Description of the condition
Anaemia, literally meaning "lack of blood", is defined as "a condition in which the number of red blood cells or their oxygen-carrying capacity is insufficient to meet physiological needs" (http://www.who.int/topics/anaemia/en/). Circulating red blood cells transport oxygen to tissues bound to iron ions within the metalloprotein, haemoglobin. In anaemia, insufficient numbers of circulating red blood cells or inadequate quantities of iron or functional haemoglobin are available to transport and release oxygen to tissues, which is essential for aerobic (oxygen-dependent) metabolism. Anaemia, defined by the World Health Organization as a haemoglobin level below 130 g/L in men and below 120 g/L in women, affects approximately one-quarter of the world's population, particularly children and pregnant women (WHO 2008). Anaemia is common in the expanding global populations of chronic disease including people affected by solid malignancies (50%), blood cancers (60% to 70%) (Ludwig 2004), human immunodeficiency virus (HIV) causing acquired immunodeficiency syndrome (40%) (Shah 2007), chronic heart failure (20%) (Ezekowitz 2003), and nearly all individuals who have advanced chronic kidney disease (CKD). Symptoms caused by insufficient oxygen delivery to tissues in anaemia include weakness and fatigue, breathlessness, light-headedness, and palpitations. Observational cohort data show that anaemia in people who have chronic disease is also consistently associated with negative effects on quality of life (Lefebvre 2006), role function (Ludwig 2004; Semba 2005), and survival (Caro 2001; Groenveld 2008; Locatelli 2004; Melekhin 2012).
Description of the intervention
Recombinant erythropoietin and its synthetic derivatives (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta; collectively known as erythropoiesis-stimulating agents (ESAs)), are widely used to treat anaemia. Erythropoietin is a glycoprotein made by peritubular cells in the kidney (with an additional smaller contribution from liver cells (15% total)) and is released in response to low tissue oxygen levels (hypoxia) through the actions of hypoxia-inducible factor and stimulates the formation and viability of red blood cells in the bone marrow (erythropoiesis). The average red blood cell survives in the circulation for 120 days although red cell survival is reduced by chronic disease. Causes of anaemia are numerous and include: reduced production of erythropoietin in response to hypoxia (CKD; chronic inflammatory conditions); abnormal bone marrow responses to the actions of erythropoietin (chronic inflammatory conditions, bone marrow failure due to infiltration or drug-related therapy); insufficient iron stores; abnormal production or function of haemoglobin (thalassaemia or haemoglobinopathies); excessive red blood cell losses (destruction within the circulation or haemorrhage); or reduced red blood cell survival (Figure 1).
Before the development of recombinant human erythropoietin in the late 1980s (Eschbach 1987), blood transfusions and iron supplementation (both oral and intravenous (IV)) were the mainstay of treatment for anaemia in populations with severe CKD, in which haemoglobin levels were commonly in the range of 70 to 80 g/L. Androgen treatment for anaemia was also used in CKD but provided small and unsustained responses in haemoglobin levels and was poorly tolerated (Neff 1981). In the pre-recombinant-erythropoietin era, blood transfusions effectively increased haemoglobin levels to provide acute symptom relief but were associated with hospitalisation, iron overload, antibody formation against blood cell antigens, sensitisation to transplant antigens, and transfusion-related infections, particularly viral hepatitis. Technological advances and successful cloning of the erythropoietin gene allowed for large-scale production of human recombinant erythropoietin which effectively and rapidly increases haemoglobin levels when administered intravenously or subcutaneously. The United States Food and Drug Administration (FDA) approved human recombinant erythropoietin for the treatment of anaemia in people with CKD on dialysis in 1989 and broadened approval to use in people with CKD without dialysis, and in patients with HIV and anaemia on zidovudine (AZT) in 1990.
