1. Evidence Based Medication Use in the NICU: Erythropoietin Dan Ellsbury MD Director, Continuous Quality Improvement Pediatrix Medical Group

2. Erythropoietin - Use Erythropoietin - Use Erythropoietin (epo): Epo is very commonly used in the NICU top 20 –Epo is among the top 20 most commonly used medications in the NICU In the NICU, epo is used in: –28.6% –28.6% of infants < 29 weeks –18.5% –18.5% of infants < 33 weeks - Clark RH, et al Pediatrics. 2006;117(6):1979-87 - Pediatrix Database Query

3. Erythropoietin - Labeling Erythropoietin - Labeling Erythropoietin (epo): not labeledEpo is not labeled for use to prevent or treat anemia in premature infants http://www.fda.gov/cder/drug/infopage/RHE/default.htm

4. Erythropoietin – Effective? Erythropoietin – Effective? Erythropoietin (epo): Use of epo in premature infants may reduce transfusions slightly The magnitude of transfusion reduction is of minimal clinical relevance Early erythropoietin for preventing RBC transfusion in preterm and/or low birth weight infants. Ohlsson A, Aher S. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004863 Late erythropoietin for preventing RBC transfusion in preterm and/or low birth weight infants. Aher S, Ohlsson A. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004868 Early versus late erythropoietin for preventing RBC transfusion in preterm and/or low birth weight infants. Aher S, Ohlsson A. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004865

5. Erythropoietin – Safe? Erythropoietin – Safe? Erythropoietin (epo): increase in severe retinopathy of prematurityWith an “early treatment” approach, use of epo in premature infants was associated with a significant increase in severe retinopathy of prematurity Early erythropoietin for preventing RBC transfusion in preterm and/or low birth weight infants. Ohlsson A, Aher S. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004863

6. Early erythropoietin for preventing RBC transfusion in preterm and/or low birth weight infants. Ohlsson A, Aher S. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004863. CONCLUSIONS (excerpt): Early administration of EPO reduces the use one or more red blood cell transfusions, the volume of red blood cells transfused, and the number of donors and transfusions the infant is exposed to following study entry. The small reductions are of limited clinical importance.The small reductions are of limited clinical importance. –Any donor exposure is likely not avoided as most studies included infants, who had received red cell transfusions prior to trial entry. There was a significant increase in the rate of ROP (stage >3).There was a significant increase in the rate of ROP (stage >3). –Animal data and observational studies in humans support a possible association between treatment with EPO and the development of ROP. EPO does not significantly decrease or increase any of the other important neonatal adverse outcomes including mortality….. Due to the limited benefits and the increased risk of ROP, early administration of EPO is not recommended.Due to the limited benefits and the increased risk of ROP, early administration of EPO is not recommended.

7. Late erythropoietin for preventing RBC transfusion in preterm and/or low birth weight infants. Late erythropoietin for preventing RBC transfusion in preterm and/or low birth weight infants. Aher S, Ohlsson A. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004868 CONCLUSIONS (excerpt): Late administration of EPO reduces the use of one or more red blood cell transfusions, the number of red blood cell transfusions per infant and the total volume of red blood cell transfused per infant. The clinical importance of the results for the latter two outcomes is marginalThe clinical importance of the results for the latter two outcomes is marginal –(< 1 transfusion per infant and 7 ml/kg of transfused red blood cells). –Any donor exposure is likely not avoided as most studies included infants who had received red cell transfusions prior to trial entry. –Late EPO does not significantly reduce or increase any of many important neonatal adverse outcomes including mortality and retinopathy of prematurity. Further research of the use of late EPO treatment to prevent donor exposure is not indicated.Further research of the use of late EPO treatment to prevent donor exposure is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when red blood cell requirements are most likely to be required and cannot be prevented by late EPO treatment.

8. Early versus late erythropoietin for preventing RBC transfusion in preterm and/or low birth weight infants. Early versus late erythropoietin for preventing RBC transfusion in preterm and/or low birth weight infants. Aher S, Ohlsson A. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004865. CONCLUSIONS (excerpt) : The use of early EPO did not significantly reduceThe use of early EPO did not significantly reduce –the primary outcome of "use of one or more red blood cell transfusions", –or "number of transfusions per infant" compared to late EPO administration. Currently there is lack of evidence that early EPO vs. late EPO confers any substantial benefits with regard to any donor blood exposure as a large proportion (14 - 30 %) of infants enrolled in these studies were exposed to donor blood prior to study entry. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage > 3 with early EPO treatment is of great concern.The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage > 3 with early EPO treatment is of great concern. No further studies comparing early vs. late administration of EPO are warranted.

9. EPO:Other Adverse Effects EPO: Other Adverse Effects FDA updated epo labeling in 2007 to reflect emerging serious adverse effects of treatment with epo, including: Pure red cell aplasia –An aplastic anemia related to the development of anti-epo antibodies Increased mortality –Increased the risk for death and for serious cardiovascular events when administered to target a hemoglobin of greater than 12 g/dL Tumor progression in some oncology patients The risk of the above with epo use in premature infants is not known at this time See details of FDA warning at: See details of FDA warning at: http://www.fda.gov/cder/drug/advisory/RHE200711.htm

10. …just say no to epo …just say no to epo Minimally effective…. Association with severe ROP… Emerging adverse effects (red cell aplasia)… Minimal data on long term safety in premature infants….

11. References 1.Ohls RK, Ehrenkranz RA, Wright LL, Lemons JA, Korones SB, Stoll BJ, Stark AR, Shankaran S, Donovan EF, Close NC, Das A. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial. Pediatrics. 2001 Oct;108(4):934-42. PMID: 11581447 2.Ohls RK, Ehrenkranz RA, Das A, Dusick AM, Yolton K, Romano E, Delaney-Black V, Papile LA, Simon NP, Steichen JJ, Lee KG; National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental outcome and growth at 18 to 22 months' corrected age in extremely low birth weight infants treated with early erythropoietin and iron. Pediatrics. 2004 Nov;114(5):1287-91. PMID: 15520109 3.Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004863. Review. PMID: 16856062 4.Aher S, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004868. Review. PMID: 16856064 5.Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2006 Jul 19;3:CD004865. Review. PMID: 16856063 EPO:References EPO: References