EXCLUDED STUDIES FROM CLINICAL REVIEW Sample size < 30 (38 studies) 1. Sheashaa HA, Khalil A, Aarman MME, El-Shahat FB, Selim A, El-Gawad SSA. Correction

of hemodialysis anemia is associated with significant increase in serum concentration of IGF-I in patients treated with erythropoietin: a randomized controlled study. Int Urol Nephrol 2005;37(1):153-8.

2. Clyne N, Jogestrand T. Effect of erythropoietin treatment on physical exercise capacity and on renal function in predialytic uremic patients. Nephron 1992;60(4):390-6.

3. Kleinman KS, Schweitzer SU, Perdue ST, Bleifer KH, Abels RI. The use of recombinant human erythropoietin in the correction of anemia in predialysis patients and its effect on renal function: a double-blind, placebo-controlled trial. Am J Kidney Dis 1989;14(6):486-95.

4. Lim VS, DeGowin RL, Zavala D, Kirchner PT, Abels R, Perry P, et al. Recombinant human erythropoietin treatment in pre-dialysis patients. A double-blind placebo-controlled trial. Ann Intern Med 1989;110(2):108-14.

5. Sikole A, Polenakovic M, Spirovska V, Polenakovic B, Masin G. Analysis of heart morphology and function following erythropoietin treatment of anemic dialysis patients. Artif Organs 1993;17(12):977-84.

6. Watson AJ, Gimenez LF, Cotton S, Walser M, Spivak JL. Treatment of the anemia of chronic renal failure with subcutaneous recombinant human erythropoietin. Am J Med 1990;89(4):432-5.

7. Furuland H, Linde T, Wikstrom B, Danielson BG. Reduced hemodialysis adequacy after hemoglobin normalization with epoetin. J Nephrol 2005;18(1):80-5.

8. Perez-Oliva JF, Casanova-Gonzalez M, Garcia-Garcia I, Porrero-Martin PJ, Valenzuela-Silva CM, Hernandez-Montero T, et al. Comparison of two recombinant erythropoietin formulations in patients with anemia due to end-stage renal disease on hemodialysis: a parallel, randomized, double blind study. BMC Nephrol 2005;6(1):5.

9. Allon M, Kleinman K, Walczyk M, Kaupke C, Messer-Mann L, Olson K, et al. Pharmacokinetics and pharmacodynamics of darbepoetin alfa and epoetin in patients undergoing dialysis. Clin Pharmacol Ther 2002;72(5):546-55.

10. Singh NP, Aggarwal L, Singh T, Anuradha S, Kohli R. Anaemia, iron studies and erythropoietin in patients of chronic renal failure. J Assoc Physicians India 1999;47(3):284-90.

11. Sikole A, Stojanovic A, Polenakovic M, Petrusevska G, Sadikario S, Saso R, et al. How erythropoietin affects bone marrow of uremic patients. Am J Nephrol 1997;17(2):128-36.

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12. Sikole A, Efremov DG, Dimovski A, Efremov GD, Polenakovic M. Hemoglobin F levels in end-stage renal disease patients after correction of anemia with erythropoietin. Nephron 1993;65(3):482-4.

13. Shand BI, Buttimore AL, Hurrell MA, Wells JE, Inkster JA, Bailey RR, et al. Hemorheology and fistula function in home hemodialysis patients following erythropoietin treatment: a prospective placebo-controlled study. Nephron 1993;64(1):53-7.

14. Boran M, Dalva I, Yazicioglu A, Cetin S. Subcutaneous versus intravenous recombinant human erythropoietin administration in hemodialysis patients. Nephron 1993;63(1):113-4.

15. Lui SF, Wong KC, Li PK, Lai KN. Once weekly versus twice weekly subcutaneous administration of recombinant human erythropoietin in haemodialysis patients. Am J Nephrol 1992;12(1-2):55-60.

16. Lui SF, Law CB, Ting SM, Li P, Lai KN. Once weekly versus twice weekly subcutaneous administration of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Clin Nephrol 1991;36(5):246-51.

17. Fritschka E, Neumayer HH, Seddighi S, Distler A, Philipp T. Effect of erythropoietin therapy on alpha receptor density in chronic dialysis patients [in German]. Med Klin 1991;86(7):353-9.

18. Vigano G, Benigni A, Mendogni D, Mingardi G, Mecca G, Remuzzi G. Recombinant human erythropoietin to correct uremic bleeding. Am J Kidney Dis 1991;18(1):44-9.

19. Lai KN, Lui SF, Leung JC, Law E, Nicholls MG. Effect of subcutaneous and intraperitoneal administration of recombinant human erythropoietin on blood pressure and vasoactive hormones in patients on continuous ambulatory peritoneal dialysis. Nephron 1991;57(4):394-400.

20. Slingeneyer A, Faller B, Laroche B, Ehmer B, Mion C. Self-administered daily subcutaneous recombinant human erythropoietin: an open randomised dose-finding study in ESRD patients receiving peritoneal dialysis. Contrib Nephrol 1991;88:159-68.

21. Acchiardo SR, Quinn BP, Moore LW, Burk LB, Miles DE. Evaluation of hemodialysis patients treated with erythropoietin. Am J Kidney Dis 1991;17(3):290-4.

22. Kohler M, Morsdorf S, Jung F, Braun B, Waldhausen P, Pindur G, et al. Recombinant human erythropoietin (rh-EPO) in chronic, dialysis-dependent renal failure: effects on macro- and microcirculation and hematologic parameters [in German]. Beitr Infusionsther 1990;26:89-95.

23. Fritschka E, Neumayer HH, Seddighi S, Thiede HM, Distler A, Philipp T. Effect of erythropoietin on parameters of sympathetic nervous activity in patients undergoing chronic haemodialysis. Br J Clin Pharmacol 1990;30 Suppl 1:135S-8S.

24. Donnelly SM, Ali MA, Churchill DN. Bioavailability of iron in hemodialysis patients treated with erythropoietin: evidence for the inhibitory role of aluminum. Am J Kidney Dis 1990;16(5):447-51.

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25. Abraham PA, Opsahl JA, Rachael KM, Asinger R, Halstenson CE. Renal function during erythropoietin therapy for anemia in predialysis chronic renal failure patients. Am J Nephrol 1990;10(2):128-36.

26. Vaziri ND, Ritchie C, Brown P, Kaupke J, Atkins K, Barker S, et al. Effect of erythropoietin administration on blood and plasma viscosity in hemodialysis patients. ASAIO Trans 1989;35(3):505-8.

27. Stone WJ, Graber SE, Krantz SB, Dessypris EN, O'Neil VL, Olsen NJ, et al. Treatment of the anemia of predialysis patients with recombinant human erythropoietin: a randomized, placebo-controlled trial. Am J Med Sci 1988;296(3):171-9.

28. Virot JS, Janin G, Guillaumie J, Michel P, Dubot P, Chevet D, et al. Must erythropoietin be injected by the subcutaneous route for every hemodialyzed patient? Am J Kidney Dis 1996;28(3):400-8.

29. Miguel Alonso JL, Traver JA, Jofre RM, Lopez JM, Otero A, Esteban JA, et al. Erythropoietin treatment in pre-dialysis patients. Nefrologia 1995;15(2):148-55.

30. Bhuiyan FK, Rashid HU, Ahmed S, Alam MR. Comparative study of two different dosages of erythropoietin in respect of response to anemia in patients with ESRD on MHD. Bangladesh Renal Journal 2004;23(2):42-51.

31. Sja'bani M, Asdie AH. RCT of erythropoietin on pruritus and quality of life in chronic hemodialyzed end stage renal disease patients. J Clin Epidemiol Vol 1997;50(1).

32. Frenken LA, Verberckmoes R, et al. An Open Study of the Safety and Efficacy of Multiple Doses of Recombinant Human Erythropoietin in End-Stage Renal Disease (Predialysis) Patients. Nephrol Dial Transplant Vol 1988;3(495).

33. Brown CD, Zhao ZH, Thomas LL, Friedman EA. Erythropoietin delays the onset of uremia in anemic azotemic diabetic predialysis patients. Journal of the American Society of Nephrology : JASN 1995;6:447A.

34. Teehan BP, Sigler MH, Brown JM, Benz RL, Gilgore GS, Schleifer CR. Hematologic and physiologic studies during correction of anaemia with recombinant human erythropoietin in predialysis patients. Transplantation Proceedings 1989;21(Suppl 2):63-6.

35. Berns JS, Rudnick MR, Cohen RM, Maloney A. Effect of normal v. anemic hematocrit on ambulatory blood pressure (abp) in erythropoietin-treated hemodialysis (hd) patients. Journal of the American Society of Nephrology : JASN 1995;6(3):520.

36. Canaud B, Bennhold I, Delons S, Donnadieu P, Foret M, Franz H, et al. What is the optimum frequency of administration of r-HuEPO for correcting anemia in hemodialysis patients? Dialysis & Transplantation 1995;24(6):306-29.

37. Leung CB, Lam TY, Chan CM, Wang A, Li P, Lai KN, et al. Pharmacodynamics of twice weekly versus thrice weekly subcutaneous administration of recombinant human erythropoietin (rhuepo) for patients on capd. 6th Asian Pacific Congress of Nephrology ~ Hong Kong Convention & Exhibition Centre ~ 5 - 9 December 1995:179.

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38. Watson AJ, Gimenez LF, Cotton S, Walser M, Spivak JL. Treatment of the anemia of chronic renal failure with subcutaneous recombinant human erythropoietin. Am J Med 1990;89(4):432-5.

Multiple publications (25 studies) Substudy of Parfrey 200554 1. Foley RN, Parfrey PS, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D, et al. The effect of

higher haemoglobin levels on left ventricular vacity volume in patients starting haemodialysis: a blinded, randomised, controlled trial in 596 patients without symptomatic cardiac disease. 41st Congress European Renal Association European Dialysis and Transplantation Association Lisbon, Portugal 2004:217

Substudy of Gouva 200456 1. Papavasiliou EC, Gouva C, Siamopoulos KC, Tselepis AD. PAF-acetylhydrolase activity in

plasma of patients with chronic kidney disease. Effect of long-term therapy with erythropoietin. Nephrol Dial Transplant 2006;21(5):1270-7.

2. Siamopoulos KC, Gouva C, Katopodis KP, Tzallas C, Nikolopoulos P, Papavasiliou EC, et al. Long-term treatment with EPO increases serum levels of high-density lipoprotein in patients with CKD. Am J Kidney Dis 2006;48(2):242-9.

3. Papavasiliou EC, Gouva C, Siamopoulos KC, Tselepis AD. Erythrocyte PAF-acetylhydrolase activity in various stages of chronic kidney disease: effect of long-term therapy with erythropoietin. Kidney Int 2005;68(1):246-55.

4. Gouva C, Katapodis K, Siamopoulos K, Investigators of the Study G. Effect of erythropoietin administration on lipid parameters in chronic renal failure patients. a randomized control trial 41st Congress European Renal Association European Dialysis and Transplantation Association Lisbon, Portugal, May 2004.

Substudy of Roger 200455 1. Roger SD, McMahon LP, Schou IMftA-IG. Impact of epoetin alfa (EPO) treatment on

cardiac and renal function in chronic kidney disease (CKD) 38th Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology 2002;7(Suppl Sept):A70-A1.

Substudy of Furuland 200353 1. Danielson BG, Furuland H, Ahlmen J, Christensson A, Linde T, Strombom U. Scandinavian

study of normalizing hemoglobin with rhu-epo in end stage renal failure. J Am Soc Nephrol 1999;10(Program & Abstracts).

2. Furuland H, Linde T, Danielson BG. Dialysis adequacy after normalization of hemoglobin with erythropoietin (EPO). Journal of the American Society of Nephrology : JASN 1998;9(Programs and Abstracts):296A

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Substudy of Locatelli 200264 1. Locatelli F, Baldamus CA, Villa G, Martinez F, de Francisco ALM, group obotc.

Therapeutic equivalence of once versus thrice weekly subcutaneous injection of epoetin beta in patients with chronic renal failure XXXVIII Congress of the European Renal Association European Dialysis & Transplant Association June 24-27 2001, Vienna, Austria 2001:210.

Substudy of Foley 200054 1. Foley RN, Parfrey PS, Morgan J, Barre PE, Campbell P, Cartier P, et al. Hemoglobin levels

and hospitalization in hemodialysis patients without symptomatic cardiac disease. Journal of the American Society of Nephrology : JASN 2002;13(Programs and Abstracts):432A.

2. Foley RN, Parfrey PS, Morgan J, Barre P, Campbell P, Cartier P. A randomized controlled trial of complete vs partial correction of anemia in hemodialysis patients with asymptomatic concentric IV hypertrophy or IV dialation. Journal of the American Society of Nephrology : JASN 1998;9(Programs and Abstracts):208A.

3. Wells GA, Coyne D, Lee KM, Foley RN, Parfrey PS, et al. Quality of life effects of normalization of hemoglobin in asymptomatic hemodialysis patients. Journal of the American Society of Nephrology : JASN 1998;1998(Programs and Abstracts):230A.

Substudy of Besarab 1998118 1. Roman RM, Lobo PI, Taylor RP, Goodkin DA, LaBrecque J, Powers KL, et al. Prospective

study of the immune effects of normalizing the hemoglobin concentration in hemodialysis patients who receive recombinant human erythropoietin. Journal of the American Society of Nephrology : JASN 1339;15(5):1339-46.

2. Conlon PJ, Kovalik E, Schumm D, Minda S, Schwab SJ. Normalization of hematocrit in hemodialysis patients with cardiac disease does not increase blood pressure. Ren Fail 2000;22(4):435-44.

3. Conlon PJ, Kovalik E, Schumm D, Minda S, Schwab SJ. Normalization of hematocrit in hemodialysis patients does not affect silent ischemia. Ren Fail 2000;22(2):205-11.

