Abstract
Background
Erythropoiesis‐stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with cardiovascular events. This is an update of a Cochrane review first published in 2014.
Objectives
To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol‐epoetin beta, and biosimilar ESAs against each other, placebo, or no treatment) to treat anaemia in adults with CKD.
Search methods
In this update, we searched the Cochrane Kidney and Transplant Register of Studies up to 29 April 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Selection criteria
Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol‐epoetin beta, a biosimilar epoetin or a biosimilar darbepoetin alfa) with another ESA, placebo or no treatment in adults with CKD were considered for inclusion.
Data collection and analysis
Two independent authors screened the search results and extracted data. Data synthesis was performed using random‐effects pairwise meta‐analysis (expressed as odds ratios (OR) and their 95% confidence intervals (CI)) and network meta‐analysis. We assessed for heterogeneity and inconsistency within meta‐analyses using standard techniques and planned subgroup and meta‐regression to explore sources of heterogeneity or inconsistency. We assessed certainty in treatment estimates for the primary outcomes (preventing blood transfusions and death (any cause)) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Main results
Sixty‐two new studies (9237 participants) were included in this update, so the review now includes 117 studies with 25,237 participants. Most studies were at high or unclear risk of bias in most methodological domains. Overall, results remain similar in this update compared to our previous review in 2014.
For preventing blood transfusion, epoetin alfa (OR 0.28, 95% CI 0.13 to 0.61; low certainty evidence) and epoetin beta (OR 0.19, 95% CI 0.08 to 0.47; low certainty evidence) may be superior to placebo, and darbepoetin alfa was probably superior to placebo (OR 0.27, 95% CI 0.11 to 0.67; moderate certainty evidence). Methoxy polyethylene glycol‐epoetin beta (OR 0.33, 95% CI 0.11 to 1.02; very low certainty evidence), a biosimilar epoetin (OR 0.34, 95% CI 0.11 to 1.03; very low certainty evidence) and a biosimilar darbepoetin alfa (OR 0.37, 95% CI 0.07 to 1.91; very low certainty evidence) had uncertain effects on preventing blood transfusion compared to placebo. The comparative effects of ESAs compared with another ESA on preventing blood transfusions were uncertain, in low to very low certainty evidence.
Effects on death (any cause) were uncertain for epoetin alfa (OR 0.79, 95% CI 0.51 to 1.22; low certainty evidence), epoetin beta (OR 0.69, 95% CI 0.40 to 1.20; low certainty evidence), methoxy polyethylene glycol‐epoetin beta (OR 1.07, 95% CI 0.67 to 1.71; very low certainty evidence), a biosimilar epoetin (OR 0.80, 95% CI 0.47 to 1.36; low certainty evidence) and a biosimilar darbepoetin alfa (OR 1.63, 95% CI 0.51 to 5.23; very low certainty evidence) compared to placebo. There was probably no difference between darbepoetin alfa and placebo on the odds of death (any cause) (OR 0.99, 95% CI 0.81 to 1.21; moderate certainty evidence). The comparative effects of ESAs compared with another ESA on death (any cause) were uncertain in low to very low certainty evidence.
Epoetin beta probably increased the odds of hypertension when compared to placebo (OR 2.17, 95% CI 1.17 to 4.00; moderate certainty evidence). Compared to placebo, epoetin alfa (OR 2.10, 95% CI 1.22 to 3.59; very low certainty evidence), darbepoetin alfa (OR 1.88, 95% CI 1.12 to 3.14; low certainty evidence) and methoxy polyethylene glycol‐epoetin beta (OR 1.98, 95% CI 1.05 to 3.74; low certainty evidence) may increase the odds of hypertension, but a biosimilar epoetin (OR 1.88, 95% CI 0.96 to 3.67; low certainty evidence) and biosimilar darbepoetin alfa (OR 1.98, 95% CI 0.84 to 4.66; low certainty evidence) had uncertain effects on hypertension. The comparative effects of all ESAs compared with another ESA, placebo or no treatment on cardiovascular death, myocardial infarction, stroke, vascular access thrombosis, kidney failure, and breathlessness were uncertain. Network analysis for fatigue was not possible due to sparse data.
Authors' conclusions
The comparative effects of different ESAs on blood transfusions, death (any cause and cardiovascular), major cardiovascular events, myocardial infarction, stroke, vascular access thrombosis, kidney failure, fatigue and breathlessness were uncertain.
Keywords: Adult; Humans; Anemia; Anemia/drug therapy; Anemia/etiology; Biosimilar Pharmaceuticals; Biosimilar Pharmaceuticals/adverse effects; Darbepoetin alfa; Darbepoetin alfa/therapeutic use; Dyspnea; Dyspnea/drug therapy; Epoetin Alfa; Epoetin Alfa/therapeutic use; Erythropoiesis; Hematinics; Hematinics/adverse effects; Hypertension; Hypertension/drug therapy; Myocardial Infarction; Myocardial Infarction/drug therapy; Network Meta-Analysis; Renal Insufficiency, Chronic; Renal Insufficiency, Chronic/complications; Renal Insufficiency, Chronic/drug therapy; Thrombosis
Plain language summary
The relative safety and effectiveness of different epoetin drugs for treating anaemia in people with chronic kidney disease
What is the issue? A low red blood cell count (anaemia) is common in people with chronic kidney disease and may cause symptoms such as tiredness or breathlessness, as well as increase the need for a blood transfusion. Epoetin drugs are injectable medications (into the skin or bloodstream) that are used to treat anaemia in people with chronic kidney disease. However, whether epoetin drugs have different benefits and harms when compared to each other is not known because research studies are not available. One way to compare different drugs when a clinical trial has been done is to use a technique called network meta‐analysis.
What did we do?
We reviewed the available studies looking at epoetin drugs in adults with chronic kidney disease (including those not needing dialysis, those needing dialysis and those who have received a kidney transplant) to assess their potential benefits and harms when compared to placebo or between different forms of epoetin drugs. We looked at whether they prevented the need for blood transfusions, reduced fatigue or breathlessness, and whether they caused death, heart disease, stroke, high blood pressure, clotting of a fistula or vascular catheter needed for dialysis, or kidney failure in people who have milder kidney disease.
What did we find?
Based on existing research, we cannot be confident that different epoetin drugs are better or worse than each other for chances of needing a blood transfusion, death, a heart attack or stroke, having a clot in a fistula or dialysis vascular catheter, or the chances of needing dialysis for people with milder kidney disease. We are also unsure whether different forms of epoetin drugs are better at improving symptoms of anaemia, such as tiredness or breathlessness, which were not reported in most available research studies.
Conclusions
Whether different forms of epoetin drugs are better or safer than each other remains unclear.
Summary of findings
Summary of findings 1. Erythropoiesis‐stimulating agents (ESAs) for anaemia in adults with chronic kidney disease (CKD).
| ESAs for anaemia in adults with CKD | |||||
| Intervention | Comparison/intervention | Nature of the evidence | Confidence in the evidence | Reasons for downgrading our confidence in the evidence* | Network treatment estimate OR (95% CI) |
| Preventing blood transfusion | |||||
| Epoetin alfa | Placebo | Mixed | Low | Study limitations (‐1) Inconsistency (‐1) |
0.28 (0.13 to 0.61) |
| Epoetin beta | Placebo | Mixed | Low | Study limitations (‐1) Inconsistency (‐1) |
0.19 (0.08 to 0.47) |
| Darbepoetin alfa | Placebo | Mixed | Moderate | Inconsistency (‐1) | 0.27 (0.11 to 0.69) |
| Methoxy polyethylene glycol‐epoetin beta |
Placebo | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
0.33 (0.11 to 1.02) |
| Biosimilar epoetin | Placebo | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
0.34 (0.11 to 1.03) |
| Biosimilar darbepoetin alfa | Placebo | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
0.37 (0.07 to 1.91) |
| Epoetin alfa | Epoetin beta | Indirect | Very low | Study limitations (‐2) Inconsistency (‐1) Imprecision (‐1) |
0.69 (0.23 to 2.06) |
| Epoetin alfa | Darbepoetin alfa | Mixed | Very low | Study limitations (‐2) Inconsistency (‐1) Imprecision (‐1) |
0.98 (0.41 to 2.37) |
| Epoetin alfa | Methoxy polyethylene glycol‐epoetin beta |
Indirect | Very low | Study limitations (‐2) Inconsistency (‐1) Imprecision (‐1) |
1.19 (0.38 to 3.75) |
| Epoetin alfa | Biosimilar epoetin | Mixed | Very low | Study limitations (‐1) Imprecision (‐1) Imprecision (‐1) |
1.21 (0.53 to 2.76) |
| Epoetin alfa | Biosimilar darbepoetin alfa | Mixed | Very low | Study limitations (‐1) Imprecision (‐1) Imprecision (‐1) |
1.34 (0.31 to 5.81) |
| Epoetin beta | Darbepoetin alfa | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
1.43 (0.47 to 4.34) |
| Epoetin beta | Methoxy polyethylene glycol‐epoetin beta |
Mixed | Very low | Study limitations (‐2) Inconsistency (‐1) Imprecision (‐1) |
1.72 (0.55 to 5.43) |
| Epoetin beta | Biosimilar epoetin | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
1.76 (0.45 to 6.79) |
| Epoetin beta | Biosimilar darbepoetin alfa | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
1.94 (0.32 to 11.59) |
| Darbepoetin alfa | Methoxy polyethylene glycol‐epoetin beta |
Mixed | Very low | Study limitations (‐2) Inconsistency (‐1) Imprecision (‐1) |
1.21 (0.50 to 2.92) |
| Darbepoetin alfa | Biosimilar epoetin | Mixed | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
1.23 (0.38 to 3.96) |
| Darbepoetin alfa | Biosimilar darbepoetin alfa | Mixed | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
1.36 (0.27 to 6.83) |
| Methoxy polyethylene glycol‐epoetin beta |
Biosimilar epoetin | Indirect | Very low | Study limitations (‐2) Inconsistency (‐1) Imprecision (‐1) |
1.02 (0.25 to 4.09) |
| Methoxy polyethylene glycol‐epoetin beta |
Biosimilar darbepoetin alfa | Indirect | Very low | Study limitations (‐2) Inconsistency (‐1) Imprecision (‐1) |
1.13 (0.19 to 6.75) |
| Biosimilar epoetin | Biosimilar darbepoetin alfa | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
1.10 (0.21 to 5.91) |
| Death (any cause) | |||||
| Epoetin alfa | Placebo | Mixed | Low | Study limitations (‐1) Imprecision (‐1) |
0.79 (0.51 to 1.22) |
| Epoetin beta | Placebo | Mixed | Low | Study limitations (‐1) Imprecision (‐1) |
0.69 (0.40 to 1.20) |
| Darbepoetin alfa | Placebo | Mixed | Moderate | Imprecision (‐1) | 0.99 (0.81 to 1.21) |
| Methoxy polyethylene glycol‐epoetin beta |
Placebo | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
1.07 (0.67 to 1.71) |
| Biosimilar epoetin | Placebo | Mixed | Low | Study limitations (‐1) Imprecision (‐1) |
0.80 (0.47 to 1.36) |
| Biosimilar darbepoetin alfa | Placebo | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
1.63 (0.51 to 5.23) |
| Epoetin alfa | Epoetin beta | Indirect | Low | Study limitations (‐1) Imprecision (‐1) |
0.88 (0.48 to 1.61) |
| Epoetin alfa | Darbepoetin alfa | Mixed | Low | Study limitations (‐1) Imprecision (‐1) |
1.26 (0.84 to 1.89) |
| Epoetin alfa | Methoxy polyethylene glycol‐epoetin beta |
Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
1.36 (0.76 to 2.43) |
| Epoetin alfa | Biosimilar epoetin | Mixed | Low | Study limitations (‐1) Imprecision (‐1) |
1.01 (0.74 to 1.39) |
| Epoetin alfa | Biosimilar darbepoetin alfa | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
2.07 (0.61 to 6.97) |
| Epoetin beta | Darbepoetin alfa | Mixed | Low | Study limitations (‐1) Imprecision (‐1) |
1.43 (0.84 to 2.44) |
| Epoetin beta | Methoxy polyethylene glycol‐epoetin beta |
Mixed | Low | Study limitations (‐1) Imprecision (‐1) |
1.54 (0.80 to 2.97) |
| Epoetin beta | Biosimilar epoetin | Mixed | Low | Study limitations (‐1) Imprecision (‐1) |
1.15 (0.59 to 2.25) |
| Epoetin beta | Biosimilar darbepoetin alfa | Indirect | Very low | Study limitations (‐1) Imprecision (‐1) |
2.35 (0.66 to 8.32) |
| Darbepoetin alfa | Methoxy polyethylene glycol‐epoetin beta |
Mixed | Low | Study limitations (‐1) Imprecision (‐1) |
1.08 (0.71 to 1.65) |
| Darbepoetin alfa | Biosimilar epoetin | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
0.80 (0.48 to 1.34) |
| Darbepoetin alfa | Biosimilar darbepoetin alfa | Mixed | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
1.64 (0.52 to 5.18) |
| Methoxy polyethylene glycol‐epoetin beta |
Biosimilar epoetin | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
0.75 (0.39 to 1.44) |
| Methoxy polyethylene glycol‐epoetin beta |
Biosimilar darbepoetin alfa | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
1.52 (0.45 to 5.18) |
| Biosimilar epoetin | Biosimilar darbepoetin alfa | Indirect | Very low | Study limitations (‐1) Inconsistency (‐1) Imprecision (‐1) |
2.04 (0.58 to 7.17) |
|
CI: Confidence interval; OR: Odds ratio *There was moderate heterogeneity in the network for preventing blood transfusion (τ = 0.53 which was between the 50th and 75th quartile of empirical distributions of heterogeneity variances specific to the type of outcome and types of treatments being compared) (Turner 2012) We downgraded for inconsistency when the network did not include a closed loop of evidence for the comparison between direct and indirect estimates. Accordingly, the presence of inconsistency could not be excluded. | |||||
| GRADE Working Group grades of evidence (GRADE 2011) High certainty: We are very confident that the true effect lies close to that of the estimate of effect Moderate certainty: We are moderately confident in the estimate of effect: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect | |||||
Background
Description of the condition
Anaemia is common amongst people with chronic kidney disease (CKD) and is defined by the World Health Organization as a haemoglobin (Hb) level below 130 g/L in men and below 120 g/L in women (WHO 2008). Anaemia affects around 10% of people with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m² and up to two‐thirds of people with an eGFR < 15 mL/min/1.73 m² (Astor 2002). Declining kidney function causes a reduction in erythropoietin (EPO) production by the kidney, which is responsible for stimulating the production of red blood cells (RBC) in the bone marrow. Other factors contributing to anaemia in people with advanced CKD include poor iron absorption from chronic inflammation, malnutrition, chronic haemolysis attributed to uraemic toxins, secondary hyperparathyroidism causing EPO resistance, and residual blood loss during haemodialysis treatment sessions (Zadrazil 2015). Anaemia can cause symptoms of insufficient oxygen delivery to tissues, such as weakness and fatigue, breathlessness, light‐headedness, and palpitations. Furthermore, anaemia in people with CKD has been associated with hospitalisation, cardiovascular events and death (Collins 2001; Weiner 2005).
Description of the intervention
Erythropoiesis‐stimulating agents (ESAs) are a group of medications made of recombinant EPO and its synthetic derivatives (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol‐epoetin beta). They are commonly used to treat anaemia in multiple chronic diseases associated with reduced production of EPO in response to hypoxia (CKD; chronic inflammatory conditions), inadequate production of RBC by the bone marrow in response to EPO (chronic inflammatory conditions, bone marrow failure due to infiltration or drug‐related therapy; insufficient iron stores; vitamin B12 deficiency), abnormal production or function of Hb (thalassaemia or haemoglobinopathies), or excessive RBC losses (destruction within the circulation or haemorrhage) (Figure 1).
1.
Overview of anaemia in chronic disease
Epoetin alfa and epoetin beta are synthesised from cultures of transformed Chinese hamster ovary cells that carry the human EPO gene, differing only in their glycosylation pattern (Macdougall 2008). Other epoetin derivatives differ in their cell culture conditions which produced different amino acid sequences in some formulations (e.g. epoetin omega) whilst leaving others unchanged (e.g. epoetin delta) (Macdougall 2008). In contrast, darbepoetin alfa was produced by adding N‐linked carbohydrate chains to epoetin, which improved its stability and increased its half‐life three‐fold (25 hours) compared to epoetin alfa (8.5 hours) (Macdougall 1999). A further increase in the half‐life of methoxy polyethylene glycol‐epoetin beta to 130 hours was made possible with the addition of a methoxy polyethylene glycol polymer chain and has permitted less frequent dosing regimens of once every two to four weeks (Provenzano 2007a).
How the intervention might work
ESAs revolutionised the treatment of anaemia in CKD, particularly reducing the transfusion‐dependence of dialysis patients and the associated need for additional hospital visits and risks of iron overload, blood‐borne infections and antigen sensitisation affecting potential future kidney transplant outcomes. However, the use of ESAs to correct the Hb level in both people with non‐dialysis CKD and dialysis‐dependent CKD consistently conferred a higher risk of cardiovascular events and death in both large randomised controlled trials (RCTs) (Besarab 1998; CHOIR 2006; CREATE 2001; TREAT 2005) and subsequent meta‐analyses of RCTs (Bohlius 2009; Palmer 2010; Phrommintikul 2007; Strippoli 2006). Furthermore, whilst placebo‐controlled RCTs demonstrated a reduction in blood transfusions with ESA use (Besarab 1998; TREAT 2005), there was no consistent improvement in quality of life (QoL) (CHOIR 2006; CREATE 2001; TREAT 2005).
Potential mechanisms underlying these observations include the presence of EPO receptors on vascular endothelial cells and smooth muscle cells, with EPO being a potent vasoconstrictor in both in vivo and in vitro studies (Agarwal 2017). The dose‐dependent association between ESA and death demonstrated in a large meta‐regression of 31 RCTs (Koulouridis 2013) and in observational studies (Kilpatrick 2008; Szczech 2008) also suggested the dose of ESA contributed to harm rather than simply achieving a high Hb level.
As a result, clinical practice guidelines for the management of anaemia in CKD have strongly recommended against the use of ESAs to correct anaemia with Hb > 13.0 g/dL, instead suggesting the use of ESAs in dialysis patients to avoid Hb < 9.0 g/dL (KDIGO 2012) and target a Hb between 10.0 to 12.0 g/dL (Padhi 2015). This echoes the Food and Drug Administration label on ESAs suggesting their use in people with CKD only when the Hb < 100 g/L with the goal of increasing Hb levels to a sufficient degree to reduce the need for blood transfusions (FDA website).
Why it is important to do this review
The previous version of this review in 2014 concluded that the comparative efficacy and safety of different ESAs remained uncertain (Palmer 2014). Since then, multiple RCTs assessing newer synthetic forms of ESAs, such as methoxy polyethylene glycol‐epoetin beta (a continuous erythropoietin‐receptor activator (CERA)) and biosimilar ESAs have been published. In particular, biosimilar ESAs may provide a more cost‐effective option in certain healthcare settings, but data on their use from RCTs were sparse in the previous version of this review (Palmer 2014). Furthermore, it is highly unlikely that large RCTs comparing each formulation of ESA will be performed to inform clinicians on whether certain ESA formulations are superior or safer than others. Therefore, an update of this review is warranted utilising the pairwise and network meta‐analysis methods to comprehensively compare the potential treatment benefits (preventing blood transfusions and improving symptoms of anaemia) and harms (death, cardiovascular events and kidney failure) of different ESAs with each other or placebo.
Objectives
To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, or methoxy polyethylene glycol‐epoetin beta, and biosimilar ESAs, against each other, placebo, or no treatment) to treat anaemia in adults with CKD.
Methods
Criteria for considering studies for this review
Types of studies
We included all RCTs comparing ESA with an ESA, placebo or standard care to treat anaemia in people with CKD. We did not restrict inclusion based on the language of publication. We did not include quasi‐RCTs (studies in which treatment allocation was by date of birth, alternation, or similar predictable method). We included studies in which allocation to treatment was not adequately concealed but considered study methodological quality in our analyses and discussion.
Types of participants
Inclusion criteria
Studies in adults ≥ 18 years with anaemia due to CKD were included. CKD was characterised by clinically relevant proteinuria, haematuria, and/or structural kidney disease with or without eGFR < 60 mL/min/1.73 m², recipients of a kidney transplant, and people with Stage 5 CKD treated with dialysis (KDIGO 2013).
Exclusion criteria
As network meta‐analysis requires reasonable homogeneity in study design and populations, we excluded studies in children and studies in which follow‐up was less than three months.
Types of interventions
We included studies of ESAs (epoetin alfa, epoetin beta, darbepoetin beta, methoxy polyethylene glycol‐epoetin beta, biosimilar) to treat or prevent anaemia in CKD administered via any route (intravenous (IV) or subcutaneous (SC)), compared with each other, placebo or standard care. Dose adaptation of ESAs and non‐randomised iron supplementation depending on haematological response were allowed. We included studies in which iron was administered as a randomised intervention in all arms of the study.
We coded the comparisons within a study where iron was a randomised co‐intervention in all study arms as follows.
ESA1 plus iron (any route) versus ESA2 plus iron (any route) = ESA1 versus ESA2
ESA plus oral iron versus oral iron = ESA versus standard care
ESA plus oral iron versus oral iron plus placebo injection = ESA versus placebo
ESA plus IV iron versus IV iron plus placebo injection = ESA versus placebo
ESA plus IV iron versus IV iron = ESA versus standard care.
We excluded studies in which iron therapy was a randomised co‐intervention combined with an ESA in a single arm of the study (e.g. ESA plus iron versus ESA alone, ESA plus iron versus placebo). Studies of hypoxia‐inducible factor stabilisers and peginesatide were excluded.
Types of outcome measures
We evaluated the following outcomes occurring at any time during study follow‐up.
Primary outcomes
We estimated the comparative effects of the competing interventions according to the following outcomes:
Response to treatment
Preventing blood transfusion
Safety
Death (any cause)
Secondary outcomes
Response to treatment
Fatigue (as defined by study authors)
Dyspnoea (as defined by study authors)
Safety
Cardiovascular death
Fatal or nonfatal myocardial infarction (MI)
Fatal or nonfatal stroke
Vascular access thrombosis
Major adverse cardiovascular event (as adjudicated by investigators)
Kidney failure.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Kidney and Transplant Register of Studies up to 29 April 2022 through contact with the Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources:
Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
Weekly searches of MEDLINE OVID SP
Searches of kidney and transplant journals and the proceedings and abstracts from major kidney and transplant conferences
Searching the current year of EMBASE OVID SP
Weekly current awareness alerts for selected kidney and transplant journals
Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of hand‐searched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website.
See Appendix 1 for search terms used in strategies for this review.
Searching other resources
Reference lists of review articles, relevant studies and clinical practice guidelines
Contacting relevant individuals/organisations seeking information about unpublished or incomplete studies.
Data collection and analysis
Selection of studies
The search strategy described was used to obtain titles and abstracts of studies that were relevant to the review. The titles and abstracts were screened independently by two authors, who discarded studies that were not applicable; however, studies and reviews that might have included relevant data or information on studies were retained initially. Two authors independently assessed retrieved abstracts and, if necessary, the full text of these studies to determine which studies satisfied the inclusion criteria. Systematic reviews were screened to identify any studies not retrieved by the electronic database search.
Data extraction and management
Data extraction was carried out independently by two authors using standard data extraction forms. Data were cross‐checked between authors and discussed. Studies reported in non‐English language journals were translated electronically 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 disagreements in data extraction were discussed with a third author.
Any further information required from the original authors or sponsors of studies included in the review was requested by written correspondence (e.g. emailing or writing to corresponding author/s), and any relevant information obtained in this manner was included in the review. Data requested included the number of events and the number of participants at risk for important dichotomous clinical outcomes (blood transfusions, death (any cause or cardiovascular), fatal or nonfatal stroke, fatal or nonfatal MI, vascular access thrombosis, kidney failure, major adverse cardiovascular events, fatigue, breathlessness). We also requested additional information on the use of iron supplementation in treatment arms where this was not clear from reading the study report.
Assessment of risk of bias in included studies
The following items were independently assessed by two authors using the risk of bias assessment tool (Higgins 2022) (see Appendix 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?
Participants and personnel (performance bias)
Outcome assessors (detection bias)
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 risk of bias (imbalance in interventions, publication only as abstract or letter, premature termination of study and industry sponsor involvement in authorship or data management and analysis)?
Measures of treatment effect
Relative treatment effects
We calculated comparative effect sizes for pairwise and network meta‐analysis as odds ratios (ORs) with their 95% confidence intervals (CIs).
Relative treatment rankings
To rank the treatments available according to safety or efficacy, we planned to use the surface under the cumulative ranking (SUCRA) probabilities which express as percentages each intervention to an imaginary intervention that is always the best without uncertainty (Salanti 2011). For example, a SUCRA of 80% means that the drug achieved 80% of the effectiveness of this imaginary drug, and accordingly, larger SUCRAs denote greater efficacy. However, the large uncertainty in the resulting estimates rendered the ranking of the competing treatments imprecise.
Unit of analysis issues
Assessment of clinical and methodological heterogeneity within treatment comparisons
To evaluate the presence of clinical heterogeneity, we generated descriptive statistics for the population characteristics across all eligible studies that compared each pair of interventions. We assessed the presence of clinical heterogeneity within pairwise comparisons by comparing these characteristics.
Assessment of transitivity across treatment comparisons
The assumption of transitivity ‐ that one can learn about treatment A versus treatment B via treatment C (e.g. learning about epoetin alfa versus darbepoetin alfa via placebo) ‐ underlies network meta‐analysis (Salanti 2012). Evaluation of the assumption is important, and its plausibility determines the validity of the network meta‐analysis results. We inferred the assumption of transitivity:
We assessed whether the included interventions were similar when they were evaluated in studies with different designs, for example, whether ESAs are administered the same way in studies comparing ESAs to placebo and in those comparing ESAs to other ESAs
We compared the distribution of the potential effect modifiers (age, stage of CKD, duration of treatment) across the different pairwise comparisons.
Dealing with missing data
In the setting of missing data or reported data which was not extractable for the meta‐analysis, we emailed the original author for raw data. We assessed attrition rates in each study, the reporting of intention‐to‐treat, as‐treated or per‐protocol populations, and the imputation methods (if any) used for dealing with missing data (Higgins 2022).
Assessment of heterogeneity
Assumptions when estimating heterogeneity
In standard pairwise meta‐analyses, we estimated different heterogeneity variances for each pairwise comparison. In network meta‐analyses, we assumed a common estimate for the heterogeneity variance across the different comparisons.
