Recombinant human erythropoietin versus placebo or no treatment for the anaemia of chronic kidney disease in people not requiring dialysis

June D Cody; Elisabeth M Hodson

doi:10.1002/14651858.CD003266.pub3

Rekombinantes humanes Erythropoietin versus Placebo oder keiner Behandlung für Blutarmut bei Personen mit chronischer Nierenerkrankung, die keine Dialyse benötigen

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Referencias

References to studies included in this review

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estudios excluidos
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otras versiones publicadas

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References to other published versions of this review

Ir a:

estudios incluidos
estudios excluidos
otras referencias

Cody J, Daly C, Campbell M, Donaldson C, Grant A, Khan I, et al. Recombinant human erythropoietin for chronic renal failure anaemia in pre‐dialysis patients. Cochrane Database of Systematic Reviews 2001, Issue 4. [DOI: 10.1002/14651858.CD003266]

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos

Abraham 1990

Methods	Study design: parallel RCT with short‐ and long‐term phases Duration of study: 8 to 12 weeks until HCT reached goal of 40% for males and 37% for females
Participants	Country: USA Setting: single centre Clinically stable for at least 1 month prior to therapy (BP, physical examination, chemistry profile, electrocardiogram, chest X‐ray, diet and medications) Kidney function: SCr > 3.0 mg/dL Anaemia: HCT < 36% Number: treatment group (4); control group (4) Mean age: 47 years Sex (M/F): treatment group (2/2); control group (3/1) Exclusion criteria: anaemia other than renal anaemia; concomitant therapy with androgen; immunosuppressant or corticosteroid therapy within 2 months; other conditions which might interfere with or complicate EPO therapy including active hepatitis; asthma or severe allergic diathesis; active ischaemic heart disease; SLE; chronic inflammatory diseases; acute rheumatoid arthritis; severe or uncontrolled hypertension (supine diastolic BP > 110 mm Hg); thrombocytopenia (< 100,000/mm³); neutropenia (< 2000/mm³); drug abuse; history of seizures; malignancy; pregnancy
Interventions	Treatment group Type of EPO: erythropoietin alfa Route of administration: IV or SC Dose: 50 to 150 units/kg 3 times/week Control group Placebo Route of administration: IV or SC Dose: not described Co‐interventions (both groups) Iron administered: If serum iron < 50 µg/dL or Fe/TIBC < 20% ferrous sulphate Folate administered: daily 1 mg Duration of study: 8 to 12 weeks until goal HCT of 40% (males) or 37% (females)
Outcomes	HCT SCr Number with an increase or introduction of antihypertensive treatment
Notes	Formed part of multicentre study (Teehan 1991) Conducted in USA Funded by Ortho Pharmaceuticals
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Unclear, reported to be randomised however method not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Unclear, states "double‐blind placebo‐controlled..."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients completed the first phase of the study
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	High risk	"Financial support and erythropoietin was provided by Ortho Pharmaceutical Corporation, Raritan, N.J., USA"

Akizawa 1993

Methods	Study design: unclear Duration of study: 12 weeks
Participants	Country: Japan Setting: not reported Participants with CKD not on dialysis Kidney function: SCr 5.7 ± 1.2 mg/dL Anaemia: not reported Number: 107 (did not specify how many were in each group) Age: not reported Sex (M/F): not reported
Interventions	Treatment group Type of EPO: not reported Route of administration: SC Dose: 6000 IU/week for 12 weeks Control group Placebo
Outcomes	GFR HCT
Notes	Abstract only Funding: not reported

Brown 1995

Methods	Study design: parallel RCT Duration of study: 1 year
Participants	Country: USA Setting: single centre Anaemic diabetic predialysis patients Kidney function: SCr 221 to 442 µmol/L Anaemia: HCT < 30% Number: treatment group (8); control group (9) Age: not reported Sex (M/F): not reported Exclusion criteria: not mentioned
Interventions	Treatment group Type of EPO: erythropoietin alfa Route of administration: SC Dose: 50 U/kg 3 times/week Control group Usual care: not reported Duration of study: 1 year
Outcomes	HCT SCr
Notes	Abstract only Funding: not reported

