Breaking the Vicious Cycle – Efficacy of Anemia Therapies

1
Breaking the Vicious Cycle Efficacy of Anemia
Therapies

• Peter Bárány
• Division of Renal MedicineDepartment of Clinical
  Science, Intervention and TechnologyKarolinska
  Institutet, Stockholm, Sweden

2
Learning Objectives

• Understand the importance of anemia treatment in
  patients with chronic kidney disease (CKD)
• Review the efficacy of erythropoiesis-stimulating
  agents (ESAs) and intravenous (i.v.) iron to
  correct anemia
• Understand the limitations of previous trials and
  how these are being addressed in forthcoming
  studies

3
Outline

• Anemia in CKD
• Anemia treatment
• Blood transfusions
• ESAs
• Iron
• Further studies are needed
• Conclusions

4
Reduced Kidney Function is Associated with
Worsening Anemia

• National Health and Nutrition Examination Survey
  (NHANES)
• Population-based epidemiological study
• 15,419 participants aged 20 years
• Conducted from 19881994

17
17
15
15
13
13
Hb level in men (g/dL)
11
11
Hb level in women (g/dL)
95th Percentile Median 5th Percentile
95th Percentile Median 5th Percentile
9
9
7
7
0
30
60
90
120
150
0
30
60
90
120
150
Estimated GFR, (mL/min/1.73 m2)
Estimated GFR, (mL/min/1.73 m2 )
GFR, glomerular filtration rate
Astor BC et al. Arch Intern Med 200216214011408
5
Anemia is Associated with Poor Survival of
Patients with CKD
Due to the negative effects of anemia,13 early
diagnosis and treatment in patients with CKD is
recommended4,5
25.0

• Dynamic, retrospective cohort study among 8761
  patients with CKD at Kaiser Permanente Northwest2
• Assessment of outcomes2
• Death
• Cardiovascular (CV) hospitalization
• End-stage renal disease (ESRD)

23.4
20.0
17.4
15.5
15.0
14.5
12.6
Rate per 100 patient-years
11.6
11.3
10.3
10.1
9.6
10.0
9.0
8.9
8.5
7.6
7.4
6.5
6.2
5.9
5.3
4.8
5.0
4.0
2.6
1.3
1.3
1.0
0.8
0.5
0.4
0.4
0.3
0.0
9.4
11.0
11.8
12.3
12.8
13.2
13.5
13.9
14.5
15.8
Mean hemoglobin (g/dL) per decile
1. Fishbane S. Heart Fail Clin 20084401410 2.
Thorp ML et al. Nephrology 200914240246 3.
Kovesdy CP et al. Kidney Int 200669560564 4.
Hörl WH et al. Nephrol Dial Transplant
200722(suppl 3)iii26 5. Gouva C et al. Kidney
Int 200466753760
6
Blood Transfusions Restricted Use is Still
Needed
7
Transfusion Use in the CKD Population

• Transfusion use is decreasing in the CKD
  population1
• Data from Medicare patients
• 301,000 CKD and 15,772,039 non-CKD
• ESA usage increased from 2.5 in 1998 to 7.5 in
  2004

150
100
Transfusion rate(per 1000 patients)
CKD
Non-CKD
50
0
1998
1999
2000
2001
2002
2003
2004
Cohort year
1. Ibrahim HN et al. Nephrol Dial Transplant
20092431383143
8
Hemoglobin Targets and Blood Transfusions in HD
Patients

• Randomized multicenter, international trial
• 596 hemodialysis (HD) patients without
  symptomatic cardiac disease
• Treated with epoetin alfa and randomized to a low
  (9.511.5 g/dL) or high (Hb 13.514.5 g/dL)
  hemoglobin (Hb) target
• High hemoglobin target was a significant
  predictor of time to first transfusion
  independent of baseline associations