Measures and tests for heterogeneity
We evaluated the presence of heterogeneity within meta‐analyses using the Cochran Q test and I² statistic (Higgins 2003) that measures the percentage of variability that cannot be attributed to random error. We considered the I² thresholds to represent heterogeneity that might not be important (0% to 40%), might be moderate heterogeneity (30% to 60%), might be substantial heterogeneity (50% to 90%), and was considerable heterogeneity (75% to 100%) considering also the magnitude and direction of treatment effects and strength of evidence for heterogeneity (P value from the Chi² test) (Higgins 2022). The assessment of statistical heterogeneity in the entire network was based on the magnitude of the heterogeneity variance parameter (τ²) estimated from the network meta‐analysis models. We compared the magnitude of a common heterogeneity variance for the specific network of interest with an empirical distribution of heterogeneity variances specific to the type of outcome and the types of treatments being compared (Turner 2012).
Assessment of statistical inconsistency
Local approaches for evaluating inconsistency
To evaluate the presence of inconsistency locally, we used the loop‐specific approach. A loop of evidence is formed by at least three treatment pairs which have been compared in studies forming a closed path. Indirect evidence can be contrasted to direct evidence, and their difference defines their disagreement (inconsistency factor). To infer whether the inconsistency factor is incompatible with zero, we looked at the magnitude of the inconsistency factors and their 95% CI (Bucher 1997). We extended the analysis to all closed triangular and quadratic loops assuming a single loop‐specific heterogeneity, and examined the estimates of inconsistency together with 95% CI for each loop using a graphical representation (Salanti 2009). This approach can be easily applied and indicates loops with large inconsistency but cannot infer consistency of the entire network or identify the particular comparison that is problematic. It should be noted that in a network of evidence, there may be many loops and estimates of inconsistency factors, and with multiple testing, there is an increased likelihood that we might find an inconsistent loop by chance. Therefore, we were cautious in deriving conclusions from this approach.
Global approaches for evaluating inconsistency
To check the assumption of consistency in the entire network, we used the design‐by‐treatment interaction model, as fully explained in Higgins 2012 (pp. 102 to 103). This method accounts for different sources of inconsistency that can occur when studies with different designs (two‐arm studies versus three‐arm studies) give different results, as well as disagreement between direct and indirect evidence. Using this approach, we inferred about the presence of inconsistency from any source in the entire network based on a Chi² test. The design‐by‐treatment model was performed in STATA using the 'mvmeta' command. Inconsistency and heterogeneity are interwoven: to distinguish between these two sources of variability, we employed the I² for inconsistency which measures the percentage of variability that cannot be attributed to random error or heterogeneity (within comparison variability).
It should be noted that, in general, the power of statistical tests for inconsistency is low, which implies that the absence of statistically significant inconsistency is not evidence of consistency.
Assessment of reporting biases
We planned to assess for the potential existence of small study bias (Higgins 2022) for comparisons in which sufficient data were available (10 or more studies) and in which there was low or no statistical heterogeneity between studies.
Data synthesis
Methods for direct treatment comparisons
First, we conducted pairwise meta‐analyses by synthesising studies that compared the same interventions using a random‐effects model (DerSimonian 1986) that contained two or more studies. We compared treatments that used the same Hb target (e.g. epoetin high target versus darbepoetin high target). For dichotomous outcomes (avoiding RBC transfusions; all‐cause and cardiovascular death; major cardiovascular event; fatal or nonfatal MI; fatal or nonfatal stroke; vascular access thrombosis; kidney failure; fatigue; breathlessness), results were expressed as an OR with 95% CI.
Methods for indirect and mixed comparisons
To determine comparative efficacy and safety, we then conducted network meta‐analyses. Network meta‐analysis is a method of synthesising information from a network of studies addressing the same questions but involving different interventions. Joint analysis of data within a network framework allows novel inferences on treatment comparisons that have not been previously addressed directly in any studies, and it may increase precision for comparisons with few data (Caldwell 2010; Lu 2004; Salanti 2008). For a given comparison, say A versus B, direct evidence is provided by studies that compare these two treatments directly (epoetin alfa versus darbepoetin alfa) as in standard direct comparisons meta‐analysis. In addition, indirect evidence for A versus B can be provided if studies that compare A versus C and B versus C are analysed jointly (e.g. epoetin alfa versus placebo studies and darbepoetin alfa versus placebo studies can allow indirect comparison of epoetin alfa versus darbepoetin alfa via the use of placebo). Network meta‐analysis aims to combine the direct and indirect evidence into a single effect size and thus may help to increase the precision of the comparison while randomisation is respected. The combination of direct and indirect evidence for any given treatment comparison can be extended when ranking more than three types of treatments according to their effectiveness or safety; every study contributes evidence in the network about a subset of the competing treatments. We performed network meta‐analysis in STATA using the 'mvmeta' command (White 2012) and self‐programmed STATA routines described in Chaimani 2013 and available at http://www.mtm.uoi.gr/index.php/stata-routines-for-network-meta-analysis.
Subgroup analysis and investigation of heterogeneity
Investigation of heterogeneity and inconsistency
We planned to perform meta‐regression or subgroup analyses to explore important heterogeneity and/or inconsistency. When we identified potential evidence of inconsistency and heterogeneity, we first checked for any mistakes and inconsistencies in data extraction and entry. We then evaluated for evidence based on the following effect modifiers as possible sources of inconsistency and/or heterogeneity. However, insufficient data precluded these analyses.
Population: iron status at baseline (iron replete versus iron deficient); stage of CKD (CKD stages 1 to 3, CKD stage 4 to 5, CKD stage 5D, transplantation); baseline Hb (< 10 g/dL, 10 to 12 g/dL, > 12 g/dL); mean age; gender; proportion with diabetes or cardiovascular disease
Intervention: dose, frequency or route; iron supplementation (fixed iron treatment, iron treatment as necessary, or not clear)
Risk of bias: allocation concealment; blinding of outcome assessment; attrition; premature termination of study; publication (full‐text publication, abstract publication, unpublished data); funding source
Study design: duration of ESA treatment (12 to 16 weeks, 16 to 24 weeks, 24 to 48 weeks, > 48 weeks); duration of follow‐up (≥ 12 months versus < 12 months); number of participants; date of publication.
Sensitivity analysis
To investigate the generalisability of the findings, we planned to perform sensitivity analyses by restricting analyses to studies with adequately concealed allocation methods and follow‐up longer than 12 months. However, insufficient data precluded these analyses.
Summary of findings and assessment of the certainty of the evidence
Summary of findings table
The main results of the review for the primary outcomes (preventing blood transfusion and death (any cause)) are presented in a summary of findings table (Table 1). The summary of findings table was provided for the network estimates only and included an overall grading of the evidence for these outcomes.
We used an adapted Grading of Recommendations Assessment, Development approach to grading evidence certainty in pairwise meta‐analyses that was developed specifically for network meta‐analysis (Salanti 2014). We considered five components of evidence certainty: study limitations, indirectness, inconsistency, imprecision, and publication bias. The interpretations of each of the grades are provided in GRADE 2011 and described in the footnote of the Table 1.
In networks in which there were no closed loops (where three or four treatments were not connected by direct comparisons in individual studies), we couldn't evaluate for consistency between direct information (two drugs compared in a study) and indirect information (two drugs compared via a third treatment strategy using network meta‐analysis), we downgraded evidence certainty because we could not show absence of inconsistency between these two sources of information.
The adjudication of each component of evidence certainty then resulted in maintaining or downgrading evidence certainty from a high‐certainty rating to moderate, low or very low.
Results
Description of studies
Results of the search
In the 2014 review, 5724 records were identified. After screening titles and abstracts, 920 reports underwent full‐text review, and 330 reports were potentially eligible. Fifty‐five studies (183 reports) were included, and 29 studies (134 reports) were excluded. In addition, we identified seven ongoing studies, and five studies were completed prior to publication; however, no results were available.
For this update, we searched the Cochrane Kidney and Transplant Register of Studies to 29 April 2022 and identified 617 reports; after screening, 480 reports were potentially eligible. Fifty‐six new studies (90 reports) were included, 207 (327 reports) were excluded, and one ongoing study was identified. Three new studies are awaiting classification (recently completed; no data available/abstract‐only publication and awaiting author; unable to access full‐text). We also identified 59 new reports of existing included, excluded, and studies awaiting classification.
We reassessed and reclassified five studies awaiting classification (Barany 1998; Carrera 2003; Nissenson 2007; Ostrvica 2010; Palazzuoli 2011) and one ongoing study (CORDATUS 2011) as included studies. We excluded two previous ongoing studies (MIRCERA PASS 2019; STIMULATE 2014), and three ongoing studies have now been completed and have been moved to studies awaiting classification as no data have been published (NCT00442702; NCT00717821; PRIMAVERA 2011). Finally, one ongoing study was a duplicate of a report in an included study (PATRONUS 2010; Besarab 2006) and has been deleted.
A total of 117 studies (322 reports, 25,237 participants) were included, 236 studies (473 reports) were excluded, six studies are awaiting classification (8 reports), and there is one ongoing study.
Figure 2 shows the results of the electronic searches.
2.
Included studies
We included 117 studies randomising 25,237 participants. Studies were published between 1989 and 2021, and 74 studies (18,880 participants) could be included in pairwise and network meta‐analyses (Characteristics of included studies). We received unpublished data from investigators of seven studies (Akizawa 2011; CORDATUS 2011; EPOCARES 2010; Hirakata 2010; Nissenson 2002; Patel 2012; TIVOLI 2013) in the original review in 2014, which remain unchanged upon review of published data. We contacted the authors of the new studies included in this update but were unable to obtain additional unpublished data.
Median follow‐up was seven months (range 3 to 40), with 48 studies (41%) reporting outcomes before 12 months, and the duration of follow‐up was unclear in 46 studies (39%).
The median age of participants was 57 years (range 45 to 84 years).
Of the 77 studies contributing outcome data, 47 studies included 12,286 dialysis patients, eight studies provided data for 454 kidney transplant recipients, and 22 studies included 7638 participants with an eGFR between 10 to 70 mL/min/1.73 m².
Among studies included in our meta‐analyses, 13 were placebo‐controlled (5814 participants), and 12 compared ESAs with standard care (1013 participants). The remainder were head‐to‐head studies of epoetin alfa versus darbepoetin alfa (11 studies, 2663 participants), epoetin beta versus darbepoetin alfa (3 studies, 379 participants), epoetin beta versus methoxy polyethylene glycol‐epoetin beta (3 studies, 541 participants), darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta (7 studies, 1611 participants), epoetin alfa versus biosimilar epoetin (16 studies, 4379 participants), epoetin alfa versus biosimilar darbepoetin alfa (1 study, 752 participants), epoetin beta versus biosimilar epoetin (1 study, 288 participants), darbepoetin alfa versus biosimilar epoetin (1 study, 74 participants), darbepoetin alfa versus biosimilar darbepoetin alfa (5 studies, 1191 participants), epoetin alfa/beta versus darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta (1 study, 175 participants), and epoetin alfa versus epoetin beta versus standard care (1 study, 52 participants).
Ongoing studies and studies awaiting classification
We identified one ongoing study (UMIN000009472). Six studies are awaiting classification: two abstracts had no published results (Aliev 1997; Muirhead 1992a); we were not able to obtain the full text for Koiwa 2019; and two studies have been completed, but no data are available (NCT00442702; NCT00717821). These studies, along with the recently completed PRIMAVERA 2011. will be included in a future update of this review.
See Characteristics of studies awaiting classification; Characteristics of ongoing studies
Excluded studies
We excluded 236 studies (473 reports). The reasons for exclusion are as follows:
Wrong study design (cross‐over study; not designed to measure effects on anaemia; Hb targets; unclear eligibility): 5 studies
Wrong population (paediatric patients): 10 studies
Compared the same ESA or the same ESA derivative in the different treatment arms: 134 studies
Type of ESA was not reported: 11 studies
Wrong intervention (not ESA): 16 studies
Wrong control group or control group unclear: 6 studies
Duration of study or duration of follow‐up less than 12 weeks: 42 studies
No extractable data or no published results: 11 studies
Study terminated: 1 study
Studies excluded from the meta‐analyses
The primary reasons for exclusion from the meta‐analyses (43 studies involving 6118 participants) were that disaggregated data for different ESA types were not available separately (for example, both epoetin alfa and beta were administered within a single study arm), outcome data were not reported in extractable format, or not relevant outcomes were reported (Aggarwal 2005; Akiba 2010; Alexander 2007; AMGEN 8701 1987; Ammer 2009; Arabul 2009; Barany 1998; Bartels 2012; Brown 1988; Carrera 2003; Chen 2008; Coyne 2000; Di Lullo 2009; Fritschka 1990; Furukawa 2015; Hidaka 2015; Iwasaki 2008; Kim 2006e; Kohler 1990; Korbet 1991; Marin 2019; MAXIMA 2007; Mehta 2019; Meier 2008; Mignon 2000; Nissenson 2007; Ostrvica 2010; PROTOS 2007; RUBRA 2008; Shaheen 1993; Shand 1993; Sikole 1993; Silverberg 2006; Sinha 2019a; Smith 2007; Smyth 2006; Teehan 1989; Tessitore 2008; Trembecki 1995a; Tsubakihara 2011; Vigano 1991; Wang 2014; Watson 1990).
Risk of bias in included studies
The risks of bias are summarised in Figure 3.
3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. The coloured bars correspond to each risk of bias adjudication summarised across all studies. The numbers shown in the bars indicate the raw number of studies which were adjudicated the corresponding risks of bias (green = low risk; yellow = unclear risk; red = high risk). The size of each coloured box within the bars indicates the proportion of studies with the adjudicated risk.
*Other threats to validity include one or more of: sponsor involved in study design, analysis, or authorship; imbalance between treatment comparisons and/or premature termination of trial
Allocation
Sequence generation
Fifteen studies (13%) reported low‐risk methods for sequence generation (Akizawa 2011; Coupes 2015; Haag‐Weber 2009; Kim 2020; Lee 2019; MAXIMA 2007; Nissenson 2002; PATRONUS 2010; Picon 2015; Pile 2020; PROTECT 2012; Thadhani 2018; TREAT 2005; Vanrenterghem 2002; Woodland 2017). One study reported a high risk of bias in sequence generation (Silverberg 2001), and the remaining 101 studies (86%) did not provide sufficient information to enable adjudication risk of bias in sequence generation (unclear risk).
Allocation concealment
Seventeen studies (15%) reported adequate methods for allocation concealment (low risk of bias) (Alexander 2007; ARCTOS 2008; Gertz 2010; Goh 2007; Hafer 2012; Hirakata 2010; Locatelli 2001; MAXIMA 2007; Nishi 2020; PATRONUS 2010; Picon 2015; PROTOS 2007; RED‐HF 2009; STRIATA 2008; Thadhani 2018; Weir 2017; Woodland 2017). One study reported a high risk of bias in allocation concealment (Fishbane 2019), and the remaining 99 studies (85%) did not provide sufficient information to enable adjudication risk of bias in allocation concealment (unclear risk).
Blinding
Performance bias
There were 25 studies (22%) reporting participants and investigators were blinded (Argani 2009; Azmandian 2018; Bennett 1991; Canadian EPO 1990; Gertz 2010; Haag‐Weber 2009; Haag‐Weber 2012; Kim 2020; Kleinman 1989; Krivoshiev 2008; Krivoshiev 2010; Marin 2019; Martin 2007; NCT02506868; Nishi 2020; Nissenson 1995; Nissenson 2002; Palazzuoli 2007; Picon 2015; PROTECT 2012; RED‐HF 2009; Shand 1993; Spinowitz 2006; TREAT 2005; Watson 1990). There were 51 studies (43%) that were open‐label (high risk of bias), and the remaining 41 studies (35%) did not provide sufficient information to enable assessment (unclear).
Detection bias
Seven studies (6%) reported adequate methods of blinding outcome assessment (Canadian EPO 1990; NCT02506868; Nishi 2020; Picon 2015; PROTECT 2012; RED‐HF 2009; TREAT 2005), one study reported a high risk of bias in blinding of outcome assessment (Sinha 2019a) and the remaining 109 studies did not provide sufficient information to assess risk (unclear risk of bias).
Incomplete outcome data
Twenty‐six studies (22%) were judged to meet the criteria for low risk of bias (fewer than 10% missing from follow‐up analyses and balanced numbers across intervention groups with similar reasons for loss to follow‐up) for low risk of incomplete outcome data bias (Al‐Ali 2015; AMICUS 2007; ARCTOS 2008; Apsangikar 2018; Bartels 2012; CORDATUS 2011; Coupes 2015; Fishbane 2018; Fishbane 2019; Hafer 2012; Mehta 2019; NCT02506868; Oh 2014; Palazzuoli 2007; Picon 2015; Pile 2020; PROTECT 2012; RED‐HF 2009; Sikole 1993; Silverberg 2001; Sinha 2019a; TIVOLI 2013; TREAT 2005; Weir 2017; Woodland 2017; Yoon 2004), 40 studies (34%) were at high risk of bias, and the remaining 51 studies (44%) did not provide sufficient information to assess the risk of bias (unclear risk).
Selective reporting
Outcomes of interest (death and cardiovascular events (fatal or nonfatal)) were reported in 34 studies (29%) (Akizawa 2011; AMICUS 2007; ARCTOS 2008; Bahlmann 1991; Bennett 1991; Bernieh 2014; Canadian EPO 1990; CORDATUS 2011; EPOCARES 2010; Fishbane 2018; Fishbane 2019; Gertz 2010; Goh 2007; Haag‐Weber 2009; Kleinman 1989; Klinkmann 1992; Krivoshiev 2010; Kuriyama 1997; Locatelli 2001; MAXIMA 2007; Milutinovic 2006; NCT02506868; Nissenson 2002; Palazzuoli 2011; Patel 2012; PATRONUS 2010; PROTECT 2012; PROTOS 2007; RED‐HF 2009; STRIATA 2008; TREAT 2005; Van Loo 1996; Vanrenterghem 2002; Weir 2017).
Other potential sources of bias
Industrial sponsor on authorship or involved in data management or analysis
Forty studies (34%) reported the sponsor was involved in the authorship of the study report or in data management or analysis (Alexander 2007; Allon 2002; AMICUS 2007; ARCTOS 2008; Azmandian 2018; Bahlmann 1991; CORDATUS 2011; Coyne 2000; Coyne 2006a; Fishbane 2018; Fishbane 2019; Gertz 2010; Haag‐Weber 2009; Haag‐Weber 2012; Kleinman 1989; Klinkmann 1992; Krivoshiev 2010; Lee 2019; Locatelli 2001; MAXIMA 2007; Nishi 2020; Nissenson 2002; Oh 2014; Patel 2012; PATRONUS 2010; Picon 2015; PROTOS 2007; RED‐HF 2009; RUBRA 2008; Sinha 2019a; Smith 2007; Smyth 2006; Spinowitz 2006; STRIATA 2008; Thadhani 2018; TIVOLI 2013; TREAT 2005; Vanrenterghem 2002; Watson 1990; Weir 2017).
Abstract or letter only
Twenty‐eight studies (24%) were published either as an abstract or letter (Alexander 2007; AMGEN 8701 1987; Ammer 2009; Barany 1998; Brown 1988; Brown 1995; Carrera 2003; Coyne 2000; Coyne 2006a; Di Lullo 2009; Hidaka 2015; Hori 2004; Iwasaki 2008; Kim 2006e; Marin 2019; Meier 2008; Mignon 2000; Nissenson 2007; Park 2014b; Silverberg 2006; Smith 2007; Smyth 2004; Smyth 2006; Tessitore 2008; TIVOLI 2013; Trembecki 1995a; Tsubakihara 2011; Wang 2014).
Imbalance in interventions
In one study, two differing ESAs were prescribed according to differing Hb targets, resulting in an imbalance in treatment doses (Akizawa 2011).
Premature termination of the study
Two studies were terminated early (Alexander 2007; Haag‐Weber 2012) due to the development of EPO antibodies (Haag‐Weber 2012) and for uncertain reasons (Alexander 2007).
Effects of interventions
See: Table 1
Overall, results remain similar in this update compared to our 2014 review. The Table 1 provides overall estimates of treatment effects and the certainty of the available evidence for the primary efficacy (preventing blood transfusion) and safety (death (any cause)) outcomes, and Table 2 shows the treatment estimates from pairwise and network meta‐analyses. Treatment estimates from pairwise comparisons are shown in italics in the lower left portion of each table section, and treatment estimates from network analyses are shown in the upper right portion of each table section.
