Darbepoetin for the anaemia of chronic kidney disease

Suetonia C Palmer; Valeria Saglimbene; Jonathan C Craig; Sankar D Navaneethan; Giovanni FM Strippoli

doi:10.1002/14651858.CD009297.pub2

. 2014 Mar 31;2014(3):CD009297. doi: 10.1002/14651858.CD009297.pub2

Darbepoetin for the anaemia of chronic kidney disease

Suetonia C Palmer ¹, Valeria Saglimbene ², Jonathan C Craig ³, Sankar D Navaneethan ⁴, Giovanni FM Strippoli ^3,^5,^6,^7,^8,^9,^✉

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC10656599 PMID: 24683046

Abstract

Background

Erythropoiesis‐stimulating agents are used to treat anaemia in people with chronic kidney disease (CKD). Several agents are available including epoetin alfa or beta as well as agents with a longer duration of action, darbepoetin alfa and methoxy polyethylene glycol‐epoetin beta.

Objectives

To assess the benefits and harms of darbepoetin alfa to treat anaemia in adults and children with CKD (stages 3 to 5, 5D, and kidney transplant recipients).

Search methods

We searched the Cochrane Renal Group's Specialised Register (to 13 January 2014) through contact with the Trials' Search Co‐ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE.

Selection criteria

We included randomised controlled trials of any darbepoetin alfa treatment of at least three months duration in adults or children with CKD (any stage).

Data collection and analysis

Data were extracted by two independent investigators. Patient‐centred outcomes (need for blood transfusion, iron therapy, progression of kidney disease, total and cardiovascular mortality, cardiovascular events, cancer, hypertension, seizures, and health‐related quality of life) and other outcomes (haemoglobin levels) were assessed using random effects meta‐analysis. We calculated risk ratios for dichotomous outcomes and mean differences for continuous outcomes, both with 95% confidence intervals.

Main results

We identified 32 studies comprising 9414 participants; 21 studies in 8328 participants could be included in our meta‐analyses. One study (4038 participants) compared darbepoetin alfa to placebo, 16 studies (2955 participants) compared darbepoetin alfa to epoetin alfa or beta, four studies (1198 participants) compared darbepoetin alfa to methoxy polyethylene glycol‐epoetin beta, three studies (420 participants) compared more frequent with less frequent darbepoetin alfa administration and four studies (303 participants) compared intravenous with subcutaneous darbepoetin alfa administration.

In a single large study, darbepoetin alfa reduced the need for blood transfusion and iron therapy compared with placebo in adults with CKD stage 3 to 5, but had little or no effect on survival, increased risks of hypertension, and had uncertain effects on quality of life. Data comparing darbepoetin alfa with epoetin alfa or beta or methoxy polyethylene glycol‐epoetin beta were sparse and inconclusive. Comparisons of differing dosing schedules and routes of administration were compared in small numbers of participants and studies. Evidence for treatment effects of darbepoetin alfa were particularly limited for children with CKD, adults with CKD stage 5D, and recipients of a kidney transplant.

Studies included in this review were generally at high or unclear risk of bias for all items (random sequence generation, allocation concealment, incomplete outcome data, blinding of participants and personnel, blinding of outcome assessment, selective outcome reporting, intention to treat analysis and other sources of bias). One large study comparing darbepoetin alfa with placebo was at low risk of bias for most items assessed.

Authors' conclusions

Data suggest that darbepoetin alfa effectively reduces need for blood transfusions in adults with CKD stage 3 to 5, but has little or no effect on mortality or quality of life. The effects of darbepoetin alfa in adults with CKD stage 5D and kidney transplant recipients and children with CKD remain uncertain as do the relative benefits and harms of darbepoetin alfa compared with other ESAs (epoetin alfa or beta and methoxy polyethylene glycol‐epoetin beta).

Plain language summary

Darbepoetin alfa to treat anaemia in people with chronic kidney disease

People who have chronic kidney disease (CKD) frequently experience anaemia. Several different medicines that treat anaemia are available including darbepoetin alfa.

We investigated whether darbepoetin alfa might have different effects in people with CKD compared to placebo or no treatment, or similar other treatment options called epoetin or methoxy polyethylene glycol‐epoetin beta, and whether differing ways of administering darbepoetin (route and frequency of treatment) might have different benefits and harms for people who have CKD.

While darbepoetin alfa reduced the need for patients to have blood transfusions to treat severe anaemia, darbepoetin alfa had little or no effect on survival or chances of needing dialysis therapy and their overall quality of life.

There were not enough studies comparing darbepoetin alfa with other similar treatment options to provide sufficient information to guide clinical decision‐making about choosing which medicine is best for an individual patient.

Little information was available about darbepoetin treatment for children who have CKD and adults who have received a kidney transplant or those treated with dialysis.

Background

Description of the condition

Anaemia is common in individuals with chronic kidney disease (CKD) largely due to reduced erythropoietin production, iron deficiency, and a shortened red blood cell life span. The observation that anaemia in CKD is associated with fatigue and impaired quality of life (Finkelstein 2009; Gerson 2004), cardiac injury, and premature death (Astor 2006; Glassock 2009; Levin 1999; Locatelli 2004a), together with the desire to avoid treatment with red cell transfusions has resulted in the routine practice of correcting anaemia with recombinant human erythropoietin and iron supplementation. Recombinant human erythropoietin (epoetin alfa or beta) stimulates bone marrow erythrocyte production and is administered 2 to 3 times each week either into the vein (intravenous, IV) or beneath the skin (subcutaneous, SC).

Description of the intervention

To simplify anaemia management by reducing the frequency of administration, erythropoiesis‐stimulating agents (ESAs) including darbepoetin alfa and methoxy polyethylene glycol‐epoetin beta have been developed and can be administered less often (once every one to two weeks for darbepoetin alfa and monthly for methoxy polyethylene glycol‐epoetin beta) than epoetin. Because of its increased sialic acid‐containing carbohydrate content, darbepoetin alfa has a longer (three‐fold) terminal half‐life in animal models and in humans (Macdougall 1999) when compared with epoetin alfa or beta. Clinical studies have shown that darbepoetin alfa is effective for achieving and maintaining target haemoglobin (Hb) levels in CKD patients (Locatelli 2000; Macdougall 2000; Macdougall 2003; Pfeffer 2009).

How the intervention might work

Clinical practice guidelines for ESAs to treat anaemia due to CKD were issued in 2001; European Best Practice Guidelines (EBPG) for anaemia management recommended the use of darbepoetin alfa or epoetin alfa or beta in all CKD patients (EBPG 2004; NESP 2001). An update of the National Kidney Foundation‐Kidney Disease Outcomes and Quality initiative (NKF‐KDOQI) guidelines on anaemia management in 2006 did not suggest any specific epoetin type when treating CKD patients (KDOQI 2006) and recommended darbepoetin alfa or epoetin alfa or beta to manage the symptoms of anaemia. Clinical studies dating back to 1998 have now consistently shown that targeting near‐normal Hb levels using ESAs is associated with increased risks of stroke and hypertension, without improving survival, quality of life, or reducing cardiovascular events (Besarab 1998; Drueke 2006; Pfeffer 2009; Singh 2006), although direct comparative studies between differing epoetins are lacking.

Guidelines for anaemia management in CKD recently published by the Kidney Disease: Improving global Outcomes (KDIGO) group in 2012 (KDIGO 2012) now recommend balancing the potential benefits from ESAs (e.g. reducing blood transfusions and anaemia‐related symptoms) against the risks for harm (e.g. stroke, dialysis vascular access loss, and hypertension). KDIGO guidelines also recommend that the choice of specific epoetin (including darbepoetin alfa) is based on pharmacokinetic information, safety data, clinical outcome data, cost and availability, and that decisions about the relative benefits and harms of differing ESAs (epoetin, darbepoetin and methoxy polyethylene glycol‐epoetin beta) are currently based on very low quality evidence.

Why it is important to do this review

Previous meta‐analyses relating to the management of anaemia with epoetins in CKD have focused on either the Hb targets or have included all epoetin agents in their analyses (Gandra 2010; Johansen 2010; Palmer 2010; Parfrey 2009; Phrommintikul 2007; Strippoli 2006). To date, no systematic review of randomised controlled trials (RCTs) has evaluated the relative benefits and harms of darbepoetin alfa directly compared with placebo or other epoetins when treating the anaemia of CKD.

Objectives

To assess the benefits and harms of darbepoetin alfa to treat anaemia in people with CKD (stages 3 to 5, and 5D, and kidney transplant recipients).

Methods

Criteria for considering studies for this review

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)

Search methods for identification of studies

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:

Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
Weekly searches of MEDLINE OVID SP
Handsearching of renal‐related journals and the proceedings of major renal conferences;
Searching of the current year of EMBASE OVID SP
Weekly current awareness alerts for selected renal journals
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

Reference lists of clinical practice guidelines, review articles and relevant studies.
Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

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.

Results

Description of studies

Results of the search

Our search of the Cochrane Renal Group's Specialised Register), Clinicaltrials.gov and the ICTRP retrieved 162 reports. We excluded 14 records on title and abstract review as they did not report a RCT, did not evaluate an appropriate intervention, were a commentary or editorial, or were of insufficient duration (Figure 1).

Flow chart showing number of reports retrieved by database searching and the number of studies included in this review

We examined 148 reports in detail and excluded 34 reports (22 studies) for the following reasons.

They did not report a RCT (10 studies; 14 reports) (Akizawa 2007b; Carrera 2003; Chen 2008; Deray 2003; Disney 2007; Macdougall 2003; Mann 2007; Murtagh 2000; Paganini 1989; Thadhani 2002)
They did not report an appropriate intervention (four studies, seven reports) (Argani 2009; Lamas 2006; McMahon 2004; Smith 2007)
Theey were of insufficient duration (eight studies; 13 reports) (COMFORT Study 2007; Iino 2003; Kawanishi 2005; Lerner 2002; Macdougall 1999; St Peter 1998; Tsubakihara 2003; Tsubakihara 2003).

We identified 13 ongoing studies (Besarab 2006; ISRCTN89787518; Ito 2011; NCT00121602; NCT00436748; NCT00442702; NCT00559273; NCT00605345; NCT00717821; NCT00773513; NCT00925587; NCT01306409; STIMULATE Study 2011) and seven studies (10 reports) are awaiting classification (insufficient information to include or exclude) (CORDATUS Study 2011; Forni 2013; Gurevich 2010; Martinez 2006; Patel 2012; PEARL 1 2013; PEARL 2 2013). These will be assessed in a future update of this review.

Included studies

We identified 32 eligible studies (91 reports; 9414 participants) evaluating darbepoetin alfa (Aarup 2004; Akizawa 2011; Allon 2002; ARCTOS Study 2008; Bommer 2004; Cervelli 2005; Chazot 2009; Coyne 2000; Coyne 2006a; Hirakata 2010; Hori 2004; Iwasaki 2008; Kim 2009a; Kwan 2005; Li 2008; Locatelli 2001; Locatelli 2004; Locatelli 2008; Nagaya 2010; Nissenson 2002; PATRONUS Study 2010; Smyth 2004; STRIATA Study 2008; Svarstad 2007; Tessitore 2008; TIVOLI Study 2011; Tolman 2005; TREAT Study 2005; Vanrenterghem 2002; Warady 2006; Watanabe 2004; Yoon 2004).