Clyne 1992

Methods	Study design: parallel RCT Duration of study: 12 weeks
Participants	Country: Sweden Setting: Karolinska Hospital and Danderyd Hospitals CKD patients Kidney function: eGFR < 25 mL/min/1.73 m² Anaemia: HCT ≤ 28% Number: treatment group (12); control group (10) Mean age ± SD (years): treatment group (46 ± 12), control group (53 ± 15) Sex (M/F): treatment group (6/6), control group (5/3) Exclusion criteria: RRT; diabetes; angina or prior acute myocardial infarction; platelet count of > 500 x 10⁹/L; epilepsy; treatment with cytotoxic agents; hormone preparations or immunosuppressants; poorly controlled hypertension; and deficiency of folic acid or vitamin B₁₂
Interventions	Treatment group Type of EPO: Epoetin beta Starting at 300 U/kg/week IV to achieve HCT > 30% for 3 months Control group No treatment for 3 months Iron supplementation Oral or IV Duration of treatment: 12 weeks
Outcomes	Number starting RRT during study period Change in QoL Hb GFR Systolic BP Number with an increase or introduction of antihypertensive treatment
Notes	Funding: unable to determine
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	"Open randomised parallel‐group study"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	High risk	Attrition was 1/12 (8%) in the epoetin beta arm and 2/10 (20%) in the control arm. As this was > 10% overall this was judged to be high risk
Selective reporting (reporting bias)	High risk	Major cardiovascular outcomes were not available
Other bias	Unclear risk	Unable to determine

Eschbach 1989

Methods	Study design: parallel RCT, short‐term phase followed by open‐label maintenance phase Duration of study: April 1987 to August 1988
Participants	Country: USA Setting: single centre CKD patients Kidney function: SCr 353 to 972 µmol/L Anaemia: HCT < 30% Number: treatment group (11); control group (6) Age range: 24 to 72 years Sex (M/F): 10/7 Exclusion criteria: inflammatory disease; immunosuppressive therapy
Interventions	Treatment group Type of EPO: erythropoietin alfa Route of administration: IV and SC Dose: 50, 100 or 150 U/kg 3 times/week Duration of study IV: 8 weeks or until target HCT reached SC: 12 weeks or until target HCT reached Control group Placebo, IV or SC 3 times/week
Outcomes	SCr HCT
Notes	Formed part of multicentre study (Teehan 1991) Funding: part funded by Ortho Pharmaceuticals
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Patients and physicians blinded were blinded to the identify of the study medication but not the dose
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients completed the short phase study
Selective reporting (reporting bias)	Low risk	All relevant outcomes reported
Other bias	High risk	Portions of this study were funded by research grants from National Institutes of Health and Ortho Pharmaceutical Corporation.

Ganguli 2003

Methods	Study design: parallel 3‐arm RCT Duration of study: 6 months
Participants	Country: India Setting: single centre Anaemic non diabetic predialysis patients Kidney function: SCr 3.42 ± 0.27 mg Anaemia: Hb 7.83 ± 24 g/dL Number: treatment group 1 (12); treatment group 2 (12); control group (12) Age range: 18 to 75 years Sex (M/F): treatment group 1 (6/6); treatment group 2 (6/6); control group (6/6) Exclusion criteria: diabetics
Interventions	Treatment group 1 Type of EPO: not reported Route of administration: SC Dose: 100 U/kg 2 divided doses a week Treatment group 2 Nandrolone 200 mg IM Control group Placebo, route and dose not reported Duration of study: 6 months
Outcomes	Anthropometric measurements Haematological parameters Serum albumin SCr Treadmill tests Work capacity QoL Progression of kidney disease
Notes	Abstracts only Treatment group 2 not included in the meta‐analyses Study could not be included in the meta‐analyses Funding: not reported

Kim 2006e

Methods	Study design: parallel RCT Duration of study: said to continue for 21 months
Participants	Country: Korea Setting: multicentre Patients with CKD not on dialysis Kidney function: SCr 1.5 to 4 mg/dL Anaemia: Hb < 10 g/dL Number: treatment group (60); control group (43) Age: not reported (reported no statistical difference between the 2 groups) Sex: not reported (reported no statistical difference between the 2 groups) Exclusion criteria: not reported
Interventions	Treatment group EPO (no dose provided) SC for 3 months of stabilisation to Hb 10 g/L Control group Placebo SC injections for 3 months Study said to continue for further 21 months but unclear whether all patients received EPO after 3 months
Outcomes	Composite of doubling of SCr Initiation of dialysis Death
Notes	Abstract only Funding: not reported

