Breaking the Vicious Cycle – Efficacy of Anemia Therapies
Peter BárányDivision of Renal MedicineDepartment of Clinical Science, Intervention and TechnologyKarolinska Institutet, Stockholm, Sweden
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
Outline
• Anemia in CKD• Anemia treatment
– Blood transfusions– ESAs– Iron
• Further studies are needed• Conclusions
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 1988–1994
Astor BC et al. Arch Intern Med 2002;162:1401–1408
GFR, glomerular filtration rate
17
0
Hb
le
ve
l in
me
n (
g/d
L)
Estimated GFR, (mL/min/1.73 m2)
30 60 90 120 150
15
13
11
9
7
95th PercentileMedian5th Percentile
17
0
Estimated GFR, (mL/min/1.73 m2 )
30 60 90 120 150
15
13
11
9
7
95th PercentileMedian5th Percentile
Hb
le
ve
l in
wo
me
n (
g/d
L)
Anemia is Associated with Poor Survival of Patients with CKD
• 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)
1. Fishbane S. Heart Fail Clin 2008;4:401–410; 2. Thorp ML et al. Nephrology 2009;14:240–246; 3. Kovesdy CP et al. Kidney Int 2006;69:560–564; 4. Hörl WH et al. Nephrol Dial Transplant 2007;22(suppl 3):iii2–6; 5. Gouva C et al. Kidney Int 2004;66:753–760
Due to the negative effects of anemia,1–3 early diagnosis and treatment in patients with CKD is recommended4,5
25.0
9.4
Ra
te p
er
10
0 p
ati
en
t-y
ea
rs
Mean hemoglobin (g/dL) per decile
10.0
5.0
11.0 11.8 12.3 12.8 13.2 13.5 13.9 14.5 15.8
4.0
0.0
20.0
15.0
2.61.3 1.3 1.0 0.8 0.5 0.4 0.4 0.3
14.5
9.6
7.6 7.45.9 6.2
5.3 4.8
6.5
23.4
15.5
12.611.6
10.311.3
8.59.0 10.1
8.9
17.4
DeathCV hospitalizationESRD
Blood Transfusions – Restricted Use is Still Needed
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
1. Ibrahim HN et al. Nephrol Dial Transplant 2009;24:3138–3143
0
50
100
150
1998 1999 2000 2001 2002 2003 2004
Cohort year
Tra
nsf
usi
on
rat
e(p
er 1
000
pat
ien
ts)
CKD
Non-CKD
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 (9.5–11.5 g/dL) or high (Hb 13.5–14.5 g/dL) hemoglobin (Hb) target
• ‘High hemoglobin target was a significant predictor of time to first transfusion independent of baseline associations’
Foley RN et al. Clin J Am Soc Nephrol 2008;3:1669–1675
Low Hb target High Hb target p
Transfusion rate (per patient per year)
0.66(95% CI=0.59–0.74)
0.26(95% CI=0.22–0.32)
<0.0001
Pretransfusion Hb level (g/dL)
7.7 (95% CI=7.5–7.9)
8.1(95% CI=7.6–8.5)
0.09
Transfusion HR 1 (reference) 0.46
(95% CI=0.29–0.72)
0.0007
HR, Hazard Ratio
The Efficacy of ESA Therapy
Numerous ESAs are Currently Available with more Development
Fishbane S. Curr Opin Nephrol Hypertens 2009;18:112–115Macdougall IC & Ashenden M. Adv Chron Kid Dis 2009;16:117–130
CERA, continuous erythropoietin receptor activator
Darbepoetin t1/2 25–72 hours Epoetin Epoetin
t1/2 6–24 hours
Methoxy PEG-epoetin
(CERA)t1/2 130 hours
Epoetin t1/2 6–24 hours
20XXHematide
1989 2002 20071990
Biosimilarepoetins
Numerous Studies have Demonstrated the Efficacy of ESAs to Improve and Maintain Hemoglobin Levels in Patients with Anemia and CKD at all Stages
KDOQITM. Am J Kidney Dis 2007;50:471–530
0
Suzuki (1989)
5001000
1500 6 7 8 9 10 11 12 13 14 15 16
Size (n)
Placebo/control mean HbLower target mean achieved HbHigher target mean achieved Hb
Hemoglobin (g/dL)
Abraham (1990)Watson (1990)
CanEPO (1990)Bahlman (1991)
Clyne (1992)Morris (1993)Sikole (1993)
Roth (1994)Nissenson (1995)Kuriyama (1997)