4. Berns JS, Rudnick MR, Cohen RM, Bower JD, Wood BC. Effects of normal hematocrit on ambulatory blood pressure in epoetin-treated hemodialysis patients with cardiac disease. Kidney Int 1999;56(1):253-60

Substudy of Roth 199447 1. Revicki DA, Brown RE, Feeny DH, Henry D, Teehan BP, Rudnick MR, et al. Health-related

quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis 1995;25(4):548-54

Substudy of Klinkmann 199345 1. Klinkmann H, Schmidt R, Wieczorek L, Scigalla P. Adverse events of subcutaneous

recombinant human erythropoietin therapy. Contrib Nephrol 1992;100:127-38. Substudy of Churchill 199058 1. Effect of recombinant human erythropoietin therapy on blood pressure in hemodialysis

patients. Canadian Erythropoietin Study Group. Am J Nephrol 1991;11(1):23-6.

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2. Laupacis A, Wong C, Churchill D. The use of generic and specific quality-of-life measures in hemodialysis patients treated with erythropoietin. The Canadian Erythropoietin Study Group. Control Clin Trials 1991;12(4 Suppl):168S-79S.

3. Laupacis A. A randomized double-blind study of recombinant human erythropoietin in anaemic hemodialysis patients. Canadian Erythropoietin Study Group. Transplant Proc 1991;23(2):1825-6.

4. Keown PA. Quality of life in end-stage renal disease patients during recombinant human erythropoietin therapy. The Canadian Erythropoietin Study Group. Contrib Nephrol 1991;88:81-6; discussion 7-9.

5. Laupacis A. Changes in quality of life and functional capacity in hemodialysis patients treated with recombinant human erythropoietin. The Canadian Erythropoietin Study Group. Seminars in Nephrology 1990;10(2 Suppl 1):11-9.

Substudy of Watson 1990119 1. Watson AJ, Gimenez L, Walser M, Cotton S, Spivak J. A prosepective double-blind study of

subcutaneous recombinant-human erythropoietin in predialysis renal failure. J Clin Pharmacol 1989;29:856

Substudy of Bommer 1988120 1. Samtleben W, Baldamus CA, Bommer J, Fassbinder W, Nonnast-Daniel B, Gurland HJ.

Blood pressure changes during treatment with recombinant human erythropoietin. Contrib Nephrol 1988;66:114-22.

No relevant clinical outcome (11 studies)

1. Bommer J, Kugel M, Schoeppe W, Brunkhorst R, Samtleben W, Bramsiepe P, et al. Dose-related effects of recombinant human erythropoietin on erythropoiesis. Results of a multicenter trial in patients with end-stage renal disease. Contrib Nephrol 1988;66:85-93.

2. Mix TCH, Brenner RM, Cooper ME, de Zeeuw D, Ivanovich P, Levey AS, et al. Rationale--Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease. Am Heart J 2005;149(3):408-13.

3. Tolman C, Richardson D, Bartlett C, Will E. Structured conversion from thrice weekly to weekly erythropoietic regimens using a computerized decision-support system: a randomized clinical study. J Am Soc Nephrol 2005;16(5):1463-70.

4. Macdougall IC, Steering Committee of the Ct, Group CS. CREATE: new strategies for early anaemia management in renal insufficiency. Nephrol Dial Transplant 2003;18 Suppl 2:ii13-6.

5. Eckardt KU, Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin Beta T. The CREATE trial--building the evidence. Nephrol Dial Transplant 2001;16 Suppl 2:16-8.

6. De Schoenmakere G, Lameire N, Dhondt A, Van Loo A, Van der Goten J, Duym P, et al. The haematopoietic effect of recombinant human erythropoietin in haemodialysis is

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independent of the mode of administration (i.v. or s.c.). Nephrol Dial Transplant 1998;13(7):1770-5.

7. Faller B, Slingeneyer A, Waller M, Michel C, Grutzmacher P, Muller HP, et al. Daily subcutaneous administration of recombinant human erythropoietin (rhEPO) in peritoneal dialysis patients: a European dose-response study. Clin Nephrol 1993;40(3):168-75.

8. Erratum: Rationale - Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): Evolving the management of cardiovascular risk in patients with chronic kidney disease Am Heart J 2005;150(1):53.

9. Aggarwal HK, Sehgal R, Singh S, Nand N, Bharti K, Chakrabarti D. Evaluation of efficacy of low dose recombinant human erythropoietin in combination with androgen therapy in anaemia of chronic renal failure. Journal Indian Academy of Clinical Medicine 2005;6(3):208-15.

10. Salek MS, Pratheepawanit N. Use of erythropoietin in early anaemia improves health-related quality of life in predialysis chronic renal failure patients Quality of Life Research 2001;10(3).

11. Weiss LG, Clyne N, Divino Fihlho J, Frisenette-Fich C, Kurkus J, Svensson B. The efficacy of once weekly compared with two or three times weekly subcutaneous epoetin beta: results from a randomized controlled multicentre trial. Swedish Study Group. Nephrol Dial Transplant 2000;15(12):2014-9.

No data relevant to meta-analysis (6 studies) 1. Korbet SM, Vonesh EF, Firanek CA. The effect of hematocrit on peritoneal transport. Am J

Kidney Dis 1991;18(5):573-8.

2. Grutzmacher P, Bergmann M, Weinreich T, Nattermann U, Reimers E, Pollok M. Beneficial and adverse effects of correction of anaemia by recombinant human erythropoietin in patients on maintenance haemodialysis. Contrib Nephrol 1988;66:104-13.

3. Muirhead N, Keown PA, et al. A Double-blind, Randomised Dose-finding Study of Recombinant Human Erythropoietin in the Anaemia of Chronic Renal Failure Nephrol Dial Transplant 1989;4(477).

4. Thadhani R, Cheriyan R, Brenner R, Ford J, Powers K, Rahman SN. Treatment of anemia with ARANESP (darbepoetin alfa) improves health related quality of life (HRQOL) in patients with chronic kidney disease (CKD) J Am Soc Nephrol 2002;13(September, Program and Abstracts).

5. Kleinman KS, Schweitzer SU. Human recombinant erythropoietin rhuEPO treatment of severe anemia associated with progressive renal failure may delay the need to initiate regular dialytic therapy. Kidney Int 1990;37:240.

6. Barany P, Svedenhag J, Katzarski K, Divino Filho J, Norman R, Freyschuss U, et al. Physiological effects of correcting anemia in hemodialysis patients (hd pts) to a normal hb Journal of the American Society of Nephrology : JASN 1996;7:1472.

A-28

Crossover design (12 studies) 1. Aarup M, Bryndum J, Dieperink H, Joffe P. Clinical implications of converting stable

haemodialysis patients from subcutaneous to intravenous administration of darbepoetin alfa. Nephrol Dial Transplant 2006;21(5):1312-6.

2. Sabovic M, Zupan IP, Salobir B, Zupan I, Cernelc P, Lavre J, et al. The effect of long-term, low-dose tranexamic acid treatment on platelet dysfunction and haemoglobin levels in haemodialysis patients. Thromb Haemost 2005;94(6):1245-50.

3. McMahon LP, Mason K, Skinner SL, Burge CM, Grigg LE, Becker GJ. Effects of haemoglobin normalization on quality of life and cardiovascular parameters in end-stage renal failure. Nephrol Dial Transplant 2000;15(9):1425-30.

4. McMahon LP, McKenna MJ, Sangkabutra T, Mason K, Sostaric S, Skinner SL, et al. Physical performance and associated electrolyte changes after haemoglobin normalization: a comparative study in haemodialysis patients. Nephrol Dial Transplant 1999;14(5):1182-7.

5. Bjarnason GA, Tobe S, Saiphoo C, Manuel AM, Franssen E, Reis MC. Erythropoietin therapy in patients with chronic renal failure on hemodialysis: A study of time-dependent activity. Blood 1997;90(10 Suppl 1 (Pt 2).

6. Jensen JD, Madsen JK, Jensen LW. Comparison of dose requirement, serum erythropoietin and blood pressure following intravenous and subcutaneous erythropoietin treatment of dialysis patients. IV and SC erythropoietin. Eur J Clin Pharmacol 1996;50(3):171-7.

7. Hon G, Vaziri ND, Kaupke CJ, Tehranzadeh A, Barton C. Lack of a fast-acting effect of erythropoietin on arterial blood pressure and endothelin level. Artificial Organs 1995;19(2):188-91.

8. Morris KP, Sharp J, Watson S, Coulthard MG. Non-cardiac benefits of human recombinant erythropoietin in end stage renal failure and anaemia. Arch Dis Child 1993;69(5):580-6.

9. Aunsholt NA, Ahlbom G, Steffensen G, Glud T. Fibrinolytic capacity in hemodialysis patients treated with recombinant human erythropoietin. Nephron 1992;62(3):284-8.

10. Aunsholt NA, Steffensen G, Ahlbom G. Influence of recombinant human erythropoietin on platelet function and coagulation factors. Blood Purif 1992;10(5-6):248-53.

11. De Marchi S, Cecchin E, Villalta D, Sepiacci G, Santini G, Bartoli E. Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia. N Engl J Med 1992;326(15):969-74.

12. Steffensen G, Aunsholt NA, Ahlbom G. Comparative crossover study of intravenously and subcutaneously administered recombinant human erythropoietin in hemodialysis patients. Blood Purif 1992;10(5-6):241-7.

A-29

APPENDIX 4: TABLES FOR CLINICAL REVIEW

Table 1A: Description of included clinical trials: ESA vs no ESA Author, year, country

Eligibility: previous ESA therapy,

Hb (g/L), modality (non-dialysis-

dependent CKD renal function)

Design: sample size,

weeks of follow-up, Hb target (g/L), control [co-

intervention]

ESA regimen: type,

initial dose (U/kg/wk),

schedule (/wk), route

Demographics: mean age (y), percent male, mean Hb (g/L),

mean renal function or median years on

dialysis

Co-morbidities: percent DM, percent CVD, percent CHF

Teplan48 2003 Czech Republic

- ≤105

Non-dialysis-dependent CKD (CrCl 22-36

mL/min)

123* 156

110-120 None [Low protein diet]

Alfa 40 2 S

52 48

103 CrCl 29 mL/min

0€

- -

Silverberg49 2001 Israel

None on-therapy <117

Non-dialysis-dependent CKD (CrCl 10-40

mL/min)

90 5†

<140 None

Alfa 2,000 U

1 S

69 56 97

SCr 266 µmol/L

32€ - -

Kuriyama46 1997 Japan

- ≤100

Non-dialysis-dependent CKD (SCr 177-354

µmol/L)

73 36

110-117 None

Beta 6,000 U

1 IV

62 54 -

SCr 261 µmol/L

56 - -

Nissenson42 1995 USA

- <100 PD

152 12‡

107-127 Placebo

Alfa 4,000 U

3 S

48 39 79

3.3 y

26 - -

Roth47 1994 USA

- ≤100

Non-dialysis-dependent CKD (SCr 266-709

µmol/L)

83 48 117

None

Alfa 50 3 S

57 32 89

GFR 10 mL/min

- - -

Klinkmann45 1993 Eastern Europe

- -

HD

362 52†

100-117 None

Beta 20 3 S

- - - -

- - -

Abraham43 (Trials 2&3) 1991 USA

- ≤86 HD

229 12

95-125 Placebo

Beta 100

3 IV

51 56 70 -

- - -

Bahlmann44 1991 Germany

- ≤93 HD

129 ≤26£

100-117 Placebo

Beta 80 1

IV

57 43 75

3.3 y

18 18 -

Bennett50 1991 USA

- <85 HD

131 12‡

95-125 Placebo

Beta 100

3 IV

52 60 70

4.4 y

- - -

USA=United States of America; ESA=erythropoietic stimulating agent; Hb=hemoglobin; CKD=chronic kidney disease; CrCl=creatinine clearance; SCr=serum creatinine; PD=peritoneal dialysis; HD=hemodialysis; S=subcutaneous; IV=intravenous; GFR=glomerular filtration rate; DM=diabetes mellitus; CVD=cardiovascular disease; CHF=chronic heart failure; the – indicates that the value was not reported *a third group treating additionally with keto acids was excluded from the review † includes only the randomized follow-up ‡ includes only the double-blind follow-up period; some patients received ESA during the open-label period £ only the first 4 wk were double-blind € percent DM as primary cause of chronic kidney disease

A-30

Table 1B: Description of included clinical trials: High vs intermediate/low target Hb protocols Author, year, country

Eligibility: previous

ESA therapy, Hb (g/L), modality

(non-dialysis-



weeks of follow-up, high and

intermediate/low Hb targets (g/L)

ESA regimen: type, initial dose

(U/kg/wk), schedule (/wk), route



dialysis

Co-morbidities: percent DM,

percent CVD, percent CHF

ACORD41 2007 International (16 countries)

- 105-130

Non-dialysis-dependent

CKD (CrCl ≥30 mL/min)

170 65

130-150 105-115

Beta 2,000 U

1 S

58 51

118 CrCl 46 mL/min

100 >20

4

Macdougall40 2007 UK

None on-therapy 105-115


CKD (SCr 150-500

µmol/L)

197 Mean 69 100-120

>90

Alfa 1,000 U/ 2,000 U

2/ 3 S

55 63

108 GFR 20 mL/min

22 93 -

CHOIR21 2006 USA

None on-therapy <110


CKD (GFR 15-50 mL/min)

1432 156

135 (initially 130-135) 113 (initially 105-110)

Alfa 10,000 U 1 or 0.5

S

66 45

101 GFR 27 mL/min

49‡ 35 23

CREATE17 2006 Europe, Mexico, Taiwan, Thailand

None on-therapy 110-125


CKD (CrCl 15-35 mL/min)

603 156

130-150 105-115

Beta 2,000 U

1 S

59 54

116 CrCl 24 mL/min

26 92 32

Rossert20 2006 Europe, Australia, Canada, Israel

- <130M <125F Non-dialysis-

dependent CKD (CrCl 25-

60 mL/min)

390 173

140-150M/ 130-140F 110-120

Alfa 25-100

1 S

- 59 - -

- - 0

Levin1 2005 Canada

- 115-125M 110-

120F Non-dialysis-

dependent CKD (CrCl 15-

79 mL/min)

152 104

120-140 90-105

Alfa 2,000 U

1 S

57 70

118 GFR 29 mL/min

38 - -

Parfrey54 2005 Europe, Canada

Some on-therapy 80-120

HD

596 96

135-145 95-115

Alfa 150/ 25

1 IV (initially IV or S)

50 60

110 0.9 y

18‡ 0 0

Gouva56 2004 Greece

- 90-116


CKD (SCr 177-531 µmol/L)

