Review of literature and report of experience with erythropoietin in ESRD populations

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

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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 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
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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
Individual 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
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Ofsthun NJ, Lazarus JM. Impact of the Change in
CMS Billing Rules for Erythropoietin on
Hemoglobin Outcomes in Dialysis Patients. Blood
Purification 2531-35, 2007
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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

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Shift in Distribution of Three Month Average
Hemoglobin Required to Achieve 0.1 of
Epo-Receiving Patients with HGB gt 12.0 g/dl
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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, 65626-633
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The 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
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Associations between Changes in Hemoglobin and
Administered Erythropoiesis Stimulating Agents
and Survival in Hemodialysis Patients
Regidor, et al JASN 171181-1191,2006
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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.

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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
  its avoidance is poor guidance for clinicians.