HR, Hazard Ratio
Foley RN et al. Clin J Am Soc Nephrol
2008316691675
9
The Efficacy of ESA Therapy
10
Numerous ESAs are Currently Available with more
Development
Darbepoetin a t1/2 2572 hours
Epoetin a t1/2 624 hours
Epoetin b t1/2 624 hours
Epoetin d
Methoxy PEG-epoetin b (CERA) t1/2 130 hours
Biosimilar epoetins
20XX Hematide
1989
2002
2007
1990
Fishbane S. Curr Opin Nephrol Hypertens
200918112115Macdougall IC Ashenden M. Adv
Chron Kid Dis 200916117130
CERA, continuous erythropoietin receptor activator
11
Numerous Studies have Demonstrated the Efficacy
of ESAs to Improve and Maintain Hemoglobin Levels
in Patients with Anemia and CKD at all Stages
Size (n)
Hemoglobin (g/dL)
1500
1000
500
0
6
7
8
9
10
11
12
13
14
15
16
Placebo/control mean Hb Lower target mean
achieved Hb Higher target mean achieved Hb
Ritz (2007)
Singh (2006)
Drüeke (2006)
Rossert (2006)
Levin (2005)
Parfrey (2005)
Roger (2004)
Gouva (2004)
Furuland (2003)
Foley (2000)
McMahon (1999)
Besarab (1998)
Kuriyama (1997)
Nissenson (1995)
Roth (1994)
Sikole (1993)
Morris (1993)
Clyne (1992)
Bahlman (1991)
CanEPO (1990)
Watson (1990)
Abraham (1990)
Suzuki (1989)
KDOQITM. Am J Kidney Dis 200750471530
12
ESAs have a Modest Effect on Aerobic Capacity in
HD Patients with Severe Anemia and Low Target

• 21 HD patients with severe anemia (15 control
  healthy subjects)
• ESA therapy to partially correct anemia (Hb 1011
  g/dL) has a modest effect on aerobic capacity

VO2 max (L/min)
Mean healthy subjects
2SD of mean
plt0.001
Before ESA therapy
After ESA therapy
VO2 max, maximum oxygen uptake
Bárány P et al. Clin Sci 199384441447
13
Patients with Severe Anemia have a Substantial
Improvement in Cardiac Function when Targeted to
an Hb 12 g/dL

• Systematic review of studies relating ESA therapy
  and cardiac outcomes
• January 1990February 2007
• 15 unique studies
• 1731 patients with CKD and ESRD
• Anemia at baseline defined as
• Severe Hb lt10 g/dL
• Moderate Hb 10 g/dL lt12 g/dL
• Target Hb
• Low Hb 12 g/dl or Hct 36
• High Hb gt12 g/dl or gtHct 36

Cannella 1990
Pascual 1991 (i)
Pascual 1991 (ii)
Portoles 1997
Massimetti 1998
Hayashi 2000
London 2001
Sikole 2002
Ayus 2005
Combined
-100
-80
-60
-40
-20
0
20
40
60
Change in LVMi (mean with 95 CI)
Patients with severe anemia had a substantial
improvement in LVMi when assigned to a target Hb
12 g/dL
Hct, hematocrit LVMi, left ventricular mass index
Parfrey PS et al. Clin J Am Soc Nephrol
20094755762
14
Correction of Moderate Anemia has No Effect on
LVMi
Moderate anemia and low Hb target
Moderate anemia and high Hb target
Foley 2000 (ii)
Foley 2000 (i)
Foley 2000 (iv)
Foley 2000 (iii)
Frank 2004
Roger 2004 (i)
Roger 2004 (ii)
Levin 2005 (ii)
Hampl 2005
Levin 2005 (ii)
Parfrey 2005 (i)
Parfrey 2005 (ii)
Ritz 2007 (ii)
Ritz 2007 (ii)
Combined
Combined
-100
-80
-60
-40
-20
0
20
40
60
-100
-80
-60
-40
-20
0
20
40
60
Change in LVMi (mean with 95 CI)
Change in LVMi (mean with 95 CI)

• Patients with moderate anemia had no improvement
  in LVMi, irrespective of target Hb

Parfrey PS et al. Clin J Am Soc Nephrol
20094755762
15
Four Large Trials have Examined the Efficacy and
Safety of ESAs to Achieve High or Low Hb Targets
DM, diabetes mellitus MI, myocardial infarction
CHF, chronic heart failure
1. Besarab A et al. N Engl J Med
1998339584590 2. Singh AK et al. N Engl J Med
200635520852098 3. Drüeke TB et al. N Engl J
Med 200635520712084 4. Pfeffer MA et al. N
Engl J Med 200936120192032
16
Diabetes and CV Disease were Common Comorbidities
in the Four Major Trials of ESAs
1. Besarab A et al. N Engl J Med 1998339584590
2. Singh AK et al. N Engl J Med
200635520852098 3. Drüeke TB et al. N Engl J
Med 200635520712084 4. Pfeffer MA et al. N
Engl J Med 200936120192032
17
Higher Hb Targets are Associated with
Improvements in QoL Parameters

• CV risk reduction by early anemia treatment with
  epoetin beta (CREATE) study
• 603 patients with CKD and anemia treated with ESA
• Randomized to Hb target of
• 1315 g/dL (group 1)
• 10.511.5 g/dL (group 2)
• Primary endpoint composite of eight CV events
• No reduced risk of CV events was observed,1
  reflecting the fact that CREATE was underpowered2

