Correspondence
Chronic Kidney Disease, Anemia, and Epoetin
N Engl J Med 2007; 356:956-959March 1, 2007
- Article
To the Editor:
In their report on the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial, which evaluated the use of recombinant erythropoietin (epoetin alfa) to treat anemia in patients with chronic kidney disease, Singh et al. (Nov. 16 issue)1 make no mention of heme iron polypeptide, an oral iron preparation. It is thought that free-radical–induced oxidative stress from intravenous iron may be responsible for tissue damage in patients with chronic kidney disease. Data in Table 1 of the article suggest that patients with a target hemoglobin level of 11.3 g per deciliter (the low-hemoglobin group) received less intravenous iron than did patients with a target hemoglobin level of 13.5 g per deciliter (the high-hemoglobin group); the oral iron intake was similar in the two groups. Oral iron administration has fewer free-radical issues than does intravenous iron therapy. Patients in the low-hemoglobin group had fewer adverse events than those in the high-hemoglobin group.
Nissenson et al.2 reported data suggesting that heme iron polypeptide is well absorbed, maintains hemoglobin levels in patients undergoing hemodialysis, and has an improved profile of gastrointestinal side effects. Both studies reported a reduction in the dose of epoetin alfa required to maintain iron levels. The potential reduction in oxidative stress with the use of an oral iron preparation such as heme iron polypeptide and the potential cost savings associated with the use of less epoetin alfa warrant consideration and research, particularly in patients with chronic kidney disease.
2 ReferencesDavid S. Riley, M.D.
University of New Mexico School of Medicine, Santa Fe, NM 87508
dsrileymd@earthlink.net 1
Singh AK ,Szczech L ,Tang KL , et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085-2098
Full Text | Web of Science | Medline2
Nissenson AR ,Berns JS ,Sakiewicz P , et al. Clinical evaluation of heme iron polypeptide: sustaining a response to rHuEPO in hemodialysis patients. Am J Kidney Dis 2003;42:325-330
CrossRef | Web of Science | Medline
To the Editor:
Singh et al. report that a higher target level of hemoglobin in patients with chronic kidney disease was associated with an increased risk with no benefit in the quality of life. However, the epoetin-replacement protocol was not physiologic. Epoetin alfa was administered subcutaneously once weekly and was modified in patients with stable hemoglobin to once every 2 weeks. Given a mean half-life of 20 hours for epoetin alfa,1 such a protocol would have resulted in a sharp rise in serum epoetin levels, followed by a decline to undetectable levels. Fluctuating epoetin levels might have had two main effects. First, they might have accentuated hemoglobin cycling. Neocytolysis starts within 24 hours after intravenous injection of epoetin.2 Weekly administration of large doses of epoetin alfa subcutaneously might have accentuated such a phenomenon. Second, intermittent exposure to high epoetin levels, particularly in the high-hemoglobin group, might result in disordered cardiac growth signals,3 thereby contributing to the adverse outcomes in such a group. Designing similar studies with the use of more physiologic epoetin replacement therapy, such as longer-acting preparations, might answer these questions.
Ashraf Mikhail, M.Sc., F.R.C.P.
Morriston Hospital, Swansea SA6 6NL, United Kingdom
ashraf.mikhail@swansea-tr. wales. nhs. uk David Goldsmith, M.A., F.R.C.P.
Guy's Hospital, London SE1 9RT, United KingdomDr. Mikhail reports receiving honoraria from Roche, Abbott, Shire, and Astellas; and Dr. Goldsmith, honoraria from Roche, Shire, and Astellas.
