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

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

Epoetin Alfa (Procrit ®)

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Revised 2008

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

Normal Vs. Low Hematocrit

ADMINISTRATION OF EPOETIN ALFA TO 42% TARGET HEMOGLOBIN NOT RECOMMENDED!

Besarab A et al.

NEJM

1998;339:585-90

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

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

CHOIR Trial - Results

Singh AK et al.

NEJM

2006;355:2085-98

CHOIR Trial - Results

Singh AK et al.

NEJM

2006;355:2085-98

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

Meta-Analysis: Results

Phrommintikul A et al.

Lancet

2007;369:381-388

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

Increased Viscosity/ Endothelial Damage Increased Platelet Adhesion Toxic Effect of Increased Iron Treatment Increased Cardiovascular Risk Extreme Hemoconcentration In HD Patient Toxic Effect of Nonbiologic ESA Treatment Increased Blood Pressure Increased Blood Volume

Fishbane S et al.

Clin J Am Soc Nephrol

2007;2:1274-1282

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 ®)

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Revised 2008

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)

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 ®)

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Revised 2008

Epoetin Alfa Dosage Adjustment Guidelines

Hemoglobin Levels

Approaches 12 g/dL or increases > 1 g/dL in any 2 week period > 12 g/dL < 10 g/dL and not increase by 1 g/dL after 4 weeks

Dosage Adjustments Frequency

Decrease dose by 25% Hold dose and resume at 25% dose reduction Increase dose by 25% Do not increase dose more frequently than

every 4 weeks

unless clinically indicated Epoetin Alfa (Procrit ®)

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Revised 2008

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