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Jamie Johnston, MD University of Pittsburgh School of Medicine

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. Stockholder Pfizer and Merck (Both < $10K) Before 2005 Talks for Pfizer, Merck, Genzyme and one for Amgen

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Jamie Johnston, MD University of Pittsburgh School of Medicine

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  1. 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

  2. Disclosures • 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

  3. Disclosure • 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

  4. History 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

  5. History 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

  6. Before rhEPO • Anemia endemic in the dialysis and pre dialysis population • Transfusion only consistent means of replacing blood

  7. Before 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

  8. 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

  9. ErythropoietinThe Good

  10. Erythropoietin 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)

  11. 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

  12. 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

  13. National 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%

  14. 1997 • 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

  15. 1998 • Nephrologists unable to meet goal • Reimbursement liberalized • Ceiling now 36.5% • If > 36.5%, full reimbursement if EPO dose decreased 20%

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

  17. Hematocrit

  18. Range is 9.27 - 14.07

  19. Erythropoietin The Bad

  20. Normalizing 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

  21. Normalizing 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

  22. 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 NEJM 355: 2085-2098, 2006

  23. Primary Outcomes 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

  24. Primary Outcomes 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

  25. 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 NEJM 355: 2071-2084, 2006

  26. Control 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 RESULTS FROM THE CREATE STUDY NEJM 355: 2071-2084, 2006

  27. Cardiovascular 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 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 RESULTS FROM THE CREATE STUDY • 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

  28. Quality 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) RESULTS FROM THE CREATE STUDY NEJM 355: 2071-2084, 2006

  29. 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

  30. FDA 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

  31. Meta-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 Lancet 369: 381-388, 2007

  32. Meta-Analysis Lancet 369: 381-388, 2007

  33. Conclusions • 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

  34. ErythropoietinThe Ugly

  35. Blockbuster Company • $1000 investment in Amgen in 1984 • Worth $452,000 in 2006 • Largest biotech company in the world

  36. Available 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)

  37. Erythropoietin sales

  38. Other 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

  39. Patient 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

  40. House 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?”

  41. 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

  42. What do we do?

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