Twenty one studies (8328 participants) were included in our meta‐analyses (Aarup 2004; Akizawa 2011; ARCTOS Study 2008; Bommer 2004; Chazot 2009; Coyne 2006a; Hirakata 2010; Hori 2004; Kim 2009a; Kwan 2005; Locatelli 2001; Nagaya 2010; Nissenson 2002; PATRONUS Study 2010; Smyth 2004; STRIATA Study 2008; TIVOLI Study 2011; Tolman 2005; TREAT Study 2005; Vanrenterghem 2002; Warady 2006).

Darbepoetin alfa versus placebo or no treatment

We identified a single large study that compared darbepoetin alfa with placebo in 4038 participants who had type 2 diabetes and CKD stages 3 and 4 (eGFR 20 to 60 mL/min/1.73 m²) (TREAT Study 2005) that could be included in our meta‐analyses. The treatment algorithm was designed to adjust the dose in the darbepoetin alfa arm to maintain the Hb level at approximately 13.0 g/dL. In the placebo arm, darbepoetin alfa was administered when the Hb level was < 9.0 g/dL. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalisation for myocardial ischaemia) and of death or ESKD. Median follow‐up duration was 29.1 months. Data comparing darbepoetin alfa with placebo were not available for patients with CKD stage 5 and 5D, kidney transplant recipients, or children with any stage of CKD.

Darbepoetin alfa versus epoetin alfa or beta

Sixteen studies compared darbepoetin alfa with epoetin alfa or beta in 2955 participants (range 30 to 522 participants) (Akizawa 2011; Allon 2002; Coyne 2000; Coyne 2006a; Hirakata 2010; Hori 2004; Iwasaki 2008; Li 2008; Locatelli 2001; Nissenson 2002; Smyth 2004; Tessitore 2008; Tolman 2005; Vanrenterghem 2002; Warady 2006; Yoon 2004). Half of these studies were published in abstract form only ( Coyne 2000; Coyne 2006a; Hori 2004; Iwasaki 2008; Smyth 2004; Tessitore 2008; Yoon 2004). Three studies enrolled adults with CKD stage 3 to 5 (Akizawa 2011; Hirakata 2010; Locatelli 2001), one enrolled children with stage 4, 5, and 5D (Warady 2006) and the remainder were in adults with CKD stage 5D (Allon 2002; Coyne 2000; Coyne 2006a; Hori 2004; Iwasaki 2008; Li 2008; Nissenson 2002; Smyth 2004; Tessitore 2008; Tolman 2005; Vanrenterghem 2002; Yoon 2004). No data were available for kidney transplant recipients.

Hb levels targeted by treatment ranged between 9.0 and 13.0 g/L. Two studies reported a higher Hb level target in the darbepoetin alfa arm than in the epoetin arm (Akizawa 2011; Hirakata 2010). In seven studies, Hb levels were kept within a target range based on baseline Hb levels (generally between 1.0 g/dL below to 1.0 to 1.5 g/dL above baseline values) (Allon 2002; Hori 2004; Li 2008; Locatelli 2001; Nissenson 2002; Vanrenterghem 2002; Yoon 2004).

Primary outcomes in the studies comparing darbepoetin alfa with epoetin alfa or beta were largely Hb levels (maintenance within a defined target, mean change during treatment, stability of Hb levels, response to treatment). In Hirakata 2010 (171 participants) the primary outcome included left ventricular mass index and quality of life. Treatment duration ranged between 16 and 54 weeks (median 28 weeks). The mean age of participants ranged between 48 and 60.9 years. One study evaluated darbepoetin versus epoetin in 124 children (mean age 12 years) (Warady 2006).

Of the 16 studies comparing darbepoetin alfa with epoetin alfa or beta, nine studies (2264 participants) reported sufficient data to be included in our meta‐analyses (Coyne 2006a; Hirakata 2010; Hori 2004; Locatelli 2001; Nissenson 2002; Smyth 2004; Tolman 2005; Vanrenterghem 2002; Warady 2006).

Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta

Four studies (1198 participants) compared darbepoetin alfa with methoxy polyethylene glycol‐epoetin beta (ARCTOS Study 2008; PATRONUS Study 2010; STRIATA Study 2008; TIVOLI Study 2011). All were published in 2008 or later and one study has so far been only been reported as an abstract (TIVOLI Study 2011). All studies enrolled adults. Two studies (803 participants) enrolled adults with CKD stage 5D (PATRONUS Study 2010; STRIATA Study 2008), one study evaluated treatment in 324 participants with CKD stages 3 and 4 (creatinine clearance 30 to 59 mL/min) (ARCTOS Study 2008) and one study evaluated treatment in 71 kidney transplant recipients (TIVOLI Study 2011). Treatment duration ranged between 28 and 52 weeks, although was this was unclear in one study (TIVOLI Study 2011).

Hb responses to treatment, Hb level variation, or mean change in Hb were primary outcomes. Mean age in treatment arms ranged between 61.8 and 66.9 years. The target Hb levels were 10 to 13.5 g/dL and within 1.0 g/dL of baseline (STRIATA Study 2008); 10 to 12 g/dL and within a 1.0 g/dL range (TIVOLI Study 2011); 11 to 13 g/dL and not below 1.0 g/dL of baseline (PATRONUS Study 2010); and ≥11 g/dL and ≥1.0 g/dL above baseline (ARCTOS Study 2008).

All four studies provided data that could be included in our meta‐analyses. No data comparing darbepoetin alfa with methoxy polyethylene glycol‐epoetin beta were available in children.

Darbepoetin alfa every two weeks versus darbepoetin every four weeks

One study (64 participants) reported data comparing equivalent doses of darbepoetin alfa administered every four weeks compared with every two weeks in abstract format only (Kwan 2005). Participants had CKD stage 5D treated with peritoneal dialysis and were treated with darbepoetin alfa over 24 weeks. The primary outcome was end of treatment Hb level. The dose of darbepoetin alfa was calculated according to epoetin dosing requirements and kept stable during treatment. Data for this comparison were available for inclusion in our meta‐analyses. No data comparing four‐weekly with two‐weekly darbepoetin alfa were available for patients with CKD stages 3 to 5, transplant recipients, or children with any stage of CKD.

Darbepoetin alfa weekly versus darbepoetin every two weeks

Two studies (356 participants) compared darbepoetin alfa every two weeks versus once a week (Locatelli 2004; Nagaya 2010). One study was an abstract publication only (Locatelli 2004). Both studies evaluated treatment in participants with CKD stage 5D. Study duration was 24 weeks (Nagaya 2010) and 30 weeks (Locatelli 2004). Primary end points were Hb levels during treatment (Locatelli 2004) and weekly dose of darbepoetin alfa at end of treatment (Nagaya 2010). Treatment was targeted to achieve Hb levels between 10 and 13 g/dL and within ‐1.0 to +1.5 g/dL of baseline (Locatelli 2004) and between 10.5 and 11.5 g/dL (Nagaya 2010). One study provided data extractable for meta‐analysis (Nagaya 2010).

No data comparing darbepoetin alfa treatment every two weeks compared to once a week were available for patients with CKD stage 3 to 5, transplant recipients, or children with any stage of CKD.

Darbepoetin alfa intravenous versus subcutaneous administration

Four studies (303 participants) compared IV administration with SC administration (Aarup 2004; Bommer 2004; Cervelli 2005; Kim 2009a). One study compared darbepoetin alfa IV administration compared with initial SC administration followed by delayed IV administration in 154 participants (Chazot 2009). Study duration ranged between 20 and 52 weeks. Administration frequency ranged between once a week and every two weeks. All studies evaluated treatment in adults treated with haemodialysis. Primary outcomes included darbepoetin alfa dose necessary to maintain the Hb level within the defined range (Aarup 2004; Bommer 2004; Kim 2009a) and variation in Hb levels (Cervelli 2005). Hb levels were maintained between 6.8 and 8.5 mmol/L and within a target range of ‐0.8 to +0.8 mmol/L of the baseline value (Aarup 2004); 10 to 13 g/dL (Bommer 2004); 11 to 13 g/dL and within ‐1.0 and +1.0 g/dL of evaluation phase level (Cervelli 2005); and 8.0 to 11.0 g/dL (Kim 2009a). Three studies provided data in a format extractable for meta‐analysis (Aarup 2004; Bommer 2004; Kim 2009a).

No data comparing darbepoetin alfa administered IV versus SC were available for patients with CKD stages 3 to 5, transplant recipients, or children with any stage of CKD.

Other comparisons

One study compared darbepoetin alfa administered every two, three and four weeks with every two weekly dosing in 25 participants with CKD stage 3 to 5 (mean eGFR 30.6 mL/min) (Svarstad 2007). Target Hb ranged between 12 to 14 g/dL and treatment duration was three months. Data were available in an abstract publication only. One study (289 participants) compared darbepoetin or epoetin given IV compared to once a week IV epoetin to maintain Hb levels at 11.0 to 13.0 g/dL for 28 weeks (Locatelli 2008). Primary end points were the changes in Hb levels and weekly dose between baseline and assessment phase. In one study, darbepoetin alfa was administered either every two weeks or every four weeks at initial doses of 30 or 60 μg/kg body weight in 32 participants with CKD stage 3 to 5 (Watanabe 2004). The randomised comparison in this study was unclear.

Risk of bias in included studies

Studies included in this review were generally at high or unclear risk of bias for all items (random sequence generation, allocation concealment, incomplete outcome data, blinding of participants and personnel, blinding of outcome assessment, selective outcome reporting, intention to treat analysis and other sources of bias (Figure 2; Figure 3). One large study comparing darbepoetin alfa with placebo was at low risk for most items assessed (TREAT Study 2005).

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Random sequence generation

Seven of 32 studies (22%) were at low risk of selection bias due to appropriate random sequence generation (Cervelli 2005; Kim 2009a; Nissenson 2002; PATRONUS Study 2010; TREAT Study 2005; Vanrenterghem 2002; Warady 2006) and one was at high risk (Tessitore 2008). For random sequence generation in each treatment comparison, the only study comparing darbepoetin with placebo (TREAT Study 2005), three studies comparing darbepoetin with epoetin (Nissenson 2002; Vanrenterghem 2002; Warady 2006), one study comparing darbepoetin with methoxy polyethylene glycol‐epoetin beta (PATRONUS Study 2010), none of the three studies comparing differing dosing frequencies (Nagaya 2010; Kwan 2005; Locatelli 2004), and two studies comparing IV with SC administration (Cervelli 2005; Kim 2009a) were at low risk of bias.

Allocation concealment

Six of 32 studies (19%) were at low risk due to adequate allocation concealment (ARCTOS Study 2008; Bommer 2004; Hirakata 2010; PATRONUS Study 2010; STRIATA Study 2008; TREAT Study 2005). In each treatment comparison, the only study comparing darbepoetin with placebo (TREAT Study 2005), one study comparing darbepoetin with epoetin (Hirakata 2010), three studies of studies comparing darbepoetin with methoxy polyethylene glycol‐epoetin beta (ARCTOS Study 2008; PATRONUS Study 2010; STRIATA Study 2008), none of the three studies comparing differing dosing frequencies, and one study comparing IV with SC administration (Bommer 2004) were at low risk of bias.

