# Presentation: 186971

## Ajay K. Singh, MB, MRCP, MBA
Clinical Chief, Renal Division
Brigham and Women’s Hospital
Associate Professor of Medicine
Harvard Medical School
Email: asingh@partners.org

**Disclosures:** _Grants:_ Ortho Biotech, Amgen, Jansen Cilag, Advanced Magnetics, Watson, Roche
-  _Speakers Bureau:_ Ortho Biotech, Pfizer, Watson; _Consultant:_ Ortho Biotech, Amgen, Merck

- Ajay K. Singh, MB, MRCP, MBA
- Clinical Chief, Renal Division
- Brigham and Women’s Hospital
- Associate Professor of Medicine
- Harvard Medical School
- Email: asingh@partners.org

- _CDRAC Meeting September 11, 2007_

## Outline

**Review of Hgb target studies: observational and RCT data**
**Treating patients to a target Hgb**
** **
**Managing the ESA hypo-responsive patient**

## Hgb Target Studies

- Dialysis (D) versus Non-dialysis (ND)-CKD
- Observational vs. RCT
- Hard-endpoints (death and/or adjudicated CVD) vs. soft-endpoints (LVH, QOL etc.)
- Post-hoc analyses of RCT’s

## HCT and Mortality in D-CKD

**1.33**

**1.12**

**1.00**

**0.96**

**1.25**

**1.11**

**1.00**

**0.97**

**0**

**0.2**

**0.4**

**0.6**

**0.8**

**1**

**1.2**

**1.4**

**< 27%**

**27% to < 30%**

**30% to < 33%**

**33% to < 36%**

**Hct **

***Relative Risk**

**All-cause death**

**Cardiac-related death**

- *After adjustment for medical diseases.Ma et al. *J Am Soc Nephrol*. 1999;10:610-619.

- N = 75,283

**Notes:**
A large, retrospective, observational study of 75,283 patients showed an association between higher hematocrit (Hct) levels and improved patient survival. Patients whose Hct levels were maintained between 33% and 36% had the best chance of survival into the next year. By comparison, patients whose Hct levels were less than 33% had a higher risk of all-cause and cardiac death. Relative risks as shown were adjusted for severity of disease.

Reference: Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol. 1999;10:610-619.

## All-Cause Death in All Patients (Incident & Prevalent)

## Largest Studies on Target Hgb in D-CKD

- Normal Hematocrit Study ≈ 1233 pts (1265)
- Besareb et al NEJM 1998
- Canada-Europe Study

**Notes:**
Changed to endpoint.

Shoul

## Trial of Anemia Correction in Dialysis pts(Normal Hematocrit Study)

|  | Low Hct | Normal Hct |
| --- | --- | --- |
| n | 618 | 615 |
| Hct | 30 | 42 (achieved 39%) |
| Epoetin dose | 160 | 460 |
| Total deaths | 150 | 183 |
| Non-fatal MI | 14 | 19 |
| RR |  | 1.3 (0.9-1.9) |

- Besarab et al. N Engl J Med 339:584-590, 1998

- “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”

## Normal Hematocrit Study: Completed Study

- P<0.001*

- * Log rank test of event free survival

- Source: FDA Briefing Document, CDRAC 2007

## Largest Studies on Target Hgb ND-CKD

- CREATE = 603 pts
- Drueke et al NEJM 2006
- The CHOIR study = 1432 pts
- Singh et al NEJM 2006

**Notes:**
Changed to endpoint.

Shoul

## Cardiovascular risk Reduction by Early Anaemia Treatment with Epoeitin-  (CREATE) Primary endpoint Time to first CV events (105 events)

**Events: 58 vs 47**
**HR=0.78 (0.53–1.14)**
**Log rank test p=0.20**

- N=603

**Drueke TB et al. N Engl J Med 2006;355:2071-2084**

## CREATE: Other results

- Cardiac Echo (n=451 : LVMI declined in both groups, no difference betw’n groups: year 1 P=0.59, year 2, P=0.65).
- QOL (SF36) better for gp 1
-   (high Hb) than gp 2 (low Hb),
-    increase of 2 to 5 (out of 100).
- Decreased QOL for gp 2.
-    At year 2, benefit shown for
-    only general health and vitality

- Drueke et al, NEJM 356:9,959 2007

## Summary (CREATE)

**Increased risk with targeting higher Hb ****HR=0.78 (0.53–1.14)**** **
**This is not a negative study -- it is underpowered; also, the span of 95% CI’s was wide**
**Higher number of dialysis initiations**
**Improvement in QOL**
**No benefit in LVH**

