Open Public Hearing Cardiorenal Drugs Advisory Committee Food and Drug Administration September 11,

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Open Public HearingCardiorenal Drugs Advisory
CommitteeFood and Drug AdministrationSeptember
11, 2007
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Kidney Transplant is the Preferred ESRD Treatment
Option
4.00
RISK EQUAL
2.84
RELATIVE RISK OF DEATH
1.00
0.32
0.25
0
106
183
244
365
546
DAYS SINCE TRANSPLANTATION
Wolfe et al. NEJM 3411725-1730 1999
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(No Transcript)
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Kidney Transplant Waitlist
Listings (2004 n64,321) Patients (2004
n60,393)
US Renal Data System 2006 Annual Report NIDDK,
Bethesda, MD, 2006
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JAMA 246135-39, 1981
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OPTN/SRTR 2006 Annual Report, Table 5.1a
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OPTN/SRTR 2006 Annual Report, Table 5.2
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Waiting time on dialysis as the strongest
modifiable risk factor for renal transplant
outcomes A paired donor kidney analysis
Meier-Kreiesche Kaplan Transplantation,
741377-1381, 2002
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Transfusion-Associated Sensitization
Karpinski, et al, JASN, 15818-824, 2004
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Blood Transfusion and Allosensitization

• High prevalence of anti-HLA antibodies after
  blood transfusion
• Can be a virtually insurmountable barrier to
  kidney transplantation
• Is associated with prolonged wait times,
  increased rejection rates after kidney
  transplant, and decreased allograft survival
• A high proportion of potential kidney transplant
  recipients continue to be transfused.
• Sensitized patients still constitute a high
  proportion of patients on transplant waiting
  lists.
• Since anemia is a risk factor for CKD progression
  to ESRD, the ESA treated CKD population is likely
  enriched in eventual transplant candidates
• Policy changes in the use of ESAs in CKD and ESRD
  patients need to carefully account for
  transfusion associated risks in the
  transplantable population

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Interactions between target and achieved Hb,
epoetin-alfa dose and outcomes in CHOIR
Correction of Hemoglobin and Outcomes in Renal
Insufficiency

• Lynda Szczech

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Key Points to Consider

• Trials to date126 randomize to an ESA algorithm
  attempting to achieve a goal hemoglobin.
• Patients who have higher level of hemoglobin
  enjoy a greater survival in observational data
  sets.3-5
• Dose of ESA has been shown in observational data
  to be inversely related to hemoglobin achieved.7
• Dose of ESA is directly related to all cause
  mortality.8
• 1. Singh AK, et al. N Engl J Med 3552085-2098,
  2006 5. Keith DS, et al. Arch Intern Med
  164659-663, 2004
• 2. Drueke TB, et al. N Engl J Med 3552071-2084,
  2006 6. Besarab A, et al. N Eng J Med
  339584-590, 1998
• 3. Collins AJ, et al.J Am Soc Nephrol
  122465-2473, 2001 7. Coladonato JA, et al. JASN
  131288-95, 2002
• 4. Al-Ahmad A, et al. J Am Coll Cardiol
  38955-962, 2001 8. Zhang Y, et al. Am J Kidney
  Dis 44866-876, 2004

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Distribution of average dose by treatment arm
Szczech, Sapp, Singh, Reddan, and Barnhart. To be
presented at ASN meeting November 2007.
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CHOIR post hoc analysis

• Methodology
• Kaplan-Meier plots
• Cox proportional hazards regression
• Outcomes
• Primary composite endpoint (presented here)
• Death, CHF, MI, and CVA
• Death (results not substantively different)
• Approach 1 Utilizes all values obtained during
  the study
• Approach 2 Landmark analysis fixed at 4 and 9 m

Szczech, Sapp, Singh, Reddan, and Barnhart. To be
presented at ASN meeting November 2007.
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Primary endpoint stratified on ability to achieve
target
Szczech, Sapp, Singh, Reddan, and Barnhart. To be
presented at ASN meeting November 2007.
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Primary endpoint stratified on dose gt 20K units
Szczech, Sapp, Singh, Reddan, and Barnhart. To be
presented at ASN meeting November 2007.
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Number of subjects achieving targets
700
600
500
400
Number of subjects
300
200
100
0
gt 13
11 to 13
lt 11
gt 11
lt 11
Group A achieved hmg
Group B achieved hmg
Szczech, Sapp, Singh, Reddan, and Barnhart. To be
presented at ASN meeting November 2007.
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Proportion of subjects in each group experiencing
primary endpoint
0.40
0.35
0.30
0.25
Proportion of subjects ineach group
experiencingprimary endpoint
0.20
0.15
0.10
0.05
0
gt 13
11 to 13
lt 11
gt 11
lt 11
Group A achieved hmg
Group B achieved hmg
Szczech, Sapp, Singh, Reddan, and Barnhart. To be
presented at ASN meeting November 2007.
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Landmark analysis 4 months (N1260)

• Parameter HR CI P
• Target A v. B 1.439 (1.050, 1.972) 0.023
• Target A v. B 1.208 (0.851, 1.713) 0.290
• Achieved Hb 0.856 (0.559, 1.309) 0.472
  
• Max EPO Dose gt20K
  1.603 (1.078,
  2.383) 0.020
• Target A v. B 1.238 (0.859, 1.784) 0.253
• Achieved Hmg 0.964 (0.619, 1.502) 0.872
• Maximum EPO Dose gt20K
  1.484 (0.983,
  2.241) 0.060 (MVA)

Szczech, Sapp, Singh, Reddan, and Barnhart. To be
presented at ASN meeting November 2007.
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Association between dose and primary outcome in
Group A (4 month Landmark)
Szczech, Sapp, Singh, Reddan, and Barnhart. To be
presented at ASN meeting November 2007.
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Association between dose and primary outcome in
Group B (4 month Landmark)
Szczech, Sapp, Singh, Reddan, and Barnhart. To be
presented at ASN meeting November 2007.
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Summary

• A target of 13.5 gm/dL is associated with worse
  outcomes as compared to a target of 11.3 gm/dL.
• Subjects achieving their desired hemoglobin
  target, irrespective of target, had better
  outcomes than those not achieving their target.
• Among subjects who achieve their desired target,
  increased risk associated with the higher goal
  could not be detected.
• High dose epoetin-alfa among subjects who do not
  achieve their target hemoglobin were associated
  with worse outcomes. The association between
  high dose and poorer outcomes may be the
  mechanism by which the results of the CHOIR ITT
  showed a target of 13.5 gm/dL caused greater risk.

Szczech, Sapp, Singh, Reddan, and Barnhart. To be
presented at ASN meeting November 2007.