NEJM: FDA to reevaluate ESAs in treatment of anemia 1

The FDA plans to convene an advisory panel in 2010 “to reevaluate the use of ESAs in the treatment of anemia due to chronic kidney disease,” according to a “Perspective” written by four FDA officials in the New England Journal of Medicine.

In response to the failure of 3 large clinical trials to establish any clinical benefits for the drugs, Ellis Unger, Aliza Thompson, Melanie Blank, and Robert Temple write that although ESAs “have been widely accepted” to maintain or increase RBC levels and to avoid transfusions, “optimal hemoglobin targets have never been established.” Several trials “endeavored to show that using ESAs to raise hemoglobin concentration to higher targets improves clinical outcomes. Unfortunately, and unexpectedly, all results have suggested the opposite.”

After reviewing the Normal Hematocrit Study, CHOIR, and TREAT trials, the FDA officials noted that the trials found only a “small and inconsistent” effect on quality-of-life measures that offered no compelling reason to offset the negative findings of the trials: “Clearly, the trials did not yield convincing evidence of any consistent quality-of-life benefit that would appear to outweigh the increased risks of nonfatal myocardial infarction, nonfatal stroke, and death.”

The authors write that “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. Clearly, more conservative hemoglobin targets– well below 12 g per deciliter– should be evaluated.”

Here is a comment from Sanjay Kaul, who is of course a member of the FDA’s Cardiovascular and Renal Drugs Advisory committee:

The important lesson to be drawn from these studies is that a critical distinction needs to be made between association and causation. Association of severity of anemia with adverse outcomes shown in observational studies has been widely interpreted as evidence for the causal role of anemia in the pathogenesis of adverse outcomes in this population. However, randomized clinical trials of anemia correction have revealed either no effect or increased morbidity and mortality in patients assigned to normal hemoglobin (Hb) targets. Establishing clinical practice on observational data alone, no matter how plausible the notion, can be a slippery slope as exemplified by the erythropoietin (EPO) experience.

To what extent does the Medicare reimbursement policy (for example, Medicare spent $2 billion dollars for EPO use in 2005, which represents nearly 25% of what they spent on dialysis services that year) drive the widespread use of this unestablished treatment strategy would be an important question to examine!

Whether this increased morbidity and mortality represents adverse consequences of anemia correction and normalization of Hb or overdose/toxicity related to non-erythropoietic effects of EPO on BP, vascular smooth muscle proliferation, angiogenesis, hemostatsis and thrombosis, etc. (the so-called “off target” effects) remains unclear.

I completely concur with the authors that caution should be exercised when escalating the EPO dosage in an attempt to achieve the desired Hb level in these patients. Although the optimal hemoglobin target has not been established in controlled trials, the CKD guidelines were recently revised to reduce the optimum target Hb to 11-12. Should the target be even lower is a key question that needs to be evaluated in randomized controlled trials.

Here are previous CardioBrief posts on ESAs: