1. Erythropoiesis stimulating agents

2. Erythropoesis stimulating agents
Erythropoiesis-stimulating agent, commonly abbreviated ESA, an agent similar to the cytokine (erythropoetin) that stimulates red blood cell production (erythropoeisis). ESAs, structurally and biologically, are similar to naturally occurring protein erythropoietin.
Erythropoietin (Epo)
Epoetin alfa (Procrit/Epogen)
Epoetin beta (NeoRecormon)
Darbepoetin alfa (Aranesp)
Methoxy polyethylene glycol-epoetin beta (Mircera)

3. Background of Erythropoiesis Stimulating Agents (ESAs):
The recombinant human erythropoetin, epoetin alfa, was approved by the FDA in 1993 for the treatment of anemia associated with chemotherapy. It is a 165-amino acid hormone
Epoetin alfa - manufactured by Amgen, Inc., - marketed as Procrit by Ortho Biotech, L.P., a subsidiary of J & J
Darbepoetin, was created by site-directed mutagenesis and differs from epoetin at five amino acid positions (A30N, H32T, P87V, Y88N and P90T). This results in two additional N-linked oligosaccharide attachments at N30 and N88.
Darbepoetin - manufactured and marketed by Amgen, Inc. - approved by the FDA for the treatment of anemia associated with chemotherapy in July of 2002.

4. Anemia
An abnormally low hemoglobin or hematocrit value - multiple conditions may cause anemia, including the loss of erythropoietin due to the destruction of kidney function by chronic kidney disease
Other conditions that may cause anemia are generally unrelated to a deficiency of erythropoietin and are exemplified by anemias due to iron deficiency, certain vitamin deficiencies, hemorrhage, and various intrinsic bone marrow disorders

5. Use of ESAs
Generally, regardless of the cause of anemia, blood transfusions may be necessary to relieve patient symptoms and maintain life when the anemic condition becomes severe
The main goal of treatment with ESAs is to increase the number of red blood cells in patients with the specific types of anemia that are responsive to the ESAs so that blood transfusions are not needed.

6. Overview of ESA Efficacy and Safety:
Treatment with an ESA significantly reduced the RR of blood transfusion by 0.64; 95% CI 0.60 to 0.68, n=6,510. On average, patients treated with ESA received one less unit of blood than the control group.
Relative risk for thromboembolic complications was 1.67; 95% CI to 2.06, n=6,769.
Overall survival HR was 1.08; 95% CI 0.99 to 1.18, n=8,167.
“Suggestive evidence” that treatment with ESAs improves quality of life.
All data from Bohlius et al. from the Cochrane Database of Systematic Reviews 2006, Issue 3 which is a review of 57 trials with 9,353 (cancer) patients.

7. What is the Correct Hemoglobin Target (or Range) for ESAs in Anemia of Chronic Renal Failure?

8. Randomized Controlled Clinical Trials of Discrete Hemoglobin Targets:
“Normal Hematocrit”
CHOIR
CREATE

9. Normal Hematocrit Study
Goal:
Assess risks and benefits of achieving a “normal” hematocrit in hemodialysis patients with clinically evident CHF or ischemic heart disease
Conducted:
1993 to 1996, with follow-up through 7/1997

10. Normal Hematocrit Study: Design
Open label
All subjects received Epoetin alfa
1:1 randomization to:
low hematocrit = 30±3% (Hgb ~10±1 g/dL); or
“normal” hematocrit = 42±3% (Hgb ~14±1 g/dL)
At entry, patients:
clinically evident ischemic heart disease or CHF
on hemodialysis
clinically stable on Epoetin alfa
1° endpoint: Time to death or non-fatal MI

11. Normal Hematocrit Study Results:
Randomization:
n = 634 to “normal” hematocrit (42 ± 3%)
n = 631 to low hematocrit (30 ± 3%)
Terminated early
“Our study was halted when differences in mortality between the groups were recognized as sufficient to make it very unlikely that continuation of the study would reveal a benefit for the normal-hematocrit group and the results were nearing the statistical boundary of a higher mortality rate in the normal hematocrit group.”
NEJM, 1998

