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Treatment of Anemia in Chronic Kidney Disease Strategies Based on Evidence

Philip A. Marsden, M.D. Anemia associated with chronic kidney disease and end-stage renal disease is due, in large part, to reduced production of renal erythropoietin and abnormalities in extracellular-fluid volume homeostasis.1 Moreover, anemia and disordered salt and water handling, which usually manifest as hypertension, predict cardiovascular and renal outcomes in patients with chronic kidney disease.2 The combination of early recognition and treatment to reduce increased blood pressure is known to improve outcomes. Thus, it is surprising, since highly effective therapies for anemia have been available for more than 20 years,3 that so little is known about whether the treatment of anemia has similar salutary effects. In this issue of the Journal, Pfeffer et al.4 report on a study that begins to address this knowledge gap. Several recombinant versions of human erythropoietin, also known as erythropoiesis-stimulating agents (ESAs), are now in clinical use. The use of these ESAs is highly prevalent in patients with end-stage renal disease, and hemoglobin levels and doses of ESAs both have increased over time.5 It was previously inferred that ESAs conferred a survival benefit among patients with chronic kidney disease who are not undergoing dialysis; this led to randomized, controlled trials lacking a placebo group.6,7 Paradoxically, and although ESAs are widely used, such trials raised concerns about the use of ESAs to normalize hemoglobin levels in patients with kidney disease and anemia. Pfeffer et al. describe the primary prespecified end-point results of the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) (ClinicalTrials.gov number, NCT00093015). This large, randomized, international, double-blind, placebo-controlled clinical trial was designed to determine whether the treatment of anemia with
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an ESA namely, darbepoetin alfa would reduce the risk of death, major cardiovascular events, and renal events among patients with chronic kidney disease, type 2 diabetes mellitus, and anemia.4 The trial randomly assigned 4038 patients with moderate iron-replete anemia who were from 623 sites in 24 countries. The median achieved hemoglobin concentrations were 12.5 g per deciliter (interquartile range, 12.0 to 12.8) in the patients who received darbepoetin alfa and 10.6 g per deciliter (interquartile range, 9.9 to 11.3) in the patients who received placebo. Events were documented in 9941 patient-years of follow-up, representing a median of 29.1 months per patient. Pfeffer et al. report no differences between the two groups in the overall rates of the primary end points (of death or a cardiovascular event or of death or end-stage renal disease). Of the patients assigned to darbepoetin alfa, 101 patients had a stroke, as compared with 53 patients assigned to placebo (hazard ratio, 1.92). The TREAT will be a key study in the treatment of patients with chronic kidney disease.4 Despite a reduction in red-cell transfusions and modest improvement in patient-reported fatigue, the current study does not confirm the findings of the earlier Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial (NCT00211120), which studied the use of epoetin alfa treatment to achieve two different target hemoglobin levels.7 Therefore, in retrospect, it is ironic that others had argued that because of its placebo group, the TREAT should be discontinued.8 The neutral effect on either primary composite outcome, together with the observed increased rates of stroke, were not predicted. Although patients with a cardiovascular event in the 3 months before randomization were excludnovember 19, 2009

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ed and the effect of darbepoetin alfa was independent of blood pressure, the risk of death or a major cardiovascular event was 31% in the entire cohort over the course of the trial a reminder of the incredible burden of cardiovascular disease in patients with chronic kidney disease. The results of the TREAT will influence practice guidelines and inform physicians, patients, and policymakers. In many of these stakeholders, the risk of stroke will outweigh the potential benefits of darbepoetin alfa. However, naysayers will not agree. The TREAT data may not be applicable to other populations, especially patients who are undergoing dialysis. Alternative dosing strategies, such as those to achieve unique rates of change, absolute levels of hemoglobin, or both, may alleviate the risk of stroke yet conserve the modest benefits observed in quality of life. Naysayers will point to differences in baseline characteristics of the patients as confounders in this study. The randomization procedure created a nominally significant imbalance in the baseline cardiovascular history, especially heart failure. Patients who received placebo had previously received ESA treatment; in fact, approximately 10% of randomly assigned patients had received an ESA 12 weeks or more before randomization. Moreover, during the study, 46% of patients assigned to placebo received at least one dose of darbepoetin alfa. Some people may argue that the investigators have discounted the differences between the two groups in the number of red-cell transfusions received; they may have a point. A substantial proportion of candidates for kidney transplantation continue to require periodic blood transfusions that carry a risk of allosensitization. Treating physicians and patients may interpret the TREAT as indicating a need to balance tradeoffs namely, the increased risk of stroke, venous thromboembolic events, and possibly deaths from cancer versus the perception of improved quality of life. A small but statistically significant increase in the Functional Assessment of Cancer TherapyFatigue score (and hence clinical improvement) was reported in the darbepoetin alfa group, as compared with the placebo group; this is a humble improvement at best.9 Like many treating physicians, I am sensitive to the quality of life versus the quantity of life. To quote the writer Robert Heinlein, The supreme irony of life is that hardly anyone gets out of it alive.
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One can anticipate substantive interest in subsequent thoughtful analyses of secondary outcomes, especially quality-of-life studies. Whether there were differences between the study groups in the rates of change in the estimated glomerular filtration rate will be of interest, as will the lower number of cardiovascular revascularizations in the darbepoetin alfa group than in the placebo group. In both of the earlier Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) (NCT00321919) and CHOIR studies, patients in the groups with high hemoglobin levels received more iron supplementation than did those in the groups with low hemoglobin levels.6,7 This difference raised concern that iron therapy might have confounded the study outcomes. The TREAT does not provide support for this concern, since more patients assigned to placebo received intravenous iron than did patients assigned to darbepoetin alfa. The study by Pfeffer et al. reinforces the idea that secondary outcomes and subgroup analyses are best viewed as hypothesis generating.4 Nephrology needs more studies such as the TREAT to test these hypotheses.
No potential conflict of interest relevant to this article was reported. This article (10.1056/NEJMe0909664) was published on October 30, 2009, at NEJM.org. From the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michaels Hospital; and the University of Toronto both in Toronto.
1. Donnelly S. Why is erythropoietin made in the kidney? The

kidney functions as a critmeter. Am J Kidney Dis 2001;38:415-25. 2. Shik J, Parfrey PS. The clinical epidemiology of cardiovascular disease in chronic kidney disease. Curr Opin Nephrol Hypertens 2005;14:550-7. 3. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: results of a combined phase I and II clinical trial. N Engl J Med 1987;316:73-8. 4. Pfeffer MA, Burdmann EA, Chen C-Y, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019-32. 5. Steinbrook R. Medicare and erythropoietin. N Engl J Med 2007;356:4-6. 6. Dreke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071-84. 7. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085-98. 8. Strippoli GF, Navaneethan SD, Craig JC. Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease. Cochrane Database Syst Rev 2006;4:CD003967. 9. Foley RN, Curtis BM, Parfrey PS. Erythropoietin therapy, hemoglobin targets, and quality of life in healthy hemodialysis patients: a randomized trial. Clin J Am Soc Nephrol 2009;4:726-33.
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