1. Comparative effects of erythropoiesis‐stimulating agents on clinical outcomes in chronic kidney disease.
| Outcomes / interventions | Comparators (treatment estimate (OR (95% CI)) | ||||||
| Epoetin alfa | Epoetin beta | Darbepoetin alfa | Methoxy polyethylene glycol‐epoetin beta | Biosimilar epoetin | Biosimilar darbepoetin alfa | Placebo | |
| Preventing blood transfusion | |||||||
| Epoetin alfa | ‐‐ | 0.69 (0.23‐2.06) | 0.98 (0.41‐2.37) | 1.19 (0.38‐3.75) | 1.21 (0.53‐2.76) | 1.34 (0.31‐5.81) | 0.28 (0.13‐0.61) |
| Epoetin beta | Not estimable | ‐‐ | 1.43 (0.47‐4.34) | 1.72 (0.55‐5.43) | 1.76 (0.45‐6.79) | 1.94 (0.32‐11.59) | 0.19 (0.08‐0.47) |
| Darbepoetin alfa | 2.31 (1.34‐3.97) | Not estimable | ‐‐ | 1.21 (0.50‐2.92) | 1.23 (0.38‐3.96) | 1.36 (0.27‐6.83) | 0.27 (0.11‐0.69) |
| Methoxy polyethylene glycol‐epoetin beta |
Not estimable | 0.41 (0.10‐1.66) | 1.36 (0.64‐2.89) | ‐‐ | 1.02 (0.25‐4.09) | 1.13 (0.19‐6.75) | 0.33 (0.11‐1.02) |
| Biosimilar epoetin | 0.90 (0.57‐1.44) | Not estimable | 0.31 (0.01‐7.79) | Not estimable | ‐‐ | 1.10 (0.21‐5.91) | 0.34 (0.11‐1.03) |
| Biosimilar darbepoetin alfa | 0.68 (0.34‐1.34) | Not estimable | 1.05 (0.07‐16.88) | Not estimable | Not estimable | ‐‐ | 0.37 (0.07‐1.91) |
| Placebo | 0.15 (0.04‐0.58) | 0.25 (0.07‐0.88) | 0.53 (0.46‐0.63) | Not estimable | Not estimable | Not estimable | ‐‐ |
| All‐cause death | |||||||
| Epoetin alfa | ‐‐ | 0.88 (0.48‐1.61) | 1.26 (0.84‐1.89) | 1.36 (0.76‐2.43) | 1.01 (0.74‐1.39) | 2.07 (0.61‐6.97) | 0.79 (0.51‐1.22) |
| Epoetin beta | Not estimable | ‐‐ | 1.43 (0.84‐2.44) | 1.54 (0.80‐2.97) | 1.15 (0.59‐2.24) | 2.35 (0.66‐8.32) | 0.69 (0.40‐1.20) |
| Darbepoetin alfa | 0.78 (0.50‐1.22) | 0.89 (0.38‐2.09) | ‐‐ | 1.08 (0.71‐1.65) | 0.80 (0.48‐1.34) | 1.64 (0.52‐5.18) | 0.99 (0.81‐1.21) |
| Methoxy polyethylene glycol‐epoetin beta | Not estimable | 0.81 (0.12‐5.35) | 1.07 (0.68‐1.68) | ‐‐ | 0.75 (0.39‐1.44) | 1.52 (0.45‐5.18) | 1.07 (0.67‐1.71) |
| Biosimilar epoetin | 1.01 (0.69‐1.47) | 0.34 (0.04‐2.82) | Not estimable | Not estimable | ‐‐ | 2.04 (0.58‐7.17) | 0.80 (0.47‐1.36) |
| Biosimilar darbepoetin alfa | Not estimable | Not estimable | 0.61 (0.19‐1.91) | Not estimable | Not estimable | ‐‐ | 1.63 (0.51‐5.23) |
| Placebo | 0.57 (0.15‐2.26) | 0.62 (0.23‐1.70) | 1.00 (0.84‐1.19) | Not estimable | Not estimable | Not estimable | ‐‐ |
| Fatigue | |||||||
| Epoetin alfa | ‐‐ | Not estimable | Not estimable | Not estimable | Not estimable | Not estimable | Not estimable |
| Epoetin beta | Not estimable | ‐‐ | Not estimable | Not estimable | Not estimable | Not estimable | Not estimable |
| Darbepoetin alfa | 0.94 (0.57‐1.55) | Not estimable | ‐‐ | Not estimable | Not estimable | Not estimable | Not estimable |
| Methoxy polyethylene glycol‐epoetin beta | Not estimable | Not estimable | 14.47 (0.72‐292.21) | ‐‐ | Not estimable | Not estimable | Not estimable |
| Biosimilar epoetin | 0.86 (0.14‐5.09) | Not estimable | Not estimable | Not estimable | ‐‐ | Not estimable | Not estimable |
| Biosimilar darbepoetin alfa | Not estimable | Not estimable | Not estimable | Not estimable | Not estimable | ‐‐ | Not estimable |
| Placebo | Not estimable | Not estimable | Not estimable | Not estimable | Not estimable | Not estimable | ‐‐ |
| Breathlessness | |||||||
| Epoetin alfa | ‐‐ | Not estimable | 1.41 (0.91‐2.18) | 0.36 (0.03‐4.34) | 1.00 (0.70‐1.42) | 5.38 (0.21‐137.78) | Not estimable |
| Epoetin beta | Not estimable | ‐‐ | Not estimable | Not estimable | Not estimable | Not estimable | Not estimable |
| Darbepoetin alfa | 0.71 (0.46‐1.10) | Not estimable | ‐‐ | 0.26 (0.02‐2.97) | 0.71 (0.41‐1.24) | 3.82 (0.15‐95.02) | Not estimable |
| Methoxy polyethylene glycol‐epoetin beta | Not estimable | Not estimable | 3.91 (0.34‐45.46) | ‐‐ | 2.78 (0.22‐34.42) | 14.95 (0.26‐851.67) | Not estimable |
| Biosimilar epoetin | 1.00 (0.70‐1.42) | Not estimable | 0.26 (0.01‐6.51) | Not estimable | ‐‐ | 5.37 (0.21‐140.26) | Not estimable |
| Biosimilar darbepoetin alfa | Not estimable | Not estimable | Not estimable | Not estimable | Not estimable | ‐‐ | Not estimable |
| Placebo | Not estimable | Not estimable | Not estimable | Not estimable | Not estimable | Not estimable | ‐‐ |
| Cardiovascular death | |||||||
| Epoetin alfa | ‐‐ | 0.31 (0.05‐1.85) | 0.57 (0.11‐2.93) | 0.82 (0.13‐5.03) | 1.17 (0.54‐2.57) | Not estimable | 1.85 (0.36‐9.62) |
| Epoetin beta | Not estimable | ‐‐ | 1.83 (0.32‐10.29) | 2.65 (0.40‐17.54) | 3.79 (0.67‐21.44) | Not estimable | 0.57 (0.10‐3.22) |
| Darbepoetin alfa | 2.15 (0.31‐14.91) | Not estimable | ‐‐ | 1.45 (0.67‐3.12) | 2.07 (0.37‐11.58) | Not estimable | 1.05 (0.87‐1.26) |
| Methoxy polyethylene glycol‐epoetin beta | Not estimable | Not estimable | 0.69 (0.32‐1.48) | ‐‐ | 1.43 (0.22‐9.39) | Not estimable | 1.52 (0.69‐3.34) |
| Biosimilar epoetin | 1.11 (0.34‐3.66) | 0.34 (0.04‐2.82) | Not estimable | Not estimable | ‐‐ | Not estimable | 2.17 (0.39‐12.17) |
| Biosimilar darbepoetin alfa | Not estimable | Not estimable | Not estimable | Not estimable | Not estimable | ‐‐ | Not estimable |
| Placebo | Not estimable | 0.45 (0.06‐3.75) | 1.05 (0.87‐1.26) | Not estimable | Not estimable | Not estimable | ‐‐ |
| Major adverse cardiovascular events | |||||||
| Epoetin alfa | ‐‐ | 0.29 (0.02‐4.85) | 5.02 (0.24‐105.39) | 2.68 (0.04‐169.33) | 1.31 (0.62‐2.75) | Not estimable | 0.21 (0.01‐4.52) |
| Epoetin beta | Not estimable | ‐‐ | 17.44 (0.27‐1107.27) | 9.30 (0.06‐1402.41) | 4.54 (0.24‐84.06) | Not estimable | 0.06 (0.00‐3.94) |
| Darbepoetin alfa | 0.20 (0.01‐4.17) | Not estimable | ‐‐ | 0.53 (0.03‐8.91) | 0.26 (0.01‐5.96) | Not estimable | 1.08 (0.96‐1.22) |
| Methoxy polyethylene glycol‐epoetin beta | Not estimable | Not estimable | 1.88 (0.11‐31.32) | ‐‐ | 0.49 (0.01‐32.91) | Not estimable | 0.58 (0.03‐9.65) |
| Biosimilar epoetin | 0.77 (0.36‐1.61) | Not estimable | Not estimable | Not estimable | ‐‐ | Not estimable | 0.28 (0.01‐6.46) |
| Biosimilar darbepoetin alfa | Not estimable | Not estimable | Not estimable | Not estimable | Not estimable | ‐‐ | Not estimable |
| Placebo | Not estimable | Not estimable | 1.08 (0.96‐1.22) | Not estimable | Not estimable | Not estimable | ‐‐ |
| Myocardial infarction | |||||||
| Epoetin alfa | ‐‐ | 0.51 (0.04‐6.07) | 0.75 (0.33‐1.71) | 0.90 (0.13‐6.10) | 0.92 (0.40‐2.12) | 2.25 (0.08‐61.98) | 1.22 (0.52‐2.85) |
| Epoetin beta | Not estimable | ‐‐ | 1.46 (0.13‐17.02) | 1.75 (0.09‐35.23) | 1.80 (0.13‐24.38) | 4.39 (0.08‐250.00) | 0.63 (0.05‐7.27) |
| Darbepoetin alfa | 1.30 (0.55‐3.08) | Not estimable | ‐‐ | 1.20 (0.21‐6.75) | 1.23 (0.38‐3.97) | 3.00 (0.12‐74.55) | 0.91 (0.73‐1.15) |
| Methoxy polyethylene glycol‐epoetin beta | Not estimable | Not estimable | 0.83 (0.15‐4.72) | ‐‐ | 1.03 (0.13‐8.32) | 2.51 (0.07‐96.52) | 1.09 (0.19‐6.27) |
| Biosimilar epoetin | 1.10 (0.47‐2.58) | Not estimable | Not estimable | Not estimable | ‐‐ | 2.44 (0.08‐74.70) | 1.12 (0.34‐3.70) |
| Biosimilar darbepoetin alfa | Not estimable | Not estimable | 0.33 (0.01‐8.28) | Not estimable | Not estimable | ‐‐ | 2.74 (0.11‐68.76) |
| Placebo | 3.46 (0.12‐100.51) | 0.34 (0.01‐8.58) | 0.91 (0.73‐1.15) | Not estimable | Not estimable | Not estimable | ‐‐ |
| Stroke | |||||||
| Epoetin alfa | ‐‐ | 0.49 (0.06‐3.93) | 0.90 (0.35‐2.35) | 0.52 (0.08‐3.42) | 1.32 (0.60‐2.88) | 0.29 (0.01‐8.41) | 2.25 (0.83‐6.15) |
| Epoetin beta | Not estimable | ‐‐ | 1.85 (0.26‐13.25) | 1.07 (0.08‐13.69) | 2.71 (0.30‐24.68) | 0.60 (0.01‐26.15) | 1.10 (0.16‐7.77) |
| Darbepoetin alfa | 0.97 (0.35‐2.70) | Not estimable | ‐‐ | 0.58 (0.12‐2.92) | 1.46 (0.44‐4.83) | 0.33 (0.01‐8.12) | 2.03 (1.49‐2.77) |
| Methoxy polyethylene glycol‐epoetin beta | Not estimable | Not estimable | 1.72 (0.34‐8.64) | ‐‐ | 2.52 (0.34‐18.74) | 0.56 (0.02‐20.48) | 1.18 (0.23‐6.10) |
| Biosimilar epoetin | 0.79 (0.35‐1.80) | Not estimable | 0.31 (0.01‐7.79) | Not estimable | ‐‐ | 0.22 (0.01‐6.87) | 2.97 (0.87‐10.16) |
| Biosimilar darbepoetin alfa | Not estimable | Not estimable | 3.06 (0.12‐76.10) | Not estimable | Not estimable | ‐‐ | 0.66 (0.03‐16.73) |
| Placebo | Not estimable | 1.40 (0.09‐22.13) | 2.02 (1.48‐2.75) | Not estimable | Not estimable | Not estimable | ‐‐ |
| Hypertension | |||||||
| Epoetin alfa | ‐‐ | 1.03 (0.57‐1.88) | 0.89 (0.64‐1.26) | 0.95 (0.56‐1.59) | 0.90 (0.57‐1.41) | 0.94 (0.44‐2.02) | 2.10 (1.22‐3.59) |
| Epoetin beta | Not estimable | ‐‐ | 0.87 (0.49‐1.54) | 0.92 (0.49‐1.72) | 0.87 (0.44‐1.70) | 0.91 (0.37‐2.25) | 2.17 (1.17‐4.00) |
| Darbepoetin alfa | 0.93 (0.68‐1.25) | 1.18 (0.38‐3.69) | ‐‐ | 1.06 (0.70‐1.59) | 1.00 (0.58‐1.73) | 1.05 (0.52‐2.15) | 1.88 (1.12‐3.14) |
| Methoxy polyethylene glycol‐epoetin beta | Not estimable | 1.44 (0.66‐3.15) | 0.91 (0.62‐1.33) | ‐‐ | 0.95 (0.49‐1.83) | 1.00 (0.44‐2.27) | 1.98 (1.05‐3.74) |
| Biosimilar epoetin | 1.21 (0.76‐1.93) | 0.74 (0.30‐1.82) | Not estimable | Not estimable | ‐‐ | 1.05 (0.44‐2.53) | 1.88 (0.96‐3.67) |
| Biosimilar darbepoetin alfa | 0.72 (0.15‐3.44) | Not estimable | 0.93 (0.51‐1.70) | Not estimable | Not estimable | ‐‐ | 1.98 (0.84‐4.66) |
| Placebo | 4.10 (2.16‐7.76) | 2.36 (1.11‐5.04) | 1.14 (0.99‐1.32) | Not estimable | Not estimable | Not estimable | ‐‐ |
| Kidney failure | |||||||
| Epoetin alfa | ‐‐ | 0.71 (0.22‐2.23) | 0.75 (0.41‐1.40) | 0.40 (0.12‐1.29) | 0.81 (0.01‐46.19) | 0.96 (0.20‐4.67) | 1.23 (0.62‐2.47) |
| Epoetin beta | Not estimable | ‐‐ | 1.07 (0.31‐3.70) | 0.57 (0.12‐2.79) | 1.15 (0.02‐72.82) | 1.36 (0.20‐9.22) | 0.87 (0.27‐2.82) |
| Darbepoetin alfa | 2.17 (0.37‐12.74) | Not estimable | ‐ | 0.53 (0.20‐1.43) | 1.08 (0.02‐59.69) | 1.27 (0.30‐5.47) | 0.93 (0.55‐1.56) |
| Methoxy polyethylene glycol‐epoetin beta | Not estimable | Not estimable | 1.87 (0.73‐4.82) | ‐‐ | 2.02 (0.03‐126.38) | 2.39 (0.41‐13.90) | 0.50 (0.16‐1.52) |
| Biosimilar epoetin | Not estimable | Not estimable | Not estimable | Not estimable | ‐‐ | 1.18 (0.02‐84.78) | 1.00 (0.02‐53.62) |
| Biosimilar darbepoetin alfa | Not estimable | Not estimable | 0.79 (0.19‐3.24) | Not estimable | Not estimable | ‐‐ | 1.18 (0.25‐5.56) |
| Placebo | 0.62 (0.16‐2.36) | 1.61 (0.26‐10.10) | 0.93 (0.62‐1.39) | Not estimable | Not estimable | Not estimable | ‐‐ |
| Vascular access thrombosis | |||||||
| Epoetin alfa | ‐‐ | 1.27 (0.42‐3.86) | 0.85 (0.60‐1.20) | 1.05 (0.54‐2.06) | 0.67 (0.17‐2.63) | 0.92 (0.38‐2.23) | 1.74 (0.63‐4.80) |
| Epoetin beta | Not estimable | ‐‐ | 0.67 (0.23‐1.96) | 0.83 (0.29‐2.33) | 0.53 (0.09‐3.05) | 0.73 (0.18‐2.95) | 2.20 (0.82‐5.92) |
| Darbepoetin alfa | 1.16 (0.75‐1.81) | Not estimable | ‐‐ | 1.24 (0.70‐2.22) | 0.79 (0.20‐3.20) | 1.09 (0.44‐2.71) | 1.47 (0.55‐3.95) |
| Methoxy polyethylene glycol‐epoetin beta | Not estimable | 1.74 (0.49‐6.24) | 0.74 (0.41‐1.36) | ‐‐ | 0.64 (0.14‐2.89) | 0.88 (0.30‐2.58) | 1.83 (0.64‐5.22) |
| Biosimilar epoetin | 2.10 (0.42‐10.42) | Not estimable | 0.31 (0.01‐7.79) | Not estimable | ‐‐ | 1.38 (0.27‐6.99) | 1.17 (0.21‐6.35) |
| Biosimilar darbepoetin alfa | 1.04 (0.37‐2.92) | Not estimable | 1.01 (0.20‐5.14) | Not estimable | Not estimable | ‐‐ | 1.61 (0.43‐6.04) |
| Placebo | 6.40 (0.80‐51.50) | 1.67 (0.47‐6.00) | 1.34 (0.30‐6.01) | Not estimable | Not estimable | Not estimable | ‐‐ |
Treatment estimates for pairwise meta‐analyses are shown in italics
Figure 4 shows the networks of evidence for the safety and efficacy of ESA drugs included in the review. Each line links the treatments which have been directly compared in studies. The thickness of the line is proportional to the number of studies included in the comparison, and the width of each circle is proportional to the number of participants included in the comparison. Figure 5 shows the summary treatment effects for ESAs when compared to placebo within networks.
4.
Networks of the treatment efficacy and safety of ESA drugs in the treatment of anaemia in chronic kidney disease
5.
Forest plots for results from network meta‐analyses comparing ESAs versus placebo
1. Response to treatment (efficacy)
1.1 Pairwise meta‐analysis (direct comparisons)
Treatment estimates for pairwise meta‐analyses are shown in italics in Table 2.
Preventing blood transfusions
ESAs compared to placebo or standard care
Data for the effects of ESA treatment compared to placebo or standard care was provided in 13 studies (5010 participants) (Bahlmann 1991; Bennett 1991; Canadian EPO 1990; Coupes 2015; Hafer 2012; Kleinman 1989; Park 2014b; Patel 2012; PROTECT 2012; Roth 1994; TREAT 2005; Van Biesen 2005; Van Loo 1996). Three agents (epoetin alfa, epoetin beta, darbepoetin alfa) were assessed against placebo or standard care. No study evaluated either methoxy polyethylene glycol‐epoetin beta with placebo or standard care.
Epoetin alfa may reduce the odds of blood transfusion compared to placebo (Analysis 1.1.1 (5 studies, 385 participants): OR 0.15, 95% CI 0.04 to 0.58; I² = 81%; low certainty evidence) (Canadian EPO 1990; Hafer 2012; Kleinman 1989; Park 2014b; Roth 1994) with evidence of heterogeneity that might be substantial. Epoetin alfa had uncertain effects on the odds of blood transfusion compared with standard care (Analysis 1.1.2 (1 study, 157 participants): OR 3.10, 95% CI 0.16 to 58.97; low certainty evidence) (Patel 2012).
Epoetin beta may reduce the odds of blood transfusion compared to placebo (Analysis 1.1.3 (4 studies, 361 participants): OR 0.25, 95% CI 0.07 to 0.88; I² = 73%; low certainty evidence) (Bahlmann 1991; Bennett 1991; Coupes 2015; PROTECT 2012). Epoetin beta had uncertain effects on the odds of blood transfusion compared with standard care (Analysis 1.1.4 (2 studies, 69 participants): OR 0.38, 95% CI 0.11 to 1.30; I²= 0%; low certainty evidence) (Van Biesen 2005; Van Loo 1996).
Darbepoetin alfa probably reduced the odds of blood transfusion compared to placebo (Analysis 1.1.5 (1 study, 4038 participants): OR 0.53, 95% CI 0.46 to 0.63; moderate certainty evidence) (TREAT 2005).
1.1. Analysis.
Comparison 1: ESA versus ESA or placebo/standard care, Outcome 1: Blood transfusion
ESAs compared to each other
Three studies (1191 participants) compared epoetin alfa with darbepoetin alfa (Akizawa 2011; Locatelli 2001; Nissenson 2002), seven studies (2335 participants) compared epoetin alfa with a biosimilar epoetin (Argani 2009; Azmandian 2018; Fishbane 2018; Fishbane 2019; Goh 2007; Krivoshiev 2008; Krivoshiev 2010), one study (752 participants) compared epoetin alfa with a biosimilar darbepoetin alfa (Martin 2007), two studies (261 participants) compared epoetin beta versus methoxy polyethylene glycol‐epoetin beta (AMICUS 2007; Oh 2014), four studies (1191 participants) compared darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta (ARCTOS 2008; CORDATUS 2011; PATRONUS 2010; TIVOLI 2013), one study (74 participants) compared darbepoetin alfa versus biosimilar epoetin (Yoon 2004), and one study (385 participants) compared darbepoetin alfa versus biosimilar epoetin (Kim 2020).
Epoetin alfa probably increased the odds of blood transfusion compared to darbepoetin alfa (Analysis 1.1.6 (3 studies, 1191 participants): OR 2.31, 95% CI 1.34 to 3.97; I² = 0%; moderate certainty evidence).
Epoetin alfa had uncertain effects on the odds of blood transfusion compared to a biosimilar epoetin (Analysis 1.1.7 (7 studies, 2335 participants): OR 0.90, 95% CI 0.57 to 1.44; I² = 0%; low certainty evidence or biosimilar darbepoetin alfa (Analysis 1.1.8 (1 study, 752 participants): OR 0.68, 95% CI 0.34 to 1.34; low certainty evidence).
Epoetin beta had uncertain effects on the odds of blood transfusion compared to methoxy polyethylene glycol‐epoetin beta (Analysis 1.1.9 (2 studies, 261 participants): OR 0.41, 95% CI 0.10 to 1.66; I² = 34%; low certainty evidence).
Darbepoetin alfa had uncertain effects on the odds of blood transfusion compared to methoxy polyethylene glycol‐epoetin beta (Analysis 1.1.10 (4 studies, 1191 participants): OR 1.36, 95% CI 0.64 to 2.89; I² = 46%; very low certainty evidence) with evidence of moderate heterogeneity, a biosimilar epoetin (Analysis 1.1.11 (1 study, 74 participants): OR 0.31, 95% CI 0.01 to 7.79; low certainty evidence), or a biosimilar darbepoetin alfa (Analysis 1.1.12 (1 study, 385 participants): OR 1.05, 95% CI 0.07 to 16.88; low certainty evidence).
Fatigue
ESAs compared to placebo or standard care
There were no placebo or standard care‐controlled studies providing extractable data for the effects of treatment on fatigue.
ESAs compared to each other
Data for the effects of ESA treatment versus another ESA on fatigue were available in five studies (908 participants) (Allon 2002; Beiraghdar 2015; EudraCT 2007‐001905‐10; Goh 2007; Nissenson 2002).
Epoetin alfa had uncertain effects on fatigue compared to darbepoetin alfa (Analysis 1.2.1 (2 studies, 551 participants): OR 0.94, 95% CI 0.57 to 1.55; I² = 0%; very low certainty evidence) (Allon 2002; Nissenson 2002) or a biosimilar epoetin (Analysis 1.2.2 (2 studies, 286 participants): OR 0.86, 95% CI 0.14 to 5.09; I² = 35%; low certainty evidence) (Beiraghdar 2015; Goh 2007).
Darbepoetin alfa had uncertain effects on fatigue compared to methoxy polyethylene glycol‐epoetin beta (Analysis 1.2.3 (1 study, 71 participants): OR 14.47, 95% CI 0.72 to 292.21; low certainty evidence) (EudraCT 2007‐001905‐10).
1.2. Analysis.
Comparison 1: ESA versus ESA or placebo/standard care, Outcome 2: Fatigue
Breathlessness
ESAs compared to placebo or standard care
There were no placebo or standard care‐controlled studies providing extractable data for the effects of treatment on breathlessness.
ESAs compared to each other
Data for the effects of ESA treatment versus another ESA on breathlessness were available in 10 studies (2970 participants) (EudraCT 2007‐001905‐10; Fishbane 2018; Fishbane 2019; Goh 2007; Haag‐Weber 2009; Lee 2019; Nissenson 2002; Picon 2015; Spinowitz 2006; Thadhani 2018).
Epoetin alfa had uncertain effects on breathlessness when compared to darbepoetin alfa (Analysis 1.3.1 (1 study, 504 participants): OR 0.71, 95% CI 0.46 to 1.10; low certainty evidence) (Nissenson 2002) or a biosimilar epoetin (Analysis 1.3.2 (7 studies, 2212 participants): OR 1.00, 95% CI 0.70 to 1.42; I² = 0%; low certainty evidence) (Fishbane 2018; Fishbane 2019; Goh 2007; Haag‐Weber 2009; Picon 2015; Spinowitz 2006; Thadhani 2018).
Darbepoetin alfa had uncertain effects on breathlessness compared to a biosimilar darbepoetin alfa (Analysis 1.3.3 (1 study, 183 participants): OR 0.26, 95% CI 0.01 to 6.51; low certainty evidence) (Lee 2019) or methoxy polyethylene glycol‐epoetin beta (Analysis 1.3.4 (1 study, 71 participants): OR 3.91, 95% CI 0.34 to 45.46; low certainty evidence) (EudraCT 2007‐001905‐10).
1.3. Analysis.
Comparison 1: ESA versus ESA or placebo/standard care, Outcome 3: Breathlessness
1.2 Network meta‐analysis (combination of direct and indirect comparisons)
Treatment estimates for network meta‐analyses are shown in Table 2, and network meta‐analyses for all ESAs against placebo are summarised in Figure 5. Studies grouped by comparison were deemed comparable for the effect modifiers of stage of CKD, Hb target with ESA treatment, age of participants and duration of follow‐up, such that the assumption of transitivity might hold and that a network meta‐analytical approach was reasonable. However, we could not assess the comparability of treatment comparisons across different studies using statistical methods due to insufficient data.
Preventing blood transfusions
Blood transfusion data were provided in 32 studies (11,197 participants with CKD; 59.3% of the participants in this review) (Akizawa 2011; AMICUS 2007; ARCTOS 2008; Argani 2009; Azmandian 2018; Bahlmann 1991; Bennett 1991; Canadian EPO 1990; CORDATUS 2011; Coupes 2015; Fishbane 2018; Fishbane 2019; Goh 2007; Hafer 2012; Kim 2020; Kleinman 1989; Krivoshiev 2008; Krivoshiev 2010; Locatelli 2001; Martin 2007; Nissenson 2002; Oh 2014; Park 2014b; Patel 2012; PATRONUS 2010; PROTECT 2012; Roth 1994; TIVOLI 2013; TREAT 2005; Van Biesen 2005; Van Loo 1996; Yoon 2004).
In low certainty evidence, epoetin alfa (OR 0.28, 95% CI 0.13 to 0.61) and epoetin beta (OR 0.19, 95% CI 0.08 to 0.47) may be superior to placebo for preventing blood transfusion. In moderate certainty evidence, darbepoetin alfa was probably superior to placebo for preventing blood transfusion (OR 0.27, 95% CI 0.11 to 0.67). In very low certainty evidence, methoxy polyethylene glycol‐epoetin beta (OR 0.33, 95% CI 0.11 to 1.02), a biosimilar epoetin (OR 0.34, 95% CI 0.11 to 1.03) and a biosimilar darbepoetin alfa (OR 0.37, 95% CI 0.07 to 1.91) had uncertain effects on preventing blood transfusion compared to placebo. In very low certainty evidence, the effects between different ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol‐epoetin beta, a biosimilar epoetin and a biosimilar darbepoetin alfa) on the odds of preventing blood transfusions were imprecise. The heterogeneity tau for this network overall was 0.58, which is consistent with moderate heterogeneity.
Fatigue
The network for this outcome provided no closed loops of evidence (Figure 4), and conventional pairwise meta‐analysis was the primary source of evidence for this outcome, showing generally imprecise estimates of comparative treatment effects.
Breathlessness
Ten studies reported breathlessness (2970 participants; 15.7% of the participants in this review) (EudraCT 2007‐001905‐10; Fishbane 2018; Fishbane 2019; Goh 2007; Haag‐Weber 2009; Lee 2019; Nissenson 2002; Picon 2015; Spinowitz 2006; Thadhani 2018).
In very low certainty evidence, the effects of epoetin alfa on the odds of breathlessness were imprecise when compared to darbepoetin alfa (OR 1.41, 95% CI 0.91 to 2.18), methoxy polyethylene glycol‐epoetin beta (OR 0.36, 95% CI 0.03 to 4.34), a biosimilar epoetin (OR 1.00, 95% CI 0.70 to 1.42) or a biosimilar darbepoetin alfa (OR 5.38, 95% CI 0.21 to 137.78). In very low certainty evidence, the effects of darbepoetin alfa on the odds of breathlessness were imprecise when compared to methoxy polyethylene glycol‐epoetin beta (OR 0.26, 95% CI 0.02 to 2.97), a biosimilar epoetin (OR 0.71, 95% CI 0.41 to 1.24) or a biosimilar darbepoetin alfa (OR 3.82, 95% CI 0.15 to 95.02). In very low certainty evidence, effects on breathlessness were also uncertain between methoxy polyethylene glycol‐epoetin beta and a biosimilar epoetin (OR 2.78, 95% CI 0.22 to 34.42) or a biosimilar darbepoetin alfa (OR 14.95, 95% CI 0.26 to 851.67), and between a biosimilar epoetin and a biosimilar darbepoetin alfa (OR 5.37, 95% CI 0.21 to 140.26). The heterogeneity tau for the network was 0.0, indicating no statistical evidence of heterogeneity.
2. Safety
2.1 Pairwise meta‐analysis (direct comparisons)
Death (any cause)
ESAs compared to placebo or standard care
Data for the effects of ESA treatment compared to placebo or standard care on death was provided in 19 studies (6500 participants) (Bahlmann 1991; Bennett 1991; Canadian EPO 1990; Coupes 2015; EPOCARES 2010; Hafer 2012; Kleinman 1989; Klinkmann 1992; Kuriyama 1997; Nissenson 1995; Palazzuoli 2007; Patel 2012; Pile 2020; PROTECT 2012; RED‐HF 2009; Roth 1994; TREAT 2005; Van Loo 1996; Yasari 2012). Four agents (epoetin alfa, epoetin beta, darbepoetin alfa and biosimilar epoetin) were assessed against placebo or standard care. No study evaluated methoxy polyethylene glycol‐epoetin beta with placebo or standard care.
The odds of death were uncertain for epoetin alfa (Analysis 1.4.1 (5 studies, 455 participants): OR 0.57, 95% CI 0.15 to 2.26; I² = 0%; low certainty evidence), epoetin beta Analysis 1.4.2 (5 studies, 442 participants): OR 0.62, 95% CI 0.23 to 1.70; I² = 0%; low certainty evidence), darbepoetin alfa (Analysis 1.4.3 (2 studies, 4854 participants): OR 1.00, 95% CI 0.84 to 1.19; I² = 31%; low certainty evidence), and biosimilar epoetin (Analysis 1.4.4 (1 study, 40 participants): no events; low certainty evidence) when compared with placebo (Bahlmann 1991; Bennett 1991; Canadian EPO 1990; Coupes 2015; Hafer 2012; Kleinman 1989; Nissenson 1995; Palazzuoli 2007; PROTECT 2012; RED‐HF 2009; Roth 1994; TREAT 2005; Yasari 2012).
The odds of death were uncertain for epoetin alfa (Analysis 1.4.5 (1 study, 157 participants): OR 1.06, 95% CI 0.39 to 2.87; low certainty evidence) and epoetin beta (Analysis 1.4.6 (5 studies, 552 participants): OR 0.76, 95% CI 0.40 to 1.43; I² = 0%; low certainty evidence) when compared with standard care (EPOCARES 2010; Klinkmann 1992; Kuriyama 1997; Patel 2012; Pile 2020; Van Loo 1996).
1.4. Analysis.
Comparison 1: ESA versus ESA or placebo/standard care, Outcome 4: Death (any cause)
ESAs compared to each other
Epoetin alfa was compared to darbepoetin alfa in nine studies (1913 participants) (Akizawa 2011; Allon 2002; Bernieh 2014; Hori 2004; Li 2008d; Locatelli 2001; Nissenson 2002; Vanrenterghem 2002; Woodland 2017), epoetin alfa was compared to a biosimilar epoetin in 13 studies (4154 participants) (Azmandian 2018; Fishbane 2018; Fishbane 2019; Goh 2007; Haag‐Weber 2009; Haag‐Weber 2012; Krivoshiev 2008; Krivoshiev 2010; Milutinovic 2006; Picon 2015; Spinowitz 2006; Thadhani 2018; Weir 2017), epoetin beta was compared versus darbepoetin alfa in three studies (377 participants) (Liao 2016a; Smyth 2004; Tolman 2005), epoetin beta was compared to methoxy polyethylene glycol‐epoetin beta in three studies (542 participants) (AMICUS 2007; Chen 2012e; Oh 2014), epoetin beta was compared to a biosimilar epoetin in one study (290 participants) (Gertz 2010), darbepoetin alfa was compared to methoxy polyethylene glycol‐epoetin beta in five studies (1500 participants) (ARCTOS 2008; CORDATUS 2011; PATRONUS 2010; STRIATA 2008; TIVOLI 2013), and darbepoetin alfa was compared to biosimilar darbepoetin alfa in three studies (335 participants) (Apsangikar 2018; NCT02506868; Nishi 2020).
