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®) Package Insert 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 antifibrinolytic activity
Others: stimulation of vascular growth &
dysregulation of production and
responsiveness of vasoactive factors
Increased
Viscosity/
Endothelial
Damage
Increased
Platelet
Adhesion
Extreme
Hemoconcentration
Toxic Effect
of Increased
Iron
Treatment
Toxic Effect
of Nonbiologic
ESA
Treatment
Increased
Cardiovascular
Risk
In HD
Patient
Increased
Blood
Volume
Increased
Blood
Pressure
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®) Package Insert 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®) Package Insert Revised 2008
Epoetin Alfa Dosage Adjustment
Guidelines
Hemoglobin
Levels
Dosage
Adjustments
Approaches 12 g/dL
or increases > 1 g/dL
in any 2 week period
> 12 g/dL
Decrease dose
by 25%
< 10 g/dL and not
increase by 1 g/dL
after 4 weeks
Frequency
Do not
increase dose
more
frequently than
Hold dose and
every 4 weeks
resume at 25%
unless
dose reduction
clinically
Increase dose by
indicated
25%
Epoetin Alfa (Procrit®) Package Insert 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