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

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.

Dialysis Facility Ownership and Epoetin Dosing in HemodialysisPatients: 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

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.

2005 Annual Report ESRD CPM Project

Distribution of Individual Patient Standard Deviations of 3 Month HGB Rolling Averages

0%

2%

4%

6%

8%

10%

12%

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5

Intra-Patient Standard Deviation of One-Month Hemoglobin Rolling Average (g/dl)

Per

cent

of P

atie

nts

Jan 00 - Dec 00 DataN=48,133 patients

25thPercentile 50th Percentile

75th Percentile

Intrapatient Standard Deviation of Three-MonthHgb Rolling Average (g/dL)

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)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Mar 06 May 06 Jul 06

LatestHgb >13 g/dl

LatestHgb<11 g/dl

Latest Hgb>12-13 g/dl

LatestHgb >13 g/dl

LatestHgb<11 g/dl

Latest Hgb>12-13 g/dl

LatestHgb >13 g/dl

TARGET RANGE

Latest Hgb11-12 g/dl

LatestHgb<11 g/dl

Latest Hgb>12-13 g/dl

TARGET RANGE

Latest Hgb11-12 g/dl

TARGET RANGE

Latest Hgb11-12 g/dl

Movement of Patients Among HGB CategoriesP

erce

nt o

f Pat

ient

Gro

up

1 Apr 06EMP

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

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

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

5,0005

.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10

.0

10

.5

11

.0

11

.5

12

.0

12

.5

13

.0

13

.5

14

.0

14

.5

15

.0

Three Month Average Hemoglobin, Rounded to 0.1 g/dl

Nu

mb

er o

f P

atie

nts

Dec'06-Feb'07 Average HGB (N=107,700)

Shifted to 0.1% Patients with 3 Mo HGB >12.0

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

3 Month Avg HGB

Actual Distribution

Shifted to 0.1% HGB > 12.0 g/dl

%<10 4.4% 60.1%%<11 15.5% 64.2%

%11-12 34.4% 1.3%%>12 50.2% 0.094%%>13 17.1% 0.0%

Mean SDActual (Blue) N=107,700

12.02 1.16

Shifted to 0.1%>12 (Red)

8.22 1.16

ESRD: Higher Hematocrit is Associated with Lower Risk of Death

1.00

1.55

1.18

0.92 0.86

0.00.2

0.40.60.8

1.01.21.4

1.61.8

<30 30-33 33-36 36-39 >39

Hematocrit (%)

Rela

tive

Risk

of D

eath

50,579 incident HD patients in the US between Jan 98 – Dec 1999Follow-up 2.5 yrs (hospitalization) and 3.0 yrs (mortality)

Li & Collins, Kid Int 2004, 65:626-633

0.0

0.5

1.0

1.5

2.0

2.5

3.0

N=1,607 1,234 4,268 3,466 11,790 9,857 18,758 16,044 6,670 5,515 1,457 1,090

Hgb < 9 9<=Hgb<10 10<=Hgb<11 11<=Hgb<12 12<=Hgb<13 Hgb >13

Baseline Hemoglobin Category (g/dl)

Re

lativ

e R

isk

of

De

ath

Unadjusted

Adjusted

Reference

*

*

*

*

*

**

* *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

Associations between Changes in Hemoglobin and Administered Erythropoiesis Stimulating Agents and Survival in Hemodialysis Patients*

*Regidor, et al JASN 17:1181-1191,2006

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.

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.