3 References1
Macdougall IC ,Eckardt KU . Novel strategies for stimulating erythropoiesis and potential new treatments for anaemia. Lancet 2006;368:947-953
CrossRef | Web of Science | Medline2
Rice L ,Alfrey CP ,Driscoll T ,Whitley CE ,Hachey DL ,Suki W . Neocytolysis contributes to the anemia of renal disease. Am J Kidney Dis 1999;33:59-62
CrossRef | Web of Science | Medline3
Fishbane S . Recombinant human erythropoietin: has treatment reached its full potential? Semin Dial 2006;19:1-4
CrossRef | Web of Science | Medline
To the Editor:
The study by Singh et al. showed an increase in cardiovascular events and deaths with normalization of hemoglobin levels in patients with chronic kidney disease. The Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial, reported by Drüeke et al.1 in the same issue, showed no significant difference in adverse events with such treatment.
However, in a nonrandomized trial, we found that treatment with erythropoietin in patients with chronic kidney disease, anemia, and left ventricular hypertrophy was associated with a decrease in prevalent left ventricular hypertrophy and a decrease in the left-ventricular-mass index during a 6-month period; these changes were not explained by changes in hemoglobin levels.2 Similarly, a subgroup analysis in a randomized trial showed that patients with left ventricular hypertrophy had a reduction in the left-ventricular-mass index during a 2-year period while they were receiving recombinant erythropoietin.3 Therefore, in the CREATE trial, it would be useful to know the proportion of patients with left ventricular hypertrophy at entry and to determine whether in this subgroup there were differences in left ventricular echocardiographic measures, cardiovascular events, and mortality between patients who received erythropoietin early and those who received it later.
Alan S. Go, M.D.
Kaiser Permanente of Northern California, Oakland, CA 94612
alan.s. go@kp. org Juan Carlos Ayus, M.D.
Texas Diabetes Institute, San Antonio, TX 78207Dr. Go reports receiving research support from Amgen.
3 References1
Drueke TB ,Locatelli F ,Clyne N , et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071-2084
Full Text | Web of Science | Medline2
Ayus JC ,Go AS ,Valderrabano F , et al. Effects of erythropoietin on left ventricular hypertrophy in adults with severe chronic renal failure and hemoglobin <10 g/dL. Kidney Int 2005;68:788-795
CrossRef | Web of Science | Medline3
Roger SD ,McMahon LP ,Clarkson A , et al. Effects of early and late intervention with epoetin alpha on left ventricular mass among patients with chronic kidney disease (stage 3 or 4): results of a randomized clinical trial. J Am Soc Nephrol 2004;15:148-156
CrossRef | Web of Science | Medline
To the Editor:
In the study by Singh et al., the higher rate of cardiovascular events among patients with chronic kidney disease who were in the high-hemoglobin group parallels the outcome reported in patients with end-stage renal disease.1 This increased risk of cardiovascular events is probably not due to the higher hemoglobin target, since the mean hemoglobin level never exceeded the target level of 13.5 g per deciliter, but may be secondary to the role of erythropoietin in inducing chronic inflammation and inhibiting fibrinolysis.2 In addition, erythropoietin triggers signaling pathways in endothelial cells, increasing their thrombogenicity by inducing expression of tissue factor.3 However, the authors do not report the rates of venous thromboembolism in the two groups. Erythropoietin use, especially in patients with cancer who are undergoing chemotherapy, has been implicated in an increased risk of venous thromboembolism.4 It is important to know whether normalization of hemoglobin levels with higher doses of erythropoietin increased the risk of venous thromboembolism in this population of patients.