Blinding

Overall, 5/32 (16%) were at low risk due to blinding of study personnel and patients (Coyne 2006a; Hori 2004; Locatelli 2004; Nissenson 2002; TREAT Study 2005) and 17 studies were at high risk (Aarup 2004; Allon 2002; ARCTOS Study 2008; Chazot 2009; Hirakata 2010; Kim 2009a; Kwan 2005; Li 2008; Locatelli 2001; Locatelli 2008; PATRONUS Study 2010; Tessitore 2008; TIVOLI Study 2011; Tolman 2005; Vanrenterghem 2002; Warady 2006).

In each treatment comparison, the only study comparing darbepoetin with placebo (TREAT Study 2005), three studies comparing darbepoetin with epoetin (Coyne 2006a; Hori 2004; Nissenson 2002), no studies comparing darbepoetin with methoxy polyethylene glycol‐epoetin beta, one study comparing differing dosing frequencies (Locatelli 2004), and no study comparing IV with SC administration were at low risk of bias due to blinding of study personnel or patients.

One study (3%) was at low risk due to blinding of outcomes assessment (TREAT Study 2005) and 16 were at high risk (Aarup 2004; Allon 2002; ARCTOS Study 2008; Chazot 2009; Hirakata 2010; Kim 2009a; Kwan 2005; Li 2008; Locatelli 2001; Locatelli 2008; PATRONUS Study 2010; STRIATA Study 2008; Tessitore 2008; TIVOLI Study 2011; Tolman 2005; Vanrenterghem 2002; Warady 2006).

Incomplete outcome data

Between 0% and 83% (median of randomised participants) could not be included in analyses within the included studies. In 8/32 studies, data to identify loss to follow‐up were not provided (Akizawa 2011; Coyne 2000; Hori 2004; Iwasaki 2008; Tessitore 2008; TIVOLI Study 2011; Watanabe 2004; Yoon 2004).

Four of 32 studies (13%) were at low risk of bias due to attrition (below 10% of randomised patients not available for inclusion in analyses) (ARCTOS Study 2008; Locatelli 2001; Locatelli 2004; Svarstad 2007). No studies comparing darbepoetin with placebo, one study comparing darbepoetin with epoetin (Locatelli 2001), one study comparing darbepoetin with methoxy polyethylene glycol‐epoetin beta (ARCTOS Study 2008), and no studies comparing differing treatment frequencies or IV with SC administration were at low risk.

Selective reporting

In eight studies (25%), published reports included all expected outcomes and were considered at low risk of bias (ARCTOS Study 2008; Locatelli 2001; Nissenson 2002; PATRONUS Study 2010; Smyth 2004; STRIATA Study 2008; Tolman 2005; TREAT Study 2005) while 22 were considered at high risk due to potential selective reporting of outcomes (Aarup 2004; Akizawa 2011; Allon 2002; Bommer 2004; Cervelli 2005; Chazot 2009; Coyne 2000; Coyne 2006a; Hirakata 2010; Hori 2004; Iwasaki 2008; Kim 2009a; Kwan 2005; Li 2008; Locatelli 2004; Locatelli 2008; Nagaya 2010; Svarstad 2007; Tessitore 2008; TIVOLI Study 2011; Watanabe 2004; Yoon 2004).

In each treatment comparison, the only study comparing darbepoetin with placebo (TREAT Study 2005), four studies comparing darbepoetin with epoetin (Locatelli 2001; Nissenson 2002; Smyth 2004; Tolman 2005), three studies comparing darbepoetin with methoxy polyethylene glycol‐epoetin beta (ARCTOS Study 2008; PATRONUS Study 2010; STRIATA Study 2008), no studies comparing differing dosing frequencies, and no studies comparing IV with SC administration were at low risk of bias due to complete reporting of outcomes.

Other potential sources of bias

Other potential sources of bias included abstract‐only publication (13/32 studies (41%)) (Akizawa 2011; Coyne 2000; Coyne 2006a; Hori 2004; Kwan 2005; Locatelli 2004; Nagaya 2010; Smyth 2004; Svarstad 2007; Tessitore 2008; TIVOLI Study 2011; Watanabe 2004; Yoon 2004), data not sufficient for inclusion in meta‐analysis (12/32 studies (38%)) (Akizawa 2011; Allon 2002; Cervelli 2005; Coyne 2000; Iwasaki 2008; Li 2008; Locatelli 2004; Locatelli 2008; Svarstad 2007; Tessitore 2008; Watanabe 2004; Yoon 2004) data not available for end of first phase of treatment in cross‐over studies (2/32 studies (6%)) (Aarup 2004; Cervelli 2005) and unequal treatment comparisons or baseline characteristics (3/32 studies (9%)) (Akizawa 2011; Cervelli 2005; Hirakata 2010).

Effects of interventions

Darbepoetin alfa versus placebo

One large study at generally low risk of bias compared darbepoetin alfa with placebo in 4038 participants with CKD stages 3 to 4. Compared to placebo, darbepoetin alfa reduced need for one or more blood transfusions (Analysis 1.1: RR 0.60, 95% CI 0.53 to 0.69) and need for iron therapy (Analysis 1.2: RR 0.75, 95% CI 0.73 to 0.78) but had little or no effect on need for RRT (Analysis 1.3: RR 1.03, 95% CI 0.90 to 1.18). Darbepoetin alfa had little or no effect on all‐cause mortality (Analysis 1.4: RR 1.05, 95% CI 0.93 to 1.19) or cardiovascular mortality (Analysis 1.5: RR 1.04, 95% CI 0.89 to 1.23) and uncertain effects on cancer (Analysis 1.6: RR 1.08, 95% CI 0.85 to 1.36). Darbepoetin alfa may increase risk of hypertension (Analysis 1.7: RR 1.11, 95% CI 0.99 to 1.24) but has uncertain effects on seizure risk (Analysis 1.8: RR 2.27, 95% CI 0.70 to 7.35). Darbepoetin alfa increased the Functional Assessment of Cancer Therapy (FACT) fatigue score (Analysis 1.9: MD 1.40, 95% CI 0.71 to 2.09) but had little or no effect on the SF‐36 energy score (Analysis 1.10: MD 0.50, 95% CI ‐0.15 to 1.15) or physical functioning score (Analysis 1.11: MD 0.20, 95% CI ‐0.39 to 0.79).

1.1 — Comparison 1 Darbepoetin versus placebo, Outcome 1 One or more blood transfusions.

1.2 — Comparison 1 Darbepoetin versus placebo, Outcome 2 Need for iron therapy.

1.3 — Comparison 1 Darbepoetin versus placebo, Outcome 3 Progression to RRT.

1.4 — Comparison 1 Darbepoetin versus placebo, Outcome 4 All‐cause mortality.

1.5 — Comparison 1 Darbepoetin versus placebo, Outcome 5 Cardiovascular mortality.

1.6 — Comparison 1 Darbepoetin versus placebo, Outcome 6 Cancer.

1.7 — Comparison 1 Darbepoetin versus placebo, Outcome 7 Hypertension.

1.8 — Comparison 1 Darbepoetin versus placebo, Outcome 8 Seizures.

1.9 — Comparison 1 Darbepoetin versus placebo, Outcome 9 Mean change in FACT‐Fatigue score.

1.10 — Comparison 1 Darbepoetin versus placebo, Outcome 10 Mean change in SF‐36 energy score.

1.11 — Comparison 1 Darbepoetin versus placebo, Outcome 11 Mean change in SF‐36 physical functioning score.

Darbepoetin alfa versus epoetin

In both adults (Analysis 2.1.1 (2 studies, 483 participants): RR 0.80, 95% CI 0.35 to 1.83; I² = 0%)) and children (Analysis 2.1.2 (1 study, 123 participants): RR 0.43, 95% CI 0.14 to 1.33), darbepoetin alfa had uncertain effects on need for blood transfusions compared to epoetin. No data were available for need for iron treatment. In children, darbepoetin alfa had uncertain effects on risk of RRT (Analysis 2.2 (1 study, 123 participants): RR 0.67, 95% CI 0.27 to 1.66) compared with epoetin. No data were available for adults.

2.1 — Comparison 2 Darbepoetin versus epoetin, Outcome 1 One or more blood transfusions.

2.2 — Comparison 2 Darbepoetin versus epoetin, Outcome 2 Progression to renal replacement therapy.

Compared to epoetin, darbepoetin alfa had uncertain effects on all‐cause mortality for both adults (Analysis 2.3.1 (6 studies, 1657 participants): RR 1.35, 95% CI 0.84 to 2.15; I² = 0%) and children (Analysis 2.3.2 (1 study, 123 participants): RR 0.52, 95% CI 0.03 to 8.08). Darbepoetin alfa had uncertain effects on cardiovascular mortality in adults (Analysis 2.4 (2 studies, 487 participants): RR 0.47, 95% CI 0.07 to 3.17; I² = 0%). No data were available for children. In adults, darbepoetin alfa had uncertain effects on risk of major cardiovascular events compared to epoetin (Analysis 2.5 (2 studies, 840 participants): RR 0.88, 95% CI 0.06 to 12.69; I² = 63%) with substantial heterogeneity in the analysis. No data were available for children.

2.3 — Comparison 2 Darbepoetin versus epoetin, Outcome 3 All‐cause mortality.

2.4 — Comparison 2 Darbepoetin versus epoetin, Outcome 4 Cardiovascular mortality.

2.5 — Comparison 2 Darbepoetin versus epoetin, Outcome 5 Major cardiovascular events.

Darbepoetin alfa had similar effects on risk of hypertension compared to epoetin in adults (Analysis 2.6.1 (4 studies, 1412 participants): RR 1.17, 95% CI 0.93 to 1.49; I² = 0%) and had uncertain effects in children (Analysis 2.6.2 (1 study, 123 participants): RR 0.96, 95% CI 0.43 to 2.23). Darbepoetin alfa also had uncertain effects on risk of seizures in adults (Analysis 2.7 (1 study, 519 participants): RR 1.17, 95% CI 0.31 to 4.46). No data were available for children. Darbepoetin alfa had similar effects on vascular access thrombosis in adults (Analysis 2.8.1 (2 studies, 925 participants): RR 1.06, 95% CI 0.63 to 1.79; I² = 0%) and uncertain effects in children (Analysis 2.8.2 (1 study, 123 participants): RR 0.17, 95% CI 0.01 to 4.20). Darbepoetin alfa had similar effects on risk of children exceeding the Hb target range (Analysis 2.9 (1 study, 123 participants): RR 1.09, 95% CI 0.57 to 2.09) and uncertain risks of injection site pain (Analysis 2.10 (1 study, 123 participants): RR 1.21, 95% CI 0.50 to 2.92).

2.6 — Comparison 2 Darbepoetin versus epoetin, Outcome 6 Hypertension.

2.7 — Comparison 2 Darbepoetin versus epoetin, Outcome 7 Seizures.

2.8 — Comparison 2 Darbepoetin versus epoetin, Outcome 8 Vascular access thrombosis.

2.9 — Comparison 2 Darbepoetin versus epoetin, Outcome 9 Exceeded Hb target ≥1 episodes.

