This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
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
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
Database and Platform Search Strategies Date of Search
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$.tw. 488
A-4
Database and Platform Search Strategies Date of Search
Coverage of Search
79 Kidney failure/ or kidney failure.tw. 7865 80 ((kidney$ or renal) adj2 (diseases$ or failure$ or insufficien$)).tw. 73272 81 ((kidney$ or renal) adj2 (diseases$ or failure$ or insufficien$)).tw. 73272 82 Terminal Kidney Failure.tw. 83 83 or/63-82 111182 84 62 and 83 3919 85 10 and 84 373 86 from 85 keep 1-373 373
Database and Platform Search Strategies Date of Search
Coverage of Search
11 Epoch.tw. 62 12 Epoietin.tw. 17 13 Epoetin alfa/ or epoetin alfa.tw. 228 14 Epoetin alpha.mp. 30 15 (Epoietin alpha or Epoietin alfa).tw. 9 16 Epogen.tw. 10 17 Eprex.tw. 23 18 Erantin.tw. 3 19 Erypo.tw. 7 20 Erythropoietic.tw. 101 21 Erythropoietin/ or Erythropoietin.tw. 1384 22 erythropoetin$.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
Database and Platform Search Strategies Date of Search
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
Database and Platform Search Strategies Date of Search
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
Database and Platform Search Strategies Date of Search
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
Aranesp (1) (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 (3) Dynepo (0) e-alpha or e-alfa (13) epo alfa (6) Epo alpha (13) Epo beta (10) Epoch (0) Epoconn (0) Epoietin (0) Epoetin alfa or epoetin alfa (13) Epoetin alpha (0) Epoietin alpha or Epoietin alfa (13) Epoetinum alfa (0) Epogen (0) Epogin (0) Eprex (0) Erantin (0) Erypo (0) Erythropoietin (3) Erythropoietic or erythropoetin or Erythropoiesis (15) erythropoetin* (1) erythropoiten-alpha (11) Espo (0) Exprex (0) Globuren (0) Heberitro (0) Heberitrorn (0) Hematopoietin (0) Hemax (0) Hemopoietin (0) huepo (0) Krn 321 or Krn321 (13) Krn 5702 or Krn5702 (13) Marogen (0) Neorecormon (0) Nesp (1) Nespo (0) Procrit (0) r-HuEPO (0) rHuEPO (0) R-Hu Epo (2) recombinant EPO (2) Recormon (0) Recormone (0) Renal Erythropoietic Factor (0) Repotin (0) Snb 5001 or Snb5001 (13) Tyb 5220 or Tyb5220 (13)
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
Database and Platform Search Strategies Date of Search
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
Database and Platform Search Strategies Date of Search
Database and Platform Search Strategies Date of Search
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)
Database and Platform Search Strategies Date of Search
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
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
A-21
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.
A-22
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.
A-23
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.
A-24
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
A-25
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.
A-26
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
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
A-27
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),
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-
dependent CKD renal function)
Design: sample size,
weeks of follow-up, high and
intermediate/low Hb targets (g/L)
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
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
Non-dialysis-dependent
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
Non-dialysis-dependent
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
Non-dialysis-dependent
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
Non-dialysis-dependent
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
Eligibility: previous
ESA therapy, Hb (g/L), modality
(non-dialysis-
dependent CKD renal function)
Design: sample size,
weeks of follow-up, high and
intermediate/low Hb targets (g/L)
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
Roger55 2004 Australia, New Zealand
- 110-130M/ 100-120F
Non-dialysis-dependent
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
Some on-therapy 90-116
Non-dialysis-dependent
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
Some on-therapy 90-110
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
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)
ESA regimens: type,
initial dose, 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
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
Non-dialysis-dependent
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-
dependent CKD renal function)
Design: sample size,
weeks of follow-up
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
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
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)
Hematopoietic regimen:
type, initial dose (U/kg/wk),
schedule (/wk), route
Demographics: mean age (y), percent male, mean Hb (g/L),
mean renal funciton or median years on
dialysis
Co-morbidities: percent DM,
percent CVD, percent CHF
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
Non-dialysis-dependent
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
Eligibility: previous
ESA therapy, Hb (g/L), modality
Design: sample
size, weeks of follow-up, Hb target
(g/L)
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
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
Statistical Analysis Description of sample size calculation
Adequate Inadequate Partial Inadequate
Was the design described as intention-to-treat?
No Yes Yes Yes
Was a regression analysis used?
No No Yes Yes
Was time to event data analyzed appropriately?
No No No No
Was time series data analyzed appropriately?
No No Yes No
Was interim analysis appropriately reported?
No No No No
Presentation of Results Were the dates of accrual reported?
