Correspondence
Pure Red-Cell Aplasia and Recombinant Erythropoietin
N Engl J Med 2002; 346:1584-1586May 16, 2002
- Article
To the Editor:
Casadevall et al. (Feb. 14 issue)1 reported 13 cases of pure red-cell aplasia and antierythropoietin antibodies in European patients who received recombinant erythropoietin (epoetin). Data submitted to the Food and Drug Administration suggest important differences among brands of epoetin with regard to recent increases in reports of pure red-cell aplasia.
Epogen, Procrit, and Eprex are brands of epoetin licensed in the United States. Epogen and Procrit are identical formulations of the same active ingredient (epoetin) distributed only in the United States. Eprex is a different product, which is distributed only outside the United States. For all biologic agents licensed in the United States, postlicensure surveillance is conducted through the MedWatch system of the Food and Drug Administration,2 which collects reports of adverse events among persons within and outside the United States.
For the period from July 1997 through December 2001, 82 cases of pure red-cell aplasia after the administration of epoetin were reported. Four patients received Epogen, none received Procrit, and 78 received Eprex (these included the patients reported by Casadevall et al.). Patients who received Eprex increased sharply in number throughout this period (Figure 1Figure 1
Pure Red-Cell Aplasia among Recipients of Epoetin According to Brand, as Reported to the Food and Drug Administration.). The distribution of Eprex increased from 16.8 million prefilled syringes and vials in 1997 to 30.9 million in 2001; corresponding figures for Epogen and Procrit combined were 23.1 million and 35.1 million in 1997 and 2001, respectively. Therefore, the amount of drug distributed appears not to account for differences among the brands in the number of cases of pure red-cell aplasia reported.The median age of patients with pure red-cell aplasia was 61 years, and 66 percent were men. The median duration of treatment with epoetin to the time to diagnosis of pure red-cell aplasia was seven months (range, one month to five years). All patients received epoetin for anemia associated with chronic renal failure.
MedWatch, a passive-surveillance system, probably underestimates the true frequency of pure red-cell aplasia. (Information on submitting MedWatch reports is available at http://www.fda.gov/medwatch or 1-800-332-1088.) Although brands distributed in the United States appear not to be linked to recent increases in the incidence of pure red-cell aplasia associated with epoetin treatment, we share the concern of Casadevall et al. about all epoetin products and will continue to monitor such reports carefully.
2 ReferencesSharon K. Gershon, Pharm.D.
Harvey Luksenburg, M.D.
Timothy R. Coté, M.D., M.P.H.
M. Miles Braun, M.D., M.P.H.
Food and Drug Administration, Rockville, MD 20852
braunm@cber.fda. gov 1
Casadevall N ,Nataf J ,Viron B , et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002;346:469-475
Full Text | Web of Science | Medline2
Kessler DA . Introducing MEDWatch: a new approach to reporting medication and device adverse effects and product problems. JAMA 1993;269:2765-2768
CrossRef | Web of Science | Medline
To the Editor:
In his editorial (Feb. 14 issue)1 on the adverse effects of therapy with epoetin, Bunn thoughtfully balances the low risk of development of red-cell aplasia secondary to the formation of antierythropoietin antibodies against the substantial benefit of epoetin therapy for anemia. Although we agree that the benefit of epoetin therapy outweighs the associated risks, we take issue with Bunn's statement that erythropoietin has “no clinically significant effects on nonhematopoietic cells.” Many nonerythroid tissues, including endothelial cells, smooth-muscle cells, and neurons, express erythropoietin and the erythropoietin receptor. Although some of these effects are probably beneficial, such as the neuroprotective effect of epoetin,2 others may be detrimental.
Several lines of evidence have shown that therapy with epoetin can result in hypertension, accelerated atherosclerosis, and thrombosis in patients receiving dialysis.3 These complications were independent of the hematocrit; thus, the pathogenic mechanism was different from hypervolemia-induced or hyperviscosity-induced hypertension or thrombosis. We have recently reported an increased frequency of vascular diseases among patients with primary familial and congenital polycythemia caused by gain-of-function mutations of the erythropoietin receptor.4,5 Development of these vascular complications was independent of either the hematocrit or the presence of common risk factors associated with the early onset of vascular diseases. In conclusion, we believe there is sufficient evidence that long-term administration of epoetin or dysregulation of the erythropoietin–erythropoietin receptor signaling pathway can be associated with clinically symptomatic vascular diseases such as those seen in patients receiving dialysis or patients with primary familial and congenital polycythemia.