2.10 — Comparison 2 Darbepoetin versus epoetin, Outcome 10 Injection site pain.

In one study in which the Hb target in the darbepoetin alfa arm was higher than in the epoetin arm, darbepoetin alfa increased Hb levels at the end of treatment (Analysis 2.11.1 (1 study, 84 participants): MD 1.33 g/dL, 95% CI 0.84 to 1.82) whereas in the study reporting treatment effects on end of treatment Hb values in which target values were similar for both darbepoetin alfa and darbepoetin alfa arms, end of treatment values were similar (Analysis 2.11.2 (1 study, 363 participants): MD ‐0.07 g/dL, 95% CI ‐0.27 to 0.13). The mean change in Hb was similar for darbepoetin alfa and epoetin treatment in both adults (Analysis 2.12 (3 studies, 1060 participants): MD 0.06 g/dL, 95% CI ‐0.08 to 0.19; I² = 0%) and children (Analysis 2.12.3 (1 study, 123 participants): MD 0.22 g/dL, 95% CI ‐0.47 to 0.91).

2.11 — Comparison 2 Darbepoetin versus epoetin, Outcome 11 End of treatment Hb.

2.12 — Comparison 2 Darbepoetin versus epoetin, Outcome 12 Mean change in Hb.

Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta

In studies comparing darbepoetin alfa with methoxy polyethylene glycol‐epoetin beta, darbepoetin alfa had inconclusive effects on need for blood transfusion therapy (Analysis 3.1 (2 studies, 799 participants): RR 0.82, 95% CI 0.58 to 1.17; I² = 0%) and similar effects on need for iron treatment (Analysis 3.2 (2 studies, 799 participants): RR 1.01, 95% CI 0.97 to 1.05; I² = 0%). Darbepoetin alfa had uncertain effects on all‐cause mortality (Analysis 3.3 (3 studies, 1122 participants): RR 0.89, 95% CI 0.53 to 1.51; I² = 3%) and cardiovascular mortality (Analysis 3.4 (1 study, 309 participants): RR 0.56, 95% CI 0.17 to 1.88). Compared to methoxy polyethylene glycol‐epoetin beta, darbepoetin alfa had uncertain effects on vascular access thrombosis (Analysis 3.5 (1 study, 309 participants): RR 0.91, 95% CI 0.43 to 1.92) and hypertension (Analysis 3.6 (3 studies, 869 participants): RR 0.77, 95% CI 0.52 to 1.13; I² = 0%). One study reported patients receiving methoxy polyethylene glycol‐epoetin beta were more likely than those receiving darbepoetin alfa to achieve the Hb target (Analysis 3.7 (1 study, 450 participants): RR 1.59, 95% CI 1.33 to 1.90). One study reported darbepoetin alfa had similar effects to methoxy polyethylene glycol‐epoetin beta on end of treatment Hb (Analysis 3.8 (1 study, 313 participants): MD 0.00 g/dL, 95% CI ‐0.23 to 0.23).

3.1 — Comparison 3 Darbepoetin versus methoxy polyethylene glycol‐epoetin beta, Outcome 1 One or more blood transfusions.

3.2 — Comparison 3 Darbepoetin versus methoxy polyethylene glycol‐epoetin beta, Outcome 2 Need for iron therapy.

3.3 — Comparison 3 Darbepoetin versus methoxy polyethylene glycol‐epoetin beta, Outcome 3 All‐cause mortality.

3.4 — Comparison 3 Darbepoetin versus methoxy polyethylene glycol‐epoetin beta, Outcome 4 Cardiovascular mortality.

3.5 — Comparison 3 Darbepoetin versus methoxy polyethylene glycol‐epoetin beta, Outcome 5 Vascular access thrombosis.

3.6 — Comparison 3 Darbepoetin versus methoxy polyethylene glycol‐epoetin beta, Outcome 6 Hypertension.

3.7 — Comparison 3 Darbepoetin versus methoxy polyethylene glycol‐epoetin beta, Outcome 7 Achieved Hb target.

3.8 — Comparison 3 Darbepoetin versus methoxy polyethylene glycol‐epoetin beta, Outcome 8 End of treatment Hb.

Darbepoetin alfa every two weeks versus darbepoetin alfa every four weeks

Darbepoetin alfa administered every two weeks compared to once every four weeks may reduce need for blood transfusions (Analysis 4.1 (1 study, 64 participants): RR 0.33, 95% CI 0.10 to 1.14) and iron therapy (Analysis 4.2 (1 study, 64 participants): RR 0.39, 95% CI 0.13 to 1.14). Treatment every two weeks had similar effects on end of treatment Hb levels (Analysis 4.3 (1 study, 64 participants): MD 0.40 g/dL, 95% CI ‐0.37 to 1.17).

4.1 — Comparison 4 Darbepoetin every 2 weeks versus every 4 weeks, Outcome 1 One or more blood transfusions.

4.2 — Comparison 4 Darbepoetin every 2 weeks versus every 4 weeks, Outcome 2 Need for iron therapy.

4.3 — Comparison 4 Darbepoetin every 2 weeks versus every 4 weeks, Outcome 3 End of treatment Hb.

Darbepoetin alfa weekly versus every two weeks

One study reported darbepoetin alfa administered every week had similar effects on end of treatment Hb compared to treatment given every two weeks (Analysis 5.1 (1 study, 39 participants): MD ‐0.30 g/dL, 95% CI ‐0.87 to 0.27).

5.1 — Comparison 5 Darbepoetin weekly versus every 2 weeks, Outcome 1 End of treatment Hb.

Intravenous versus subcutaneous treatment

IV darbepoetin alfa therapy had uncertain effects on need for blood transfusions (Analysis 6.1 (2 studies, 183 participants): RR 1.15, 95% CI 0.30 to 4.38), all‐cause mortality (Analysis 6.2 (2 studies, 183 participants): RR 1.28, 95% CI 0.32 to 5.06; I² = 0%), cardiovascular mortality (Analysis 6.3 (2 studies, 183 participants): RR 1.15, 95% CI 0.30 to 4.38) and major cardiovascular events (Analysis 6.4 (1 study, 105 participants): RR 1.31, 95% CI 0.23 to 7.54) compared to SC administration. IV and SC darbepoetin alfa therapy had similar effects on end of treatment Hb levels (Analysis 6.5 (3 studies, 284 participants): MD ‐0.10 g/dL, 95% CI ‐0.34 to 0.14; I² = 0%) and change in Hb levels during treatment (Analysis 6.6 (1 study, 65 participants): MD 0.23 g/dL, 95% CI ‐0.32 to 0.78).

6.1 — Comparison 6 Darbepoetin intravenous versus subcutaneous administration, Outcome 1 One or more blood transfusions.

6.2 — Comparison 6 Darbepoetin intravenous versus subcutaneous administration, Outcome 2 All‐cause mortality.

6.3 — Comparison 6 Darbepoetin intravenous versus subcutaneous administration, Outcome 3 Cardiovascular mortality.

6.4 — Comparison 6 Darbepoetin intravenous versus subcutaneous administration, Outcome 4 Major cardiovascular events.

6.5 — Comparison 6 Darbepoetin intravenous versus subcutaneous administration, Outcome 5 End of treatment Hb.

6.6 — Comparison 6 Darbepoetin intravenous versus subcutaneous administration, Outcome 6 Mean change in Hb.

Stratified analyses and meta‐regression

There was no heterogeneity in treatment effects between studies in which two or more studies were included except for the effects of darbepoetin alfa versus epoetin on major cardiovascular events. Insufficient data were available for stratified or meta‐regression analyses or random effects meta‐regression. When we excluded Akizawa 2011 from analyses as this study had differing haemoglobin targets for the darbepoetin alfa and the epoetin arms, the meta‐analyses results were substantively similar.

Discussion

Summary of main results

In high‐quality evidence, data from one large study involving 4038 adults with diabetes and CKD stage 3 to 4 indicated that, compared to placebo, darbepoetin alfa reduced the need for blood transfusions and iron therapy but had small or uncertain effects on mortality and need for dialysis treatment. Darbepoetin alfa did not clearly increase risk of cancer or seizures, but may have worsened hypertension. Placebo‐controlled RCTs to guide darbepoetin alfa treatment in children and adults with CKD stage 5 or kidney transplantation were not available.

Compared to epoetin, darbepoetin alfa had uncertain effects on need for blood transfusions, all‐cause and cardiovascular mortality, major cardiovascular events, hypertension, seizures and had comparable effects to epoetin for risk of dialysis vascular access thrombosis and end of treatment Hb levels. Data comparing darbepoetin alfa with epoetin on need for iron therapy and cancer were absent for adults. In children with CKD stages 4 and 5, compared to epoetin, darbepoetin alfa treatment had uncertain effects on need for blood transfusion and risk of progression to RRT, all‐cause mortality, hypertension, dialysis vascular access thrombosis, exceeding Hb target level and injection site pain as well as Hb levels during treatment. Compared with methoxy polyethylene glycol‐epoetin beta, darbepoetin alfa had similar effects on need for blood transfusions and iron therapy and uncertain effects on all‐cause and cardiovascular mortality, dialysis vascular access thrombosis and hypertension in adults. In one study, adults treated with darbepoetin alfa were less likely to achieve a prespecified Hb target than those treated with methoxy polyethylene glycol‐epoetin beta.

In studies comparing differing dosing frequencies or routes of administration of darbepoetin alfa, compared to treatment every four weeks, darbepoetin alfa administered every two weeks in adults with CKD stage 5D had uncertain effects on need for blood transfusion and iron therapy and end of treatment Hb levels, while administration every two weeks had uncertain effects on Hb levels compared with weekly treatment. Data for patient‐level outcomes (e.g. mortality) comparing differing dosing frequencies were largely absent. Treatment effects for IV compared to SC darbepoetin alfa in adults with CKD stage 5D were inconclusive for the need for blood transfusions, as well as risks of all‐cause and cardiovascular mortality and major cardiovascular events; effects on Hb levels were similar between treatment groups.

Overall completeness and applicability of evidence

Overall, data for effectiveness of darbepoetin alfa therapy compared to placebo or other ESAs on patient‐relevant outcomes were dominated by a single placebo‐controlled study in adults with CKD stage 3 to 5 (TREAT Study 2005). Evidence comparing darbepoetin alfa against placebo were not available for adults with CKD stage 5D and kidney transplant recipients as well as children with all stages of CKD. Information directly comparing darbepoetin alfa with epoetin was largely restricted to adults with CKD stage 5D and treatment effects for risks of most patient‐relevant outcomes including mortality and major cardiovascular events were uncertain. Similarly, data directly comparing treatment effects of darbepoetin alfa with the longer‐acting methoxy polyethylene glycol‐epoetin beta were limited to adults with CKD. Evidence of the effectiveness of differing dosing frequencies and routes of administration for darbepoetin alfa were restricted to adults with CKD stage 5D, with largely inconclusive results.

