# Presentation: 209846

## FDA Perspectives onErythropoiesis-Stimulating Agents (ESAs) for Anemia of Chronic Renal Failure:Hemoglobin Target and Dose Optimization

- Joint Meeting of the Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee
**Ellis F. Unger, M.D.**
**Deputy Director for Science (Acting)**
**Office of Surveillance and Epidemiology (OSE)**
**Center for Drug Evaluation and Research (CDER)**
**September 11, 2007**

## Outline

**What is the correct hemoglobin target for ESAs for anemia of chronic renal failure?**
**Randomized controlled clinical trials**
**Observational data**
**ESA responsiveness**
**Dose optimization challenges**
**Potential path forward**

## Approved Erythropoiesis-Stimulating Agents (ESAs) for Anemia of Chronic Renal Failure:

**Epoetin alfa (Epogen® /Procrit®): 1989**
**Darbepoetin alfa (Aranesp®): 2001**

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

## Randomized Controlled Clinical Trials of Discrete Hemoglobin Targets:

**“****Normal Hematocrit”**
**CHOIR**
**CREATE****	**

## 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**

## 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**

## 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**

## Normal Hematocrit Study Results:

**Mean (95% CI) Hematocrit by Study Month (NEJM, 1998)**

**Hematocrit (%)**

**Time (months)**

## Normal Hematocrit Study Results:

**Death or Non-Fatal MI by Study Month (NEJM, 1998)**

**Probability of death or non-fatal MI (%)**

**Time (months)**

**final log rank p = 0.01**

## 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%) | 1.19 | 1.03 to 1.39 |

## Normal Hematocrit Study:

**Normal Hematocrit Study:**

**Negative Association Between Mean Hemoglobin (throughout study) and Mortality:**

**Lower target**

**Higher target**

- FDA analysis of data collected through 7/5/97

- n=

## Normal Hematocrit Study Summary:

**Hemodialysis patients with clinically evident CHF or ischemic HD**
**Targeting a hematocrit of 42 ± 3% versus     30 ± 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.**

## 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                                             ****	****11.3 or 13.5 g/dL**
** ****Primary endpoint: composite of mortality, CHF hospitalization, non-fatal stroke, non-fatal MI**

## 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**

## CHOIR Study Results

**Mean (95% CI) Hemoglobin by Study Month (NEJM, 2006)**

**mean hemoglobin (g/dL)**

**time (months)**

## CHOIR Study Results

**CHOIR Study Results**

**Primary Composite Endpoint**

**Probability of composite event**

**Time (months)**

**High hemoglobin group**

**Low hemoglobin group**

## 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 | 12 (1.7%) | 11 (1.5%) | 1.09 (0.49, 2.46) |

## CHOIR Study Results

**CHOIR Study Results**

**Lower target**

**Higher target**

- n=

- FDA exploratory analysis

**Negative Association Between Mean Hemoglobin (throughout study) and Mortality:**

## 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.**

## 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**

## 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)**

## CREATE Study Results

**Median (SD) Hemoglobin by Study Month**
**NEJM, 2006**

## 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**

## Observational Data – 58,058 U.S. HD Patients: 

**Regidor DL, Kopple JD, Kovesdy CP, et al. *****J Am Soc Nephrol*****. 2006;17:1181.**

**Database from DaVita, Inc.**

## 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*****.”**
**www.kidney.org/professionals/KDOQI/guidelines_anemia/cpr21.htm**

## Data to Support Ideal Hemoglobin Target (1):

**Normal hematocrit**
**(hemodialysis)**

**CHOIR**
**(pre-dialysis)**

**10**

**14**

**11.3**

**13.5**

**↓ ****morbidity/mortality**
- ↑ **morbidity/mortality**

**?**

**Observational data, *****by association only***

**↓ ****morbidity/mortality**
- ↑ **morbidity/mortality**

## 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.**

## 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.**

## Dose Optimization Challenges; 
ESA Responsiveness 

**ESA Responsiveness**** **

## Dose Optimization Challenges; 
ESA Responsiveness 

**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?**

## Survival by Hemoglobin (Normal HCT Study)

**Survival by Hemoglobin (Normal HCT Study)**

**Less responsive to ESAs**

**Lower target**

**Higher target**

- FDA analysis of data collected through 7/5/97

- n=

## Survival by Mean Weight-Adjusted Epoetin Alfa Dose (Normal HCT Study)

**time (months)**

**Fraction surviving**

**Dose and responsiveness are inversely rated**

**Highest dose; less responsive to ESAs**

**FDA exploratory analysis**

## 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      4 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**

## 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 ****** **slope of hemoglobin-time relation throughout the 2- to 6-week period (linear regression).**

## 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**

## 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**

## Initial Epoetin Alfa Responsiveness Does Not Predict Subsequent Mortality in the NHCT Study

- FDA exploratory analysis

## Initial Epoetin Alfa Responsiveness Does Not Predict Subsequent Mortality in the NHCT Study

- FDA exploratory analysis

## Initial Epoetin Alfa Responsiveness Does Not Predict Overall Hgb Response in the NHCT Study

**Initial Epoetin Alfa Responsiveness Does Not Predict Overall Hgb Response in the NHCT Study**

- less initial response      more initial response

- FDA exploratory analysis

**0**

**Hgb rate of change with initial 50% increase in EPO dose (g/dL/week)**

**Mean Hgb throughout study (g/dL)**

## 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.

## ESA-Hyporesponsiveness in a Single Patient:

## 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 

## 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.

## Dose Optimization Challenges

## 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?**

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

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

## 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**

## Normal Hematocrit Study:“Dynamic” Analysis of Relations Between Serious Cardiovascular Events, Prevailing Hemoglobin, and Preceding Hemoglobin Rate of Change

**Hemoglobin rate of change (g/dL/wk)**

**[Hemoglobin] (g/dL)**

**serious CV events/ patient-yr**

**FDA Analysis**

## 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?**

## Dose Optimization Challenges: Development of ESA Dosing Algorithms

**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**

## 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**

## 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)**

- _[Return to Unger](file:///FDAers%20Backups/Ungerbackup.ppt)_