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Frequency of administration of erythropoiesis-stimulating agents for the anaemia of end-stage kidney disease in dialysis patients

  1. Deirdre Hahn1,*,
  2. June D Cody2,
  3. Elisabeth M Hodson3

Editorial Group: Cochrane Kidney and Transplant Group

Published Online: 28 MAY 2014

Assessed as up-to-date: 13 MAR 2013

DOI: 10.1002/14651858.CD003895.pub3


How to Cite

Hahn D, Cody JD, Hodson EM. Frequency of administration of erythropoiesis-stimulating agents for the anaemia of end-stage kidney disease in dialysis patients. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD003895. DOI: 10.1002/14651858.CD003895.pub3.

Author Information

  1. 1

    The Children's Hospital at Westmead, Department of Nephrology, Westmead, NSW, Australia

  2. 2

    University of Aberdeen, Cochrane Incontinence Review Group, Foresterhill, Aberdeen, UK

  3. 3

    The Children's Hospital at Westmead, Centre for Kidney Research, Westmead, NSW, Australia

*Deirdre Hahn, Department of Nephrology, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia. Deirdre.hahn@health.nsw.gov.au.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 28 MAY 2014

SEARCH

 
Characteristics of included studies [ordered by study ID]
AMICUS Study 2007

Methods
  • Study design: parallel group, phase III RCT
  • Time frame: March 2004 to December 2005
  • Duration of follow-up: 24 weeks


Participants
  • Countries: international
  • Setting: 42 tertiary centres
  • Age ≥18 years; No ESA for ≥ 12 weeks; CKD on PD/HD ≥ 2 weeks before screening; baseline Hb 8 to 11 g/dL; adequate iron status: serum ferritin ≥100 ng/mL or TSAT ≥ 20%. HD: Kt/v ≥1.2 or URR ≥ 65%
  • Number: treatment group 1 (135); treatment group 2 (46)
  • Mean age ± SD (years): treatment group 1 (54.7 ± 14.43); treatment group 2 (53.4 ± 15.19)
  • Sex (M/F): treatment group 1 (82/55); treatment group 2 (32/14)
  • Exclusion criteria: ESA therapy ≤ 12 weeks previously; non-renal cause of anaemia; CRP ≥ 30 mg/L; poorly controlled hypertension; presence of severe disease (e.g. MI, stroke); overt GI bleeding requiring blood transfusion < 8 weeks before screening; life expectancy ≤ 12 months


InterventionsTreatment group 1

  • CERA IV
    • Starting dose: 0.40 μg/kg every 2 weeks, for 24 weeks
    • Adjustments performed according to a predefined protocol, but no more frequently than once every 4 weeks
    • Doses titrated to achieve individual increases ≥ 1.0 g/dL versus baseline and single Hb levels ≥ 11 g/dL


Treatment group 2

  • EPO
    • Dose: 3 times/wk IV with dosing based on approved recommendations, continued for 24 weeks
    • Doses titrated to achieve individual increases ≥ 1.0 g/dL versus baseline and single Hb levels ≥ 11 g/dL


Co-interventions

  • participants received IV iron to maintain adequate iron status


Outcomes
  • Change in Hb during correction period
  • Number reaching target Hb
  • Change in ESA dose
  • Quality of life
  • Adverse effects: total, serious, leading to withdrawal of therapy, hypertension, AV fistula thrombosis, mortality


Notes
  • Loss to follow-up/excluded: withdrawals from ITT population; kidney transplant, refusal of treatment, dialysis no longer required, transfusion, insufficient Hb results, missing administration of study medication.
  • Additional data requested from authors: information on randomisation procedures and ITT data were requested from the authors: response received


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation, computer generated

Allocation concealment (selection bias)Low risk Central allocation with IVRS

Blinding of participants and personnel (performance bias)
All outcomes
Low riskOpen label study but primary outcome was laboratory based and unlikely to be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen label study but primary outcome was laboratory based and unlikely to be influenced by blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskEfficacy data and safety data available for all patients

Selective reporting (reporting bias)Low riskStudy protocol not available but published results include all expected outcomes

Other biasHigh riskRoche sponsored

BA16285 Study 2007

Methods
  • Study design: parallel RCT
  • Study duration: NS
  • Duration of follow-up: 19 weeks, with 12 month extension


Participants
  • Country: USA
  • Setting: 14 centres
  • Age ≥18 years; HD ≥ 3 months; Kt/V ≥ 1.2; URR > 65%; IV EPO > 3 months; baseline Hb 10 to12 g/dL; adequate iron status; ferritin > 100 ng/mL; TSAT > 20%
  • Number
    • Treatment group A: 30; weekly dosing (15); two weekly dosing (15)
    • Treatment group B: 30; weekly dosing (15); two weekly dosing (15)
    • Treatment group C: 31; weekly dosing (16); two weekly dosing (15)
  • Mean age SD (years)
    • Treatment group A: weekly dosing (50.2 ± 9.9); two weekly dosing (58.6 ± 12.6)
    • Treatment group B: weekly dosing (53.8 ± 12.7); two weekly dosing (62.8 ± 15.8)
    • Treatment group C: weekly dosing (60.1 ± 11.9); two weekly dosing (62.5 ± 10.8)
  • Sex (M/F)
    • Treatment group A: weekly dosing (13/2); two weekly dosing (7/8)
    • Treatment group B: weekly dosing (9/6); two weekly dosing (9/6)
    • Treatment group C: weekly dosing (10/6); two weekly dosing (12/3)
  • Exclusion criteria: non-renal cause of anaemia; B₁₂ or folate deficiency; conditions with inadequate response to ESA (Infection/inflammation, hyperparathyroidism); blood transfusions 3 months previously; MI/coronary artery disease


InterventionsTreatment group A

  • CERA: 0.25 µg
  • EPO: 150 U
  • Dose: once/wk or once every 2 weeks for 19 weeks


Treatment group B

  • CERA: 0.4 µg
  • EPO: 150 U
  • Dose: once/wk or once every 2 weeks for 19 weeks


Treatment group C

  • CERA: 0.6 µg
  • EPO: 150 U
  • Dose: once/wk or once every 2 weeks for 19 weeks


Other information

  • Dose adjustments permitted in all groups after 6 weeks to maintain within ± 1.5 g/dL of baseline


Co-interventions

  • NS


Outcomes
  • Change in Hb from baseline
  • Change in HCT from baseline
  • Mortality
  • Adverse events


Notes
  • Additional data on sequence generation and allocation concealment and ITT data requested from authors: response received from author regarding randomisation


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation, computer generated

Allocation concealment (selection bias)Low riskCentral randomisation, computer generated

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low risk10/91 did not complete core period but all patients included in ITT analysis. Reasons for withdrawal: adverse events, treatment refusal, inadvertent coadministration of EPO, insufficient therapeutic response, transplant, anaemia not related to CKD

Selective reporting (reporting bias)High riskPublished results did not include ESA dosage. Results of ITT analysis only available graphically and cannot be entered in meta-analysis.

Other biasHigh riskFunded F. Hoffman La Roche Ltd

BA16286 Study 2007

Methods
  • Study design: parallel RCT
  • Study duration: NS
  • Duration of follow-up: 19 weeks with 12 month extension


Participants
  • Countries: Italy, USA, Spain, Germany
  • Setting: multicentre
  • Age ≥ 18 years; CKD; anaemia; dialysis, HD/PD ≥ 3 months; Kt/v ≥1.2 HD, Kt/v ≥ 1.8 PD; SC EPO ≥ 3/12; stable Hb 10 to 12 g/dL; adequate iron stores, ferritin ≥ 100 ng/mL


  • Number
    • Treatment group A: 46; weekly dosing (15); three weekly dosing (15); four weekly dosing (15)
    • Treatment group B: 44; weekly dosing (16); three weekly dosing (16); four weekly dosing (12)
    • Treatment group C: 47; weekly dosing (16); three weekly dosing (15); four weekly dosing (16)
  • Mean age SD (years)
    • Treatment group A: weekly dosing (67 ± 13.0); three weekly dosing (65.6 ± 11.3); four weekly dosing (64.8 ± 10.3)
    • Treatment group B: weekly dosing (61.8 ± 13.5); three weekly dosing (64.1 ± 12.8); four weekly dosing (67.3 ± 13.3)
    • Treatment group C: weekly dosing (62.7 ± 13.7); three weekly dosing (58.9 ± 13.1); four weekly dosing (64.1 ± 13.3)
  • Sex (M/F)
    • Treatment group A: weekly dosing (11/5); three weekly dosing (7/8); four weekly dosing (10/5)
    • Treatment group B: weekly dosing (10/6); three weekly dosing (11/5); four weekly dosing (5/7)
    • Treatment group C: weekly dosing (12/4); three weekly dosing (10/5); four weekly dosing (9/6)
  • Exclusion criteria: life expectancy < 6 months; severe disease e.g. MI, unstable CAD; poorly controlled BP; blood transfusions in last 3 months; non-renal causes of anaemia; infection; inflammation (RA/SLE); GI bleeding; B₁₂ or folate deficiency; severe hyperparathyroidism


InterventionsTreatment group A

  • CERA: 0.4 µg
  • EPO: 150 U
  • Dose: once/wk; once every 3 weeks, once/mo for 19 weeks


Treatment group B

  • CERA: 0.8 µg
  • EPO: 150 U EPO
  • Dose: once/wk, once every 3 weeks, once/mo for 19 weeks


Treatment group C

  • CERA: 1.2 µg
  • EPO: 150 U
  • Dose: once/wk, once every 3 weeks, once/mo for 19 weeks


Other information

  • Dose adjustments were allowed in all groups after 6 weeks to maintain Hb within ± 1.5 g/dL of baseline


Co-interventions

  • NS


Outcomes
  • Change in Hb level
  • Change in HCT
  • Mortality
  • Adverse effects


Notes
  • Additional information randomisation and allocation concealment and ITT data requested from authors: no response obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided: "phase II, randomised, open label"

Allocation concealment (selection bias)Unclear riskNo information provided: "assignment in sequential fashion"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low risk11/137 withdrawn; 2 died, 2 withdrew because of adverse events, 3 insufficient therapeutic response, 1 transplant, 1 failure to return, 1 holiday, 1 hospitalisation; all patients included in ITT analysis

Selective reporting (reporting bias)High risk No outcome data provided on ESA dosage. Data on ITT analysis only available graphically and could not be included in meta-analysis

Other biasHigh riskFunded by F. Hoffmann La Roche Ltd

Brahm 1999

Methods
  • Study design: cross-over RCT
  • Study duration: NS
  • Duration of follow-up: 8 to 20 week run-in/correction period; 24 week treatment duration


Participants
  • Country: Denmark
  • Setting: single centre
  • Stable patients on CAPD for at least 6 months; Hb ≤ 6.0 mmol/L or requiring blood transfusions; patients with stable target Hb within ± 0.2 mmol/L for at least 4 weeks entered study; CAPD
  • Number: 30 consecutively recruited to correction period, 22 randomised to once, twice, or three times weekly or daily
  • Mean age (range): 51 years (21 to 64)
  • Sex (M/F): 10/12
  • Exclusion criteria: NS


InterventionsEPO (SC)