The odds of death (any cause) with epoetin alfa were uncertain when compared to darbepoetin alfa (Analysis 1.4.7 (9 studies, 1913 participants): OR 0.78, 95% CI 0.50 to 1.22; I² = 0%; low certainty evidence) or biosimilar epoetin (Analysis 1.4.8 (13 studies, 4154 participants): OR 1.01, 95% CI 0.69 to 1.47; I² = 22%; low certainty evidence).
The odds of death (any cause) with epoetin beta were uncertain when compared to darbepoetin alfa (Analysis 1.4.9 (3 studies, 377 participants): OR 0.89, 95% CI 0.38 to 2.09; I² = 0%; low certainty evidence), methoxy polyethylene glycol‐epoetin beta (Analysis 1.4.10 (3 studies, 542 participants): OR 0.81, 95% CI 0.12 to 5.35; I² = 0%; low certainty evidence) or a biosimilar epoetin (Analysis 1.4.11 (1 study, 290 participants): OR 0.34, 95% CI 0.04 to 2.82; low certainty evidence).
The odds of death (any cause) with darbepoetin alfa were uncertain when compared to methoxy polyethylene glycol‐epoetin beta (Analysis 1.4.12 (5 studies, 1498 participants): OR 1.07, 95% CI 0.68 to 1.68; I² = 0%; low certainty evidence) or a biosimilar darbepoetin alfa (Analysis 1.4.13 (3 studies, 335 participants): OR 0.61, 95% CI 0.19 to 1.91; I² = 0%; low certainty evidence).
Cardiovascular death
ESAs compared to placebo or standard care
Data for the effects of ESA treatment compared to placebo or standard care on cardiovascular death were provided in six studies (4766 participants) (Bahlmann 1991; Bennett 1991; EPOCARES 2010; Klinkmann 1992; Kuriyama 1997; TREAT 2005). Two agents (epoetin beta and darbepoetin alfa) were assessed against placebo or standard care. No study evaluated either epoetin alfa or methoxy polyethylene glycol‐epoetin beta with placebo or standard care.
The odds of cardiovascular death were uncertain for epoetin beta (Analysis 1.5.1 (2 studies, 260 participants): OR 0.45, 95% CI 0.06 to 3.75, I² = 0%; very low certainty evidence) and darbepoetin alfa (Analysis 1.5.2 (1 study, 4038 participants): OR 1.05, 95% CI 0.87 to 1.26; low certainty evidence) when compared to placebo (Bahlmann 1991; Bennett 1991; TREAT 2005).
The odds of cardiovascular death were uncertain for epoetin beta (Analysis 1.5.3 (3 studies, 430 participants): OR 0.28, 95% CI 0.08 to 1.03; I² = 0%; low certainty evidence) when compared with standard care (EPOCARES 2010; Klinkmann 1992; Kuriyama 1997).
1.5. Analysis.
Comparison 1: ESA versus ESA or placebo/standard care, Outcome 5: Cardiovascular death
ESAs compared to each other
Epoetin alfa was compared to darbepoetin alfa in two studies (487 participants) (Akizawa 2011; Locatelli 2001) and a biosimilar epoetin in four studies (1508 participants) (Fishbane 2018; Fishbane 2019; Goh 2007; Haag‐Weber 2009). Epoetin beta was compared to a biosimilar epoetin in one study (290 participants) (Gertz 2010). Darbepoetin alfa was compared to methoxy polyethylene glycol‐epoetin beta in three studies (938 participants) (ARCTOS 2008; CORDATUS 2011; STRIATA 2008).
The odds of cardiovascular death were uncertain for epoetin alfa when compared to darbepoetin alfa (Analysis 1.5.4 (2 studies, 487 participants): OR 2.15, 95% CI 0.31 to 14.91; I² = 0%; low certainty evidence) or a biosimilar epoetin (Analysis 1.5.5 (4 studies, 1508 participants): OR 1.11, 95% CI 0.34 to 3.66; I² = 37%; low certainty evidence).
The odds of cardiovascular death were uncertain for epoetin beta when compared to a biosimilar epoetin (Analysis 1.5.6 (1 study, 290 participants): OR 0.34, 95% CI 0.04 to 2.82; low certainty evidence).
The odds of cardiovascular death were uncertain for darbepoetin alfa when compared to methoxy polyethylene glycol‐epoetin beta (Analysis 1.5.7 (3 studies, 938 participants): OR 0.69, 95% CI 0.32 to 1.48; I² = 0%; low certainty evidence).
Myocardial infarction
ESAs compared to placebo or standard care
Data for the effects of ESA treatment compared to placebo or standard care on MI were provided in six studies (5169 participants) (Kleinman 1989; Palazzuoli 2011; Patel 2012; PROTECT 2012; RED‐HF 2009; TREAT 2005). Three agents (epoetin alfa, epoetin beta and darbepoetin alfa) were assessed against placebo or standard care. No study evaluated methoxy polyethylene glycol‐epoetin beta with placebo or standard care.
The odds of MI were uncertain for epoetin alfa (Analysis 1.6.1 (1 study, 14 participants): OR 3.46, 95% CI 0.12 to 100.51; low certainty evidence), darbepoetin alfa (Analysis 1.6.2 (2 studies, 4854 participants): OR 0.91, 95% CI 0.73 to 1.15; I² = 0%; low certainty evidence), and epoetin beta (Analysis 1.6.3 (1 study, 92 participants): OR 0.34, 95% CI 0.01 to 8.58; very low certainty evidence) when compared to placebo (Kleinman 1989; PROTECT 2012; RED‐HF 2009; TREAT 2005).
The odds of MI were uncertain for epoetin alfa (Analysis 1.6.4 (2 studies, 183 participants): OR 1.01, 95% CI 0.04 to 25.26; I² = 0%; low certainty evidence) and epoetin beta (Analysis 1.6.5 (1 study, 26 participants): no events) when compared to standard care (Palazzuoli 2011; Patel 2012).
1.6. Analysis.
Comparison 1: ESA versus ESA or placebo/standard care, Outcome 6: Myocardial infarction
ESAs compared to each other
Epoetin alfa was compared to darbepoetin alfa in three studies (1347 participants) (Akizawa 2011; Nissenson 2002; Vanrenterghem 2002), and a biosimilar epoetin in five studies (1429 participants) (Beiraghdar 2015; Fishbane 2019; Goh 2007; Krivoshiev 2010; Weir 2017). Darbepoetin alfa was compared to methoxy polyethylene glycol‐epoetin beta in three studies (739 participants) (Al‐Ali 2015; ARCTOS 2008; CORDATUS 2011), and a biosimilar darbepoetin alfa in one study (195 participants) (NCT02506868).
The odds of MI were uncertain for epoetin alfa when compared to darbepoetin alfa (Analysis 1.6.6 (3 studies, 1347 participants): OR 1.30, 95% CI 0.55 to 3.08; I² = 0%; very low certainty evidence) or a biosimilar epoetin (Analysis 1.6.7 (5 studies, 1429 participants): OR 1.10, 95% CI 0.47 to 2.58; I² = 0%; low certainty evidence).
The odds of MI were uncertain for darbepoetin alfa when compared to methoxy polyethylene glycol‐epoetin beta (Analysis 1.6.8 (3 studies, 739 participants): OR 0.83, 95% CI 0.15 to 4.72; I² = 0%; low certainty evidence) or a biosimilar darbepoetin alfa (Analysis 1.6.9 (1 study, 195 participants): OR 0.33, 95% CI 0.01 to 8.28; low certainty evidence).
Stroke
ESAs compared to placebo or standard care
Data for the effects of ESA treatment compared to placebo or standard care on stroke were provided in six studies (5242 participants) (Bahlmann 1991; EPOCARES 2010; Patel 2012; PROTECT 2012; RED‐HF 2009; TREAT 2005). Three agents (epoetin alfa, epoetin beta and darbepoetin alfa) were assessed against placebo or standard care. No study evaluated methoxy polyethylene glycol‐epoetin beta with placebo or standard care.
The odds of stroke were uncertain for epoetin beta when compared to placebo (Analysis 1.7.1 (2 studies, 198 participants): OR 1.40, 95% CI 0.09 to 22.13; I² = 35%; low certainty evidence) but were probably increased with darbepoetin alfa compared to placebo (Analysis 1.7.2 (2 studies, 4854 participants): OR 2.02, 95% CI 1.48 to 2.75; I² = 0%; moderate certainty evidence) (Bahlmann 1991; PROTECT 2012; RED‐HF 2009; TREAT 2005).
The odds of stroke were uncertain for epoetin alfa (Analysis 1.7.3 (1 study, 157 participants): OR 0.99, 95% CI 0.10 to 9.82; low certainty evidence) and epoetin beta (Analysis 1.7.4 (1 study, 33 participants): OR 0.20, 95% CI 0.01 to 5.39; low certainty evidence) compared to standard care (EPOCARES 2010; Patel 2012).
1.7. Analysis.
Comparison 1: ESA versus ESA or placebo/standard care, Outcome 7: Stroke
ESAs compared to each other
Epoetin alfa was compared to darbepoetin alfa in four studies (1518 participants) (Akizawa 2011; Hirakata 2010; Nissenson 2002; Vanrenterghem 2002) and a biosimilar epoetin in five studies (1260 participants) (Beiraghdar 2015; Goh 2007; Krivoshiev 2010; Milutinovic 2006; Weir 2017). Darbepoetin alfa was compared to methoxy polyethylene glycol‐epoetin beta in three studies (664 participants) (ARCTOS 2008; CORDATUS 2011; Ohki 2020), a biosimilar epoetin in one study (74 participants) (Yoon 2004), and a biosimilar darbepoetin alfa in one study (195 participants) (NCT02506868).
The odds of stroke were uncertain for epoetin alfa when compared to darbepoetin alfa (Analysis 1.7.5 (4 studies, 1518 participants): OR 0.97, 95% CI 0.35 to 2.70; I² = 0%; very low certainty evidence) or a biosimilar epoetin (Analysis 1.7.6 (5 studies, 1260 participants): OR 0.79, 95% CI 0.35 to 1.80; I² = 0%; low certainty evidence).
The odds of stroke were uncertain for darbepoetin alfa when compared to methoxy polyethylene glycol‐epoetin beta (Analysis 1.7.7 (3 studies, 664 participants): OR 1.72, 95% CI 0.34 to 8.64; I² = 0%; low certainty evidence), a biosimilar epoetin (Analysis 1.7.8 (1 study, 74 participants): OR 0.31, 95% CI 0.01 to 7.79; low certainty evidence), or a biosimilar darbepoetin alfa (Analysis 1.7.9 (1 study, 195 participants): OR 3.06, 95% CI 0.12 to 76.10; low certainty evidence).
Hypertension
ESAs compared to placebo or standard care
Data for the effects of ESA treatment compared to placebo or standard care on hypertension were provided in nine studies (5097 participants) (Bahlmann 1991; Bennett 1991; Canadian EPO 1990; Clyne 1992; Coupes 2015; Klinkmann 1992; Nissenson 1995; Patel 2012; TREAT 2005). Three agents (epoetin alfa, epoetin beta and darbepoetin alfa) were assessed against placebo or standard care. No study evaluated methoxy polyethylene glycol‐epoetin beta with placebo or standard care.
The odds of hypertension were probably increased with epoetin alfa (Analysis 1.8.1 (2 studies; 251 participants): OR 4.10, 95% CI 2.16 to 7.76; I² = 0%; moderate certainty evidence), epoetin beta (Analysis 1.8.2 (3 studies, 269 participants): OR 2.36, 95% CI 1.11 to 5.04; I² = 0%; moderate certainty evidence), and darbepoetin alfa (Analysis 1.8.3 (1 study, 4038 participants): OR 1.14, 95% CI 0.99 to 1.32; moderate certainty evidence) when compared to placebo (Bahlmann 1991; Bennett 1991; Canadian EPO 1990; Coupes 2015; Nissenson 1995; TREAT 2005).
The odds of hypertension were uncertain for epoetin alfa compared to standard care (Analysis 1.8.4 (1 study, 157 participants): OR 5.31, 95% CI 0.30 to 95.20; low certainty evidence) but were increased with epoetin beta compared to standard care (Analysis 1.8.5 (2 studies, 382 participants): OR 2.99, 95% CI 1.34 to 6.69; I² = 0%; moderate certainty evidence) (Clyne 1992; Klinkmann 1992; Patel 2012).
1.8. Analysis.
Comparison 1: ESA versus ESA or placebo/standard care, Outcome 8: Hypertension
ESAs compared to each other
Epoetin alfa was compared to darbepoetin alfa in six studies (2090 participants) (Akizawa 2011; Coyne 2006a; Hirakata 2010; Locatelli 2001; Nissenson 2002; Vanrenterghem 2002), a biosimilar epoetin in seven studies (1940 participants) (Argani 2009; Beiraghdar 2015; Fishbane 2018; Goh 2007; Krivoshiev 2010; Milutinovic 2006; Weir 2017), and a biosimilar darbepoetin alfa in one study (746 participants) (Martin 2007). Epoetin beta was compared to darbepoetin alfa in one study (162 participants) (Tolman 2005), methoxy polyethylene glycol‐epoetin beta in two studies (261 participants) (AMICUS 2007; Oh 2014), and a biosimilar epoetin in one study (290 participants) (Gertz 2010). Darbepoetin alfa was compared to methoxy polyethylene glycol‐epoetin beta in six studies (1568 participants) (ARCTOS 2008; CORDATUS 2011; EudraCT 2007‐001905‐10; PATRONUS 2010; STRIATA 2008; TIVOLI 2013) and a biosimilar darbepoetin alfa in three studies (609 participants) (Lee 2019; NCT02506868; Nishi 2020).
The odds of hypertension were uncertain for epoetin alfa compared to darbepoetin alfa (Analysis 1.8.6 (6 studies, 2090 participants): OR 0.93, 95% CI 0.68 to 1.25; I² = 32%; low certainty evidence) with evidence of moderate heterogeneity, a biosimilar epoetin (Analysis 1.8.7 (7 studies, 1940 participants): OR 1.21, 95% CI 0.76 to 1.93; I² = 27%; low certainty evidence), or a biosimilar darbepoetin alfa (Analysis 1.8.8 (1 study, 746 participants): OR 0.72, 95% CI 0.15 to 3.44; low certainty evidence).
The odds of hypertension were uncertain for epoetin beta compared to darbepoetin alfa (Analysis 1.8.9 (1 study, 162 participants): OR 1.18, 95% CI 0.38 to 3.69; low certainty evidence), methoxy polyethylene glycol‐epoetin beta (Analysis 1.8.10 (2 studies, 261 participants): OR 1.44, 95% CI 0.66 to 3.15; I² = 0%; low certainty evidence), or a biosimilar epoetin (Analysis 1.8.11 (1 study, 290 participants): OR 0.74, 95% CI 0.30 to 1.82; low certainty evidence).
The odds of hypertension were uncertain for darbepoetin alfa compared to methoxy polyethylene glycol‐epoetin beta (Analysis 1.8.12 (6 studies, 1568 participants): OR 0.91, 95% CI 0.62 to 1.33; I² = 27%; low certainty evidence) or a biosimilar darbepoetin alfa (Analysis 1.8.13 (3 studies, 609 participants): OR 0.93, 95% CI 0.51 to 1.70; I² = 3%; low certainty evidence).
Vascular access thrombosis
ESAs compared to placebo or standard care
Data for the effects of ESA treatment compared to placebo or standard care on thrombosis of vascular access were provided in six studies (4677 participants) (Bahlmann 1991; Canadian EPO 1990; Kleinman 1989; Klinkmann 1992; PROTECT 2012; TREAT 2005). Three agents (epoetin alfa, epoetin beta and darbepoetin alfa) were assessed against placebo or standard care. No study evaluated methoxy polyethylene glycol‐epoetin beta with placebo or standard care.
The odds of vascular access thrombosis were uncertain for epoetin alfa (Analysis 1.9.1 (2 studies, 132 participants): OR 6.40, 95% CI 0.80 to 51.50; low certainty evidence), epoetin beta (Analysis 1.9 .2(2 studies, 191 participants): OR 1.67, 95% CI 0.47 to 6.00; I² = 11%; low certainty evidence) and darbepoetin alfa (Analysis 1.9.3 (1 study, 4038 participants): OR 1.34, 95% CI 0.30 to 6.01; low certainty evidence) compared to placebo (Bahlmann 1991; Canadian EPO 1990; PROTECT 2012; TREAT 2005).
The odds of vascular access thrombosis were uncertain for epoetin beta (Analysis 1.9.4 (1 study, 363 participants): OR 1.40, 95% CI 0.72 to 2.73; low certainty evidence) when compared to standard care (Klinkmann 1992).
1.9. Analysis.
Comparison 1: ESA versus ESA or placebo/standard care, Outcome 9: Vascular access thrombosis
ESAs compared to each other
Epoetin alfa was compared to darbepoetin alfa in five studies (1745 participants) (Bernieh 2014; Coyne 2006a; Hirakata 2010; Nissenson 2002; Vanrenterghem 2002), a biosimilar epoetin in two studies (115 participants) (Bren 2001; Milutinovic 2006), and a biosimilar darbepoetin alfa in one study (746 participants) (Martin 2007). Epoetin beta was compared to methoxy polyethylene glycol‐epoetin beta in one study (181 participants) (AMICUS 2007). Darbepoetin alfa was compared to methoxy polyethylene glycol‐epoetin beta in two studies (600 participants) (Al‐Ali 2015; PATRONUS 2010), a biosimilar epoetin in one study (74 participants) (Yoon 2004), and a biosimilar darbepoetin alfa in one study (195 participants) (NCT02506868).
The odds of vascular access thrombosis were uncertain for epoetin alfa when compared to darbepoetin alfa (Analysis 1.9.5 (5 studies, 1745 participants): OR 1.16, 95% CI 0.75 to 1.81; I² = 16%; low certainty evidence), a biosimilar epoetin (Analysis 1.9.6 (2 studies, 115 participants): OR 2.10, 95% CI 0.42 to 10.42; I² = 7%; very low certainty evidence), or a biosimilar darbepoetin alfa (Analysis 1.9.7 (1 study, 746 participants): OR 1.04, 95% CI 0.37 to 2.92; low certainty evidence).
The odds of vascular access thrombosis were uncertain for epoetin beta when compared to methoxy polyethylene glycol‐epoetin beta (Analysis 1.9.8 (1 study, 181 participants): OR 1.74, 95% CI 0.49 to 6.24; low certainty evidence).
The odds of vascular access thrombosis were uncertain for darbepoetin alfa when compared to methoxy polyethylene glycol‐epoetin beta (Analysis 1.9.9 (2 studies, 600 participants): OR 0.74, 95% CI 0.41 to 1.36; I² = 0%; low certainty evidence), a biosimilar epoetin (Analysis 1.9.10 (1 study, 74 participants): OR 0.31, 95% CI 0.01 to 7.79; low certainty evidence), or a biosimilar darbepoetin alfa (Analysis 1.9.11 (1 study, 195 participants): OR 1.01, 95% CI 0.20 to 5.14; low certainty evidence).
Kidney failure
ESAs compared to placebo or standard care
Data for the effects of ESA treatment compared to placebo or standard care on kidney failure were provided in 10 studies (5339 participants) (Brown 1995; EPOCARES 2010; Hafer 2012; Kuriyama 1997; Pile 2020; PROTECT 2012; RED‐HF 2009; Silverberg 2001; TREAT 2005; Yasari 2012). Three agents (epoetin alfa, epoetin beta, darbepoetin alfa and biosimilar epoetin) were assessed against placebo or standard care. No study evaluated either methoxy polyethylene glycol‐epoetin beta with placebo or standard care.
The odds of kidney failure were uncertain for epoetin alfa (Analysis 1.10.1 (1 study, 85 participants): OR 0.62, 95% CI 0.16 to 2.36; low certainty evidence), epoetin beta (Analysis 1.10.2 (1 study, 92 participants): OR 1.61, 95% CI 0.26 to 10.10; low certainty evidence), and a biosimilar epoetin compared to placebo (Analysis 1.10.3 (1 study, 40 participants): no events; low certainty evidence) (Hafer 2012; PROTECT 2012; Yasari 2012).
The odds of kidney failure were uncertain for darbepoetin alfa compared to placebo (Analysis 1.10.4 (2 studies, 4854 participants): OR 0.93, 95% CI 0.62 to 1.39; I² = 39%; low certainty evidence) with evidence of moderate heterogeneity (RED‐HF 2009; TREAT 2005).
The odds of kidney failure were uncertain for epoetin alfa (Analysis 1.10.5 (2 studies, 107 participants): OR 0.61, 95% CI 0.24 to 1.55; I² = 0%; low certainty evidence) when compared to standard care (Brown 1995; Silverberg 2001).
The risk of kidney failure may be lower for epoetin beta (Analysis 1.10.6 (3 studies, 161 participants): OR 0.31, 95% CI 0.13 to 0.76; I² = 0%; low certainty evidence) when compared to standard care (EPOCARES 2010; Kuriyama 1997; Pile 2020).
1.10. Analysis.
Comparison 1: ESA versus ESA or placebo/standard care, Outcome 10: Kidney failure
ESAs compared to each other
Epoetin alfa was compared to darbepoetin alfa in two studies (492 participants) (Akizawa 2011; Hirakata 2010). Darbepoetin alfa was compared to methoxy polyethylene glycol‐epoetin beta in two studies (341 participants) (CORDATUS 2011; Ohki 2020) and a biosimilar darbepoetin alfa in one study (183 participants) (Lee 2019).
The odds of kidney failure were uncertain for epoetin alfa when compared to darbepoetin alfa (Analysis 1.10.7 (2 studies, 492 participants): OR 2.17, 95% CI 0.37 to 12.74; I² = 48%; very low certainty evidence) with evidence of moderate heterogeneity.
The odds of kidney failure were uncertain for darbepoetin alfa when compared to methoxy polyethylene glycol‐epoetin beta (Analysis 1.10.8 (2 studies, 341 participants): OR 1.87, 95% CI 0.73 to 4.82; I² = 0%; very low certainty evidence) or a biosimilar darbepoetin alfa (Analysis 1.10.9 (1 study, 183 participants): OR 0.79, 95% CI 0.19 to 3.24; low certainty evidence).
Major cardiovascular events
ESAs compared to placebo or standard care
Data for the effects of ESA treatment compared to placebo or standard care on major cardiovascular events were provided in four studies (5044 participants) (EPOCARES 2010; Patel 2012; RED‐HF 2009; TREAT 2005; Van Loo 1996). Three agents (epoetin alfa, epoetin beta and darbepoetin alfa) were assessed against placebo or standard care. No study evaluated methoxy polyethylene glycol‐epoetin beta with placebo or standard care.
Darbepoetin alfa has uncertain effects on major cardiovascular events compared to placebo (Analysis 1.11.1 (2 studies, 4854 participants): OR 1.08, 95% CI 0.96 to 1.22; I² = 0%; low certainty evidence) (RED‐HF 2009; TREAT 2005).
Epoetin alfa (Analysis 1.11.2 (1 study, 157 participants): OR 2.40, 95% CI 0.29 to 20.11; low certainty evidence) and epoetin beta (Analysis 1.11.3 (2 studies, 62 participants): OR 0.61, 95% CI 0.07 to 4.98; low certainty evidence) have uncertain effects on major cardiovascular events when compared to standard care (EPOCARES 2010; Patel 2012; Van Loo 1996).
1.11. Analysis.
Comparison 1: ESA versus ESA or placebo/standard care, Outcome 11: Major cardiovascular events
ESAs compared to each other
Epoetin alfa was compared to darbepoetin alfa in one study (321 participants) (Akizawa 2011) and a biosimilar epoetin in four studies (1748 participants) (Fishbane 2018; Fishbane 2019; Krivoshiev 2010; Weir 2017). Darbepoetin alfa was compared to methoxy polyethylene glycol‐epoetin beta in one study (71 participants) (EudraCT 2007‐001905‐10).
The odds of a major cardiovascular event were uncertain for epoetin alfa when compared to darbepoetin alfa (Analysis 1.11.4 (1 study, 321 participants): OR 0.20, 95% CI 0.01 to 4.17; low certainty evidence) or a biosimilar epoetin (Analysis 1.11.5 (4 studies, 1748 participants): OR 0.77, 95% CI 0.36 to 1.61; I² = 0%; low certainty evidence).
The odds of a major cardiovascular event were uncertain for darbepoetin alfa when compared to methoxy polyethylene glycol‐epoetin beta (Analysis 1.11.6 (1 study, 71 participants): OR 1.88, 95% CI 0.11 to 31.32; low certainty evidence).
2.2 Network meta‐analysis (combination of direct and indirect comparisons)
Treatment estimates for network meta‐analyses are shown in Table 2, and network meta‐analyses for all ESAs against placebo are summarised in Figure 5. Studies grouped by comparison were deemed comparable for the effect modifiers of stage of CKD, Hb target with ESA treatment, age of participants and duration and follow‐up, such that the assumption of transitivity might hold and that a network meta‐analytical approach was reasonable. Overall, SUCRA rankings of the differing ESAs were imprecise, with wide CI rendering the analyses clinically irrelevant. Therefore, treatment rankings are not provided in the results.
Death (any cause)
Death (any cause) data were provided in 56 studies (15,842 participants with CKD; 83.9% of the participants in this review) (Akizawa 2011; Allon 2002; AMICUS 2007; Apsangikar 2018; ARCTOS 2008; Azmandian 2018; Bahlmann 1991; Bennett 1991; Bernieh 2014; Canadian EPO 1990; Chen 2012e; CORDATUS 2011; Coupes 2015; EPOCARES 2010; Fishbane 2018; Fishbane 2019; Gertz 2010; Goh 2007; Haag‐Weber 2009; Haag‐Weber 2012; Hafer 2012; Hori 2004; Kleinman 1989; Klinkmann 1992; Krivoshiev 2008; Krivoshiev 2010; Kuriyama 1997; Li 2008d; Liao 2016a; Locatelli 2001; Milutinovic 2006; NCT02506868; Nishi 2020; Nissenson 1995; Nissenson 2002; Oh 2014; Palazzuoli 2007; Patel 2012; PATRONUS 2010; Picon 2015; Pile 2020; PROTECT 2012; RED‐HF 2009; Roth 1994; Smyth 2004; Spinowitz 2006; STRIATA 2008; Thadhani 2018; TIVOLI 2013; Tolman 2005; TREAT 2005; Van Loo 1996; Vanrenterghem 2002; Weir 2017; Woodland 2017; Yasari 2012).