Kleinman 1989

Methods	Study design: parallel RCT Duration of study: 12 weeks or until reaching a HCT 38% to 40%
Participants	Country: USA Setting: single centre Inclusion criteria: stable laboratory parameters; adequate serum folate and B₁₂ levels and iron stores, as reflected by serum iron; total iron binding capacity and ferritin; ensured that anaemia was not caused by a vitamin or elemental iron deficiency; no evidence of chronic gastrointestinal blood loss Kidney function: SCr 265 to 972 µmol/L Anaemia: HCT < 30% Number: treatment group (7); control group (7) Age range: 38 to 73 years Sex M/F: treatment group (5/2); control group (4/3) Exclusion criteria: marked obesity or inanition; active hepatitis or hepatic disease; asthma; severe atopic illness; significant cardiovascular, pulmonary, malignant, or haematologic diseases; severe or uncontrolled hypertensive disease; neurological disease or history of seizure activity; presence of gross haematuria, sickle cell anaemia, untreated ischaemic heart disease of 3 months duration or presence of clinically significant gastrointestinal disease; systemic diseases such as lupus erythematosus, rheumatoid arthritis or other inflammatory diseases or infectious states that might interfere with the effects of EPO; thrombocytopenia or leukopenia; alcohol or drug abuse; acute illness within 7 days of initiation of the screening period; androgen therapy for chronic anaemia corticosteroid and other immunosuppressive medications were discontinued 2 and 1 months respectively before study entry
Interventions	Treatment group Type of EPO: erythropoietin alfa Dose: 100 U/kg 3 times/week Route of administration: SC Control group Placebo: Route of administration: SC Dose: 3 times/week Iron administered All received oral iron Duration of study: 12 weeks or until HCT of 38% or 40%
Outcomes	Change in quality of life measures Discontinued due to adverse events Increase or introduction of antihypertensive treatment Need for blood transfusions
Notes	Funding: EPO prepared by recombinant DNA technology (Amgen Corporation) "After the 12‐week control period, the seven placebo patients received r‐HuEPO subcutaneously at a dose of 150 U/kg until the target hematocrit of 38% to 40% was reached. The difference in dosages between the two groups was determined by the Ortho Pharmaceutical Corporation before the study"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo controlled
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	1 patient withdrew from EPO group
Selective reporting (reporting bias)	Unclear risk	Unable to determine
Other bias	High risk	Ortho Pharmaceutical Corporation was an author on the paper

Kristal 2008

Methods	Study design: quasi‐RCT Duration of study: 20 weeks; 2000 to 2001
Participants	Country: Israel Setting: unclear Patients with CKD stages 4‐5 not on dialysis or EPO Kidney function: not reported Anaemia: Hb 8.1 to 11 g/dL Number: treatment group (20); control group (20) Mean age ± SEM (years): treatment group (70.2 ± 2.0); control group (67.2 ± 2.7) Sex (M/F): treatment group (4/16); control group (6/14) Exclusion criteria: not reported
Interventions	Treatment group Type of EPO: Eprex Dose: 6000 IU/week Route of administration: SC Control group No treatment All patients received oral maintenance iron supplementation, calcium bicarbonate, statins, beta‐blockers, and calcium channel blockers
Outcomes	SCr Calculated GFR Hb
Notes	Primary outcomes of study related to non‐erythropoietic actions of EPO Funding: "This work was partially supported by a grant from by the R.W. Johnson Pharmaceutical Research Institute, a division of Ortho‐McNeil Pharmaceutical, Inc."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	High risk	Patients allocated in order according to visit to clinic (information from authors)
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding; open label
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Relevant outcomes were laboratory based and unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	12/40 (30%) did not complete study (3/20 in treatment group and 9/20 in control group)
Selective reporting (reporting bias)	High risk	No report of adverse effects
Other bias	Unclear risk	Unable to determine

