Abstract: We identified 56 eligible studies involving 15,596 adults with CKD. Risks of bias in the included studies was generally high or unclear for more than half of studies in all of the risk of bias domains we assessed; no study was low risk for allocation concealment, blinding of outcome assessment and attrition from follow-up. In network analyses, there was moderate to low confidence that epoetin alfa (OR 0.18, 95% CI 0.05 to 0.59), epoetin beta (OR 0.09, 95% CI 0.02 to 0.38), darbepoetin alfa (OR 0.17, 95% CI 0.05 to 0.57), and methoxy polyethylene glycol-epoetin beta (OR 0.15, 95% CI 0.03 to 0.70) prevented blood transfusions compared to placebo. In very low quality evidence, biosimilar ESA therapy was possibly no better than placebo for preventing blood transfusions (OR 0.27, 95% CI 0.05 to 1.47) with considerable imprecision in estimated effects. We could not discern whether all ESAs were similar or different in their effects on preventing blood transfusions and our confidence in the comparative effectiveness of different ESAs was generally very low. Similarly, the comparative effects of ESAs compared with another ESA, placebo or no treatment on all-cause mortality were imprecise. All proprietary ESAs increased the odds of hypertension compared to placebo (epoetin alfa OR 2.31, 95% CI 1.27 to 4.23; epoetin beta OR 2.57, 95% CI 1.23 to 5.39; darbepoetin alfa OR 1.83, 95% CI 1.05 to 3.21; methoxy polyethylene glycol-epoetin beta OR 1.96, 95% CI 0.98 to 3.92), while the effect of biosimilar ESAs on developing hypertension was less certain (OR 1.18, 95% CI 0.47 to 2.99). Our confidence in the comparative effects of ESAs on hypertension was low due to considerable imprecision in treatment estimates. The comparative effects of all ESAs on cardiovascular mortality, myocardial infarction (MI), stroke, and vascular access thrombosis were uncertain and network analyses for major cardiovascular events, end-stage kidney disease (ESKD), fatigue and breathlessness were not possible. Effects of ESAs on fatigue were described heterogeneously in the available studies in ways that were not useable for analyses. In the CKD setting, there is currently insufficient evidence to suggest the superiority of any ESA formulation based on available safety and efficacy data. Directly comparative data for the effectiveness of different ESA formulations based on patient-centred outcomes (such as quality of life, fatigue, and functional status) are sparse and poorly reported and current research studies are unable to inform care. All proprietary ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta) prevent blood transfusions but information for biosimilar ESAs is less conclusive. Comparative treatment effects of different ESA formulations on other patient-important outcomes such as survival, MI, stroke, breathlessness and fatigue are very uncertain. For consumers, clinicians and funders, considerations such as drug cost and availability and preferences for dosing frequency might be considered as the basis for individualising anaemia care due to lack of data for comparative differences in clinical benefits and harms.

Plain-language summary: Several drugs are available to treat anaemia for people who have kidney disease but whether these drugs are similar or different in their ability to improve symptoms of anaemia, such as tiredness and breathlessness, and whether they are equally safe based on their risks of causing a stroke or a heart attack, is not clear. This is because research studies that compare the effects of one drug directly with another are not common. We have found 56 studies that measure the safety and how these drugs help to improve how patients who have kidney disease feel, function and survive that have involved 15,596 people. Our last search of the literature was in February 2014. We are somewhat confident that four of the drugs (epoetin alfa, epoetin beta, darbepoetin beta and methoxy polyethylene glycol-epoetin beta) are better than a placebo injection to prevent patients needing to have a blood transfusion. We are less certain that biosimilar drugs are better than placebo to help patients avoid a blood transfusion. All erythropoiesis-stimulating agents cause high blood pressure, but we cannot be very sure if biosimilar products have effects on blood pressure. We cannot be confident in the other important effects of these drugs - we are not sure whether the drugs are similar or different in their effects on the chances of death, a heart attack or stroke; the risk of having a clot in a fistula or vascular catheter needed for dialysis; or the chances of needing dialysis for people who have milder kidney disease. We are unsure whether the different drugs are better at improving symptoms such as tiredness or breathlessness than others as the available research studies generally do not measure these aspects of treatment very well. Overall, whether different drugs are safer or better at treating symptoms of anaemia for people with kidney disease is poorly known. It is likely that most if not all the drugs prevent the need for a patient to require a blood transfusion. The choice of which drug to use to treat anaemia when a patient has kidney disease can be decided between patients and health professionals based on shared preferences for how frequently the drug is given and considering drug costs and availability.