Topic: With the continued safety review of erythropoiesis-stimulating agents (ESAs), the U.S. Food and Drug Administration (FDA) has issued additional modifications to the product labeling for ESAs recommending more conservative dosing in patients with chronic kidney disease (CKD).
Background: Since FDA approval of epoetin alfa in 1989, ESA therapy has become an integral part of the care for patients with CKD. However, ESA dosing and target hemoglobin (Hb) concentrations have been the subject of much debate in recent years. Improvements in patient quality of life, reduction in hospitalizations, and improvement in left ventricular hypertrophy with partial correction of anemia to Hb of 11 g/dL have begged the question of whether complete correction of Hb to levels of 12 g/dL and above is beneficial. However, results from randomized trials demonstrated lack of benefit and increased risk of cardiovascular events and stroke with ESA therapy targeted to higher Hb concentrations (above 12 g/dL), prompting a more conservative approach.1-4
In March 2007, the FDA required manufacturers of ESAs to modify their product labeling to reflect Hb target of 10-12 g/dL. Additional safety precautions were implemented in March 2010 with the FDA initiating a risk evaluation and mitigation strategy (REMS) for epoetin alfa and darbepoetin alfa.5
The Medicare Improvements for Patients and Providers Act of 2008 (MIPPA) required CMS to develop a plan to bundle ESAs and other separately billable drugs into a single case-mix adjusted payment to dialysis facilities with payment reductions implemented based on quality measures. Quality measures with regard to anemia included the percentage of Medicare patients receiving ESAs with average Hb levels less than 10 g/dL and greater than 12 g/dL (i.e., maintaining a target Hb between 10-12 g/dL was considered optimal).6
New Information: On June 24, 2011 the FDA notified healthcare professionals of modified recommendations for more conservative use of ESAs. Manufacturers revised the precautions, black boxed warning, and dosing sections of ESA product labeling.7 The labeling now warns that dosing ESAs to target Hb levels greater than 11 g/dL for CKD patients increases the risk for death, serious cardiovascular reactions, and stroke without providing additional benefit.8-10 Practitioners are advised to individualize therapy to use the lowest ESA dose necessary to decrease the need for red blood cell transfusions. Initiation of therapy should be considered in all CKD patients once Hb is below 10 g/dL and, in non-dialysis patients, only if both of the following additional criteria are met: 1) the rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion, and 2) reducing the risk of alloimmunization and/or other RBC-transfusion-related risks is the goal.7 The ESA dose should be decreased or interrupted when Hb is above 10 g/dL in CKD patients not receiving dialysis or above 11 g/dL in patients receiving dialysis.8-10
On November 1, 2011 CMS also removed the requirement that dialysis providers maintain Hb levels above 10 g/dL because no lower level of hemoglobin was ...