1. Review of literature and report of experience with erythropoietin in ESRD populations Summary to FDA Cardio Renal Committee J. Michael Lazarus, M.D. CMO Fresenius Medical Care NA September 11, 2007

2. Different Disease Categories ESRD or dialysis patients are different from CKD patients and are particularly different from cancer patients –Anemia of uremia is related to the disease process (renal failure and insufficient erythropoietin production) - not another therapy (i.e. chemotherapy). –Anemia of uremia is permanent and is a major contributor of symptoms and co- morbidity. –ESRD patients have a high incidence of cardiovascular disease (for the most part medial atherosclerosis) which is related in large part to anemia. –ESRD patients are not on chemotherapeutic agents (less than 1% of ESRD patients being admitted for treatment of cancer in 2006). –ESRD patients have thrombocytopenia and abnormal platelet function, not the hypercoaguable state often found in cancer patients. –ESRD patients receive large doses of heparin on a regular basis. –Unlike CKD patients, hypertension and volume overload are controlled in ESRD patients by dialysis. –ESRD patients respond differently to ESAs than CKD and particularly cancer patients- the dosing ranges are significantly different The FDA must develop separate and distinct indications, dosage recommendations and warnings for erythropoietin for these different categories of patients.

3. Dialysis Facility Ownership and Epoetin Dosing in Hemodialysis Patients: A Dialysis Provider’s Perspective. American Journal of Kidney Diseases, Vol 50, No 3 (September), 2007: pp 366-370 Addendum- Parfrey et al JASN 2005 Goal = 13.5 to 14.0g/dl and achieved=13.3g/dl

4. There may be evidence of death risk in ESRD patients at achieved hemoglobin values of 13.0 to 13.5g/dl but that information comes from only one of three RCTs. There is no scientific evidence for a safety concern at a hemoglobin level of 12.0g/dl in ESRD patients.

5. 2005 Annual Report ESRD CPM Project

6. N=48,133 patients Lacson E, Ofsthun N, Lazarus JM. Effect of Variability in Anemia Management on Hemoglobin Outcomes in ESRD. AJKD 41:111-124, 2003 Individual Patient Variability among Patients with N>=10 Hemoglobin Values (Jan-Dec 2000)

7. Ofsthun NJ, Lazarus JM. Impact of the Change in CMS Billing Rules for Erythropoietin on Hemoglobin Outcomes in Dialysis Patients. Blood Purification 25:31-35, 2007

8. Variable ESRD patient response to erythropoietin administration Creates a distribution curve of hemoglobin values in ESRD patients with a standard deviation of 1.1 Results in a distribution curve of hemoglobin values that is very “stable” although there is marked movement of patients within the distribution curve. Prevents physicians from being able to change the “shape” of the distribution curve (ie eliminate patient at the extremes). Caused a “shift” of the curve- both to the left and to the right in response to Medicare, Medicaid and FI policies

9. Shift in Distribution of Three Month Average Hemoglobin Required to Achieve 0.1% of Epo-Receiving Patients with HGB > 12.0 g/dl

10. ESRD: Higher Hematocrit is Associated with Lower Risk of Death 50,579 incident HD patients in the US between Jan 98 – Dec 1999 Follow-up 2.5 yrs (hospitalization) and 3.0 yrs (mortality) Li & Collins, Kid Int 2004, 65:626-633

11. * * * * * * * * * NS * statistically significant difference from reference; 95% confidence intervals shown The Effects of Higher Hemoglobin levels on Mortality and Hospitalization in Hemodialysis Patients* July 1998 to July 2000 *Ofsthun et al KI 63:1908-1914, 2003

12. Associations between Changes in Hemoglobin and Administered Erythropoiesis Stimulating Agents and Survival in Hemodialysis Patients* *Regidor, et al JASN 17:1181-1191,2006

13. Role and timing of Transfusions in ESRD Patients –Prior to erythropoietin availability the vast majority of dialysis patients received multiple transfusions at varying levels of hemoglobin to remain asymptomatic. (Average ~1u RBC/4weeks in my practice and 6- 8 per year in Amgen data). –The level of hemoglobin at which transfusions were administered differed widely because of variability of response to ESAs Iron overload, risks of hepatitis, and risks of AIDS caused reluctance to transfuse until the patients were extremely symptomatic despite the severe CV consequences of prolonged anemia. Many ESRD patients awaiting transplantation refused (or their physicians advocated against) RBC transfusions because of the problem of sensitization despite profound symptoms and worsening of heart and CNS disease which had severe consequences after “successful” renal transplantation. –Physicians did not and do not transfuse at some preconceived or pre-identified hemoglobin level.

14. Summary ESRD (Dialysis) patients are vastly different. Hemoglobin of 12.0g/dl is not scientifically supported as the level of adverse event concern. Variability of response to ESAs in ESRD patients mandates –distinction between “target” and “achieved” hemoglobin in the PI. –makes the concepts of modifying a dose when “approaching a target” and dosing to “avoid transfusions” confusing and impractical. Transfusion is a treatment- not an outcome and it’s avoidance is poor guidance for clinicians.