n engl j med 361;21 nejm.org november 19, 2009 2089

e d i t o r i a l s

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

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 homeo-stasis.1 Moreover, anemia and disordered salt and water handling, which usually manifest as hyper-tension, predict cardiovascular and renal outcomes in patients with chronic kidney disease.2 The com-bination of early recognition and treatment to re-duce increased blood pressure is known to im-prove 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 sim-ilar salutary effects. In this issue of the Journal, Pfeffer et al.4 report on a study that begins to ad-dress this knowledge gap.

Several recombinant versions of human eryth-ropoietin, also known as erythropoiesis-stimulat-ing 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 kid-ney disease who are not undergoing dialysis; this led to randomized, controlled trials lacking a pla-cebo group.6,7 Para doxically, 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 Cardio-vascular 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

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 treat-ment 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 epoe-tin 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 discontin-ued.8 The neutral effect on either primary com-posite outcome, together with the observed in-creased rates of stroke, were not predicted. Although patients with a cardiovascular event in the 3 months before randomization were exclud-

The New England Journal of Medicine Downloaded from www.nejm.org on November 18, 2010. For personal use only. No other uses without permission.

Copyright © 2009 Massachusetts Medical Society. All rights reserved.

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 361;21 nejm.org november 19, 20092090

ed and the effect of darbepoetin alfa was indepen-dent of blood pressure, the risk of death or a ma-jor 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 prac-tice guidelines and inform physicians, patients, and policymakers. In many of these stakeholders, the risk of stroke will outweigh the potential ben-efits of darbepoetin alfa. However, naysayers will not agree.

The TREAT data may not be applicable to other populations, especially patients who are under-going dialysis. Alternative dosing strategies, such as those to achieve unique rates of change, ab-solute levels of hemoglobin, or both, may alleviate the risk of stroke yet conserve the modest bene-fits observed in quality of life. Naysayers will point to differences in baseline characteristics of the patients as confounders in this study. The ran-domization procedure created a nominally signifi-cant imbalance in the baseline cardiovascular history, especially heart failure. Patients who re-ceived placebo had previously received ESA treat-ment; 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 re-ceived at least one dose of darbepoetin alfa. Some people may argue that the investigators have dis-counted 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 trade-offs — namely, the increased risk of stroke, ve-nous 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 Therapy–Fatigue score (and hence clinical im-provement) 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.”

One can anticipate substantive interest in sub-sequent thoughtful analyses of secondary out-comes, especially quality-of-life studies. Whether there were differences between the study groups in the rates of change in the estimated glomeru-lar filtration rate will be of interest, as will the lower number of cardiovascular revasculariza-tions in the darbepoetin alfa group than in the placebo group. In both of the earlier Cardiovas-cular 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 supplemen-tation than did those in the groups with low he-moglobin 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 hypoth-esis generating.4 Nephrology needs more studies such as the TREAT to test these hypotheses.

No potential conflict of interest relevant to this article was re-ported.

This article (10.1056/NEJMe0909664) was published on Octo-ber 30, 2009, at NEJM.org.

From the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael’s Hospital; and the University of Toronto — both in Toronto.

Donnelly S. Why is erythropoietin made in the kidney? The 1. kidney functions as a critmeter. Am J Kidney Dis 2001;38:415-25.

Shik J, Parfrey PS. The clinical epidemiology of cardiovascu-2. lar disease in chronic kidney disease. Curr Opin Nephrol Hyper-tens 2005;14:550-7.

Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson 3. 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.

Pfeffer MA, Burdmann EA, Chen C-Y, et al. A trial of darbe-4. poetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019-32.

Steinbrook R. Medicare and erythropoietin. N Engl J Med 5. 2007;356:4-6.

Drüeke TB, Locatelli F, Clyne N, et al. Normalization of he-6. moglobin level in patients with chronic kidney disease and ane-mia. N Engl J Med 2006;355:2071-84.

Singh AK, Szczech L, Tang KL, et al. Correction of anemia 7. with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085-98.

Strippoli GF, Navaneethan SD, Craig JC. Haemoglobin and 8. haematocrit targets for the anaemia of chronic kidney disease. Cochrane Database Syst Rev 2006;4:CD003967.

Foley RN, Curtis BM, Parfrey PS. Erythropoietin therapy, he-9. moglobin targets, and quality of life in healthy hemodialysis pa-tients: a randomized trial. Clin J Am Soc Nephrol 2009;4:726-33.Copyright © 2009 Massachusetts Medical Society.

The New England Journal of Medicine Downloaded from www.nejm.org on November 18, 2010. For personal use only. No other uses without permission.

Copyright © 2009 Massachusetts Medical Society. All rights reserved.