88 Median 98 ≥130 ≥90

Alfa 50 1 S

66 57

101 CrCl 24 mL/min

0 - 0

A-31

Author, year, country



(non-dialysis-



weeks of follow-up, high and

intermediate/low Hb targets (g/L)

ESA regimen: type, initial dose

(U/kg/wk), schedule (/wk), route



dialysis



Roger55 2004 Australia, New Zealand

- 110-130M/ 100-120F


CKD (CrCl 15-50 mL/min)

155 104

120-130 90-100

Alfa - - S

54 46

112 CrCl 25 mL/min

29 - -

Furuland53* 2003 Scandinavia



CKD (CrCl <30 mL/min)/

HD

72/ 293 48 (76 in Sweden)

145-160M/ 135-150F 90-120

Alfa 50 3 S

59/ 65 50/ 69

108/ 110 SCr 361 µmol/L/

2.8 y

21/ 19 18£/ 34£

2/ 15

Foley18†

2000 Canada


HD

70/ 76 48

130-140 95-105

Alfa - - S

61/ 62 45/ 78

- 5.6 y/ 3.5 y

29‡/ 30‡ - 0

Besarab16 1998 USA

On-therapy 90-110

HD

1233 126

130-150 90-100

Alfa 146

1 IV or S

65 49

103 -

56 100 100

CESG58 1990 Canada

- <90 HD

118 26

115-130 90-110 Placebo

Alfa 100

3 IV

45 60 70

SCr 1074 µmol/L

- - -

UK=United Kingdom; USA=United States of America; CESG=Canadian Erythropoietin Study Group; ESA=erythropoietic stimulating agent; Hb=hemoglobin; CKD=chronic kidney disease; CrCl=creatinine clearance; SCr=serum creatinine; GFR=glomerular filtration rate; HD=hemodialysis; M=male; F=female; S=subcutaneous; IV=intravenous; DM=diabetes mellitus; CVD=cardiovascular disease; CHF=chronic heart failure; the – indicates that the value was not reported *data are stratified by modality subgroups: non-dialysis-dependent CKD, HD. The peritoneal patients were exclude because the group sample sizes were less than 30. † data are stratified by concentric left ventricular hypertrophy and left ventricular dilation subgroups ‡ percent DM as primary cause of chronic kidney disease £ percent with ischemic heart disease

A-32

Table 1C: Description of included clinical trials: Darbepoetin vs epoetin Author, year, country



(non-dialysis-


Design: sample

size, weeks of follow-up, Hb target

(g/L)

ESA regimens: type,

initial dose, schedule (/wk),

route



dialysis



Molina59 2004 Spain

On-therapy ≤100 HD

105 24

110-130

Darbe/ Alfa -/ - 2-3

IV or S

62 48

122 -

11 - -

Nissenson60 2002 USA, Canada

On-therapy 95-125

HD

507 28

90-130

Darbe/ Alfa Pretrial dose

1/ 3 IV

58 57

112 -

35 - -

Locatelli61 2001 Australia, Western Europe

- ≤110


CKD (CrCl <30 mL/min)

166 24

93-127

Darbe/ Alfa 0.45 μg/kg/wk/ 50

U/kg/wk 1/ 2 S

60 53 94

CrCl 16 mL/min

24 - -

USA=United States of America; ESA=erythropoietic stimulating agent; Hb=hemoglobin; CKD=chronic kidney disease; HD=hemodialysis; CrCl=creatinine clearance; Darbe=darbepoetin; S=subcutaneous; IV=intravenous; DM=diabetes mellitus; CVD=cardiovascular disease; CHF=chronic heart failure; the – indicates that the value was not reported

A-33

Table 1D: Description of included clinical trials: Dose comparisons Author, year, country

Eligibility: previous ESA

therapy, Hb (g/L),

modality (non-dialysis-



weeks of follow-up

ESA regimen: type,





dialysis



Abraham43 (Trial 1) 1991 USA

- ≤86 HD

121 20

Beta 25 vs 100 vs 200

3 IV

52 51 70 -

- - -

Teehan62 1991 USA

None on-therapy ≤130M/ ≤110W

Non-dialysis-dependent CKD

(SCr 260-880 µmol/L)

117 8†

Alfa 50 vs 100 vs 150 vs

placebo 3

IV

57 61 95 -

- 0 0

Pollok72 1989 Germany

- <93 HD

95 12*

Beta 40 vs 80 vs 120

3 -

51 49 74 -

6‡ - -

Sobata70 (Trial A) 1989 USA

- <85 HD

131 4*

Beta 25 vs 100 vs 200

3 IV

- -

72 -

- - -

Suzuki69 1989 Japan

- ≤75 HD

179 8

Beta 1,500 U vs 3,000 U vs

placebo 3

IV

46 -

64 5.3 y

- - -

Maeda71 1988 Japan

- -

HD

89 8

- 1,500 U vs 3,000 U vs

6,000 U 3 -

- - - -

- - -

USA=United States of America; ESA=erythropoietic stimulating agent; Hb=hemoglobin; CKD=chronic kidney disease; HD=hemodialysis; SCr=serum creatinine; S=subcutaneous; IV=intravenous; DM=diabetes mellitus; CVD=cardiovascular disease; CHF=chronic heart failure; the – indicates that the value was not reported *only the fixed dose follow-up † includes only the single-blind follow-up ‡ percent DM as primary cause of chronic kidney disease

A-34

Table 1E: Description of included clinical trials: Schedule comparisons Author, year, country



(non-dialysis-


Design: sample


(g/L)

Hematopoietic regimen:

type, initial dose (U/kg/wk),



mean renal funciton or median years on

dialysis



Mircescu63 2006 Romania

On-therapy ≤100 HD

207 24

100-120

Beta Mean 71 1 vs 0.5

S

49 57

114 4.7 y

- - 0

Locatelli39 2005 Western Europe

On-therapy 100-130

HD

308 25-30

100-130

Darbe Pretrial dose

1 vs 0.5 IV

61 58 - -

- - -

PROMPT65 2005 USA

On-therapy <110


CKD (GFR ≤30 mL/min)

519 16

Alfa 40,000 U

1 vs 0.5 vs 0.33 vs 0.25 S

69 51

119 GFR 21 mL/min

46 3 -

Locatelli64 2002 Western Europe

On-therapy 93-127

HD

173 24

93-127

Beta Pretrial dose

1 vs 3 S

49 40

111 -

10* - -

USA=United States of America; ESA=erythropoietic stimulating agent; Hb=hemoglobin; CKD=chronic kidney disease; HD=hemodialysis; GFR=glomerular filtration rate; S=subcutaneous; DM=diabetes mellitus; CVD=cardiovascular disease; CHF=chronic heart failure; the – indicates that the value was not reported *percent DM as primary cause of chronic kidney disease

A-35

Table 1F: Description of included clinical trials: Route of administration comparisons Author, year, country



Design: sample


(g/L)

ESA regimen: type,





dialysis



Kaufman68 1998 USA

On therapy 100-110

HD

208 30

100-110

Alfa 50% of pretrial dose

3 S vs IV

60 98

105 3.7 y

- - -

Schaller66 1994 Germany

- 68-72 HD

90 12*

100-117

Beta 40 3

S vs IV

48 46 -

2.8 y

- - -

Muirhead67 1992 Canada

Some on-therapy

<95 HD

128 24

105-125

Alfa 50 3

S vs IV

58 55 79

4.2 y

- - -

USA=United States of America; ESA=erythropoietic stimulating agent; Hb=hemoglobin; HD=hemodialysis; S=subcutaneous; IV=intravenous; CrCl=creatinine clearance; DM=diabetes mellitus; CVD=cardiovascular disease; CHF=chronic heart failure; the – indicates that the value was not reported * only first 8 wk were double blind

A-36

Table 2A: Quality assessment of included clinical trials: ESA vs no ESA

Teplan 200348

Silverberg 200149

Kuriyama 199746

Nissenson 199542 Roth 199447

Study Design

Description of participant selection

Adequate Adequate Adequate Adequate Adequate

Description of non-eligible patients

Inadequate Inadequate Inadequate Inadequate Inadequate

Description of randomization assessment

Inadequate Adequate Adequate Adequate Adequate

Was the allocation to treatment concealed?†

Unclear Inadequate Unclear Adequate Unclear

Description of the therapeutic regimen

Adequate Adequate Adequate Adequate Adequate

Was the trial described as double blind?†

No No No Yes₤ No

Was there a description of withdrawals and dropouts?†

No Yes (0%) Partial (15%)

Yes (6%) Partial (22%)

Description of blinding assessment

- - - Inadequate -

Statistical Analysis

Description of sample size calculation

Inadequate Inadequate Inadequate Inadequate Inadequate

Was the design described as intention-to-treat?

No No No Yes No

Was a regression analysis used?

Yes No Yes Yes Yes

Was time to event data analyzed appropriately?

No No Yes No Yes

Was time series data analyzed appropriately?

Yes No No No Yes

Was interim analysis appropriately reported?

No No No No No

Presentation of Results

Were the dates of accrual reported?

Inadequate Inadequate Partial Adequate Inadequate

Were confidence intervals reported?

Partial Partial Partial Partial Partial

Were adverse events reported?

Inadequate Inadequate Inadequate Partial Inadequate

Funding

What were the source(s) of funding?†

Mixed NR NR Private Private

NR=not reported; Mixed=public and private sources of funding; the – indicates that the value was not applicable †items have empirical evidence

£method of double-blinding described and appropriate

A-37

Table 2A: Quality assessment of included clinical trials: ESA vs no ESA (continued) Klinkmann

199345 Abraham 199143

(Trials 2&3) Bahlmann 199144 Bennett 199150

Study Design


Adequate Adequate Partial Adequate


Inadequate Inadequate Inadequate Inadequate


Inadequate Partial Partial Adequate


Unclear Unclear Unclear Unclear


Adequate Adequate Partial Adequate


No Yes Yes Yes


Yes (6%) Partial (8%) Yes (12%) Yes (12%)


- Inadequate Inadequate Inadequate





No No No No


No Yes No Yes


No No No No


No No No No


No No No No





Adequate Partial Inadequate Partial


Adequate Inadequate Adequate Partial

Funding

What were the source(s) of funding?†

NR Mixed NR Private


A-38

Table 2B: Quality assessment of included clinical trials: High vs intermediate/low target Hb protocols

ACORD 200741

Macdougall 200740

CHOIR 200621

CREATE 200617

Rossert 200620

Levin 20051

Study Design Description of participant selection

Adequate Adequate Adequate Adequate Adequate Adequate


Partial Inadequate Inadequate Inadequate Inadequate Adequate




Adequate Adequate Unclear Adequate Unclear Adequate




No No Single No No Single


Yes (23%) Partial (7%) Yes (21%) Yes (14%) Yes (38%) Yes (11%)


- - Inadequate - - Inadequate

Statistical Analysis Description of sample size calculation

Adequate Partial Adequate Adequate Adequate Adequate


Yes Yes Yes Yes Yes Yes


No Yes Yes Yes No Yes


Yes No Yes Yes No No


No No Yes No No No


No No Yes Yes No No

Presentation of Results Were the dates of accrual reported?

Inadequate Inadequate Inadequate Adequate Adequate Inadequate


Partial Partial Partial Partial Partial Partial



Funding What were the source(s) of funding?† Private Private Private Private Private Private



A-39

Table 2B: Quality assessment of included clinical trials: High vs intermediate/low target Hb protocols (continued)

Parfrey 200554

Gouva 200456

Roger 200455

Furuland 200353

Foley 200018

Besarab 199816

CESG 199058

Study Design


Adequate Adequate Partial Adequate Adequate Adequate Adequate


Inadequate Inadequate Partial Inadequate Inadequate Inadequate Inadequate


Adequate Adequate Adequate Adequate Adequate Adequate Adequate


Adequate Adequate Adequate Unclear Unclear Unclear Unclear


Adequate Adequate Partial Adequate Inadequate Adequate Partial


Yes No Single No Single No Yes


Yes (24%) Yes (3%) Yes (18%) Yes (11%) Partial (8%) No Yes (7%)


Inadequate - Inadequate - Inadequate - Partial



Adequate Adequate Adequate Adequate Adequate Adequate Partial


Yes Yes Yes Yes No Yes No


Yes Yes Yes Yes Yes Yes Yes


Yes Yes Yes Yes No Yes No


No No No No Yes No Yes


No No No No No Yes No



Partial Adequate Adequate Adequate Adequate Adequate Inadequate


Adequate Adequate Partial Partial Adequate Partial Inadequate


Adequate Adequate Inadequate Partial Adequate Adequate Adequate

Funding

What were the source(s) of funding?† Private NR Private Private Private Private NR


A-40

Table 2C: Quality assessment of included clinical trials: Darbepoetin vs epoetin

Molina 200459

Nissenson 200260

Locatelli 200161

Study Design


Partial Adequate Adequate


Inadequate Adequate Inadequate


Adequate Adequate Adequate


Unclear Adequate Adequate


Partial Adequate Adequate


Yes Yes No


Yes (0%) Yes (8%) No


Inadequate Inadequate -



Inadequate Adequate Partial


No Yes No


No Yes No


No No No


No No No


No No No



Inadequate Inadequate Inadequate


Partial Partial Adequate


Adequate Adequate Adequate

Funding

What were the source(s) of funding?† NR Private Private

NR=not reported; the – indicates that the value was not applicable †items have empirical evidence

A-41

Table 2D: Quality assessment included clinical trials: Dose comparisons

Abraham 199143

(Trial 1)

Teehan 199162

Pollok 198972

Sobota 198970

(Trial A)

Suzuki 198969 Maeda 198871

Study Design Description of participant selection Adequate Adequate Adequate Partial Partial Inadequate Description of non-eligible patients

Inadequate Inadequate Inadequate Inadequate Inadequate Inadequate


Partial Inadequate Inadequate Inadequate Adequate Inadequate


Unclear Unclear Unclear Unclear Unclear Unclear


Adequate Adequate Partial Inadequate Adequate Inadequate


No Single No Yes Yes£ Yes


Partial (6%) Yes (9%) Partial (2%) No Partial (3%) No

Description of blinding assessment - Inadequate - Inadequate Inadequate Inadequate