  • Once, twice, or three times/wk or daily
  • Dose
    • Correction period initial dose 50 U/kg twice/wk, dose adjusted in two-week intervals to reach target Hb during 8 to 20 weeks. Increase in HCT aimed at 1%/wk
  • Duration of study
    • Correction period 8 to 20 weeks (median 12 weeks).
    • RCT period: four periods of 8 to16 weeks (median 12 weeks)
  • Type of EPO: NS


Outcomes
  • Change in dose of EPO with different frequency regimens to maintain HCT 35%
  • Adverse effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSaid to be randomised

Allocation concealment (selection bias)Unclear riskNS

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPrimary outcome was laboratory based and not likely to be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPrimary outcome was laboratory based and not likely to be influenced by blinding

Incomplete outcome data (attrition bias)
All outcomes
High risk27% not analysed and of 22, only 13 completed all 4 cross-over periods; loss to follow-up: 8/30 (27%) dropped out during correction period 13/22 (59%) completed all four frequency regimens

Selective reporting (reporting bias)High riskCross-over study; data reported for correction periods and not patients so data cannot be included in meta-analysis

Other biasUnclear riskFunding: NS

Canaud 1995

Methods
  • Study design: open-label, parallel RCT
  • Study duration: NS
  • Duration of follow-up: 16 weeks


Participants
  • Countries: Europe
  • Setting: 10 dialysis centres
  • ESKD on regular HD; anaemia corrected for ≥12 months x 3 weekly IV
  • Number: treatment group 1 (18); treatment group 2 (20); treatment group 3 (16); treatment group 4 (22)
  • Mean age ± SD (years): NS
  • Sex (M/F): 56/60
  • Exclusion criteria: iron deficiency; uncorrected folate and/or Vitamin B₁₂ deficiency; corticotherapy; uncontrolled hypertension; acute illness; surgery; secondary hyperparathyroidism; aluminium intoxication


InterventionsTreatment group 1

  • EPO: IV, 3 times/wk


Treatment group 2

  • EPO: SC, once/wk


Treatment group 3

  • EPO: SC, 3 times/wk


Treatment group 4

  • EPO: SC, daily SC


Other information

  • Dose: Initial dose as for previous control period
  • Dose adjustments at 4 weekly intervals to maintain Hb level between 9 and 12 g/dL
  • Type of EPO: Alpha


Co-interventions

  • Iron supplement, IV and oral


Outcomes
  • Number failing to achieve target Hb/HCT
  • Mean Hb achieved at end of maintenance phase
  • Mean EPO dose given during maintenance phase
  • Numbers commencing or increasing antihypertensive therapy


Notes
  • Only data from SC groups included in meta-analyses


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStated to be randomised but no other information provided: "open, randomised, multicentre study"

Allocation concealment (selection bias)Unclear riskNS

Blinding of participants and personnel (performance bias)
All outcomes
Low riskOpen-labelled study. Primary outcome was laboratory based and not likely to be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen-labelled study. Primary outcome was laboratory based and not likely to be influenced by blinding

Incomplete outcome data (attrition bias)
All outcomes
High risk40 (34%) of 116 patients withdrawn from final analysis and this loss could influence the results: transplantation (7), death (1), lost to follow-up (3), unable to self-inject (1), final Hb at week 16 higher than target Hb > 12 g/dL (11)

Selective reporting (reporting bias)Low riskSpecified essential outcomes included

Other biasHigh riskStudy overseen by Cilag laboratories

Carrera 2003

Methods
  • Study design: parallel RCT
  • Time frame: NS
  • Duration of follow-up: 10 months


Participants
  • Country: Portugal
  • Setting: single centre
  • Age: ≥18 years; HD; 6 months on IV rHuEPO; Hb stable 11.0 to 12.5 g/dL
  • Number (completed/evaluated): treatment group 1 (18/24); treatment group 2 (13/20)
  • Mean age ± SD (years): treatment group 1 (57.7 ± 11.78); treatment group 2 (61.5 ± 22.6)
  • Sex (M/F): treatment group 1 (16/2); treatment group 2 (7/6)
  • Exclusion criteria: no active bleeding, infection or inflammation


InterventionsTreatment group 1

  • DA: IV weekly for 10 months
  • Dose calculated according to previous dose when 200 IU EPO = 1 μg DA
  • Dose at baseline: 35.70 µg/wk (95% CI 26.90 to 47.40)


Treatment group 2

  • rHuEPO: IV 3 times/wk for 10 months
  • Continued previous dose
  • Dose at baseline: 5837 IU/wk (95% CI 3670 to 9281 IU/wk)
  • Doses of EPO and DA were titrated to maintain Hb in the range 11.0 to 12.5 g/dL


Co-interventions

  • Iron supplements as necessary


Outcomes
  • Hb at end of study
  • Change in Hb
  • ESA dose at end of study
  • Iron parameters at end of study
  • Adverse effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStudy stated to be randomised but no other information provided: "randomised study"

Allocation concealment (selection bias)Unclear riskStudy stated to be randomised but no other information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPrimary outcome was laboratory based and not likely to be influenced by blinding. Study participants and personnel not blinded

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPrimary outcome was laboratory based and not likely to be influenced by blinding. Study participants and personnel not blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskData only reported on patients, who completed study. 13 (29.5%) did not complete the study; DA group: died (2), transplants (2), surgery (2); rHuEPO group: died (3), transplant (1), surgery (3)

Selective reporting (reporting bias)Low riskStudy protocol not available but published results include all expected outcomes

Other biasUnclear riskFunding: NS

Coyne 2000

Methods
  • Study design: parallel RCT
  • Study duration: NS
  • Duration of follow-up: 20 weeks


Participants
  • Country: USA
  • Setting: multicentre
  • Dialysis patients; no rHuEPO in previous 12 weeks; baseline Hb ≤ 10.0 g/dL
  • Number: treatment group 1 (90); treatment group 2 (31)
  • Mean age ± SD (years): NS
  • M/F: NS
  • Exclusion criteria: NS


InterventionsTreatment group 1

  • DA: 0.45 µg/kg IV or SC once/wk, continued for 20 weeks


Treatment group 2

  • rHuEPO: 50 U/kg 3 times/wk (150 U/kg/wk), continued for 20 weeks


Other information

  • Dose adjustments made as necessary to achieve target Hb


Co-interventions

  • NS


Outcomes
  • % achieving target Hb
  • Adverse events


Notes
  • Loss to follow-up: no information about any losses to follow-up or patients excluded from analyses
  • Additional data requested from author and information on randomisation was obtained
  • Abstract only


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomization was centrally performed using an IVRS system" (information from author)

Allocation concealment (selection bias)Low risk"Randomization was centrally performed using an IVRS system" (information from author)

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPrimary outcome was laboratory based and not likely to be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPrimary outcome was laboratory based and not likely to be influenced by blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR; data provided as % and unclear whether all patients completed study

Selective reporting (reporting bias)Unclear riskAbstract only, not all results available

Other biasUnclear riskNS

Coyne 2006a

Methods
  • Study design: parallel, RCT
  • Time frame: 29 May 2002 to 23 June 2004
  • Duration of follow-up: 28 weeks


Participants
  • Country: USA
  • Setting: multicentre
  • Undergoing HD; Hb 9.5 to 12.5 g/dL; TSAT ≥ 20%; stable doses of IV rHuEPO
  • Number: treatment group 1 (200); treatment group 2 (206)
  • Mean age ± SD: 57.6 ± 13 years
  • Sex (M/F): 211/196
  • Exclusion criteria: NS


InterventionsTreatment group 1

  • DA: IV once/wk
  • Placebo: twice/wk
  • Dose based on previous EPO dose; continued for 28 weeks


Treatment group 2

  • rHuEPO: IV 3 times/wk
  • Continued previous dose; continued for 28 weeks


Other information

  • Dose in both groups titrated to maintain Hb 10 to 12 g/dL


Co-interventions

  • NS


Outcomes
  • Change in Hb
  • Hb at end of study
  • ESA dose at end of study
  • Adverse effects: total due to ESA; serious due to ESA; AV fistula, thrombosis; hypertension


Notes
  • Additional information obtained from www.amgentrials.com
  • End point analysed: all subjects who received one dose and had at least one Hb measurement during evaluation period
  • Additional data requested from author and information on randomisation was obtained
  • Abstract only


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomization was centrally performed using an IVRS system" (information from author)

Allocation concealment (selection bias)Low risk"Randomization was centrally performed using an IVRS system" (information from author)

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDA group received placebo IV twice weekly

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDA group received placebo IV twice weekly

Incomplete outcome data (attrition bias)
All outcomes
Low risk406/407 included in safety analysis. 363, who had at least one evaluation Hb, were included in efficacy analysis

Selective reporting (reporting bias)Low riskIncludes expected outcomes

Other biasHigh riskGrant/research support: Amgen

Frifelt 1996

Methods
  • Study design: parallel RCT
  • Study duration: NS
  • Duration of follow-up: NS


Participants
  • Country: Denmark
  • Setting: single centre
  • Hb < 9.7 g/dL; CAPD ≥ 3 months; age ≥ 18 years; rHuEPO started and adjusted before randomisation to reach target Hb 10.5 to 12.0 g/dL
  • Number: treatment group 1 (16); treatment group 2 (17)
  • Mean age ± SD (years): NS
  • Sex (M/F): NS
  • Exclusion criteria: immunosuppressive therapy; moderate or severe hypertension; anaemia due to other causes


InterventionsTreatment group 1

  • rHuEPO: SC once/wk for 3 months starting at 60 U/kg/wk
  • Doses adjusted to maintain target Hb


Treatment group 2

  • rHuEPO: SC 3 times/wk for 3 months starting at 60 U/kg/wk
  • Doses adjusted to maintain target Hb


Other information

  • Type of EPO: recormon beta


Co-interventions

  • IV and oral iron supplementation


Outcomes
  • Hb levels at end of study
  • rHuEPO doses end of study


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"randomised, prospective study"

Allocation concealment (selection bias)Unclear riskNot mentioned

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPrimary outcome was laboratory based and not likely to be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPrimary outcome was laboratory based and not likely to be influenced by blinding

Incomplete outcome data (attrition bias)
All outcomes
High risk15% (6/39) excluded and missing data could have influenced final result; peritonitis (4); cerebral ischaemia (1); death due to AMI (1)

Selective reporting (reporting bias)High risk No reports on mortality and incomplete reporting of adverse effects. Results available only as median and IQR and cannot be entered in meta-analyses

Other biasHigh riskFunded study by Ercopharm, Kvistgaard, Denmark

Hori 2004

Methods
  • Study design: RCT
  • Study duration: NS
  • Duration of follow-up: 28 weeks


Participants
  • Country: Japan
  • Setting: multicentre
  • HD; rHuEPO 2 to 3 times/wk
  • Number: treatment group 1 (61); treatment group 2 (59)
  • Mean age ± SD (years): NS
  • Sex (M/F): NS
  • Exclusion criteria: NS


InterventionsTreatment group 1

  • DA: once/wk for 28 weeks
  • Initial dose: NS
  • Study drug dose adjusted to maintain Hb within ± 1.0 g/dL of baseline Hb and between 9 and12 g/dL


Treatment group 2

  • rHuEPO: 2 to 3 times/wk; continued previous dose for 28 weeks
  • Study drug dose adjusted to maintain Hb within ± 1.0 g/dL of baseline Hb and between 9 and 12 g/dL


Co-interventions

  • NS


Outcomes
  • Hb difference between groups at end of study
  • Adverse events: total due to ESA, serious due to ESA