Quality of the evidence

Data comparing darbepoetin alfa against placebo were generally at low risk of bias within a single well‐conducted study (TREAT Study 2005) although treatment effects may not be widely applicable to patients not included in the study population (adults with diabetes and CKD stages 3 to 5). Data to assess effectiveness of darbepoetin alfa compared with epoetin or methoxy polyethylene glycol‐epoetin beta were at higher risk of bias, providing treatment effects with confidence intervals that included a range of plausible values below clinical significance or that included harm. Data comparing darbepoetin alfa with epoetin or methoxy polyethylene glycol‐epoetin beta were limited frequently by studies that selectively reported clinical outcomes, provided incomplete data during follow‐up for many patients, and did not clearly blind study personnel and patients to assigned treatment. Similarly, data comparing more versus less frequent darbepoetin alfa administration and IV with SC therapy were at generally high risk of bias, suggesting that treatment summary effects for these treatment comparisons may be less reliable.

Potential biases in the review process

While this review was conducted according to rigorous methods developed by the Cochrane Collaboration, residual bias within the review process were inevitably present. While we searched the Cochrane Renal Group's Specialised Register of studies that included grey literature sources obtained by systematic handsearching of relevant renal conference proceedings and journals, it is possible that relevant but unpublished data (those studies with neutral or negative effects) may have been missed. Analysis for evidence of such publication bias was not possible due to the small number of studies available in each meta‐analysis. Second, many studies did not prospectively and systematically collect data for patient‐relevant outcomes including mortality, need for blood transfusions, and major cardiovascular events; we cannot be sure that the outcomes in these studies were the same or similar to those in the studies that did report these outcomes and which could be included in meta‐analyses. Finally, few studies included children or kidney transplant recipients. Treatment estimates derived from studies in adults with CKD may not be applicable to these other specific populations.

Agreements and disagreements with other studies or reviews

An earlier updated systematic review published in 2010 evaluated treatment effects for epoetin alfa or beta or darbepoetin alfa versus placebo or different doses of ESAs as needed to achieve higher versus lower target Hb levels (Palmer 2010). Indirect comparisons of treatment effects for darbepoetin alfa compared with either epoetin or methoxy polyethylene glycol‐epoetin beta were not possible in this review due to insufficient data.

Authors' conclusions

Implications for practice.

Currently, available data dominated by a single study suggest that darbepoetin alfa reduces the need for blood transfusion therapy but may increase risks of hypertension and does not clinically improve quality of life or survival in adults with diabetes and CKD stage 3 to 5. On the basis of this review, it remains unclear whether specific classes of ESAs (darbepoetin alfa, epoetin or methoxy polyethylene glycol‐epoetin beta) have differing effectiveness and safety when treating anaemia in people with CKD and especially for children with CKD and adult recipients of a kidney transplant.

Implications for research.

The relative effectiveness and safety of different types of erythropoietin‐stimulating agents (darbepoetin alfa, epoetin, and methoxy polyethylene glycol‐epoetin beta) remain uncertain due to a lack of directly comparative studies measuring patient‐relevant outcomes. Given that additional comparative studies of darbepoetin alfa are unlikely and that a large number of studies of anaemia treatment are already available, a network meta‐analysis of RCTs would allow the integration of direct treatment comparisons within studies and indirect treatment comparisons between studies and provide information about the relative benefits and harms of different ESAs (epoetin, darbepoetin alfa, and methoxy polyethylene glycol‐epoetin beta) when treating anaemia in chronic disease.

What's new

Date	Event	Description
2 October 2014	Amended	Minor edit to study name to match Specialised Register

Date	Event	Description
13 May 2014	Amended	Minor edits made to study names to match Specialised Register
15 April 2014	Amended	Contact details updated.

Database	Search terms
CENTRAL	("darbepoetin alfa" or "darbepoetin alpha"):ti,ab,kw in Clinical Trials (novel erythropoiesis stimulating protein*):ti,ab,kw in Clinical Trials (aranesp):ti,ab,kw in Clinical Trials (nesp):ti,ab,kw in Clinical Trials (#1 OR #2 OR #3 OR #4) MeSH descriptor Renal Dialysis explode all trees (hemodialysis or haemodialysis):ti,ab,kw in Clinical Trials (hemofiltration or haemofiltration):ti,ab,kw in Clinical Trials (hemodiafiltration or haemodiafiltration):ti,ab,kw in Clinical Trials MeSH descriptor Renal Insufficiency, this term only MeSH descriptor Kidney Failure, this term only MeSH descriptor Renal Insufficiency, Chronic explode all trees MeSH descriptor Kidney Diseases, this term only (end‐stage renal or end‐stage kidney or endstage renal or endstage kidney):ti,ab,kw in Clinical Trials (ESRF or ESKF or ESRD or ESKD):ti,ab,kw in Clinical Trials (predialysis or pre‐dialysis):ti,ab,kw in Clinical Trials (#6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16) (#5 AND #17)
MEDLINE	novel erythropoiesis stimulating protein$.tw. ("darbepoetin alfa" or "darbepoetin alpha").tw. aranesp.tw. nesp.tw. or/1‐4 exp Renal Dialysis/ (hemodialysis or haemodialysis).tw. (hemofiltration or haemofiltration).tw. (hemodiafiltration or haemodiafiltration).tw. dialysis.tw. (CAPD or CCPD or APD).tw. Renal Insufficiency/ Kidney Failure/ exp Renal Insufficiency, Chronic/ Kidney Diseases/ Uremia/ (end‐stage renal or end‐stage kidney or endstage renal or endstage kidney).tw. (ESRF or ESKF or ESRD or ESKD).tw. (chronic kidney or chronic renal).tw. (CKF or CKD or CRF or CRD).tw. (predialysis or pre‐dialysis).tw. ur?emi$.tw.
EMBASE	novel erythropoiesis stimulating protein/ nesp.tw. (darbepoetin alfa$ or darbepoetin alpha$).tw. aranesp.tw. or/1‐4 exp Renal Replacement Therapy/ (hemodialysis or haemodialysis).tw. (hemofiltration or haemofiltration).tw. (hemodiafiltration or haemodiafiltration).tw. dialysis.tw. (PD or CAPD or CCPD or APD).tw. Kidney Disease/ Chronic Kidney Disease/ Kidney Failure/ Chronic Kidney Failure/ Uremia/ (chronic kidney or chronic renal).tw. (CKF or CKD or CRF or CRD).tw. (end‐stage renal or end‐stage kidney or endstage renal or endstage kidney).tw. (ESRF or ESKF or ESRD or ESKD).tw. (predialysis or pre‐dialysis).tw. ur?emi$.tw. or/6‐22

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 One or more blood transfusions	1	Risk Ratio (IV, Random, 95% CI)	Totals not selected
2 Need for iron therapy	1	Risk Ratio (IV, Random, 95% CI)	Totals not selected
3 Progression to RRT	1	Risk Ratio (IV, Random, 95% CI)	Totals not selected
4 All‐cause mortality	1	Risk Ratio (IV, Random, 95% CI)	Totals not selected
5 Cardiovascular mortality	1	Risk Ratio (IV, Random, 95% CI)	Totals not selected
6 Cancer	1	Risk Ratio (IV, Random, 95% CI)	Totals not selected
7 Hypertension	1	Risk Ratio (IV, Random, 95% CI)	Totals not selected
8 Seizures	1	Risk Ratio (IV, Random, 95% CI)	Totals not selected
9 Mean change in FACT‐Fatigue score	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
10 Mean change in SF‐36 energy score	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
11 Mean change in SF‐36 physical functioning score	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 One or more blood transfusions	3		Risk Ratio (IV, Random, 95% CI)	Subtotals only
1.1 Adults	2	483	Risk Ratio (IV, Random, 95% CI)	0.80 [0.35, 1.83]
1.2 Children	1	123	Risk Ratio (IV, Random, 95% CI)	0.43 [0.14, 1.33]
2 Progression to renal replacement therapy	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only
2.1 Adults	0	0	Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Children	1	123	Risk Ratio (IV, Random, 95% CI)	0.67 [0.27, 1.66]
3 All‐cause mortality	7		Risk Ratio (IV, Random, 95% CI)	Subtotals only
3.1 Adults	6	1657	Risk Ratio (IV, Random, 95% CI)	1.35 [0.84, 2.15]
3.2 Children	1	123	Risk Ratio (IV, Random, 95% CI)	0.52 [0.03, 8.08]
4 Cardiovascular mortality	2		Risk Ratio (IV, Random, 95% CI)	Subtotals only
4.1 Adults	2	487	Risk Ratio (IV, Random, 95% CI)	0.47 [0.07, 3.17]
4.2 Children	0	0	Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5 Major cardiovascular events	2		Risk Ratio (IV, Random, 95% CI)	Subtotals only
5.1 Adults	2	840	Risk Ratio (IV, Random, 95% CI)	0.88 [0.06, 12.69]
5.2 Children	0	0	Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6 Hypertension	5		Risk Ratio (IV, Random, 95% CI)	Subtotals only
6.1 Adults	4	1412	Risk Ratio (IV, Random, 95% CI)	1.17 [0.93, 1.49]
6.2 Children	1	123	Risk Ratio (IV, Random, 95% CI)	0.96 [0.42, 2.23]
7 Seizures	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only
7.1 Adults	1	519	Risk Ratio (IV, Random, 95% CI)	1.17 [0.31, 4.46]
7.2 Children	0	0	Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
8 Vascular access thrombosis	3		Risk Ratio (IV, Random, 95% CI)	Subtotals only
8.1 Adults	2	925	Risk Ratio (IV, Random, 95% CI)	1.06 [0.63, 1.79]
8.2 Children	1	123	Risk Ratio (IV, Random, 95% CI)	0.17 [0.01, 4.20]
9 Exceeded Hb target ≥1 episodes	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only
9.1 Adults	0	0	Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
9.2 Children	1	123	Risk Ratio (IV, Random, 95% CI)	1.09 [0.57, 2.09]
10 Injection site pain	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only
10.1 Adults	0	0	Risk Ratio (IV, Random, 95% CI)	0.0 [0.0, 0.0]
10.2 Children	1	123	Risk Ratio (IV, Random, 95% CI)	1.21 [0.50, 2.92]
11 End of treatment Hb	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
11.1 Adults ‐ different haemoglobin target	1	84	Mean Difference (IV, Random, 95% CI)	1.33 [0.84, 1.82]
11.2 Adults ‐ same haemoglobin target	1	363	Mean Difference (IV, Random, 95% CI)	‐0.07 [‐0.27, 0.13]
11.3 Children	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
12 Mean change in Hb	4		Mean Difference (IV, Random, 95% CI)	Subtotals only
12.1 Adults	3	1060	Mean Difference (IV, Random, 95% CI)	0.06 [‐0.08, 0.19]
12.2 Children	1	123	Mean Difference (IV, Random, 95% CI)	0.22 [‐0.47, 0.91]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 One or more blood transfusions	2	799	Risk Ratio (IV, Random, 95% CI)	0.82 [0.58, 1.17]
2 Need for iron therapy	2	799	Risk Ratio (IV, Random, 95% CI)	1.01 [0.97, 1.05]
3 All‐cause mortality	3	1122	Risk Ratio (IV, Random, 95% CI)	0.89 [0.53, 1.51]
4 Cardiovascular mortality	1	309	Risk Ratio (IV, Random, 95% CI)	0.56 [0.17, 1.88]
5 Vascular access thrombosis	1	309	Risk Ratio (IV, Random, 95% CI)	0.91 [0.43, 1.92]
6 Hypertension	3	869	Risk Ratio (IV, Random, 95% CI)	0.77 [0.52, 1.13]
7 Achieved Hb target	1	490	Risk Ratio (IV, Random, 95% CI)	1.59 [1.33, 1.90]
8 End of treatment Hb	1	313	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.23, 0.23]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 One or more blood transfusions	2	183	Risk Ratio (IV, Random, 95% CI)	1.15 [0.30, 4.38]
2 All‐cause mortality	2	183	Risk Ratio (IV, Random, 95% CI)	1.28 [0.32, 5.06]
3 Cardiovascular mortality	2	183	Risk Ratio (IV, Random, 95% CI)	1.15 [0.30, 4.38]
4 Major cardiovascular events	1	105	Risk Ratio (IV, Random, 95% CI)	1.31 [0.23, 7.54]
5 End of treatment Hb	3	284	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.34, 0.14]
6 Mean change in Hb	1	65	Mean Difference (IV, Random, 95% CI)	0.23 [‐0.32, 0.78]

Methods	Study design: prospective cross‐over RCT Time frame: NS Follow‐up period: 20 weeks
Participants	Setting: single centre Country: Denmark Stage of CKD: stage 5D Inclusion criteria: clinically stable patients (> 18 y) receiving HD ≥ 3 months, with stable dose of rHuEpo or darbepoetin alfa for ≥ 8 weeks (defined as < 20% change in dose), stable Hb concentration in the range of 6.8 to 8.5 mmol/L and a sufficient iron supply (serum ferritin ≥ 200 μg/L or TSAT ≥ 20%) Number: treatment group 1 (35); treatment group 2 (34) Mean age ± SD (years): treatment group 1 (64.4 ± 14.1); treatment group 2 (55.4 ± 13) Sex (M/F): treatment group 1 (19/16); treatment group 2 (20/14) Exclusion criteria: received haemodiafiltration; home HD; undergone major surgery during the last 3 months (excluding vascular access surgery); ongoing infection; evidence of uncontrolled hyperparathyroidism (PTH > 70 pmol/L); clinical signs of recurrent disease; received RBC transfusion < 8 weeks before screening; active bleeding; lack of compliance; pregnant or lactating females
Interventions	Treatment group 1 Darbepoetin alfa, IV once weekly Treatment group 2 Darbepoetin alfa, SC once weekly Dose was adjusted to maintain each patient’s Hb concentration within a target range of ± 0.8 mmol/L of the mean baseline Hb and between 6.8 and 8.5 mmol/L throughout the study period
Outcomes	All‐cause mortality CV mortality Blood transfusion
Notes	Data not available for end of treatment first phase
*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)	High risk	Open‐label
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Open‐label
Incomplete outcome data (attrition bias)   All outcomes	High risk	13/71 lost to follow‐up (18.3%)
Selective reporting (reporting bias)	High risk	Important primary outcomes not reported
Other bias	High risk	Data not available for end of first phase of treatment
Intention to treat	High risk	Not performed

Methods	Study design: parallel RCT Time frame: November 2005 to April 2007 Follow‐up period: 48 weeks
Participants	Setting: multicentre Country: Japan Stage of CKD: stage 3‐5 Inclusion criteria: adult CKD patients not on dialysis; Hb < 10.0 g/dL Number: treatment group (161); control group (160) Mean age ± SD (years): treatment group (65.2 ± 11.8); control group (64.1 ± 11.7) Sex (M/F): treatment group (80/81); control group (71/89) Exclusion criteria: uncontrolled hypertension; congestive heart failure (above class III on the New York Heart Association classification); malignancy; blood disease or active bleeding; critical allergy
Interventions	Treatment group Darbepoetin alfa, SC (high Hb target: 11.0 to 12.0 g/dL) Administered once every 2 weeks, or once every 4 weeks Control group rHuEPO, SC (low Hb target: 9.0 to 11.0 g/dL) Administered once/wk or once every 2 weeks
Outcomes	Health‐related quality of life Adverse events Major cardiovascular events
Notes	Abstract publication Overall patients: 322
*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)	Unclear risk	Not described
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not described
Selective reporting (reporting bias)	High risk	Important patient‐level outcomes not reported
Other bias	High risk	Uneven dosing comparisons, abstract only, unclear number at risk
Intention to treat	Unclear risk	Not described

Methods	Study design: parallel, open‐label parallel RCT Time frame: NS Follow‐up period: 52 weeks
Participants	Setting: multicentre (4) Country: USA Stage of CKD: stage 5D Inclusion criteria: HD for at least 3 months and receiving stable IV epoetin therapy (≤ 25% change in dose) 3 times weekly for at least 2 months before the study; mean baseline Hb between 9.5 and 12.5 g/dL and adequate iron stores (TSAT ≥ 20%). Number: treatment group 1 (17); treatment group 2 (17); control group (15) Mean age ± SD (years): treatment group 1 (55.8 ± 16.3); treatment group 2 (59.1 ± 13.9); control group (55.2 ± 16.6) Sex (M/F): treatment group 1 (11/6); treatment group 2 (8/7); control group (12/3) Exclusion criteria: uncontrolled hypertension (diastolic BP > 100 mm Hg on one‐third of measurements within 3 months before enrolment); congestive heart failure (NYHA class III or IV); haematologic disorders that could cause anaemia, systemic infections, or inflammatory states or other disorders that could interfere with the response to darbepoetin or epoetin
Interventions	Treatment group Darbepoetin alfa, IV once/wk Treatment group 2 Darbepoetin alfa, IV 3 times/wk Control group Epoetin 3 times/wk
Outcomes	End of treatment Hb Mean dose intervention Time to achieve Hb target (intervention) Hb steady Adverse events
Notes
*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)	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Open‐label study
Incomplete outcome data (attrition bias)   All outcomes	High risk	11/47 lost to follow‐up (23%)
Selective reporting (reporting bias)	High risk	Important patient‐level outcomes not described
Other bias	Unclear risk	Not described
Intention to treat	Unclear risk	Not described

Methods	Study design: cross‐over RCT Time frame: May 2002 to August 2002 Follow‐up period: 24 weeks
Participants	Setting: single centre (in‐centre or satellite centre) Country: Australia Stage of CKD: stage 5D Inclusion criteria: ≥18 years of age; ≥ 1 month HD treatment; current treatment with twice or thrice weekly SC epoetin alpha therapy or once/wk darbepoetin alfa; single pool Kt/V ≥1.2; URR ≥ 65%; CRP < 25 mg/L; B12 140 to 700 pmol/L; folate 8.0‐34.0 nmol/L; iPTH < 50 pmol/L; iron replete (TSAT ≥ 25% and ferritin ≥ 200 µg/L) Number: 53 (24 analysed) Mean age ± SD: 60.3 ± 16.3 years Sex (M/F): 36/17 Exclusion criteria: inability to give informed consent or comply with treatment regimen; home HD therapy; CAPD therapy; malignancy; uncontrolled hypertension; history of seizure activity; sensitivity to IV iron therapy or darbepoetin; serum aluminium concentration > 50 mg/L; current or previous participation in another clinical study < 3 months prior to entry
Interventions	Treatment group 1 Darbepoetin alfa, IV once/wk Treatment group 2 Darbepoetin alfa, SC once/wk
Outcomes	No outcomes of interest were measured
Notes	Cross over study not included in the meta‐analysis as data for the end of the first phase of treatment not available. Overall patients 53
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated code
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias)	Unclear risk	Not described
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias)   All outcomes	High risk	29/53 lost to follow‐up (55%)
Selective reporting (reporting bias)	High risk	Important patient‐centred outcomes not described
Other bias	High risk	Data for end of first phase of treatment not available; not included in meta‐analyses
Intention to treat	High risk	Not performed

Methods	Study design: parallel RCT Time frame: Follow‐up period: 28 weeks
Participants	Setting: multicentre Country: Japan Stage of CKD: stage 5D Inclusion criteria: HD 3 times/wk and rHuEPO 2 or 3 times/wk Number: treatment group (61); control group (59) Mean age ± SD (years): NS Sex (M/F): NS Exclusion criteria: NS
Interventions	Treatment group Darbepoetin alfa, IV once/wk Control group rHuEPO, IV 2 or 3 times/wk
Outcomes	All‐cause mortality End of treatment Hb
Notes	Abstract publication
*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)	Low risk	Double blind study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not described
Selective reporting (reporting bias)	High risk	Important patient‐centred outcomes not described
Other bias	High risk	Abstract publication only
Intention to treat	Unclear risk	Not described

Methods	Study design: multicentre, parallel, RCT Time frame: Follow‐up period: 52 weeks
Participants	Setting: multicentre (82) Country: Europe, Canada, Australia Stage of CKD: stage 5D Inclusion criteria: ≥18 years, had stable chronic renal anaemia (Hb range 11–13 g/dL) and were on regular HD three times/wk for ≥12 weeks before screening and during the 4‐week screening/baseline period; undergone continuous once/wk maintenance IV darbepoetin alfa therapy for ≥ 8 weeks before screening and during the screening/baseline period; adequate iron status, defined as serum ferritin ≥100 μg/L, TSAT ≥ 20% or <10% hypochromic RBC Number: treatment group (245); control group (245) Mean age ± SD (years): treatment group (65.5 ± 13.9); control group (66.2 ± 13.6) Sex (M/F): treatment group (156/89); control group (148/97) Exclusion criteria: overt bleeding that necessitated RBC transfusion within 8 weeks of the start of screening or during the screening/baseline period; a non‐renal cause of anaemia; CRP > 30 mg/L; the likelihood of early withdrawal; life expectancy of < 12 months
Interventions	Treatment group Darbepoetin alfa, IV every 2 weeks for 26 weeks then every 4 weeks for 26 weeks Control group Methoxy polyethylene glycol‐epoetin beta, IV every 4 weeks for 52 weeks
Outcomes	All‐cause mortality Hypertension Mean dose intervention End of treatment Hb Hb steady state Blood transfusions Iron replacement intervention Achievement of Hb target
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Generated by a computer at a coordinating centre
Allocation concealment (selection bias)	Low risk	Allocation assigned by investigators who received the randomisation code by telephone
Blinding of participants and personnel (performance bias)	High risk	Not described
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Not described
Incomplete outcome data (attrition bias)   All outcomes	High risk	154/489 lost to follow‐up (31%)
Selective reporting (reporting bias)	Low risk	Patient‐relevant outcomes described
Other bias	High risk	Withdrawal due to insufficient treatment response
Intention to treat	High risk	Not performed

Methods	Study design: parallel pilot RCT Time frame: NS Follow‐up period: 24 weeks
Participants	Setting: single centre Country: UK Stage of CKD: stage 5D Inclusion criteria: HD patients receiving SC Darbepoetin alfa beta Number: treatment group (12); control group (13) Mean age (years): treatment group (57.5); control group (63.7) Sex (M/F): NS Exclusion criteria: NS
Interventions	Treatment group Darbepoetin alfa, IV once/wk, dividing their previous weekly dose of darbepoetin alfa beta by 200 Control group Epoetin beta, same dose IV they had been receiving SC
Outcomes	All‐cause mortality Adverse events Mean dose intervention End of treatment Hb Blood transfusions
Notes	Abstract publication
*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)	Unclear risk	Not described
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias)   All outcomes	High risk	25/30 lost to follow‐up (83%)
Selective reporting (reporting bias)	Low risk	All relevant outcomes described
Other bias	High risk	Abstract publication only
Intention to treat	High risk	Not performed