Group 1
Group 2
5
p0.003
plt0.001
plt0.001
p0.01
p0.006
plt0.001
4
3
2
1
0
Change from baseline in quality of life score
-1
-2
-3
-4
-5
-6
-7
General Health
MentalHealth
Physical Function
Physical Role
Social Function
Vitality
Higher Hb targets in pre-dialysis CKD patients
are associated with significant improvements in
quality of life (QoL) parameters
1. Drüeke TB et al. N Engl J Med
200635520712084 2. Levin A. Nephrol Dial
Transplant 200722309312
18
Greater ESA Doses are Significantly Associated
with Greater Hb Concentrations

• Dialysis Outcomes and Practice Patterns Study
  (DOPPS)
• Analysis of data from 11,041 HD patients in 12
  countries
• Seven countries 19962001 and 12 countries
  20012004

12.5
Sweden
12.0
US
Spain
Canada
Belgium
AUS/NZ
11.5
Germany
Italy
Mean Hb level (g/dL)
UK
11.0
France
10.5
Japan
10.0
9.5
4
6
8
10
12
14
16
18
Mean epoetin dose x 103 (units/patient/wk)
Van Wyck D et al. Clin J Am Soc Nephrol
200721314 Pisoni RL et al. Am J Kidney Dis
20044494111
19
ESA Therapy Effectively Corrects Hb Levels
Compared with Placebo

• Trial to Reduce cardiovascular Events with
  Aranesp Therapy (TREAT)
• Randomized, double-blind, placebo-controlled
  trial
• 4038 pre-dialysis CKD patients with diabetes and
  anemia (Hb 11 g/dL) randomized to receive ESA
  (n2012) or placebo (n2026)
• Primary endpoint composite outcomes of death,
  CV events or ESRD

Renal composite (ESRD or death)
50
Darbepoetin alfa
40
Hazard ratio, 1.06 (95 CI, 0.951.19) p0.29
Placebo
30
Patients with event ()
20
10
0
13.5
0
6
12
18
24
30
36
42
48
Months since randomization
13.0
Darbepoetin alfa
12.5
ESRD
12.0
50
11.5
40
Mean Hb (g/dL)
Hazard ratio, 1.02 (95 CI, 0.871.18) p0.83
Placebo
11.0
30
Darbepoetin alfa
10.5
Patients with event ()
Placebo
20
10.0
10
9.5
0.0
0
0
6
12
18
24
30
36
42
48
0
6
12
18
24
30
36
42
48
Months since randomization
Months since randomization
ESA therapy effectively corrected Hb levels
compared with placebo, however, no difference
was observed in disease progression or mortality
Pfeffer MA et al. N Engl J Med 200936120192032
20
The Efficacy of Iron Therapy
21
Numerous I.v. Iron Preparations are Available
Methoxy PEG-epoetin b (CERA) t1/2 130 hours
Darbepoetin a t1/2 2572 hours
Epoetin d
Epoetin a t1/2 624 hours
Epoetin b t1/2 624 hours
Biosimilar epoetins
20XX Hematide
2000s
1990s
1950s
2010
1970s
Sodium ferric gluconate 12 kDa t1/2 12 hours
Iron sucrose 45 kDa t1/2 5 hours
Ferric carboxymaltose 150 kDa t1/2 16 hours
Ferumoxytol 308750kDa t1/2 9.314.5 hours
High MW iron dextran 265 kDa t1/2 60 hours
Low MW iron dextran 7290 kDa t1/2 535 hours
Fishbane S. Curr Opin Nephrol Hypertens
200918112115Macdougall IC Ashenden M. Adv
Chron Kid Dis 200916117130
MW, molecular weight
22
Functional Iron Deficiency was Described Early
in Epoetin-treated CKD5D Patients

• Combined Phase I and II trial data for
  recombinant human erythropoietin (rHuEPO) in 25
  HD patients with anemia
• rHuEPO administration induced a fall in
  transferrin saturation (TSAT) and serum iron
  levels

1000 mg i.v. iron dextran
45
Anephric
35
Hematocrit ()
200 mL RBCs
25
15
6.0
4.0
Reticulocytes Corrected ()
2.0
0
-8
0
8
20
24
16
12
4
-12
-4
Weeks
One of the clinical features seen with this form
of treatment was a state of functional iron
deficiency
rHuEPO 50 U/kg 3x/wk
saturated 52 13 26 ferritin
885 578 1035
Eschbach JW et al. N Engl J Med 19873167378
23
Parenteral Iron Therapy is Effective in
Hemodialysis Patients

