Transcript Use and Overuse: How the Marketing of One Drug May Have

Use and Overuse:
How the Marketing of One Drug
May Have Harmed the Patients It
Was Supposed to Help
Jamie Johnston, MD
University of Pittsburgh
School of Medicine
Disclosures
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Stockholder
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Before 2005 Talks for
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Pfizer and Merck (Both < $10K)
Pfizer, Merck, Genzyme and one for Amgen
Renal division had educational grant from
Amgen
Trinkets and food
Disclosure
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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
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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
History of Erythropoietin
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1893-1977
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1977
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hypoxia and bone marrow stimulation
Miyake et al isolated erythropoietin from 2500
liters of urine from patients with aplastic
anemia
1984
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Lai et al characterized molecular structure
History of Erythropoietin
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1984 - human EPO gene cloned and expressed
1986-89
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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
Before rhEPO
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Anemia endemic in the dialysis and pre
dialysis population
Transfusion only consistent means of
replacing blood
Before rhEPO
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Transfusion associated problems
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Decreased transplant success
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Hepatitis B
Other blood borne viral infections
Sensitization of the patient to possible kidney
transplants
Iron Overload Syndromes
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hemochromatosis
Hemochromatosis
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Characteristic skin pigmentation change
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Iron deposition in
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yellowish-green (90%)
Liver (95%), Diabetes Mellitus (65%),
arthropathy (25-50%) Heart (15%)
CHF in 10% especially young people
Death
Erythropoietin
The Good
Erythropoietin Use
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Transfusions in the dialysis population
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Well being
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90% decrease
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)
What level of Hemoglobin?
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Increased risk of death if Hgb < 10-11
Increased risk of hospitalization if Hct < 36
In patients with cardiac disease, partial
correction of anemia
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Decreases exercise-induced cardiac ischemia
Improves left ventricular hypertrophy
What level of Hemoglobin?
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In 1993 only 46% of hemodialysis patients
had 3 month Hct >30%
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Average was 29.6%
Despite increase in reimbursement in 1991 for
EPO to $11 per 1000 units
Not replacing iron – no profit from this
National Anemia Cooperative Project
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Anemia Treatment algorithm
Instituted Quality Improvement at dialysis
units
Results
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By 1997 79% of hemodialysis patients had
Hct > 30%
43% of patients had a Hct > 33%
1997
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National Kidney Foundation Dialysis
Outcome Quality Improvement
(NKF/DOQI)
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Target Hct - 33-36%
No payment for EPO if three month rolling
average of Hct > 36%
Conservative use of erythropoietin
1998
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Nephrologists unable to meet goal
Reimbursement liberalized
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Ceiling now 36.5%
If > 36.5%, full reimbursement if EPO dose
decreased 20%
Problems
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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
Erythropoietin
The Bad
Normalizing Hct
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Besarab et al NEJM 1998;339:584
1223 patients with CHF or IHD
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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
Normalizing Hct
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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
Primary Outcomes
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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
Primary Outcomes
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Higher rates of composite events in the
high Hgb group was explained by a
combination of
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Higher death rate
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Higher rate of CHF hospitalization
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48% higher in high Hgb group (p=0.07)
41% higher in high Hgb group (p=0.07)
Improvement in QOL in both groups
without statistical significance
NEJM 355: 2085-2098, 2006
The CREATE Study
Cardiovascular Risk Reduction by Early Anemia
Treatment with Epoetin Beta
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603 patients, 3 year follow up
Patient characteristics
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(Funded by F Hoffman-LaRoche)
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
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Control of blood pressure
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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
Cardiovascular Events
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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
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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
Quality of Life
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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
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general health (P=0.008) and
vitality (P=0.01)
NEJM 355: 2071-2084, 2006
More bad news….
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ESA associated with development of Pure
red cell aplasia (especially
subcutaneously)
ESA to treat cancer caused anemia
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Danish study where head and neck cancer
worsened
FDA Warning
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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
Meta-Analysis
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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
Meta-Analysis
Lancet 369: 381-388, 2007
Conclusions
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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
Erythropoietin
The Ugly
Blockbuster Company
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$1000 investment in Amgen in 1984
Worth $452,000 in 2006
Largest biotech company in the world
Available forms of Erythropoietin
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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)
Erythropoietin sales
Other Trends
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Amgen & others increasingly visible
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Support for national meetings
Support for divisions
Support for experts (high ranking academics,
division chiefs)
Consulting fees
 Honoraria for speaking
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Experts determine hospital formulary
Patient Care Guidelines
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Central Medicare and Medicaid System
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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
House Committee on Ways and Means
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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?”
It hasn’t stopped…
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After last year’s talk
NEJM article
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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
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What do we do?