In low certainty evidence, epoetin alfa (OR 0.79, 95% CI 0.51 to 1.22), epoetin beta (OR 0.69, 95% CI 0.40 to 1.20), and a biosimilar epoetin (OR 0.80, 95% CI 0.47 to 1.36) had uncertain effects on death from any cause compared to placebo. In moderate certainty evidence, there was probably no difference between darbepoetin alfa and placebo on the odds of death from any cause (OR 0.99, 95% CI 0.81 to 1.21). In very low certainty evidence, methoxy polyethylene glycol‐epoetin beta (OR 1.07, 95% CI 0.67 to 1.71) and a biosimilar darbepoetin alfa (OR 1.63, 95% CI 0.51 to 5.23) had uncertain effects on death from any cause compared to placebo. In low to very low certainty evidence, the effects of any ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol‐epoetin beta, a biosimilar epoetin and a biosimilar darbepoetin alfa) on the odds of death from any cause were imprecise when compared with other ESA. The heterogeneity tau for the network was 0.01, indicating no statistical evidence of heterogeneity.
Cardiovascular death
Cardiovascular death was reported in 16 studies (7951 participants; 42.1% of the participants in this review) (Akizawa 2011; ARCTOS 2008; Bahlmann 1991; Bennett 1991; CORDATUS 2011; EPOCARES 2010; Fishbane 2018; Fishbane 2019; Gertz 2010; Goh 2007; Haag‐Weber 2009; Klinkmann 1992; Kuriyama 1997; Locatelli 2001; STRIATA 2008; TREAT 2005).
In very low certainty evidence, epoetin alfa (OR 1.85, 95% CI 0.36 to 9.62), epoetin beta (OR 0.57, 95% CI 0.10 to 3.22), darbepoetin alfa (OR 1.05, 95% CI 0.87 to 1.26), methoxy polyethylene glycol‐epoetin beta (OR 1.52, 95% CI 0.69 to 3.34), a biosimilar epoetin (OR 2.17, 95% CI 0.39 to 12.17), and a biosimilar darbepoetin alfa (OR 2.05, 95% CI 0.24 to 17.75) had uncertain effects on cardiovascular death compared to placebo. In very low certainty evidence, the effects of any ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol‐epoetin beta, and a biosimilar epoetin) on the odds of cardiovascular death were imprecise when compared with other ESA. The heterogeneity tau for the network was 0.0, indicating no statistical evidence of heterogeneity.
Myocardial infarction
Twenty studies reported MI (8878 participants; 47.0% of the participants in this review) (Akizawa 2011; Al‐Ali 2015; ARCTOS 2008; Beiraghdar 2015; CORDATUS 2011; Fishbane 2019; Goh 2007; Kleinman 1989; Krivoshiev 2010; NCT02506868; Nissenson 2002; Palazzuoli 2011; Patel 2012; PROTECT 2012; RED‐HF 2009; TREAT 2005; Vanrenterghem 2002; Weir 2017).
In low certainty evidence, epoetin alfa (OR 1.22, 95% CI 0.52 to 2.85), epoetin beta (OR 0.63, 95% CI 0.05 to 7.27), and a biosimilar darbepoetin alfa (OR 2.74, 95% CI 0.11 to 68.76) had uncertain effects on MI compared to placebo. In moderate certainty evidence, there was probably no difference between darbepoetin alfa and placebo on the odds of MI (OR 0.91, 95% CI 0.73 to 1.15). In very low certainty evidence, methoxy polyethylene glycol‐epoetin beta (OR 1.09, 95% CI 0.19 to 6.27) and a biosimilar epoetin (OR 1.12, 95% CI 0.34 to 3.70) had uncertain effects on MI compared to placebo. In low to very low certainty evidence, the effects of any ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol‐epoetin beta, a biosimilar epoetin and a biosimilar darbepoetin alfa) on the odds of MI were imprecise when compared with other ESA. The heterogeneity tau for the network was 0.0, indicating no statistical evidence of heterogeneity.
Stroke
Twenty studies reported stroke events (8953 participants; 47.4% of the participants in this review) (Akizawa 2011; ARCTOS 2008; Bahlmann 1991; Beiraghdar 2015; CORDATUS 2011; EPOCARES 2010; Goh 2007; Hirakata 2010; Krivoshiev 2010; Milutinovic 2006; NCT02506868; Nissenson 2002; Ohki 2020; Patel 2012; PROTECT 2012; RED‐HF 2009; TREAT 2005; Vanrenterghem 2002; Weir 2017; Yoon 2004).
In moderate certainty evidence, darbepoetin alfa probably increased the odds of stroke when compared to placebo (OR 2.03, 95% CI 1.49 to 2.77). In very low certainty evidence, epoetin alfa (OR 2.25, 95% CI 0.83 to 6.15), epoetin beta (OR 1.10, 95% CI 0.16 to 7.77), methoxy polyethylene glycol‐epoetin beta (OR 1.18, 95% CI 0.23 to 6.10) and a biosimilar epoetin (OR 2.97, 95% CI 0.87 to 10.16) had uncertain effects on stroke compared to placebo. In low certainty evidence, a biosimilar darbepoetin alfa (OR 0.66, 95% CI 0.03 to 16.73) had uncertain effects on stroke compared to placebo. In low to very low certainty evidence, the effects of any ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol‐epoetin beta, a biosimilar epoetin and a biosimilar darbepoetin alfa) on the odds of stroke were imprecise when compared with other ESA. The heterogeneity tau for the network was 0.0, indicating no statistical evidence of heterogeneity.
Hypertension
Hypertension data were provided in 36 studies (12,763 participants; 67.6% of participants in this review) (Akizawa 2011; AMICUS 2007; ARCTOS 2008; Argani 2009; Bahlmann 1991; Beiraghdar 2015; Bennett 1991; Canadian EPO 1990; Clyne 1992; CORDATUS 2011; Coyne 2006a; Coupes 2015; EudraCT 2007‐001905‐10; Fishbane 2018; Gertz 2010; Goh 2007; Hirakata 2010; Klinkmann 1992; Krivoshiev 2010; Lee 2019; Locatelli 2001; Martin 2007; Milutinovic 2006; NCT02506868; Nishi 2020; Nissenson 1995; Nissenson 2002; Oh 2014; Patel 2012; PATRONUS 2010; STRIATA 2008; TIVOLI 2013; Tolman 2005; TREAT 2005; Vanrenterghem 2002; Weir 2017).
In moderate certainty evidence, epoetin beta probably increased the odds of hypertension when compared to placebo (OR 2.17, 95% CI 1.17 to 4.00). In very low certainty evidence, epoetin alfa (OR 2.10, 95% CI 1.22 to 3.59) may increase the odds of hypertension when compared to placebo. In low certainty evidence, darbepoetin alfa (OR 1.88, 95% CI 1.12 to 3.14) and methoxy polyethylene glycol‐epoetin beta (OR 1.98, 95% CI 1.05 to 3.74) may increase the odds of hypertension when compared to placebo. In low certainty evidence, a biosimilar epoetin (OR 1.88, 95% CI 0.96 to 3.67) and a biosimilar darbepoetin alfa (OR 1.98, 95% CI 0.84 to 4.66) had uncertain effects on hypertension when compared to placebo. In low to very low certainty evidence, the effects of any ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol‐epoetin beta, a biosimilar epoetin and a biosimilar darbepoetin alfa) on the odds of hypertension were imprecise when compared with other ESA. The heterogeneity tau for this network overall was 0.11, which is consistent with mild heterogeneity.
Kidney failure
Fifteen studies reported on the progression to kidney failure (6355 participants; 33.7% of the participants in this review) (Akizawa 2011; Brown 1995; CORDATUS 2011; EPOCARES 2010; Hafer 2012; Hirakata 2010; Kuriyama 1997; Lee 2019; Ohki 2020; Pile 2020; PROTECT 2012; RED‐HF 2009; Silverberg 2001; TREAT 2005; Yasari 2012).
In low certainty evidence, epoetin alfa (OR 1.23, 95% CI 0.62 to 2.47), epoetin beta (OR 0.87, 95% CI 0.27 to 2.82) and darbepoetin alfa (OR 0.93, 95% CI 0.55 to 1.56) had uncertain effects on kidney failure when compared to placebo. In very low certainty evidence, methoxy polyethylene glycol‐epoetin beta (OR 0.50, 95% CI 0.16 to 1.52), biosimilar epoetin (OR 1.00, 95% CI 0.02 to 53.62) and a biosimilar darbepoetin alfa (OR 1.18, 95% CI 0.25 to 5.56) had uncertain effects on kidney failure when compared to placebo. In low to very low certainty evidence, the effects of any ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol‐epoetin beta, a biosimilar epoetin and a biosimilar darbepoetin alfa) on the odds of kidney failure were imprecise when compared with other ESA. The heterogeneity tau for the network was 0.03, indicating no statistical evidence of heterogeneity.
Vascular access thrombosis
Nineteen studies provided data on vascular access thrombosis (8381 participants; 44.4% of the participants in this review) (Al‐Ali 2015; AMICUS 2007; Bahlmann 1991; Bernieh 2014; Bren 2001; Canadian EPO 1990; Coyne 2006a; Hirakata 2010; Kleinman 1989; Klinkmann 1992; Martin 2007; Milutinovic 2006; NCT02506868; Nissenson 2002; PATRONUS 2010; PROTECT 2012; TREAT 2005; Vanrenterghem 2002; Yoon 2004).
In low certainty evidence, epoetin alfa (OR 1.74, 95% CI 0.63 to 4.80), epoetin beta (OR 2.20, 95% CI 0.82 to 5.92), darbepoetin alfa (OR 1.47, 95% CI 0.55 to 3.95), and methoxy polyethylene glycol‐epoetin beta (OR 1.83, 95% CI 0.64 to 5.22) had uncertain effects on vascular access thrombosis when compared to placebo. In very low certainty evidence, a biosimilar epoetin (OR 1.17, 95% CI 0.21 to 6.35) and a biosimilar darbepoetin alfa (OR 1.61, 95% CI 0.43 to 6.04) had uncertain effects on vascular access thrombosis when compared to placebo. In low to very low certainty evidence, the effects of any ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol‐epoetin beta, a biosimilar epoetin and a biosimilar darbepoetin alfa) on the odds of vascular access thrombosis were imprecise when compared with other ESA. The heterogeneity tau for the network was 0.0, indicating no statistical evidence of heterogeneity.
Major cardiovascular events
Eleven studies provided data on major cardiovascular events (7213 participants; 38.2% of the participants in this review) (Akizawa 2011; EPOCARES 2010; EudraCT 2007‐001905‐10; Fishbane 2018; Fishbane 2019; Krivoshiev 2010; Patel 2012; RED‐HF 2009; TREAT 2005; Van Loo 1996; Weir 2017).
In low certainty evidence, darbepoetin alfa (OR 1.08, 95% CI 0.96 to 1.22) had uncertain effects on major cardiovascular events when compared to placebo. In very low certainty evidence, epoetin alfa (OR 0.21, 95% CI 0.01 to 4.52), epoetin beta (OR 0.06, 95% CI 0.00 to 3.94), methoxy polyethylene glycol‐epoetin beta (OR 0.58, 95% CI 0.03 to 9.65), a biosimilar epoetin (OR 0.28, 95% CI 0.01 to 6.46) and a biosimilar darbepoetin alfa (OR 0.09, 95% CI 0.00 to 3.68) had uncertain effects on major cardiovascular events when compared to placebo. In very low certainty evidence, the effects of any ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol‐epoetin beta, and a biosimilar epoetin) on the odds of major cardiovascular events were imprecise when compared with other ESA. The heterogeneity tau for the network was 0.0, indicating no statistical evidence of heterogeneity.
3. Assessment of heterogeneity and inconsistency within network analyses
There was important clinical diversity in studies based on the age of the participants, stage of CKD and duration of treatment. Treatment estimates from direct and indirect evidence in networks with closed loops did not show evidence of statistical inconsistency except for one of the nine loops for hypertension (Table 3). However, there was significant imprecision for both direct and indirect estimates with wide CIs. Furthermore, the networks for cardiovascular death, major cardiovascular events and fatigue did not include a closed loop of evidence for comparison between direct and indirect estimates. Therefore global inconsistency in these networks could not be excluded, and we downgraded the credibility of the evidence provided by these networks as the risk of important inconsistency was high. The heterogeneity variance in networks for preventing blood transfusion (τ = 0.58) and hypertension (τ = 0.11) demonstrated the presence of moderate and low heterogeneity, respectively, though there was no heterogeneity in networks for each of the other outcomes. There was no evidence of global inconsistency in any of the networks as a whole.
2. Evaluation of consistency using loop specific approach.
| Treatments included in the loop of evidence | Inconsistency factor* | 95% CI |
| Death (any cause) | ||
| Epoetin alfa – epoetin beta – darbepoetin alfa – biosimilar epoetin | 1.28 | 0.00 to 3.62 |
| Epoetin alfa – epoetin beta – biosimilar epoetin – no treatment | 0.78 | 0.00 to 3.32 |
| Epoetin beta – biosimilar epoetin – placebo | 0.61 | 0.00 to 5.23 |
| Epoetin alfa – biosimilar epoetin – placebo | 0.51 | 0.00 to 4.72 |
| Epoetin alfa – epoetin beta – darbepoetin alfa – no treatment | 0.49 | 0.00 to 2.00 |
| Epoetin beta – darbepoetin alfa – placebo | 0.39 | 0.00 to 1.69 |
| Epoetin alfa – epoetin beta – no treatment – placebo | 0.34 | 0.00 to 2.37 |
| Epoetin alfa – darbepoetin alfa – placebo | 0.24 | 0.00 to 1.62 |
| Epoetin beta – darbepoetin alfa – methoxy polyethylene glycol‐epoetin beta | 0.01 | 0.00 to 1.95 |
| Preventing blood transfusion | ||
| Epoetin alfa – epoetin beta – no treatment – placebo | 2.55 | 0.00 to 7.12 |
| Epoetin alfa – darbepoetin alfa – placebo | 1.71 | 0.00 to 4.72 |
| Epoetin alfa – darbepoetin alfa – biosimilar darbepoetin alfa | 1.27 | 0.00 to 4.18 |
| Epoetin alfa – darbepoetin alfa – biosimilar epoetin | 0.25 | 0.00 to 3.56 |
| Epoetin beta – darbepoetin alfa ‐ methoxy polyethylene glycol‐epoetin beta ‐ placebo | 0.11 | 0.00 to 2.69 |
| Myocardial infarction | ||
| Epoetin alfa – epoetin beta – placebo | 2.25 | 0.00 to 8.38 |
| Epoetin alfa – darbepoetin alfa – placebo | 1.07 | 0.00 to 4.55 |
| Epoetin alfa – epoetin beta – no treatment | 0.63 | 0.00 to 7.11 |
| Stroke | ||
| Epoetin alfa – darbepoetin alfa – biosimilar epoetin | 0.99 | 0.00 to 4.47 |
| Hypertension | ||
| Epoetin alfa – darbepoetin alfa – placebo | 1.36 | 0.53 to 2.18 |
| Epoetin alfa – epoetin beta – darbepoetin alfa – no treatment | 0.82 | 0.00 to 4.14 |
| Epoetin beta – epoetin beta – darbepoetin alfa – biosimilar epoetin | 0.73 | 0.00 to 2.48 |
| Epoetin beta – darbepoetin alfa – placebo | 0.56 | 0.00 to 1.93 |
| Epoetin beta – darbepoetin alfa – methoxy polyethylene glycol‐epoetin beta | 0.29 | 0.00 to 1.79 |
| Epoetin alfa – darbepoetin alfa – biosimilar darbepoetin alfa | 0.20 | 0.00 to 2.02 |
| Epoetin alfa – epoetin beta – biosimilar epoetin – no treatment | 0.08 | 0.00 to 3.32 |
| Epoetin alfa – epoetin beta – biosimilar epoetin – placebo | 0.07 | 0.00 to 1.47 |
| Epoetin alfa – epoetin beta – no treatment – placebo | 0.02 | 0.00 to 3.18 |
| Vascular access thrombosis | ||
| Epoetin alfa – darbepoetin alfa – biosimilar epoetin | 1.75 | 0.00 to 5.51 |
| Epoetin alfa – darbepoetin alfa – placebo | 1.04 | 0.00 to 3.51 |
| Epoetin beta – darbepoetin alfa – methoxy polyethylene glycol‐epoetin beta – placebo | 0.67 | 0.00 to 3.04 |
| Epoetin alfa – darbepoetin alfa – biosimilar darbepoetin alfa | 0.12 | 0.00 to 2.26 |
| Kidney failure | ||
| Epoetin alfa – epoetin beta – no treatment – placebo | 1.65 | 0.00 to 4.26 |
| Epoetin alfa – darbepoetin alfa – placebo | 0.79 | 0.00 to 2.71 |
*The inconsistency factor is the absolute difference in the log odds ratio (OR) estimated from indirect and direct treatment comparisons and is reported together with the 95% confidence interval (CI). A 95% CI that includes zero indicates that the result is compatible with zero inconsistency between effect estimates using indirect (network meta‐analysis) and direct (conventional pairwise meta‐analysis) treatment comparisons. We used the 'ifplot' command in STATA to estimate inconsistency (Chaimani 2013) allowing for all comparisons within a loop to share a common heterogeneity variance
4. Subgroup and sensitivity analyses
Subgroup and meta‐regression analyses to explore potential sources of heterogeneity and inconsistency in networks were precluded by sparse data for direct treatment comparisons (only the comparison of epoetin alfa versus biosimilar epoetin on the odds of death from any cause possessed 10 or more studies but did not demonstrate significant heterogeneity (I² = 22%). Differences in treatment estimates between studies and between direct and indirect evidence in network analyses may have been due to differing prescribing approaches to ESA or iron supplementation, differing policies for blood transfusions, differing stages of CKD and the effect of study methodological limitations (especially the lack of allocation concealment, lack of blinded outcome assessment and incomplete outcome data in most studies) on outcome adjudication.
5. Grading of the evidence
When grading our confidence in the evidence using the methods of Del Giovane 2012, we first generated contribution matrices for the networks providing evidence for the primary outcomes (Figure 6 for preventing blood transfusions; Figure 7 for death (any cause)). In these matrices, the size of each square is proportional to the weight attached to each direct summary effect (horizontal axis) for the estimation of each network summary effect (vertical axis), with the numbers re‐expressing weights as percentages. We then evaluated the risk of bias assessments for treatment comparisons obtained in network meta‐analyses proportional to study contributions (Figure 8 for preventing blood transfusions; Figure 9 for death (any cause)). We then considered the overall study limitations obtained from the risk of bias assessments, imprecision in estimated treatment effects and inconsistency within networks.
6.
Contributions matrix: percentage contribution of each direct estimate to the network meta‐analysis estimates for preventing blood transfusions. Rows correspond to network meta‐analysis odds ratios (separated for mixed and indirect evidence) and the columns correspond to direct meta‐analysis odds ratios. The size of the shaded boxes are proportional to the percentage contribution of each direct estimate to the network meta‐analysis and to the entire network (lowest row). The last row shows the number of included direct comparisons. The names of the treatment comparisons are shown in the first column. For example, information for the network estimate of epoetin alfa versus darbepoetin alfa is derived from both direct and indirect evidence (generating a mixed estimate). Of this mixed network estimate, trials directly comparing darbepoetin alfa versus placebo contribute 98.1% of the information to the network estimate of effect and trials directly comparing epoetin alfa versus placebo contribute 14.2% of the network estimated effect, etc. We used the 'netweight' command in STATA to generate the plot. The contribution matrix shows how much each direct comparison in the network contributes to each network (mixed or indirect) estimate.
7.
Contributions matrix: percentage contribution of each direct estimate to the network meta‐analysis estimates for death (any cause). Rows correspond to network meta‐analysis odds ratios (separated for mixed and indirect evidence) and the columns correspond to direct meta‐analysis odds ratios. The size of the shaded boxes are proportional to the percentage contribution of each direct estimate to the network meta‐analysis and to the entire network (lowest row). The last row shows the number of included direct comparisons. The names of the treatment comparisons are shown in the first column. For example, information for the network estimate of epoetin alfa versus darbepoetin alfa is derived from both direct and indirect evidence (generating a mixed estimate). Of this mixed network estimate, trials directly comparing darbepoetin alfa versus placebo contribute 96.2% of the information to the network estimate of effect and trials directly comparing epoetin alfa versus placebo contribute 10.8% of the network estimated effect, etc. We used the 'netweight' command in STATA to generate the plot. The contribution matrix shows how much each direct comparison in the network contributes to each network (mixed or indirect) estimate.
8.
Study limitations distribution for each network estimate for pairwise comparisons of erythropoiesis‐stimulating agents on the primary efficacy outcome (preventing blood transfusions). Calculations are based on the contributions of direct evidence to the network estimates and the overall risks of bias from all bias domains (sequence generation, allocation concealment, blinding of participants and investigators, blinding of outcome assessment, attrition from follow‐up, selective outcome reporting and other sources of bias) within studies contributing to the direct evidence. The colours represent risk (green, low; yellow unclear; red, high). The direct comparisons are described in the vertical axis.
9.
Study limitations distribution for each network estimate for pairwise comparisons of erythropoiesis‐stimulating agents on the primary safety outcome (death (any cause)). Calculations are based on the contributions of direct evidence to the network estimates and the overall risks of bias from all bias domains (sequence generation, allocation concealment, blinding of participants and investigators, blinding of outcome assessment, attrition from follow‐up, selective outcome reporting and other sources of bias) within studies contributing to the direct evidence. The colours represent risk (green, low; yellow unclear; red, high). The direct comparisons are described in the vertical axis
For each comparison, the certainty of the evidence for preventing blood transfusions and death (any cause) was frequently downgraded from high certainty due to important study limitations and imprecision (Table 1). Our confidence in the treatment estimates was generally moderate or low for comparisons of ESAs against placebo and was low or very low certainty between two ESAs.
Discussion
Summary of main results
This review and network meta‐analysis of the effects of ESA treatment for anaemia in CKD included 117 studies involving 25,237 adults. In this update from 2014 to 2021, we included an additional 61 studies involving 9237 participants and found the effects of ESA on patient outcomes to be similar to the original review in 2014. Network meta‐analysis showed that epoetin alfa, epoetin beta and darbepoetin alfa prevented blood transfusions compared to placebo, with ORs ranging between 0.19 and 0.33 in moderate to very low certainty evidence. The efficacy of methoxy polyethylene glycol‐epoetin beta, a biosimilar epoetin, and a biosimilar darbepoetin alfa for preventing blood transfusions compared to placebo was uncertain, in very low certainty evidence. The comparative efficacy of different ESAs in preventing blood transfusions was also uncertain (very low certainty evidence). No placebo or standard care‐controlled studies reported other potential beneficial effects of ESAs, such as reductions in fatigue and breathlessness, and the comparative effectiveness of different ESAs on these outcomes was inconclusive due to sparse data.
Epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol‐epoetin beta increased the odds of hypertension to a similar extent when compared with placebo. There were no differences between any ESA compared with placebo or each other for their effects on death (any cause and cardiovascular), MI, major cardiovascular events, vascular access thrombosis, or kidney failure.
For the primary outcomes of preventing blood transfusion and death (any cause), evidence from network meta‐analyses comparing ESA against placebo were generally moderate or low certainty while treatment estimates for head‐to‐head comparisons between ESAs were generally of very low certainty. Our confidence in the results was downgraded by methodological limitations in the contributing studies and imprecise treatment estimates. Inconsistency between direct and indirect evidence in analysis for hypertension, the presence of moderate heterogeneity in the network of evidence for preventing blood transfusions, and the inability to exclude the presence of significant inconsistency in the networks for major cardiovascular events and fatigue also reduced our confidence in the treatment estimates derived by network analysis.
Overall completeness and applicability of evidence
We included all eligible studies to April 2022 of ESA formulations that are currently available for the treatment of anaemia in CKD, but we did not include other interventions for anaemia, such as iron supplementation or hypoxia‐inducible factor prolyl‐hydroxylase inhibitors. Epoetin alfa and darbepoetin alfa were the most studied ESAs, contributing to outcome data for 7849 participants (49.5%) in the network of evidence for death (any cause) and 5701 participants (50.9%) in the network of evidence for preventing blood transfusions. Biosimilar epoetins (epoetin alfa, epoetin delta, epoetin omega, epoetin theta, and epoetin zeta) and biosimilar darbepoetin alfa were reported in 24 studies providing 3719 (19.7%) of participants in the meta‐analyses. In addition, selective outcome reporting reduced our certainty in the estimated treatment effects.
Our review mainly included participants with kidney failure dependent on dialysis or those with moderate‐to‐advanced CKD (eGFR < 60 mL/min/1.73 m²). Data on the use of ESAs in kidney transplant recipients were relatively sparse, and the findings of this review may not be directly applicable to this clinical setting. In addition, it was unclear how many participants in studies on dialysis were conducted in the setting of peritoneal dialysis.
Selective outcome reporting (defined as the absence of reporting on death and cardiovascular outcomes) was present in 42 studies (56.8% of studies in this review), and few studies reported on patient‐important outcomes, including symptoms of anaemia such as breathlessness and fatigue. Therefore, the only patient‐level benefit of ESA in the treatment of anaemia in CKD was the prevention of blood transfusions. Future studies evaluating treatments of anaemia in CKD should focus on the Standardised Outcomes in Nephrology (SONG) (SONG 2018), which represent a set of core outcomes based on the shared priorities of patients, caregivers, clinicians, researchers, and policymakers.
Quality of the evidence
Risks of bias
Similar to the previous version of this review in 2014, study risk of bias was generally high or unclear, which reduced our confidence in the study results. Only two studies were at low risk of bias for allocation concealment, blinding of outcome assessment and attrition from follow‐up (Picon 2015; RED‐HF 2009). Allocation concealment was reported using low‐risk methods in 17 studies (15%), and blinding of outcome assessment was reported in seven studies (6%). Therefore it is likely that investigators were aware of treatment allocation when adjudicating outcomes in the majority of the included studies, which may have affected estimates of treatment effect. There was complete outcome data in only 25 studies (22%), with 40 studies (34%) reporting incomplete outcome data, and missing data were unclearly documented in 51 studies (44%). As a result, our confidence in all outcomes was downgraded due to significant methodological limitations in the included studies.
Heterogeneity
There was moderate to substantial heterogeneity in the pairwise meta‐analyses comparing epoetin alfa versus placebo and epoetin beta versus placebo on the odds of preventing blood transfusion. However, there was insufficient power in these analyses (each including only four to five studies) to explore the source of heterogeneity through subgroup or meta‐regression analyses but could potentially be explained by the heterogeneity of the stage of CKD across the studies in these analyses. Multiple analyses also demonstrated moderate heterogeneity in the treatment estimates, such as methoxy polyethylene glycol‐epoetin beta compared with darbepoetin alfa for preventing blood transfusion and darbepoetin alfa compared to epoetin alfa or placebo for kidney failure. This lowered our confidence in these results though there was no evidence of significant heterogeneity in the other comparisons.
