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Pharmaceutical erythropoietins, such as epoetin α (Epogen and Procrit) and darbepoetin α (Aranesp), are FDA approved to treat symptomatic anemia caused by chronic kidney disease (CKD) and cancer chemotherapy. However, several recent trials have heightened concerns about the safety of these agents, particularly when they are used to induce hemoglobin (Hb) levels >12 g/dL.
In an international trial, 603 nondialyzed CKD patients with Hb levels of 11–12.5 g/dL were randomized to receive epoetin β (unavailable in the U.S.) to correct anemia completely (target Hb level, 13–15 g/dL) or to receive epoetin β only when Hb levels fell below 10.5 mg/dL (target Hb level, 10.5–11.5 g/dL). The likelihood of first cardiovascular events was the same in both groups. However, patients in the complete-correction group were significantly more likely to experience headaches and hypertension and to require hemodialysis (Journal Watch Nov 15 2006).
In a U.S. trial, 1432 nondialyzed CKD patients with Hb levels <11 g/dL were randomized to receive epoetin α to achieve target Hb levels of 13.5 g/dL or 11.3 mg/dL. The trial was stopped early, because patients in the high-target group experienced significantly more endpoint events (death, myocardial infarction, heart failure, and stroke) than did patients in the low-target group (Journal Watch Nov 15 2006). A meta-analysis of nine randomized trials (including the two described above) confirmed poorer outcomes in CKD patients who were treated to achieve high Hb targets than in similar patients whose targets were lower (Journal Watch Feb 15 2007).
The results of recent trials also have raised concerns about the safety of pharmaceutical erythropoietins in cancer patients. For example, in one trial, patients with advanced non–small cell lung cancer and hemoglobin levels ≤12 g/dL were randomized to receive epoetin α (target Hb level, 12–14 g/dL) or placebo. The trial was stopped early, because an interim data analysis revealed significantly shorter median survival in the epoetin group than in the placebo group (Journal Watch Apr 17 2007).
These and other findings prompted the FDA to issue advisories in 2007 about pharmaceutical erythropoietins. The FDA warns that these drugs can stimulate tumor growth and shorten survival in patients with various cancers and that they can increase risk for death and adverse cardiovascular events when they are dosed to achieve Hb levels >12 g/dL. The FDA recommends using the lowest effective dose of pharmaceutical erythropoietin to avoid blood transfusions and withholding these drugs if Hb levels are >12 g/dL. The latest FDA alert is available on the FDA website.
As if the results of recent trials and the FDA warnings weren’t troubling enough, the New York Times reported that the manufacturers of pharmaceutical erythropoietins have paid physicians hundreds of millions of dollars in rebates for prescribing these agents. Obviously, this practice raises ethical concerns about inappropriate prescribing practices. The full article is available on the NYT website.