According to a study published in the New England Journal of Medicine, darbepoetin alfa (Aranesp®) failed to meet either of its two composite endpoints in patients with type 2 diabetes, anemia, and kidney disease. In addition, patients who took Aranesp were almost twice as likely to suffer a stroke compared with those in the placebo group.
Patients with diabetes and chronic kidney disease often have an accompanying anemia characterized by low hemoglobin. Aranesp is an erythropoietin-stimulating agent (ESA), which stimulates red blood cells to produce more hemoglobin. However, there is a paucity of data to determine whether taking an ESA has an effect on clinical outcomes.
The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) was a clinical trial conducted at 623 sites in 24 countries. The study enrolled 4038 patients (median age, 68 years) with type 2 diabetes, chronic kidney disease, and moderate anemia (hemoglobin ≤ 11.0 g/dL) to either the ESA (n=2012) or placebo (n=2026). The ESA group was treated to target hemoglobin of 13 g/dL. Patients in the placebo group received a rescue dose of the ESA if hemoglobin dropped to less than 9.0 g/dL; 46% received at least 1 rescue dose during the study. The median age of the patients was 68 years and none had undergone dialysis. The 2 primary endpoints were the composite outcomes of death or a cardiovascular event and death or end-stage renal disease.
After a median duration of 29.1 months, patients in the ESA group showed no significant difference in the overall rates of death or cardiovascular event (31.4%) versus placebo (P=29.7%; P=0.41) and death or end-stage renal disease (32.4%) versus placebo (30.5%; P=0.29). Compared with placebo, treatment with the ESA resulted in a mean improvement in self-reported fatigue scores (P<0.001), a reduction in cardiac revascularization (P=0.02), and in the need for red-cell transfusions (P<0.001). Aside from fatigue, quality of life did not differ between the two groups. Of note is that fatal or nonfatal stroke occurred in almost twice the number of patients on the ESA (n=101) than on placebo (n=53; hazard ratio [HR], 1.92; 95% CI, 1.38 to 2.68; P<0.001). Among a
small subgroup of patients who reported a history of malignancy at baseline (n=348), cancer death was significantly more common in the ESA group (P=0.002).
ESAs are widely used in patients with end-stage renal disease with a concurrent increase in hemoglobin levels. In a scientific “leap,” it was assumed that these medications would lead to improved survival in patients with chronic kidney disease, which led to the development of controlled trials without a placebo group. This study provides evidence-based information to help clinicians and policy makers make decisions about the risk versus the benefit of ESAs; in some patients, the increased risk of stroke and a possible increased mortality among those with a history of cancer may outweigh the potential benefits of these agents.
This study was funded by Amgen, the manufacturer of Aranesp.