Inconsistency
Inconsistency between treatment estimates from direct head‐to‐head studies and mixed evidence (from both direct and indirect evidence) from network analyses was present in one of the nine loops in the network for hypertension and could not be excluded for the networks for cardiovascular death, major cardiovascular events and fatigue. Therefore, our confidence in the results obtained from network meta‐analysis was reduced due to inconsistency in the evidence contributing to the treatment estimate from network meta‐analysis or due to our inability to exclude significant inconsistency. Lastly, due to relatively few studies contributing to each comparison, CIs for both direct and indirect treatment estimates were wide and important inconsistency within analyses could not be excluded.
Potential biases in the review process
This review evaluated the potential benefits and harms of ESA on patient‐level outcomes in people with CKD, was performed using a sensitive search strategy designed by an information specialist and was conducted with rigorous methodology, including study selection and data extraction by independent authors and evidence certainty adjudicated using the GRADE framework. However, our review still has a number of limitations. First, apart from a few large studies (e.g. TREAT 2005), observed events for most outcomes were relatively low, resulting in significant imprecision and inconclusive evidence for most outcomes. Most studies were not powered to detect differences in patient‐level outcomes such as death, cardiovascular events and kidney failure, with a median study size of 137 participants and a median follow‐up duration of seven months. For example, using the adjusted death rates reported by The United States Renal Data System from 2017 to 2018 (98 per 1000 patient‐years in people with pre‐dialysis CKD, 165 per 1000 patient‐years in people with dialysis‐dependent CKD and 29 per 1000 patient‐years in kidney transplant recipients) (USRDS 2019; USRDS 2020), a study of the median size and duration of the included studies in this review would only detect two to 13 deaths, which is unlikely sufficient to be able to detect a difference related to ESA treatment. Second, most studies were at high or unclear risks of bias for most methodological domains, which downgraded the evidence certainty for all outcomes and limited the confidence in the estimated treatment safety and efficacy of ESA reported in this review. Third, there was significant heterogeneity in direct evidence for a few meta‐analyses and inconsistency between direct and indirect evidence in one of the loops in the network for hypertension, which could not be further explored using subgroup or meta‐regression analyses due to a lack of studies in each comparison. Fourth, data for the benefits of ESA, such as reductions in fatigue and breathlessness, were sparse or absent, and data on health‐related QoL was not extracted in this review. Fifth, the odds of hypertension due to ESA treatment may be underreported due commencement of anti‐hypertensive agents by study investigators. However, most of the included studies did not report the number of anti‐hypertensive medications at the end of treatment to confirm this potential bias. Lastly, this review excluded other treatments for anaemia in CKD, such as iron supplementation, hypoxia‐inducible factor stabilisers and peginesatide. Therefore, the comparative efficacy and safety of different treatments for anaemia in CKD remain uncertain.
Agreements and disagreements with other studies or reviews
In this review, we found that all formulations of ESA reduced the odds of receiving a blood transfusion but increased the odds of developing hypertension compared to placebo. With the exception of an increased odds of stroke with darbepoetin alfa compared to placebo, the comparative efficacy and safety between different ESAs with each other or placebo on death (any cause or cardiovascular), major cardiovascular events, MI, stroke, vascular access thrombosis, kidney failure, fatigue and breathlessness were uncertain. These results are consistent with another network meta‐analysis of epoetin alfa, darbepoetin alfa and hypoxia‐inducible factor stabilisers in people with CKD not on dialysis, which found no difference between epoetin alfa and darbepoetin alfa on the risk of death (any cause) (Zheng 2020). However, this review focused on the surrogate outcome of change in Hb level, which does not inform on patient‐level clinical outcomes, and we did not examine other ESA formulations or other patient‐level outcomes.
We did not find a significant difference between different ESA formulations for any outcome of interest in people with any stage of CKD, which is consistent with a previous systematic review (which also included all ESA formulations) (Amato 2018). However, our review also performed a network meta‐analysis to include both direct and indirect evidence to inform on the efficacy and safety of ESA in the treatment of anaemia in CKD. A recent observational study in Japan reported an increased risk of death with long‐acting ESA (darbepoetin alfa or methoxy polyethylene glycol‐epoetin beta) compared to short‐acting ESA (epoetin alfa or epoetin beta) in people with CKD on dialysis, which is not consistent with our findings (Sakaguchi 2019). Despite the multivariate Cox regression model used adjusting for known confounders, the strengths of this study's conclusions were limited due to the grouping of different ESA formulations and the possibility of unknown confounders, which can only be accounted for in the setting of RCTs. Furthermore, the type of ESA prescribed was missing in 28% of the study population, which may have been a source of bias in this study. Finally, similar findings have been demonstrated in multiple previous systematic reviews of ESA treatment in people undergoing cancer treatment, which found ESAs prevented blood transfusions compared to standard care (Bohlius 2005; Tonelli 2009), but the comparative effect between differing ESA formulations on the prevention of blood transfusions, death, and thromboembolic events was uncertain (AHRQ 2006; AHRQ 2013).
Authors' conclusions
Implications for practice.
Our review showed that epoetin alfa, epoetin beta and darbepoetin alfa were superior to placebo for the prevention of blood transfusion in moderate to very low evidence certainty but increased the odds of hypertension compared to placebo. Effects on death (any cause or cardiovascular), major cardiovascular events, MI, stroke, vascular access thrombosis or kidney failure were generally uncertain between any ESA formulation and placebo in moderate to very low evidence certainty and between differing ESA formulations in low to very low certainty evidence. The other potential benefits of ESA, such as reduction in fatigue and breathlessness, remain uncertain due to sparse data. Current data from RCTs are insufficient to definitively inform on the comparative efficacy and safety of differing ESA formulations. Therefore, the choice of differing ESA formulations is likely to be informed by drug cost, availability and patient preferences for treatment frequency rather than by their comparative effects on clinical outcomes.
Implications for research.
Despite the inclusion of 61 studies (9237 participants) since the previous version of this review in 2014, few studies were adequately powered to detect differences in patient‐level outcomes. Therefore, future large RCTs reporting on patient‐level outcomes related to the potential benefits (including patient‐reported outcome measures such as fatigue, breathlessness and QoL) and harms of ESAs are required. In addition, the emergence of hypoxia‐inducible factor stabilisers as an attractive novel treatment for anaemia in CKD warrants its inclusion in future versions of this review. Future studies likewise need to move from the short‐term reporting of surrogate outcomes such as Hb levels to patient‐level outcomes in adequately powered RCTs. Standardised reporting of outcomes focused on the SONG core outcomes (SONG 2018) will also ensure the goals of future research reflect the priorities of patients, caregivers, clinicians, researchers, and policymakers, which is essential for informing best clinical practice.
What's new
| Date | Event | Description |
|---|---|---|
| 10 February 2023 | New search has been performed | Sixty‐two new studies added |
| 10 February 2023 | New citation required but conclusions have not changed | New studies added, with no change to conclusions |
History
Protocol first published: Issue 7, 2013 Review first published: Issue 12, 2014
| Date | Event | Description |
|---|---|---|
| 17 October 2019 | Amended | Search strategies for MEDLINE, EMBASE, CENTRAL modified |
Acknowledgements
We wish to acknowledge the support of the editorial office at the Cochrane Kidney and Transplant. We are also very grateful to our Information Specialist, Ruth Mitchell. We wish to thank the referees for their comments and feedback during the preparation of this review. We wish to thank Stefan Dannenmaier, Joanna Przeździecka‐Dołyk and Michelle Ryu for translating articles for this review.
We wish to thank Dimitris Mavridis, Georgia Salanti and Natasha Wiebe who were authors on the previous version of this review.
Appendices
Appendix 1. Electronic search strategies
| Database | Search terms |
| CENTRAL |
|
| MEDLINE |
|
| EMBASE |
|
Appendix 2. Risk of bias assessment tool
| 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; minimisation (minimisation 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 standardised 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 standardised 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 |
Data and analyses
Comparison 1. ESA versus ESA or placebo/standard care.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Blood transfusion | 32 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1.1 Epoetin alfa versus placebo | 5 | 385 | Odds Ratio (M‐H, Random, 95% CI) | 0.15 [0.04, 0.58] |
| 1.1.2 Epoetin alfa versus standard care | 1 | 157 | Odds Ratio (M‐H, Random, 95% CI) | 3.10 [0.16, 58.97] |
| 1.1.3 Epoetin beta versus placebo | 4 | 361 | Odds Ratio (M‐H, Random, 95% CI) | 0.25 [0.07, 0.88] |
| 1.1.4 Epoetin beta versus standard care | 2 | 69 | Odds Ratio (M‐H, Random, 95% CI) | 0.38 [0.11, 1.30] |
| 1.1.5 Darbepoetin alfa versus placebo | 1 | 4038 | Odds Ratio (M‐H, Random, 95% CI) | 0.53 [0.46, 0.63] |
| 1.1.6 Epoetin alfa versus darbepoetin alfa | 3 | 1191 | Odds Ratio (M‐H, Random, 95% CI) | 2.31 [1.34, 3.97] |
| 1.1.7 Epoetin alfa versus biosimilar epoetin | 7 | 2335 | Odds Ratio (M‐H, Random, 95% CI) | 0.90 [0.57, 1.44] |
| 1.1.8 Epoetin alfa versus biosimilar darbepoetin alfa | 1 | 752 | Odds Ratio (M‐H, Random, 95% CI) | 0.68 [0.34, 1.34] |
| 1.1.9 Epoetin beta versus methoxy polyethylene glycol‐epoetin beta | 2 | 261 | Odds Ratio (M‐H, Random, 95% CI) | 0.41 [0.10, 1.66] |
| 1.1.10 Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta | 4 | 1191 | Odds Ratio (M‐H, Random, 95% CI) | 1.36 [0.64, 2.89] |
| 1.1.11 Darbepoetin alfa versus biosimilar epoetin | 1 | 74 | Odds Ratio (M‐H, Random, 95% CI) | 0.31 [0.01, 7.79] |
| 1.1.12 Darbepoetin alfa versus biosimilar darbepoetin alfa | 1 | 385 | Odds Ratio (M‐H, Random, 95% CI) | 1.05 [0.07, 16.88] |
| 1.2 Fatigue | 5 | Odds Ratio (IV, Random, 95% CI) | Subtotals only | |
| 1.2.1 Epoetin alfa versus darbepoetin alfa | 2 | 551 | Odds Ratio (IV, Random, 95% CI) | 0.94 [0.57, 1.55] |
| 1.2.2 Epoetin alfa v biosimilar epoetin | 2 | 286 | Odds Ratio (IV, Random, 95% CI) | 0.86 [0.14, 5.09] |
| 1.2.3 Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta | 1 | 71 | Odds Ratio (IV, Random, 95% CI) | 14.47 [0.72, 292.21] |
| 1.3 Breathlessness | 10 | Odds Ratio (IV, Random, 95% CI) | Subtotals only | |
| 1.3.1 Epoetin alfa versus darbepoetin alfa | 1 | 504 | Odds Ratio (IV, Random, 95% CI) | 0.71 [0.46, 1.10] |
| 1.3.2 Epoetin alfa versus biosimilar epoetin | 7 | 2212 | Odds Ratio (IV, Random, 95% CI) | 1.00 [0.70, 1.42] |
| 1.3.3 Darbepoetin alfa versus biosimilar darbepoetin alfa | 1 | 183 | Odds Ratio (IV, Random, 95% CI) | 0.26 [0.01, 6.51] |
| 1.3.4 Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta | 1 | 71 | Odds Ratio (IV, Random, 95% CI) | 3.91 [0.34, 45.46] |
| 1.4 Death (any cause) | 56 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.4.1 Epoetin alfa versus placebo | 5 | 455 | Odds Ratio (M‐H, Random, 95% CI) | 0.57 [0.15, 2.26] |
| 1.4.2 Epoetin beta versus placebo | 5 | 442 | Odds Ratio (M‐H, Random, 95% CI) | 0.62 [0.23, 1.70] |
| 1.4.3 Darbepoetin alfa versus placebo | 2 | 4854 | Odds Ratio (M‐H, Random, 95% CI) | 1.00 [0.84, 1.19] |
| 1.4.4 Biosimilar epoetin versus placebo | 1 | 40 | Odds Ratio (M‐H, Random, 95% CI) | Not estimable |
| 1.4.5 Epoetin alfa versus standard care | 1 | 157 | Odds Ratio (M‐H, Random, 95% CI) | 1.06 [0.39, 2.87] |
| 1.4.6 Epoetin beta versus standard care | 5 | 552 | Odds Ratio (M‐H, Random, 95% CI) | 0.76 [0.40, 1.43] |
| 1.4.7 Epoetin alfa versus darbepoetin alfa | 9 | 1914 | Odds Ratio (M‐H, Random, 95% CI) | 0.78 [0.50, 1.22] |
| 1.4.8 Epoetin alfa versus biosimilar epoetin | 13 | 4154 | Odds Ratio (M‐H, Random, 95% CI) | 1.01 [0.69, 1.47] |
| 1.4.9 Epoetin beta versus darbepoetin alfa | 3 | 377 | Odds Ratio (M‐H, Random, 95% CI) | 0.89 [0.38, 2.09] |
| 1.4.10 Epoetin beta versus methoxy polyethylene glycol‐epoetin beta | 3 | 542 | Odds Ratio (M‐H, Random, 95% CI) | 0.81 [0.12, 5.35] |
| 1.4.11 Epoetin beta versus biosimilar epoetin | 1 | 290 | Odds Ratio (M‐H, Random, 95% CI) | 0.34 [0.04, 2.82] |
| 1.4.12 Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta | 5 | 1498 | Odds Ratio (M‐H, Random, 95% CI) | 1.07 [0.68, 1.68] |
| 1.4.13 Darbepoetin alfa versus biosimilar darbepoetin alfa | 3 | 566 | Odds Ratio (M‐H, Random, 95% CI) | 0.61 [0.19, 1.91] |
| 1.5 Cardiovascular death | 16 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.5.1 Epoetin beta versus placebo | 2 | 260 | Odds Ratio (M‐H, Random, 95% CI) | 0.45 [0.06, 3.75] |
| 1.5.2 Darbepoetin alfa versus placebo | 1 | 4038 | Odds Ratio (M‐H, Random, 95% CI) | 1.05 [0.87, 1.26] |
| 1.5.3 Epoetin beta versus standard care | 3 | 430 | Odds Ratio (M‐H, Random, 95% CI) | 0.28 [0.08, 1.03] |
| 1.5.4 Epoetin alfa versus darbepoetin alfa | 2 | 487 | Odds Ratio (M‐H, Random, 95% CI) | 2.15 [0.31, 14.91] |
| 1.5.5 Epoetin alfa versus biosimilar epoetin | 4 | 1508 | Odds Ratio (M‐H, Random, 95% CI) | 1.11 [0.34, 3.66] |
| 1.5.6 Epoetin beta versus biosimilar epoetin | 1 | 290 | Odds Ratio (M‐H, Random, 95% CI) | 0.34 [0.04, 2.82] |
| 1.5.7 Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta | 3 | 938 | Odds Ratio (M‐H, Random, 95% CI) | 0.69 [0.32, 1.48] |
| 1.6 Myocardial infarction | 18 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.6.1 Epoetin alfa versus placebo | 1 | 14 | Odds Ratio (M‐H, Random, 95% CI) | 3.46 [0.12, 100.51] |
| 1.6.2 Darbepoetin alfa versus placebo | 2 | 4854 | Odds Ratio (M‐H, Random, 95% CI) | 0.91 [0.73, 1.15] |
| 1.6.3 Epoetin beta versus placebo | 1 | 92 | Odds Ratio (M‐H, Random, 95% CI) | 0.34 [0.01, 8.58] |
| 1.6.4 Epoetin alfa versus standard care | 2 | 183 | Odds Ratio (M‐H, Random, 95% CI) | 1.01 [0.04, 25.26] |
| 1.6.5 Epoetin beta versus standard care | 1 | 26 | Odds Ratio (M‐H, Random, 95% CI) | Not estimable |
| 1.6.6 Epoetin alfa versus darbepoetin alfa | 3 | 1347 | Odds Ratio (M‐H, Random, 95% CI) | 1.30 [0.55, 3.08] |
| 1.6.7 Epoetin alfa versus biosimilar epoetin | 5 | 1429 | Odds Ratio (M‐H, Random, 95% CI) | 1.10 [0.47, 2.58] |
| 1.6.8 Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta | 3 | 739 | Odds Ratio (M‐H, Random, 95% CI) | 0.83 [0.15, 4.72] |
| 1.6.9 Darbepoetin alfa versus biosimilar darbepoetin alfa | 1 | 195 | Odds Ratio (M‐H, Random, 95% CI) | 0.33 [0.01, 8.28] |
| 1.7 Stroke | 20 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.7.1 Epoetin beta versus placebo | 2 | 198 | Odds Ratio (M‐H, Random, 95% CI) | 1.40 [0.09, 22.13] |
| 1.7.2 Darbepoetin alfa versus placebo | 2 | 4854 | Odds Ratio (M‐H, Random, 95% CI) | 2.02 [1.48, 2.75] |
| 1.7.3 Epoetin alfa versus standard care | 1 | 157 | Odds Ratio (M‐H, Random, 95% CI) | 0.99 [0.10, 9.82] |
| 1.7.4 Epoetin beta versus standard care | 1 | 33 | Odds Ratio (M‐H, Random, 95% CI) | 0.20 [0.01, 5.39] |
| 1.7.5 Epoetin alfa versus darbepoetin alfa | 4 | 1518 | Odds Ratio (M‐H, Random, 95% CI) | 0.97 [0.35, 2.70] |
| 1.7.6 Epoetin alfa versus biosimilar epoetin | 5 | 1260 | Odds Ratio (M‐H, Random, 95% CI) | 0.79 [0.35, 1.80] |
| 1.7.7 Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta | 3 | 664 | Odds Ratio (M‐H, Random, 95% CI) | 1.72 [0.34, 8.64] |
| 1.7.8 Darbepoetin alfa versus biosimilar epoetin | 1 | 74 | Odds Ratio (M‐H, Random, 95% CI) | 0.31 [0.01, 7.79] |
| 1.7.9 Darbepoetin alfa versus biosimilar darbepoetin alfa | 1 | 195 | Odds Ratio (M‐H, Random, 95% CI) | 3.06 [0.12, 76.10] |
| 1.8 Hypertension | 36 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.8.1 Epoetin alfa versus placebo | 2 | 251 | Odds Ratio (M‐H, Random, 95% CI) | 4.10 [2.16, 7.76] |
| 1.8.2 Epoetin beta versus placebo | 3 | 269 | Odds Ratio (M‐H, Random, 95% CI) | 2.36 [1.11, 5.04] |
| 1.8.3 Darbepoetin alfa versus placebo | 1 | 4038 | Odds Ratio (M‐H, Random, 95% CI) | 1.14 [0.99, 1.32] |
| 1.8.4 Epoetin alfa versus standard care | 1 | 157 | Odds Ratio (M‐H, Random, 95% CI) | 5.31 [0.30, 95.20] |
| 1.8.5 Epoetin beta versus standard care | 2 | 382 | Odds Ratio (M‐H, Random, 95% CI) | 2.99 [1.34, 6.69] |
| 1.8.6 Epoetin alfa versus darbepoetin alfa | 6 | 2090 | Odds Ratio (M‐H, Random, 95% CI) | 0.93 [0.68, 1.25] |
| 1.8.7 Epoetin alfa versus biosimilar epoetin | 7 | 1940 | Odds Ratio (M‐H, Random, 95% CI) | 1.21 [0.76, 1.93] |
| 1.8.8 Epoetin alfa versus biosimilar darbepoetin alfa | 1 | 746 | Odds Ratio (M‐H, Random, 95% CI) | 0.72 [0.15, 3.44] |
| 1.8.9 Epoetin beta versus darbepoetin alfa | 1 | 162 | Odds Ratio (M‐H, Random, 95% CI) | 1.18 [0.38, 3.69] |
| 1.8.10 Epoetin beta versus methoxy polyethylene glycol‐epoetin beta | 2 | 261 | Odds Ratio (M‐H, Random, 95% CI) | 1.44 [0.66, 3.15] |
| 1.8.11 Epoetin beta versus biosimilar epoetin | 1 | 290 | Odds Ratio (M‐H, Random, 95% CI) | 0.74 [0.30, 1.82] |
| 1.8.12 Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta | 6 | 1568 | Odds Ratio (M‐H, Random, 95% CI) | 0.91 [0.62, 1.33] |
| 1.8.13 Darbepoetin alfa versus biosimilar darbepoetin alfa | 3 | 609 | Odds Ratio (M‐H, Random, 95% CI) | 0.93 [0.51, 1.70] |
| 1.9 Vascular access thrombosis | 19 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.9.1 Epoetin alfa versus placebo | 2 | 132 | Odds Ratio (M‐H, Random, 95% CI) | 6.40 [0.80, 51.50] |
| 1.9.2 Epoetin beta versus placebo | 2 | 191 | Odds Ratio (M‐H, Random, 95% CI) | 1.67 [0.47, 6.00] |
| 1.9.3 Darbepoetin alfa versus placebo | 1 | 4038 | Odds Ratio (M‐H, Random, 95% CI) | 1.34 [0.30, 6.01] |
| 1.9.4 Epoetin beta versus standard care | 1 | 362 | Odds Ratio (M‐H, Random, 95% CI) | 1.40 [0.72, 2.73] |
| 1.9.5 Epoetin alfa versus darbepoetin alfa | 5 | 1745 | Odds Ratio (M‐H, Random, 95% CI) | 1.16 [0.75, 1.81] |
| 1.9.6 Epoetin alfa versus biosimilar epoetin | 2 | 115 | Odds Ratio (M‐H, Random, 95% CI) | 2.10 [0.42, 10.42] |
| 1.9.7 Epoetin alfa versus biosimilar darbepoetin alfa | 1 | 746 | Odds Ratio (M‐H, Random, 95% CI) | 1.04 [0.37, 2.92] |
| 1.9.8 Epoetin beta versus methoxy polyethylene glycol‐epoetin beta | 1 | 181 | Odds Ratio (M‐H, Random, 95% CI) | 1.74 [0.49, 6.24] |
| 1.9.9 Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta | 2 | 600 | Odds Ratio (M‐H, Random, 95% CI) | 0.74 [0.41, 1.36] |
| 1.9.10 Darbepoetin alfa versus biosimilar epoetin | 1 | 74 | Odds Ratio (M‐H, Random, 95% CI) | 0.31 [0.01, 7.79] |
| 1.9.11 Darbepoetin alfa versus biosimilar darbepoetin alfa | 1 | 195 | Odds Ratio (M‐H, Random, 95% CI) | 1.01 [0.20, 5.14] |
| 1.10 Kidney failure | 15 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.10.1 Epoetin alfa versus placebo | 1 | 85 | Odds Ratio (M‐H, Random, 95% CI) | 0.62 [0.16, 2.36] |
| 1.10.2 Epoetin beta versus placebo | 1 | 92 | Odds Ratio (M‐H, Random, 95% CI) | 1.61 [0.26, 10.10] |
| 1.10.3 Biosimilar epoetin versus placebo | 1 | 40 | Odds Ratio (M‐H, Random, 95% CI) | Not estimable |
| 1.10.4 Darbepoetin alfa versus placebo | 2 | 4854 | Odds Ratio (M‐H, Random, 95% CI) | 0.93 [0.62, 1.39] |
| 1.10.5 Epoetin alfa versus standard care | 2 | 107 | Odds Ratio (M‐H, Random, 95% CI) | 0.61 [0.24, 1.55] |
| 1.10.6 Epoetin beta versus standard care | 3 | 161 | Odds Ratio (M‐H, Random, 95% CI) | 0.31 [0.13, 0.76] |
| 1.10.7 Epoetin alfa versus darbepoetin alfa | 2 | 492 | Odds Ratio (M‐H, Random, 95% CI) | 2.17 [0.37, 12.74] |
| 1.10.8 Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta | 2 | 341 | Odds Ratio (M‐H, Random, 95% CI) | 1.87 [0.73, 4.82] |
| 1.10.9 Darbepoetin alfa versus biosimilar darbepoetin alfa | 1 | 183 | Odds Ratio (M‐H, Random, 95% CI) | 0.79 [0.19, 3.24] |
| 1.11 Major cardiovascular events | 11 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.11.1 Darbepoetin alfa versus placebo | 2 | 4854 | Odds Ratio (M‐H, Random, 95% CI) | 1.08 [0.96, 1.22] |
| 1.11.2 Epoetin alfa versus standard care | 1 | 157 | Odds Ratio (M‐H, Random, 95% CI) | 2.40 [0.29, 20.11] |
| 1.11.3 Epoetin beta versus standard care | 2 | 62 | Odds Ratio (M‐H, Random, 95% CI) | 0.61 [0.07, 4.98] |
| 1.11.4 Epoetin alfa versus darbepoetin alfa | 1 | 321 | Odds Ratio (M‐H, Random, 95% CI) | 0.20 [0.01, 4.17] |
| 1.11.5 Epoetin alfa versus biosimilar epoetin | 4 | 1748 | Odds Ratio (M‐H, Random, 95% CI) | 0.77 [0.36, 1.61] |
| 1.11.6 Darbepoetin alfa versus methoxy polyethylene glycol‐epoetin beta | 1 | 71 | Odds Ratio (M‐H, Random, 95% CI) | 1.88 [0.11, 31.32] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Aggarwal 2005.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 3 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Group C
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | End‐of study biochemistry such as kidney function and electrolytes were not reported as specified in methods |
| Other bias | High risk | Only male participants. Balanced groups. Funding source unclear |
Akiba 2010.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Lost to follow‐up 14% in epoetin alfa arm and 17% in biosimilar epoetin kappa arm. As this was > 10% this was judged high risk |
| Selective reporting (reporting bias) | High risk | No data for cardiovascular outcomes |
| Other bias | Low risk | None apparent |
Akizawa 2011.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: November 2005 to April 2007 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Eligible patients were assigned to either of two groups by a computer according to a minimisation method" |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "We conducted this randomised, multicentre, open‐label, parallel group study..." |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not reported for secondary outcomes |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Attrition was 49/160 (30.6%) in the intervention group and 43/161 (26.7%) in the control group. As this was > 10% of all randomised participants, we adjudicated this as high risk |
| Selective reporting (reporting bias) | Low risk | Low risk (extractable data for major cardiovascular events were available) |
| Other bias | High risk | There was an imbalance in the doses used when comparing two different epoetin drugs |
Al‐Ali 2015.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 36 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Group C
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | No dropouts |
| Selective reporting (reporting bias) | High risk | Death outcomes not reported |
| Other bias | Unclear risk | Balanced groups; funding source unclear |
Alexander 2007.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Low risk | Randomly assigned by a central randomisation centre. Randomisation numbers were allocated sequentially to patients in the order in which they were enrolled |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 14/62 lost to follow‐up in the darbepoetin alfa arm (23%), and 16/19 lost to follow‐up in the control arm (84%). As this was imbalanced between groups and > 10%, this judged to be high risk |
| Selective reporting (reporting bias) | High risk | Data for major cardiovascular events not available |
| Other bias | High risk | Industrial sponsor on authorship; abstract‐only publication |
Allon 2002.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "This was a multicenter, randomized, open‐label study." |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Not clearly described |
| Selective reporting (reporting bias) | High risk | Cardiovascular outcomes not reported |
| Other bias | High risk | Employees of the sponsor were authors |
AMGEN 8701 1987.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 12 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement in abstract |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement in abstract |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but method not reported in the abstract |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement in abstract |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement in abstract |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Balanced groups, role of sponsor unclear |
AMICUS 2007.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: March 2004 to December 2005 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "AMICUS was an open‐label, randomized, multicenter, epoetin‐controlled, parallel‐group, phase 3 study" |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Attrition 3/46 in intervention arm (6.5%) and 3/135 in control arm (2.2%). As these were similar and the overall attrition was <10% this was adjudicated as low risk |
| Selective reporting (reporting bias) | Low risk | Death outcomes reported |
| Other bias | High risk | Employees of the sponsor were authors |
Ammer 2009.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 28 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement in this abstract |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement in this abstract |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement in this abstract |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement in this abstract |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Hb level reported as per methods but details of safety data not described |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Funding source unclear |
Apsangikar 2018.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 24 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Performed by statistician but not further described |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Complete outcome data with ITT analysis |
| Selective reporting (reporting bias) | High risk | Cardiovascular outcomes not reported |
| Other bias | Low risk | No other bias detected |
Arabul 2009.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: during 2007 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement sufficiently to adjudicate |
| Selective reporting (reporting bias) | High risk | No extractable data for meta‐analysis |
| Other bias | Low risk | None apparent |
ARCTOS 2008.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: June 2004 to January 2006 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Low risk | Quote: "Patients were assigned to study treatment via a central randomization center with stratification by geographic region." |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "ARCTOS was an open‐label, randomized, multicenter, darbepoetin alfa– controlled, parallel‐group Phase III study" |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Attrition 11/162 (6.8%) in the intervention arm and 17/162 (10.55 in the control arm. As this was similar between groups and below 10% overall, we adjudicated this as low risk |
| Selective reporting (reporting bias) | Low risk | All major expected outcomes reported |
| Other bias | High risk | Sponsor employees were listed on the authorship |
Argani 2009.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 3 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Covered syringe with ESA injection prepared by nurse |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | Electrolyte disorders, hypotension not reported as per methods |
| Other bias | High risk | Older population in biosimilar ESA group |
Azmandian 2018.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 26 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Prefilled syringes were relabeled and coded by an independent party to become indiscernible from each other |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Per‐protocol analysis with 36.5% dropouts |
| Selective reporting (reporting bias) | High risk | Cardiovascular outcomes not reported |
| Other bias | High risk | Sponsor employees were listed on the authorship |
Bahlmann 1991.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Double blinded for the first 4 weeks then open label |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Attrition 10/63 (15.9%) in intervention arm and 20/66 (30.3%) in the control arm. As this was higher than 10% overall, this was judged high risk |
| Selective reporting (reporting bias) | Low risk | Major cardiovascular events were extractable for meta‐analysis |
| Other bias | High risk | Sponsor employees were listed on the authorship |
Barany 1998.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement in this abstract |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement in this abstract |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement in this abstract |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement in this abstract |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement in this abstract |
| Selective reporting (reporting bias) | High risk | Only exercise tolerance and Hb change reported in abstract |
| Other bias | Unclear risk | Unclear from abstract |
Bartels 2012.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 8 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Not blinded |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Per‐protocol analysis but no dropouts |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Low risk | Balanced groups; pharmaceutical company grant but investigator initiated with no pharmaceutical company authors on authors list |
Beiraghdar 2015.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 3 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but method not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | Death outcomes not reported |
| Other bias | Low risk | No pharmaceutical involvement; balanced groups |
Bennett 1991.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Attrition 8/90 (8.9%) in intervention arm and 1/40 (0.25%) in control arm. As this was markedly different between groups we judged this as high‐risk |
| Selective reporting (reporting bias) | Low risk | Major cardiovascular events reported |
| Other bias | Low risk | None apparent |
Bernieh 2014.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 6 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes |
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | Low risk | All outcomes reported as per methods, death outcomes available |
| Other bias | High risk | High proportion of males in epoetin group |
Bren 2001.