4 ReferencesAneel A. Ashrani, M.B., B.S.
S. Vincent Rajkumar, M.D.
Mayo Clinic College of Medicine, Rochester, MN 55905
ashrani.aneel@mayo. edu 1
Besarab A ,Bolton WK ,Browne JK , et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998;339:584-590
Full Text | Web of Science | Medline2
Tobu M ,Iqbal O ,Fareed D , et al. Erythropoietin-induced thrombosis as a result of increased inflammation and thrombin activatable fibrinolytic inhibitor. Clin Appl Thromb Hemost 2004;10:225-232
CrossRef | Web of Science | Medline3
Fuste B ,Serradell M ,Escolar G , et al. Erythropoietin triggers a signaling pathway in endothelial cells and increases the thrombogenicity of their extracellular matrices in vitro. Thromb Haemost 2002;88:678-685
Web of Science | Medline4
Bohlius J ,Wilson J ,Seidenfeld J , et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006;98:708-714
CrossRef | Web of Science | Medline
To the Editor:
In the study by Singh et al., the starting dose of epoetin alfa was 10,000 units per week for 3 consecutive weeks, regardless of weight or baseline hemoglobin level. Subsequent doses of epoetin alfa were administered on the basis of a prespecified algorithm. Against the tested hypothesis, an achieved mean increase in the hemoglobin level of 2.5 g per deciliter in the high-hemoglobin group was accompanied by increased composite events and greater risk. Did such a high starting dose of epoetin alfa contribute to the negative findings? The authors do not outline the rationale for using this dose versus the lower doses recommended in the product information.1 How was this dose selected? Was it chosen by the investigators or by the sponsor? Treatment regimens have changed, with newer erythropoiesis-stimulating agents that have longer durations of action and extended intervals of administration (now up to monthly).2,3 Could the decision by the CHOIR investigators to use high-dose epoetin weekly rather than every other week reflect an attempt to increase acceptability in a competitive market?
Simon D. Roger, M.D.
Gosford Hospital, Gosford 2250, Australia
sroger@nsccahs.health. nsw. gov. au Dr. Roger reports serving on advisory boards for and receiving funds from Amgen, Janssen-Cilag, and Hoffmann–La Roche.
3 References1
Procrit (epoetin alfa): full prescribing information. Thousand Oaks, CA: Amgen, 2006 (package insert). (Accessed February 8, 2007, at http://www.procrit.com/common/prescribing_information/PROCRIT/PDF/ProcritBooklet.pdf.)
2
Ling B ,Walczyk M ,Agarwal A ,Carroll W ,Liu W ,Brenner R . Darbepoetin alfa administered once monthly maintains hemoglobin concentrations in patients with chronic kidney disease. Clin Nephrol 2005;63:327-334
Web of Science | Medline3
Sulowicz W ,Locatelli F ,Balla J , et al. Subcutaneous (SC) C.E.R.A. (Continuous Erythropoietin Receptor Activator) administered once every two weeks or once monthly maintains haemoglobin (Hb) levels in patients with chronic kidney disease (CKD) on dialysis. Nephrol Dial Transplant 2006;21:Suppl 4:iv-156
Author/Editor Response
Riley suggests that iron therapy is an important adjunct to the management of anemia associated with chronic kidney disease. During the CHOIR trial, iron supplementation was provided to support erythropoiesis. Most iron supplementation was administered orally, as shown in Table 1 of our report. At baseline, 30.9% of patients in the high-hemoglobin group and 29.2% in the low-hemoglobin group received iron supplementation. During the study, the overall use of iron increased to 52.0% in the high-hemoglobin group and 48.3% in the low-hemoglobin group.
Mikhail and Goldsmith argue that hemoglobin cycling among patients in the CHOIR trial could have affected outcomes. However, the phenomenon of hemoglobin cycling has not been well characterized in patients with chronic kidney disease who are not undergoing dialysis. It is also unclear whether longer-acting erythropoiesis-stimulating agents are associated with less hemoglobin cycling and lower rates of neocytolysis. The CHOIR study was not designed to determine the differential roles of the hemoglobin level and the dose of epoetin in determining the outcome. Therefore, we agree that additional studies will be required.
Ashrani and Rajkumar ask whether there was a higher rate of thrombotic vascular events among patients in the high-hemoglobin group. These events are reported in Table 3 of our article. There were 126 thrombotic vascular events of any type in the high-hemoglobin group (18.4%) and 120 such events in the low-hemoglobin group (17.4%, P=0.65). There were 74 clinically relevant thrombotic vascular events in the high-hemoglobin group (10.8%) and 82 such events in the low-hemoglobin group (11.9%, P=0.51). Thus, there was no significant difference in the rate of thrombotic vascular events between the two groups.