12. Normal Hematocrit Study Results:
Time (months)
Mean (95% CI) Hematocrit by Study Month (NEJM, 1998)

13. Normal Hematocrit Study Results:
final log rank p = 0.01
Normal hematocrit group
Low hematocrit group
Probability of death or non-fatal MI (%)
Time (months)
Death or Non-Fatal MI by Study Month (NEJM, 1998)

14. Normal Hematocrit Study Results:
Components of Primary Endpoint
Target RR
95% CI
42% (Normal Hct)
N = 634
30% (Low Hct)
N = 631
Death
221 (35%)
185 (29%)
1.19
1.01 to 1.40
Non-fatal MI
20 (3.2%)
16 (2.5%)
1.24
0.65 to 2.38
Either
241 (38%)
201 (32%)
1.03 to 1.39

15. Normal Hematocrit Study:
Negative Association Between Mean Hemoglobin (throughout study) and Mortality:
Lower target
Higher target n=
FDA analysis of data collected through 7/5/97

16. Normal Hematocrit Study Summary:
Hemodialysis patients with clinically evident CHF or ischemic HD
Targeting a hematocrit of 42 ± 3% versus ± 3% (Hgb ~14 ± 1 versus ~10 ± 1 g/dL) associated with increased mortality and cardiovascular morbidity.
Somewhat paradoxically, higher mean hemoglobin concentrations were associated with survival in both treatment arms.

17. CHOIR Study Design Open label, Epoetin alfa Patients
no Epoetin alfa in past 3 months
not on dialysis
hemoglobin < 11 g/dL
1:1 randomization to hemoglobin or 13.5 g/dL
Primary endpoint: composite of mortality, CHF hospitalization, non-fatal stroke, non-fatal MI

18. DSMB = Data and Safety Monitoring Board
CHOIR Study Results
Randomization:
715 to hemoglobin of 13.5 g/dL
717 to hemoglobin of 11.3 g/dL
Terminated early
“The DSMB recommended that the study be terminated in May 2005 at the time of the second interim analysis…because the conditional power for demonstrating a benefit for the high-hemoglobin group was less than 5% for all plausible values of the true effect for the remaining data.” NEJM, 2006
DSMB = Data and Safety Monitoring Board

19. CHOIR Study Results
mean hemoglobin (g/dL)
time (months)
Mean (95% CI) Hemoglobin by Study Month (NEJM, 2006)

20. Primary Composite Endpoint Probability of composite event
CHOIR Study Results
Primary Composite Endpoint
High hemoglobin group
Probability of composite event
Low hemoglobin group
Time (months)

21. CHOIR Study Results: 1° Endpoint Components
13.5 Hgb
N = 715
11.3 Hgb
N = 717
RR (95% CI)
Any component
125 (17.5%)
97 (13.5%)
1.29 (1.01, 1.65)
Death
39 (5.5%)
26 (3.6%)
1.50 (0.93, 2.44)
CHF hospitalization
59 (8.3%)
42 (5.9%)
1.41 (0.96, 2.06)
Non-fatal MI
12 (1.7%)
13 (1.8%)
0.93 (0.43, 2.01)
Non-fatal stroke
11 (1.5%)
1.09 (0.49, 2.46)

22. CHOIR Study Results
Negative Association Between Mean Hemoglobin (throughout study) and Mortality:
Lower target
Higher target n=
FDA exploratory analysis

23. CHOIR Summary
For pre-dialysis patients, administration of Epoetin alfa to target a Hgb of ~13.5 versus 11.3 g/dL is associated with increased mortality and CHF hospitalization.
Paradoxically, higher mean hemoglobin concentrations were associated with survival in both treatment arms.

24. CREATE Study Design Open label, Epoetin beta Patients
mild anemia (hemoglobin 11 to 12.5 g/dL)
not on dialysis
no prior ESAs
1:1 randomization to normal hemoglobin (13 – 15 g/dL) or subnormal hemoglobin (11 – 12.5 g/dL)
Epoetin beta begun in subnormal group once hemoglobin < 10.5 g/dL

25. CREATE Study Design & Results
Primary composite endpoint: sudden death, MI, acute heart failure, stroke, TIA, angina requiring hospitalization, peripheral vascular disease complication or cardiac arrhythmia requiring hospitalization
Randomization:
301 to normal hemoglobin (13–15 g/dL)
302 to subnormal hemoglobin (11–12.5 g/dL)

26. Median (SD) Hemoglobin by Study Month
CREATE Study Results
Median (SD) Hemoglobin by Study Month
NEJM, 2006

27. CREATE Study Results Primary endpoint events (NEJM, 2006):
- 58/301 in normal hemoglobin group
- 47/302 in sub-normal hemoglobin group
HR 0.78 (95% CI 0.53 – 1.12)
Few endpoint events despite broad composite endpoint
Results directionally support lower hemoglobin target

28. Observational Data – 58,058 U.S. HD Patients:
Database from DaVita, Inc.
Regidor DL, Kopple JD, Kovesdy CP, et al. J Am Soc Nephrol. 2006;17:1181.

