Healthy kidneys produce the hormone erythropoietin, which stimulates production of red blood cells in the bone marrow. Anaemia is a common problem for people with advanced chronic kidney disease, due to reduced endogenous erythropoietin production. A new Cochrane Review by Palmer and colleagues examines the evidence for erythropoiesis-stimulating agents (ESA) for anaemia in adults with chronic kidney disease. This review differs from an earlier review by some of the same authors in that it employs the Bayesian statistical approach of network meta-analysis. This technique allows for both direct and indirect comparisons of different treatments for the same or similar conditions (in this case ESA for anaemia), even when most trials tested a treatment against placebo and did not compare treatment interventions directly.
In contrast to the 2010 systematic review, which examined the benefits and harms of ESAs in general and their differing effects depending on haemoglobin targets, the new review aims to combine the trial results from all the different ESAs to allow some ranking of differences in benefits and harms across the different agents or classes of agents used. This is important because until recently most of the available ESAs have been expensive recombinant proteins restricted to economies with more advanced health systems and dialysis programs, and different countries have favoured different products (e.g. more epoetin alfa in the United States but more epoetin beta in Europe). The use of ESAs has increased substantially in most countries where they are used, and although this has been linked to reimbursement policies in the United States, a recent study suggests that this increase is happening in most other countries as well, regardless of reimbursement policies. Perhaps because of these increases in global costs, recent years have seen the advent of biosimilar agents, which are less expensive and so potentially might be used in more resource-poor settings. The downside is that the biosimilars may not be subject to the same stringent quality control in their manufacture. Quality issues in production of ESAs have been associated with creation of more immunogenic proteins, which in turn drive antibody production and cause pure red cell aplasia (PRCA). PRCA is an extremely rare complication with established ESA, but it probably occurs at a higher rate in those using biosimilars. PRCA is a problem for dialysis patients because it generally makes them dependent on blood transfusions for management of their anaemia. Blood transfusion stimulates immunological sensitisation in recipients and potentially development of antibodies to any potential donor population, which then can impact their chances of receiving a kidney transplant.
What are the strengths and limitations of network meta-analysis in this context? The key strength is that the trial designs of the 40 included studies are likely to be quite similar, in terms of the patient populations (adults with CKD and anaemia, mostly on dialysis, and with similar prevalence of comorbid conditions), the treatments used (epoetin alfa, darbepoetin alfa, epoetin beta, methoxy polyethylene glycol-epoetin beta, and biosimilar epoetin – all injectable recombinant proteins), and the outcomes assessed (mortality, cardiovascular events, benefits: blood transfusions requirements, and harms: hypertension, vascular access thrombosis). There may be significant differences in some of the studies (e.g. non-dialysis versus dialysis patient populations), but in general terms the trial contexts and methodology would be expected to be similar. Network meta-analysis allows estimates of comparative efficacy between the different ESAs even if they were not compared directly against each other in the included trials. Therefore, it is possible that by pooling the results of several trials of treatment versus placebo that all show a benefit, you might have enough statistical power to generate a ranking and reveal that one particular treatment is more efficacious than the others. This is in contrast to conventional meta-analysis, which is limited to pair-wise direct comparisons of interventions in the original trials. So the conclusions of the authors that no ESA is superior to any other and that they all reduce the need for blood transfusions, is likely to be true.
Limitations of the meta-analysis must also be considered. In this review, the main limitation is that the comparative efficacy of the different agents for some patient-level outcomes is hampered by poor reporting in the trials, whereas the benefit of the various ESAs for preventing blood transfusions (compared to placebo) seems to be clear. Another consideration for the interpretation of meta-analysis compared with the interpretation of a single trial is the question of harms of a treatment. In general, harms tend to be reported less consistently and less often than benefits in randomised controlled trials. A recent publication highlighted that inconsistent reporting of harms can be compounded by meta-analysis, leading to conclusions tending to lean towards benefits. In the case of ESAs this is highlighted by the impact of one large and well-reported study of ESAs, the Trial to Reduce Cardiovascular Events with Aranesp (TREAT) study. In this trial the use of ESAs in over 4000 non-dialysis chronic kidney disease patients was associated with an increased risk of stroke. This study seems to have been primarily responsible for a significant change in ESA prescribing in the United States in recent years. The appreciation of this harmful effect might have been somewhat diluted in a meta-analysis where contributing trials failed to report stroke as an outcome.
A significant question for policy makers and funding bodies will be whether the cheaper, biosimilar agents can be used in place of expensive, established brands of ESA (the various epoetins) for the treatment of adults with anaemia and chronic kidney disease. The new meta-analysis is not able to answer that question definitively because the clinical trial evidence for the biosimilars is not as robust as it is for the proprietary agents. As with any meta-analysis, the conclusions must be considered in the context of the quality of the trial data from which they are derived. In this case, we need further head-to-head trials of biosimilar ESAs versus the more established agents to prove that they are as safe and as effective. Unfortunately, without economic imperative, such trials are unlikely to be conducted. This leaves funding bodies with the difficult issue of having to balance costs of treatment with uncertainty about risks.
David W Mudge1, Angela C Webster2
1Consultant Nephrologist and Associate Professor of Medicine, University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland, Australia; Editor, Cochrane Renal Group (firstname.lastname@example.org) 2Consultant Nephrologist and Associate Professor of Clinical Epidemiology, University of Sydney, Sydney, New South Wales, Australia; Deputy Co-ordinating Editor, Cochrane Renal Group (email@example.com).
How to cite: Mudge DW, Webster AC. Erythropoiesis-stimulating agents for anaemia in chronic kidney disease: are they all the same? [editorial]. Cochrane Database of Systematic Reviews 2014;(12):ED000093.
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Competing interests: The authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available upon request). DM has received speaker's honoraria from Amgen; a conference travel grant from Amgen; a conference travel grant and conference registration fee payment from Janssen-Cilag; and conference registration fee payment from Novartis. AW declares no potential conflicts of interest.
Provenance and peer review: This editorial was commissioned and was not externally peer reviewed.
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