Roger questions the dose of epoetin used in the CHOIR study and the motivations behind the choice of the initial dose. It is clear that doses of erythropoietin that were used in several studies conducted outside the United States, including the CREATE trial and others,1 were lower than those used in the CHOIR study. The reasons for international differences in prescribing patterns for erythropoietin remain unclear. The initial dose of epoetin and the dosing algorithm for the CHOIR study were developed jointly by the principal investigators and the sponsor and were the subject of much deliberation by the study leaders. It is also notable that the mean epoetin dose required in the CHOIR study among patients in the high-hemoglobin group was higher than the initial dose of 10,000 units per week. The chosen dose was selected to reflect dosing strategies in use in the United States at the time of the initiation of the study and reflected doses used in an earlier U.S.-based study.2
2 ReferencesAjay K. Singh, M.B., B.S.
Brigham and Women's Hospital, Boston, MA 02115
asingh@partners.org Marsha Wolfson, M.D.
Ortho Biotech Clinical Affairs, Bridgewater, NJ 08807Donal Reddan, M.B., B.S.
National University of Ireland, Galway, Ireland1
Roger SD ,McMahon LP ,Clarkson A , et al. Effects of early and late intervention with epoetin alpha on left ventricular mass among patients with chronic kidney disease (stage 3 or 4): results of a randomized clinical trial. J Am Soc Nephrol 2004;15:148-156
CrossRef | Web of Science | Medline2
Provenzano R ,Garcia-Mayol L ,Suchinda P , et al. Once-weekly epoetin alfa for treating the anemia of chronic kidney disease. Clin Nephrol 2004;61:392-405
Web of Science | Medline
Author/Editor Response
Go and Ayus ask what percentage of patients in the CREATE trial had left ventricular hypertrophy at baseline and whether there were possible differences in outcomes in this subgroup with respect to responses to early correction of anemia, as compared with late correction. Approximately half of our patients had an increase in the left-ventricular-mass index at baseline, as compared with normal values, although the increase was predominantly moderate.1 We observed a decline in the mean left-ventricular-mass index over time, as Go and Ayus and their colleagues reported in their study.2 However, in the CREATE study, the decline was observed in both treatment groups, indicating that the results of uncontrolled within-patient comparisons should be interpreted with caution. It must also be noted that in the study by Ayus et al., baseline hemoglobin levels were lower (9.1 g per deciliter) than in the group with standard anemia correction in the CREATE trial (a baseline of 11.6 g per deciliter, with values below 10.5 g per deciliter triggering epoetin treatment). If only the subgroup of patients in the CREATE trial who had an increase in the left-ventricular-mass index is considered, there was no difference in the primary end point of combined cardiovascular events between the two treatment groups, a finding that parallels the results for the entire study population.
2 ReferencesTilman B. Drüeke, M.D.
Necker Hospital, F-75015 Paris, France
drueke@necker.fr Kai-Uwe Eckardt, M.D.
Universitätsklinikum Erlangen, D-91054 Erlangen, GermanyArmin Scherhag, M.D.
Hoffmann–La Roche, CH-4070 Basel, Switzerland1
Eckardt K-U ,Macdougall I ,Locatelli F , et al. Effects of epoetin beta on left ventricular mass in patients with chronic kidney disease: echocardiographic results from the CREATE study. J Am Soc Nephrol 2005;16:37A-37A2
Ayus JC ,Go AS ,Valderrabano F , et al. Effects of erythropoietin on left ventricular hypertrophy in adults with severe chronic renal failure and hemoglobin <10 g/dL. Kidney Int 2005;68:788-795
CrossRef | Web of Science | Medline