## CHOIR

**1432 patients, 130 centers, US only**
**Epoetin-alfa**

**Randomization**

**High target Hb****(13.5 g/dl)**
**n=715**
**312 completed 36 mo **
**or withdrew at study termination **
**with no primary event**
**125 primary event**
**278 Withdrew before **
**early termination of study**
**Required RRT (47.1%)**
**Withdrew for Other Reasons (21%)**

**Low target Hb****(11.3 g/dl)**
**n=717**
**349 completed 36 mo **
**or withdrew at study termination **
**with no primary event **
**97 primary event**
**278 Withdrew before **
**early termination of study**
**Required RRT (41.0%)**
**Withdrew for Other Reasons (22%)**

- Median f/u 16 months

## CHOIR Data Management

- Study Sponsor: Johnson and Johnson (Ortho Biotech Clinical Affairs)
- Site queries and Monitoring activities by DCRI
- Data base queried and locked at Duke Clinical Research Institute
- Only copy of data-base provided to sponsor
- All primary analyses performed by Duke
- Secondary analyses performed by Sponsor but confirmed by Duke
- Full access to data for PI’s and paper written by PI’s
- Data analyzed as “Intention to Treat” ie all patients included
- 	(FDA Guidelines to Industry E9)

- Singh et al,New Engl J Med 2006; 355:2085-98

## Endpoints

- Primary Endpoint: Composite event consist of
- Death
- Myocardial infarction
- Stroke
- CHF hospitalization (excluding RRT)

- Singh et al,New Engl J Med 2006; 355:2085-98

**Notes:**
Changed to endpoint.

Shoul

## Baseline Characteristics

|  | High Hb (13.5 g/dL) | Low Hb (11.3 g/dL |
| --- | --- | --- |
| Age | 66.0+14.3 | 66.3 +13.5 |
| Gender (female) % | 56.2 | 54.1 |
| Race     (Black) % | 28.6 | 29.3 |
| Ethnicity (Hispanic) % | 12.5 | 13.5 |
| History of Smoking Tobacco % | 47.5 | 44.6 |
| BMI | 30.4 | 30.4 |
| Hemoglobin (g/dL) | 10.1+0.9 | 10.1+0.9 |
| Hematocrit (%) | 31.4 | 31.4 |
| Transferrin Saturation (%) | 25.2 | 24.6 |
| Creatinine Clearance (mL/min)  | 36.7+17.0 | 37.1+17.9 |
| eGFR (ml/min/1.73m2) | 27.0+8.7 | 27.3+9.1 |
| Etiology of CKD |  |  |
|      Diabetes % | 46.8  | 50.8 |
|      Hypertension % | 29.9 | 27.5 |
|      Other % | 23.3 | 21.6  |

## Cardiovascular History

|  | High Hb
Hb 13.5 g/dL | Low Hb
Hb 11.3 g/dL |
| --- | --- | --- |
| Hypertension % | 95.8 | 93.2* |
| Myocardial Infarction % | 16.4 | 15.0 |
| CABG % | 17.4 | 13.5** |
| PCI % | 10.9 | 11.9 |
| CHF % | 24.4 | 22.9 |
| Atrial Fibrillation % | 9.4 | 8.6 |
| CVA % | 9.8 | 10.0 |
| PVD % | 16.4 | 16.4 |
| MI/CVA/CABG/PCI/LEA % | 36.3 | 34.5 |

- *P=0.03 for comparison with high-Hb group
- **P=0.05 for comparison with high-Hb group

## Epoetin-alfa dosing and Hb Monitoring 

- Epoetin-alfa dosing and Hb Monitoring

- Epoetin-alfa dosing:
- Epoetin-alfa 10,000 Units s.c. q week x 3 weeks
- After three weeks at this level, Epoetin-alfa was adjusted based on Hb response using an algorithm provided to the sites.
- Epoetin-alfa dosed weekly initially.  When Hb reached target and epoetin-alfa was not adjusted for one month, the dose was doubled and delivered once every two weeks.
- Hb Monitoring:
- Initially every other week
- When Hb reached target and stabilized, monitoring changed to monthly.

