Types of studies

All RCTs and quasi‐RCTs (studies in which the allocation of treatment is not truly random, such as allocation by birth date, alternation, hospital number, or other predictable methods) of darbepoetin alpha alone or in combination with other non‐randomised co‐interventions (e.g. iron supplementation, or red cell transfusion) in individuals with anaemia and CKD (ESA‐naive patients and conversion from other ESAs) were included. The first period of randomised cross‐over studies was also considered. Studies were considered without language restriction. Studies were of at least three months in duration.

Types of participants

• Individuals with stage 3, 4, and 5 CKD (including patients on dialysis) as defined by the NKF‐KDOQI guidelines.

  • Stage 3: glomerular filtration rate (GFR) 30 to 59 mL/min/1.73 m²

  • Stage 4: GFR 16 to 29 mL/min/1.73 m²

  • Stage 5: GFR < 15 mL/min/1.73 m²

  • Stage 5D: GFR < 15 mL/min/1.73 m² (treated with dialysis)

• Kidney transplant recipients

• Adults and children

Types of interventions

Studies of darbepoetin alfa by any route (SC or IV) or dose, compared with epoetin alfa or beta, methoxy polyethylene glycol‐epoetin beta, placebo, or no treatment were included.

The following comparisons were considered for inclusion.

• Darbepoetin alfa versus placebo or no treatment

• Darbepoetin alfa versus epoetin alfa or beta

• Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta

• Darbepoetin alfa (IV versus SC)

• Darbepoetin alfa with different strategies of administration (e.g. using higher versus lower doses, targeting higher versus lower Hb levels) and different dosing regimens (frequent versus extended dosing regimens)

Types of outcome measures

• Achieving and maintaining Hb levels as recommended by the NKF‐KDOQI guidelines. The following parameters were analysed for each planned treatment comparison.

  • Number of individuals achieving the recommended Hb levels during the study period

  • Time to achieve a Hb concentration of 11 g/dL (days)

  • Mean change in Hb (mg/dL) and haematocrit (HCT) values (%) at the end of treatment period

  • Number of blood transfusions during the study period

  • Number of individuals requiring one or more red cell transfusions.

  • Number of individuals requiring iron supplementation during the study period

  • Number of patients who exceed a Hb concentration of 12 g/dL or more on one or more occasions during the study period

  • Number of patients who fall below or exceed the therapeutic Hb target range of the included studies (e.g. 11 to 12 g/dL)

• Progression of CKD in patients not yet requiring renal replacement therapy (RRT: haemodialysis, peritoneal dialysis or kidney transplantation).

  • End of treatment GFR (mL/min/1.73 m²)

  • Change in GFR (mL/min/1.73 m²) based on Modification of Diet in Renal Disease (MDRD) equation or other estimating equations (eGFR), as reported in the studies

  • Number of patients with doubling of serum creatinine or who develop CKD defined as GFR < 60 mL/min/1.73 m²

  • Progression of CKD to end‐stage kidney disease (ESKD) requiring RRT

• Clinical outcomes

  • Cardiovascular events: non‐fatal myocardial infarction; fatal or non‐fatal myocardial infarction; non‐fatal stroke; fatal or non‐fatal stroke; need for revascularization procedures (any vascular ‐ coronary artery, carotid artery, peripheral vascular)

  • Hospital admissions: number of individuals who are hospitalised one or more times/number of individuals at risk, or mean number of days of hospitalisation/number of days at risk

  • Cardiovascular mortality

  • All‐cause mortality

  • Vascular access thrombosis: number of individuals with one or more episodes of thrombosis; number of individuals with one or more episodes of requiring surgical intervention for vascular access (loss of unassisted patency)

  • Cancer: onset of new documented cancer, or as defined by the investigators

• Quality of life

  • End of treatment scores obtained using validated tools such as 36‐item Short Form General Health Survey questionnaire (SF‐36) and Kidney Disease Quality of Life (KDQOL) tool or others as mentioned in the studies. We will assess the studies for evidence of selective reporting of outcomes, reviewing study protocols where necessary. If studies report quality of life outcomes using heterogeneous outcomes, we will tabulate these outcomes when meta‐analysis is not possible.

