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FDA advisory panel: Target hemoglobin still 12 g/dL
Not enough data to warrant restriction of erythropoietin agents in kidney disease.
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A joint FDA advisory panel voted 15-4 to not impose additional restrictions on administration of erythropoiesis-stimulating agents to people with anemia resulting from chronic kidney disease.
The Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee recommended against setting an upper target hemoglobin level of 11 g/dL for patients with kidney disease.
The FDA changed the drugs’ label in March to indicate that prescribers should use the lowest erythropoiesis-stimulating agents (ESA) dose that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for red blood cell transfusion. ESA increased the risk for death and for serious cardiovascular events when administered to target a hemoglobin of greater than 12 g/dL.
The panel was asked whether a target range or an upper level should be recommended to avoid physicians keeping patients at too low of a hemoglobin. Most panel members said there were not enough data to suggest that the effects of an 11 g/dL target were different than those of a 12 g/dL target. Some panel members favored a target range of 10 g/dL to 12 g/dL, which was suggested by manufacturers.
“We are in a difficult situation here, being asked to advise in the absence of data,” said acting panel chair Richard Platt, MD, professor of medicine at Harvard Medical School. “It should be extraordinary that after hundreds of thousands of individuals have been treated, neither the patients nor the clinicians really know how to best use this very important therapeutic agent. But it is not extraordinary because this information gap no doubt pervades so much of therapeutics.”
Erythropoietin agents have been under harsh scrutiny after several studies have indicated higher than normal doses of the drug are related to adverse cardiovascular events and death. Earlier this year, the FDA placed black box warnings on epoetin alfa (Procrit, Johnson & Johnson; Epogen, Amgen) and darbepoetin alfa (Aranesp, Amgen).
In May, the Oncologic Drugs Advisory Committee recommended additional restrictions for use of the agents in treating chemotherapy-related anemia, based on data suggesting the drugs worsen tumors. The Centers for Medicaid and Medicare Services has also issued a national coverage determination that restricts erythropoietin treatment for Medicare recipients.
The questions of safety were primarily raised from two trials: the Normal Hematocrit Cardiac Trial (NHCT), a prospective trial in patients receiving dialysis, and the Correction of Hemoglobin and Outcomes in Renal Insufficiency trial (CHOIR), a similar trial in patients not yet receiving dialysis.
In the NHCT trial, researchers compared the effects of a 14 ± 1 g/dL target hemoglobin with a 10 ± 1 g/dL target hemoglobin. For CHOIR, researchers compared a 13.5 g/dL target hemoglobin with an 11.3 g/dL target hemoglobin. Both trials showed that patients with the higher hemoglobin targets had more cardiovascular events and death.
However, there are no data suggesting a target hemoglobin level of 12 g/dL is associated with adverse events, thus the committee’s recommendation to leave the suggested target at 12 g/dL.
“We do not have any evidence that 12 is worse than 11, but we have evidence that 13 and 14 might be,” said panel member Michael Lincoff, MD, professor in the department of cardiovascular medicine at the Cleveland Clinic Foundation. “In the absence of other data, we should be working with what we do have, which is observational data suggesting 10 to 12 g/dL is a reasonable range. Our goal here is to establish a safe target, and 12 is a reasonable number.” – by Emily Shafer