Notes
  • Abstract only


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStudy stated to be randomised but no further information given

Allocation concealment (selection bias)Unclear riskInformation not provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPrimary outcome was laboratory based and unlikely to be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPrimary outcome was laboratory based and unlikely to be influenced by blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information on completeness of follow-up

Selective reporting (reporting bias)Unclear riskAbstract only

Other biasHigh riskFunding Kirin Brewery Company

Kwan 2005

Methods
  • Study design: open-label RCT
  • Study duration: NS
  • Duration of follow-up: 24 weeks


Participants
  • Country: Hong Kong
  • Setting: single centre
  • PD; weekly SC EPO
  • Number: treatment group 1 (30); treatment group 2 (34)
  • Mean age ± SD: 51.2 ± 13.3 years
  • Sex (M/F): 26/64
  • Exclusion criteria: NS


InterventionsTreatment group 1

  • DA: SC every 4 weeks
  • Dose calculated from previous EPO dose


Treatment group 2

  • DA: SC every 2 weeks
  • Dose calculated from previous EPO dose


Other information

  • Duration of study: 24 weeks
  • Dose was kept stable in both groups during duration of study


Co-interventions

  • Oral and IV iron administered according to unit policy


Outcomes
  • Final Hb at 24 weeks (evaluation)
  • Number requiring transfusion
  • Number requiring iron supplements


Notes
  • Abstract only


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information about sequence generation process to permit judgement

Allocation concealment (selection bias)Unclear riskRandomisation stated but no information on method used is available

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNot blinded but primary outcome is laboratory based and unlikely to be subject to bias

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding of outcome assessment, and outcome unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information to permit judgement; 9 (14%) excluded from evaluation but group and reasons not stated

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasHigh riskGrant/research support (Kirin). Drug supplied by Kirin

Lago 1996

Methods
  • Study design: parallel RCT
  • Study duration: NS
  • Duration of follow-up: 12 months


Participants
  • Country: Spain
  • Setting: single centre
  • Stable HD patients
  • Number: treatment group 1 (21); treatment group 2 (9)
  • Mean age ± SD (years): treatment group 1 (55.2 ± 15.9); treatment group 2 (63 ± 16.2)
  • Sex (M/F) treatment group 1 (9/12); treatment group 2 (4/5)
  • Exclusion criteria: NS


InterventionsTreatment group 1

  • EPO: SC once/wk for 12 months


Treatment group 2

  • EPO: SC 3 times/wk for 12 months


Other information

  • Dose: NS
  • Target Hb: 10.5 mg/dL
  • Type of EPO: NS


Co-interventions

  • NS


Outcomes
  • Hb and HCT at study end


Notes
  • Letter


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information about the sequence generation process to permit judgement

Allocation concealment (selection bias)Unclear riskStudy stated to be randomised but no further information given

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding, but outcome unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding of outcome, but unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
High risk6/21 in experimental group and 2/9 in control group did not complete study

Selective reporting (reporting bias)Unclear riskLetter only. Only Hb levels reported

Other biasUnclear riskNo mention of funding source

Lee 2008

Methods
  • Study design: open-label, parallel RCT
  • Study duration: July 2004 to April 2005
  • Duration of follow-up: 12 weeks


Participants
  • Country: Korea
  • Setting: multicentre
  • Regular HD ≥ 3 months; age ≥18 years; stable EPO dose 3000 to 12,000 U/wk. Hb 9 to 12 g/dL; stable iron stores
  • Number: treatment group 1 (44); treatment group 2 (39)
  • Mean age ± SD (years): treatment group 1 (55.7 ± 10.1); treatment group 2 (53.3 ± 12.9)
  • Sex (M/F): treatment group 1 (24/20); treatment group 2 (23/16)
  • Exclusion criteria: uncontrolled HT; DBP ≥110 mm Hg; hyperparathyroidism ≥ 800 pg/mL; acute infection/inflammation; severe CCF; GI bleed; pregnancy; immunosuppressive or androgen therapy; malignancy; epilepsy; transfused ≤ 2 months previous; sensitivity to EPO


InterventionsTreatment group 1

  • EPO: SC once/wk for 12 weeks
  • Starting dose previous total weekly dose


Treatment group 2

  • EPO: SC 2 to 3 times/wk for 12 weeks
  • Continue previous dose


Other information

  • Type of ESA: EPO alfa
  • Dose adjusted in both groups to maintain Hb level at 9 to 12.0 g/dL


Co-interventions

  • All received IV iron therapy


Outcomes
  • Final Hb at 12 weeks
  • Mean EPO dose at week 10
  • Proportion of patients keeping a stable Hb level
  • Adverse effects


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information about sequence generation process to permit judgement

Allocation concealment (selection bias)Low riskRandomised by central randomisation. Stratified for EPO dose

Blinding of participants and personnel (performance bias)
All outcomes
Low riskOpen-label study but primary outcome was laboratory measure and unlikely to be subject to bias

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen-label study but primary outcome was laboratory measure and unlikely to be subject to bias

Incomplete outcome data (attrition bias)
All outcomes
Low riskReported ITT and PP data. Loss to follow-up/withdrawal post randomisation: 4 in each group (protocol violation; dose change in study period; Hb ≥ 12 at randomisation). Loss to follow-up unlikely to influence results

Selective reporting (reporting bias)High riskNo information on mortality and incomplete information on adverse effects

Other biasHigh riskSupported/funded by LG Life Sciences Co Ltd

Leung 1995

Methods
  • Study design: parallel RCT
  • Study duration: NS
  • Duration of follow-up: NS


Participants
  • Country: Hong Kong
  • Setting: single centre
  • Stable CAPD
  • Number: treatment group 1 (20); treatment group 2 (20)
  • Mean age ± SD (years): NS
  • Sex (M/F): NS
  • Exclusion criteria: NS


InterventionsTreatment group 1

  • EPO: SC twice/wk for 16 weeks


Treatment group 2

  • EPO: SC 3 times/wk for 16 weeks


Other information

  • Dose in both groups: initial 100 U/kg/wk then adjusted to increase Hb by 1 g/dL/mo with a target Hb of 10 to 12 g/dL
  • Type of EPO: NS


Co-interventions

  • Anti-hypertensive


Outcomes
  • Hb at end of study
  • Average weekly dose of EPO
  • Weekly EPO dose at end of study
  • Number of antihypertensive drugs


Notes
  • Abstract only


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information about sequence generation to permit judgement

Allocation concealment (selection bias)Unclear riskRandomisation stated but no information on method used is available

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPrimary outcome was laboratory measure and unlikely to be subject to bias

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPrimary outcome was laboratory measure and unlikely to be subject to bias

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data unlikely to influence results; 2/20 in each group, no reasons given. 10% participants excluded from analysis

Selective reporting (reporting bias)Unclear riskNo information provided on mortality and incomplete information on adverse effects. All data provided without standard deviations so cannot be included in meta-analyses

Other biasUnclear riskFunding sources not mentioned

Locatelli 2002

Methods
  • Study design: RCT
  • Study duration: NS
  • Duration of follow-up: 24 weeks


Participants
  • Countries: Italy, Germany, France, Spain
  • Setting 19 dialysis centres
  • Stable HD for the last 3 months; age ≥ 18 years; delivered dialysis dose ≥ 1.2; SC epoetin-ß 3 times/wk over the last 3 months; mean dose 30 to 240 IU/kg in the last 2 weeks before start of study Stable HCT 28 to 38%; adequate iron status, ferritin level 100 ng/mL and transferrin saturation > 20%
  • Number: treatment group 1 (69); treatment group 2 (63)
  • Mean age ± SD (years): treatment group 1 (63.6 ± 14.8); treatment group 2 (62.0 ± 12.4)
  • Sex (M/F): treatment group 1 (38/31); treatment group 2 (32/31)
  • Exclusion criteria: haemoglobinopathy; haemolysis or GI bleeding; hypertension requiring interruption of epoetin treatment in last 6 months; acute infection or systemic inflammatory disease; malignancy; epilepsy; severe hyperparathyroidism; serum aluminium level > 50 ng/mL; vitamin B₁₂ > 200 pg/mL; folic acid > 2 ng/mL; thrombocyte count < 500,000/µL; pregnancy or lactation; no blood transfusion within last 3 months; no history of hypersensitivity to epoetin B


InterventionsTreatment group 1

  • EPO: SC once/wk for 24 weeks
  • First 12 weeks excluded from analysis to avoid carry over effect of epoetin treatment prior to randomisation
  • Dose: after randomisation, weekly dose corresponded to individual mean weekly doses in the pre-study period


Treatment group 2

  • EPO: SC 3 times/wk for 24 weeks


Other information

  • Adjustments in both groups were indicated if HCT differed from baseline by ± 3%


Co-interventions

  • Iron supplementation as required


Outcomes
  • Difference between groups in mean time-adjusted AUC for HCT for PP and ITT populations
  • Median change in weekly epoetin-ß dose/kg of body weight
  • Number needing transfusion
  • Adverse events: hypertension, AV fistula thromboses


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStratified by centre, but no further information provided

Allocation concealment (selection bias)Low riskCentral randomisation

Blinding of participants and personnel (performance bias)
All outcomes
Low riskOpen-label study but primary outcome was laboratory measure and unlikely to be subject to bias

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen-label study but primary outcome was laboratory measure and unlikely to be subject to bias

Incomplete outcome data (attrition bias)
All outcomes
Low risk16% (27/173) lost to follow-up or withdrawn but reasons for missing data unlikely to be related to true outcome: death (6), adverse events (5), protocol violations (4), improvement in anaemia (2), refusal of treatment (2), administrative reasons (7), loss to follow-up (1)

Selective reporting (reporting bias)High riskReported outcomes consistent with expected but data not provided in format that can be entered in meta-analysis

Other biasHigh riskSupported in part by Hoffmann-La Roche Ltd, Switzerland

Locatelli 2004

Methods
  • Study design: parallel RCT
  • Study duration/time frame: 25 August 2002 to 29 September 2003
  • Duration of follow-up: 30 weeks


Participants
  • Countries: UK, Europe
  • Setting: multicentre
  • Age: ≥ 18 years; HD ≥ 6 months; on stable IV rHuEPO 1 to 3 times/wk; baseline Hb 10.0 to 13.0 g/dL
  • Number: treatment group 1 (154); treatment group 2 (154)
  • Mean age ± SD (years): NS
  • Sex (M/F): NS
  • Exclusion criteria: seizures ≤ 6 months; CHF; uncontrolled hypertension; current malignancy; surgery within 3 months; systemic haematological disease; RBC transfusion 12 weeks before screening


InterventionsTreatment group 1

  • DA: IV every two weeks for 30 weeks
  • Starting dose was previous weekly EPO dose in units divided by 200 multiplied by 2


Treatment group 2

  • DA: IV every week for 30 weeks
  • Starting dose was previous weekly EPO dose in units divided by 200.


