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?