Untangling the Association between Anemia Treatment and Stroke Risk in CKD.

Abstract

Randomized, controlled trials (RCTs) of erythropoietic-stimulating agents (ESAs) suggest an association between ESA dose and stroke, but it remains unclear whether the causal pathway is the ESA dose itself, target hemoglobin (Hgb), achieved Hgb, or comorbidities that may lead to ESA hyporesponsiveness. The most striking association was seen in the Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease (TREAT) (1), which demonstrated 1.92 increased incidence of stroke ( P <0.001) among anemic subjects treated with darbepoetin to target Hgb of 13.5 g/dl versus those treated with placebo (rescue therapy with darbepoetin for Hgb<9.0 g/dl). The publication of TREAT was followed by a change in the US Food and Drug Administration (FDA) label for all ESAs, with a black box warning of “serious adverse cardiovascular reactions and stroke when [these agents are] administered to target a hemoglobin level of greater than 11 g/dl; no trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks” (2). Previously, Parfrey et al. (3) performed an RCT examining full (target Hgb =13.5–14.5 g/dl) versus partial (target Hgb =9.5–11.5 g/dl) anemia correction among patients on incident hemodialysis; patients treated to the higher Hgb target experienced more cerebrovascular disorders ( P =0.05). More recently, the Reduction of Events by Darbepoetin in Heart Failure RCT of patients with systolic heart failure and anemia confirmed 1.94 relative risk (RR) of stroke (95% confidence interval [95% CI], 1.43 to 2.63) among darbepoetin-treated (versus placebo-treated) subjects who would have met inclusion criteria for TREAT (4). Although the Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease (CHOIR) study (5) did not demonstrate increased stroke risk among patients with nondialysis CKD treated with epoetin alfa to target Hgb of 13.5 versus 11.3 g/dl, occurrence of the primary composite cardiovascular end point, …