| Study characteristics | ||
| Methods | Study design: cross‐over RCT Study duration: 24 weeks for each cross‐over treatment period |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | Death outcomes not reported |
| Other bias | Unclear risk | Baseline characteristics not described between groups |
Brown 1988.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 3 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but method not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 23% dropped out. No mention of ITT |
| Selective reporting (reporting bias) | High risk | Only HCT reported in the abstract |
| Other bias | Unclear risk | Unclear in the abstract |
Brown 1995.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not clearly reported |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Attrition was not unclear reported |
| Selective reporting (reporting bias) | High risk | Cardiovascular outcomes not reported |
| Other bias | High risk | Abstract‐only publication; funded by Ortho Biotech |
Canadian EPO 1990.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group 1 (high dose)
Treatment group 2 (low dose)
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Blinded for adverse reactions, other clinical events, and QoL assessment |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Attrition 5/38 (13%) in high dose epoetin alfa arm, 6/40 (15%) in low dose epoetin alfa arm and 8/40 (20%) in placebo arm. As this was cumulatively > 10% then this was judged high risk |
| Selective reporting (reporting bias) | Low risk | Data for death (any cause) and major cardiovascular events were available |
| Other bias | Low risk | None apparent |
Carrera 2003.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Unclear funding source |
Chen 2008.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: June to September 2004 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | "Prospective open‐label single centre study..." |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Attrition was 4/20 (20% in the epoetin alfa arm and 6/22 (27%) in the darbepoetin alfa arm. As this was > 10% overall, this was judged as high risk |
| Selective reporting (reporting bias) | High risk | No data for cardiovascular events were available |
| Other bias | Low risk | None apparent |
Chen 2012e.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 28/281 lost to follow‐up (10% of randomised participants) |
| Selective reporting (reporting bias) | High risk | Cardiovascular outcomes not reported |
| Other bias | Low risk | None apparent |
Clyne 1992.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "Open randomised parallel‐group study" |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Attrition was 1/12 (8%) in the epoetin beta arm and 2/10 (20%) in the control arm. As this was > 10% overall this was judged to be high risk |
| Selective reporting (reporting bias) | High risk | Major cardiovascular outcomes were not available |
| Other bias | Low risk | None apparent |
CORDATUS 2011.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "The CORDATUS study was an open‐label, randomized, controlled, multicentre, parallel‐group study in patients with CKD not on dialysis." |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Attrition 17/154 in the darbepoetin alfa group (11%) and 12/153 (7.8%) in the methoxy polyethylene glycol‐epoetin beta group. As this was below 10% overall, we judged attrition to be low risk |
| Selective reporting (reporting bias) | Low risk | Data for major cardiovascular outcomes were available |
| Other bias | High risk | Industry sponsor employees on authorship |
Coupes 2015.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 90 days |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment
Control
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer generated randomisation list |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but method insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 3% dropped out. ITT analysis |
| Selective reporting (reporting bias) | High risk | Cardiovascular events not reported |
| Other bias | Low risk | Balanced groups. Pharmaceutical company not involved in authorship |
Coyne 2000.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Unmatched interventions |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No data extractable for meta‐analysis |
| Other bias | High risk | Industry sponsor on authorship |
Coyne 2006a.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Unmatched interventions |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | Cardiovascular events not available for analysis |
| Other bias | High risk | Industrial sponsor on authorship |
Di Lullo 2009.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 1 year |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Unclear in this abstract |
EPOCARES 2010.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Quote: "Open‐label randomised trial" |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | Low risk | Major cardiovascular outcomes available |
| Other bias | Low risk | None apparent |
EudraCT 2007‐001905‐10.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 28 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | Death outcomes not available |
| Other bias | Unclear risk | Principal Investigators are not employed by sponsor. Unclear baseline characteristics between groups |
Fishbane 2018.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 24 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but method Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 14% dropped out but ITT analysis |
| Selective reporting (reporting bias) | Low risk | All outcomes reported as per methods |
| Other bias | High risk | Pharmaceutical employee on authors list |
Fishbane 2019.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 16 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | High risk | Study drug assignments for each phase were obtained by site personnel, unblinded with respect to study treatment, via an Interactive Voice Response System/Interactive Web‐based Response System |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but method Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 14% dropped out but ITT analysis |
| Selective reporting (reporting bias) | Low risk | All outcomes reported as per methods |
| Other bias | High risk | Pharmaceutical employee on authors list |
Fritschka 1990.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 6 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment
Control
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in meta‐analysis
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Unclear funding source and baseline characteristics |
Furukawa 2015.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 48 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes reported |
| Other bias | Unclear risk | Balanced groups. Unclear funding source |
Gertz 2010.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Low risk | Interactive voice‐response system |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Drug administered by third party who was aware of treatment assignment |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 20/95 lost to follow‐up in epoetin beta arm (21%) and 34/193 lost to follow‐up in biosimilar epoetin theta arm (18%). As this was > 10%, this was judged to be high risk |
| Selective reporting (reporting bias) | Low risk | Data for major cardiovascular events available |
| Other bias | High risk | Sponsor on authorship and involved in statistical analysis |
Goh 2007.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes extracted for meta‐analysis
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Low risk | Randomised centrally |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Not double‐dummy controlled |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Discrepancy in proportion of patients lost in biosimilar ESA arm |
| Selective reporting (reporting bias) | Low risk | All patient‐relevant outcomes reported |
| Other bias | Low risk | None apparent |
Haag‐Weber 2009.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computerised sequence |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | The principal investigator adjudicated deaths with an independent expert but unclear whether they were blinded to treatment allocation |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Attrition 22/164 in epoetin alfa arm (13.4%) and 53/314 in biosimilar arm (16.9%). As this was above 10% this was judged as high risk |
| Selective reporting (reporting bias) | Low risk | Data for cardiovascular events provided |
| Other bias | High risk | Sponsor on authorship |
Haag‐Weber 2012.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Attrition was 44/163 in epoetin alfa arm (27%) and 30/174 (17.2%) in the biosimilar ESA arm. As this was > 10%, then adjudicated as high risk |
| Selective reporting (reporting bias) | High risk | Data for major cardiovascular events not provided |
| Other bias | High risk | Sponsor on authorship: premature termination |
Hafer 2012.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 12 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Low risk | Identical appearance placebo |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 2% dropped out and ITT analysis |
| Selective reporting (reporting bias) | High risk | Cardiovascular outcomes not reported |
| Other bias | Unclear risk | Balanced groups, unclear funding source |
Hidaka 2015.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 6 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | Only Hb level and CD34 reported in this abstract |
| Other bias | Unclear risk | Insufficient information to permit judgement |
Hirakata 2010.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: July 2004 to December 2005 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group 1
Control group 2
Control group 3
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Low risk | Centrally allocated |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Attrition 8/43 (19%) in 30 µg darbepoetin alfa arm; 8/42 (19%) in 60 µg darbepoetin alfa arm; 7 /43 (16%) in 90 µg darbepoetin alfa arm; and 5/43 (12%) in epoetin alfa arm. As this was > 10% this was judged as high risk |
| Selective reporting (reporting bias) | High risk | No death data |
| Other bias | Low risk | None apparent |
Hori 2004.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | Cardiovascular outcomes not reported |
| Other bias | High risk | Insufficient information to permit judgement |
Iwasaki 2008.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 4 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No major cardiovascular event data provided |
| Other bias | Unclear risk | Insufficient information to permit judgement |
Kim 2006e.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 46 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | Unable to extract individual components of composite outcome for inclusion into meta‐analysis |
| Other bias | Unclear risk | Insufficient information to permit judgement |
Kim 2020.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 24 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomised via stratified permuted blocks |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 19% dropped out with per‐protocol analysis, not ITT analysis |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes reported |
| Other bias | Low risk | No pharma involvement in authorship. Balanced groups at baseline |
Kleinman 1989.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | Low risk | Major cardiovascular event data available |
| Other bias | High risk | Sponsor on authorship |
Klinkmann 1992.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 34/181 (19%) lost in epoetin alfa group and 39/181 (21.5%) lost in control group. As this is > 10% this was judged to be high risk |
| Selective reporting (reporting bias) | Low risk | Major cardiovascular event data available |
| Other bias | High risk | Industrial sponsor on authorship |
Kohler 1990.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 6 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Unclear funding source and baseline group characteristics |
Korbet 1991.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 9 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 38% dropped out |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | High risk | Funding source unclear, baseline characteristics not compared between groups |
Krivoshiev 2008.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 27 December 2004 to 24 January 2006 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group:
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomisation list provided by an independent clinical research organisation |
| Allocation concealment (selection bias) | Unclear risk | Patients enrolled at each centre were allocated consecutive numbers |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 46/304 lost to follow‐up in epoetin alfa arm (15%) and 32/305 lost to follow‐up in biosimilar epoetin arm (10%). As this was > 10%, this was adjudicated as high risk |
| Selective reporting (reporting bias) | High risk | No reporting of cardiovascular events |
| Other bias | Low risk | None apparent |
Krivoshiev 2010.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 65/230 lost to follow‐up in epoetin alfa arm (28%) and 78/232 lost to follow‐up in biosimilar epoetin arm (34%). As this was > 10%, this was adjudicated as high risk |
| Selective reporting (reporting bias) | Low risk | Data for cardiovascular events available |
| Other bias | High risk | Sponsor on authorship |
Kuriyama 1997.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: Started 1 January 1993 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | Low risk | Data for cardiovascular outcomes available |
| Other bias | Low risk | None apparent |
Lee 2019.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 24 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Stratified permuted block randomisation |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 23% dropped out and per protocol analysis |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | High risk | Pharmaceutical company involved in data analysis but not in manuscript preparation and authors not affiliated with pharmaceutical company. Balanced groups |
Li 2008d.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 4/23 lost from epoetin alfa arm (17%) and 4/22 lost from darbepoetin alfa arm (17%). As this was > 10% this was judged as high risk |
| Selective reporting (reporting bias) | High risk | Cardiovascular outcomes not reported |
| Other bias | Low risk | None apparent |
Liao 2016a.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 24 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 32% dropped out, ITT analysis for safety analysis but unclear for primary outcome |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Balanced groups, unclear funding source |
Locatelli 2001.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Low risk | Central allocation |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 32/166 lost to follow‐up (19.3%). As this was > 10%, this was judged to be high risk |
| Selective reporting (reporting bias) | Low risk | Data for major cardiovascular events available |
| Other bias | High risk | Industrial sponsor on authorship |
Marin 2019.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 4 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | Unclear risk | No cardiovascular outcomes reported |
| Other bias | Unclear risk | Insufficient information to permit judgement |
Martin 2007.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 39/192 lost to follow‐up in the epoetin alfa arm (20%), and 130/560 lost to follow‐up in the epoetin delta arm (23%). As this was > 10%, this was adjudicated as high risk |
| Selective reporting (reporting bias) | High risk | No death data |
| Other bias | Low risk | None apparent |
MAXIMA 2007.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: patients randomised between April to August 2004 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomisation numbers were generated by computer at a co‐ordinating centre |
| Allocation concealment (selection bias) | Low risk | Allocated sequentially by centre, in the order in which patients were enrolled. Investigators received numbers by telephone and recorded them on patients’ case‐report forms |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 46/226 lost from epoetin arm (20.4%) and 110/337 lost from methoxy polyethylene glycol‐epoetin beta arm (32.6%). As this was > 10%, this was judged as high risk |
| Selective reporting (reporting bias) | Low risk | Death and cardiovascular events reported |
| Other bias | High risk | Industry sponsor on authorship |
Mehta 2019.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 36 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | ITT analysis |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Unclear whether sponsors involved in manuscript preparation and whether authors had conflicts of interest |
Meier 2008.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 36 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Insufficient information to permit judgement |
Mignon 2000.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 12 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Insufficient information to permit judgement |
Milutinovic 2006.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analysis
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Recruiting physician blinded to randomisation list |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 1/38 lost to follow‐up in epoetin arm (2.6%) and 5/39 lost to follow‐up in biosimilar epoetin omega arm (12.8%). As there was a marked difference between arms, this was judged as high risk |
| Selective reporting (reporting bias) | Low risk | Major cardiovascular events available |
| Other bias | Low risk | None apparent |
NCT02506868.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 52 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessor blinded |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Complete outcome data |
| Selective reporting (reporting bias) | Low risk | Cardiovascular outcomes reported |
| Other bias | Unclear risk | Unclear whether pharma involvement in authorship |
Nishi 2020.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 24 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Low risk | Allocation by Interactive Web Response System of an independent organisation |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | To maintain blinding of the patient and assessor, the study drug was administered by other un‐blinded study staff |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | To maintain blinding of the patient and assessor, the study drug was administered by other un‐blinded study staff |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 18% dropped out, no mention of ITT analysis |
| Selective reporting (reporting bias) | Low risk | Reporting death |
| Other bias | High risk | Pharmaceutical employee in authorship |
Nissenson 1995.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 27 September 1989 to 10 January 1992 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | The randomisation sequence was designed to ensure that approximately equal numbers of patients were randomised. At each centre, treatment unit numbers were assigned consecutively by date of randomisation |
| Allocation concealment (selection bias) | Unclear risk | The randomisation sequence was designed to ensure that approximately equal numbers of patients were randomised. At each centre, treatment unit numbers were assigned consecutively by date of randomisation |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 9/78 in epoetin alfa arm lost to follow‐up (11.5%) and 7/74 in placebo arm lost to follow‐up (9.5%). As the loss to follow‐up in the trial overall was > 10% this was judged as high risk |
| Selective reporting (reporting bias) | High risk | No data for major cardiovascular events |
| Other bias | Low risk | None apparent |
Nissenson 2002.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Central computerised system |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 54/338 loss from epoetin alfa arm (16%) and 27/169 lost from darbepoetin alfa arm (16%). As this is higher than 10%, we judged this to be high risk |
| Selective reporting (reporting bias) | Low risk | Death and cardiovascular events reported |
| Other bias | High risk | Industrial sponsor on authorship |
Nissenson 2007.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analysis
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Insufficient information to permit judgement |
Oh 2014.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 24 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 38% droppped out but ITT analysis |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcome |
| Other bias | High risk | Roche provided statistical analysis but no involvement in manuscript preparation and authors had no conflicts of interest. However, epoetin group had higher BMI and more likely to have AVF |
Ohki 2020.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 24 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 25% dropped out with no ITT analysis |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes specified in methods |
| Other bias | Low risk | No pharma involvement |
Ostrvica 2010.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group A
Control group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement. Unclear if ITT analysis |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Funding source unclear. Balanced group characteristics |
Palazzuoli 2007.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double‐blind placebo‐controlled study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement for death (any cause) |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 5/56 lost to follow‐up and reasons given (< 10%) |
| Selective reporting (reporting bias) | High risk | No data for cardiovascular events extractable for analysis |
| Other bias | Low risk | None apparent |
Palazzuoli 2011.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 12 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group A
Control group B
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 14% dropped out (unclear distribution between groups). Unclear if ITT analysis |
| Selective reporting (reporting bias) | Low risk | Cardiovascular outcomes reported though no events |
| Other bias | Low risk | ESA supplied by respective pharmaceutical companies though no conflicts of interest or pharmaceutical involvement in manuscript preparation |
Park 2014b.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 12 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment
Control
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Insufficient information to permit judgement |
Patel 2012.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 27/118 lost to follow‐up in epoetin alfa arm (22.9%) and 10/39 lost to follow‐up in standard treatment arm (25.6%) |
| Selective reporting (reporting bias) | Low risk | Data for major cardiovascular events available |
| Other bias | High risk | Sponsor on authorship; change in protocol; medical writing assistance by sponsor |
PATRONUS 2010.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: randomised between December 2006 and November 2007 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomisation numbers were generated by computer at a coordinating centre |
| Allocation concealment (selection bias) | Low risk | Allocated to the two treatment groups in a 1:1 ratio using a permuted block randomisation with a block size of four. Investigators received numbers by telephone and recorded them on electronic case‐report forms |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 97/245 lost to follow‐up in methoxy polyethylene glycol‐epoetin beta arm (40%) and 58/245 lost to follow‐up in darbepoetin alfa arm (24%). As this is > 10% and there is a marked difference between groups, this is judged as high risk |
| Selective reporting (reporting bias) | Low risk | Death and cardiovascular events reported |
| Other bias | High risk | Industrial sponsor on authorship |
Picon 2015.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 6 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer generated |
| Allocation concealment (selection bias) | Low risk | Allocation by independent statistician, identical syringes |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | The physicians and all other personnel remained blind to the treatment allocation |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | The physicians and all other personnel remained blind to the treatment allocation |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 30% dropped out but ITT analysis and all participants included in analysis |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes and vascular access thrombosis in each grou could not be extracted for meta‐analysis |
| Other bias | High risk | Balanced groups, funding source involved in manuscript writing |
Pile 2020.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 2 years |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer randomisation |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 9% dropped out, ITT analysis |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Low risk | Sponsor not involved in manuscript preparation, authors had no conflicts of interest, balanced groups apart from high MMF dose in no treatment group |
PROTECT 2012.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 12 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes |
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomisation allocation sequence was generated by a random‐number table |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | The patients, physicians, data managers and investigators were kept blinded throughout the study |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | The patients, physicians, data managers and investigators were kept blinded throughout the study |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Complete data |
| Selective reporting (reporting bias) | Low risk | Cardiovascular outcomes available |
| Other bias | Unclear risk | Unclear role of sponsor |
PROTOS 2007.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: March 2004 to September 2005 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Low risk | Randomly assigned to treatment via a central randomisation centre |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 74/381 lost to follow‐up in methoxy polyethylene glycol‐epoetin beta arm (19%) and 24/191 lost to follow‐up in epoetin alfa or epoetin beta arm (13%). As this is > 10% and there was a difference between trial arms, this was judged as high risk |
| Selective reporting (reporting bias) | Low risk | Death and cardiovascular events reported |
| Other bias | High risk | Industrial sponsor on authorship |
RED‐HF 2009.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 28 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Low risk | Unique patient identification number through the interactive voice response system (IVRS) |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Investigators and patients are blinded to study‐drug assignment andboth placebo and darbepoetin are identical in appearance andpackagin |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | All endpoints were adjudicated by a clinical endpoints committee masked to treatment assignment |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Complete data |
| Selective reporting (reporting bias) | Low risk | Cardiovascular outcomes available |
| Other bias | High risk | Pharmaceutical employee in authorship |
Roth 1994.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not reported |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 23/43 lost to follow‐up in epoetin alfa arm (53%) and 25/40 lost to follow‐up in control arm (53%). As this was >10%, this was considered high risk |
| Selective reporting (reporting bias) | High risk | Data for major cardiovascular events/death not available |
| Other bias | Low risk | None apparent |
RUBRA 2008.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes extracted for meta‐analysis
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 45/168 lost to follow‐up in methoxy polyethylene glycol‐epoetin beta arm (27%) and 35/168 lost to follow‐up in epoetin alfa or beta arm (21%). As this was > 10%, this was judged high risk |
| Selective reporting (reporting bias) | High risk | Data for cardiovascular death or events not available |
| Other bias | High risk | Industrial sponsor on authorship |
Shaheen 1993.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | Data for cardiovascular events not extractable for analysis |
| Other bias | Low risk | None apparent |
Shand 1993.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | > 10% of randomised participants not included in analyses |
| Selective reporting (reporting bias) | High risk | Data not available for analysis |
| Other bias | Low risk | None apparent |
Sikole 1993.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 2/40 lost to follow‐up (5%). As this was < 10% this was judged low risk |
| Selective reporting (reporting bias) | High risk | Data for cardiovascular events not available |
| Other bias | Low risk | None apparent |
Silverberg 2001.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 12 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | Alternatively assigning patients into 2 groups |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo in control group |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Complete data |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Unclear role of sponsor or author conflicts of interest |
Silverberg 2006.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 12 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | High risk | Iron continued in treatment group after 3 months but stopped in control group |
Sinha 2019a.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 36 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in meta‐analysis
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | A designated statistician (Sristek, India) generated the allocation sequence but details not further described |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Not blinded |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Not blinded |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 26% dropped out but ITT analysis |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | High risk | Authors included employees of sponsor |
Smith 2007.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes extracted for meta‐analysis
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No data for cardiovascular events provided |
| Other bias | High risk | Sponsor on authorship; abstract only |
Smyth 2004.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 6 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 17% dropped out; unclear if ITT analysis |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes. Blood transfusion outcome unable to be extracted as it wasn't reported which group the single transfusion occurred in |
| Other bias | Unclear risk | Insufficient information to permit judgement |
Smyth 2006.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 24 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | High risk | Author was an employee of sponsor |
Spinowitz 2006.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 9/78 (11.5%) lost to follow‐up after randomisation which was > 10% |
| Selective reporting (reporting bias) | High risk | Major cardiovascular events not provided |
| Other bias | High risk | Sponsor on authorship |
STRIATA 2008.