Adequate Inadequate Adequate Inadequate
Were confidence intervals reported?
Adequate Adequate Partial Partial
Were adverse events reported?
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
£method of double-blinding described and appropriate
A-43
Table 2F: Quality assessment of included clinical trials: SC vs IV route of administration
Kaufman 199868
Schaller 199466 Muirhead 199267
Study Design
Description of participant selection
Adequate Partial Adequate
Description of non-eligible patients
Inadequate Inadequate Inadequate
Description of randomization assessment
Adequate Partial Adequate
Was the allocation to treatment concealed?†
Unclear Unclear Unclear
Description of the therapeutic regimen
Adequate Adequate Partial
Was the trial described as double blind?†
No Yes Single
Was there a description of withdrawals and dropouts?†
Yes (21%) No Yes (23%)
Description of blinding assessment
- Inadequate Inadequate
Statistical Analysis
Description of sample size calculation
Inadequate Inadequate Inadequate
Was the design described as intention-to-treat?
Yes No No
Was a regression analysis used?
No Yes No
Was time to event data analyzed appropriately?
No No Yes
Was time series data analyzed appropriately?
No No No
Was interim analysis appropriately reported?
No No No
Presentation of Results
Were the dates of accrual reported?
Inadequate Inadequate Inadequate
Were confidence intervals reported?
Partial Inadequate Partial
Were adverse events reported?
Inadequate Inadequate Adequate
Funding
What were the source(s) of funding?† Mixed Private Private
NR=not reported; Mixed=public and private sources of funding; the – indicates that the value was not applicable †items have empirical evidence
A-44
Table 3: Meta-regression results for all-cause mortality: High vs intermediate/low target Hb protocols
(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
A-45
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
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
A-46
Table 6: All-cause mortality in indirect comparisons Independent variable All CKD
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
A-47
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
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
A-55
Figure 3D: Hospitalization: High vs intermediate/low target Hb protocols
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
A-57
Figure 3F: Red cell transfusions: High vs intermediate/low target Hb protocols
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
A-59
Figure 3L: Hypertension: High vs intermediate/low target Hb protocols
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
A-65
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, 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
A-66
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.”
Y=yes; the – indicates that the value was not applicable
A-72
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
Estimate Range Source
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
Estimate Range Source
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
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
A-75
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 $250 - Tretiak 199699
Table 5: Base case cost-utility analyses for patients on dialysis Model Strategy Cost
($) 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
A-77
Table 6: Base case cost-utility analyses for non-dialysis-dependent CKD patients 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 ($/QALY)
No ESA 234K 2.73
Low 329K 95K 3.23 0.51 186,000
Intermediate 350K 116K 3.43 0.70 165,000
Model 1ND RR of death combined non-dialysis-dependent CKD and dialysis for both non-dialysis-dependent CKD death risk and death risk after beginning dialysis Observed utilities as described in Table 2
High 325K 95K 2.92 0.20 475,000
No ESA 234K 2.73
Low 334K 101K 3.29 0.56 180,000
Intermediate 350K 116K 3.43 0.70 165,000
Model 2ND RR of death combined non-dialysis-dependent CKD and dialysis for both non-dialysis-dependent CKD death risk and death risk after beginning dialysis RR of death for low =1.0 for non-dialysis-dependent CKD Observed utilities as described in Table 2
High 325K 95K 2.92 0.20 475,000
No ESA 234K 2.73
Low 340K 107K 3.34 0.62 172,000
Intermediate 350K 116K 3.43 0.70 165,000
Model 3ND RR of death combined non-dialysis-dependent CKD and dialysis for both non-dialysis-dependent CKD death risk and death risk after beginning dialysis RR of death for low =1.0 for non-dialysis-dependent CKD and dialysis Observed utilities as described in Table 2
High 325K 95K 2.92 0.20 475,000
No ESA 234K 2.73
Low 340K 107K 3.43 0.70 153,000
Intermediate 350K 116K 3.43 0.70 165,000
Model 4ND RR of death combined non-dialysis-dependent CKD and dialysis for both non-dialysis-dependent CKD death risk and death risk after beginning dialysis RR of death for low = 1.0 for non-dialysis-dependent CKD and dialysis Utilities for low = intermediate