No No No No No No


Yes No No No No No


No No No No No No


No No No No No No

Was interim analysis appropriately reported? No No No No No No




Partial Inadequate Adequate Partial Partial Partial


Inadequate Partial Inadequate Partial Adequate Partial

Funding What were the source(s) of funding?† Mixed Private NR NR NR NR



A-42

Table 2E: Quality assessment included clinical trials: Schedule comparisons

Mircescu 200663

Locatelli 200539* PROMPT 200565 Locatelli 200264

Study Design Description of participant selection

Adequate Partial Adequate Adequate


Adequate Partial Inadequate Inadequate


Adequate Adequate Adequate Adequate


Adequate Unclear Unclear Unclear


Adequate Adequate Adequate Adequate


No Yes£ No No


Yes (2%) Partial (15%) Partial (18%) Partial (12%)


- Inadequate - -


Adequate Inadequate Partial Inadequate


No Yes Yes Yes


No No Yes Yes


No No No No


No No Yes No


No No No No


Adequate Inadequate Adequate Inadequate


Adequate Adequate Partial Partial


Inadequate Partial Adequate Adequate

Funding

What were the source(s) of funding?† Private Private Private Private

NR=not reported; Mixed=public and private sources of funding; the – indicates that the value was not applicable *abstract and data from grey literature †items have empirical evidence


A-43

Table 2F: Quality assessment of included clinical trials: SC vs IV route of administration

Kaufman 199868

Schaller 199466 Muirhead 199267

Study Design


Adequate Partial Adequate




Adequate Partial Adequate


Unclear Unclear Unclear


Adequate Adequate Partial


No Yes Single


Yes (21%) No Yes (23%)


- Inadequate Inadequate





Yes No No


No Yes No


No No Yes


No No No


No No No





Partial Inadequate Partial


Inadequate Inadequate Adequate

Funding

What were the source(s) of funding?† Mixed Private Private


A-44

Table 3: Meta-regression results for all-cause mortality: High vs intermediate/low target Hb protocols

Explanatory variable Summary of effect

Median (range) n (%) No. of studies/

No. of participants RRR (95% CI) P-value

No prior treatment with ESA

- 4 (36) 11/5,201 1.15 (0.63,2.09) 0.66

Dialysis (not non-dialysis-dependent CKD)

- 4 (36) 11/5,201 0.85 (0.50,1.42) 0.53

Weeks of follow-up

98 wk (48,173) - 11/5,201 1.01 (0.99,1.04) per 4 wk 0.26

Achieved Hb in ESA group

131 g/L (126,143) - 9/4,853 1.15 (0.69,1.94) per 5 g/L 0.59

Achieved Hb in control group

115 g/L (100,148) - 9/4,853 0.95 (0.87,1.04) per 5 g/L 0.28

Required dose in ESA group 4758 U

(1992,21312) - 6/2,919 1.03 (0.93,1.15) per 1000 U 0.52

Required dose in control group 3141 U

(1773,3552) - 6/2,919 1.06 (0.92,1.21 per 1000 U 0.41

Beta (not alfa)

- 1 (9) 11/5,201 1.38 (0.69,2.75) 0.36

1/wk schedule (not 3/wk)

- 7 (78) 9/4,859 1.02 (0.48,2.15) 0.97

IV (not subcutaneous)

- 2 (18) 11/5,201 0.90 (0.51,1.57) 0.70

Mean age

60 y (50,66) - 10/4,811 1.19 (0.97,1.44) per 5 y 0.09

Percent male

59% (45,70) - 11/5,201 0.88 (0.77,0.99) per 5% 0.04

Percent DM

25% (0,56) - 10/4,811 1.03 (0.98,1.09) per 5% 0.24

Percent DM Excluding ESRD only

24% (0,56) - 7/2,637 1.01 (0.95,1.08) per 5% 0.68

Quality items

Unclear allocation concealment (not adequate)

- 6 (55) 11/5,201 1.28 (0.76,2.16) 0.35

Not double-blind

- 10 (91) 11/5,201 1.84 (0.90,3.77) 0.10

Inadequate description of withdrawals

- 3 (27) 11/5,201 1.10 (0.60,1.99) 0.77

Loss-to-follow >10%

- 7 (64) 11/5,201 0.98 (0.54,1.75) 0.93

Not intention-to-treat

- 1 (9) 11/5,201 1.20 (0.26,5.50) 0.82

Private funding (not NR)

- 10 (91) 11/5,201 1.59 (0.36,7.10) 0.54

ESA=erythropoietic stimulating agents; CKD=chronic kidney disease; Hb=hemoglobin; IV=intravenous; DM=diabetes mellitus; NR=not reported; RRR=relative risk ratio; wk=week; y=year; the ‘-‘ means not applicable Bolded results are significant at P≤0.05

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Table 4: Days of hospitalization: High vs intermediate/low target Hb protocols High Low Test n Mean SD n mean SD p-value

CREATE 200621 (only cardiovascular)

301 33 - 302 28 - ANCOVA NS

Rossert 200620 195 9.7 11.4 195 9 9 -

P=0.68

Furuland 200353 216 4.8 9.4 200 8.3 8.8 T-test

NS SD=standard deviation; ANCOVA=analysis of covariance; NS=non-significant; the – indicates that the value was not applicable Note, the reported statistics (means and SDs) and tests were not appropriate for this data. The large SDs indicate that the data were right-tail skewed.

Table 5: SF-36: High vs intermediate/low target Hb protocols Weeks of

therapy n Physical

function Role

physical Bodily pain

General health

Mental health

Role emotional

Social function

Vitality

Non-dialysis-dependent CKD trials

ACORD 200741 65 170 - - - High P=0.04

- - - -

CHOIR 200621 156 1432 NS P=0.49

NS P=0.32

NS P=0.15

NS P=0.87

NS P=0.31

Low P=0.01

NS P=0.16

NS P=0.58

CREATE 200617* 52/104 603 High/NS P<0.001/-

High/NS P=0.01/-

NS High/High P=0.003/P=

0.008

High/NS P<0.001/-

NS High/NS P=0.006/-

High/High P<0.001/P=

0.01 Rossert 200620 17 390 NS

P=0.08 NS

P=0.06 NS

P=0.30 NS

P=0.32 NS

P=0.69 NS

P=0.38 NS

P=0.60 High

P=0.04 Roger 200455 104 155 NS - - - NS - - -

Dialysis trials Parfrey 200554 96 596 - - - - - - NS

P=0.56 High

P=0.01 Foley 200018 48 146 NS NS NS NS NS NS NS NS

Besarab 199816† 52 1233 High P=0.03

NS NS NS NS NS NS NS

CKD=chronic kidney disease; NS=non-significant; the – indicates that the value was not reported; NS=non-significant; high=significant and favoured the high Hb target protocol; low=significant and favoured the intermediate/low Hb target protocol *First set of results are for year 1, second set are for year 2 †Results are based on unit increases in hematocrit, not target group differences

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Table 6: All-cause mortality in indirect comparisons Independent variable All CKD

OR (95% CI) Non-dialysis-

dependent CKD OR (95% CI)

Dialysis OR (95% CI)

Hb target groups

High

1.20 (0.90,1.60) 1.20 (0.90,1.60) 1.52 (0.54,4.26)

Intermediate

1.0 1.0 1.0

Low

0.95 (0.65,1.38) 0.95 (0.65,1.38) 1.20 (0.42,3.46)

No ESA

1.24 (0.68,2.27) 1.23 (0.67,2.25) 1.56 (0.51,4.71)

Alternative* Hb target groups

High

1.24 (1.02,1.50) 1.24 (1.02,1.50) 1.57 (0.58,4.26)

Intermediate/low

1.0 1.0 1.0

No ESA

1.25 (0.69,2.27) 1.23 (0.68,2.25) 1.57 (0.52,4.69)

Achieved Hb groups

>125 g/L

1.31 (1.02,1.84) 1.37 (1.02,1.83) 1.63 (0.56,4.79)

105.1-125 g/L

1.0 1.0 1.0

90.1-105 g/L

1.07 (0.75,1.54) 1.07 (0.75,1.54) 1.28 (0.43,3.78)

≤90 g/L

0.65 (0.20,2.09) 0.65 (0.20,210) 0.77 (0.17,3.57)

Hb=hemoglobin; ESA=erythropoietic stimulating agents; SC=subcutaneous; CKD=chronic kidney disease; OR=odds ratio; CI=confidence interval; IV=intravenous *Given that no studies compared “low” and “intermediate” groups in the same study, combining the low/intermediate groups into one larger group required less indirect comparison (and therefore less methodologic uncertainty) as all of the included RCTs comparing targets included at least one study arm with a hemoglobin target in the low/intermediate (i.e., 90-120 g/L) range. Bolded results are significant at P≤0.05

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APPENDIX 5: FIGURES FOR CLINICAL REVIEW

Figure 1: Funnel plot of all-cause mortality: High vs intermediate/low target Hb protocols

This funnel plot is a simple scatter plot of each trial’s precision (inversion of standard error) on the y-axis against each trial’s log RR on the x-axis. Since small trials have less precision and large trials have more, the scatter should form an inverted funnel when there are no systematic missing trials. Markers are sized according to the trial’s sample size; larger trials are marked with larger circles. A vertical line is drawn through our overall log RR (0.126, that is, a RR risk of 1.13) to aid the eye in detecting symmetry (an inverted funnel) or asymmetry. Our funnel plot appears mildly asymmetric. Therefore, there are possibly missing studies favouring a intermediate/low target Hb protocol. RR=relative risk

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Figure 2A: All-cause mortality: ESA vs no ESA

CKD=chronic kidney disease; ESA=erythropoietic stimulating agents; RR=relative risk; CI=confidence interval Weeks of follow-up: 36 Kuriyama 1997; 26 Roth 1994; 12 Nissenson 1995; ≤26 Bahlmann 1991; 12 Bennett 1991; 26 CESG 1990; 52 Klinkmann 1993

Figure 2B: Cardiovascular mortality: ESA vs no ESA

CKD=chronic kidney disease; ESA=erythropoietic stimulating agents; RR=relative risk; CI=confidence interval Weeks of follow-up: 36 Kuriyama 1997; ≤26 Bahlmann 1991; 52 Klinkmann 1993

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Figure 2C: Cardiovascular events: ESA vs no ESA

MI=myocardial infarction; HF=heart failure; ESA=erythropoietic stimulating agents; RR=relative risk; CI=confidence interval Weeks of follow-up: 52 Klinkmann 1993; 26 Roth 1994; 24 Bahlmann 1991 No clinical definitions of cardiovascular events were reported by the authors.

Figure 2D: Change in health-related quality of life: ESA vs no ESA

KDQ=Kidney Disease Questionnaire; ESA=erythropoietic stimulating agents; RR=relative risk; CI=confidence interval; H=high arm; L=low arm Weeks of follow-up: 26 CESG 1990

Figure 2E: Red cell transfusions: ESA vs no ESA

CKD=chronic kidney disease; ESA=erythropoietic stimulating agents; RR=relative risk; CI=confidence interval Weeks of follow-up: 26 Roth 1994; ≤26 Bahlmann 1991; 8 CESG 1990

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Figure 2F: Risk of initiation of dialysis: ESA vs no ESA

ESA=erythropoietic stimulating agents; RR=relative risk; CI=confidence interval Weeks of follow-up: 36 Kuriyama 1997; 26 Roth 1994; 5 Silverberg 2001

Figure 2G: Change in GFR/CrCl (mL/min): ESA vs no ESA

ESA=erythropoietic stimulating agents; WMD=weighted mean difference; CI=confidence interval; GFR=glomerular filtration rate; CrCl=creatinine clearance Weeks of follow-up: 48 Roth 1994; 156 Teplan 2003

Figure 2H: Change in SCr (μmol/L): ESA vs no ESA

ESA=erythropoietic stimulating agents; WMD=weighted mean difference; CI=confidence interval; SCr=serum creatinine Weeks of follow-up: 48 Roth 1994; 5 Silverberg 2001; 156 Teplan 2003

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Figure 2I: Change in blood pressure (mmHg): ESA vs no ESA

MAP=mean arterial pressure; ESA=erythropoietic stimulating agents; WMD=weighted mean difference; CI=confidence interval; H=high arm; L=low arm Weeks of follow-up: 12 Abraham 1991 Trial 2&3; 12 Bennett 1991; 24 CESG 1990; 156 Teplan 2003; ≤48 Roth 1994

Figure 2J: Hypertension: ESA vs no ESA

ESA=erythropoietic stimulating agents; RR=relative risk; CI=confidence interval Weeks of follow-up: 12 Abraham 1991 Trial 2&3; 24 Bahlmann 1991; 24 CESG 1990; 48 Roth 1994; 12 Bennett 1991

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Figure 2K: Adverse events: ESA vs no ESA

ESA=erythropoietic stimulating agents; RR=relative risk; CI=confidence interval Weeks of follow-up: 24 CESG 1990; 52 Klinkmann 1993; 12 Nissenson 1995; 8 Teehan 1991; 12 Bennett 1991; 48 Roth 1994

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Figure 3A: All-cause mortality: High vs intermediate/low target Hb protocols

CKD=chronic kidney disease; RR=relative risk; CI=confidence interval; ND=non-dialysis-dependent CKD; D=dialysis Weeks of follow-up: 156 CHOIR 2006; 156 CREATE 2006; 48 Furuland 2003; ~98 Gouva 2004; 104 Levin 2005; <156 Macdougall 2007; 104 Roger 2004; 173 Rossert 2006; 126 Besarab 1998; 26 CESG 1990; 48 Foley 2000; 96 Parfrey 2005

Figure 3B: Cardiovascular mortality: High vs intermediate/low target Hb protocols

CKD=chronic kidney disease; RR=relative risk; CI=confidence interval; ND=non-dialysis-dependent CKD; D=dialysis Weeks of follow-up: 156 CREATE 2006; 48 Furuland 2003; ~98 Gouva 2004; 104 Roger 2004; 126 Besarab 1998; 96 Parfrey 2005

