Editorial
Anemia Treatment in Patients with Chronic Kidney Disease
N Engl J Med 2013; 368:387-389January 24, 2013DOI: 10.1056/NEJMe1215043
- Article
Anemia develops in most persons with progressive chronic kidney disease. When it becomes severe, the administration of erythropoiesis-stimulating agents (ESAs) is generally required, along with the repletion of iron stores and the correction of other causes of anemia. The introduction of ESAs 30 years ago markedly improved the lives of many patients with chronic kidney disease, who until then had severe, often transfusion-dependent anemia.1
Two types of recombinant human erythropoietin (epoetin alfa and epoetin beta) have been available since ESAs first came into use; both types are highly effective but short-acting (approved for dosing three times a week). Subsequently, two second-generation ESAs with an extended duration of action were developed — darbepoetin alfa, which has an altered glycosylation pattern, and a continuous erythropoietin-receptor activator called methoxy polyethylene glycol-epoetin beta (PEG-EPO) (Mircera, Hoffmann–La Roche), which contains a polyethylene-glycol moiety. Darbepoetin alfa is approved for dosing every 2 weeks worldwide, and PEG-EPO for dosing once a month in Europe. In addition to the original formulations, biologically similar and “copy” ESAs have been developed. In all cases, the production of first- and second-generation ESAs involves the use of complex recombinant DNA technology and mammalian cell lines. The Kidney Disease: Improving Global Outcomes (KDIGO) work group recently suggested that only ESAs that have been formally approved by an independent regulatory agency (level of evidence 2D) should be prescribed, a recommendation created to avoid potentially serious and unanticipated adverse events.2
On the basis of observational studies conducted during the early days of erythropoietin usage, clinicians aimed to normalize hemoglobin levels in patients with chronic kidney disease. However, randomized, controlled trials later showed that partial correction of anemia was preferable to complete correction, a practice aimed at reducing the risk of cardiovascular events and other potential adverse events. Subsequently, KDIGO suggested that in general, ESAs should not be used to maintain hemoglobin levels above 11.5 g per deciliter in adult patients with chronic kidney disease (level of evidence 2C).2 However, it is unclear whether the negative effects of the complete correction of anemia are due primarily to high hemoglobin levels per se, to excessive ESA doses, or to both.3
In the past decade, several new approaches to the correction of anemia have been tried, including erythropoietin gene therapy,4 the stabilization of hypoxia-inducible factor,5 and peptide-based erythropoietic agents, such as the dimeric pegylated peptide, peginesatide.6 Such peptide-based erythropoietic agents are not homologous with erythropoietin and therefore exhibit no antibody cross-activity. This means that patients with transfusion-dependent chronic kidney disease with antibody-mediated pure red-cell aplasia may be “rescued” upon treatment with drugs of this class.7
In this issue of the Journal, Macdougall et al.8 and Fishbane et al.9 report the results of four event-driven, randomized, controlled, open-label trials that compared the efficacy and safety of peginesatide with standard ESA therapy. In one pair of studies, PEARL 1 and 2 (Peginesatide for the Correction of Anemia in Patients with Chronic Renal Failure Not on Dialysis and Not Receiving Treatment with Erythropoiesis-Stimulating Agents), anemic patients with chronic kidney disease stages 3, 4, or 5 who were not yet receiving hemodialysis were treated with peginesatide once per month or darbepoetin alfa once every 2 weeks. In the other pair of studies, EMERALD 1 and 2 (Efficacy and Safety of Peginesatide for the Maintenance Treatment of Anemia in Patients with Chronic Renal Failure Who Were Receiving Hemodialysis and Were Previously Treated with Epoetin), patients with anemia who had been undergoing hemodialysis received either peginesatide once per month or epoetin alfa one to three times per week. In both articles, peginesatide is shown to be noninferior to standard ESAs in increasing and maintaining hemoglobin levels within a target range of 11 to 12 g per deciliter (the PEARL studies) or 10 to 12 g per deciliter (the EMERALD studies). However, although the cardiovascular composite safety end points for the groups receiving peginesatide and the groups receiving standard ESAs were similar in the patients receiving hemodialysis, the hazard ratio with peginesatide for the patients not receiving hemodialysis was 1.32 (95% confidence interval, 0.97 to 1.81), and there was also an increased incidence of sudden death, unstable angina, and arrhythmia among these patients. Moreover, the rate of acute kidney failure and back pain of unknown mechanism was twice as high among the patients receiving peginesatide and not undergoing hemodialysis.