29. NKF K/DOQI Guidelines (2006)
“Cohort-based observational trials and cross-sectional analyses of large medical databases…consistently show that higher achieved hemoglobin values (including ≥ 12 g/dL) are associated with improved patient outcomes …. The failure of observational associations to be confirmed by interventional trials renders use of observational evidence unsuitable to support the development of an intervention guideline statement.”

30. Data to Support Ideal Hemoglobin Target (1):
↓ morbidity/mortality
↑ morbidity/mortality
Normal hematocrit
(hemodialysis) 10 14 ?
↓ morbidity/mortality
↑ morbidity/mortality
11.3
CHOIR
(pre-dialysis)
13.5
Observational data, by association only

31. Data to Support Ideal Hemoglobin Target (2):
Observational data from HD patients
Exploratory analyses of NHCT and CHOIR
associations between higher mean hemoglobin concentration achieved and survival
Association does not prove causality
Achieved hemoglobin ≠ hemoglobin target.
J-shape relation suggests that there is some Hgb concentration that is excessive in the CRF population.

32. Data to Support Ideal Hemoglobin Target (3)
Perhaps patients who achieve higher hemoglobin concentrations have less advanced renal disease and lower CV disease burden  better outcomes.
We are not aware of a RCT that demonstrates, in a convincing way, that a higher hemoglobin target is associated with less cardiovascular morbidity and mortality than a lower target.

33. Dose Optimization Challenges;
ESA Responsiveness

34. Dose Optimization Challenges;
ESA Responsiveness
1. Could we prospectively identify hypo-responders, at higher risk of cardiovascular events? 2. If hypo-responders could be identified, how should they be treated?

35. Survival by Hemoglobin (Normal HCT Study)
Less responsive to ESAs
Lower target
Higher target n=
FDA analysis of data collected through 7/5/97

36. Survival by Mean Weight-Adjusted Epoetin Alfa Dose (Normal HCT Study)
Dose and responsiveness are inversely rated
Fraction surviving
Highest dose; less responsive to ESAs
FDA exploratory analysis
time (months)

37. Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (1)
FDA exploratory analysis
NHCT study provided unique opportunity to assess ESA-responsiveness.
Stable HD patients, maintained on Epoetin alfa; hematocrit 27 to 33% for weeks
Subjects randomized to “normal” hemoglobin target group had standard protocol-mandated ESA “challenge”
Epoetin alfa dose increased by factor of 1.5 on study entry

38. Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (2)
Epoetin alfa-responsiveness calculated for patients who received constant weekly Epoetin alfa dosing for 2 to 6 weeks following study entry.
Responsiveness º slope of hemoglobin-time relation throughout the 2- to 6-week period (linear regression).

39. Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (3)
618 patients randomized to “normal” hemoglobin target
EPO-responsiveness could be calculated for 414:
117 patients experienced a decrease in hemoglobin, despite a 50% increase in Epoetin alfa dose
297 patients experienced no change or an increase in hemoglobin: divided in quintiles

40. Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (4)
Assessments:
Survival by initial Epoetin alfa-responsiveness
Overall Epoetin alfa responsiveness (mean hemoglobin concentration throughout study) by initial Epoetin alfa response

41. FDA exploratory analysis
Initial Epoetin Alfa Responsiveness Does Not Predict Subsequent Mortality in the NHCT Study
FDA exploratory analysis

42. FDA exploratory analysis
Initial Epoetin Alfa Responsiveness Does Not Predict Subsequent Mortality in the NHCT Study
FDA exploratory analysis

43. Initial Epoetin Alfa Responsiveness Does Not Predict Overall Hgb Response in the NHCT Study
less initial response more initial response
Mean Hgb throughout study (g/dL)
Hgb rate of change with initial 50% increase in EPO dose (g/dL/week)
FDA exploratory analysis

44. Could we prospectively identify hypo-responders, at higher risk of cardiovascular events? In the NHCT Study, where patients had protocol-mandated 50% increase in EPO dose on study entry: Initial Hgb response did not predict subsequent mortality, and did not predict overall Hgb response. * ESA responsiveness may need to be assessed on ongoing basis.