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Figure 3C: Cardiovascular events: High vs intermediate/low target Hb protocols

MI=myocardial infarction; HF=heart failure; RR=relative risk; CI=confidence interval Weeks of follow-up: 65 ACORD 2007; 126 Besarab 1998; 156 CHOIR 2006; 156 CREATE 2006; 96 Parfrey 2005; 173 Rossert 2006 MI clinical definitions: Besarab 1998 – clinical suspicion, peak serum creatine kinase concentration >1.5 times the upper limit of the normal range, high fraction of creatine kinase MB; CHOIR 2006 – chest pain ≥15 min, abnormal cardiac enzyme levels, suspicious electrocardiographical findings; CREATE 2006 – resulting in hospitalization. No other clinical definitions of MI were reported. Stroke clinical definitions: CHOIR 2006 - new neurologic deficit of sudden onset that was not reversible within 24 h and that was not reversible within 24 h and that was not due to a readily identifiable nonvascular cause. No other clinical definitions of stroke were reported. HF clinical definitions: Besarab 1998 – resulting in hospitalization; CHOIR 2006 – resulting in hospitalization; CREATE 2006 – resulting in hospitalization; Parfrey 2005 - dyspnea at rest with two of the following 1) increased jugular venous pressure, bilateral basal crackles, radiographic pulmonary hypertension, and radiographic interstitial edema. Revascularization clinical definition: Besarab 1998 – coronary-artery bypass grafting

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Figure 3D: Hospitalization: High vs intermediate/low target Hb protocols

CVD=cardiovascular disease; RR=relative risk; CI=confidence interval Weeks of follow-up: 126 Besarab 1998; 156 CHOIR 2006; ~98 Gouva 2004; 173 Rossert 2006; 156 CREATE 2006

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Figure 3E: Change in health-related quality of life: High vs intermediate/low target Hb protocols

* the weighted mean differences were not adjusted for baseline values, hence the raw data shows final means and standard deviations rather than change-from-baseline means and standard deviations KDQ=Kidney Disease Questionnaire; SF-36=Medical Outcomes 36-item Short Form; WMD=weighted mean difference; CI=confidence interval Weeks of follow-up: 26 CESG 1990; 48 Foley 2000; 48 Furuland 2003; 156 CHOIR 2006; 52 CREATE 2006; 104 Roger 2004; 17 Rossert 2006; 65 ACORD 2007; ≤96 Parfrey 2005

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Figure 3F: Red cell transfusions: High vs intermediate/low target Hb protocols

CKD=chronic kidney disease; RR=relative risk; CI=confidence interval Weeks of follow-up: 156 CREATE 2006; 173 Rossert 2006; 126 Besarab 1998; 8 CESG 1990

Figure 3G: Risk of initiation of dialysis: High vs intermediate/low target Hb protocols

RR=relative risk; CI=confidence interval Weeks of follow-up: 156 CHOIR 2006; 156 CREATE 2006; ~98 Gouva 2004; 104 Levin 2005; <156 Macdougall 2007

Figure 3H: Change in GFR/CrCl (mL/min): High vs intermediate/low target Hb protocols

WMD=weighted mean difference; CI=confidence interval; Pre=predialysis; GFR=glomerular filtration rate; CrCl=creatinine clearance Weeks of follow-up: 65 ACORD 2007; 156 CREATE 2006; 48 Furuland 2003; 12 Gouva 2004; 104 Levin 2005; <156 Macdougall 2007; 104 Roger 2004

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Figure 3I: Change in SCr (μmol/L): High vs intermediate/low target Hb protocols

WMD=weighted mean difference; CI=confidence interval; SCr=serum creatinine Weeks of follow-up: 12 Gouva 2004; <156 Macdougall 2007

Figure 3J: Vascular access loss: High vs intermediate/low target Hb protocols

RR=relative risk; CI=confidence interval Weeks of follow-up: 126 Besarab 1998; 26 CESG 1990; 156 CREATE 2006; 48 Foley 2000; 48 Furuland 2003; 96 Parfrey 2005

Figure 3K: Change in blood pressure (mmHg): High vs intermediate/low target Hb protocols

* the weighted mean differences were not adjusted for baseline values, hence the raw data shows final means and standard deviations rather than change-from-baseline means and standard deviations; WMD=weighted mean difference; CI=confidence interval; ND=non-dialysis-dependent CKD; Weeks of follow-up: 24 CESG 1990; 156 CHOIR 2006; 156 CREATE 2006; 48 Furuland 2003; ≤104 Levin 2005; ≤96 Parfrey 2005; 104 Roger 2004; ~30 Rossert 2006

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Figure 3L: Hypertension: High vs intermediate/low target Hb protocols

SBP=systolic blood pressure; RR=relative risk; CI=confidence interval Weeks of follow-up: 104 Levin 2005; ≤96 Parfrey 2005; ≤40 Rossert 2006; 24 CESG 1990; 156 CREATE 2006

Figure 3M: Change in left ventricular mass index (g/m2): High vs intermediate/low target Hb protocols

CKD=chronic kidney disease; WMD=weighted mean difference; CI=confidence interval Weeks of follow-up: 65 ACORD 2007; 104 CREATE 2006; 104 Levin 2005; 104 Roger 2004

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Figure 3N: Adverse events: High vs intermediate/low target Hb protocols

RR=relative risk; CI=confidence interval; ND=non-dialysis-dependent CKD; D=dialysis Weeks of follow-up: 24 CESG 1990; 48 Furuland 2003; <156 Macdougall 2007; 96 Parfrey 2005; 104 Roger 2004; 156 CHOIR 2006; 104 Levin 2005; ≤173 Rossert 2006; 156 CREATE 2006

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Figure 4A: All-cause mortality: Darbepoetin vs epoetin

CKD=chronic kidney disease; Darbe=darbepoetin; EPO=epoetin; RR=relative risk; CI=confidence interval Weeks of follow-up: 24 Locatelli 2001; 28 Nissenson 2002

Figure 4B: Red cell transfusions: Darbepoetin vs epoetin

CKD=chronic kidney disease; Darbe=darbepoetin; EPO=epoetin; RR=relative risk; CI=confidence interval Weeks of follow-up: 24 Locatelli 2001; 28 Nissenson 2002

Figure 4C: Vascular access loss: Darbepoetin vs epoetin

Darbe=darbepoetin; EPO=epoetin; RR=relative risk; CI=confidence interval Weeks of follow-up: 28 Nissenson 2002; 24 Molina 2004

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Figure 4D: Adverse events: Darbepoetin vs epoetin

Darbe=darbepoetin; EPO=epoetin; RR=relative risk; CI=confidence interval Weeks of follow-up: 24 Locatelli 2001; 28 Nissenson 2002

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Figure 5A: All-cause mortality: SC vs IV route of administration

IV=intravenous; RR=relative risk; CI=confidence interval Weeks of follow-up: 24 Muirhead 1992; 26 Kaufman 1998

Figure 5B: Hypertension: SC vs IV route of administration

IV=intravenous; RR=relative risk; CI=confidence interval Weeks of follow-up: 8 Schaller 1994; 24 Muirhead 1992

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APPENDIX 6: TABLES FOR REVIEW OF ECONOMIC STUDIES

Table 1: Description of included economic studies Harris 199176 Leese 199078 Hynes 200277 Piccoli 199581 Remak 200379 Tonelli 200322 Objective Examine the effects of

EPO using a “low” target Hb, 90-100 g/L, on quality of life and cost

Compare costs and QOL of standard treatment of anemia vs treatment with EPO

Determine potential cost savings to Medicare using subcutaneous compared with intravenous administration of EPO

Identify the most cost-effective of 3 EPO practices

Analyze the factors influencing cost-effectiveness of a health care intervention over time using erythropoietin as a case study

Determine cost-effectiveness of higher Hb targets

Population HD patients HD patients

HD Medicare recipients in the US

CAPD patients HD and PD patients HD patients (simulated)

Setting Australia Spain, Germany, France, Italy and UK

US Japan UK US

Comparator(s) EPO target Hb 90-100 g/L (pre-post, baseline Hb mean 67 g/L) Control group (no EPO) for for hospitalization data

EPO 4,000 U ~3x/wk vs no treatment (blood transfusion as required)

EPO target Hct of 30-33% (IV vs SC)

EPO target Hct 33% (doses of 6,000, 9,000 or 12,000 U) (schedules of 1/wk, 1/2wk or 1/4wk)

EPO (average dose 6,160 U/wk) vs no treatment (blood transfusion as required)

EPO target Hb ( 95-105 vs 110-120 vs 120-125 vs 140 g/L)

Form of economic analysis

Unclear (aspects of cost-minimization analysis)

Cost-utility analysis Cost-minimization Cost-minimization Cost-utility analysis Cost-utility analysis

Perspective Societal Health care purchaser Health care purchaser (US Medicare)

Health care purchaser (indirect costs assumed equal in all arms)

Health Care purchaser Health care purchaser

Clinical effectiveness data source

Observational pre-post study (6 and 12 mo of follow-up, 30 participants)

Multi-site observational pre-post study (169 participants, from 5 countries)

Unblinded RCT (208 participants)

Unblinded RCT (41 participants)

Meta-analysis of pre-post design studies

RCTs identified from systematic review

Quality of life Time trade off Life satisfaction using the KDQ26,121 and the SIP122,123 Note: QOL was not used as measure of effectiveness in a cost-

Gudex and Kind questionnaire124 Rosser matrix125,126

Not assessed Assumed same in all arms Time trade off from 2 previous published studies using target hemoglobin of 95-110 g/L and 90-100 g/L57,76

RCT data (limited) Transformation of SF-3627 scores into utility scores Assumption of linear benefit of QOL at higher Hb targets

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Harris 199176 Leese 199078 Hynes 200277 Piccoli 199581 Remak 200379 Tonelli 200322 effectiveness or –utility ratio

Costs Direct medical: EPO costs, hospitalizations, outpatient visits, treatment while on dialysis (e.g., transfusion) Productivity costs for patient and family: employment, benefits, home productivity, leisure

Cost-modelling using data from published literature, retrospective cost analysis, healthcare funding organizations, and a small unpublished internal QOL study in Italy and Spain Cost categories include: EPO acquisition, transfusions, and treatment of adverse effects (to both EPO and transfusions)

EPO costs EPO costs (administration, dispensing, preparation), syringes, additional blood tests, blood pressure monitoring

EPO costs, iron costs, administration, complications, hospitalization, blood transfusion. Informed by expert opinion (n=5) where study data lacking

EPO costs Annual costs of dialysis, transplantation, hospitalization, physical claims, and iron sucrose

Model details No model Model used to estimate costs No formal model (simple tree assumed)

Decision tree Re-analysis using model from Leese78

Markov model Health states of “hemodialysis”, “renal transplant” and “dead”

Sensitivity analysis approach

None performed Country specific sensitivity analysis based on local usage, costs, and adverse effects Tested assumption of increased survival by 10%

Fraction of persons who are on IV switching to SC (range 25-100%) EPO reduction varied between 95% CI from RCT (32%, 95% CI 14-50) Dose reduction from observational data (range 10-50%)

95% CI of response probabilities reported in study Time horizon increased from 20wk to 1y Drug and administration costs

Identified plausible range, specific emphasis on model inputs that have changed over time from the original analysis by Leese et al.78

Focus on EPO dose required to achieve target Hb and QOL achieved for each target

Currency and year AUD (year NR) USD and local currencies (year NR)

USD 1998 USD (year NR) UK pounds sterling 2000

USD 2001

Important parameters from sensitivity analysis

Not applicable Cost per QALY range by country France $83,964–168,797 Germany $64,171–153,298 Italy $115,774–595,967 Spain $266,023–349,215 UK $112,880–176,077

Range of cost savings: $15M/y for a 10% reduction in dose, with 25% switching from IV to SC $295M/y for a 50% reduction in dose, with 100% switching from IV to SC

Higher doses become more attractive as the cost per administration of epoetin increases

Compared with the orginal study by Leese,78 the ICUR has dropped primarily due to: Decreased EPO dose (~55% drop in ICUR) Decrease in cost per unit

Substantial increases in QOL Reduction in hospitalization Lower dose of agent to achieve target Hb

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Harris 199176 Leese 199078 Hynes 200277 Piccoli 199581 Remak 200379 Tonelli 200322 of EPO (~50 drop in ICUR)

Base case results Net cost savings of $1,166.25/y per patient

Cost per QALY range $58,600-349,000 (depending on country and assumptions) Weighted average $137,000

Direct cost savings of $47M/y for a 33% reduction in dose, with 25% switching from IV to SC

At 20 wk: $1,090-1,236 for 6,000 U $1,460-1,601 for 9,000 U $1,553-1,668 for 12,000 U (administration costs $1-10)

Incremental cost per QALY gained £17,067

Incremental cost per QALY gained $55,295 for 110-120 vs 95-105 g/L $613,015 for 120-125 vs 110-120 g/L $828,215 for 140 vs 120-125 g/L

Conclusions “…improvements in quality of life and activity can be achieved in hemodialysis patients treated with relatively low doses of EPO..., and resulting benefits more than cover the cost of this therapy.”

“…EPO offers the possibility of measurable gains in quality of life for patients, but… the costs of the treatment are considerably greater than any likely resources savings…”

“Administering EPO subcutaneously would provide substantial cost savings to Medicare.”

“[EPO dose of 6,000 U] is the least costly of the 3 regimens studied in CAPD patients…” “The most cost-effective strategy was to use the lowest effective dose, reserving the highest dosage for patients who do not response after 2 months.”

“After 10 years of further experience with the use of EPO the cost-effectiveness ratio now falls within the range considered acceptable by NICE in the UK”

“Aiming for Hb targets in excess of 120 g/L is associated with unfavorable cost-effectiveness ratios and should not be undertaken based on current data.”

