Equivalent Doses Matter, Rather Than Types

We read the article by Sakaguchi et al.¹ with much interest, it raised important issues in clinical practice. However, we would like to point out a specific issue in the management of anemia in Japan that might be misleading to readers elsewhere. The maximum dose allowed by the package insert differs considerably across the four types of erythropoiesis-stimulating agents (ESAs) available in Japan. The maximum allowed dose of epoetin α/β/κ is 9000 IU/wk, whereas those of darbepoetin and epoetin β pegol are 180 µg/wk and 250 µg/2 wk, respectively. In Sakaguchi et al.’s study, the dosing of each ESA seems to follow these regulations; the ESA doses in the highest tertile were 7618±2071 IU/wk, 56.1±26.3 µg/wk, 181.6±65.4 µg/mo, and 7841±2144 IU/wk, for epoetin α/β, darbepoetin α, epoetin β pegol, and epoetin κ, respectively, as shown in their Supplemental Table 4. Conversion ratios from epoetin to ESAs with longer t_1/2s have been debated because the ratios can vary according to the patient’s condition or even the time course of ESA therapy. For example, the conversion ratio from epoetin to darbepoetin is reported to be 200–400 IU/µg in many studies.^2,3 Even when adopting 200 IU/µg, which is an underestimation of darbepoetin activity, 56.1 µg of darbepoetin would have action equivalent to 11,220 IU of epoetin, which is a modest estimate. Yet, by adopting a higher conversion ratio, the equivalent dose would be much larger. A similar issue is also true for epoetin β pegol. We appreciate the authors’ efforts to eliminate bias, which is inevitable in an observational study, but the fact that differences in mortality by ESA type increased in a dose-dependent manner clearly shows that it was the higher doses of ESA that were associated with worse survival and not ESA type per se. ESA hyporesponsiveness is well known to be associated with worse survival.⁴ The outcomes for the entire population might have been swayed by the presence of patients requiring higher equivalent doses of long-acting ESAs, which in Japan can be prescribed at higher doses than epoetin. We therefore consider that the title of the article is misleading, and that it was in fact a higher dose of long-acting ESAs that was associated with worse survival. Elucidating the true association between ESA type and mortality is reserved for future prospective studies with between-group adjustments for doses of ESA.

Disclosures

Dr. Hanafusa and Prof. Tsuchiya have received lecture fees from Kyowa Hakko Kirin, Chugai Pharmaceutical, and Kissei Pharmaceutical. Dr. Hanafusa is an academic consultant for the Dialysis Outcomes and Practice Pattern Study program and is receiving fees from Kyowa Hakko Kirin. However, these have no bearing or influence on the content of this article.