5 ReferencesLubomir Sokol, M.D., Ph.D.
University of South Florida, Tampa, FL 33612Josef T. Prchal, M.D.
Baylor College of Medicine, Houston, TX 33612
jprchal@bcm.tmc. edu 1
Bunn HF . Drug-induced autoimmune red-cell aplasia. N Engl J Med 2002;346:522-523
Full Text | Web of Science | Medline2
Celik M ,Gokmen N ,Erbayraktar S , et al. Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci U S A 2002;99:2258-2263
CrossRef | Web of Science | Medline3
Vaziri ND . Mechanism of erythropoietin-induced hypertension. Am J Kidney Dis 1999;33:821-828
CrossRef | Web of Science | Medline4
Prchal JT ,Semenza GL ,Prchal JF ,Sokol L . Primary polycythemia. Science 1995;268:1831-1832
CrossRef | Web of Science | Medline5
Sokol L ,Kralovics R ,Hubbell G ,Prchal JT . A novel erythropoietin receptor mutation associated with primary familial polycythemia and severe cardiovascular and peripheral vascular disease. Blood 2001;98:225a-225a abstract.
Web of Science
Author/Editor Response
The authors reply:
To the Editor: Gershon et al. support our conclusions that Eprex is involved in the recent occurrence of pure red-cell aplasia in patients with chronic renal failure who are treated with recombinant erythropoietin. Since the publication of our paper, we have detected neutralizing antierythropoietin antibodies in 19 more patients with chronic renal failure.
Overall, we have detected neutralizing antierythropoietin antibodies in serum from 39 patients referred to our laboratory: 26 from France, 6 from the United Kingdom, 4 from Australia, 2 from Switzerland, and 1 from Canada. Of these 39 patients, 36 were receiving Eprex at the time of the onset of anemia, 2 received Neorecormon exclusively, and 1 had been receiving Eprex and was switched to Neorecormon one month before the diagnosis of anemia.
Among the 82 cases of pure red-cell aplasia reported by Gershon et al., the presence of antierythropoietin antibodies was not demonstrated in all the patients. Although the presence of neutralizing antibodies is likely, it should be demonstrated if immunosuppressive treatment is under consideration.
Nicole Casadevall, M.D.
Hôtel-Dieu, 75004 Paris, France
nicole.casadevall@htd. ap-hop-paris. fr Patrick Mayeux, Ph.D.
Institut de Génétique Moléculaire, 75014 Paris, FranceAuthor/Editor Response
The editorialist replies:
To the Editor: Sokol and Prchal take issue with my statement that erythropoietin has “no clinically significant effects on nonhematopoietic cells.” In support of possible adverse effects on blood pressure, atherosclerosis, and thrombosis, they cite a thought-provoking review that focuses on in vitro and in vivo effects of epoetin, along with correspondence and an abstract describing families with mutations of the erythropoietin receptor. Several million patients have been treated with epoetin. Its efficacy and safety have been truly remarkable. Nevertheless, there is understandable concern about whether epoetin might have clinically significant adverse effects on the cardiovascular system.
Accelerated atherosclerosis was well known to be a major cause of death among patients with end-stage renal disease before epoetin therapy became available in 1986. The treatment of patients receiving dialysis with epoetin has resulted in improved cardiac function, cardiac dimensions, and exercise capacity. It is difficult to assess the effects of epoetin per se, independent of its effect on increasing red-cell mass. Besarab et al.1 compared 618 patients receiving relatively high doses of epoetin to achieve a mean hematocrit of 42 with 615 patients receiving lower doses sufficient to maintain a mean hematocrit of 30. In these patients, there was no significant correlation between the dose of epoetin and blood pressure, thrombosis of venous-access sites, or mortality.
I am unaware of any reports of adverse cardiovascular effects when epoetin has been administered to patients with anemia who do not have renal disease. In like manner, patients with severe chronic anemias often maintain, over several decades, markedly elevated levels of endogenous erythropoietin — higher than what is achieved with subcutaneous epoetin therapy — and yet do not appear to be at increased risk for atherosclerosis, hypertension, or thrombosis. Thus, if either therapeutic or endogenous erythropoietin affects the cardiovascular system adversely, the effects are likely to be rather subtle and of questionable significance.
1 ReferencesH. Franklin Bunn, M.D.
Harvard Medical School, Boston, MA 02115
bunn@calvin.bwh. harvard. 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 | Medline
- Citing Articles (47)
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