Kuriyama 1997

Methods	Study design: parallel RCT Duration of study: commenced 1 January 1993
Participants	Country: Japan Setting: single centre Predialysis patients aged 30 and 75 years Kidney function: SCr 2 to 4 mg/dL Anaemia: HCT < 30% Number: treatment group (43; control group (31) Mean age ± SD (years): treatment group (63.8 ± 10.6); control group (59.2 ± 13.4) Sex (males): treatment group (55%); control group (52%) Exclusion criteria: iron deficiency anaemia; transfusion dependency; presence of any other systemic disease; any inflammatory condition or infection that might interfere with the effect of EPO
Interventions	Treatment group Type of EPO: not reported Dose: 6,000 IU once a week varied to achieve target HCT of 33% to 35% Route of administration: IV Control group No treatment Iron: at the investigators discretion Duration of study: 36 weeks
Outcomes	Patients whose creatinine doubled regarded as having reached kidney death Inability to attend regularly and death from non‐kidney disease Number commencing dialysis HCT
Notes	Funding: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	Control group received no treatment
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Unclear risk	Unable to determine
Other bias	Unclear risk	Unable to determine

Lim 1989

Methods	Study design: 4‐arm parallel RCT Duration of study: 8 weeks
Participants	Country: USA Setting: single centre Adults with renal insufficiency Kidney function: SCr 548.08 ± 70.72 µmol/L Anaemia: HCT 27% ± 1% Number: treatment group (11); control group (3) Age range: 30 to 70 years Sex M/F: 10/4 Exclusion criteria: active lupus; malignancy; haemolysis; bleeding; clinically unstable; taking steroid or immunosuppressive medication
Interventions	Treatment group Type of EPO: not reported Dose: 50, 100 and 150 U/kg 3 times/week Route of administration: IV Control group Placebo Route of administration: IV Iron administered: ferrous sulphate 300 mg orally 3 x day Folate administered: folic acid 1 mg orally daily Duration of study: 8 weeks
Outcomes	Change in quality of life measures Number discontinued due to adverse events Number with an increase or introduction of antihypertensive treatment Number who need blood transfusions Number experiencing seizures Exercise tolerance HCT levels
Notes	Formed part of multicentre study (Teehan 1991)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Third party
Allocation concealment (selection bias)	Low risk	Adequate, third party
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blind
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unable to determine
Selective reporting (reporting bias)	Unclear risk	Unable to determine
Other bias	Unclear risk	Unable to determine

Roth 1994

Methods	Study design: parallel RCT duration of study: 48 weeks
Participants	Country: USA Setting: 11 centres CKD patients aged 18 to 75 years; mean arterial pressure controllable below 114 mm Hg; not currently receiving HD treatment Kidney function: SCr 265.2 to 707.2 µmol/L Anaemia: HCT < 30% Number: treatment group (43); control group (40) Mean age ± SE (years): treatment group (56.5 ± 11.4); control group (58.4 ± 13.2) Sex (females): treatment group (65%); control group (70%) Exclusion criteria: proteinuria > 5g/d; iron deficiency anaemia; transfusion dependency; presence of any other systemic disease, inflammatory condition, infection that might interfere with effects of EPO
Interventions	Treatment group Type of EPO: not reported Dose: 50 U/kg 3 times/week which could be increased 75 U/kg/week on a monthly basis to a maximum of 450 U/kg/week Route of administration: SC; could self‐administer after 1st month Control group No treatment Iron administered: investigators discretion Folate administered: no Duration of study: 48 weeks
Outcomes	Number of starting RRT during study period Number discontinued due to adverse events GFR Decrease in GFR Increase in SCr level Number with an increase or introduction of antihypertensive treatment Number who need blood transfusions Mortality
Notes	Funding: "Supported by a grant from the R. W. Johnson Pharmaceutical Research Institute and Ortho Biotech Inc. Raritan. NJ."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open label
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Nor reported
Incomplete outcome data (attrition bias) All outcomes	High risk	23/43 in the EPO group and 25/40 in the control group did not complete the study
Selective reporting (reporting bias)	Unclear risk	Unable to determine
Other bias	High risk	Funded by Ortho Biotech