**Notes:**
Last pass: make sure all abbreviations used are consistent.

## Mean Weekly Doses of Epoetin alfa and Hgb

- Mean Weekly Dose
- 11,215 units

- Mean Weekly Dose
- 6276 units

- Mean Hb 12.6 g/dL

- Mean Hb 11.3 g/dL

- Singh et al,New Engl J Med 2006; 355:2085-98

## Kaplan-Meier Plot of the Time to the Primary Composite Event between Randomization and Termination: ITT Population

- 715
- 717

- 587
- 594

- 457
- 499

- 270
- 293

- 55
- 44

- 101
- 107

- 0
- 3

- At risk

- Hazard ratio  1.337  (1.025, 1.743)
- P= 0.0312

**125**

**97**

- Singh et al,New Engl J Med 2006; 355:2085-98

## CHOIR Sensitivity Analyses for Primary Outcome

- Per Protocol Analysis
- ITT population except for subjects who did not meet criteria required by the protocol, either underwent incorrect randomization, did not receive any dose of study medication, had no Hb measurements after randomization, or did not meet all criteria for inclusion
- Excluded 37 patients
- 1395 patients
-  Hazard Ratio 1.34 (95% CI: 1.03, 1.75; P=0.03)

- Singh et al,New Engl J Med 2006; 355:2085-98

## CHOIR Components of the Primary Endpoint

**CHF Hospitalization (where RRT did not occur)**

**Myocardial Infarction**

**Stroke**

**Death**

- p = 0.0727

- p = 0.0674

- p = 0.9803

- p = 0.7836

**Hazard ratio  1.483  (0.969, 2.268)**

**Hazard ratio  1.409  (0.967, 2.054)**

**Hazard ratio  1.010  (0.454, 2.249)**

**Hazard ratio  0.915  (0.484, 1.729)**

**65 deaths**

- Singh et al,New Engl J Med 2006; 355:2085-98

## CHOIR: QOL

- 3 instruments
- LASA
- KDQ
- SF-36

**QOL Increased in both groups**
**No difference between groups**

- Singh et al,New Engl J Med 2006; 355:2085-98

## CHOIR Adverse Events

| Adverse Event | High Hb (n=686) 
N (%) | Low Hb (N=688)
N (%) | P Value |
| --- | --- | --- | --- |
| Any Event | 607 (88.5) | 589 (85.6) | 0.11 |
| Thrombovascular event
    Any Event
    Any Clinically relevant event | 
126 (18.4)
74 (10.8) | 
120 (17.4)
82 (11.9) | 
0.65
0.51 |
| Any SAE | 376 (54.8) | 334 (48.5) | 0.02 |
| Any SAE associated with Epoetin alfa | 10 (1.5) | 3 (0.4) | 0.05 |
| SAE’s (occurred in >2% of patients) |  |  |  |
|     CHF | 77 (11.2) | 51 (7.4) | 0.02 |
|     MI | 10 (1.5) | 19 (2.8) | 0.09 |
|     GI Hemorrhage | 18 (2.6) | 18 (2.6) | 0.99 |
|     Chest Pain | 23 (3.4) | 16 (2.3) | 0.25 |
|     Cellulitis | 16 (2.3) | 11 (1.6) | 0.33 |
|     Pneumonia | 32 (4.7) | 28 (4.1) | 0.59 |
|     Renal Failure | 95 (13.8) | 73 (10.6) | 0.07 |

- Singh et al,New Engl J Med 2006; 355:2085-98

## Summary (CHOIR)

**Increased risk with targeting Hb to 13.5 g/dL and achieving 12.6 g/dL (34%  P=0.03)**
**Strong trends for Death (48%  P=0.07) and CHF Hospitalization (41%  P=0.07)**
**Trend for Time to RRT (19% P=0.15)**
**Higher rate of Cardiovascular (23% P=0.03) and All Hospitalization (18% P 0.03)**
**No Incremental QOL of benefit with higher Hb**
**Higher number of SAE’s in higher Hb group (15%  P=0.02)**

- Singh et al,New Engl J Med 2006; 355:2085-98

## Phrommintikul et al al, Lancet 2007

**Phrommintikul et al al, Lancet 2007**

## Post-Hoc studies

**NHS (Amgen) -- to be presented at CDRAC**
**CREATE -- TBA**
**USRDS data (Cotter) --to be presented at CDRAC**
**CHOIR (****Szczech**** et al, Duke) **

## The Association Between Epoetin-alfa Dose and Outcomes in CHOIR  Lynda Szczech, Ajay Singh, Shelly Sapp Donal Reddan, and Huiman Barnhart

- _Hypothesis_
- Examining the associations between epoetin-alfa dose, achieved hemoglobin, targeted hemoglobin, and outcomes.

