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Epoetin Alfa & Increased Mortality Maria Shin, Pharm.D. Pharmacy Resident (PGY-1) Kingsbrook Jewish Medical Center Clinical Instructor of Pharmacy Practice.

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Presentation on theme: "Epoetin Alfa & Increased Mortality Maria Shin, Pharm.D. Pharmacy Resident (PGY-1) Kingsbrook Jewish Medical Center Clinical Instructor of Pharmacy Practice."— Presentation transcript:

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) patients 30% (Hb ~10 g/dL) 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: 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:

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:

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

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

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 , p=0.031) Arteriovenous access thrombosis (RR=1.34, 95% CI , p=0.0001) Uncontrolled hypertension (RR=1.27, 95% CI , p=0.004) MI incidence same between the groups Phrommintikul A et al. Lancet 2007;369:

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

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:

14 Application to Clinical Practice Target lower hemoglobin levels Maintain Hb levels between 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 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


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