Stone 1988

Methods	Study design: parallel 4‐arm RCT Duration of study: 8 weeks
Participants	Country: USA Setting: multicentre Patients with chronic renal insufficiency Kidney function: CrCl 0.17 to 0.51 mL/s (10 to 30 mL/min) Anaemia: PCV < 41% males; 35% females Number: treatment group (9); control group (3) Mean age (range): 62 years (45 to 73 years) Sex M/F: 11/1 Exclusion criteria: severe allergic disorders; asthma; active hepatitis; history of seizures; malignancy; uncontrolled hypertension; ischaemic heart disease; neutropenia; iron deficiency; haemolytic anaemia; thrombocytopenia
Interventions	Treatment group Type of EPO: erythropoietin alfa Dose: 50, 100 or 150 U/kg 3 times/week Route of administration: IV Administered by: 1st and last dose in hospital all others in outpatient clinic Control group Placebo 3 times/week Route of administration: IV Administered by: 1st and last dose in hospital all others in outpatient clinic Iron administered: ferrous sulphate 300 mg 3 times/day Folate administered: 1 mg daily Duration of study: 8 weeks
Outcomes	Number progressing to dialysis Number with increase or introduction of antihypertensives Mortality
Notes	Formed part of multicentre study (Teehan 1991) Funded in part by a grant from Ortho Pharmaceutical Corporation
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blind, placebo controlled
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unable to determine
Selective reporting (reporting bias)	Unclear risk	Unable to determine
Other bias	High risk	Funded by Ortho Pharmaceutical

Teehan 1989

Methods	Study duration: parallel RCT Study duration: 3 months
Participants	Country: USA Setting: single centre Predialysis CKD patients Kidney function: mean SCr 5.1 ± 2.4 mg/dL Anaemia: mean HCT 25.2% ± 3.5% Number: treatment group (6); control group (6) Age: not reported Sex M/F: 6/6 Exclusion criteria: patients with gastrointestinal bleeding; acute or chronic infection; sickle‐cell anaemia; collagen vascular disease; known seizure disorder; drug or alcohol abuse; recent myocardial infarction; pregnancy; deficiencies of iron folic acid, or vitamin B₁₂
Interventions	Treatment group Type of EPO: not reported Dose: 100 U/kg 3 times/week Route of administration: SC Control group Placebo 3 times/week SC
Outcomes	Haematology
Notes	It was assumed that this study included a different set of patients from the multicentre study (Teehan 1991) since the methods were different i.e. different dosing regimen, different route of administration, different outcome measures and different study duration Funding: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo controlled
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not reported
Selective reporting (reporting bias)	High risk	Data for cardiovascular outcomes not available
Other bias	Unclear risk	Unable to determine

Teehan 1991

Methods	Study design: parallel 4‐arm study Duration of study: 8 weeks
Participants	Country: USA Setting: multicentre (15 centres) Anaemic predialysis patients Kidney function: SCr 260 to 880 µmol/L Anaemia: HCT < 38% male; < 32% women Number: treatment group (88); control group (29) Mean age (range): 57.1 years (24 to 79 years) Sex M/F: 71/46 Exclusion criteria: significant clinical conditions affecting the hepatic; cardiovascular hematologic (other than anaemia); neurologic; or pulmonary systems
Interventions	Treatment group Type of EPO: not reported Dose: 50, 100 or 150 u/kg 3 times/week Route of administration: IV Control group Placebo, 3 times/week IV Folate administered: yes Duration of study: 8 weeks or until HCT reached 40% for men or 37% for women
Outcomes	Number discontinued due to adverse events Number with an increase or introduction of antihypertensive treatment Number experiencing seizures HCT
Notes	Multicentre study including patients from Abraham 1990; Eschbach 1989; Lim 1989; Stone 1988 Funded in part by a grant from Ortho Pharmaceutical Corporation
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blind
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	106/117 completed the study
Selective reporting (reporting bias)	Unclear risk	Unable to determine
Other bias	High risk	Part funded by Ortho Pharmaceuticals