Clinical guidelines published soon after initial drug approval suggested that patients with CKD and haemoglobin concentrations below 80 g/L who were symptomatic should receive erythropoietin in conjunction with sufficient iron supplementation once other causes of anaemia were excluded (Macdougall 1990). However, rapid widespread uptake of ESAs occurred in numerous clinical settings and, by 2007, clinical practice guidelines recommended the use of erythropoietin to achieve target haemoglobin levels of 110 to 120 g/L in people with CKD (KDOQI 2007). Erythropoietin prescription also subsequently expanded to treat anaemia in cancer and heart failure populations, as well as for people undergoing surgery likely to require blood transfusion who could not undergo pre-operative blood collection. Presently, epoetin alfa is approved by the FDA for treatment of anaemia due to CKD, zidovudine in HIV-infected patients, effects of concomitant myelosuppressive chemotherapy and to reduce red blood cell transfusions in patients undergoing elective, noncardiac, nonvascular surgery. Darbepoetin alfa is currently approved by the FDA for the treatment of anaemia resulting from CKD or myelosuppressive chemotherapy (FDA website).
How the intervention might work
Despite an association between low haemoglobin levels and higher mortality in uncontrolled studies, prompting speculation that correcting anaemia with ESAs might lower cardiovascular events and mortality, the opposite was observed in subsequent meta-analyses of randomised controlled trials (RCTs) for ESAs (Bohlius 2009; Palmer 2010; Phrommintikul 2007; Strippoli 2006). Correction of anaemia and maintenance of haemoglobin levels to near normal levels with ESAs reduced the need for red blood cell transfusions, but increased mortality, cardiovascular events and cancer-progression, without consistently improving quality of life. The precise mechanisms for treatment-related harm are not understood, but observational studies suggest that impaired haemoglobin responses to erythropoietin treatment, together with higher erythropoietin doses are associated with increased treatment-related toxicity (Kilpatrick 2008; Szczech 2008).
Treatment guidelines for ESAs to treat anaemia have become more conservative over the last decade and FDA labelling now suggests that ESA treatment should be considered in people with CKD when the haemoglobin level is less than 100 g/L, and treatment objectives are to increase haemoglobin levels sufficient to reduce the need for red cell transfusions (FDA website). Clinical practice guidelines have also responded to increasing evidence of harm when higher haemoglobin levels are targeted by ESA treatment (Bohlius 2009; Palmer 2010; Phrommintikul 2007). Recent clinical practice guidelines for the use of ESAs to treat anaemia in CKD suggest the potential benefits of reducing blood transfusions and anaemia-related symptoms should be balanced against the risks of harm (e.g., stroke, vascular access loss and hypertension) for individual patients. Currently guidelines do not suggest specific haemoglobin targets for patients not treated with dialysis, while for dialysis patients the recommended approach is to use ESA therapy to avoid a haemoglobin level below 9.0 g/dL (KDIGO 2010).
Why it is important to do this review
Darbepoetin alfa and methoxy polyethylene glycol-epoetin beta (a continuous erythropoietin-receptor activator (CERA)) are newer synthetic forms of naturally-occurring erythropoietin that have a longer duration of action (Macdougall 2008). These agents have similar effects on haemoglobin concentrations as epoetin alfa and beta and require less frequent administration (Macdougall 2001; Levin 2007). Darbepoetin alfa treatment in people with earlier stages of CKD and diabetes mellitus has been shown to nearly halve the risk of blood transfusion but has no beneficial effects on survival and increases the risk of stroke and death related to cancer recurrence (TREAT 2009).
The apparent narrow therapeutic balance between potential treatment benefits (avoidance of red blood cell transfusions) and hazards (cardiovascular events, mortality, and cancer disease progression or recurrence) together with the availability of several agents in this drug class (epoetin alfa, epoetin beta, darbepoetin alfa and methoxy polyethylene glycol-epoetin beta) to treat anaemia builds the case for a comprehensive and systematic head-to-head comparison of the available ESAs to treat anaemia. However, large-scale trials directly comparing different ESAs have been relatively uncommon and the comparative efficacy and safety of each agent relative to each other is poorly understood. In the era of increasing caution in prescribing ESAs to increase haemoglobin levels due to the potential hazards of targeting higher haemoglobin levels, it is plausible that a patient could be randomised in a single multi-arm trial to receive any ESA to treat anaemia.
We will conduct a systematic review and meta-analysis that aims to compare multiple ESAs for the treatment of anaemia in adults with CKD and if deemed appropriate and feasible, we will undertake a network meta-analysis (NMA) to rank the efficacy and acceptability of all available treatments.