1. Epoetin Alfa & Increased Mortality Maria Shin, Pharm.D. Pharmacy Resident (PGY-1) Kingsbrook Jewish Medical Center Clinical Instructor of Pharmacy Practice Arnold & Marie Schwartz College of Pharmacy and Health Sciences at Long Island University

2. Epoetin Alfa Overview Stimulates red blood cell production Used for treatment of anemia in Chronic renal failure Zidovudine-treated HIV-infected patients Cancer patients on chemotherapy Reduction of allogeneic blood transfusion in surgery patients

3. Epoetin Alfa (Procrit®) Package Insert Revised 2008

4. Normal Vs. Low Hematocrit Clinical Trial Open-label randomized prospective trial 1233 hemodialysis patients with cardiac disease Ischemic heart disease Congestive heart failure Target different hematocrit [hemoglobin (Hb)] 42% (Hb ~14 g/dL) - 618 patients 30% (Hb ~10 g/dL) - 615 patients Primary End point: length of time to death or first nonfatal myocardial infarction (MI) Besarab A et al. NEJM 1998;339:585-90

5. Normal Vs. Low Hematocrit Besarab A et al. NEJM 1998;339:585-90 ADMINISTRATION OF EPOETIN ALFA TO 42% TARGET HEMOGLOBIN NOT RECOMMENDED!

6. CHOIR Trial Randomized prospective trial 1432 anemic patients with chronic renal failure Baseline Hgb levels < 11 g/dL Target different hemoglobin (Hb) levels 13.5 vs 11.3 g/dL 715 patients in higher hgb group 717 patients in lower hgb group Endpoints: mortality and QOL Singh AK et al. NEJM 2006;355:2085-98

7. CHOIR Trial - Results Trial stopped prematurely at 10 months Major cardiovascular event 125 (17.5%) in higher hb group 97 (13.5%) in lower hb group HR 1.3 (95% CI 1.0 – 1.7, p=0.03) Greater risks for death and serious cardiovascular events in higher Hgb group Quality-of-life scores similar in both groups Singh AK et al. NEJM 2006;355:2085-98

8. CHOIR Trial - Results Singh AK et al. NEJM 2006;355:2085-98

9. CHOIR Trial - Results Singh AK et al. NEJM 2006;355:2085-98

10. Meta-Analysis Nine randomized controlled trials with 5143 patients with chronic kidney disease (CKD) Poorer outcomes with high Hb targets (>12 g/dL) versus lower (<12 g/dL) Increased risk of all-cause mortality (RR=1.17, 95% CI 1.01-1.35, p=0.031) Arteriovenous access thrombosis (RR=1.34, 95% CI 1.16-1.54, p=0.0001) Uncontrolled hypertension (RR=1.27, 95% CI 1.08-1.50, p=0.004) MI incidence same between the groups Phrommintikul A et al. Lancet 2007;369:381-388

11. Meta-Analysis: Results Phrommintikul A et al. Lancet 2007;369:381-388

12. Epoetin Alfa & Increased Mortality Mechanism unclear Higher hemoglobin target Increased risk of cardiovascular thrombosis Raised blood pressure Epoetin alfa increases blood viscosity (increased erythrocyte mass) Increased inflammation and anti- fibrinolytic activity Others: stimulation of vascular growth & dysregulation of production and responsiveness of vasoactive factors

13. Toxic Effect of Increased Iron Treatment Increased Viscosity/ Endothelial Damage Increased Platelet Adhesion Extreme Hemoconcentration In HD Patient Increased Blood Pressure Increased Cardiovascular Risk Increased Blood Volume Toxic Effect of Nonbiologic ESA Treatment Fishbane S et al. Clin J Am Soc Nephrol 2007;2:1274-1282

14. Application to Clinical Practice Target lower hemoglobin levels Maintain Hb levels between 10-12 g/dL NOT > 13 g/dL DO NOT target hemoglobin rise of > 1g/dL over 2 weeks Epoetin Alfa (Procrit®) Package Insert Revised 2008

15. KDOQI Guidelines “In patients with CKD, Hb should be 11.0 g/dL or greater.” “There is insufficient evidence to recommend routinely maintaining Hb levels at 13.0 g/dL or greater in ESA-treated patients.” NKF KDOQI Guidelines AJKD 2006;47(5, Suppl 3)

16. Epoetin Alfa Dosing Guidelines Chronic renal failure 50-100 units/kg 3 times/week Cancer patients on chemotherapy 150 units/kg 3 times/week or 40,000 units once weekly Zidovudine-treated, HIV-infected patients 100 units/kg 3 times/week for 8 weeks Epoetin Alfa (Procrit®) Package Insert Revised 2008

17. Epoetin Alfa Dosage Adjustment Guidelines Hemoglobin Levels Dosage Adjustments Frequency Approaches 12 g/dL or increases > 1 g/dL in any 2 week period Decrease dose by 25% Do not increase dose more frequently than every 4 weeks unless clinically indicated > 12 g/dLHold dose and resume at 25% dose reduction < 10 g/dL and not increase by 1 g/dL after 4 weeks Increase dose by 25% Epoetin Alfa (Procrit®) Package Insert Revised 2008

18. Patient Counseling Frequent blood tests are required Blood pressure may increase - monitor Report symptoms of edema (swollen extremities, etc) severe headache, dizziness, blurred vision, pain