| Study characteristics | ||
| Methods |
|
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Low risk | Randomly assigned by a central randomisation centre. Randomisation numbers were allocated sequentially to patients in the order in which they were enrolled |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 30/156 lost to follow‐up in darbepoetin arm (19%) and 34/157 (22%) lost to follow‐up in methoxy polyethylene glycol‐epoetin beta arm. As this was >10% in both arms, this was considered high risk |
| Selective reporting (reporting bias) | Low risk | Data for cardiovascular events available |
| Other bias | High risk | Industrial sponsor on authorship |
Teehan 1989.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants |
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | Data for cardiovascular outcomes not available |
| Other bias | Low risk | None apparent |
Tessitore 2008.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 54 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Insufficient information to permit judgement |
Thadhani 2018.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 24 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation schedule |
| Allocation concealment (selection bias) | Low risk | Interactive response system |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 14% dropped out for primary outcome and no ITT analysis |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes extractable |
| Other bias | High risk | Author was employee of sponsor |
TIVOLI 2013.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: participants screened between February 2008 and July 2009 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes |
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 3/24 lost to follow‐up in darbepoetin arm (13%) and 1/46 lost to follow‐up in methoxy polyethylene glycol‐epoetin beta arm (2%). As this was < 10% overall and differences between arms were not reliable due to small numbers of events, this was adjudicated as low risk |
| Selective reporting (reporting bias) | High risk | Data for cardiovascular events not available |
| Other bias | High risk | Published as letter only; writing supported and funded by sponsor |
Tolman 2005.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | 26/107 in epoetin beta arm (24%) lost to follow‐up and 29/112 in darbepoetin alfa arm (26%) lost to follow‐up. As this was > 10%, this was judged as high risk |
| Selective reporting (reporting bias) | High risk | Data for cardiovascular events not available |
| Other bias | Low risk | None apparent |
TREAT 2005.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: enrolment 25 August 2004 to 4 December 2007 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer generated |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Adjudicated by an endpoint committee whose members were unaware of the treatment assignments and the HCT and Hb values were redacted from the documents under review |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 153/2102 (7.5%) lost to follow‐up in darbepoetin alfa arm and 164/2026 (8.1%) lost to follow‐up in placebo arm. As this was < 10%, this was judged low risk |
| Selective reporting (reporting bias) | Low risk | Data for cardiovascular events available |
| Other bias | High risk | Imbalance of percentage with CV disease: interim analyses; sponsor provided independent statistical support |
Trembecki 1995a.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 12 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Not reported |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Funding source unclear. Baseline group characteristics not reported |
Tsubakihara 2011.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 24 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Insufficient information to permit judgement |
Van Biesen 2005.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | Data for cardiovascular events not available |
| Other bias | Low risk | None apparent |
Van Loo 1996.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 1 September 1993 to 31 August 1994 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | Low risk | Data for major cardiovascular events available |
| Other bias | Low risk | None apparent |
Vanrenterghem 2002.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: recruited between November 1997 and July 1998 |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Central computerised system |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | "Open‐label comparative study" |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Attrition 63/175 (36%) in epoetin alfa arm and 123/347 (35%) in darbepoetin alfa arm |
| Selective reporting (reporting bias) | Low risk | Death and cardiovascular events data available |
| Other bias | High risk | Industrial sponsor on authorship |
Vigano 1991.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 24 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Unclear baseline group characteristics |
Wang 2014.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: not reported |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcomes
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgemen |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Insufficient information to permit judgement |
Watson 1990.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 12 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double blind |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Selective reporting (reporting bias) | High risk | No cardiovascular events reported |
| Other bias | High risk | Sponsor responsible for randomisation |
Weir 2017.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 52 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Low risk | Interactive response technology |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Double blind but method Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | 3% dropped out and ITT analysis |
| Selective reporting (reporting bias) | Low risk | Death and cardiovascular outcomes reported |
| Other bias | High risk | An author is an employee of Sandoz Inc Vascular access thrombosis reported with other thrombotic events and could not be extracted |
Woodland 2017.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 12 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Variable, block randomisation procedure |
| Allocation concealment (selection bias) | Low risk | Sealed opaque envelopes |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | ITT analysis, complete data |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | Unclear risk | Darbepoetin group had high proportion of males, heart failure and less stroke |
Yasari 2012.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 6 months |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group
Control group
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear if any dropouts. No ITT analysis mentioned |
| Selective reporting (reporting bias) | High risk | No cardiovascular outcomes |
| Other bias | High risk | The first and second authors are the editor‐ in‐ chief and editorial manager of the publishing journal of the article |
Yoon 2004.
| Study characteristics | ||
| Methods | Study design: RCT Study duration: 20 weeks |
|
| Participants | Study characteristics
Baseline characteristics
|
|
| Interventions | Treatment group A
Treatment group B
Iron supplementation
|
|
| Outcomes | Primary study outcome
Outcomes included in the meta‐analyses
|
|
| Notes | Other relevant information
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Allocation concealment (selection bias) | Unclear risk | Insufficient information to permit judgement |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Insufficient information to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Complete data with ITT analysis |
| Selective reporting (reporting bias) | High risk | Stroke but no other cardiovascular outcomes reported |
| Other bias | High risk | Significantly higher proportion of females in darbepoetin alfa group |
AKI: acute kidney injury; AUC: area under the curve; BP: blood pressure; CKD: chronic kidney disease; CrCl: creatinine clearance; CRP: C‐reactive protein; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ECG: echocardiogram; ESA: erythropoiesis‐stimulating agents; ESKD: end‐stage kidney disease; GI: gastrointestinal; Hb: haemoglobin; HCT: haematocrit; HD: haemodialysis; HRQoL: health‐related quality of life; iPTH: intact parathyroid hormone; IQR: interquartile range; IV: intravenous; KRT: kidney replacement therapy; LFT: liver function test; LVEF: left ventricular ejection fraction; MI: myocardial infarction; NSAID: nonsteroidal anti‐inflammatory drug; NYHA: New York Heart Association; PD: peritoneal dialysis; PTH: parathyroid hormone; QoL: quality of life; RBC: red blood cell; RCT: randomised controlled trial; RPF: renal plasma flow; rHuEPO: recombinant human erythropoietin; TSAT: transferrin saturation; SBP: systolic blood pressure; SC: subcutaneous; SCr: serum creatinine; WCC: white cell count
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Aarup 2006 | Wrong intervention: not comparing different ESAs |
| Abraham 1990 | Wrong study design: two‐phase study; 4 patients randomised to placebo and 4 to varying doses of rHuEPO (50 to 150 units/kg) for 8 to 12 weeks until HCT goal achieved then all received long‐term rHuEPO to maintain goal HCT |
| Abraham 1991 | Wrong duration: mean duration of follow‐up less than 3 months |
| Acchiardo 1991a | Other: type of ESA not specified |
| ACORD 2004 | Wrong intervention: not comparing different ESAs |
| Aggarwal 2002 | Wrong intervention: not comparing different ESAs |
| Akiba 1992 | Wrong intervention: not comparing different ESAs |
| Al‐Otaibi 2019 | Wrong intervention: not comparing different ESAs |
| Amon 1992 | Wrong intervention: not comparing different ESAs |
| Ateshkadi 1993 | Wrong intervention: not comparing different ESAs |
| Aunsholt 1992 | Wrong intervention: not comparing different ESAs |
| Ayli 2004 | Wrong intervention: ESA not the intervention |
| Azevedo 1996 | Other: duration of follow‐up not reported; only outcome reported was pain |
| BA16260 2006 | Wrong intervention: not comparing different ESAs |
| BA16285 2007 | Wrong intervention: not comparing different ESAs |
| BA16286 2007 | Wrong intervention: not comparing different ESAs |
| Basile 1993 | Wrong intervention: not comparing different ESAs |
| Beiraghdar 2012 | Wrong duration: duration of follow‐up less than 3 months |
| Berns 1992 | Wrong control: comparison group was nandrolone decanoate |
| Besarab 1992 | Wrong study design: combination of one RCT involving different doses of epoetin and another RCT comparing epoetin and placebo. Results of placebo‐controlled period not reported |
| Besarab 1998 | Wrong intervention: not comparing different ESAs |
| Bhuiyan 2004 | Wrong intervention: not comparing different ESAs |
| Bommer 2008 | Wrong intervention: not comparing different ESAs |
| Boran 1993 | Wrong intervention: not comparing different ESAs |
| Bovy 1997 | Wrong intervention: not comparing different ESAs |
| Brahm 1991 | Wrong intervention: not comparing different ESAs |
| Brahm 1999 | Wrong intervention: not comparing different ESAs |
| Brandt 1999 | Wrong population: paediatric study population |
| Brier 2010 | Wrong intervention: not comparing different ESAs |
| Brimble 2003 | Wrong intervention: not comparing different ESAs |
| Broyan 1991 | Wrong duration: duration of follow‐up less than 3 months |
| C.E.DOSE 2010 | Wrong intervention: not comparing different ESAs |
| Canaud 1995 | Wrong intervention: not comparing different ESAs |
| CAPRIT 2012 | Wrong intervention: not comparing different ESAs |
| Cervelli 2005 | Wrong intervention: not comparing different ESAs |
| Chazot 2009 | Wrong intervention: not comparing different ESAs |
| CHOIR 2006 | Wrong intervention: not comparing different ESAs |
| Cianciaruso 2008 | Wrong intervention: not comparing different ESAs |
| COMFORT 2008 | Wrong duration: duration of follow‐up less than 3 months |
| CREATE 2001 | Wrong intervention: not comparing different ESAs |
| Debusmann 1991 | Wrong intervention: not comparing different ESAs |
| De Marchi 1991 | Wrong control: desferrioxamine |
| De Marchi 1992 | Wrong duration: duration of follow‐up less than 3 months |
| De Marchi 1994 | Other: type of ESA not specified |
| De Marchi 1998 | Other: type of ESA not specified |
| De Schoenmakere 1998 | Wrong intervention: not comparing different ESAs |
| Ding 1995a | Wrong intervention: not comparing different ESAs |
| Dix 1999 | Wrong duration: duration of follow‐up less than 3 months |
| Do 2006 | Wrong intervention: not comparing different ESAs |
| Duliege 2005 | Wrong intervention: use of peginesatide |
| ECAP 2006 | Wrong intervention: not comparing different ESAs |
| Eidemak 1990 | Wrong intervention: not comparing different ESAs |
| Eschbach 1989 | Wrong intervention: not comparing different ESAs |
| Faller 1993 | Wrong intervention: not comparing different ESAs |
| Fan 1992 | Wrong intervention: not comparing different ESAs |
| Foley 2000 | Wrong intervention: not comparing different ESAs |
| Forni 2013 | Wrong duration: 4 cross‐over periods, each only 6 weeks duration |
| Frenken 1989 | Wrong intervention: not comparing different ESAs |
| Frenken 1991 | Wrong study design: comparing local tolerance of rHuEPO, Recormon and saline injections, given 1 hour apart |
| Frifelt 1996 | Wrong intervention: not comparing different ESAs |
| Fujikawa 2019 | Wrong intervention: not comparing different ESAs |
| Furukawa 1992 | Wrong intervention: not comparing different ESAs |
| Gaughan 1997 | Wrong intervention: not comparing different ESAs |
| Gaweda 2014 | Wrong intervention: not comparing different ESAs |
| Gouva 2004 | Wrong intervention: not comparing different ESAs |
| Granolleras 1991 | Wrong duration: duration of follow‐up less than 3 months |
| Gurevich 2009 | Wrong intervention: use of peginesatide |
| Healy 2001 | Wrong intervention: not comparing different ESAs |
| Hsu 2004 | Wrong intervention: intervention not ESA |
| Hung 2005 | Wrong intervention: intervention not ESA |
| Hustrini 2019 | Wrong duration: duration of study less than 3 months |
| Iino 2003 | Wrong intervention: not comparing different ESAs |
| ISRCTN73108732 | Other: no published results, study no longer recruiting and no response from study contact author |
| ISRCTN89787518 | Other: no study contact, no published results, study no longer recruiting |
| ISRCTN96315193 | Wrong control: comparison group L‐carnitine |
| Itoh 2007 | Wrong intervention: not comparing different ESAs |
| Jabs 1994 | Wrong population: paediatric study population |
| Jang 2008 | Wrong intervention: not comparing different ESAs |
| Jensen 1996 | Wrong intervention: not comparing different ESAs |
| Johnson 1999 | Wrong intervention: not comparing different ESAs |
| Kakimoto‐Shino 2014 | Wrong duration: duration of follow‐up less than 3 months |
| Kang 1998 | Wrong duration: duration of follow‐up less than 3 months |
| Kaufman 1998 | Wrong intervention: not comparing different ESAs |
| Kawanishi 2005 | Wrong duration: duration of study less than 3 months |
| Kim 2001a | Wrong duration: duration of study less than 3 months |
| Kim 2009a | Wrong intervention: not comparing different ESAs |
| Kinugasa 2011 | Wrong intervention: not comparing different ESAs |
| Knebel 2008 | Wrong population: paediatric study population |
| Kobayashi 2010 | Wrong intervention: not comparing different ESAs |
| Koronis 2000 | Wrong intervnetion: ESA not the intervention |
| Koshikawa 1993a | Wrong intervention: not comparing different ESAs |
| Kovacevic 1995 | Wrong intervention: not comparing different ESAs |
| Kronborg 1994 | Wrong study design: duration of study not reported (only seems to report pain after a single injection of ESA) |
| Kuroki 2015 | Wrong duration: duration of follow‐up less than 3 months |
| Kwan 2005 | Wrong intervention: not comparing different ESAs |
| Lamas 2006 | Wrong intervention: intervention not an ESA |
| Lee 2008 | Wrong intervention: not comparing different ESAs |
| Lee 2009 | Wrong intervention: not comparing different ESAs |
| Lee 2009c | Wrong study design: cross‐over study with only 4 weeks of individual treatment periods |
| Leikis 2004 | Wrong intervention: not comparing different ESAs |
| Lerner 2002 | Wrong population: paediatric study population |
| Leung 1995 | Wrong intervention: not comparing different ESAs |
| Levin 2005 | Wrong intervention: not comparing different ESAs |
| Li 2004 | Wrong intervention: intervention not an ESA |
| Lillevang 1990 | Wrong duration: mean duration of follow‐up less than 3 months |
| Lim 1989 | Wrong duration: mean duration of follow‐up less than 3 months |
| Lim 2012 | Wrong intervention: not comparing different ESAs |
| Linde 2001 | Wrong intervention: not comparing different ESAs |
| Lindsay 1993 | Wrong intervention: intervention not an ESA |
| Locatelli 2002 | Wrong intervention: not comparing different ESAs |
| Locatelli 2004 | Wrong intervention: not comparing different ESAs |
| Locatelli 2008 | Wrong intervention: not comparing different ESAs |
| Lubis 2005 | Wrong duration: duration of follow‐up less than 3 months |
| Lui 1990 | Wrong intervention: not comparing different ESAs |
| Lui 1991 | Wrong intervention: not comparing different ESAs |
| Lui 1992 | Wrong intervention: not comparing different ESAs |
| Macdougall 1999 | Wrong duration: duration of follow‐up less than 3 months |
| Macdougall 2003 | Wrong intervention: not comparing different ESAs |
| Macdougall 2006 | Wrong intervention: not comparing different ESAs |
| Macdougall 2007 | Wrong intervention: not comparing different ESAs |
| Macdougall 2007a | Wrong intervention: not comparing different ESAs |
| Maeda 1988 | Wrong intervention: not comparing different ESAs |
| Marcas 2003 | Wrong intervention: not comparing different ESAs |
| Marigliano 1992 | Wrong intervention: not comparing different ESAs |
| Martinez 2006 | Wrong intervention: not continuous ESA treatment. Median treatment length only 8 weeks in darbepoetin arm and 2 weeks in epoetin arm |
| McMahon 1990 | Wrong intervention: not comparing different ESAs |
| McMahon 1999 | Wrong intervention: not comparing different ESAs |
| Mehta 2016 | Wrong duration: duration of study less than 3 months |
| Meisl 1990 | Other: type of ESA not specified |
| Mesjasz 2004 | Wrong control: intermittent blood transfusion |
| Minakata 2000 | Wrong study design: cross‐over study with inadequate duration in each treatment period (8 weeks) |
| MIRCERA PASS 2019 | Wrong control: darbepoetin or epoetin without subgroup analysis |
| Mircescu 2006 | Wrong intervention: not comparing different ESAs |
| Morozova 2019 | Wrong duration: duration of study less than 3 months |
| Morris 1993 | Wrong population: paediatric study population |
| Morsli 1993 | Wrong intervention: not comparing different ESAs |
| Muirhead 1989 | Wrong intervention: not comparing different ESAs |
| Muirhead 1992 | Wrong intervention: not comparing different ESAs |
| Murtagh 2000 | Wrong intervention: not comparing different ESAs |
| N0055116759 | Other: no results available despite attempted contact with authors |
| Na 2014a | Wrong study design: cross‐over study with individual arms only 6 weeks duration |
| Nagaya 2010 | Wrong intervention: not comparing different ESAs |
| NCT00121602 | Wrong intervention: not comparing different ESAs |
| NCT00240734 | Terminated: stopped for slow enrolment after enrolling only 11 of 180 patients in six months |
| NCT00337935 | Other: comparison group not defined ('standard of care'). No study contact to obtain further information |
| NCT00492427 | Other: no study contact or published results. and study no longer recruiting |
| NCT00563355 | Other: no published results, study no longer recruiting. and study contact reports no outcomes of interest |
| NCT00968617 | Terminated: no comparative group results |
| NCT01290328 | Terminated: low enrolment, termination of funding |
| NCT01306409 | Other: no published results, study no longer recruiting, and study contact reports no outcomes of interest |
| Neo‐PDGF 2010 | Wrong duration: duration of study less than 3 months |
| Nesic 2005 | Wrong intervention: not comparing different ESAs |
| Nomoto 1994 | Wrong intervention: not comparing different ESAs |
| OPATIJA 2012 | Other: type of ESA not specified |
| Ortiz 1997 | Wrong intervention: not comparing different ESAs |
| Osikov 2014 | Wrong duration: duration of follow‐up less than 3 months |
| Otsuka 2015 | Wrong study design: cross‐over study and individual treatment period only 2 months |
| Paganini 1991 | Wrong intervention: not comparing different ESAs |
| Paganini 1995 | Wrong intervention: not comparing different ESAs |
| PARAMOUNT‐HD 2019 | Wrong intervention: not comparing different ESAs |
| Parfrey 2005 | Wrong intervention: not comparing different ESAs |
| Perez‐Oliva 2005 | Wrong duration: duration of study less than 3 months |
| Pergola 2009 | Wrong intervention: not comparing different ESAs |
| Pergola 2010 | Wrong intervention: not comparing different ESAs |
| PREDICT 2016 | Wrong intervention: not comparing different ESAs |
| PROMPT 2005 | Wrong intervention: not comparing different ESAs |
| Provenzano 2007 | Wrong intervention: not comparing different ESAs |
| Quinn 1989 | Other: type of ESA not specified |
| Qureshi 2007 | Wrong intervention: not comparing different ESAs |
| RADIANCE‐CKD 2021 | Wrong intervention: not comparing different ESAs |
| Ramos 1997 | Wrong duration: duration of study less than 3 months |
| Richardson 2000 | Wrong intervention: not comparing different ESAs |
| Rocha 1998 | Wrong intervention: not comparing different ESAs |
| Roger 1991 | Wrong intervention: intervention is not an ESA |
| Roger 2014 | Wrong intervention: not comparing different ESAs |
| Roman 2004 | Wrong intervention: not comparing different ESAs |
| Salek 2001 | Wrong intervention: not comparing different ESAs |
| Samtleben 1988 | Wrong intervention: not comparing different ESAs |
| Satirapoj 2014 | Wrong intervention: not comparing different ESAs |
| Satirapoj 2017 | Wrong intervention: not comparing different ESAs |
| Saxena 1997 | Wrong intervention: intervention not an ESA |
| Schaller 1994 | Wrong intervention: not comparing different ESAs |
| Schmitt 2006 | Wrong population: paediatric study population |
| Sen 1996 | Other: type of ESA not specified |
| Shaheen 1997 | Other: type of ESA not specified |
| Sheashaa 2005a | Wrong intervention: not comparing different ESAs |
| Sheashaa 2005b | Other: type of ESA not specified |
| Shun 1999 | Wrong intervention: not comparing different ESAs |
| Singh 1999 | Wrong duration: duration of follow‐up less than 3 months |
| Sja'bani 1997 | Wrong duration: duration of study less than 3 months |
| SLIMHEART 2004 | Wrong intervention: not comparing different ESAs |
| Slingeneyer 1991 | Wrong intervention: not comparing different ESAs |
| Sohmiya 1998 | Wrong intervention: not comparing different ESAs |
| Song 2002a | Wrong intervention: not comparing different ESAs |
| Spaia 1995 | Wrong intervention: not comparing different ESAs |
| Spinowitz 2008 | Wrong intervention: not comparing different ESAs |
| Starklint 2003 | Wrong duration: duration of follow‐up less than 3 months |
| START‐CKD 2021 | Wrong intervention: not comparing different ESAs |
| Steffensen 1992 | Wrong intervention: not comparing different ESAs |
| Steffensen 2011 | Wrong intervention: not comparing different ESAs |
| Stein 1994 | Wrong intervention: not comparing different ESAs |
| STIMULATE 2014 | Terminated: recruitment issues |
| Stockenhuber 1990 | Wrong intervention: not comparing different ESAs |
| Stockenhuber 1991 | Wrong intervention: not comparing different ESAs |
| Stone 1988 | Wrong duration: duration of follow‐up less than 3 months for placebo‐controlled period. Not comparing different ESAs for maintenance period |
| St Peter 1998 | Wrong duration: duration of follow‐up less than 3 months |
| Sunder‐Plassmann 1995 | Wrong intervention: not comparing different ESAs |
| Suzuki 1989 | Wrong duration: duration of follow‐up less than 3 months |
| Svarstad 2007 | Wrong intervention: not comparing different ESAs |
| Tan 2010a | Wrong duration: duration of follow‐up less than 3 months |
| Taub 1999 | Wrong duration: duration of follow‐up less than 3 months |
| Taylor 1993 | Wrong intervention: not comparing different ESAs |
| Teehan 1991 | Wrong duration: duration of follow‐up less than 3 months |
| Toida 2014 | Wrong intervention: not comparing different ESAs |
| Tsubakihara 2003 | Wrong intervention: not comparing different ESAs |
| Tsujita 2019 | Wrong study design: high Hb versus low Hb group |
| UMIN000005068 | Other: no study contact or published results, study no longer recruiting |
| UMIN000008073 | Other: no published results, study no longer recruiting, and no response from study contact |
| van den Oever 2020 | Wrong intervention: not comparing different ESAs |
| Veys 1992 | Wrong duration: duration of follow‐up less than 3 months |
| Virot 1996 | Wrong intervention: not comparing different ESAs |
| Wang 2004b | Other: type of ESA not specified |
| Warady 2006 | Wrong population: paediatric study population |
| Warady 2018 | Wrong population: paediatric study population |
| Watanabe 2004 | Wrong intervention: not comparing different ESAs |
| Watkins 1991 | Wrong population: paediatric study population |
| Weiss 2000 | Wrong intervention: not comparing different ESAs |
| Weiss 2003 | Wrong intervention: intervention not an ESA |
| Wizemann 1990 | Wrong duration: duration of study less than 3 months |
| Wizemann 2008 | Wrong study design: cross‐over study |
| Yalcinkaya 1997 | Wrong population: paediatric study population |
| Yamazaki 1993 | Wrong intervention: not comparing different ESAs |
| Yeo 2005 | Wrong intervention: not comparing different ESAs |
| Yu 1998 | Wrong intervention: not comparing different ESAs |
| Yue 2004 | Other: type of ESA not specified |
| Zheng 1992 | Wrong intervention: not comparing different ESAs |
ESA: erythropoiesis‐stimulating agents; HCT: haematocrit; RCT: randomised controlled trial; RHuEPO: recombinant human erythropoietin
Characteristics of studies awaiting classification [ordered by study ID]
Aliev 1997.
| Methods | Publication not available |
| Participants | ‐‐ |
| Interventions | ‐‐ |
| Outcomes | ‐‐ |
| Notes | ‐‐ |
Koiwa 2019.
| Methods | Study design: RCT Study duration: 52 weeks |
| Participants | Study characteristics
Baseline characteristics
|
| Interventions | Treatment group
Control group
Iron supplementation
|
| Outcomes | Primary study outcome
Outcomes to be included in the meta‐analyses
|
| Notes | Other relevant information
|
Muirhead 1992a.
| Methods | Publication not available |
| Participants | ‐‐ |
| Interventions | ‐‐ |
| Outcomes | ‐‐ |
| Notes | ‐‐ |
NCT00442702.
| Methods |
|
| Participants |
|
| Interventions |
|
| Outcomes | Primary outcome measures
Secondary outcome measures
|
| Notes | No publications provided by sponsor |
NCT00717821.
| Methods |
|
| Participants |
|
| Interventions |
|
| Outcomes | Primary outcome measures
Secondary outcome measures
|
| Notes | No publications provided by sponsor to clinicaltrials.gov |
PRIMAVERA 2011.
| Methods |
|
| Participants |
|
| Interventions |
|
| Outcomes |
|
| Notes |
CERA: continuous erythropoietin receptor activator; CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; ESA: erythropoiesis‐stimulating agent; Hb: haemoglobin; HD: haemodialysis; IV: intravenous; RBC: red blood cell; RCT: randomised controlled trial; SC: subcutaneous; SCr: serum creatinine; UACR: urinary albumin:creatinine ratio
Characteristics of ongoing studies [ordered by study ID]
UMIN000009472.
| Study name | Investigation of responses to erythropoiesis stimulating agents (ESA) for the initial treatment of renal anemia in patients with chronic kidney disease |
| Methods | Parallel RCT |
| Participants |
Inclusion criteria
Exclusion criteria
|
| Interventions | CERA group
rHuEPO group
|
| Outcomes | Primary outcomes
Secondary outcomes
|
| Starting date | Planned starting date: 5 December 2012 |
| Contact information | Koji Mitsuiki koji@fukuoka‐med.jrc.or.jp |
| Notes |
CERA: continuous erythropoietin receptor activator; eGFR: estimated glomerular filtration rate; ESA: erythropoiesis‐stimulating agent; Hb: haemoglobin; HD: haemodialysis; PD: peritoneal dialysis; RBC: red blood cell; rHuEPO: recombinant human erythropoietin; SC: subcutaneous
Differences between protocol and review
We did not include the outcomes of end of treatment Hb level as this is a surrogate outcome and not indicative of efficacy or safety. We did not include continuous measures (number of blood transfusions or number of hospital admissions for blood transfusions) in the final review as these were largely not reported in the included studies. We have not included cancer as an outcome as this was relevant to an earlier version of the protocol (which included all populations receiving ESA therapy, not just CKD but which we subsequently excluded from the published protocol as assumptions of transitivity were likely to have been breached using this approach). We added biosimilar ESAs as a single node of interest in the review (which was not mentioned in the protocol) as these are of interest to patients, clinicians and policy‐makers and the network analysis approach is the ideal vehicle to consider the comparative safety and efficacy of these ESA formulations.
Contributions of authors
Draft the protocol: SP, GS, JC, GFMS
Study selection: SP, VS
Extract data from studies: SP, VS
Enter data into RevMan: SP
Carry out the analysis: SP
Interpret the analysis: SP, VS, JC, GFMS
Revising the review drafts for important intellectual content: SP, JC, MT, GFMS
Draft the final review: SP
Disagreement resolution: GFMS
Update the review: SP
Sources of support
Internal sources
Cochrane Kidney and Transplant, Australia
External sources
No sources of support provided
Declarations of interest
Suetonia C Palmer: none known
Valeria Saglimbene: none known
Jonathan C Craig: none known
Marcello Tonelli: Dr Tonelli has received an investigator‐initiated grant and honoraria from Amgen Australia for an academic lecture series ‐‐ neither were related to ESA or anaemia. All honoraria were donated to charity
Giovanni FM Strippoli: none known
New search for studies and content updated (no change to conclusions)
References
References to studies included in this review
Aggarwal 2005 {published data only}
- Aggarwal HK, Sehgal R, Singh S, Nand N, Bharti K, Chakrabarti D. Evaluation of efficacy of low dose recombinant human erythropoietin in combination with androgen therapy in anaemia of chronic renal failure. Journal Indian Academy of Clinical Medicine 2005;6(3):208-15. [EMBASE: 41657807] [Google Scholar]
Akiba 2010 {published data only}
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