FDA Pleads for More Research on Anemia Drugs

FDA officials used the pages of the New England Journal of Medicine to call for more studies of erythropoiesis-stimulating agents (ESAs) in an effort to improve their safe use.

"It is time to establish, through randomized trials, the optimal hemoglobin target, dosing algorithm, and monitoring approach for patients with anemia from chronic kidney disease," wrote Robert Temple, MD, a top official in the FDA's Center for Drug Evaluation and Research, and colleagues in a "Perspective" piece published online.

They also promised that an FDA advisory committee would "reevaluate" use of these drugs in kidney disease patients sometime this year.

The officials were responding to a series of clinical studies in which efforts to raise hemoglobin levels into the normal range in patients with anemia from chronic kidney disease may do more harm than good.

ESAs, which also include erythropoietin (Epogen, Procrit), have also been found to worsen outcomes in cancer patients. (See Anemia Drugs Increase Mortality in Cancer Patients)

The most recent and perhaps most damning trial in kidney disease patients was reported in October. A 4,000-patient trial of darbepoetin alfa (Aranesp) failed to improve most clinical outcomes compared with placebo and nearly doubled the risk of stroke. (See ASN: No Clinical Benefit for ESA in Anemic Patients with Diabetes, CKD)

That trial, called TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy), followed two others that also suggested that risks outweighed benefits of normal-range hemoglobin targets in kidney disease patients: the Normal Hematocrit Study in 1998 and Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) in 2006.

Both trials dosed patients to achieve hemoglobin targets in the range of 13 to 14 g/dL.

Temple and colleagues said that when the TREAT study's sponsor, Amgen, told the agency in 2004 that it was planning the trial, the initial design called for a target of 13 g/dL.

"The FDA expressed concerns to the company that [this] target was excessive, higher than that recommended in ESA labeling and not supported by safety data," they wrote.

The agency gave Amgen the go-ahead only after it negotiated "conservative dosing and monitoring schemes to limit overshoots of the hemoglobin target, oscillations in the concentration, and rapid rates of increase," and made sure Amgen formed an independent data and safety monitoring committee, Temple and colleagues added.

"Despite these measures, the TREAT investigators documented adverse consequences of using an ESA to raise hemoglobin levels," they wrote.

Through a median follow-up of 29.1 months, all-cause death or a cardiovascular event -- including nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia -- occurred in 31.4% of patients receiving darbepoetin alfa and 29.7% of those receiving placebo (HR 1.05, 95% CI 0.94 to 1.17).

Rates of fatal or nonfatal stroke were 5% in the darbepoietin group versus 2.6% with placebo (HR 1.92, 95% CI 1.38 to 2.68).

Temple and colleagues noted that these event rates translated to "more than one death or cardiovascular event per patient per month in both groups."

On the other hand, TREAT did show that the drug significantly reduced patients' fatigue, need for revascularization, and a composite outcome of death or end-stage renal disease. But, Temple and colleagues wrote, neither TREAT nor the earlier studies provided "convincing evidence of any consistent quality-of-life benefit" to offset the increased risks.

These studies, the FDA officials wrote, "raise major concerns regarding the use of ESAs to increase hemoglobin concentrations . . . above a level intended solely to avert the need for erythrocyte transfusions."

But they acknowledged that more modest increases in hemoglobin might still be beneficial on balance -- hence, their plea for more trials.

"Clearly, more conservative hemoglobin targets -- well below 12 g/dL -- should be evaluated," they argued.

The FDA officials also suggested that "more frequent hemoglobin monitoring and more cautious dosing algorithms," perhaps augmented with computers, may help stabilize hemoglobin levels near these lower targets.