Which ESA Is Safer in Chronic Kidney Disease Patients?

Epoetin alfa (EPO) and darbepoetin alfa (DPO) are two erythropoiesis-stimulating agents (ESAs) commonly used for treatment of anemia in chronic kidney disease (CKD). DPO has a higher receptor affinity and longer half-life due to additional carbohydrate side chains as compared to EPO (carbohydrate concentration 51% vs. 40%).  ESAs are known to have pleiotropic properties including roles in vascular repair and neoangiogenesis. It is possible that that EPO and DPO have different non-hematopoietic effects due to biologic differences. Hence, safety becomes an important concern for both the agents.

Below is a table summarizing differences between EPO and DPO.

EPO DPO
Molecular Weight 30.4 KDa 37.1 KDa
Carbohydrate Content 40% 51%
Year Introduced 1989 2001
Route IV. SQ IV, SQ
Half Life 8.5 h (IV), 24 h (SQ) 25.3 h (IV), 48.8 h (SQ)
Starting Dose 50-100 units/kg thrice weekly 0.45 mcg/kg once weekly or 0.75 mcg/kg every 2 weeks
Side Effects Hypertension, headache (15%), influenza like syndrome (5%), pain at injection site, pure red cell aplasia (with s/c use), tumor progression/recurrence, stroke, increased risk of death/CVS events/blood clots if Hb> 13

Palmer et al from Cochrane Renal Group recently conducted a meta-analysis comparing the safety of different ESAs in CKD. They concluded that there is insufficient evidence to demonstrate superiority of one form of ESAs over another.  The authors felt that outcomes such as survival, cardiac events, fatigue, and stroke are important patient centered outcomes. The data on such events was inconclusive.

In the recently published AJKD study, Wilhelm-Leen and Winkelmayer conducted a meta-analysis of randomized control trials comparing EPO vs DPO with all-cause mortality as the primary outcome.  Patients with CKD and ESRD were included in this analysis. Nine studies were identified that included 2024 patients with a follow up ranging from 20-52 weeks. There was no significant difference in mortality between CKD patients randomly assigned to DPO vs EPO (OR, 1.33; 95% CI, 0.88-2.01).

One of the major limitations of the study is short follow up; all but one study had a follow up of 28 weeks or less.  Also, all the studies lacked statistical power for detection of a mortality and non-fatal cardiovascular events difference.  Thirdly, ESRD patients, as compared to the non-dialysis CKD population, were associated with higher mortality, and 8 out of 10 included studies were conducted in ESRD patients.  This could have affected outcome analysis. And finally, it is important to note that the senior author served as a scientific advisor to Amgen, the pharmaceutical company that manufactures Epogen and Aranesp. Almost all studies were industry sponsored which may have contributed to additional bias in this meta analysis.

Due to current paucity of data, we will need larger randomized trials conducted independently to better characterize the long-term safety profile of ESAs. Till then the question still remains, is one ESA superior over the other?

Silvi Shah, MD
Nephrology Fellow, Cleveland Clinic

Kenar Jhaveri, MD
AJKD Blog Editor

To view the article abstract or full-text (subscription required), please visit AJKD.org.

[Note: The original version of this post included a misstatement regarding the mortality risk associated with DPO and incorrectly stated that the first author of the AJKD article was a scientific advisor to Amgen.]

 

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