2. 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

3. 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 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

4. 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 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

5. 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 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

6. 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 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

7. Before 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

8. 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 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

9. 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 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

10. Erythropoietin The Good

11. 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) 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)

12. 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

13. 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

15. 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% 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%

16. 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 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

17. 1998 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%

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

19. Hematocrit

20. Range is 9.27 - 14.07

21. Erythropoietin The Bad

22. 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 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

23. 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 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

25. The CHOIR Study Correction 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

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

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

28. The CREATE Study 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

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

30. 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 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

31. 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

34. 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

35. 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 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

36. 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 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

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

38. 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 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

39. Erythropoietin The Ugly

40. Blockbuster 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

41. 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) 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)

42. Erythropoietin sales

43. 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 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

44. 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 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

45. 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?” 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?”

46. 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

47. What do we do?