EPO=epoetin; Hb=hemoglobin; HD=hemodialysis; KDQ=Kidney Disease Questionnaire; SIP=Sickness Impact Profile; QOL=quality of life; AUD=Australian dollar; NR=not reported; UK=United Kingdom; USD=American dollar; QALY=quality-adjusted life years; US=United States; Hct=hematocrit; SC=subcutaneous; IV=intravenous; RCT=randomized controlled trial; CI=confidence interval; CAPD=continuous ambulatory peritoneal dialysis; ICUR=incremental cost-utitlity ratio; NICE=National Institute for Clinical Excellence

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Table 2: Quality assessment of included economic studies Harris 199176 Leese 199078 Hynes 200277 Piccoli 199581 Remak 200279 Tonelli 200322

Study Design: Study question

Is the economic importance of the research question outlined? Y=1


Is the research question clearly stated? Y=1 Yes Yes Yes Yes Yes Yes

Is the viewpoint(s) for the analysis clearly stated and justified? Y=1

Partial Yes Partial Partial Yes Yes

Specify viewpoint: Society Purchaser of health care or third

party payer

Purchaser of health care or third

party payer

Purchaser of health care or third

party payer

Purchaser of health care or third party payer

Purchaser of health care or third party payer

Study Design: Selection of alternatives

Is the rationale for choice of the alternative program(s) or intervention(s) described? Y=1


Are the alternatives under comparison clearly described? Y=1

Yes Partial Yes Yes Yes Yes

Study design: Form of evaluation

Is the form of economic evaluation clearly stated? Y=1

No Yes Yes Yes Yes Yes

Specify form of economic evaluation: - Cost utility analysis

Cost minimisation analysis

Cost minimisation analysis

Cost utility analysis Cost utility analysis

Is the choice of form of economic evaluation justified in relation to the question(s) being addressed? Y=1


Data collection: Effectiveness data

Is the source(s) of the data reported? Y=1 Yes Yes Yes Yes Yes Yes

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Harris 199176 Leese 199078 Hynes 200277 Piccoli 199581 Remak 200279 Tonelli 200322

Specify source: Single study Ad hoc of several sources

Single study, Ad hoc of several

sources

Single study Meta-analysis of pre-post design trials (transfusion &

hospitalization)

Systematic review or meta-analysis,

Ad hoc of several sources

If the economic evaluation is based on a single study, are the details of the design and the results given?

Yes - Yes Yes - -

Specify single study detail: Selection of study population,

intention to treat or evaluable cohort

- Selection of study population, method of

allocation of subjects, intention-

to-treat or evaluable cohort, effect size with

confidence intervals

Selection of study population, method of

allocation of subjects, intention-

to-treat or evaluable cohort, effect size with

confidence intervals

- -

If the economic evaluation is based on an overview or meta-analysis, are the details of the review steps and the results given?

- - - - Yes Yes

Specify details of review steps and results: - - - - Search strategy, selection criteria, method of synthesis,

effect size and confidence intervals

Search strategy, selection criteria, method of synthesis,

effect size and confidence intervals

Data collection: Benefit measurement and valuation

Is the primary outcome measure(s) for the economic evaluation clearly stated? Y=1

No Yes No No Yes Yes

Are health benefits valued? Yes Yes No No Yes Yes

If health benefits have been valued, are the details of the methods (e.g., Time trade off, standard gamble) reported?

Yes Yes - - Yes Yes

If health benefits have been valued, is a description of the patients reported?

Yes Yes - - Yes Yes

Are changes to productivity included? Yes No No No No No

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If changes to productivity are included, are they reported separately?

Yes - - - - -

If changes to productivity are included, is the relevance to the research question discussed?

Yes - - - - -

Data collection: Costing

Are the quantities of resources reported separately from their unit costs? Y=1


Are the methods for estimation of quantities and unit cost described? Y=1


Are the currency and price date reported? Y=1

No Yes No No Yes Yes

If the currency and price date are reported, are the details of any adjustments for inflation or currency conversions given? Y=1

- Yes - - Partial Yes

Data collection: Modelling

Are details of any model used reported? Y=1

- No - Yes No (previously published) Yes

Did the authors provide a justification for the choice of model used? Y=1

- - - Yes Yes Yes

Did the authors provide a justification for the choice of key parameters on which the model was based? Y=1

- Partial - Yes Yes Yes

Analysis and interpretation of results: Adjustments for timing of costs and benefits

Is the time horizon of costs and benefits given? Y=1

Yes Unclear Unclear Yes Unclear Yes

Is the discount rate(s) given? - Yes No - Yes Yes

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If the discount rate is given, is the choice of rate(s) justified?

- Yes - - Yes Yes

If costs or benefits are not discounted, is an explanation given?

- - - - - -

Analysis and interpretation of results: Allowance of uncertainty

If stochastic data is reported, are details of statistical tests and confidence intervals reported?

Yes No No Yes Yes Yes

Is a sensitivity analysis reported? Y=1 No Yes Yes Yes Yes Yes

If sensitivity analysis is reported, are details of the approach reported? Y=1

- Yes Yes Yes Yes Yes

If a sensitivity analysis is reported, is justification given for the choice of variables? Y=1

- Yes Partial Yes Yes Yes

If a sensitivity analysis is reported, are the ranges for the variables reported? Y=1

- Yes Partial Yes Yes Yes

Analysis and interpretation of results: Presentation of results

Are relevant alternatives compared? Y=1 Yes Yes Yes Yes Yes Yes

If relevant alternatives are compared, is an incremental analyses reported? Y=1

No Yes - No Yes Yes

Are major outcomes reported in both disaggregated and aggregated form? Y=1

No Yes - - Partial Yes

Is an answer to the original study question given? Y=1


If an answer to the original study question is given, do the conclusions follow clearly from the data reported? Y=1


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If an answer to original study question is given, are there appropriate qualifications and reservations? Y=1


Check list (not covered in BMJ)

Does the study discuss the generalisability of the results to other settings and patient/client groups? Y=1

No Yes Yes No Yes Yes

Does the article indicate that there is no potential conflict of interest of study researcher(s) and funder(s)?

No No No No No (Author employed by

industry)

Partial

Are ethical and distributional issues discussed appropriately?

Partial Unclear Yes No Yes Yes

Funding

Industry funding Private Private Public - Private None

Overall quality

Quality Score (maximum score 28) 11 23 16 21 25 28

Y=yes; the – indicates that the value was not applicable

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APPENDIX 7: TABLES FOR ECONOMIC EVALUATION

Table 1: Baseline economic model parameters for clinical events Variable

Estimate Range Source

Probability of being over 65

0.51 CORR

Annual risk of mortality for dialysis patients under 65, intermediate target

0.077 0.072 – 0.083 (95% CI)

CORR

Annual risk of mortality for dialysis patients over 65, intermediate target

0.212 0.202 – 0.223 (95% CI)

CORR

Annual risk of transplant for patients under 65 (constant for all Hb targets)

0.007 0.006 – 0.10 (95% CI)

Tonelli 200687

Annual risk of transplant for patients over 65 (constant for all Hb targets)

0.102 0.096 – 0.356 (95% CI)

Tonelli 200687

Annual risk of starting dialysis post-transplant (constant for both age groups and Hb targets)

0.04 USRDS

Risk of death with transplant (constant for both age groups and Hb targets)

0.08 Wolfe 1999127

Annual risk of death post-transplant (constant for both age groups and Hb targets)

0.03 Wolfe 1999127

Annual risk of beginning dialysis for those under 65

0.26 AKDN

Annual risk of beginning dialysis for those over 65

0.07 AKDN

Annual risk of death for those not on dialysis for those under 65

0.07 AKDN

Annual risk of death for those not on dialysis for those over 65

0.28 AKDN

Hb=hemoglobin; CI=confidence interval; CORR=Canadian Organ Replacement Registry; USRDS=United States Renal Disease System; AKDN=Alberta Kidney Disease Network

A-73

Table 2: Estimates of effectiveness Variable


Odds ratio of death of a high Hb target compared to a low target, non-dialysis-dependent CKD and dialysis combined

1.27 0.98-1.64 (95% CI)

Meta-analysis

Odds ratio of death of a low Hb target compared to an intermediate target, non-dialysis-dependent CKD and dialysis combined

1.05 0.72-1.54 (95% CI)

Meta-analysis

Odds ratio of death of no ESA compared to an intermediate Hb target, non-dialysis-dependent CKD and dialysis combined

1.32 0.60-2.63 (95% CI)

Meta-analysis

Relative risk of hospitalisation of a high Hb target compared to an intermediate, a low and no ESA*

1.06 1.00-1.13 (95% CI)

Meta-analysis

Relative risk of starting dialysis of no ESA compared to an intermediate Hb target, and low**

1.31 0.78-2.22 (95% CI)

Meta-analysis

Relative risk of starting dialysis of a high Hb target compared to an intermediate, and low

0.93 0.79-1.11 (95% CI)

Meta-analysis

*The risk of hospitalisation was assumed to be equal among the no treatment, low and intermediate hemoglobin target groups **The risk of starting dialysis was assumed to equal for the low target group and the intermediate group Hb=hemoglobin; CKD=chronic kidney disease; ESA=erythropoietic stimulating agents; CI=confidence interval

A-74

Table 3: Baseline utility estimates Variable


Utility for functioning transplant

0.816 Laupacis 1996128

Utility for patients on dialysis under 65, intermediate target

0.639 0.582-0.696 (95% CI) Manns 200395

Utility for patients on dialysis over 65, intermediate target

0.572 0.507-0.636 (95% CI) Manns 200395

Utility for patients on dialysis under 65, high target 0.640 0.648-0.637 (95% CI) Meta-analysis of mean change in SF-36 Domain scores of high target compared to intermediate, converted to change in

utility using beaver dam conversion, applied to baseline under 65 110 utility

Utility for patients on dialysis over 65, high target 0.573 0.581-0.570 (95% CI) Meta-analysis of mean change in SF-36

Domain scores of high target compared to intermediate, converted to change in

utility using beaver dam conversion, applied to baseline over 65 110 utility

Utility for patients on dialysis under 65, low target 0.609 ± 25% Half of the additional decrement in utility

comparing patients managed with ESA to an intermediate target and those managed without ESA in CESG study57 applied to

baseline under 65 110 utility (Decrement of 0.03)

Utility for patients on dialysis over 65, low target 0.542 ± 25% Half of the additional decrement in utility

comparing patients managed with ESA to an intermediate target and those managed without ESA in CESG study57 applied to

baseline over 65 110 utility (Decrement of 0.03)

Utility for patients on dialysis under 65, managed without ESA

0.579 ± 25% The difference in the utility from baseline to 6 months between those managed with

ESA to an intermediate target hemoglobin vs those managed without

ESA in CESG study57 applied to baseline under 65 110 utility (Decrement of 0.06)

Utility for patients on dialysis over 65, managed without ESA

0.512 ± 25% The difference in the utility from baseline to 6 months between those managed with

ESA to an intermediate target Hb vs those managed without ESA in CESG study57 applied to baseline over 65 110

utility (Decrement of 0.06)

Utility for non-dialysis-dependent CKD patients 0.595 CHOIR study21 baseline low Hb group,

Beaver dam conversion Note, a detailed description of the methods used to derive these quality of life estimates is provided in the methods section. CKD=chronic kidney disease; CI=confidence interval; SF-36=Medical Outcomes Study 36-item Short Form; ESA=erythropoietic stimulating agents; Hb=hemoglobin

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Table 4: Baseline costs (2005 CAD) by clinical status Variable Estimate Range Source Annual cost of transplant

$34,035 $31,731-37,339 Laupacis 1996128

Annual cost of hemodialysis

$47,776 ±25% Lee 2002101

Cost of transplant

$80,940 $77,636-84,244 Laupacis 1996128

Annual hospitalization cost of non-dialysis-dependent CKD patient

$14,584 $4,296-15,694 (IQR)

AKDN

Annual hospitalization cost of dialysis patient

$20,418 ±50% USRDS

Cost of erythropoietin (per 1000 U) $15.32 $14.25 Ontario drug benefit list

Cost of one red cell transfusion $250 - Tretiak 199699

CAD=Canadian dollars; CKD=chronic kidney disease; IQR=inter-quartile range; AKDN=Alberta Kidney Disease Network

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Table 5: Base case cost-utility analyses for patients on dialysis Model Strategy Cost

($) Incremental

cost compared to no ESA

($)

Effectiveness (QALY)

Incremental effectiveness compared to

no ESA (QALY)

Incremental cost-utility ratio compared to no

ESA ($/QALY)

No ESA 359K 3.49

Low 446K 87K 4.12 0.63 138,000

Intermediate 473K 114K 4.39 0.90 127,000

Model 1D RR of death combined non-dialysis-dependent CKD and dialysis Observed utilities as described in Table 2

High 457K 98K 3.85 0.36 272,000

No ESA 359K 3.49

Low 460K 100K 4.24 0.75 133,000

Intermediate 473K 114K 4.39 0.90 127,000

Model 2D RR of death combined non-dialysis-dependent CKD and dialysis RR of death for low = 1.0 Observed utilities as described in Table 2

High 457K 98K 3.85 0.36 272,000

No ESA 359K 3.49

Low 460K 100K 4.39 0.90 111,000

Intermediate 473K 114K 4.39 0.90 127,000

Model 3D RR of death combined non-dialysis-dependent CKD and dialysis RR of death for low = 1.0 Utilities for low g/L = 110 g/L

High 457K 98K 3.85 0.36 272,000

No ESA 359K 3.49

Low 460K 100K 4.39 0.90 111,000

Intermediate 473K 114K 4.39 0.90 127,000

Model 4D RR of death combined non-dialysis-dependent CKD and dialysis RR of death for low = 1.0 Utilities for low = intermediate = high

High 457K 98K 3.84 0.35 280,000

No ESA 292K 2.85

Low 460K 168K 4.24 1.39 120,000

Intermediate 473K 181K 4.39 1.54 117,000

Model 5D RR of death based only on dialysis (excluding non-dialysis-dependent CKD studies)* RR of death for low =1.0 Observed utilities as described in Table 2

High 450K 159K 3.79 0.94 169,000

* Odds ratios for death excluding non-dialysis-dependent CKD studies: Patients managed without ESA compared to intermediate: 1.85 low compared to intermediate: 1.54 high compared to intermediate: 1.30 D=dialysis; CKD=chronic kidney disease; RR=relative risk; ESA=erythropoietic stimulating agents; QALY=quality-adjusted life years

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Table 6: Base case cost-utility analyses for non-dialysis-dependent CKD patients Model Strategy Cost

