CKD Anemia and the FDA label for Epogen
Ajay K. Singh MBBS, FRCP
Brigham and Women's Hospital
Harvard Medical School
The recent modification of the epoetin and darbepoetin label by the FDA represents a watershed moment in the use of erythropoiesis stimulating agents (ESAs) in the treatment of anemia in chronic kidney disease (CKD) patients.
Ajay K. Singh MBBS, FRCP
Brigham and Women's Hospital
Harvard Medical School
The recent modification of the epoetin and darbepoetin label by the FDA represents a watershed moment in the use of erythropoiesis stimulating agents (ESAs) in the treatment of anemia in chronic kidney disease (CKD) patients.
The FDA drug safety communication announced June 2011 (1,2), recommended that there should be a shift away from the hemoglobin concentration as a target for anemia management to one of individualizing treatment to prevent blood transfusion by using the lowest possible dose of ESA. For patients with chronic kidney disease (CKD) not on dialysis, the label now recommends either interruption or reduction in the dose of erythropoeisis stimulating agent (ESA) once the hemoglobin (Hb) level rises above 10 g/dL. For dialysis patients, the advisory recommends either interruption or reduction of ESA dose if the Hb rises beyond 11 g/dL. The label emphasizes the importance of using the lowest possible dosage of ESA. The ESA label now explicitly states that there is risk of ESA therapy at any Hb level.
Many millions of patients have been exposed to ESA, some at very high dosages, and many unwittingly at high risk of the adverse effects of these drugs. For example, it is now recognized that patients who have had a prior stroke are at especially high risk of having another stroke if exposed to ESA treatment.
The delay in recognizing the risk of correcting anemia with ESAs reflects multiple factors. Perhaps, the most important reason is the complex and ill-understood pathophysiology underlying the adverse risk. Healthy individuals exposed to modest dosage of ESA probably have minimal risk. On the other hand, the use of high dosages of ESA in the clinical context of an inflamed patient with CKD or cancer may be key. Other factors include a delay in performing the trials, underpowering of studies, and the use of surrogate outcomes.
Who should be blamed for the delay? There is plenty of blame to go around. For sure, the nephrology community, because it did not demand the appropriate studies before using large dosages of ESAs. Some blame must be placed at the door-step of pharmaceutical companies for assuming that ESAs were safe at the high dosages that were being used, and the regulatory authorities for allowing such rampant off-label use of ESAs without ensuring that properly designed studies were in place. Although dialysis providers in the US were perversely incentivized to use more ESA to generate greater profit, the payors paid when they should have asked more questions about why large doses were necessary.
What we need now is a balanced approach to anemia management. The first step is to embrace the FDA label for ESA and use modest dosages of ESA only when necessary and individualized for the patient. What we don’t need are complex algorithms or anemia protocols that continue to treat every anemic patient the same. What we also need is a well-powered randomized study that directly evaluates whether ESAs are responsible for the adverse risk rather than the higher Hb concentration.
