Level 2: Mid-level evidence
The FDA previously updated the boxed warning for all erythropoiesis-stimulating agents (darbepoetin [Aranesp], epoetin alfa (Epogen, Procrit]) because of increased risk of serious and life-threatening side effects or mortality in cancer patients (FDA MedWatch 2007 Mar 9; full-text available online free of charge at: www.fda.gov/medwatch /safety/2007/safety07.htm#ESA, accessed June 6, 2008). A previously published Cochrane review of 57 randomized trials evaluated recombinant human erythropoietin or darbepoetin in 9,353 cancer patients with anemia and concluded that erythropoietin or darbepoetin may reduce the need for transfusions, but their use was associated with increased risk of venous thromboembolism (Cochrane Database Syst Rev. 2006:CD003407).
Consistent with previous findings, a recently published systematic review also concluded that erythropoietin or darbepoetin may increase the risk of venous thromboembolism and possibly mortality in cancer patients (JAMA. 2008;299:914-924). The systematic review included 54 randomized trials with 13,766 cancer patients who were treated with recombinant human erythropoietin or darbepoetin for anemia. Compared with control, erythropoietin/darbepoetin was associated with higher rates of venous thromboembolism (7.2% vs. 4.9%, P<0.005, NNH 43 in 38 trials with 8,172 patients) and increased mortality (hazard ratio 1.1, 95% CI 1.01-1.2, P=0.03 in 51 trials with 13,611 patients). There was no assessment of trial quality.