Other information

  • Dose was titrated for each patient throughout the study to maintain Hb within -1.0 to + 1.5 g/dL of baseline and between 10.0 and 13.0 g/dL


Co-interventions

  • NS


Outcomes
  • Final Hb
  • Instability of Hb concentrations
  • DA alfa dosing requirements
  • RBC transfusions
  • Adverse events


Notes
  • Multiple abstracts
  • Additional information from www.amgentrials.com
  • Data sought from authors: randomisation process


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSequence generation not stated. Stratified by centre according to EPO dose "randomly assigned"

Allocation concealment (selection bias)Unclear riskRandomisation stated but no information on method used available

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBlinding maintained by placebo injections weekly in patients on 2 weekly regimen. Unclear whether both participants and personnel blinded. Primary outcome is laboratory measurement

Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding maintained by placebo injections weekly in patients on 2 weekly regimen

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear. Abstracts only; 213/307 (69%) were included in primary analysis; deaths (19), adverse events (5)

Selective reporting (reporting bias)High riskImportant outcomes provided but data for primary outcome only provided for PP population

Other biasHigh riskFunding Amgen Inc, Thousand Oaks, CA

Lui 1991

Methods
  • Study design: parallel RCT
  • Study duration: NS
  • Duration of follow-up: 16 weeks


Participants
  • Country: Hong Kong
  • Setting: single centre
  • CAPD at least 6 months. Hb levels < 8 g/dL
  • Number: treatment group 1 (10); treatment group 2 (10)
  • Mean age ± SD (years): treatment group 1 (49 ± 11); treatment group 2 (40 ± 12)
  • Sex (M/F): treatment group 1 (3/7); treatment group 2 (3/7)
  • Exclusion criteria: anaemia due to other causes; uncontrolled hypertension


InterventionsTreatment group 1

  • EPO: IV once/wk for 16 weeks


Treatment group 1

  • EPO: IV twice/wk for 16 weeks


Other information

  • Dose for each group: starting dose 100 U/kg week with adjustments for target Hb of 10 g/dL
  • Type of EPO: alpha


Co-interventions

  • Iron supplements given to all patients unless iron overload


Outcomes
  • Mean Hb or HCT at end of maintenance phase
  • Average EPO dose during the study
  • Number of patients with an increase or introduction of antihypertensive treatment


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSaid to be randomised. No other information provided

Allocation concealment (selection bias)Unclear riskSaid to be randomised. No other information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskLaboratory outcome, blinding unlikely to influence outcome

Blinding of outcome assessment (detection bias)
All outcomes
Low riskLaboratory outcome, blinding unlikely to influence outcome

Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for missing data unlikely to be related to true outcome; loss to follow-up/withdrawal: 3/20 (15%) excluded; peritonitis (2), failure to respond to therapy (1)

Selective reporting (reporting bias)High riskNo report of mortality and incomplete reporting of adverse events

Other biasHigh riskEpoetin supplied by Jansen Cilag. Supported by Cilag Research

Lui 1992

Methods
  • Study design: parallel RCT
  • Study duration: NS
  • Duration of follow-up: 12 weeks


Participants
  • Country: Hong Kong
  • Setting: single centre
  • HD for at least 6 months of dialysis; pre-treatment Hb < 8 g/dL
  • Number: treatment group (10); treatment group (10)
  • Mean age ± SD (years): treatment group 1 (41 ± 8); treatment group 2 (38 ± 6)
  • Sex (M/F): treatment group 1 (6/4); treatment group (7/3)
  • Exclusion criteria: uncontrolled hypertension


InterventionsTreatment group 1

  • EPO: starting dose SC 100 U/kg body weight once/wk for 12 weeks
  • Adjusted to maintain target Hb 10 g/dL


Treatment group 2

  • EPO: starting dose 100 U/kg body weight twice/wk for 12 weeks
  • Adjusted to maintain target Hb 10 g/dL


Other information

  • Type of EPO: alpha


Co-interventions

  • Iron administered unless evidence of gross degree of iron overload; antihypertensives, metoprolol and nifedipine


Outcomes
  • Number who failed to achieve/maintain target Hb or HCT during correction/maintenance phase
  • Mean Hb or HCT at end of correction phase
  • Change in Hb
  • Average EPO dose used during study
  • Number with increase/introduction of antihypertensive treatment


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskPatients said to be randomised. No other information provided

Allocation concealment (selection bias)Unclear riskPatients said to be randomised. No other information provided

Blinding of participants and personnel (performance bias)
All outcomes
Low riskLaboratory outcome, blinding unlikely to influence outcome

Blinding of outcome assessment (detection bias)
All outcomes
Low riskLaboratory outcome, blinding unlikely to influence outcome

Incomplete outcome data (attrition bias)
All outcomes
Low riskNumbers and reasons for withdrawals stated and unlikely to affect results

Selective reporting (reporting bias)High risk No information on mortality and limited information on adverse effects

Other biasHigh riskSupported by Cilag Research

MAXIMA Study 2007

Methods
  • Study design: parallel RCT
  • Study duration: recruitment April 2004 to August 2004; completed August 2005
  • Duration of follow-up: 52 weeks


Participants
  • Countries: USA, Canada, Europe
  • Setting. 96 centres
  • CKD 5D; HD ≥ 12 weeks; stable Hb (10.5 to 13.0 g/L); rHuEPO 8 weeks before screening; adequate iron status; PD patients included theoretically, but none participated as not receiving IV ESA
  • Number: treatment group 1 (233); treatment group 2 (224); treatment group 3 (226)
  • Mean age ± SD (years): treatment group 1 (55 ± 15.2); treatment group 2 (59 ± 15); treatment group 3 (58.6 ± 15.1) 5 years (SD)
  • Sex (M/F): treatment group 1 (133/90); treatment group 2 (126/98); treatment group 3 (134/92)
  • Exclusion criteria: overt bleeding requiring transfusion ≤ 8 weeks before study; CRP ≥ 30 mg/L; life expectancy ≤ 12 months; likelihood of early withdrawal


InterventionsTreatment group 1

  • CERA: twice/mo for 52 weeks
  • Route of administration: IV and SC
  • Dosage
    • 60 µg CERA if previous dose < 8000 U rHuEPO
    • 100 µg CERA if previous dose 8000 to 16,000 U rHuEPO
    • 180 µg if previous dose > 16,000 U rHuEPO


Treatment group 2

  • CERA: once/mo for 52 weeks
  • Route of administration: IV and SC
  • Dosage
    • 120 µg CERA if previous dose < 8000 U rHuEPO
    • 200 µg CERA if previous dose 8000 to16000 U rHuEPO
    • 360 µg CERA if previous dose > 16,000U rHuEPO


Treatment group 3

  • rHuEPO: 3 times/wk for 52 weeks
  • Route of administration: IV and SC


Other information

  • Assessment period weeks 28 to 36. Follow up to 52 weeks
  • Dosages of CERA were adjusted according to protocol and not more often than every 4 weeks. Dosages of rHuEPO were adjusted according to their labels


Co-interventions

  • Iron supplementation


Outcomes
  • Change in Hb
  • Adverse events: AV thrombus, hypertension, seizures, SAE due to ESA
  • Mortality
  • ESA dose


Notes
  • Information requested from authors regarding ITT data: none received


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom computer numbers generated by computer at coordinating centre

Allocation concealment (selection bias)Low riskRandomisation at coordinating centre

Blinding of participants and personnel (performance bias)
All outcomes
Low riskLaboratory endpoint, therefore unlikely to be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskLaboratory endpoint, therefore unlikely to be influenced by blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients accounted; loss to follow-up/excluded: adverse events (8), deaths (26), insufficient therapy (1), refused treatment (12), other (36), failure to return for follow-up (2)

Selective reporting (reporting bias)High riskExpected outcomes reported but ITT data only shown in graph. PP data in text and tables

Other biasHigh riskIndustry funded, Hoffman La Roche

Miranda 1990

Methods
  • Study design: parallel RCT
  • Study duration: NS
  • Duration of study: 9 months


Participants
  • Country: Spain
  • Setting: single centre
  • CAPD; Hb < 8 g/dL
  • Number: treatment group 1 (8); treatment group 2 (7)
  • Mean age ± SD (years): treatment group 1 (44 ± 12); treatment group 2 (56 ± 17): years (SD)
  • Sex (M/F): NS
  • Exclusion criteria: NS


InterventionsTreatment group 1

  • rHuEPO: SC 20 U/kg/d for 9 months


Treatment group 2

  • rHuEPO: SC 2000 U twice/wk for 9 months


Co-interventions

  • Iron administered; target Hb 10.5 g/dL


Outcomes
  • Hb levels at the end of the study
  • EPO doses at the end of the study
  • Adverse effects


Notes
  • Third group given intraperitoneal rHuEPO daily not included


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNS

Allocation concealment (selection bias)Unclear riskUnclear

Blinding of participants and personnel (performance bias)
All outcomes
Low riskLaboratory outcome, unlikely to be influenced by blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskLaboratory outcome, unlikely to be influenced by blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear whether all patients completed study

Selective reporting (reporting bias)High riskInformation provided graphically or for combined groups of patients so could not be included in meta-analyses

Other biasUnclear riskFunding sources NS

Mircescu 2006

Methods
  • Study design: parallel RCT
  • Duration of study: 1 March 2004 to 31 January 2005
  • Duration of follow-up: 24 weeks


Participants
  • Country: Romania
  • Setting: multicentre
  • HD 6 months (Kt/v 1.2); Hb > 10 g/dL; adequate iron stores; ferritin 100 to 88 ng/mL; TSAT 20 to 50%; once weekly SC EPO for 2 months before enrolment ≥ 18 years
  • Number: treatment group 1 (104); treatment group 2 (103)
  • Mean age ± SD (years): treatment group 1 (49.6 ± 13.3); treatment group 2 (48.0 ± 12.9)
  • Sex (M/F): treatment group 1 (57/47); treatment group 2 (62/41)
  • Exclusion criteria: CHF; hepatic disease; CRP > 12 mg/L; severe hyperparathyroidism (PTH > 800 ng/mL); serum B₁₂ or folate deficiency; poor BP control; malnutrition; albumin < 40 g/L; blood transfusions in last 2 months


InterventionsTreatment group 1

  • rHuEPO: SC every 2 weeks, same cumulative dose administered every other week for 24 weeks


Treatment group 2

  • rHuEPO SC once/wk, continued the previous once weekly schedule


Other information

  • Dose adjustments were made to maintain Hb levels in both groups


Co-interventions

  • Iron therapy was continued according to Romanian Best Practice Guidelines


Outcomes
  • Final or change in Hb
  • Number reaching target HB
  • Change in median EPO dose
  • Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRenal Registry Romania. Numbered containers

Allocation concealment (selection bias)Low riskCentral randomisation. Renal Registry Romania

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low risk4/207 excluded from analyses (4 withdrew after randomisation (2 from each group)), unlikely to influence results

Selective reporting (reporting bias)High riskNo information on mortality

Other biasHigh riskFunding for laboratory tests from F. Hoffman la Roche Ltd

Muirhead 1989

Methods
  • Study design: cross-over RCT
  • Study duration: NS
  • Duration of follow-up: NS


Participants
  • Country: Canada
  • Setting: single centre
  • HD patients; 12 weeks rHuEPO; stable Hb 10.5 to 12.5 g/dL
  • Number: 19
  • Mean age ± SD (years): NS
  • Sex (M/F): NS
  • Exclusion criteria: NS


InterventionsTreatment group 1

  • rHuEPO: IV once/wk
    • Received total weekly dose as a weekly injection. Continued for 12 weeks, then crossed-over
  • Matched placebo: twice/wk


Treatment group 2

  • rHuEPO: IV 3 times/wk for 12 weeks then crossed-over
  • Dose adjustment was made according to Hb and total weekly rHuEPO dose


Co-interventions

  • NS


Outcomes
  • Change in Hb
  • Adverse events


Notes
  • Abstract only
  • Only data for the whole group


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNS

Allocation concealment (selection bias)Unclear riskNS

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo given to weekly rHuEPO group. Patients and staff did not know frequency

Blinding of outcome assessment (detection bias)
All outcomes
Low riskUnclear if outcome assessors blinded but outcome of Hb unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
High risk31% did not complete the study

Selective reporting (reporting bias)High riskData only available for combined groups

Other biasUnclear riskNS

Murtagh 2000

Methods
  • Study design: RCT
  • Study duration: NS
  • Duration of follow-up: 16 weeks


Participants
  • Country: Ireland
  • Setting: single centre
  • HD patients; Hb < 10 g/dL; no rHuEPO in previous 3 months
  • Number: 10
  • Mean age ± SD (years): NS
  • Sex (M/F): 8/2
  • Exclusion criteria: NS


InterventionsTreatment group 1

  • DA: IV 3 times/wk
  • Total dose: 0.75 μg/kg/wk in divided doses for 16 weeks


Treatment group 2

  • DA: IC once/wk
  • Dose: 0.75 μg/kg/wk for 16 weeks


Co-interventions

  • NS


Outcomes
  • Final Hb
  • Adverse events


Notes
  • Abstract only
  • Results for intervention groups not provided separately for each treatment regimen


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNS

Allocation concealment (selection bias)Unclear riskNS

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll 10 patients completed the initial 16 weeks

Selective reporting (reporting bias)High riskData only provided for combined groups

Other biasUnclear riskFunding source: NS

Nagaya 2010

Methods
  • Study design: prospective RCT
  • Study duration: NS
  • Duration of follow-up: 24 weeks


Participants
  • Country: Japan
  • Setting: single centre
  • HD; age ≥18 years
  • Number (randomised/evaluated): treatment group 1 (24/20); treatment group 2 (24/19)
  • Mean age ± SD (years): treatment group 1 (66.9 ± 9.3); treatment group 2 (68.8 ± 9.9)
  • Sex (M/F): treatment group 1 (12/8); treatment group 2 (11/8)
  • Exclusion criteria: underlying malignancy; haemorrhagic disease; CHF; uncontrolled hypertension; transfusion; surgery post-screening


InterventionsTreatment group 1

  • DA: IV at 2 weekly intervals; dose double of previous weekly dose; continued for 24 weeks
  • Weekly dose: 0.43 ± 0.19 µg/kg/wk
  • DA adjusted to maintain Hb level 10.5 to 11.5 g/dL


Treatment group 2

  • DA: IV once/wk for 24 weeks; continued dose used prior to randomisation
  • Weekly dose: 0.49 ± 0.22 µg/kg/wk
  • DA doses titrated according to international guidelines
  • DA adjusted to maintain Hb level 10.5 to 11.5 g/dL


Co-interventions

  • IV iron supplementation


Outcomes
  • Weekly dose of DA at week 24
  • Final Hb at 24 weeks
  • Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information about sequence generation process to permit judgement "prospective and randomised"

Allocation concealment (selection bias)Unclear riskStudy stated to be randomised but further information not given

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding but outcome is unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding of outcome assessment, but outcome assessment unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
High riskPatients excluded: 48 randomised, PP 39 (loss to follow-up/withdrawal: 9/48 (18.8%); surgery (4), transfer to another institution (2), death (10), haematologic disease (1), nasal bleeding (1); missing data may have influenced outcome

Selective reporting (reporting bias)High riskInsufficient information on adverse effects

Other biasLow riskGrant from Japan Dialysis outcome Research Group

Nissenson 2002

Methods
  • Design: parallel group, non-inferiority RCT
  • Study duration: NS
  • Duration of follow-up: 28 weeks


Participants
  • Countries: Canada, USA
  • Setting: multicentre, Canada (5); USA (35)
  • Aged ≥18 years; HD ≥ 12 weeks; IV EPO-α for 8 weeks; stable Hb concentration 9.5 to 12.5 g/dL; stable iron stores
  • Number: treatment group 1 (169); treatment group 2 (338)
  • Mean age, range (years): treatment group 1 (58.0, 20 to 86); treatment group 2 (57.8, 21 to 90)
  • Sex (M/F): treatment group 1 (94/75); treatment group 2 (191/147)
  • Exclusion criteria: haematologic, inflammatory or infectious conditions; transfusion in previous 8 weeks


InterventionsTreatment group 1

  • DA: based on total weekly dose of EPO at time of randomisation (200 U EPO = 1 μg DA); IV once/wk
  • Placebo: IV twice/wk for 28 weeks


Treatment group 2

  • rHuEPO: continued previous dose given IV 3 times/wk for 28 weeks


Other information

  • Dose adjustments made in each treatment group to maintain individual patient's Hb within -1.0 to + 1.5 g/dL of baseline value and within range of 9.0 to 13.0 g/dL throughout 28 week study period


Co-interventions

  • Iron supplementation administered according to individual unit policy


Outcomes
  • To assess that DA at reduced dose frequency is effective and as well tolerated as epoetin
  • Hb within target range


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStratified by centre. No information provided on sequence generation

Allocation concealment (selection bias)Low riskCentral computer allocation

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDA group received placebo twice per week

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPlacebo-controlled. Primary outcome was laboratory-based and unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low risk4/507 excluded from ITT analysis and unlikely to influence results; loss to follow-up/withdrawal: 81/507. Protocol violation (1), intolerable AE (24), withdrawal requested (11), death (28), kidney transplant (15), administration decision (2), change in dialysis modality (1)

Selective reporting (reporting bias)High riskInformation provided on all expected outcomes but ITT data available from figures and could not be included in meta-analyses

Other biasHigh riskSupported by Amgen

Paganini 1991

Methods
  • Study design: RCT
  • Study duration: NS
  • Duration of follow-up: 27 to 38 weeks


Participants
  • Country: USA
  • Setting: 6 centres
  • Stable HD patients; IV EPO > 3 years
  • Number: treatment group 1 (25); treatment group 2 (33)
  • Mean age ± SD (years): NS
  • Sex (M/F): NS
  • Exclusion criteria: NS


InterventionsTreatment group 1

  • EPO: SC once/wk
  • Mean weekly dose at baseline: 254 ± 198 U/kg


Treatment group 2

  • EPO: 3 times/wk


Co-interventions

  • Iron and folic acid


Outcomes
  • HCT at the end of the study
  • EPO dose at end of study


Notes
  • Abstract only


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNS

Allocation concealment (selection bias)Unclear riskNS

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding, unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear if all patients completed the study

Selective reporting (reporting bias)Unclear riskNo report of mortality or adverse effects

Other biasUnclear riskNo information

PROTOS Study 2007

Methods
  • Study design: open-label, parallel group, comparator controlled, phase III RCT
  • Study duration: March 2004 to September 2005
  • Duration of follow-up: 1 year


Participants
  • Countries: international
  • Setting: 92 centres
  • Aged ≥18 years; PD or HD ≥ 12 weeks; Kt/V≥ 1.2 or URR ≥ 65% for HD; weekly Kt/V ≥1.8 for PD patients; Hb concentration 10.5 to 13.0 g/dL; SC rHuEPO maintenance therapy; ferritin ≥ 100 ng/mL or TSAT ≥ 20%
  • Number: treatment group 1 (190); treatment group 2 (191); treatment group 3 (191)
  • Mean age ± SD (years): treatment group 1 (62.3 ± 15.4); treatment group 2 (60.59 ± 15.4); treatment group 3 (60.4 ± 14.7)
  • Sex (M/F): treatment group 1 (117/74); treatment group 2 (108/82); treatment group 3 (110/81)
  • Exclusion criteria: GI bleeding or bleeding requiring transfusion < 8 weeks before screening; non-renal causes of anaemia; uncontrolled or symptomatic inflammatory disease, e.g. SLE, RA; CRP > 30 mg/L; platelets > 500 x 10⁹/L; PRCA; CHF; poorly controlled hypertension; high likelihood of withdrawal/interruption of the study (MI, stroke); Life expectancy < 12 months


InterventionsTreatment group 1

  • CERA: every 2 weeks
  • Starting dose: SC 60 μg/2 wk


Treatment group 2

  • CERA: every 4 weeks
  • Starting dose: SC 120 μg/4 wk


Treatment group 3

  • rHuEPO: given one to three/wk with dose based on approved recommendations to maintain Hb as above


Other information

  • During titration and evaluation periods CERA dose was adjusted to maintain Hb within ± 1.0 g/dL of baseline and 10.0 to 13.5 g/dL. CERA dose adjustments were performed according to a predefined protocol and no more frequently than once every 4 weeks


Co-interventions

  • Iron supplementations were performed according to each centre's practice and adjusted to maintain adequate stores


Outcomes
  • Mean change in Hb
  • Adverse effects: hypertension, AV fistula thrombosis, AE leading to withdrawal and death


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation with geographic stratification

Allocation concealment (selection bias)Low riskCentral randomisation

Blinding of participants and personnel (performance bias)
All outcomes
Low riskOpen-label study but laboratory endpoint unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOpen-label study but laboratory endpoint unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted

Selective reporting (reporting bias)High riskData provided for PP not ITT population. ITT data only available graphically so PP data only included in meta-analyses (98 excluded from ITT population). Withdrawal/loss to follow-up: 111/572. Death (41), kidney transplantation (39), treatment refusal (13), AEs (2), insufficient therapeutic response (2), other (13)

Other biasHigh riskFunding F. Hoffman La Roche Ltd

RUBRA Study 2008

Methods
  • Study design: parallel group, open-label RCT
  • Time frame: NS
  • Duration of study: 36 weeks; evaluation 29 to 36 weeks


Participants
  • Country: international
  • Setting: multicentre
  • Aged ≥ 18 years; HD or PD ≥ 12 weeks; stable on EPO ≥ 8 weeks; baseline Hb 10.5 to 13.0 g/dL; adequate iron stores, serum ferritin ≥100 ng/mL or TSAT ≥ 20%
  • Number: treatment group 1 (104); treatment group 2 (168)
  • Mean age ± SD (years): treatment group 1 (59.8 ± 14.4); treatment group 2 (60.1 ± 13.9)
  • Sex (M/F): treatment group 1 (104/64); treatment group 2 (113/55)
  • Exclusion criteria: blood transfusions < 8 weeks; GI bleeding; non-renal causes of anaemia; CAD; liver disease; uncontrolled hypertension


InterventionsTreatment group 1

  • CERA: SC or IV every two weeks
  • Initial dose based on EPO dose received during week preceding randomisation. Patients receiving weekly EPO > 8000, 8000 to 16,000 or > 16,000 IU were administered a starting CERA twice weekly dose of 60, 100 or 180 μg respectively


Treatment group 2

  • EPO: continued, once/wk or 3 times/wk SC/IV


Other information

  • Dose adjustments were permitted for safety at any point during the study to maintain individual's Hb within 1g/dL of baseline value and within 10.0 to 13.5 g/dL. For CERA dose adjustment was not permitted more frequently than once every 4 weeks


Co-interventions

  • Iron supplementation was performed according to individual centre practice


Outcomes
  • Final Hb
  • Number reaching target Hb
  • Median dose of ESA
  • Adverse events


Notes
  • Information on sequence generation and allocation concealment requested from authors: no information received


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNS

Allocation concealment (selection bias)Unclear riskStratified by geographical region and route of administration