• Regression analysis of 13 studies of parenteral
  iron in ESRD patients demonstrated improvements
  in iron status (ferritin and TSAT)
• On average, the ESA dose was decreased by 42
  with an 18 increase in Hb

70
60
50
40
Change in hemoglobin ()
r0.56 plt0.05
30
20
10
0
0
10
20
30
40
50
60
70
80
Reduction in ESA dose ()
Besarab A et al. J Am Soc Nephrol
19991020292043
24
I.v. Iron Therapy is Associated with Improved
Survival in HD Patients

• Epidemiological study conducted in the US1
• Prospectively collected data over 2 years from an
  historical cohort from the DaVita database
• 58,058 maintenance HD patients
• Three types of i.v. iron
• Iron sucrose
• Sodium ferric gluconate
• Iron dextran

2.0
2.0
Unadjusted Case mix Case mix and MICS
Unadjusted Case mix Case mix and MICS
1.5
1.5
1.0
1.0
CV mortalityhazard ratio
All-cause mortality hazard ratio
0.8
0.8
0.6
0.6
0.4
0.4
0
0
1199
400
1199
400
200399
200399
I.v. iron dose (mg/month)
I.v. iron dose (mg/month)
MICS malnutrition-inflammation complex syndrome
1. Kalantar-Zadeh K et al. J Am Soc Nephrol
20051630703080
25
Greater Increase in Hb with I.v. Iron Sucrose
Versus Oral Iron

• Randomized controlled multicenter trial
• Pre-dialysis CKD patients Stage 35
• I.v. iron sucrose (n79) versus oral ferrous
  sulfate (n82)

I.v. iron
Oral iron
I.v. iron
Oral iron
60
1.0


0.8
40


Patients achieving 1 g/dL increase in Hb ()
0.6

Change in Hb (g/dL)



0.4
20
0.2



0
0.0
0
14
28
42
56
0
14
28
42
56
Time after start of treatment (days)
Time after start of treatment (days)
plt0.05 plt0.01 plt0.001 from baseline
plt0.05 after 42 weeks between groups
Adapted from Van Wyck DB et al. Kidney Int
20056828462856
26
More Patients Achieve Target Hb Level with i.v.
Iron Sucrose Versus Oral Iron

• Randomized open-label, multicenter trial
• 96 pre-dialysis CKD patients
• I.v. iron sucrose (n48) versus oral ferrous
  sulfate (n48)

p0.028
1.2
60
I.v. iron
Oral iron
54.2
plt0.0001
1.0
50
plt0.0001
0.8
40
31.3
Mean Hb change from baseline (g/dL)
Patient response ()
0.6
plt0.0001
30
plt0.0001
p0.017
0.4
20
0.2
10
p0.002
0
0
I.v. iron
Oral iron
Baseline
15
36
43
Study day
Achieving Hb gt11.0 g/dL p values are versus
baseline values
Adapted from Charytan C et al. Nephron Clin Pract
2005100c55-62
27
Greater Increase in Hb with I.v. Ferumoxytol
Versus Oral Iron in ESA-treated Patients

• Randomized open-label, multicenter trial
• 304 pre-dialysis CKD patients (Stage 15) with
  anemia
• I.v. ferumoxytol (n228) versus oral ferrous
  fumerate (n76)

p0.001
1.16
55.4
1.2
60
1.0
50
0.8
40
Mean change in Hb from baseline (g/dL)
Patient response ()
0.6
30
24.2
0.4
20
0.19
0.2
10
0.0
0
I.v. iron (n83)
Oral iron (n33)
I.v. iron (n83)
Oral iron (n33)
Achieving 1g/dL increase from baseline
Spinowitz BS et al. J Am Soc Nephrol
20081915991605
28
Efficacy is Higher with I.v. Ferric
Carboxymaltose Versus Oral Iron

• Randomized multicenter trial
• 255 pre-dialysis CKD patients (creatinine
  clearance 45 mL/min/1.73 m2) with anemia
• I.v. ferric carboxymaltose (n152) versus oral
  ferrous sulfate (n103)

100
plt0.001
75
60.4
Patient response ()
50
34.7
25
0
I.v. iron (n144)
Oral iron (n101)
Achieving 1g/dL increase from baseline at any
time during the study
Benjamin J Qunibi W. 42nd ASN Renal Week, 27
October1 November 2009, San Diego, USA. Poster
SA-PO2422
29
Efficacy is Higher with I.v. Ferric
Carboxymaltose Versus Oral Iron ESA

