Jamie Johnston, MD
University of Pittsburgh
School of Medicine

 Stockholder
 Pfizer and Merck (Both < $10K)
 Before 2005 Talks for
 Pfizer, Merck, Genzyme and one for Amgen
 Renal division had educational grant from
Amgen
 Trinkets and food

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Designated as “Thought Leader”
 The real meaning behind this!
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NPR Oct 21, 2010, “All Things Considered”
 ProPublica Database
 17,000 doctors
 $250,000,000
 384 doctors received greater than $100,000 in last 18 months, 45 not board specialized
 2013 – all will be listed by US gov’t

 1893-1977
 hypoxia and bone marrow stimulation
 1977
 Miyake et al isolated erythropoietin from 2500 liters of urine from patients with aplastic anemia
 1984
 Lai et al characterized molecular structure

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1984 - human EPO gene cloned and expressed
1986-89
 Clinical trials proved the rhEPO was effective in raising Hgb levels in HD, PD, predialysis and anephric patients
July 1989 - FDA approved
By 1990 - 2000 treated
By 1991 - 175,000

 Anemia endemic in the dialysis and pre dialysis population
 Transfusion only consistent means of replacing blood

 Transfusion associated problems
 Hepatitis B
 Other blood borne viral infections
 Decreased transplant success
 Sensitization of the patient to possible kidney transplants
 Iron Overload Syndromes
 hemochromatosis

 Characteristic skin pigmentation change
 yellowish-green (90%)
 Iron deposition in
 Liver (95%), Diabetes Mellitus (65%), arthropathy (25-50%) Heart (15%)
 CHF in 10% especially young people
 Death

 Transfusions in the dialysis population
 90% decrease
 Well being
 70-90% of patients report improved energy level, sleep, appetite, sexual function, well being.
 Decreased cold intolerance
 1989 - EPO reimbursed at $40/dose
(amount didn’t matter)

 Increased risk of death if Hgb < 10-11
 Increased risk of hospitalization if Hct < 36
 In patients with cardiac disease, partial correction of anemia
 Decreases exercise-induced cardiac ischemia
 Improves left ventricular hypertrophy

 In 1993 only 46% of hemodialysis patients had 3 month Hct >30%
 Average was 29.6%
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 Despite increase in reimbursement in 1991 for
EPO to $11 per 1000 units
Not replacing iron – no profit from this

 Anemia Treatment algorithm
 Instituted Quality Improvement at dialysis units
 Results
 By 1997 79% of hemodialysis patients had
Hct > 30%
 43% of patients had a Hct > 33%

 National Kidney Foundation Dialysis
Outcome Quality Improvement
(NKF/DOQI)
 Target Hct - 33-36%
 No payment for EPO if three month rolling average of Hct > 36%
 Conservative use of erythropoietin

 Nephrologists unable to meet goal
 Reimbursement liberalized
 Ceiling now 36.5%
 If > 36.5%, full reimbursement if EPO dose decreased 20%

 EPO in use for 9 years without any understanding of optimal Hgb/Hct
 The problem with a natural distribution curve and a government regulation

Hematocrit

Range is 9.27 - 14.07

 Besarab et al NEJM 1998;339:584
 1223 patients with CHF or IHD
 On dialysis
 Group 1 - Hct of 42 Group 2 - Hct of 30
 Primary endpoints - death, non fatal MI
 Study halted at 29 mo, median duration 14 mo
 Supported by Amgen

 Besarab et al NEJM 1998;339:584
 Group 1
(high)
: 183 deaths, 19 nonfatal MI
 Group 2 : 150 deaths, 14 nonfatal MI
 Risk ratio Group 1 v Group 2 was 1.3 with confidence intervals of 0.9 - 1.9

The CHOIR Study
Correction of Hemoglobin and Outcomes in Renal
Insufficiency (funded by Ortho Biotech)
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Hypothesis – stable high Hgb level will decrease the risk of cardiovascular outcomes when compared to a lower Hgb level
Open label, randomized trial
130 centers in the United States
1432 patients with CKD
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715 randomized to target Hgb of 13.5 g/dl
717 randomized to target Hgb of 11.3 g/dl
Eligibility
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Age>18 years old eGFR of 15 to 50 ml/min
NEJM 355: 2085-2098, 2006

RESULTS FROM THE CHOIR STUDY
 222 composite events occurred
 125 events in the high Hgb group
 97 events among the low Hgb group
 p=0.03
 Hazard ratio 1.34 with a 95% Cl
NEJM 355: 2085-2098, 2006