Methods	Study design: cross‐over, pilot RCT Time frame: NS Follow‐up period: 54 weeks
Participants	Setting: single centre Country: Italy Stage of CKD: stage 5D Inclusion criteria: stable HD patients on maintenance IV epoetin (using 2000, 4000 or 10,000 IU doses) and IV NaFe gluconate (20 to 62 mg/HD session) Number: 18 Mean age ± SD (years): NS Sex (M/F): NS Exclusion criteria: NS
Interventions	Treatment group Darbepoetin alfa, 20 or 50 μg IV doses Control group Erythropoietin alpha, 2000, 4000 or 10000 IU IV doses
Outcomes	End of treatment Hb Mean dose intervention
Notes	Abstract publication
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Coin tossing
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias)	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Open‐label study
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not described
Selective reporting (reporting bias)	High risk	Important patient‐centred outcomes not described
Other bias	High risk	Abstract publication only
Intention to treat	Unclear risk	Not described

Methods	Study design: parallel RCT Time frame: NS Follow‐up period: 36 weeks
Participants	Setting: single centre Country: UK Stage of CKD: stage 5D Inclusion criteria: prevalent HD patients (receiving HD 90 d), ≥ 18 years regardless of individual iron status, transfusion burden, Hb at randomisation, or comorbidities Number: treatment group (112); control group (105) Age; range (years): treatment group (64; 51 to 73); control group (63; 46 to 72) Sex (M/F): treatment group (40/72); control group (52/53) Exclusion criteria: inability to give informed consent; receiving home HD, unsuitability for IV iron or erythropoietic agents; uncontrolled hypertension at randomisation (DBP ≥ 100 mm Hg)
Interventions	Treatment group Darbepoetin alfa, SC once/wk Control group Epoetin, SC once/wk
Outcomes	Mean change in Hb Hb steady state Mean dose intervention Blood transfusion Adverse events
Notes
*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)	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Open‐label study
Incomplete outcome data (attrition bias)   All outcomes	High risk	55/217 lost to follow‐up (25%)
Selective reporting (reporting bias)	Low risk	Patient‐relevant outcomes described
Other bias	Unclear risk	Unclear
Intention to treat	High risk	Not performed

Study	Reason for exclusion
Akizawa 2007b	Not RCT
Argani 2009	Not appropriate intervention
Carrera 2003	Not RCT
Chen 2008	Not RCT
COMFORT Study 2007	Short duration
Deray 2003	Commentary
Disney 2007	Not RCT
Iino 2003	Short duration
Kawanishi 2005	Short duration
Lamas 2006	Not appropriate intervention
Lerner 2002	Short duration
Macdougall 1999	Short duration
Macdougall 2003	Not RCT
Mann 2007	Not RCT (post hoc analysis of 8 RCTs)
McMahon 2004	Not appropriate intervention
Murtagh 2000	Not RCT
Paganini 1989	Not RCT
Schmitt 2006	Short duration
Smith 2007	Not appropriate intervention
St Peter 1998	Short duration
Thadhani 2002	Not RCT
Tsubakihara 2003	Short duration

Trial name or title	Randomized comparison of IV C.E.R.A. (Continuous Erythropoietin Receptor Activator) and darbepoetin alfa (DA) at extended administration intervals for the maintenance of Hb levels in patients with CKD on dialysis
Methods	Country: unclear  Study design: parallel RCT  Stage of CKD: stage 5D  Follow‐up period: unclear
Participants	Estimated enrolment: 488 Inclusion criteria: HD iron‐replete patients (> 18 years) with baseline Hb 11.0 to 13.0 g/dL on previous maintenance therapy with IV darbepoetin alfa once/wk Exclusion criteria: unclear
Interventions	Treatment group IV methoxy polyethylene glycol‐epoetin beta once a month Control group IV darbepoetin alfa once every 2 weeks, once a month after week 27
Outcomes	Proportion of patients with average Hb 10.5 g/dL and average change from baseline ‐1.0 g/dL
Starting date	April 2006
Contact information	Not available
Notes

Trial name or title	Randomised controlled trial of maintaining low serum ferritin levels in patients receiving darbepoetin (Aranesp®)
Methods	Country: UK  Study design: parallel RCT  Stage of CKD: stage 5D  Follow‐up period: unclear
Participants	Estimated enrolment: not provided at time of registration Inclusion criteria: patients drawn from the population of HD patients attending Leeds General Infirmary Renal Unit Exclusion criteria: not provided at time of registration
Interventions	Maintenance of normal ferritin Maintenance of elevated ferritin (standard therapy)
Outcomes	Hb (g/dL) Darbepoetin (µg/kg/wk) Serum Ferritin Iron dose (mg/kg/wk) TSAT% CRP
Starting date	Anticipated start date:01/11/2002
Contact information	Dr R Dedi Renal and Liver Services  St James's University Hospital  Beckett Street Leeds LS1 3EX United Kingdom Tel +44 (0)113 243 3144 Fax +44 (0)113 242 6496 Email comdhfo@stjames.leeds.ac.uk
Notes	Completed

Trial name or title	The effect of darbepoetin for renal anemia and iron kinetics in chronic kidney disease (CKD) patients
Methods	Country: Japan  Study design: cross‐over RCT  Stage of CKD: Stage 3 to 5  Follow‐up period: unclear
Participants	Estimated enrolment: 20 Inclusion criteria: CKD patients (20 to 85 years old) with Hb < 11.0 mg/dL Exclusion criteria: severe heart failure; impossible control of hypertension
Interventions	Epoetin Darbepoetin
Outcomes	The mean Hb change and the achievement rate of Hb target concentration Iron kinetics
Starting date	February 2010
Contact information	Takayasu Ito 3‐11 Kotobuki‐cho Kuwana city Mie prefecture Japan Email: takayassu@msn.com Yamamoto General Hospital Internal Medicine
Notes	Open public recruiting

PERMALINK

Darbepoetin for the anaemia of chronic kidney disease

Suetonia C Palmer

Valeria Saglimbene

Jonathan C Craig

Sankar D Navaneethan

Giovanni FM Strippoli

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

Darbepoetin alfa versus placebo or no treatment

Darbepoetin alfa versus epoetin alfa or beta

Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta

Darbepoetin alfa every two weeks versus darbepoetin every four weeks

Darbepoetin alfa weekly versus darbepoetin every two weeks

Darbepoetin alfa intravenous versus subcutaneous administration

Other comparisons

Risk of bias in included studies

2.

3.

Allocation

Random sequence generation

Allocation concealment

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Darbepoetin alfa versus placebo

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

1.4. Analysis.

1.5. Analysis.

1.6. Analysis.

1.7. Analysis.

1.8. Analysis.

1.9. Analysis.

1.10. Analysis.

1.11. Analysis.

Darbepoetin alfa versus epoetin

2.1. Analysis.

2.2. Analysis.

Trial name or title	Randomised, double‐blind, equivalence study of the efficacy of darbepoetin alfa manufactured by serum free bioreactor technology and darbepoetin alfa manufactured by roller‐bottle technology for the treatment of anaemia in patients with chronic kidney disease receiving haemodialysis
Methods	Country: multinational  Study design: multicentre, double‐blind, parallel RCT  Stage of CKD: stage 5D  Follow‐up period: 30 weeks
Participants	Estimated enrolment: 446 Inclusion criteria: diagnosis of CKD and receiving HD for≥ 3 months before enrolment; no prior exposure to EPREX® or NeoRecorman®; baseline Hb between 10 and 13 g/dL; on stable weekly or once every other week IV or SC darbepoetin therapy for at least 6 weeks prior to screening (stable is defined as < 25% change in weekly dose and no change in frequency); adequate iron stores (serum ferritin ≥ 100 mg/L); before any study‐specific procedure, the appropriate written informed consent must be obtained Exclusion criteria: scheduled to receive a kidney transplant; uncontrolled hypertension, defined as a predialysis SBP > 180 mm Hg and/or DBP of >110 mm Hg; acute myocardial ischemias; hospitalizations for congestive heart failure, MI, deep vein thrombosis, cerebrovascular event (stroke or transient ischaemic attack) within 12 weeks before enrolment; PTH > 1500 pg/mL; major surgery within 12 weeks before enrolment (excluding vascular access surgery); currently receiving antibiotic therapy for systemic infection; known positive HIV antibody or positive hepatitis B surface antigen; clinical evidence of current malignancy and/or receiving systemic chemotherapy/radiotherapy with the exception of basal cell or squamous cell carcinoma of the skin and cervical intraepithelial neoplasia; RBC transfusions within 8 weeks before enrolment; androgen therapy within 8 weeks before enrolment; systemic haematologic disease (e.g. sickle cell anaemia, myelodysplastic syndromes, haematologic malignancy; myeloma; haemolytic anaemia); any disorder that may impact (in the judgment of the investigator) the ability to give informed consent for participation in this study; pregnant or breast‐feeding women, all subjects must practice adequate contraception (in the judgment of the investigator) throughout this study; treatment with an investigational agent or device within 30 days before enrolment or scheduled to receive an investigational agent other than those specified by this protocol during the course of this study; subject has known sensitivity to any of the products to be administered during dosing.
Interventions	Darbepoetin alfa (roller bottle), SC or IV, once/wk or once every two weeks Darbepoetin alfa (serum free), SC or IV, once/wk or once every two weeks
Outcomes	Change in Hb level between the screening/baseline period and the evaluation period The ratio of weekly dosing requirements between baseline and the evaluation period Change from baseline Hb over time Proportion of subjects maintaining mean Hb within target range during evaluation period Average darbepoetin alfa dose over evaluation period Change from baseline dose over time
Starting date	March 2005
Contact information	Global Development Leader, Amgen Inc.
Notes	Last Updated in clinicaltrial.gov: February 2008

Trial name or title	A multi‐centre, double‐blind, randomised study evaluating de novo weekly and once every two week darbepoetin alfa dosing for the correction of anaemia in paediatric subjects with chronic kidney disease receiving and not receiving dialysis
Methods	Country: multinational  Study design: multicentre, single‐blind, parallel RCT  Stage of CKD: Stage 3 to 5 (paediatric)  Follow‐up period: Unclear
Participants	Estimated enrolment: 150 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 haematologic 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 ischaemia, hospitalisation for congestive heart failure, MI, stroke or transient ischaemia attack; prior history (within 6 months prior to randomisation) of thromboembolism
Interventions	Darbepoetin alfa once/wk, IV or SC Darbepoetin alfa once every 2 weeks, IV or SC
Outcomes	Proportion of subjects achieving a Hb ≥ 10.0 g/dL at any time point after the first dose during the study Health‐related quality of life in paediatric CKD subjects ≥ 2 years old over the duration of the study Pharmacokinetic data in subjects < 6 years of age Safety and tolerability of darbepoetin alfa administered once/wk and once every 2 weeks Hb values over the duration of the study Doses over the duration of the study
Starting date	August 2008
Contact information	Global Development Leader, Amgen Inc. Amgen Call Center 866‐572‐6436
Notes	Estimated Study Completion Date: July 2013