High 325K 95K 2.92 0.20 475,000
No ESA 234K 2.73 Model 5ND RR of death combined non-dialysis-dependent CKD and dialysis for both non-dialysis-dependent
Low 340K 107K 3.43 0.70 153,000
A-78
Model Strategy Cost ($)
Incremental cost
compared to no ESA ($)
Effectiveness (QALY)
Incremental effectiveness
compared to no ESA
(QALY)
Incremental cost-utility
ratio compared to
no ESA ($/QALY)
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
A-79
Table 7: One-way sensitivity analysis for patients on dialysis Scenario 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 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 = $14.25 per 1000 units as per listing in Ontario and Yukon
Applied to Model 1ND Dialysis costs = 0 Transplant costs = 0
High 186K 107K 2.92 0.20 535,000
No ESA 233K 2.71
Low 329K 96K 3.23 0.52 184,000
Intermediate 350K 117K 3.43 0.72 162,000
Model 1ND RR of transplant with no ESA compared to ESA = 0.9
High 325K 92K 2.92 0.21 438,000
No ESA 397K 3.96
Low 525K 129K 4.71 0.75 172,000
Intermediate 558K 162K 5.09 1.05 154,000
Model 1ND RR of transplant with no ESA compared to ESA = 0.9 In patients under 65
High 529K 133K 4.35 0.39 341,000
No ESA 76K 1.51 Model 1ND RR of transplant with no ESA compared to ESA = 0.9 In patients over 65
Low 140K 64K 1.81 0.30 213,000
A-86
Scenario Strategy Cost ($)
Incremental cost
compared to no ESA
($)
Effectiveness (QALY)
Incremental effectiveness compared to
no ESA (QALY)
Incremental cost-utility ratio
compared to no ESA
($/QALY)
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
Model 1ND RR of transplant with no ESA compared to ESA = 0.75
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
Model 1ND RR of transplant with no ESA compared to ESA = 0.75 In patients under 65
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
Model 1ND RR of transplant with no ESA compared to ESA = 0.50
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
Model 1ND RR of transplant with no ESA compared to ESA = 0.50 In patients under 65
High 529K 135K 4.35 0.44 306,000
Model 1ND RR of transplant with no
No ESA 71K 1.43
A-87
Scenario 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
($/QALY)
Low 140K 68K 1.81 0.38 179,000
Intermediate 149K 78K 1.90 0.47 165,000
ESA compared to ESA = 0.50 In patients over 65
High 129K 58K 1.54 0.11 527,000
No ESA 239K 2.73
Low 330K 91K 3.23 0.51 178,000
Intermediate 351K 112K 3.43 0.70 160,000
Model 1ND Rate of transfusion with no ESA 0.44 units per month compared to 0.09 units per month with ESA (Nissenson et al42)
High 326K 88K 2.92 0.20 440,000
ESA administered subcutaneously – all models considered No ESA 234K 2.73
Low 324K 90K 3.23 0.51 176,000
Intermediate 342K 109K 3.43 0.70 155,000
Model 1ND
High 314K 80K 2.92 0.20 400,000
No ESA 234K 2.73
Low 329K 95K 3.29 0.56 169,000
Intermediate 342K 109K 3.43 0.70 155,000
Model 2ND
High 314K 80K 2.92 0.20 400,000
No ESA 234K 2.73
Low 335K 102K 3.34 0.62 164,000
Intermediate 342K 109K 3.43 0.70 155,000
Model 3ND
High 314K 80K 2.92 0.20 400,000
No ESA 234K 2.73
Low 335K 102K 3.43 0.70 145,000
Intermediate 342K 109K 3.43 0.70 155,000
Model 4ND
High 314K 80K 2.92 0.20 400,000
A-88
Scenario Strategy Cost ($)
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 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
A-89
Table 11: Dialysis model considering three treatment strategies Scenario 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
($/QALY)
No ESA 372K 3.61 ESA dosing intermediate/low = 7035 U/wk ESA dosing high = 15565 U/wk OR of death for no ESA compared to intermediate/low = 1.25 OR of death for high compared to intermediate/low = 1.24
Intermediate/Low 466K 94K 4.39 0.79 118,000
ESA=erythropoietic stimulating agents; OR=odds ratio; QALY=quality-adjusted life years
A-90
Table 12: Non-dialysis-dependent CKD model considering three treatment strategies Scenario Strategy Cost
($) 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 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
A-91
APPENDIX 8: FIGURES FOR ECONOMIC EVALUATION
Figure 1: Dialysis-dependent model
Hb=hemoglobin
A-92
Figure 2 : Non-dialysis-dependent CKD model
Hb=hemoglobin
A-93
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
A-97
APPENDIX 9: TABLES FOR HEALTH SERVICES IMPACT
Table 1. Population and budget impact of varying Hb targets in Canada
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
A-98
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)
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
A-99
Table 4: High and low prevalence estimates of non-dialysis-dependent CKD in Canada
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
A-100
Table 5: Budget impact of treating anemia in non-dialysis-dependent CKD (Stage 3-5) in Canada