RESULTS FROM THE CHOIR STUDY
 Higher rates of composite events in the high Hgb group was explained by a combination of
 Higher death rate
 48% higher in high Hgb group (p=0.07)
 Higher rate of CHF hospitalization
 41% higher in high Hgb group (p=0.07)
 Improvement in QOL in both groups without statistical significance
NEJM 355: 2085-2098, 2006

Cardiovascular Risk Reduction by Early Anemia
Treatment with Epoetin Beta
(Funded by F Hoffman-LaRoche)
 603 patients, 3 year follow up
 Patient characteristics
 Mean GFR 25 ml/min (range 15 to 35) calculated by the Cockcroft-Gault and MDRD equations
 Baseline Hgb had to be 11 to 12.5 g/dl
 Groups were targeted for Hgb 13.5 g/dl vs.
Hgb 11.5 g/dl
 Echocardiography was performed at baseline and then annually or at initiation of hemodialysis
NEJM 355: 2071-2084, 2006

RESULTS FROM THE CREATE STUDY
 Control of blood pressure
 Mean blood pressures did not differ between groups
 Incidence of hypertension was higher in the high
Hgb group (P=0.005)
 Higher use of beta blockers in group 1 (high Hgb)
 In all groups the number of antihypertensive drugs increased over the time of the study
NEJM 355: 2071-2084, 2006

RESULTS FROM THE CREATE STUDY
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A total of 105 patients had cardiovascular events
No significant difference (hazard ratio 0.78; 95% CI; P=0.20)
Censoring data by start of dialytic therapy did not change the hazard ratio
 Group 1 (High Hgb)
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58 events
10% deaths
4% deaths from cardiac cause
7% cardiovascular intervention
61% hospital admission
33 days duration of hospital stay
 Group 2 (Low Hgb)
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47 events
21 deaths (7%)
3% deaths from cardiac cause
6% cardiovascular intervention
59% hospital admission
28.3 days duration of hospital stay
NEJM 355: 2071-2084, 2006

RESULTS FROM THE CREATE STUDY
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Measured by SF-36
Statistically significantly better in Group 1 in year 1
Differences between groups may not be clinically significant
By year two the difference was maintained for
 general health (P=0.008) and
 vitality (P=0.01)
NEJM 355: 2071-2084, 2006

 ESA associated with development of Pure red cell aplasia (especially subcutaneously)
 ESA to treat cancer caused anemia
 Danish study where head and neck cancer worsened

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March 2007
Recommends:
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Using the lowest dose possible to increase
Hgb concentration
Implicates ESAs for increased death and cardiovascular events
ESAs should be withheld if the Hgb>12

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Reviewed 255 relevant articles and 122 abstracts regarding mortality in anemic patients with CKD between
2000-2006
9 clinical trials were selected that met stringent criteria:
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Randomized and controlled
Targeted different Hgb levels
Data had sufficient quality
Hgb ranges were disparate
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High ranges up to 16 mg/dl
Low ranges as low as 9 mg/dl
Lancet 369: 381-388, 2007

Lancet 369: 381-388, 2007

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Studies indicate that risk for death may be higher with higher Hgb levels
No study has shown a reduction in mortality with higher targets of Hgb
No study has determined the ideal or optimal level of
Hgb
There is a high degree of overlap in in target Hgb levels in the medical literature
Keeping patients within tight limits of Hgb levels is quite difficult

 $1000 investment in Amgen in 1984
 Worth $452,000 in 2006
 Largest biotech company in the world

 Amgen - Epogen, Procrit, Aranesp
 Ortho Biotech (J and J) - Markets procrit in the US. Makes Eprex for sale in Europe
 Shire Labs - Dynepo
 Hoffman La Roche C.E.R.A - continuous erythropoietin receptor activator,
Neorecormon (epoetin beta)

 Amgen & others increasingly visible
 Support for national meetings
 Support for divisions
 Support for experts (high ranking academics, division chiefs)
 Consulting fees
 Honoraria for speaking
 Experts determine hospital formulary

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Central Medicare and Medicaid System
 EPO Monitoring Policy Group
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24 members
75% have financial associations with Amgen or Johnson &
Johnson
National Kidney Foundation
DOQI - 15 of 21 in work group had ties to industry
American Kidney Fund - Amgen funds clinical
Fellowship Program

 Hearing on Patient safety and Quality
Issues in ESRD Treatment
 Dec 6, 2006
 Rep. Pete Stark
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…”almost $20 million dollars in corporate donations from the Platinum friends, Amgen,
DaVita.
…”It’s a cozy club, isn’t it?”

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After last year’s talk
 NEJM article
 Use of Aranesp doubled stroke risk
 Patients with Type 2 DM, CKD, moderate anemia
 N = 4038
 Strokes in 101 receiving aranesp and 53 receiving placebo