Teplan 2001b

Methods	Study design: parallel 3‐arm RCT Duration of study: 3 years
Participants	Country: Czech Republic Setting: single centre Predialysis CKD patients with good compliance to diet Kidney function: 22 to 36 mL/min/1.73m² Anaemia: Hb < 11.5 g/dL, HCT < 32% Number: treatment group 1 (35); treatment group 2 (38), control group (32) Age range: 26 to 78 years Sex M/F: 50/55 Exclusion criteria: not reported
Interventions	Treatment group 1 EPO + low protein diet + keto acids Type of EPO: not reported Dose: 40 U/kg/week Route of administration: unclear Treatment group 2 EPO + low protein diet Type of EPO: not reported Dose: 40 U/kg/week Route of administration: unclear Control group Low protein diet Duration of study: 3 years
Outcomes	GFR (CrCl and inulin clearance) Serum branched chain amino acids Albumin Transferrin BMI HDL cholesterol Proteinuria Serum triglycerides Serum fractional leucine excretion
Notes	Abstract only Funding: not reported

Teplan 2003

Methods	Study design: parallel 3‐arm RCT Duration of study: 36 months
Participants	Country: Czech Republic Setting: multicentre study Patients with good compliance to diet preceding entry to study Kidney function: CrCl (29.4 ± 8.2 mL/min); SCr (2.79 ± 0.97 mg/dL) Anaemia: Hb < 10.5 g/dL Number: treatment group 1 (63); treatment group 2 (61); control group (62) Mean age ± SD: 52 ± 8 years Sex M/F: treatment group 1 (31/32); treatment group 2 (29/32); control group (30/32) Exclusion criteria: diabetic kidney disease; polycystic kidney disease
Interventions	Treatment group 1 EPO + low protein diet + keto acids EPO: epoetin alfa and epoetin beta Dose: 40 U/kg twice a week Route of administration: SC Keto acids: 100 mg/kg/d Treatment group 2 EPO + low protein diet Control group Low protein diet: 0.6 g protein/kg/d Duration of study: 36 months
Outcomes	CrCl Inulin clearance SCr Serum urea Serum leucine Serum albumin Proteinuria Serum cholesterol Serum LDL cholesterol Serum triglyceride Serum HDL cholesterol Hb BP
Notes	Author confirmed sealed envelopes were used for allocation concealment Funding: "Supported by grant no. 305/01/0578 from the Grant Agency of the Czech Republic."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Low risk	Adequate; sealed envelopes
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open label
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Unclear risk	Only biochemical parameters reported
Other bias	Unclear risk	Unable to determine

Wang 2004b

Methods	Study design: parallel RCT Duration of study: 48 weeks
Participants	Country: Hong Kong Setting: single centre Patients with CKD not on dialysis Kidney function: SCr 150 to 750 µmol/L Anaemia: Hb < 11 g/dL Number: treatment group (32); control group (34) Age: not reported Sex (M/F): not reported Exclusion criteria: not reported
Interventions	Treatment group EPO 4000 IU weekly SC. Dose titrated to achieve and maintain Hb 12 to 14 g/dL Control group No treatment
Outcomes	GFR Hb
Notes	Abstract only Other outcomes were surrogate markers for vascular function Funding: not reported

Watson 1990

Methods	Study design: parallel RCT Duration of study: 12 weeks
Participants	Country: USA Setting: single centre Patients with pre‐existing CKD Kidney function: not reported Anaemia: not reported Number: treatment group (5); control group (6) Age range: 43 to 79 years Sex M/F: 6/5 Exclusion criteria:
Interventions	Treatment group Type of EPO: not reported Route of administration: SC Dose: 100 U/kg 3 times/week Control group Placebo Duration of study: 12 weeks or until target HCT of 38% is achieved
Outcomes	HCT Number discontinued due to adverse events GFR SCr Number experiencing seizures
Notes	Funding: "supported in part by Orth Pharmaceuticals Inc. and by grants DK 32008 and CRC 5‐M01RR00722 from the National Institutes of Health"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Performed by a third party
Allocation concealment (selection bias)	Low risk	Performed by a third party
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Stated double blind; placebo used
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Unclear risk	Unable to determine
Other bias	High risk	Funded by Ortho Pharmaceuticals

BP ‐ blood pressure; CKD ‐ chronic kidney disease; CrCl ‐ creatinine clearance; EPO ‐ erythropoietin; GFR ‐ glomerular filtration rate; Hb ‐ haemoglobin; HCT ‐ haematocrit; HDL ‐ high‐density lipoprotein; IV ‐ intravenous; LDL ‐ low‐density lipoprotein; M/F ‐ male/female; PCV ‐ packed cell volume; QoL ‐ quality of life; RCT ‐ randomised control trial; RRT ‐ renal replacement therapy; SC ‐ subcutaneous; SCr ‐ serum creatinine; SD ‐ standard deviation; SE ‐ standard error

