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 hormoneEpoetin alfa - manufactured by Amgen, Inc., - marketed as Procrit by Ortho Biotech, L.P., a subsidiary of J & JDarbepoetin, 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 AnemiaAn 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 diseaseOther 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 ESAsGenerally, regardless of the cause of anemia, blood transfusions may be necessary to relieve patient symptoms and maintain life when the anemic condition becomes severeThe 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?
9 Normal Hematocrit Study Goal:Assess risks and benefits of achieving a “normal” hematocrit in hemodialysis patients with clinically evident CHF or ischemic heart diseaseConducted:1993 to 1996, with follow-up through 7/1997
10 Normal Hematocrit Study: Design Open labelAll subjects received Epoetin alfa1:1 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 CHFon hemodialysisclinically stable on Epoetin alfa1° 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 = 0.01Normal hematocrit groupLow hematocrit groupProbability 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 EndpointTargetRR95% CI42% (Normal Hct)N = 63430% (Low Hct)N = 631Death221 (35%)185 (29%)1.191.01 to 1.40Non-fatal MI20 (3.2%)16 (2.5%)1.240.65 to 2.38Either241 (38%)201 (32%)1.03 to 1.39
15 Normal Hematocrit Study: Negative Association Between Mean Hemoglobin (throughout study) and Mortality:Lower targetHigher targetn=FDA analysis of data collected through 7/5/97
16 Normal Hematocrit Study Summary: Hemodialysis patients with clinically evident CHF or ischemic HDTargeting 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 monthsnot on dialysishemoglobin < 11 g/dL1:1 randomization to hemoglobin or 13.5 g/dLPrimary endpoint: composite of mortality, CHF hospitalization, non-fatal stroke, non-fatal MI
18 DSMB = Data and Safety Monitoring Board CHOIR Study ResultsRandomization:715 to hemoglobin of 13.5 g/dL717 to hemoglobin of 11.3 g/dLTerminated 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, 2006DSMB = Data and Safety Monitoring Board
19 CHOIR Study Resultsmean hemoglobin (g/dL)time (months)Mean (95% CI) Hemoglobin by Study Month (NEJM, 2006)
20 Primary Composite Endpoint Probability of composite event CHOIR Study ResultsPrimary Composite EndpointHigh hemoglobin groupProbability of composite eventLow hemoglobin groupTime (months)
22 CHOIR Study ResultsNegative Association Between Mean Hemoglobin (throughout study) and Mortality:Lower targetHigher targetn=FDA exploratory analysis
23 CHOIR SummaryFor 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 dialysisno prior ESAs1:1 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 hospitalizationRandomization: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 ResultsMedian (SD) Hemoglobin by Study MonthNEJM, 2006
27 CREATE Study Results Primary endpoint events (NEJM, 2006): - 58/301 in normal hemoglobin group- 47/302 in sub-normal hemoglobin groupHR 0.78 (95% CI 0.53 – 1.12)Few endpoint events despite broad composite endpointResults 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/mortalityNormal hematocrit(hemodialysis)1014?↓ morbidity/mortality↑ morbidity/mortality11.3CHOIR(pre-dialysis)13.5Observational data, by association only
31 Data to Support Ideal Hemoglobin Target (2): Observational data from HD patientsExploratory analyses of NHCT and CHOIRassociations between higher mean hemoglobin concentration achieved and survivalAssociation does not prove causalityAchieved 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 Responsiveness1. 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 ESAsLower targetHigher targetn=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 ratedFraction survivingHighest dose; less responsive to ESAsFDA exploratory analysistime (months)
37 Prospective Evaluation of ESA- Responsiveness (Normal HCT Study) (1) FDA exploratory analysisNHCT study provided unique opportunity to assess ESA-responsiveness.Stable HD patients, maintained on Epoetin alfa; hematocrit 27 to 33% for weeksSubjects 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 targetEPO-responsiveness could be calculated for 414:117 patients experienced a decrease in hemoglobin, despite a 50% increase in Epoetin alfa dose297 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-responsivenessOverall 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 StudyFDA exploratory analysis
42 FDA exploratory analysis Initial Epoetin Alfa Responsiveness Does Not Predict Subsequent Mortality in the NHCT StudyFDA exploratory analysis
43 Initial Epoetin Alfa Responsiveness Does Not Predict Overall Hgb Response in the NHCT Study less initial response more initial responseMean 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.
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.
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 StudyWeek 50, hemoglobin 9.9, rate of change 0.6 g/dL/weekWeek 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 Changeserious 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 eventsDue to underlying patient characteristics?Worth trying to prevent?
55 Dose Optimization Challenges: Development of ESA Dosing Algorithms Limit hemoglobin oscillationsPrevent excessive hemoglobin rates of changePrevent overshootProvide appropriate means to identify and treat hypo-responders
56 Review of literature and report of experience with erythropoietin in ESRD populations 56
57 Different Disease Categories ESRD or dialysis patients are different from CKD patients and are particularly different from cancer patientsAnemia 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 differentThe 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: ppAddendum- Parfrey et al JASN 2005Goal = 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 1999Follow-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 shown61
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 ofvariability of response to ESAsIron 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 mandatesdistinction 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 patientsData to support a hemoglobin target as high as 12 g/dL are observational in nature and of limited utility:association ≠ causalityachieved hemoglobin ≠ target hemoglobinUnknown if ESA-hyporesponsive and/or high-risk patients should be treated differentlyLittle 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 eventsStrategy could consider “futility”Test prospectively in RCT(s)