($) Incremental

cost compared to no ESA ($)


Incremental effectiveness

compared to no ESA

(QALY)

Incremental cost-utility

ratio compared to

no ESA ($/QALY)

No ESA 234K 2.73

Low 329K 95K 3.23 0.51 186,000

Intermediate 350K 116K 3.43 0.70 165,000

Model 1ND RR of death combined non-dialysis-dependent CKD and dialysis for both non-dialysis-dependent CKD death risk and death risk after beginning dialysis Observed utilities as described in Table 2

High 325K 95K 2.92 0.20 475,000

No ESA 234K 2.73

Low 334K 101K 3.29 0.56 180,000

Intermediate 350K 116K 3.43 0.70 165,000

Model 2ND RR of death combined non-dialysis-dependent CKD and dialysis for both non-dialysis-dependent CKD death risk and death risk after beginning dialysis RR of death for low =1.0 for non-dialysis-dependent CKD Observed utilities as described in Table 2

High 325K 95K 2.92 0.20 475,000

No ESA 234K 2.73

Low 340K 107K 3.34 0.62 172,000

Intermediate 350K 116K 3.43 0.70 165,000

Model 3ND RR of death combined non-dialysis-dependent CKD and dialysis for both non-dialysis-dependent CKD death risk and death risk after beginning dialysis RR of death for low =1.0 for non-dialysis-dependent CKD and dialysis Observed utilities as described in Table 2

High 325K 95K 2.92 0.20 475,000

No ESA 234K 2.73

Low 340K 107K 3.43 0.70 153,000

Intermediate 350K 116K 3.43 0.70 165,000

Model 4ND RR of death combined non-dialysis-dependent CKD and dialysis for both non-dialysis-dependent CKD death risk and death risk after beginning dialysis RR of death for low = 1.0 for non-dialysis-dependent CKD and dialysis Utilities for low = intermediate

High 325K 95K 2.92 0.20 475,000

No ESA 234K 2.73 Model 5ND RR of death combined non-dialysis-dependent CKD and dialysis for both non-dialysis-dependent

Low 340K 107K 3.43 0.70 153,000

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Model Strategy Cost ($)

Incremental cost

compared to no ESA ($)



compared to no ESA

(QALY)

Incremental cost-utility

ratio compared to

no ESA ($/QALY)

Intermediate 350K 116K 3.43 0.70 165,000 CKD death risk and death risk after beginning dialysis RR of death for low =1.0 for non-dialysis-dependent CKD and dialysis Utilities for low = intermediate = high

High 325K 95K 2.92 0.20 475,000

No ESA 212K 2.59

Low 340K 129K 3.34 0.75 172,000

Intermediate 350K 138K 3.43 0.83 166,000

Model 6ND RR of death for non-dialysis-dependent CKD based only on non-dialysis-dependent CKD studies* RR of death for dialysis based only on dialysis studies** RR of death for low =1.0 for non-dialysis-dependent CKD and dialysis Observed utilities as described in Table 2

High 346K 134K 3.13 0.54 248,000

* Odds ratios for death for non-dialysis-dependent CKD excluding dialysis studies: Patients managed without ESA compared to intermediate: 1.10 low compared to intermediate: 0.73 high compared to intermediate: 1.02 ** Odds ratios for death for dialysis excluding non-dialysis-dependent CKD studies: Patients managed without ESA compared to intermediate: 1.85 low compared to intermediate: 1.54 high compared to intermediate: 1.30

ND=non-dialysis-dependent CKD; CKD=chronic kidney disease; RR=relative risk; ESA=erythropoietic stimulating agents; QALY=quality-adjusted life years

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Table 7: One-way sensitivity analysis for patients on dialysis Scenario Strategy Cost

($) Incremental

cost compared to

no ESA ($)



no ESA (QALY)

Incremental cost-utility ratio

compared to no ESA

($/QALY) No ESA 304K 2.96

Low 382K 78K 3.54 0.58 134,000

Intermediate 406K 102K 3.27 0.31 329,000

Applied to Model 1D Increase in mortality by 25%

High 387K 83K 3.79 0.82 101,000

No ESA 439K 4.23

Low 536K 97K 4.92 0.69 141,000

Intermediate 565K 127K 5.22 0.99 128,000

Applied to Model 1D Decrease in mortality by 25%

High 556K 117K 4.66 0.42 278,000

No ESA 359K 3.49

Low 444K 85K 4.12 0.63 135,000

Intermediate 470K 110K 4.39 0.90 122,000

Applied to Model 1D Cost of ESA = $14.25 per 1000 units as per listing in Ontario and Yukon

High 452K 92K 3.85 0.36 256,000

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Table 8: One-way sensitivity analysis for non-dialysis-dependent CKD patients Scenario Strategy Cost

($) Incrementa

l cost compared to no ESA

($)



compared to no ESA

(QALY)


ESA ($/QALY)

No ESA 214K 2.46

Low 301K 87K 2.93 0.47 185,000

Intermediate 321K 107K 3.12 0.66 162,000

Applied to Model 1ND Increase in non-dialysis-dependent CKD mortality by 25%

High 295K 81K 2.62 0.16 506,000

No ESA 191K 2.25

Low 275K 84K 2.71 0.46 182,000

Intermediate 293K 102K 2.88 0.63 161,000

Applied to Model 1ND Increase in non-dialysis-dependent CKD mortality by 25% Increase in dialysis mortality by 25%

High 268K 78K 2.42 0.17 458,000

No ESA 258K 3.07

Low 364K 106K 3.62 0.55 192,000

Intermediate 386K 128K 3.82 0.76 168,000

Applied to Model 1ND Decrease in non-dialysis-dependent CKD mortality by 25%

High 364K 106K 3.31 0.24 441,000

No ESA 298K 3.42

Low 407K 109K 3.98 0.56 194,000

Intermediate 431K 133K 4.21 0.79 179,000

Applied to Model 1ND Decrease in non-dialysis-dependent CKD mortality by 25% Decrease in dialysis mortality by 25%

High 409K 112K 3.65 0.23 486,000

No ESA 234K 2.73

Low 327K 88K 2.23 0.51 172,000

Intermediate 347K 94K 2.92 0.70 134,000

Applied to Model 1ND Cost of ESA = $14.25 per 1000 units as per listing in Ontario and Yukon

High 322K 114K 3.43 0.20 570,000

D=dialysis; ND=non-dialysis-dependent CKD; CKD=chronic kidney disease; RR=relative risk; ESA=erythropoietic stimulating agents; QALY=quality-adjusted life years

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Table 9: Scenario analyses for patients on dialysis Scenario Strategy Cost

($) Incremental




compared to no ESA

(QALY)


ESA ($/QALY)

No ESA 448K 3.93

Low 565K 117K 4.72 0.79 148,000

Intermediate 602K 154K 5.09 1.16 132,000

Model 1D Patients Under 65 Only

High 589K 141K 4.72 0.50 282,000

No ESA 275K 3.06

Low 332K 58K 3.54 0.48 120,000

Intermediate 349K 74K 3.72 0.66 112,000

Model 1D Patients Over 65 Only

High 330K 56K 3.28 0.22 254,000

No ESA 88K 3.49

Low 135K 48K 4.12 0.63 76,000

Intermediate 153K 65K 4.39 0.90 72,000

Model 1D Dialysis costs = 0 Transplant costs = 0

High 178K 90K 3.85 0.36 250,000

No ESA 356K 3.41

Low 446K 91K 4.12 0.71 128,000

Intermediate 473K 117K 4.39 0.98 119,000

Model 1D RR of transplant with no ESA compared to ESA = 0.9

High 457K 101K 3.85 0.44 246,000

No ESA 447K 3.92

Low 565K 118K 4.72 0.81 145,000

Intermediate 602K 155K 5.09 1.17 132,000

Model 1D RR of transplant with no ESA compared to ESA = 0.9 In patients under 65

High 589K 142K 4.44 0.52 273,000

No ESA 267K 2.92 Model 1D RR of transplant with no ESA compared to ESA = 0.9 In patients over 65 Low 332K 65K 3.54 0.62 104,000

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Scenario Strategy Cost ($)

Incremental cost




compared to no ESA

(QALY)


ESA ($/QALY)

Intermediate 349K 82K 3.72 0.80 102,000

High 330K 63K 3.28 0.36 175,000

No ESA 350K 3.29

Low 446K 97K 4.12 0.84 115,000

Intermediate 473K 123K 4.39 1.11 110,000


High 457K 107K 3.85 0.56 191,000

No ESA 446K 3.89

Low 565K 119K 4.72 0.83 163,000

Intermediate 602K 156K 5.09 1.20 130,000


High 589K 143K 4.44 0.55 260,000

No ESA 257K 2.71

Low 332K 76K 3.54 0.84 90,000

Intermediate 349K 92K 3.72 1.02 90,000

Model 1D RR of transplant with no ESA compared to ESA = 0.75 In patients over 65

High 330K 74K 3.28 0.58 127,000

No ESA 339K 3.07

Low 446K 107K 4.12 1.05 102,000

Intermediate 473K 134K 4.39 1.32 102,000


High 457K 118K 3.85 0.78 151,000

No ESA 445K 3.84

Low 565K 120K 4.72 0.88 136,000

Intermediate 602K 157K 5.09 1.25 125,000


High 589K 144K 4.44 0.59 257,000

Model 1D RR of transplant with no

No ESA 237K 2.32

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Incremental cost




compared to no ESA

(QALY)


ESA ($/QALY)

Low 332K 95K 3.54 1.22 77,000

Intermediate 349K 112K 3.72 1.40 80,000

ESA compared to ESA = 0.50 In patients over 65

High 330K 93K 3.28 0.96 96,000

No ESA 368K 3.49

Low 448K 81K 4.12 0.63 128,000

Intermediate 475K 107K 4.39 0.90 118,000

Model 1D Rate of transfusion with no ESA 0.44 units per month compared to 0.09 units per month with ESA (Nissenson et al42)

High 459K 91K 3.85 0.36 252,000

ESA administered subcutaneously – all models considered No ESA 359K 3.49

Low 437K 78K 4.12 0.63 123,000

Intermediate 435K 100K 4.39 0.90 111,000

Model 1D

High 460K 75K 3.85 0.36 208,000

No ESA 359K 3.49

Low 450K 91K 4.24 0.75 121,000

Intermediate 435K 100K 4.39 0.90 111,000

Model 2D

High 460K 75K 3.85 0.36 208,000

No ESA 359K 3.49

Low 450K 91K 4.39 0.90 101,000

Intermediate 435K 100K 4.39 0.90 111,000

Model 3D

High 460K 75K 3.85 0.36 208,000

No ESA 359K 3.49

Low 450K 91K 4.39 0.90 101,000

Model 4D

Intermediate 435K 100K 4.39 0.90 111,000

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Incremental cost




compared to no ESA

(QALY)


ESA ($/QALY)

High 460K 75K 3.84 0.35 214,000

No ESA 292K 2.85

Low 450K 159K 4.24 1.39 114,000

Intermediate 460K 168K 4.39 1.54 109,000

Model 5D

High 428K 137K 3.79 0.94 145,000

D=dialysis; RR=relative risk; ESA=erythropoietic stimulating agents; QALY=quality-adjusted life years

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Table 10: Scenario analyses for non-dialysis-dependent CKD patients Scenario Strategy Cost

($) Incrementa

l cost compared to no ESA

($)



no ESA (QALY)


compared to no ESA

($/QALY)

No ESA 397K 3.97

Low 525K 128K 4.71 0.74 172,000

Intermediate 558K 161K 5.01 1.04 154,000

Model 1ND Patients Under 65 Only

High 529K 132K 4.35 0.38 347,000

No ESA 77K 1.53

Low 140K 63K 1.81 0.28 225,000

Intermediate 149K 73K 1.90 0.38 192,000

Model 1ND Patients Over 65 Only

High 129K 53K 1.54 0.01 5,300,000

No ESA 79K 2.73

Low 162K 83K 3.23 0.51 162,000

Intermediate 176K 97K 3.43 0.70 139,000

Applied to Model 1ND Dialysis costs = 0 Transplant costs = 0

High 186K 107K 2.92 0.20 535,000

No ESA 233K 2.71

Low 329K 96K 3.23 0.52 184,000

Intermediate 350K 117K 3.43 0.72 162,000

Model 1ND RR of transplant with no ESA compared to ESA = 0.9

High 325K 92K 2.92 0.21 438,000

No ESA 397K 3.96

Low 525K 129K 4.71 0.75 172,000

Intermediate 558K 162K 5.09 1.05 154,000

Model 1ND RR of transplant with no ESA compared to ESA = 0.9 In patients under 65

High 529K 133K 4.35 0.39 341,000

No ESA 76K 1.51 Model 1ND RR of transplant with no ESA compared to ESA = 0.9 In patients over 65

Low 140K 64K 1.81 0.30 213,000

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Incremental cost

compared to no ESA

($)



no ESA (QALY)


compared to no ESA

($/QALY)

Intermediate 149K 74K 1.90 0.39 189,000

High 129K 54K 1.54 0.03 1,800,000

No ESA 232K 2.87

Low 329K 97K 3.23 0.55 176,000

Intermediate 350K 118K 3.43 0.74 159,000


High 325K 94K 2.92 0.23 408,000

No ESA 396K 3.94

Low 525K 129K 4.71 0.77 167,000

Intermediate 558K 162K 5.09 1.07 151,000


High 529K 133K 4.35 0.41 324,000

No ESA 74K 1.48

Low 140K 66K 1.81 0.33 200,000

Intermediate 149K 75K 1.90 0.42 178,000

Model 1ND RR of transplant with no ESA compared to ESA = 0.75 In patients over 65

High 129K 55K 1.54 0.06 916,000

No ESA 230K 2.65

Low 329K 99K 3.23 0.59 167,000

Intermediate 350K 120K 3.43 0.78 153,000


High 325K 95K 2.92 0.27 351,000

No ESA 395K 3.91

Low 525K 131K 4.71 0.80 163,000

Intermediate 558K 163K 5.09 1.10 148,000


High 529K 135K 4.35 0.44 306,000

Model 1ND RR of transplant with no

No ESA 71K 1.43

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Incremental cost

compared to no ESA

($)



no ESA (QALY)


compared to no ESA

($/QALY)