There is no clear explanation for these unexpected adverse events. Baseline differences between the groups receiving hemodialysis and the groups not receiving hemodialysis included older age and more patients with a history of cardiovascular disease among the latter groups, although fewer patients in the latter groups had a history of diabetes and fewer were black. Probably more important are the facts that in the PEARL studies, which concerned patients not receiving hemodialysis, the groups treated with peginesatide were slightly older and had higher rates of diabetes and cardiovascular disease than the group treated with darbepoetin. Although the investigators adjusted for baseline differences and other covariates and performed sensitivity analyses, which reduced the hazard ratio, these adjustments did not fully account for the harmful effects. The target levels for hemoglobin and the dosage of peginesatide cannot be held responsible, since the target ranges were quite close and higher doses of peginesatide were used in the hemodialysis population, which was larger, without apparent harm. There also was no evidence of a difference in iron status or inflammatory state between the groups receiving hemodialysis and the groups not receiving hemodialysis. Although the ESA comparator was different — darbepoetin in the PEARL studies versus epoetin alfa in the EMERALD studies, there is no known difference in safety profile between these two compounds.2 Clearly, the underlying cause for the observed increase in composite safety end-point events requires further study, including examination of the potential for cardiovascular or systemic peginesatide toxicity in experimental models of chronic kidney failure.
Where do we go from here? Peginesatide can be used for anemia correction in patients undergoing hemodialysis, in which case its efficacy profile is similar to the profiles of established ESAs, but concerns remain about its safety in patients not receiving hemodialysis. Peginesatide has been recently approved in the United States for patients undergoing hemodialysis, but not for patients who are not receiving hemodialysis. Is there any advantage of using peginesatide rather than the existing ESAs? Less frequent dosing may be an advantage under certain circumstances. Peginesatide does not induce pure red-cell aplasia, but antibody development against this compound, although infrequent, may reduce its efficacy. As with any new class of drugs, prolonged experience and monitoring are necessary. Another important issue is cost. At a time when the prescription of much cheaper, biologically similar ESAs is steadily growing outside the United States,10 expensive new drugs will be competitive only if proven to result in better patient outcomes. Such outcomes remain to be demonstrated for peginesatide and other new types of ESAs that are in development.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
Source Information
From the Unité 1088 de l'Inserm, UFR de Médecine et de Pharmacie, Université de Picardie Jules Verne, Amiens, France.
- References
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Macdougall IC . New anemia therapies: translating novel strategies from bench to bedside. Am J Kidney Dis 2012;59:444-451
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Macdougall IC ,Rossert J ,Casadevall N , et al. A peptide-based erythropoietin-receptor agonist for pure red-cell aplasia. N Engl J Med 2009;361:1848-1855
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Macdougall IC ,Provenzano R ,Sharma A , et al. Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis. N Engl J Med 2013;368:320-332
Full Text | Web of Science | Medline9
Fishbane S ,Schiller B ,Locatelli F , et al. Peginesatide in patients with anemia undergoing hemodialysis. N Engl J Med 2013;368:307-319
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- Citing Articles (1)
Citing Articles
1
Holger Schmid. (2013) Peginesatide for the treatment of renal disease-induced anemia. Expert Opinion on Pharmacotherapy 14:7, 937-948