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Brown 1988	All patients received EPO
CREATE Study 2001	Comparing the same ESA derivative in different treatment arms
EPOCARES Study 2010	Ineligible population
Frenken 1989	All patients received EPO
Frenken 1992	All patients received EPO
Furukawa 1992	All patients received EPO
Jabs 1994	Not randomised
Koene 1990	All patients received EPO
Macdougall 2007	Compares early with late commencement of EPO
Marcas 2003	All patients received EPO
Meloni 2003	Unclear how patients allocated to groups. Written to authors for clarification
Mignon 2001	All patients received EPO
Muirhead 1992	Haemodialysis patients
N0287023177	All patients received EPO
Palazzuoli 2007	Ineligible population. Cardiac failure patients
Pratt 2006	Compares EPO delta with EPO alpha
Schwartz 1989	Data only from EPO treated patients
Singh 1999	Randomised study. Not all participants were predialysis some had commenced dialysis
Teehan 1990	Unclear if randomised. Wrote to authors all patients received EPO
Yamazaki 1993	All patients received EPO
Zheng 1992	All patients received EPO

EPO ‐ erythropoietin

Data and analyses

Open in table viewer

Comparison 1. rHuEPO versus placebo or no rHuEPO

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number starting RRT Show forest plot	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.1 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 1 Number starting RRT.
1.1 Starting RRT during the study period	5	207	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.43, 1.14]
1.2 Starting RRT in the follow‐up to the study	1	8	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.50, 17.95]
2 GFR Show forest plot	7	283	Mean Difference (IV, Random, 95% CI)	‐2.11 [‐3.08, ‐1.15]
Open in figure viewer Analysis 1.2 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 2 GFR.
3 Reduction in GFR Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.3 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 3 Reduction in GFR.
4 Serum creatinine Show forest plot	8	327	Mean Difference (IV, Random, 95% CI)	27.86 [‐32.04, 87.76]
Open in figure viewer Analysis 1.4 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 4 Serum creatinine.
5 Increase in serum creatinine Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.5 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 5 Increase in serum creatinine.
6 Haemoglobin Show forest plot	4	237	Mean Difference (IV, Random, 95% CI)	‐1.90 [‐2.34, ‐1.47]
Open in figure viewer Analysis 1.6 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 6 Haemoglobin.
7 Haematocrit Show forest plot	7	145	Mean Difference (IV, Random, 95% CI)	‐9.85 [‐11.34, ‐8.35]
Open in figure viewer Analysis 1.7 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 7 Haematocrit.
8 Number of patients transfused Show forest plot	3	111	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.12, 0.83]
Open in figure viewer Analysis 1.8 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 8 Number of patients transfused.
9 Quality of life measures Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.9 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 9 Quality of life measures.
10 Change in exercise capacity Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.10 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 10 Change in exercise capacity.
11 Systolic blood pressure Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.11 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 11 Systolic blood pressure.
12 Diastolic blood pressure Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.12 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 12 Diastolic blood pressure.
13 Number with an increase or introduction of antihypertensive treatment Show forest plot	4	232	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.76, 2.11]
Open in figure viewer Analysis 1.13 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 13 Number with an increase or introduction of antihypertensive treatment.
14 Number discontinued due to adverse events Show forest plot	4	223	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.28, 2.59]
Open in figure viewer Analysis 1.14 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 14 Number discontinued due to adverse events.
15 Seizures Show forest plot	3	140	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.02, 1.94]
Open in figure viewer Analysis 1.15 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 15 Seizures.
16 Mortality Show forest plot	4	182	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.13, 2.88]
Open in figure viewer Analysis 1.16 Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 16 Mortality.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
The empty rows relate to abstract‐only publications ‐ risk of bias could not be assessed

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Analysis 1.1

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 1 Number starting RRT.

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Analysis 1.2

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 2 GFR.

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Analysis 1.3

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 3 Reduction in GFR.

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Analysis 1.4

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 4 Serum creatinine.

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Analysis 1.5

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 5 Increase in serum creatinine.

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Analysis 1.6

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 6 Haemoglobin.