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients accounted; 54/282 (19%) withdrew due to AEs (4), death (16), transplantation (16), insufficient therapeutic response (1), refusal of treatment (1), failure to return (1), other (12)

Selective reporting (reporting bias)High riskAll important outcomes provided. ITT data only available graphically and PP data entered in meta-analyses

Other biasHigh riskFunded by Roche

STRIATA Study 2008

Methods
  • Study design: open-label, parallel RCT
  • Study duration: NS
  • Duration of follow-up: 52 weeks


Participants
  • Countries: Europe (12 countries), Australia, Canada
  • Setting: multicentre (48 centres)
  • Aged ≥18 years; chronic anaemia receiving HD; Kt/V ≥ 1.2 or urea reduction ≥ 65%; PD weekly Kt/V ≥ 1.8 for ≥ 12 weeks; IV DA therapy weekly or 2 weekly ≥ 8 weeks
  • Number (randomised/evaluated): treatment group 1 (157/123); treatment group 2 (156/126)
  • Mean age ± SD (years): treatment group 1 (62.49 ± 16.17); treatment group 2 (61.8 ± 14.74)
  • Sex (M/F): treatment group 1 (100/57); treatment group 2 (81/75)
  • Exclusion criteria: non-renal causes of anaemia; CRP > 30 mg/L; life expectancy < 12 months


InterventionsTreatment group 1

  • CERA: IV 2 weekly
  • Starting CERA dose calculated according to DA dose before randomisation. 60 μg to 180 μg/2 weeks


Treatment group 2

  • DA: IV weekly or 2 weekly according to previous dose
  • During dose titration and evaluation, doses in both groups were adjusted to maintain Hb within 1.0 g/dL of baseline or Hb values between 10 and 13.5 g/dL


Other information

  • Dose adjustments for CERA were performed not more frequently than once every 4 weeks


Co-interventions

  • IV iron supplements as required in both treatment groups


Outcomes
  • Mean Hb change between baseline and evaluation (29 to 36 weeks)
  • Proportion patients maintaining Hb ± 1 g/dL of baseline during evaluation.
  • Incidence of RBC transfusions
  • Adverse effects


Notes
  • Request for ITT data (only available graphically in report) made to authors: no information obtained


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization numbers "allocated sequentially for each study centre"

Allocation concealment (selection bias)Low risk"Central randomization centre"

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients accounted for. Loss to follow-up/withdrawals: death (22), transplantation (20), refusal of treatment (7), adverse events (2), failure to return (2), patient vacation, patient decision, patient instability, protocol violation, discontinuation of dialysis (11)

Selective reporting (reporting bias)High riskITT data only provided graphically and PP data entered in meta-analyses

Other biasHigh riskFunded by F.Hoffman- La Roche Ltd. Basel Switzerland; data analyses conducted by sponsor

Tessitore 2008

Methods
  • Study design: pilot cross-over RCT
  • Study duration: NS
  • Duration of follow-up: 54 weeks


Participants
  • Country: Italy
  • Setting: single centre
  • Stable HD patients on IV EPO and IV iron
  • Number: treatment group 1 (18); treatment group 2 (18)
  • Mean age ± SD (years): NS
  • Sex (M/F): NS
  • Exclusion criteria: NS


InterventionsTreatment group 1

  • DA: 20 or 50 μg doses IV for 39 weeks; converted from EPO according to 200 U rHuEPO equivalent to 1 μg DA


Treatment group 2

  • rHuEPO: 2000, 4000, 10,000 U for 39 weeks according to previous dose


Other information

  • Dose adjustments: NS
  • 15 week titration and 39 week evaluation


Co-interventions

  • IV NaFe gluconate


Outcomes
  • Final Hb
  • Final rHuEPO dose


Notes
  • Abstract only


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNS

Allocation concealment (selection bias)Low riskCoin toss

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear if all patients included in analysis

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskInformation not provided

Vanrenterghem 2002

Methods
  • Study design: parallel RCT
  • Study duration: November 1997 to July 1998
  • Duration of follow-up: 52 weeks


Participants
  • Countries: Europe, Australia
  • Setting: multicentre
  • HD/PD; age ≥18 years; stable rHuEPO for 3 months; stable Hb 9.5 to 12.5 g/dL; adequate iron stores serum ferritin > 100 μg/L
  • Number (randomised/evaluated): treatment group 1 (347/224); treatment group 2 (175/112)
  • Mean age, range (years): treatment group 1 (60.1,18 to 88); treatment group 2 (60.9, 22 to 87)
  • Sex (M/F): treatment group 1 (188/159); treatment group 2 (100/75)
  • Exclusion criteria: haematological, inflammatory or infectious conditions; blood transfusion < 1 month before enrolment


InterventionsTreatment group 1

  • DA: patients on rHuEPO once/wk converted to DA once every 2 weeks for 52 weeks
  • Patients on EPO 2 to 3 times/wk converted to DA once/wk for 52 weeks
  • Dose adjusted to maintain individual's Hb within -1.0 to + 1.5 g/dL of baseline and between 9 and 13 g/dL


Treatment group 2

  • EPO: IV/SC once, twice or 3 times/wk for 52 weeks
  • Dose adjusted to maintain Hb within -1.0 to + 1.5 g/dL of baseline, and 9 to 13 g/dL
  • Evaluation at weeks 25 to 32


Co-interventions

  • IV iron therapy as required


Outcomes
  • Change in Hb
  • ESA dosage
  • Mortality
  • Adverse events


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNS

Allocation concealment (selection bias)Low riskCentral randomisation. Stratified by centre and EPO dose at study entry

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients accounted; loss to follow-up/withdrawals: 133 did not complete 52 weeks of study. Main reason was death (52), transplant and withdrawal requested; rates were similar between groups during evaluation period

Selective reporting (reporting bias)High riskResults provided for per protocol population with all results only provided graphically

Other biasHigh riskAmgen Inc funded study

Weiss 2000

Methods
  • Study design: open-label, parallel group RCT
  • Study duration: NS
  • Duration of follow-up: 24 weeks


Participants
  • Country: Sweden
  • Setting: multicentre
  • HD patients aged 18 to 80 years; Hb 10 to 12.5 g/dL; serum ferritin > 200 µg/L and/or TSAT > 20%; Kt/V > 1
  • Number (randomised/evaluated): treatment group 1 (118/88); treatment group 2 (40/30)
  • Mean age ± SD (years): treatment group 1 (66 ± 12); treatment group 2 (65 ± 13)
  • Sex (M/F): treatment group 1 (75/43); treatment group 2 (27/13)
  • Exclusion criteria: uncontrolled hypertension; serum aluminium > 100 µg/L; B₁₂ or folic acid deficiency; ongoing infection; known epilepsy; known hyperparathyroidism; pregnancy or lactation


InterventionsTreatment group 1

  • rHuEPO (epoetin-ß): SC weekly for 24 weeks
  • Dose/wk equivalent to previous total weekly dose


Treatment group 2

  • rHuEPO: SC twice or 3 times/wk as pre-trial for 24 weeks
  • Same rHuEPO dose and frequency continued as pre trial


Co-interventions

  • Iron when necessary


Outcomes
  • % maintaining stable Hb without requiring increase in total weekly dose of EPO
  • Hb at the end of study
  • Weekly EPO dose at end of study
  • Mortality


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNS

Allocation concealment (selection bias)Low riskCentral randomisation 3:1 ratio. Stratified by sex and age

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
High risk25% withdrew from each group before evaluation; withdrawals 30 and 10 patients respectively in once weekly and control groups withdrew prior to week 16

Selective reporting (reporting bias)Low riskExpected outcomes reported

Other biasHigh riskFunded by Amgen

Yoon 2004

Methods
  • Study design: RCT
  • Study duration: NS
  • Duration of follow-up: NS


Participants
  • Country: Korea
  • Setting: multicentre
  • HD patients, SC or IV rHuEPO
  • Number: 74
  • Mean age ± SD (years): NS
  • Sex (M/F): NS
  • Exclusion criteria: NS


InterventionsTreatment group 1

  • rHuEPO once/wk received DA every 2 weeks SC/IV for 20 weeks
  • rHuEPO 2 to 3 times/wk received DA once/wk SC/IV for 20 weeks


Treatment group 2

  • rHuEPO continued SC/IV for 20 weeks


Other information

  • rHuEPO and DA doses titrated to maintain Hb concentrations within range 8.0 to 13.0 g/dL or within -1.0 to +1.5 g/dL of patient's baseline values


Co-interventions

  • Iron therapy: NS


Outcomes
  • Change in Hb from baseline to evaluation


Notes
  • Abstract only
  • DA analysed as one group


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNS

Allocation concealment (selection bias)Unclear riskNS

Blinding of participants and personnel (performance bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo blinding but outcome of Hb unlikely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient data to enable assessment

Selective reporting (reporting bias)Unclear riskInsufficient data to enable assessment

Other biasUnclear riskFunding: NS

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Allon 2002Pharmacokinetic study

BA16260 Study 2006Dose finding study

Bennett 1991Participants not on dialysis

Besarab 1998Haematocrit target study

Bhuiyan 2004Dose varied, not frequency

Brandt 1999Dose varied, not frequency

Brown 1988Haematocrit target study

Canadian EPO Study 1990Injection frequency was not randomised; participants were randomised to placebo (Group 1) and two groups maintaining Hb from 95 to 110 g/L (Group 2) or 115 to 130 g/L (Group 3)

Castro 1994Unclear how patients were allocated to groups; no reply from study author

Chazot 2009Dose study

Dougherty 2004Dose dependent study not on dialysis

Fan 1992Unclear how patients were allocated to groups, wrote to authors, no response

Hirakata 2010Participants not on dialysis

Icardi 1990Different routes of administration (not frequency)

Ifudu 1998No control group, no change in frequency

Iwasaki 2008Examined conversion ratios for EPO to darbepoetin

Kawanishi 2005Dose escalation study

Kim 2009aCompared different routes of administration

Knebel 2008Pharmacokinetic study

Locatelli 2008Control group received either weekly darbepoetin or rHuEPO 2 to 3 times weekly; numbers receiving each control intervention could not be separated.

Macdougall 2003Dose escalation study

Macdougall 2006Participants not on dialysis

Macdougall 2007aStudy terminated by sponsor for commercial reasons. No results available

Martin 2007Dose only varied, not frequency

Moiz 2000Only varied dosage, not frequency

Muirhead 1992Injection frequency was not randomised; participants randomised to placebo (Group 1) and two groups maintaining Hb from 95 to 110 g/L (Group 2) or 115 to 130 g/L (Group 3)

Nissenson 1995Safety and efficacy study of EPO vs. placebo

Parfrey 2005Hb target study

PATRONUS Study 2009Compared CERA and darbepoetin at same dose intervals

Pawlak 2007Study of metalloproteinases with ESA

Provenzano 2006Described two phase-2 studies. Dialysis and non-dialysis patients not separated

Raftery 2000Not RCT

Schmitt 2006Not relevant. Focus on pain

Smith 2007Pharmacokinetic study

Smyth 2006Not a frequency study

Spaia 1995No mention of randomisation. Changed both dose and frequency

Spinowitz 2006Dosage, no change in frequency

Stockenhuber 1990Study of EPO effect on stem cells

Tan 1990aNot a frequency study

Tolman 2005Computer-assisted anaemia management

Wang 2000Not clear how patients were allocated to treatment. Cross-over study, wrote to authors to establish if patients were randomised - no reply

Yalcinkaya 1997Primary randomisation was to two different doses of rHuEPO

 
Characteristics of studies awaiting assessment [ordered by study ID]
EMERALD 1 Study 2013

Methods
  • Study design: open-label, parallel RCT
  • Start date: September 2007

ParticipantsInclusion criteria

  • Participants with CKD on HD for ≥ 3 months prior to randomisation
  • On IV epoetin alfa maintenance therapy continuously prescribed for a minimum of 8 weeks prior to randomisation
  • Four consecutive Hb values with a mean ≥ 10.0 and ≤ 12.0 g/dL during the screening period


Exclusion criteria

  • Females who are pregnant or breast-feeding; known intolerance to any ESA or pegylated molecule or to all parenteral iron supplementation products
  • Known bleeding or coagulation disorder
  • Known hematologic disease or cause of anaemia other than kidney disease
  • Poorly controlled hypertension
  • Evidence of active malignancy within one year prior to randomisation
  • Temporary (untunneled) dialysis access catheter
  • A scheduled kidney transplant
  • A scheduled surgery that may be expected to lead to significant blood loss

InterventionsPeginesatide

  • IV injection once every 4 weeks. The starting dose was based on the participant's total weekly epoetin alfa dose during the last week of the screening period; the first dose was administered one week after the last epoetin alfa dose. The dose was adjusted to maintain haemoglobin levels in a target range of 10.0 to 12.0 g/dL and ± 1.5 g/dL from baseline during the titration and evaluation periods, and 10.0 to 12.0 g/dL during the long-term safety and efficacy period


Epoetin alfa

  • Continued to receive commercially available epoetin alfa by intravenous injection, at the same starting dose and frequency as received during the last week of the screening period, with the first study dose of epoetin alfa administered after randomisation at Week 0. The dose was adjusted to maintain haemoglobin levels in a target range of 10.0 to 12.0 g/dL and ± 1.5 g/dL from baseline during the titration and evaluation periods, and 10.0 to 12.0 g/dL during the long-term safety and efficacy period

Outcomes
  • Mean change in Hb between baseline and the evaluation period (baseline and Weeks 29-36)
  • Proportion of participants who receive RBC transfusions during the titration and evaluation periods
  • Proportion of participants whose mean Hb level during the evaluation period is within the target range of 10.0 to 12.0 g/dL

Notes

EMERALD 2 Study 2013

Methods
  • Study design: open-label, parallel RCT
  • Start date: October 2007

ParticipantsInclusion criteria

  1. Participants with CKD on HD for ≥ 3 months prior to randomisation
  2. On IV epoetin alfa or beta maintenance therapy continuously prescribed for a minimum of 8 weeks prior to randomisation
  3. Four consecutive Hb values with a mean ≥ 10.0 and ≤ 12.0 g/dL during the screening period


Exclusion criteria

  1. Females who are pregnant or breast-feeding
  2. Known intolerance to any ESA or pegylated molecule or to all parenteral iron supplementation products
  3. Known bleeding or coagulation disorder
  4. Known hematologic disease or cause of anaemia other than kidney disease
  5. Poorly controlled hypertension.
  6. Evidence of active malignancy within one year prior to randomisation
  7. Temporary (untunneled) dialysis access catheter
  8. A scheduled kidney transplant
  9. A scheduled surgery that may be expected to lead to significant blood loss

InterventionsPeginesatide

  • IV or SC injection once every 4 weeks. The starting dose was based on the participant's total weekly epoetin alfa or beta dose during the last week of the screening period; the first dose was administered one week after the last epoetin alfa or beta dose. The dose was adjusted to maintain haemoglobin levels in a target range of 10.0 to 12.0 g/dL and ± 1.5 g/dL from baseline during the titration and evaluation periods, and 10.0 to 12.0 g/dL during the long-term safety and efficacy period


Epoetin alfa or beta

  • Continued to receive commercially available epoetin alfa by IV or SC injection, at the same starting dose and frequency as received during the last week of the screening period, with the first study dose of epoetin alfa administered after randomisation at Week 0. The dose was adjusted to maintain haemoglobin levels in a target range of 10.0 to 12.0 g/dL and ± 1.5 g/dL from baseline during the titration and evaluation periods, and 10.0 to 12.0 g/dL during the long-term safety and efficacy period

Outcomes
  • Mean change in Hb between baseline and the evaluation period (baseline and weeks 29 to 36)
  • Proportion of participants who receive RBC transfusions during the titration and evaluation periods
  • Proportion of participants whose mean Hb level during the evaluation period is within the target range of 10.0 to 12.0 g/dL

Notes

 
Characteristics of ongoing studies [ordered by study ID]
NCT00436748

Trial name or titleA multi-center, double-blind, randomized study evaluating de novo weekly and once every two week darbepoetin alfa dosing for the correction of anemia in pediatric subjects with chronic kidney disease receiving and not receiving dialysis

Methods
  • Parallel RCT

ParticipantsCountries: USA, Belgium, Latvia, Lithuania, Mexico, Poland, Puerto Rico, Russian Federation, Slovakia, UK

Inclusion criteria

  • Current diagnosis of CKD, either receiving or not receiving dialysis
  • Anaemic, with two consecutive screening Hb values drawn at least 7 days apart < 11.0 g/dL
  • TSAT ≥ 20%


Exclusion criteria

  • Any ESA use within 12 weeks prior to randomisation
  • other hematologic disorders
  • upper or lower GI bleeding within 6 months prior to randomisation
  • uncontrolled hypertension
  • prior history (within 12 weeks prior to randomisation) of acute myocardial ischaemic, hospitalisation for congestive heart failure, myocardial infarction, stroke or transient ischaemic attack
  • prior history (within 6 months prior to randomisation) of thromboembolism

InterventionsTreatment group 1

  • Darbepoetin alfa: once/wk; 10, 20, 30, 40, 50, 60, 80, 100, 150, 200, or 300 µg IV or SC


Treatment group 2

  • Darbepoetin alfa: once every 2 weeks; 10, 20, 30, 40, 50, 60, 80, 100, 150, 200, or 300 µg IV or SC

OutcomesPrimary outcome measures

  • Proportion of subjects achieving a Hb value ≥ 10.0 g/dL at any time point after the first dose during the study is > 0.8 when administered de novo darbepoetin alfa


Secondary outcome measures

  • To assess the health-related quality of life in paediatric CKD subjects ≥ 2 years over the duration of the study
  • To obtain pharmacokinetic data in subjects < 6 years of age
  • To assess the safety and tolerability of darbepoetin alfa administered once/wk and once every 2 weeks
  • To estimate Hb values over the duration of the study in the both arms
  • To estimate doses over the duration of the study in both arms

Starting dateAugust 2008

Contact informationAmgen Call Centre

Notes

NCT00717821

Trial name or titleA randomized, controlled, open label, french multicenter parallel group study to compare the hemoglobin maintenance with once monthly administration of mircera versus epoetin beta or darbepoetin alfa in patients with chronic kidney disease on hemodialysis

Methods
  • Open-label, parallel RCT

ParticipantsInclusion criteria

  • Adult patients,≥18 years
  • regular long term HD with same schedule for ≥ 12 weeks
  • continuous IV or SC maintenance epoetin beta or darbepoetin alfa therapy, with the same dosing interval during the previous month, and no change in total weekly dose


Exclusion criteria

  • transfusion of red blood cells during previous 2 months
  • significant acute or chronic bleeding
  • poorly controlled hypertension requiring hospitalisation or interruption of epoetin beta/darbepoetin alfa treatment in previous 6 months
  • weekly dose of epoetin beta >16000 UI, or weekly dose of darbepoetin alfa >80 µg during previous month

InterventionsTreatment group 1

  • Methoxy polyethylene glycol-epoetin beta (Mircera): 120 µg or 200 µg IV or SC (starting dose)


Treatment group 2

  • Epoetin beta or darbepoetin alfa: as prescribed

OutcomesPrimary outcome measures

  • Percentage of patients maintaining average Hb concentration within target range (10 to 12 g/dL) during evaluation period


Secondary outcome measures

  • Mean change in Hb concentration between reference and evaluation period, and mean time spent in Hb range of 10 to 12g/dL during evaluation period
  • Dose adjustments, RBC transfusions, adverse events

Starting dateOctober 2008

Contact informationHoffmann-La Roche

Notes

 
Comparison 1. CERA versus other ESA

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Final Hb5Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 CERA every 2 weeks versus rHuEPO
41126Mean Difference (IV, Random, 95% CI)0.08 [-0.04, 0.21]

    1.2 CERA every 4 weeks versus rHuEPO
2672Mean Difference (IV, Random, 95% CI)-0.03 [-0.17, 0.12]

    1.3 CERA every 2 weeks versus darbepoetin
1249Mean Difference (IV, Random, 95% CI)0.30 [0.05, 0.55]

 2 All-cause mortality5Risk Ratio (IV, Random, 95% CI)Subtotals only

    2.1 CERA every 2 weeks versus rHuEPO
41341Risk Ratio (IV, Random, 95% CI)1.03 [0.67, 1.57]

    2.2 CERA every 4 weeks versus rHuEPO
2827Risk Ratio (IV, Random, 95% CI)1.15 [0.70, 1.89]

    2.3 CERA every 2 weeks versus darbepoetin
1313Risk Ratio (IV, Random, 95% CI)0.93 [0.44, 1.97]

 3 Number of adverse events due to hypertension5Risk Ratio (IV, Random, 95% CI)Subtotals only

    3.1 CERA every 2 weeks versus rHuEPO
41341Risk Ratio (IV, Random, 95% CI)0.93 [0.69, 1.26]

    3.2 CERA every 4 weeks versus rHuEPO
2827Risk Ratio (IV, Random, 95% CI)1.00 [0.71, 1.40]

    3.3 CERA every 2 weeks versus darbepoetin
1309Risk Ratio (IV, Random, 95% CI)0.91 [0.43, 1.92]

 4 Transfusions52481Risk Ratio (IV, Random, 95% CI)0.93 [0.72, 1.20]

    4.1 CERA every 2 weeks versus rHuEPO
41341Risk Ratio (IV, Random, 95% CI)0.92 [0.64, 1.32]

    4.2 CERA every 4 weeks versus rHuEPO
2827Risk Ratio (IV, Random, 95% CI)1.01 [0.65, 1.57]

    4.3 CERA every 2 weeks versus darbepoetin
1313Risk Ratio (IV, Random, 95% CI)0.79 [0.42, 1.51]

 5 Number of adverse events due to access thrombosis52477Risk Ratio (IV, Random, 95% CI)0.99 [0.69, 1.42]

    5.1 CERA every 2 weeks versus rHuEPO
41341Risk Ratio (IV, Random, 95% CI)0.96 [0.56, 1.65]

    5.2 CERA every 4 weeks versus rHuEPO
2827Risk Ratio (IV, Random, 95% CI)1.16 [0.53, 2.54]

    5.3 CERA every 2 weeks versus darbepoetin
1309Risk Ratio (IV, Random, 95% CI)0.51 [0.05, 5.56]

 
Comparison 2. CERA frequencies

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Final haemoglobin2675Mean Difference (IV, Random, 95% CI)-0.11 [-0.35, 0.14]