45. ESA-Hyporesponsiveness in a Single Patient:

46. Conclusions: Dose Optimization Challenges; ESA Responsiveness (1) - Prospective identification of hypo-responders may be difficult (i.e., erythropoietic response to an ESA challenge) - Identification of hypo-responders is feasible in practice

47. Conclusions: Dose Optimization Challenges; ESA Responsiveness (2) For hypo-responsive patients, the labeling suggests a search for causative factors, but does not explicitly state a maximum ESA dose, or what constitutes an adequate attempt to raise hemoglobin. Key Unanswered Question: whether less responsive patients or those with specific risk factors would experience fewer cardiovascular events if attempts were not made to raise their hemoglobin to some “ideal” target.

48. Dose Optimization Challenges

49. Dose Optimization Challenges
ESA labeling warns against excessive rate of rise of Hgb (> 1 g/dL per 2 weeks)
Is risk related to hemoglobin response?

50. Dose Optimization Challenges: Cycling in a Subject from the Normal Hematocrit Study

51. Dose Optimization Challenges: Cycling in a Subject from the Normal Hematocrit Study

52. Week 50, hemoglobin 9.9, rate of change 0.6 g/dL/week
Dose Optimization Challenges: Cycling in a Subject from the Normal Hematocrit Study
Week 50, hemoglobin 9.9, rate of change 0.6 g/dL/week
Week 49, hemoglobin 9.3

53. serious CV events/ patient-yr Hemoglobin rate of change (g/dL/wk)
Normal Hematocrit Study: “Dynamic” Analysis of Relations Between Serious Cardiovascular Events, Prevailing Hemoglobin, and Preceding Hemoglobin Rate of Change
serious CV events/ patient-yr
[Hemoglobin] (g/dL)
Hemoglobin rate of change (g/dL/wk)
FDA Analysis

54. Dose Optimization Challenges
ESA labeling warns against excessive rate of rise of Hgb (> 1 g/dL per 2 weeks)
Hemoglobin oscillations are associated with serious cardiovascular events
Due to underlying patient characteristics?
Worth trying to prevent?

55. Dose Optimization Challenges: Development of ESA Dosing Algorithms
Limit hemoglobin oscillations
Prevent excessive hemoglobin rates of change
Prevent overshoot
Provide appropriate means to identify and treat hypo-responders

56. Review of literature and report of experience with erythropoietin in ESRD populations56

57. 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.

58. 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
Addendum- Parfrey et al JASN 2005
Goal = 13.5 to 14.0g/dl and achieved=13.3g/dl

59. 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.

60. 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: 60

61. The Effects of Higher Hemoglobin levels on Mortality and Hospitalization in Hemodialysis Patients*
July 1998 to July 2000 * * * * * * NS * * *
Fig 1
*Ofsthun et al KI 63: , 2003
* statistically significant difference from reference; 95% confidence intervals shown 61

62. 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.

63. Summary of ESAs in ESRD 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.

64. Summary:
Best RCT data available: “Ideal” hemoglobin target is 10 g/dL for HD patients; 11.3 g/dL for pre-dialysis patients
Data to support a hemoglobin target as high as 12 g/dL are observational in nature and of limited utility:
association ≠ causality
achieved hemoglobin ≠ target hemoglobin
Unknown if ESA-hyporesponsive and/or high-risk patients should be treated differently
Little data to show that current labeling addresses how best to reduce hemoglobin overshoot and cycling

65. Potential Path Forward
Hemoglobin target: conduct prospective, randomized, controlled cardiovascular outcome study(ies) to determine optimum hemoglobin target(s)
Consider, a priori, disparate targets based on risk factor(s)
Develop new dosing paradigm(s):
Special dosing strategies might be considered for hypo-responsive patients and those at higher risk of CV events
Strategy could consider “futility”
Test prospectively in RCT(s)

66. THANK YOU !