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Analysis 1.7

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 7 Haematocrit.

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Analysis 1.8

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 8 Number of patients transfused.

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Analysis 1.9

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 9 Quality of life measures.

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Analysis 1.10

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 10 Change in exercise capacity.

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Analysis 1.11

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 11 Systolic blood pressure.

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Analysis 1.12

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 12 Diastolic blood pressure.

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Analysis 1.13

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 13 Number with an increase or introduction of antihypertensive treatment.

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Analysis 1.14

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 14 Number discontinued due to adverse events.

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Analysis 1.15

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 15 Seizures.

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Analysis 1.16

Comparison 1 rHuEPO versus placebo or no rHuEPO, Outcome 16 Mortality.

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Comparison 1. rHuEPO versus placebo or no rHuEPO

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number starting RRT Show forest plot	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Starting RRT during the study period	5	207	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.43, 1.14]
1.2 Starting RRT in the follow‐up to the study	1	8	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.50, 17.95]
2 GFR Show forest plot	7	283	Mean Difference (IV, Random, 95% CI)	‐2.11 [‐3.08, ‐1.15]

3 Reduction in GFR Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

4 Serum creatinine Show forest plot	8	327	Mean Difference (IV, Random, 95% CI)	27.86 [‐32.04, 87.76]

5 Increase in serum creatinine Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

6 Haemoglobin Show forest plot	4	237	Mean Difference (IV, Random, 95% CI)	‐1.90 [‐2.34, ‐1.47]

7 Haematocrit Show forest plot	7	145	Mean Difference (IV, Random, 95% CI)	‐9.85 [‐11.34, ‐8.35]

8 Number of patients transfused Show forest plot	3	111	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.12, 0.83]

9 Quality of life measures Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

10 Change in exercise capacity Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

11 Systolic blood pressure Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

12 Diastolic blood pressure Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

13 Number with an increase or introduction of antihypertensive treatment Show forest plot	4	232	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.76, 2.11]

14 Number discontinued due to adverse events Show forest plot	4	223	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.28, 2.59]

15 Seizures Show forest plot	3	140	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.02, 1.94]

16 Mortality Show forest plot	4	182	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.13, 2.88]

Comparison 1. rHuEPO versus placebo or no rHuEPO

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Referencias

References to studies included in this review

Abraham 1990 {published data only}

Akizawa 1993 {published data only}

Brown 1995 {published data only}

Clyne 1992 {published data only}

Eschbach 1989 {published data only}

Ganguli 2003 {published data only}

Kim 2006e {published data only}

Kleinman 1989 {published data only}

Kristal 2008 {published data only}

Kuriyama 1997 {published data only}

Lim 1989 {published data only}

Roth 1994 {published data only}

Stone 1988 {published data only}

Teehan 1989 {published data only}

Teehan 1991 {published data only}

Teplan 2001b {published data only}

Teplan 2003 {published data only}

Wang 2004b {published data only}

Watson 1990 {published data only}

References to studies excluded from this review

Brown 1988 {published data only}

CREATE Study 2001 {published data only}

EPOCARES Study 2010 {published data only}

Frenken 1989 {published data only}

Frenken 1992 {published data only}

Furukawa 1992 {published data only}

Jabs 1994 {published data only}

Koene 1990 {published data only (unpublished sought but not used)}

Macdougall 2007 {published data only}

Marcas 2003 {published data only}

Meloni 2003 {published data only}

Mignon 2001 {published data only}

Muirhead 1992 {published data only}

N0287023177 {published data only}

Palazzuoli 2007 {published data only}

Pratt 2006 {published data only}

Schwartz 1989 {published data only}

Singh 1999 {published data only}

Teehan 1990 {published data only}

Yamazaki 1993 {published data only}

Zheng 1992 {published data only}

Additional references

Canadian EPO Study Group 1990

Garcia 1985

Harnett 1995

Higgins 2003

Higgins 2011

Jensen 1994

Koch 1991

Levin 1996

Lin 1985

Lundin 1989

Muirhead 1994

Palmer 2012

Palmer 2014

Sheingold 1990

Thompson 1994

Ward 1990

Winearls 1986

References to other published versions of this review

Cody 2001

Cody 2005

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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Instituciones a las que se accedió previamente

Usuarios institucionales

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