Epoetin Alfa May Reduce Mortality in Certain Critically Ill Patients

Key Point

Epoetin alfa does not reduce the need for red-cell transfusions in critically ill patients with anemia, but may decrease mortality risk in trauma patients.

Although recombinant human erythropoietin (epoetin alfa) treatment could hypothetically raise concentrations of hemoglobin in critically ill patients with anemia—thus reducing the need for red-cell transfusions—findings published in the September 6 New England Journal of Medicine suggest that epoetin alfa’s benefits are selective and also come with drawbacks. Howard L. Corwin, MD, and colleagues found that the treatment does not appear to lower the incidence of red-cell transfusions in critically ill patients overall and may increase the risk of thrombotic events, but epoetin alfa may also reduce mortality in patients with trauma.

“Our prestudy hypothesis was that improvement in clinical outcome with the use of epoetin alfa would result from the prevention of adverse effects of transfused red cells,” the investigators stated. “This was clearly not the case. The reduction in mortality was found in the absence of a reduction in the incidence of transfusion and suggests that the effect is due to nonhematopoietic actions of erythropoietin.”

NO TRANSFUSION RATE REDUCTION

Dr. Corwin, of the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, and colleagues enrolled 1,460 medical, surgical, and trauma patients between 48 and 96 hours after ICU admission. All patients were 18 or older and had hemoglobin concentrations lower than 12 g/dL. The participants were randomized to receive epoetin alfa by means of subcutaneous injection (40,000 units weekly) or placebo for a maximum of three weeks, and followed for 140 days. Among patients receiving epoetin alfa, 28.2% received one dose, 32.2% received two doses, and 38.9% received all three doses.

A total of 46% of patients in the epoetin alfa group received a red-cell transfusion, versus 48.3% in the placebo group; a mean of 4.5 and 4.3 red-cell units were transfused in the epoetin alfa and placebo groups, respectively, which was a nonsignificant difference. However, at day 29, hemoglobin concentration increased by 1.6 g/dL from baseline in the treatment group, compared with 1.2 g/dL in the placebo group (absolute hemoglobin concentrations were 11.2 g/dL and 10.8 g/dL in the epoetin alfa and placebo groups, respectively). By day 42, there was no significant difference in hemoglobin concentration between the two groups. The absence of reduction in transfusion rate, which was demonstrated in earlier trials, appeared to be a result of changes in transfusion practice that have occurred over the last several years, the researchers stated.

MORTALITY AND THROMBOTIC EVENTS

Mortality rates at day 29 were significantly lower in the epoetin alfa group (8.5%), compared with the placebo group (11.4%). Among trauma patients in particular, mortality rates were 3.5% and 6.6%, respectively. At day 140, mortality rates were 14.2% and 16.8% among all patients in the treatment and placebo groups, respectively, and 6.0% and 9.2% among trauma patients. While the reduced mortality rate in the trauma patients was statistically significant, there was no significant reduction in mortality rates among surgical and medical nontrauma patients receiving epoetin alfa, compared with placebo. Dr. Corwin and colleagues stated that it was not clear whether the absence of a mortality benefit among nontrauma patients occurred “because the study was underpowered for nontrauma patients or whether in fact only certain subgroups within the medical or surgical populations have a benefit.”

In addition, 94.8% of patients in the epoetin alfa group and 94.4% of patients in the placebo group experienced at least one adverse event; 44.0% and 43.5% of patients in the treatment and placebo groups, respectively, experienced a serious adverse event. Rates for thrombotic vascular events were 16.5% in the treatment group, compared with 11.5% in the placebo group. Among those who received all three doses of epoetin alfa, there was a thrombotic vascular event rate of 22.8%, compared with 16.1% in the placebo group. Among patients who received two doses, rates were 13.6% and 9.5% for the treatment and placebo groups, respectively, and 11.1% and 6.5% among those who received one dose. A post-hoc analysis found that the risk of thrombotic events with epoetin alfa was not increased in patients receiving prophylactic or therapeutic anticoagulation at the time epoetin alfa was initiated.

“In contrast to studies of erythropoietin in patients with cancer and those with renal failure, the findings in this trial are notable in two respects: first, the increase in the incidence of thrombotic events occurred with a hemoglobin target below 12 [g/dL]; and second, the duration of therapy was brief (three or fewer doses),” the researchers pointed out.

Due to the timing of both decreased mortality risk and the moderate increase in hemoglobin concentration seen in patients who received epoetin alfa therapy compared with those who received placebo, the nonhematopoietic effects of epoetin alfa, and not the increase in hemoglobin, the researchers stated. In addition to producing mature erythrocytes via bone marrow stimulation, erythropoietin also acts as a cytokine with antiapoptotic activity.

“In this role, erythropoietin has been shown in preclinical and small clinical studies to protect cells from hypoxemia and ischemia,” Dr. Corwin’s research team pointed out. “Multiple tissues express erythropoietin and the erythropoietin receptor in response to stress and also to mediate local stress responses. These nonhematopoietic activities of erythropoietin in the protection of cells suggest a role for erythropoietin in critically ill patients.”

MORTALITY BENEFIT IN TRAUMA PATIENTS

“On the basis of the available data, we believe that epoetin alfa could benefit trauma patients remaining in an ICU for more than 48 hours and who have hemoglobin concentrations below 12 [g/dL] and no history of thrombotic disease, provided they meet all the other inclusion criteria and do not have any of the exclusion criteria in the study,” the investigators concluded. However, the researchers emphasized that before the 48-hour threshold, epoetin alfa should not be administered to the critically ill without further study, as the risks may outweigh the benefits. “The use of epoetin alfa is not supported for patients admitted to the ICU with a nontraumatic surgical or medical diagnosis, unless they have an approved indication for epoetin alfa.”

In an accompanying editorial, Deborah Cook, MD, and Mark Crowther, MD, both of McMaster University in Hamilton, Ontario, also cautioned against assigning a role for epoetin alfa in critically ill patients.

“As this study illustrates, large, rigorous investigations involving vulnerable, critically ill patients are crucial to help inform clinicians about what to do, what to consider, and what to avoid,” the editorialists noted.

“Without a clear indication for initiating erythropoietin in all critically ill patients, new prescriptions for this drug should be restricted to randomized trials with independent research oversight carefully examining fatal and nonfatal clinically important outcomes.”           

—John Merriman

Suggested Reading
Cook D, Crowther M. Targeting anemia with erythropoietin during critical illness. N Engl J Med. 2007;357(10):1037-1039.
Corwin HL, Gettinger A, Fabian TC, et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med. 2007;357(10):965-976.

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