• I.v. ferric carboxymaltose administration alone
  achieves a greater Hb response rate (1 g/dL
  increase from baseline at any time during the
  study) than either oral iron alone or oral iron
  ESA

100
80
60
Patient response rate ()
50.0
40
29.9
20
0
Oral Iron ESA (n24)
Oral iron only (n77)
plt0.008 plt0.002 Achieving 1g/dL increase
from baseline at any time during the study
Benjamin J Qunibi W. 42nd ASN Renal Week, 27
October1 November 2009, San Diego, USA. Poster
SA-PO2422
30
I.v. Iron is Effective without ESAs in Patients
with CKD

• Longitudinal open-label, single-arm, prospective
  study in a single nephrology centre
• 60 pre-dialysis CKD patients
• 58 completed the study
• Treated with i.v. iron sucrose for 12 months

100
80
75
76
Patients achieving targets ()
50
49
44
Hb gt10 g/dL
25
Serum ferritin gt100 ng/mL and TSAT gt20
0
Baseline
12 months
plt0.05 versus baseline
Mircescu G et al. Nephrol Dial Transplant
200621120124
31
I.v. Ferric Gluconate Improves Anemia more than
ESA alone in HD Patients

• Dialysis Patients Response to IV Iron with
  Elevated Ferritin (DRIVE) trial
• Randomized, controlled, open-label, multicenter
  trial
• 134 HD-CKD patients with anemia
• Ferritin 5001200 ng/mL, TSAT lt25
• I.v. sodium ferric gluconate (n68) versus no
  iron (n66)
• Primary endpoint Hb change from baseline

12.2


12.0
I.v. iron Control
11.8
11.9
11.9
11.7
11.6
11.4
11.3
11.2
11.3
Hb level (g/dL)
11.2
11.0
11.1
10.8
10.8
10.9
10.7
p 0.028
10.6
10.7
10.4
10.4
10.5
10.2
10.2
10.0
Week 0
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6(LOCF)
LOCF, last observation carried forward
Study week
Coyne DW et al. J Am Soc Nephrol 200718975984
32
Past I.v. Iron Trials have Limitations

• Lack of endpoint studies
• Several studies demonstrating the efficacy of
  i.v. iron alone or in combination with ESAs are
  low powered with small cohorts and limited
  follow-up periods
• Not all CKD stages studied
• Studies in HD are not representative of CKD 34
  populations
• Patients with comorbidity excluded
• Most anemia therapy studies in patients with CKD
  exclude individuals with comorbidities such as
  inflammatory disease and heart failure

33
Where Do We Go From Here?
34
Where Do We Go From Here?

• Endpoint studies of i.v. iron and ESA
• Are the reduced ESA doses beneficial?
• Studies in patients with cardio-renal syndrome
• I.v. iron in early anemia
• FIND-CKD study
• Observational studies of patients with
  comorbidity

35
FIND-CKD
Ferric carboxymaltose high dose (ferritin
target 400600 µg/L) 254 patients
Screening (up to 4 weeks)

• Ferric carboxymaltose low dose (ferritin
  target 100200 µg/L) 254 patients

R
ND-CKD ESA-naïve Hb 910.5 g/dL Ferritin lt100
µg/L

• Oral iron, daily ferrous sulphate508 patients

Visits every 2 weeks (weeks 08), then every 4
weeks (weeks 852), dosing every 4 weeks
Rescreening permitted
Anemia management per standard practice
No ESA (weeks 08)
Primary objective To evaluate the long-term
efficacy of ferric carboxymaltose (using targeted
ferritin levels to determine dosing) or oral iron
to delay and/or reduce ESA use in ND-CKD patients
with iron-deficiency anemia Secondary objectives
To evaluate the ESA requirements, to evaluate the
long-term safety and tolerability of iron therapy
and evaluate the health resource and economic
burden of the treatment of anemia of ND-CKD
Macdougall IC et al. 42nd ASN Renal Week, 27
October1 November 2009, San Diego, USA. Poster
SAPO2402
36
Conclusions

• Iron first
• Early treatment of anemia in patients with CKD
  should include effective iron supplementation
• Most studies demonstrate the superiority of i.v.
  versus oral iron
• Low Hb levels are associated with poor prognosis
  and increased mortality
• However, interventional ESA trials have not shown
  a beneficial effect of anemia correction on
  survival
• ESA treatment to a low target (1012 g/dL) is
  associated with positive effects on QoL and
  physical function
• A restrictive transfusion policy is recommended