No TREATment with darbepoetin dosed to hemoglobin 13 grams per deciliter in type 2 diabetes with pre-dialysis chronic kidney disease--safety warnings for erythropoiesis-stimulating agents.

In what a key observer described as “another example ... where an intervention to modify a surrogate endpoint failed to translate into the expected improvement in patient outcome,”1 Pfeffer et al. (October 2009) found a nearly 2-fold increased risk of stroke in patients with diabetes, anemia, and pre-dialysis chronic kidney disease (CKD) dosed with darbepoetin alfa to a target hemoglobin (Hb) of 13 grams per deciliter (gm per dL).2 The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) enrolled 4,038 patients from August 25, 2004, through December 4, 2007, and was completed on March 28, 2009, with median follow-up of 29.1 months. Comparing patients randomly assigned to treatment with darbepoetin alfa (n = 2,012) versus placebo (n = 2,026), investigators found a hazard ratio (HR) of 1.92 (95% CI = 1.38-2.68, P < 0.001) for an increased risk of stroke (absolute rate = 5.0% for darbepoetin alfa vs. 2.6% for placebo). TREAT investigators also observed no significant reduction in the incidence of the 2 primary endpoint outcomes. Of the patients treated with darbepoetin alfa, 31.4% (n = 632) experienced the primary composite endpoint of death from any cause, stroke or cardiovascular events (myocardial infarction [MI], heart failure or myocardial ischemia) compared with 29.7% (n = 602) for placebo (HR = 1.05, 95% CI = 0.94-1.17, P = 0.41). There was also no significant difference between the darbepoetin and placebo groups in the other primary composite endpoint of death or end-stage renal disease (ESRD), 32.4% (n = 652) for darbepoetin alfa versus 30.5% (n = 618) with placebo (HR = 1.06, 95% CI = 0.95-1.19, P = 0.29). Just 1 week prior to the report by Pfeffer et al., published online on October 30, 2009, a report by Heinze et al. published online on October 23, 2009 found that dosing erythropoiesisstimulating agents (ESAs) to Hb concentrations greater than 12.5 gm per dL in renal transplant recipients was associated with increased mortality.3 Heinze et al. also found a nonlinear relationship between mortality and Hb concentration, with the increased risk of mortality significant at Hb concentrations greater than 14 gm per dL. This nonrandomized cohort study of 1,794 renal transplant recipients in the Austrian Dialysis and Transplant Registry who received a transplant between January 1, 1992, and December 31, 2004, and survived at least 3 months (median 5.6-year follow-up) found that the 10-year survival rate was 57% in patients who received ESAs versus 78% in patients not treated with ESAs (P < 0.001). After adjustment for confounding, Hb levels less than 12.5 gm per dL were associated with increased risk of mortality both in ESA-treated patients (HR = 4.7, 95% CI = 2.110.5 for 11.0 gm per dL vs. 12.5 gm per dL) and in patients not treated with ESAs (HR = 2.5, 95% CI = 1.5-4.0). For patients with Hb levels of at least 12.5 gm per dL, an interaction between ESA use and Hb level was observed; Hb levels higher than 12.5 gm per dL were associated with increased mortality in ESA-treated patients (HR = 2.8, 95% CI = 1.0-7.9 for 14.0 gm per dL vs. 12.5 gm per dL) but not in patients not treated with ESAs (HR = 0.7, 95% CI = 0.4-1.5). These findings precipitated the recommendation by the authors that renal transplant patients with Hb concentration greater than 12.5 gm per dL should not receive ESAs.