 2 All-cause mortality2822Risk Ratio (M-H, Random, 95% CI)1.03 [0.60, 1.78]

 3 Number of adverse effects due to hypertension2822Risk Ratio (M-H, Random, 95% CI)1.18 [0.83, 1.67]

 4 Transfusion2822Risk Ratio (M-H, Random, 95% CI)1.11 [0.52, 2.37]

 5 Number of adverse events due to access thrombosis2822Risk Ratio (M-H, Random, 95% CI)0.96 [0.64, 1.43]

 
Comparison 3. Darbepoetin every 2 weeks versus once/week

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Final/change in Hb2252Mean Difference (IV, Random, 95% CI)0.04 [-0.45, 0.52]

 2 Final ESA/change in dose2252Mean Difference (IV, Random, 95% CI)-8.03 [-21.64, 5.59]

 3 All-cause-mortality1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 4 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    4.1 Total treatment-related adverse events
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.2 Transfusions
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 4. Darbepoetin every 2 weeks versus once/month

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Final/change in HB1Mean Difference (IV, Random, 95% CI)Totals not selected

 2 Adverse events1Risk Ratio (M-H, Random, 95% CI)Totals not selected

    2.1 Transfusions
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 5. Darbepoetin versus rHuEPO

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Final/change in Hb61245Mean Difference (IV, Random, 95% CI)0.02 [-0.09, 0.12]

 2 Final/change in ESA dose3757Mean Difference (IV, Random, 95% CI)-12.27 [-21.72, -2.82]

 3 All-cause mortality51596Risk Ratio (M-H, Random, 95% CI)1.29 [0.82, 2.02]

 4 Hypertension41475Risk Difference (M-H, Random, 95% CI)-0.01 [-0.06, 0.05]

 5 Transfusion31069Risk Difference (M-H, Random, 95% CI)-0.02 [-0.05, -7.42]

 6 Total treatment-related adverse events3570Risk Difference (M-H, Random, 95% CI)0.01 [-0.03, 0.05]

 7 Access thrombosis/vascular complication41475Risk Difference (M-H, Random, 95% CI)-0.01 [-0.03, 0.00]

 
Comparison 6. rHuEPO once/week versus 2 to 3 times/week

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Final/change in Hb or HCT7363Std. Mean Difference (IV, Random, 95% CI)-0.17 [-0.39, 0.05]

 2 Final/change in EPO dose5217Mean Difference (IV, Random, 95% CI)8.47 [-1.01, 17.95]

 3 Adverse effects5Risk Difference (IV, Random, 95% CI)Subtotals only

    3.1 Hypertension
4175Risk Difference (IV, Random, 95% CI)-0.00 [-0.12, 0.11]

    3.2 Transfusions
1173Risk Difference (IV, Random, 95% CI)-0.02 [-0.10, 0.06]

    3.3 Access problems
1173Risk Difference (IV, Random, 95% CI)-0.01 [-0.06, 0.04]

 
Comparison 7. rHuEPO once/week versus every 2 weeks

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Final/change in Hb1Mean Difference (IV, Random, 95% CI)Totals not selected

 2 Final rHuEPO dose1Mean Difference (IV, Random, 95% CI)Totals not selected

 3 Systolic blood pressure1Mean Difference (IV, Random, 95% CI)Totals not selected

 4 Diastolic blood pressure1Mean Difference (IV, Random, 95% CI)Totals not selected

 
Comparison 8. rHuEPO daily versus weekly

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Final Hb1Mean Difference (IV, Random, 95% CI)Totals not selected

 2 Final/change in EPO dose1Mean Difference (IV, Random, 95% CI)Totals not selected

 
Summary of findings for the main comparison. CERA versus other ESA for the anaemia of end-stage kidney disease in dialysis patients

CERA versus other ESA for the anaemia of end-stage kidney disease in dialysis patients

Patient or population: patients with the anaemia of end-stage kidney disease undergoing dialysis
Settings: tertiary centres
Intervention: CERA versus other ESA

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlCERAversus other ESA

Final Hb g/dL: CERA every 2 weeks versus rHuEPOMean final Hb g/dL: CERA every 2 weeks versus rHuEPO in the intervention groups was 0.08 higher (0.04 lower to 0.21 higher)1126 (4)⊕⊕⊕⊕
high

Final Hb g/dL: CERA every 4 week versus rHuEPOMean final Hb g/dL: CERA every 4 weeks versus rHuEPO in the intervention groups was 0.03 lower (0.17 lower to 0.12 higher)672 (2)⊕⊕⊕⊕
high

Final Hb g/dL: CERA every 2 week versus darbepoetinMean final Hb g/dL: CERA every 2 weeks versus darbepoetin in the intervention groups was 0.3 higher (0.05 to 0.55 higher)249 (1)⊕⊕⊕⊝
moderate¹

All-cause mortality: CERA every 2 weeks versus rHuEPOStudy populationRR 1.03
(0.67 to 1.57)
1341 (4)⊕⊕⊕⊝
moderate²

62 per 100064 per 1000 (41 to 97)

Moderate

61 per 100063 per 1000 (41 to 96)

Transfusions: CERA every 2 weeks versus rHuEPOStudy populationRR 0.92
(0.64 to 1.32)
1341 (4)⊕⊕⊕⊝
moderate²

90 per 100083 per 1000 (58 to 119)

Moderate

88 per 100081 per 1000 (56 to 116)

Numbers of adverse events due to hypertension: CERA every 2 weeks versus rHuEPOStudy populationRR 0.93
(0.69 to 1.26)
1341 (4)⊕⊕⊕⊕
high

151 per 1000140 per 1000 (104 to 190)

Moderate

149 per 1000139 per 1000 (103 to 188)

Numbers of adverse events due to access thrombosis: CERA every 2 weeks versus rHuEPOStudy populationRR 0.96
(0.56 to 1.65)
1341 (4)⊕⊕⊕⊝
moderate³

92 per 100088 per 1000 (52 to 152)

Moderate

85 per 100082 per 1000 (48 to 140)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

 ¹ One study, 249 participants
² Small numbers of events
³ Heterogeneity among studies
 
Summary of findings 2. Different frequencies of CERA for the anaemia of end-stage kidney disease in dialysis patients

Different frequencies of CERA for the anaemia of end-stage kidney disease in dialysis patients

Patient or population: patients with the anaemia of end-stage kidney disease undergoing dialysis
Settings: tertiary
Intervention: different frequencies of CERA

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlDifferent frequencies of CERA

Final Hb (g/dL)Mean final Hb in the intervention groups was
0.11 lower (0.35 lower to 0.14 higher)
675 (2)⊕⊕⊕⊝
moderate¹

All-cause mortalityStudy populationRR 1.03
(0.6 to 1.78)
822 (2)⊕⊕⊕⊕
high

78 per 100080 per 1000 (47 to 139)

Moderate

77 per 100079 per 1000 (46 to 137)

TransfusionStudy populationRR 1.11
(0.52 to 2.37)
822 (2)⊕⊕⊕⊝
moderate¹

80 per 100089 per 1000 (42 to 190)

Moderate

79 per 100088 per 1000 (41 to 187)

Numbers of adverse effects due to hypertensionStudy populationRR 1.18
(0.83 to 1.67)
822 (2)⊕⊕⊕⊕
high

122 per 1000144 per 1000 (101 to 203)

Moderate

123 per 1000145 per 1000 (102 to 205)

Numbers of adverse events due to access thrombosisStudy populationRR 0.96
(0.64 to 1.43)
822 (2)⊕⊕⊕⊕
high

105 per 1000100 per 1000 (67 to 150)

Moderate

104 per 1000100 per 1000 (67 to 149)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

 ¹ Heterogeneity among studies
 
Summary of findings 3. Darbepoetin versus rHuEPO for the anaemia of end-stage kidney disease in dialysis patients

Darbepoetin versus rHuEPO for the anaemia of end-stage kidney disease in dialysis patients

Patient or population: patients with the anaemia of end-stage kidney disease in dialysis patients
Settings: tertiary
Intervention: darbepoetin versus rHuEPO

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlDarbepoetin versusrHuEPO

Final/change in Hb (g/dL)Mean final/change in Hb in the intervention groups was 0.02 higher (0.09 lower to 0.12 higher)1245 (6)⊕⊕⊕⊝
moderate¹

Final/change in ESA doseMean final/change in ESA dose in the intervention groups was 12.27 lower (21.72 to 2.82 lower)757 (3)⊕⊕⊝⊝
low¹,²

All-cause mortalityStudy populationRR 1.29
(0.82 to 2.02)
1596 (5)⊕⊕⊕⊝
moderate¹

55 per 100071 per 1000 (45 to 112)

Moderate

64 per 100083 per 1000 (52 to 129)

Total treatment-related adverse eventsStudy populationSee comment570 (3)Risks were calculated from pooled risk differences

84 per 100091 per 1000 (54 to 134)

Moderate

17 per 100018 per 1000 (11 to 27)

HypertensionStudy populationSee comment1475 (4)⊕⊕⊝⊝
low¹,²
Risks were calculated from pooled risk differences

144 per 1000137 per 1000 (84 to 194)

Moderate

70 per 100067 per 1000 (41 to 95)

Access thrombosis/vascular complicationStudy populationSee comment1475 (4)⊕⊕⊕⊝
moderate¹
Risks were calculated from pooled risk differences

95 per 100081 per 1000 (65 to 95)

Moderate

29 per 100025 per 1000 (20 to 29)

TransfusionStudy populationSee comment1069 (3)⊕⊕⊕⊝
moderate¹
Risks were calculated from pooled risk differences

53 per 100029 per 1000 (3 to 53)

Moderate

50 per 100028 per 1000 (3 to 50)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

 ¹ High risk of bias for several domains in each study
² Significant heterogeneity between studies
 
Summary of findings 4. rHuEPO once/week versus rHuEPO 2 to 3 times/week for the anaemia of end-stage kidney disease in dialysis patients

rHuEPO once/week versus with rHuEPO 2 to 3 times/week for the anaemia of end-stage kidney disease in dialysis patients

Patient or population: patients with the anaemia of end-stage kidney disease undergoing dialysis
Settings: tertiary
Intervention: rHuEPO once/week
Comparison: rHuEPO 2 to 3 times/week

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

RHuEPO 2 to 3 times/weekRHuEPO once/week

Final/change in HbMean final/change in Hb in the intervention groups was 0.17 SD lower (0.39 lower to 0.05 higher)363 (7)⊕⊕⊝⊝
low¹,²
SMD -0.17 (-0.39 to 0.05)

Final/change in EPO doseMean final/change in EPO dose in the intervention groups was 8.47 higher
(1.01 lower to 17.95 higher)
217 (5)⊕⊕⊝⊝
low¹

Adverse effects: transfusionsStudy populationSee comment173 (1)See commentRisks were calculated from pooled risk differences

90 per 100071 per 1000 (-10 to 150)

Moderate

90 per 100071 per 1000 (-10 to 150)

Adverse effects: hypertensionStudy populationSee comment175 (4)⊕⊕⊝⊝
low¹
Risks were calculated from pooled risk differences

265 per 1000260 per 1000 (146 to 374)

Moderate

240 per 1000235 per 1000 (132 to 338)

Adverse effects: access problemsStudy populationSee comment173 (1)See commentRisks were calculated from pooled risk differences

34 per 100024 per 1000 (-26 to 74)

Moderate

34 per 100024 per 1000 (-27 to 74)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

 ¹ Significant risk of bias in several domains in all studies
² Small patient numbers