Use and Overuse: How the Marketing of One Drug May Have Harmed the Patients It Was Supposed to Help...
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Transcript of Use and Overuse: How the Marketing of One Drug May Have Harmed the Patients It Was Supposed to Help...
Use and Overuse: How the Marketing of One Drug
May Have Harmed the Patients It Was Supposed to Help
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
Jamie Johnston, MD
University of Pittsburgh
School of Medicine
DisclosuresDisclosures
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
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
DisclosureDisclosure Designated as “Thought Leader” The real meaning behind this!
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
Designated as “Thought Leader” The real meaning behind this!
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
History of ErythropoietinHistory of Erythropoietin
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
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
History of ErythropoietinHistory of Erythropoietin
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
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
Before rhEPOBefore rhEPO
Anemia endemic in the dialysis and pre dialysis population
Transfusion only consistent means of replacing blood
Anemia endemic in the dialysis and pre dialysis population
Transfusion only consistent means of replacing blood
Before rhEPOBefore rhEPO
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
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
HemochromatosisHemochromatosis
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
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
ErythropoietinThe Good
ErythropoietinThe Good
Erythropoietin UseErythropoietin Use
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)
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)
What level of Hemoglobin?What level of Hemoglobin?
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
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
What level of Hemoglobin?What level of Hemoglobin?
In 1993 only 46% of hemodialysis patients had 3 month Hct >30% Average was 29.6% Despite increase in reimbursement in 1991 for
EPO to $11 per 1000 units Not replacing iron – no profit from this
In 1993 only 46% of hemodialysis patients had 3 month Hct >30% 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 ProjectNational Anemia Cooperative Project
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%
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%
19971997
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
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
19981998
Nephrologists unable to meet goal Reimbursement liberalized
Ceiling now 36.5% If > 36.5%, full reimbursement if EPO dose
decreased 20%
Nephrologists unable to meet goal Reimbursement liberalized
Ceiling now 36.5% If > 36.5%, full reimbursement if EPO dose
decreased 20%
ProblemsProblems
EPO in use for 9 years without any understanding of optimal Hgb/Hct
The problem with a natural distribution curve and a government regulation
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
Erythropoietin The Bad
Normalizing HctNormalizing Hct
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 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
Normalizing HctNormalizing Hct
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
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 StudyCorrection of Hemoglobin and Outcomes in Renal
Insufficiency (funded by Ortho Biotech)
The CHOIR StudyCorrection of Hemoglobin and Outcomes in Renal
Insufficiency (funded by Ortho Biotech) 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
715 randomized to target Hgb of 13.5 g/dl 717 randomized to target Hgb of 11.3 g/dl
Eligibility Age>18 years old eGFR of 15 to 50 ml/min
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
715 randomized to target Hgb of 13.5 g/dl 717 randomized to target Hgb of 11.3 g/dl
Eligibility Age>18 years old eGFR of 15 to 50 ml/min
NEJM 355: 2085-2098, 2006
Primary OutcomesPrimary OutcomesPrimary OutcomesPrimary Outcomes
222 composite events occurred222 composite events occurred 125 events in the high Hgb group125 events in the high Hgb group 97 events among the low Hgb group97 events among the low Hgb group p=0.03p=0.03 Hazard ratio 1.34 with a 95% ClHazard ratio 1.34 with a 95% Cl
222 composite events occurred222 composite events occurred 125 events in the high Hgb group125 events in the high Hgb group 97 events among the low Hgb group97 events among the low Hgb group p=0.03p=0.03 Hazard ratio 1.34 with a 95% ClHazard ratio 1.34 with a 95% Cl
NEJM 355: 2085-2098, 2006
RESULTS FROM THE CHOIR STUDY
Primary OutcomesPrimary OutcomesPrimary OutcomesPrimary Outcomes
