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Long-acting anemia drugs show higher risk of mortality
A study of almost 195,000 patients on hemodialysis in Japan showed a higher risk of mortality among those treated with longer-acting anemia drugs compared to those treated with shorter-acting drugs.
“Despite the widespread use of erythropoietin-stimulating agents (ESAs) to treat anemia in patients undergoing hemodialysis, the relative mortality risks associated with use of different types of ESAs are unknown,” Yusuke Sakaguchi, MD, from the Committee of Renal Data Registry, Japanese Society for Dialysis Therapy in Tokyo, and colleagues wrote.
To compare the mortality risk between the two patient groups, registry researchers conducted a nationwide cohort study of 194,698 patients on hemodialysis in Japan who received either a short-acting (epoetin alpha/beta or epoetin kappa) or a long-acting (darbepoetin or epoetin beta pegol) ESA. For each anemia drug type, the proportion of patients using each type of ESA was epoetin (EPO)-alpha/beta, (n=50,809, 26.1%); EPO-kappa, n=19,822 (10.2%); darbepoetin-alpha (DPO), n=97,391 (50.0%); and epoetin-beta pegol (continuous erythropoiesis receptor activator [CERA]), n=26,676 (13.7%), the researchers wrote.
During the 2-year follow-up, 31,557 patients died. Long-acting ESA users had a 13% higher rate of deaths compared with short-acting ESA users.
“This difference in risk was pronounced among patients receiving high doses of ESA,” the authors wrote. “Long-acting ESA use was associated with an increased rate of death from cardiovascular diseases, infection and malignancies.”
The authors said they “unexpectedly found that the long-acting ESA use was associated with a higher rate of infection-related death. Interestingly, experimental studies revealed immuno-suppressive effects of erythropoietin. Therefore, aggressive use of ESA might increase the susceptibility to infectious diseases,” they wrote.
Among the four types of ESAs used in the study, the mortality rate was the highest in DPO users and the lowest in EPO-alpha/beta users, the authors wrote.
“Although the underlying mechanisms are unknown, the prognosis of patients receiving EPO-[kappa], a biosimilar product of EPO-[alpha], was slightly worse than that of those receiving EPO-[alpha/beta].”
In the instrumental variable analysis, “long-acting ESA users remained at a significantly higher risk of death,” the authors wrote. “Compared with anemic [hemoglobin 9 g/dl to 9.9 g/dl] short-acting ESA users, long-acting ESA users who achieved more optimal hemoglobin levels [10 g/dl to 10.9 g/dl] showed a higher mortality rate.” –by Mark E. Neumann
Disclosures: Sakaguchi has received grants and honorariums from Chugai Pharmaceutical Co. Ltd., Kissei Pharmaceutical Co. Ltd. and Kyowa Hakko Kirin Co. Please see the full study for a list of other researchers’ relevant financial disclosures.
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This is a retrospective study of Japanese dialysis patients receiving ESAs. It compares mortality risk between patients receiving short-acting ESAs (epoetin) and long-acting ESAs (darbepoetin and methoxy polyethylene glycol-epoetin beta [CERA]).
As a retrospective study, it is subject to residual confounding and is hypothesis generating; it cannot conclusively establish cause and effect. The authors used sophisticated statistical modeling to minimize the chance of residual confounding, including three levels of adjustment for patient and facility characteristics, propensity score matching and instrumental variable analysis.
The usage in the study of short-acting vs. long-acting ESAs – 36.3% and 63.7% of patients, respectively – was similar to U.S. prescribing patterns. Irrespective of the adjustment model, patients receiving long-acting ESAs had a higher rate of death from all causes, cardiovascular disease, cardiac disease, stroke, non-cardiovascular disease, stroke and malignancy. The hazard ratio for long-acting ESAs and all-cause mortality ranged from 1.11 to 1.20 depending upon the model used but was always statistically significant. The statistically significant hazard ratio persisted for all patient subgroups except those with the lowest ESA dose and lowest erythropoietin resistance index, suggesting that the toxicity of long-acting ESAs is dose related.
Interestingly, the toxicity of long-acting ESAs was not proportionate to their duration of action as patients receiving darbepoetin had a higher all-cause mortality rate than those receiving CERA. Since CERA stands for continuous erythropoietin receptor activator, one could speculate that the toxicity of longer-acting ESAs might be related to the duration of receptor activation leading to off-target effects on non-erythropoietic tissues. However, since darbepoetin was associated with higher all-cause mortality than CERA, despite the shorter duration of action of the former, it is possible that the modification of the recombinant epoetin molecule or the darbepoetin vehicle contributes to its toxicity.
It should be noted that a previous study (Winkelmayer W, et al. Am J Kidney Dis. 2015; doi:10.1053/j.ajkd.2015.02.339) comparing long-term outcomes among dialysis facilities using primarily darbepoetin vs. epoetin found no differences between the groups. Limitations of the Sakaguchi and colleagues study include missing data, lack of information regarding iron supplementation (which tends to be conservative in Japanese patients), potential crossover of ESA use and the single ethnicity of the patients, which may limit extrapolation to other populations.
Only a long-term randomized controlled trial comparing short-acting vs. long-acting ESAs can conclusively prove a cause and effect relationship between ESA duration of action and mortality risk. Such a study is unlikely to occur as newer agents for the treatment of anemia, such as hypoxia inducible factor stabilizers, are on the horizon.
Indiana University School of Medicine
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