The FDA's Perspective on the Risk for Rapid Rise in Hemoglobin in Treating CKD Anemia

The Trial to Reduce Cardiovascular Endpoints with Aranesp Therapy (TREAT) (1) has prompted the Food and Drug Administration (FDA) to reevaluate the use of erythropoiesis-stimulating agents (ESAs) in the treatment of chronic kidney disease (CKD) anemia (2). An FDA public advisory committee meeting in 2010 is anticipated. The TREAT study reported, against placebo, minimal benefit and increased risk of ESA therapy (1). Before TREAT, Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) (3), Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin β (CREATE) (4), and Normal Hematocrit (5) studies also demonstrated either no benefit or increased risk of targeting a higher hemoglobin (Hb) concentration. Consequently, attention has shifted from the benefits of ESAs to their risks (6). Most nephrologists will be eager to receive guidance from the convened FDA panel on how to interpret these trials in terms of clinical practice. In a recent New England Journal of Medicine Perspective article, Unger et al. (2) from the FDA reviewed the evidence from TREAT and the Normal Hematocrit and CHOIR studies. Unger et al. raised again, among several factors, the issue of too rapid an increase in Hb as being an important factor in determining clinical outcomes in patients who have CKD and anemia and are treated with an ESA. Here, I examine the strength of this evidence and evaluate the FDA's emphasis on the rate of increase of Hb in ESA treatment of CKD anemia. The FDA's concern regarding the potential risk of too rapid an increase in Hb dates back to a review conducted by the Center for Biologics Evaluation and Research (CBER) in 2001 (7). The CBER performed exploratory safety analyses of the Aranesp licensing application and observed an association between Hb rate of rise >0.5 g/dl per wk and the risk for cardiovascular and thromboembolic …