Higher rates of composite events in the Higher rates of composite events in the high Hgb group was explained by a high Hgb group was explained by a combination ofcombination of Higher death rateHigher death rate
48% higher in high Hgb group (p=0.07)48% higher in high Hgb group (p=0.07) Higher rate of CHF hospitalizationHigher rate of CHF hospitalization
41% higher in high Hgb group (p=0.07)41% higher in high Hgb group (p=0.07)
Improvement in QOL in both groups Improvement in QOL in both groups without statistical significancewithout statistical significance
Higher rates of composite events in the Higher rates of composite events in the high Hgb group was explained by a high Hgb group was explained by a combination ofcombination of Higher death rateHigher death rate
48% higher in high Hgb group (p=0.07)48% higher in high Hgb group (p=0.07) Higher rate of CHF hospitalizationHigher rate of CHF hospitalization
41% higher in high Hgb group (p=0.07)41% higher in high Hgb group (p=0.07)
Improvement in QOL in both groups Improvement in QOL in both groups without statistical significancewithout statistical significance
NEJM 355: 2085-2098, 2006
RESULTS FROM THE CHOIR STUDY
The CREATE StudyCardiovascular Risk Reduction by Early Anemia
Treatment with Epoetin Beta (Funded by F Hoffman-LaRoche)
The CREATE StudyCardiovascular 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
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
Control of Blood PressureControl of Blood Pressure
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
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
Cardiovascular EventsCardiovascular Events
Group 1 (High Hgb) 58 events 10% deaths 4% deaths from cardiac
cause 7% cardiovascular
intervention 61% hospital admission 33 days duration of hospital
stay
Group 1 (High Hgb) 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) 47 events 21 deaths (7%) 3% deaths from cardiac
cause 6% cardiovascular
intervention 59% hospital admission 28.3 days duration of hospital
stay
Group 2 (Low Hgb) 47 events 21 deaths (7%) 3% deaths from cardiac
cause 6% cardiovascular
intervention 59% hospital admission 28.3 days duration of hospital
stay
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
NEJM 355: 2071-2084, 2006
RESULTS FROM THE CREATE STUDY
Quality of LifeQuality of Life 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)
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)
RESULTS FROM THE CREATE STUDY
NEJM 355: 2071-2084, 2006
More bad news….More bad news….
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
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
FDA WarningFDA Warning
March 2007 Recommends:
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
March 2007 Recommends:
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-AnalysisMeta-Analysis
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: Randomized and controlled Targeted different Hgb levels Data had sufficient quality
Hgb ranges were disparate High ranges up to 16 mg/dl Low ranges as low as 9 mg/dl
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: Randomized and controlled Targeted different Hgb levels Data had sufficient quality
Hgb ranges were disparate High ranges up to 16 mg/dl Low ranges as low as 9 mg/dl
Lancet 369: 381-388, 2007
Meta-AnalysisMeta-Analysis
Lancet 369: 381-388, 2007
ConclusionsConclusions
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
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
ErythropoietinThe Ugly
ErythropoietinThe Ugly
Blockbuster CompanyBlockbuster Company
$1000 investment in Amgen in 1984 Worth $452,000 in 2006 Largest biotech company in the world
$1000 investment in Amgen in 1984 Worth $452,000 in 2006 Largest biotech company in the world
Available forms of ErythropoietinAvailable forms of Erythropoietin
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 - 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 salesErythropoietin sales
Other TrendsOther Trends
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
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
Patient Care GuidelinesPatient Care Guidelines
Central Medicare and Medicaid System EPO Monitoring Policy Group
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
Central Medicare and Medicaid System EPO Monitoring Policy Group
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 MeansHouse Committee on Ways and Means
Hearing on Patient safety and Quality Issues in ESRD Treatment
Dec 6, 2006 Rep. Pete Stark
…”almost $20 million dollars in corporate donations from the Platinum friends, Amgen, DaVita.
…”It’s a cozy club, isn’t it?”
Hearing on Patient safety and Quality Issues in ESRD Treatment
Dec 6, 2006 Rep. Pete Stark
…”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…It hasn’t stopped…
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
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
What do we do?What do we do?