Trial name or title	An open‐label, randomized, multi‐center, parallel group non‐inferiority study of subcutaneous injections of RO0503821 given once monthly vs. darbepoetin alfa given according to local label in patients with chronic kidney disease who are not on dialysis
Methods	Country: multinational  Study design: open‐label, multi‐centre, parallel non‐inferiority RCT  Stage of CKD: stage 3 to 5  Follow‐up period: 40 weeks
Participants	Treatment group Number:114 Age: 71.3 (11.03) Sex (M/F):48/66 Control group Number:114 Age: 69.6 (14.02) Sex (M/F):48/66 Inclusion criteria: adult patients, ≥18 years; CKD, not requiring dialysis; receiving darbepoetin alfa maintenance therapy for ≥ 8 weeks before screening, and during screening/baseline period. Exclusion criteria: overt gastrointestinal bleeding within 8 weeks before screening, or during screening/baseline period; transfusion of RBC within 8 weeks before screening, or during screening/baseline period; active malignant disease; previous treatment with Mircera
Interventions	Darbepoetin alfa, SC once/mo Darbepoetin alfa, SC once/wk, once every 2 weeks or once every month as per local labelling specifications.
Outcomes	Change in Hb concentration from baseline to the evaluation period Change in Hb concentration from baseline over time Number of participants with RBC transfusions Participants with adverse events
Starting date	September 2007
Contact information	Hoffmann‐La Roche
Notes	Study completion date: August 2010 Primary completion date: August 2010 (Final data collection date for primary outcome measure)

Trial name or title	An open‐label, randomised, multicenter, parallel‐group study to demonstrate correction of anaemia using once every 4 weeks subcutaneous injections of in patients with chronic kidney disease who are not on dialysis
Methods	Country: multinational  Study design: open‐label, multi‐centre, parallel RCT  Stage of CKD: stage 3 to 5  Follow‐up period: 28 weeks
Participants	Estimated enrolment: 307 Inclusion criteria: adult patients, ≥18 years; CKD; anaemia; not on dialysis Exclusion criteria: previous therapy with any ESA within 12 weeks prior to screening; kidney allograft in place; immunosuppressive therapy in the 12 weeks prior to screening
Interventions	Methoxy polyethylene glycol‐epoetin beta, SC 1.2 µg/kg/mo, starting dose Darbepoetin alfa, SC 0.45 µg/kg/wk, starting dose
Outcomes	Hb response rate, and change in average Hb concentration Hb values and change over time Time to target Hb response incidence of RBC transfusions percentage of patients with stable Hb response number of dose adjustments required Percentage of patients with ≥ 1 Hb > 12 g/dL AEs, laboratory parameters Vital signs
Starting date	Not available
Contact information	Hoffmann‐La Roche
Notes	Completed in June 2010

Trial name or title	An open label randomised controlled study to compare the efficacy, safety and tolerability of once‐monthly administration of subcutaneous versus darbepoetin alfa for the maintenance of haemoglobin levels in renal transplant recipients with chronic renal anaemia
Methods	Country: Spain  Setting/design: open‐label, parallel RCT  Stage of CKD: transplant  Follow‐up period: 24 weeks
Participants	Estimated enrolment: 71 Inclusion criteria: adult patients, ≥18 years of age; kidney transplant recipients with stage 3 or 4 CKD; functioning graft of >6 months and <10 years after kidney transplantation, with no signs of acute rejection; stable maintenance subcutaneous darbepoetin alfa therapy every 2 weeks Exclusion criteria: transfusion of red blood cells during previous 2 months; poorly controlled hypertension; significant acute or chronic bleeding; need for dialysis therapy expected in next 6 months
Interventions	Methoxy polyethylene glycol‐epoetin beta:120, 200 or 360 µg SC 4‐weekly starting dose Darbepoetin alfa, as prescribed
Outcomes	Percentage of patients maintaining average Hb concentration within ± 1g/dL of reference Hb, and between 10 to 12 g/dL Change in Hb concentration, and percentage of patients maintaining Hb concentration in 10 to 12 g/dL range Mean time in 10 to 12 g/dL range Percentage of patients needing dose adjustments Incidence of RBC transfusions AEs, laboratory parameters
Starting date	Not available
Contact information	Not available
Notes	Completed in January 2011

Trial name or title	A randomised, controlled, open‐label, French multicenter parallel group study to compare the haemoglobin maintenance with once monthly administration of versus epoetin beta or darbepoetin alfa in patients with chronic kidney disease on hemodialysis
Methods	Country: France  Study design: open‐label, multicentre parallel RCT  Stage of CKD: dialysis  Follow‐up period: 24 weeks
Participants	Estimated enrolment: 421 Inclusion criteria: adult patients, ≥18 years of age; 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 RBC 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 > 16,000 UI, or weekly dose of darbepoetin alfa > 80 µg during previous month
Interventions	Methoxy polyethylene glycol‐epoetin beta: 120 µg or 200 µg IV or SC (starting dose) Epoetin beta or darbepoetin alfa, as prescribed
Outcomes	Percentage of patients maintaining average Hb concentration within target range (10 to 12 g/dL) Mean change in Hb concentration between reference and evaluation period, and mean time spent in Hb range of 10 to 12 g/dL Dose adjustments RBC transfusions AEs
Starting date	September 2008
Contact information	Hoffmann‐La Roche
Notes	This study is ongoing, but not recruiting participants

Trial name or title	A randomized, open label study to assess all‐cause mortality and cardiovascular mortality in patients with chronic kidney disease on dialysis and those not on renal replacement therapy under treatment with reference ESAs
Methods	Country: multinational  Study design: multicentre, open‐label RCT  Stage of CKD: stage 3 to 5, 5D  Follow‐up period: event driven
Participants	Estimated enrolment: 2800 Inclusion criteria: male or female patients > 18 years with symptomatic anaemia associated with CKD; patients with renal anaemia (Hb < 11.0 g/dL) not treated with an ESA or on maintenance ESA therapy; if receiving HD or PD, with the same mode of dialysis for at least 3 months before screening, and continuous IV or SC maintenance therapy with ESAs at the same dosing interval for at least 2 months before screening; Hb concentration between 10 and 12g/dL; adequate iron status (ferritin ≥ 100 µg/L or TSAT ≥ 20% Exclusion criteria: uncontrolled hypertension; history of haemoglobinopathy; anaemia due to haemolysis; pure red cell aplasia
Interventions	Methoxy polyethylene glycol‐epoetin beta: 0.6 µg/kg IV every 2 weeks in patients not already receiving ESAs; starting dose 120, 200 or 360 µg monthly in patients receiving maintenance ESA therapy. ESAs (darbepoetin alfa, epoetin alfa or epoetin beta) as prescribed
Outcomes	Time to composite of all‐cause mortality and non‐fatal cardiovascular events (MI, stroke) Time to the individual components of the composite end point: time to death, time to non‐fatal cardiovascular events (MI or stroke), time to MI and time to stroke Incidence of adverse events, and serious adverse events; vital signs, laboratory parameters, ECG
Starting date	December 2008
Contact information	Hoffmann‐La Roche
Notes	This study is currently recruiting participants

Trial name or title	A multicenter, randomised, double‐blind study comparing de novo once monthly and once every 2 week darbepoetin alfa dosing for the correction of anaemia in subjects with chronic kidney disease not receiving dialysis
Methods	Country: multinational  Study design: multicentre, double‐blind RCT  Stage of CKD: stage 3 to 5  Follow‐up period: 33 weeks
Participants	Estimated enrolment: 540 Inclusion criteria: ≥ 18 years; diagnosis of CKD with eGFR of 15 to 59 mL/min/1.73 m²; two consecutive screening Hb values taken at least 7 days apart must each be < 10.0 g/dL; TSAT ≥ 15% Exclusion criteria: upper or lower GI bleeding within 6 months before enrolment; ESA use within 12 weeks before enrolment; uncontrolled hypertension; systemic haematologic disorders; prior history within 12 weeks before enrolment of events including: acute myocardial ischaemia, unstable angina, MI, hospitalisation for congestive heart failure, stroke or transient ischaemic attack, limb ischaemia, deep vein thrombosis, thromboembolism; grand mal seizure within 6 months prior to enrolment; evidence of, or received chemotherapy or radiation therapy for a malignancy within 5 years prior to enrolment; RBC transfusion within 12 weeks prior to enrolment; androgen therapy within 8 weeks prior to enrolment; pregnancy or breast feeding, or inadequate contraception; currently receiving immunosuppressive therapy
Interventions	Darbepoetin alfa: once per month Darbepoetin alfa: once every 2 weeks
Outcomes	Hb change between baseline Achievement of both a Hb ≥ 10.0 g/dL and a ≥ 1.0 g/dL increase from baseline at any time point Darbepoetin alfa doses over duration of study Safety profiles Hb at each scheduled time point during the study Ratio of darbepoetin alfa doses over the duration of the study and during the evaluation period Dose at first Hb ≥ 10.0 g/dL and a ≥ 1.0 g/dL increase from baseline
Starting date	June 2009
Contact information	Global Development Leader, Amgen Inc.
Notes	This study is currently recruiting participants.

Trial name or title	Neocytolysis in the treatment of renal anemia With erythropoieses stimulating agents (ESA)
Methods	Cross‐over open‐label RCT
Participants	Adults treated with dialysis and Hb between 11 and 13 g/dL within the last 2 months on an ESA for at least 8 weeks
Interventions	Sequential application of epoetin, methoxy polyethylene glycol‐epoetin beta and darbepoetin
Outcomes	Reticulocyte count on day 7
Starting date	January 2011
Contact information	Michael Dickenmann, MD, Transplantation Immunology and Nephrology, University Hospital, Basel, Switzerland
Notes	Likely to be excluded due to short duration

Trial name or title	A randomised single‐blind study to improve health‐related quality of life as measured by the sf‐36 vitality score by correcting anaemia with Aranesp (darbepoetin alfa) in the elderly
Methods	Country: multinational  Study design: multicentre, single‐blind, placebo‐controlled, parallel RCT  Stage of CKD: stage 3 to 5  Follow‐up period: 36 weeks
Participants	Estimated enrolment: 51 Inclusion criteria: stage 3 to 5 CKD not on dialysis; subjects ≥ 70 years; Hb < 110 g/L at screening; TSAT ≥ 15% at screening Exclusion criteria: clinical history of type 2 diabetes mellitus; anticipating or scheduled to go on RRT in the next year, including renal transplant; uncontrolled hypertension on two separate measurements during screening; use of any erythropoietic protein within 12 weeks of screening
Interventions	Darbepoetin alfa SC once every 2 weeks Placebo SC once every 2 weeks
Outcomes	SF‐36 vitality subscale score Proportion of subjects achieving a Hb greater than or equal to 110g/L Mean Hb SF‐36 subscale scores, FACT‐An subscale scores and EQ‐5D scores Grip strength Lower extremity function
Starting date	August 2006
Contact information	Global Development Leader, Amgen Inc.
Notes	Active, not recruiting