Low 140K 68K 1.81 0.38 179,000

Intermediate 149K 78K 1.90 0.47 165,000

ESA compared to ESA = 0.50 In patients over 65

High 129K 58K 1.54 0.11 527,000

No ESA 239K 2.73

Low 330K 91K 3.23 0.51 178,000

Intermediate 351K 112K 3.43 0.70 160,000

Model 1ND Rate of transfusion with no ESA 0.44 units per month compared to 0.09 units per month with ESA (Nissenson et al42)

High 326K 88K 2.92 0.20 440,000

ESA administered subcutaneously – all models considered No ESA 234K 2.73

Low 324K 90K 3.23 0.51 176,000

Intermediate 342K 109K 3.43 0.70 155,000

Model 1ND

High 314K 80K 2.92 0.20 400,000

No ESA 234K 2.73

Low 329K 95K 3.29 0.56 169,000

Intermediate 342K 109K 3.43 0.70 155,000

Model 2ND

High 314K 80K 2.92 0.20 400,000

No ESA 234K 2.73

Low 335K 102K 3.34 0.62 164,000

Intermediate 342K 109K 3.43 0.70 155,000

Model 3ND

High 314K 80K 2.92 0.20 400,000

No ESA 234K 2.73

Low 335K 102K 3.43 0.70 145,000

Intermediate 342K 109K 3.43 0.70 155,000

Model 4ND

High 314K 80K 2.92 0.20 400,000

A-88


Incremental cost

compared to no ESA

($)



no ESA (QALY)


compared to no ESA

($/QALY)

No ESA 234K 2.73

Low 335K 102K 3.43 0.70 145,000

Intermediate 342K 109K 3.43 0.70 155,000

Model 5ND

High 314K 80K 2.92 0.20 400,000

No ESA 212K 2.59

Low 335K 124K 3.34 0.75 165,000

Intermediate 342K 131K 3.43 0.83 157,000

Model 6ND

High 334K 122K 3.13 0.54 226,000

ND=non-dialysis-dependent CKD; CKD=chronic kidney disease; RR=relative risk; ESA=erythropoietic stimulating agents; QALY=quality-adjusted life years

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Table 11: Dialysis model considering three treatment strategies Scenario Strategy Cost

($) Incremental

cost compared to no ESA

($)



no ESA (QALY)


compared to no ESA

($/QALY)

No ESA 372K 3.61 ESA dosing intermediate/low = 7035 U/wk ESA dosing high = 15565 U/wk OR of death for no ESA compared to intermediate/low = 1.25 OR of death for high compared to intermediate/low = 1.24

Intermediate/Low 466K 94K 4.39 0.79 118,000

ESA=erythropoietic stimulating agents; OR=odds ratio; QALY=quality-adjusted life years

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Table 12: Non-dialysis-dependent CKD model considering three treatment strategies Scenario Strategy Cost

($) Incremental




compared to no ESA

(QALY)


compared to no ESA

($/QALY)

No ESA 244K 2.83

Intermediate/Low 345K 101K 3.24 0.59 171,000

Non-dialysis-dependent CKD ESA dosing intermediate/low = 3041 U/wk Non-dialysis-dependent CKD ESA dosing high = 6728 U/wk Dialysis ESA dosing intermediate/low = 7035 U/wk Dialysis ESA dosing high = 15565 U/wk OR of death for no ESA compared to intermediate/low = 1.25 (both dialysis and non-dialysis-dependent CKD) OR of death for high compared to intermediate/low = 1.24 (both dialysis and non-dialysis-dependent CKD)

High 329K 86K 2.96 0.13 661,000

CKD=chronic kidney disease; ESA=erythropoietic stimulating agents; OR=odds ratio; QALY=quality-adjusted life years

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APPENDIX 8: FIGURES FOR ECONOMIC EVALUATION

Figure 1: Dialysis-dependent model

Hb=hemoglobin

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Figure 2 : Non-dialysis-dependent CKD model

Hb=hemoglobin

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Figure 3: Modelled survival curve for dialysis patients

A-94

Figure 4: Modelled survival curve for non-dialysis-dependent CKD patients

A-95

Figure 5: Cost-utility graphs for Models 1-5D for dialysis patients

A B

C D

E

A-96

Figure 6: Cost-utility graphs for Models 1-6ND for non-dialysis-dependent CKD patients

A B

C D

E F

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APPENDIX 9: TABLES FOR HEALTH SERVICES IMPACT

Table 1. Population and budget impact of varying Hb targets in Canada

AB BC MN NB NF NS ON QC SK Canada

HD patients 1361 1522 762 373 327 405 6807 3249 486 15,292 PD patients

239 570 189 181 47

127 1490 657 119 3628

Total Dialysis 1600 2101 951 554 374 532 8297 3906 605 18,920

Low hemoglobin target (90-105 g/L) (Cost/y)

HD(SC) + PD

7,533,727 9,892,725 4,477,859 2,608,553 1,761,009 2,504,964 39,067,083 18,391,711 2,848,691 89,086,323 (4709 /patient)

HD(IV) + PD

10,673,832 13,404,290 6,235,948 3,469,140 2,515,464 3,439,382 54,772,220 25,887,817 3,969,992 124,368,085 (6573 /patient)

Intermediate hemoglobin target (105-120 g/L) (Cost/y)

HD(SC) + PD 10,522,492 13,817,347 6,254,306 3,643,413 2,459,633

3,498,729 54,565,698 25,688,034 3,978,817 124,428,469 (6577 /patient)

HD(IV) + PD 14,908,333 18,722,012 8,709,861 4,845,410 3,513,394 4,803,846 76,501,345 36,157,979 5,544,959 173,707,141 (9394 /patient)

High hemoglobin target (120-145 g/L) (Cost/y)

HD(SC) + PD

20,530,075 26,958,555 12,202,564 7,108,539 4,798,905 6,826,250 106,461,272 50,119,047 7,762,935 242,768,141 (12,832 /patient)

HD (IV) + PD

29,087,139

36,527,880 16,993,513 9,453,715 6,854,864

9,372,621 149,259,165 70,546,600 10,818,580 338,914,077 (18,329 /patient)

Number of prevalent hemodialysis (HD) and peritoneal dialysis (PD) patients in Canada by region as of 2004, from: Canadian Institute for Health Information, Treatment of End-Stage Organ Failure in Canada, 1995 to 2004129 All PD patients assumed to receive subcutaneous (SC) EPO Range of HD dose ranges between all SC and all intravenous (IV) Dose conversion from SC to IV based on Kaufman et al68 Dose per week to achieve target hemoglobin based on negative binomial model (see section 6.3) Cost per unit of ESA based on current formulary costs from Alberta Blue Cross AB includes the population of the Northwest Territories and Nunavut BC includes the population of the Yukon NS includes the population of Prince Edward Island HD=hemodialysis; PD=peritoneal dialysis; SC=subcutaneous; IV=intravenous

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Table 2: CKD prevalence estimates from AKDN data CKD Stage

Fraction of Population – High Estimate

(AKDN n = 673,298)

Fraction of Population – Low Estimate (AB n = 3.2M)

3 63,867

9.49 % 1.99 %

4 4,71o

0.70 % 0.15 %

5 680

0.10 % 0.02 %

3-5

69,257 10.29 % 2.16 %

CKD=chronic kidney disease, AKDN=Alberta Kidney Disease Network

Table 3: Fraction of persons with anemia by CKD stage from AKDN data Hemoglobin and ESA

treatment status

Stage 3 (n=63,867)

Stage 4 (n=4,710)

Stage 5 (n=680)

Stage 3-5 (n=69,257)

<90 g/L

373 99 31 503

90–100 g/L

1143 273 63 1479

On ESA

207 264 174 645

Fraction if treat at <90 g/L

0.94% 7.93% 31.3% 1.71%

Fraction if treat at <100 g/L

2.78% 13.90% 40.85% 3.91%

Fraction of eligible patients currently treated if treat at

<90 g/L

35.7% 72.7% 84.9% 56.2%

Fraction eligible patients currently treated if treat at

<100 g/L

12.0% 41.5% 64.9% 24.5%

- Use or non-use of ESA determined by medications covered by Alberta Blue Cross over an 18 month time frame for each patients

- Persons below threshold hemoglobin do not include patients on ESA values - Persons missing hemoglobin measurement excluded from denominator (1839, 133, and 24 in Stages 3,4,5 CKD

respectively) - Fraction eligible patients already treated defined by number of persons on ESA divided by those with hemoglobin below

threshold and those on ESA ESA=erythropoietic stimulating agents

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Table 4: High and low prevalence estimates of non-dialysis-dependent CKD in Canada

Canada ON QC BC AB MN SK NS NB NL PEI

Total Population 2006

32,623,500

12,687,000

7,651,500 4,310,500 3,375,800 1,177,800 985,400 934,400 749,200 509,700 138,500

Stage 3 CKD

3,094,566 - 649,693

1,203,450 -252,660

725,798 -152,379

408,881 - 85,843

320,218 - 67,229

111,723 - 23,456

93,472 - 19,624

88,634 - 18,608

71,067 - 14,920

48,349 - 10,151 13,138 - 2,758

Stage 4 CKD

228,215 - 47,913

88,751 - 18,633

53,525 - 11,237

30,154 - 6,331

23,615 - 4,958

8,239 - 1,730

6,893 - 1,447

6,537 - 1,372

5,241 - 1,100

3,566 - 749 969 - 203

Stage 5 CKD

32,948 - 6,917

12,813 - 2,690

7,728 - 1,622

4,353 - 914

3,409 - 716

1,190 - 250

995 - 209 944 - 198 757 - 159 515 - 108 140 - 29

Stage 3-5 CKD

3,355,729 - 704,523

1,305,014 - 273,983

787,051 -165,239

443,388 - 93,088

347,243 - 72,902

121,151 - 25,435

101,361 - 21,280

96,115 - 20,179

77,064 - 16,179

52,429 - 11,007 14,246 - 2,991

High and low range of estimate population with stages 3 through 5 CKD based on data presented in Appendix 9, Table 2. Population estimates from Statistics Canada 2006110 CKD=chronic kidney disease

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Table 5: Budget impact of treating anemia in non-dialysis-dependent CKD (Stage 3-5) in Canada

Canada ON QC BC AB MN SK NS NB NL PEI

Low hemoglobin target (90-105 g/L) (Cost/y)

Stage 3 CKD 1,063,244 - 223,224

413,486 - 86,810

249,373 - 52,355

140,485 - 29,494

110,022 - 23,099

38,386 - 8,059

32,116 - 6,743

30,453 - 6,394

24,417 - 5,126

16,612 - 3,488

4,514 - 948

Stage 4 CKD 665,159 - 139,648

258,675 - 54,308

156,006 - 32,753

87,887 - 18,451

68,829 - 14,450

24,014 - 5,042

20,091- 4,218

19,051 - 4,000

15,275 - 3,207

10,392 - 2,182

2,824 - 593

Stage 5 CKD 378,389 - 79,441

147,152 - 30,894

88,747 - 18,632

49,996 - 10,496

39,155 - 8,220

13,661- 2 2,868

11,429 - 2,400

10,838 - 2,275

8,690 - 1,824

5,912 - 1,241

1,606 - 337

Stage 3-5 CKD

2,106,792- 442,313

819,313- 172,012

494,126- 103,740

278,368- 58,442

218,006 - 72,902

76,061- 15,969

63,636- 13,360

60,343- 12,669

48,383 - 10,158

32,916 - 6,911

8,944 - 1,878

Intermediate hemoglobin target (105-120 g/L) (Cost/y)

Stage 3 CKD 4,411,987 - 926,281

1,715,784 - 360,223

1,034,785 - 217,249

582,950 - 122,388

456,542 - 95,849

159,285 - 33,441

133,265 - 27,979

126,368 - 26,530

101,321 - 21,272

68,932 - 14,472

18,731 - 3,932

Stage 4 CKD 1,627,872 - 341,766

633,066 - 132,910

381,800 - 80,158

215,089 - 45,157

168,448 - 35,365

58,771 - 12,339

49,170 - 10,323

46,625 - 9,789

37,384 - 7,849

25,433 - 5,340

6,911 - 1,451

Stage 5 CKD 690,976 - 145,068

268,715 - 56,416

162,061 - 34,024

91,298 - 19,168

71,501 - 15,011

24,946 - 5,237

20,871 - 4,382

19,791 - 4,155

15,868 - 3,331

10,796 - 2,266

2,933 - 616

Stage 3-5 CKD

6,730,836 - 1,413,115

2,617,565 - 549,548

1,578,647 - 331,431

889,336 - 186,713

696,490 - 146,226

243,002 - 51,017

203,306 - 42,683

192,784 - 40,474

154,574 - 32,452

105,161 - 22,078

28,575 - 5,999

High hemoglobin target (120-145 g/L) (Cost/y)

Stage 3 CKD 8,608,049 - 1,807,229

3,347,597 - 702,816

2,018,928 - 423,867

1,137,370 - 238,787

890,740 - 187,008

310,775 - 65,246

260,008 - 54,588

246,551 - 51,763

197,684 - 41,503

134,490 - 28,236

36,545 - 7,672

Stage 4 CKD 3,176,076 - 666,806

1,235,149 - 259,315

744,915 - 156,392

419,651 - 88,104

328,653 - 68,999

114,665 - 24,074

95,934 - 20,141

90,969- 19,099

72,939 - 15,313

49,622 - 10,418

13,484 - 2,831

Stage 5 CKD 1,348,136 - 283,036

524,278 - 110,070

316,191 - 66,383

178,127 - 37,397

139,502 - 29,288

48,671 - 10,218

40,721 - 8,549

38,613 - 8,107

30,960 - 6,500

21,063 - 4,422

5,723 - 1,202

Stage 3-5 CKD

13,132,261 - 2,757,070

5,107,024 - 1,072,201

3,080,034 - 646,642

1,735,148 - 364,288

1,358,894 - 285,295

285,295 - 99,538

396,663 - 83,278

376,133 - 78,968

301,583 - 63,316

205,175 - 43,076

55,752 - 11,705

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APPENDIX 10: FORMS

appendix 1: literature search strategies

Documents