- Szczech et al, ASN 2007

## Post hoc survival analysis

- Methodology:
- Kaplan-Meier plots
- Cox proportional hazards regression
- Outcomes:
- Primary composite endpoint
- Death
- CHF
- MI
- CVA
- Death
- Approaches
- 1: Utilizes all values obtained during the study
- 2: Landmark analysis fixed at 4 and 9 month periods

- Szczech et al, ASN 2007

**Notes:**
This slide begins the post hoc analyses of this presentation.

## Distribution of average dose by treatment arm

## Number of subjects achieving targets 

- Szczech et al, ASN 2007

## Proportion of subjects in each group experiencing primary endpoint

- Szczech et al, ASN 2007

## Association between dose and primary outcome (4 and 9 month Landmark)

- Szczech et al, ASN 2007

## Summary-1

- Observational studies show that higher Hgb values associated with a modest survival advantage. This is a confounded relationship.
- Normal Hematocrit and CHOIR  (D-CKD and ND-CKD) show statistically significantly worse outcome for hard end-points
- Cannot rule out an epoetin dose effect
- Post-hoc analysis from CHOIR supports both a Hgb level and  a dose effect  in patients who don’t achieve target (among likely hypo-responders)

## Outline

**Review of Hgb target studies: observational and RCT data**
**Treating patients to a target Hgb**
** **
**Managing the ESA hypo-responsive patient**

## Hgb and Epogen Dose 1991-2006

**Normal HCT** **Study**

- Sources: USRDS 2006, GAO Report, 2006, Steinbrook: Lancet, 2006

**Normal HCT Study**

**FDA Label Change**

**FDA Label Change**

## Potential Explanations for Hgb levels >12 g/dL in Dialysis Patients

- Curve Shifting
- Chain-specific factors (protocol-specific, profit-status)
- Anemia Algorithm
- Physiologic Factors (Hgb cycling, patient specific factors)

## Distribution of Anemia Hct Targets

**Hct**

**30%**

**33%**

**% of Patients**

**39%**

**36%**

## Hgb Cycling

- Fishbane S, et al. Kidney Int. 2005;68:1337-1343.

- In HD patients, Hgb levels continually rise and fall in undulations or cycles
- >90% of patients had 3.3_+_1.1 Hgb cycles per patient/year
- Mean amplitude 2.51_+_0.89 g/dL
- Mean duration of Hb excursions 5.1 wks

- Fishbane et al, KI 2005

## Case Report

_**Case Report**_
- 67-yr old African American Woman
- Depression, Dementia.
- Admitted with clotted graft

- Keithi-Reddy, 2007  KI, submitted

## Hgb Overshoot by Dialysis Facility

- N=44,834 incident Medicare, epoeitin treated pts, initiated HD 6/30/03-7/1/204
- Adjusted for
- Age, gender, race, cause of kidney failure, ME form comorbidity and initial Hgb
- Source: Collins, ASN 2006

**Collin’s Conclusion: “Degree of overshooting appears to be associated with specific ownership groups” (independent of other factors)**

## DaVita

- DCI

- Source: Collins, ASN 2006

## HCT’s and Epogen Dose in US Dialysis Facilities

- Modified from Thamer M et al JAMA 2007

## 208 pts randomized, 157 maintenance phase, 138 completed study

- Iron replete pts, excluded hyper (epo<30 U/Kg/wk) and hyporesponders (epo>500 U/Kg/wk)
- 26 w maintenance phase
- Goal HCT 30-33%
- Physiologic Factors (Hgb cycling, patient specific factors)

- Patel et al, 2007 manuscript in preparation

## Hgb Cycling

- Patel et al, 2007 manuscript in preparation

## Discontinuation vs. Reduction in Epogen

| Discontinuation Protocol | Reduction Protocol |
| --- | --- |
| When Hgb >13 g/dL, discontinue EPO
 Resume EPO with a 25% dose reduction when Hgb reaches <12.5 g/dL | When Hgb >13 g/dL, decrease EPO immediately by 25%.
 If the last Hgb of the prior month >13 g/dL, decrease EPO by 75% on the 1st of the next month
When Hgb >15 g/dL, discontinue EPO. 
 Resume when Hgb <13 g/dL with a 25% dose reduction
 |
| Maximum EPO dose = 900 units/kg/week | Maximum EPO dose = 500,000 units/month and 900 units/kg/week |

- Weiner et al, In press JASN 2007

-  Of 1704 pts, n=825 were present for all of the 14 months
-  15,804 pt-months Hgb evaluated
-   Mean first monthly Hgb for study period 11.8 ± 1.4 g/dL
-   Median monthly EPO dose 43,000 (interquartile range: 19,500-87,100) units
-   3,300 (1,500-6,700) units per hemodialysis session.