• Adverse events

  • Seizures

  • Hyperkalaemia

  • Vascular access thrombosis

  • Hypertension (one or more hypertensive events requiring additional antihypertensive medication or as defined by the investigators; end of treatment blood pressure)

  • Injection site‐related events (e.g. lipodystrophy, burning sensation)

Electronic searches

We searched the Cochrane Renal Group's Specialised Register (up to 13 January 2014) through contact with the Trials' Search Co‐ordinator using search terms relevant to this review.

The Cochrane Renal Group’s Specialised Register contains studies identified from:

1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

2. Weekly searches of MEDLINE OVID SP

3. Handsearching of renal‐related journals and the proceedings of major renal conferences;

4. Searching of the current year of EMBASE OVID SP

5. Weekly current awareness alerts for selected renal journals

6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Renal Group.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

1. Reference lists of clinical practice guidelines, review articles and relevant studies.

2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Selection of studies

The search strategy was used to obtain citations that were relevant to this review. The titles and abstracts of all retrieved citations were screened by two or more independent authors who discarded citations that were not applicable. All citations for studies and reviews that might have reported relevant data or information on available studies were retained initially. The same authors independently assessed the full text of these citations to determine which report studies that satisfied the inclusion criteria. Reasons for exclusion from the review at this stage were recorded.

Data extraction and management

Data extraction was carried out independently by two authors using standard data extraction forms. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was used in the analyses. Where relevant outcomes were only published in earlier versions these data were used. Any discrepancy between published versions was highlighted. Disagreements during the study identification and data extraction process were resolved in consultation with the other authors.

Assessment of risk of bias in included studies

The following items were assessed independently by two authors using the risk of bias assessment tool (Higgins 2011) (seeAppendix 2).

• Was there adequate sequence generation (selection bias)?

• Was allocation adequately concealed (selection bias)?

• Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?

  • Participants and personnel

  • Outcome assessors

• Were incomplete outcome data adequately addressed (attrition bias)?

• Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

• Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (all‐cause mortality, doubling of serum creatinine, progression to ESKD, adverse effects of treatment, number of patients who were hospitalised) results were expressed as risk ratios (RR) together with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (change in mean Hb and HCT values, blood pressure, change in GFR, days of hospitalisation), the mean difference (MD) was used.

Dealing with missing data

Any further information required from the original author was requested by written correspondence (e.g. emailing or writing to corresponding author) and any relevant information obtained in this manner was included in the review. Evaluation of important numerical data such as screened and randomised patients as well as intention‐to‐treat, as‐treated and per‐protocol populations were carefully performed. Attrition rates (e.g. drop‐outs, losses to follow‐up and withdrawals) were investigated. Issues of missing data and imputation methods (e.g. last‐observation‐carried‐forward) were critically appraised (Higgins 2011) where possible.

Assessment of heterogeneity

Heterogeneity was analysed using a Chi² test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% corresponded to low, medium and high levels of heterogeneity.

Assessment of reporting biases

Insufficient data were available to generate funnel plots to assess for the potential existence of small study bias (Higgins 2011).

Data synthesis

Data were pooled using the random‐effects model but the fixed‐effect model was also analysed to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses were prespecified to explore possible sources of heterogeneity (e.g. participants, treatments and study quality). Heterogeneity among participants could be related to age, stage of CKD and modalities of dialysis used. Heterogeneity in interventions could be related to dose and duration of darbepoetin alpha treatment, route of administration and the use of iron supplements. Prespecified subgroup analyses included:

• CKD stage: stages 3 to 5 versus stage 5D

• Study design: darbepoetin alfa compared to epoetin alfa versus darbepoetin alfa compared to placebo or no treatment.

• Baseline Hb: ≥ 11 g/dL versus< 11 g/dL

• Baseline age: ≥ 60 years versus< 60 years

• Proportion with cardiovascular disease: ≥ 70% versus < 70%

• Proportion with diabetes mellitus: ≥ 25% versus < 25%

• Proportion with hypertension: ≥ 70% versus < 70%

• Duration of intervention: < 5 months, 5 to 12 months, 1 to 2 years, > 2 years

• Risks of bias items: allocation concealment, selective reporting

• Number of participants: < 500, ≥ 500

• Paediatric versus adult participants.

Sensitivity analysis

We planned sensitivity analyses in order to explore the influence of the following factors on effect size, although insufficient data were available to complete such analyses.

• Repeating the analysis excluding unpublished studies.

• Repeating the analysis taking account of risk of bias items, as specified above.

• Repeating the analysis excluding any very long or large studies to establish how much they dominate the results.

• Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.