Title: Review of literature and report of experience with erythropoietin in ESRD populations
1Review 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
2Different 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.
3Dialysis Facility Ownership and Epoetin Dosing in
Hemodialysis Patients A Dialysis Providers
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 achieved13.3g/dl
4There 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.
52005 Annual Report ESRD CPM Project
6Individual Patient Variability among Patients
with Ngt10 Hemoglobin Values (Jan-Dec 2000)
N48,133 patients
Lacson E, Ofsthun N, Lazarus JM. Effect of
Variability in Anemia Management on Hemoglobin
Outcomes in ESRD. AJKD 41111-124, 2003
7Ofsthun NJ, Lazarus JM. Impact of the Change in
CMS Billing Rules for Erythropoietin on
Hemoglobin Outcomes in Dialysis Patients. Blood
Purification 2531-35, 2007
8Variable 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
9Shift in Distribution of Three Month Average
Hemoglobin Required to Achieve 0.1 of
Epo-Receiving Patients with HGB gt 12.0 g/dl
10ESRD 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, 65626-633
11The Effects of Higher Hemoglobin levels on
Mortality and Hospitalization in Hemodialysis
Patients
July 1998 to July 2000
NS
statistically significant difference from
reference 95 confidence intervals shown
Ofsthun et al KI 631908-1914, 2003
12Associations between Changes in Hemoglobin and
Administered Erythropoiesis Stimulating Agents
and Survival in Hemodialysis Patients
Regidor, et al JASN 171181-1191,2006
13Role 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.
14Summary
- 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
its avoidance is poor guidance for clinicians.