## Summary of Results

- Discontinuation protocol resulted in less patients with Hgb>13 g/dL (P<0.001)
- Discontinuation of epo did not result in higher proportion of Hgb belows <11 g/dL or <10 g/dL
- Discontinuation of epo resulted in lower doses of epoetin being used
- Discontinuation did not result in increased Hgb variability

## Summary-2

- Majority of patients within US have Hgb>12 g/dL (beyond FDA label)
- Is this inevitable or modifiable?
- Factors
- “Curve shifting” -- for-profit  status, chain-specific algorithm, dialysis unit protocol, route of administration, other factors (pt factors, etc)
- Significance of Hgb cycling unproven
- If the label recognizes Hgb cycling as a reason to justify Hgb values >12 g/dL, is it muddying a distinction between biologic phenomenon and practice factors?

## Outline

**Review of Hgb target studies: observational and RCT data**
**Treating patients to a target Hgb**
** **
**Managing the ESA hypo-responsive patient**

## The ESA Hyporesponsive Patient

**Definitions vary**
**Represents approximately 30-40% of dialysis patients**
**Characterized by markers of the acute phase response (low serum albumin, elevated CRP, elevated ferritin)**
**Guidelines caution treating with iron if serum ferritin>500 ng/ml; therefore, in order to raise Hgb > 11 g/dL, patients treated with high doses of epoetin**

## Prospective, randomized, controlled, parallel-group, multicenter, clinical trial

**Prospective, randomized, controlled, parallel-group, multicenter, clinical trial**
**Major inclusion criteria**
**Serum ferritin 500-1200 ng/mL**
**TSAT ≤25%**
**Hgb ≤11.0 g/dL**
**Receiving EPO dose ≥225 IU/kg/wk or ≥22,500 IU/wk with no change in dose or route of administration for 14 days from screening**
**≤****125 mg of IV iron per week in any of the 4 weeks prior to screening**
**Patients are randomized in a 1:1 ratio to receive**
**IV iron group: 1 g of ferric gluconate (125 mg x 8 HD sessions) plus 25% increase in EPO**
**Control group: 25% increase in EPO alone**

## DRIVE Trial:Patient Demographics

- Coyne et al, JASN 2007

## Hematologic Response Change in Weekly Hb

- Coyne et al, JASN 2007

## DRIVE Adverse events

_**Adverse events did not differ significantly between groups**_
- Infections
- 13 infections in 10 pts in control group
- 12 infections in 8 pts in iron group
- Cardiac events
- 4 pts in each of 2 groups
- Vascular adverse events
- 13 control gp
- 5 in iron group
- SAE’s
- 14 in control gp in 9 patients
-  12 in Iron gp in 9 patients
- Deaths
-   One patient died in each group.

## Epoetin Dose Decreased Significantly at week 12 following Use of IV Iron (Drive II)

**Epoetin dose was significantly lower at 12 weeks in the IV ron group compared to the Control group (epoetin difference ~9,600 u/wk, p=0.017)**
**Control group epoetin doses remained significantly elevated (p=0.0004)**
**IV Iron group EPO doses returned to baseline level (p=0.6039)**

- DRIVE		DRIVE II

## Goal of Study

- Do baseline and inflammation markers predict the response of Hb to treatment?
- Serum ferritin and TSAT not found to be predictive of Hb response in ferric gluconate patients
- In control group, no marker predicted likelihoodof response
- Regardless of response marker level, giving IV iron results in greater Hb response than not giving iron (0.5-0.7 g/dL effect at wk 6, p<0.05)

- Singh AK  et al Kidney Int. 2007

## Conclusions

**Target Hgb**
**< 12 g/dL**
**RCTs in both D-CKD and ND-CKD**
**CHOIR Post-hoc analysis: Hgb level and Epo dose**
**Getting to Target**
**Problem of Hgb cycling**
**Causes of Hgb cycling multifactorial **
**Difficult to achieve Hgb in narrow range: broader range or no range**
**Hyporesponsive patient**
**30-40% of D-CKD**
**DRIVE 1 and 2 support greater role for iron therapy**
**Using iron is cost-effective**