Should erythropoiesis-stimulating agents be used in predialysis patients?

Anemia results from insufficient production of erythropoietin by the kidneys and is a common complication of chronic kidney disease. It is present in most patients with stage 4 and 5 chronic kidney disease. Studies have linked untreated anemia in chronic kidney disease to worsening cardiovascular complications, possible acceleration to end-stage renal disease, and death. Administration of erythropoiesis-stimulating agents has become standard therapy for patients with erythropoietin-deficient an emia who are receiving dialysis. Despite recent concerns regarding the safety of these agents in the predialysis population, these agents should be used for certain carefully selected patients. A number of studies have examined the use of erythropoiesisstimulating agents in the predialysis period and its impact on outcomes after initiation of dialysis. In one observational study of almost 90 000 elderly patients with US Medicare coverage, those who were least consistently treated with erythropoiesisstimulating agents in the 2 years before initiation of dialysis had a higher relative risk of death than those who received the most consistent treatment with these agents (relative risk [RR] 1.46, 95% confidence interval [CI] 1.245–1.713). The results of a second study involving a cohort of almost 5000 patients implied a lower risk of death after initiation of dialysis if erythropoiesisstimulating agents were administered before initiation of this therapy (RR 0.81, 95% CI 0.71–0.91). Further analysis of retrospective claims data for almost 6000 patients who were receiving hemodialysis indicated that predialysis treatment in the 2 years before the onset of end-stage renal disease significantly lowered the risk of cardiovascular events relative to untreated patients (RR 0.7, 95% CI 0.61–0.82). In a systematic review of 15 studies involving a total of 461 predialysis patients with anemia, Cody and others concluded that treatment with erythropoiesis-stimulating agents corrects anemia, avoids the requirement for blood transfusions, and improves quality of life and exercise capacity. The avoidance of blood transfusions may be of particular importance to patients awaiting kidney transplantation. Gandra and others, in their assessment of the effect of treatment with erythropoiesis-stimulating agents on quality of life, reviewed 14 studies performed between 1980 and 2008 that measured energy, fatigue, and/or limitation of physical function/role or activity. The authors concluded that this form of treatment improves hemoglobin concentrations, with associated improvements in self-reported energy and physical function. Three randomized controlled trials have examined the use of erythropoiesis-stimulating agents in the predialysis population. The Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) study was an open-label randomized trial of 600 patients with chronic kidney disease who were not receiving dialysis and who did not have diabetes mellitus. Patients were randomly assigned to receive epoetin beta for full correction of anemia (target hemoglobin 130–150 g/L) or partial correction of anemia (target hemoglobin 105–115 g/L). After 3 years of follow-up, there were no differences between the groups in terms of cardiovascular events, but a prespecified secondary analysis showed a higher risk of end-stage renal disease requiring dialysis among the patients with the higher target for hemoglobin concentration. The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study was an open-label randomized trial of epoetin alfa given to just over 1400 patients who had chronic kidney disease with or without diabetes. The study compared higher and lower target concentrations of hemoglobin (135 versus 113 g/L) in terms of a primary composite end point of death, myocardial infarction, admission to hospital for congestive heart failure, and stroke. The study was terminated early after median 16-month duration of follow up because of an increase in the rate of the composite end point in the higherhemoglobin group (hazard ratio [HR] 1.34, 95% CI 1.03–1.74). This higher rate was driven by higher rates of death and admission to hospital for congestive heart failure. In addition, there was a strong trend toward a higher rate of end-stage renal disease in the higher-hemoglobin group. The latest trial, the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), was unique in that it was a placebo-controlled trial. In this study, 4000 patients with chronic kidney disease and type 2 diabetes were randomly assigned to treatment with darbepoetin alfa (target hemoglobin 130 g/L) or placebo (with rescue therapy if hemoglobin fell below 90 g/L). Forty-six percent of patients in the placebo arm required rescue therapy with darbepoetin. The median level of hemoglobin achieved was 125 g/L in the active treatment arm and 106 g/L in the placebo arm. There were no differences between study groups for the composite cardiovascular outcome (cardiovascular events including death, myocardial infarction, myocardial ischemia, congestive heart failure, and stroke) or the renal outcome (death or end-stage renal disease). However, the rate of fatal or nonfatal stroke was higher in the active treatment arm (HR 1.92, 95% CI 1.38–2.68). Rates of thromboembolism were also higher in the treatment group, and in the subgroup of patients with a history of malignancy, there were higher rates of cancer-related deaths. Taken together, these studies may indicate to clinicians that the use of erythropoiesis-stimulating agents should be avoided in predialysis patients because of a lack of improvement in cardiovascular and renal outcomes and potential safety concerns.