Besarab (1998)McMahon (1999)
Foley (2000)Furuland (2003)
Gouva (2004)Roger (2004)
Parfrey (2005)Levin (2005)
Rossert (2006)Drüeke (2006)
Singh (2006)Ritz (2007)
VO
2 m
ax (
L/m
in)
8007006005004003002000
1
2
3
4
5
Total hemoglobin (g)
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 10–11 g/dL) has a modest effect on aerobic capacity
Bárány P et al. Clin Sci 1993;84:441–447
VO2 max, maximum oxygen uptake
Before ESA therapy
Mean healthy subjects
± 2SD of mean
After ESA therapy
p<0.001
Parfrey PS et al. Clin J Am Soc Nephrol 2009;4:755–762
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 1990–February 2007– 15 unique studies– 1731 patients with CKD
and ESRD– Anemia at baseline defined as:
• Severe: Hb <10 g/dL
• Moderate: Hb ≥10 g/dL <12 g/dL
– Target Hb• Low: Hb ≤12 g/dl or ≤Hct 36%
• High: Hb >12 g/dl or >Hct 36%
Patients with severe anemia had a substantial improvement in LVMi when assigned to a target Hb ≤12 g/dL
Change in LVMi (mean with 95% CI)
-100
Combined
-80 -60 -40 -20 0 20 40 60
Ayus 2005
Sikole 2002
London 2001
Hayashi 2000
Massimetti 1998
Portoles 1997
Pascual 1991 (ii)
Pascual 1991 (i)
Cannella 1990
Hct, hematocrit; LVMi, left ventricular mass index
Parfrey PS et al. Clin J Am Soc Nephrol 2009;4:755–762
Correction of Moderate Anemia has No Effect on LVMi
Patients with moderate anemia had no improvement in LVMi, irrespective of target Hb
Moderate anemia and low Hb target Moderate anemia and high Hb target
Change in LVMi (mean with 95% CI)
-100
Combined
-80 -60 -40 -20 0 20 40 60
Ritz 2007 (ii)
Levin 2005 (ii)
Roger 2004 (i)
Foley 2000 (iii)
Foley 2000 (i)
Parfrey 2005 (i)
Change in LVMi (mean with 95% CI)
-100
Combined
-80 -60 -40 -20 0 20 40 60
Ritz 2007 (ii)
Hampl 2005
Roger 2004 (ii)
Foley 2000 (iv)
Foley 2000 (ii)
Levin 2005 (ii)
Frank 2004
Parfrey 2005 (ii)
Four Large Trials have Examined the Efficacy and Safety of ESAs to Achieve High or Low Hb Targets
Normal HCT1 CHOIR2 CREATE3 TREAT4
Region USA USA EuropeAmericas,
Europe, Australia
N 1233 1432 603 4038
PatientsCKD5D with
cardiac diseaseCKD 3–4 CKD 3–4
CKD 3–4 with Type 2 DM
eGFR, mL/min/1.73 m2 HD patients 15–50 15–35 20–60
Target/achieved Hb, g/dLLowHigh
Hct 30±3 %Hct 42±3 %
11.313.5/12.6
10.5–11.513.0–15.0
Placebo/ESA at ≥9.013.0
Follow-up, months 30 16 35 48
Primary outcome Death, MIDeath, MI, stroke,
CHF hospitalizationCV events
Death, CV events, ESRD
HR (95 % CI) 1.3 (0.9–1.8) 1.34 (1.03–1.74)0.78
(0.53–1.14)1.05 (0.94–1.17)
1. Besarab A et al. N Engl J Med 1998;339:584–590; 2. Singh AK et al. N Engl J Med 2006;355:2085–2098; 3. Drüeke TB et al. N Engl J Med 2006;355:2071–2084; 4. Pfeffer MA et al. N Engl J Med 2009;361:2019–2032
DM, diabetes mellitus; MI, myocardial infarction; CHF, chronic heart failure
Diabetes and CV Disease were Common Comorbidities in the Four Major Trials of ESAs
Normal HCT1 CHOIR2 CREATE3 TREAT4
Region USA USA EuropeAmericas,
Europe, Australia
N 1233 1432 603 4038
PatientsCKD5D with
cardiac diseaseCKD 3–4 CKD 3–4
CKD 3–4 with Type 2 DM
DM, % 56 N/A 26 100
History of CV disease, %
MICHFCerebrovascular diseasePeripheral vascular disease
2446–
39
16241016
13232
18331121
1. Besarab A et al. N Engl J Med 1998;339:584–590 2. Singh AK et al. N Engl J Med 2006;355:2085–2098; 3. Drüeke TB et al. N Engl J Med 2006;355:2071–2084; 4. Pfeffer MA et al. N Engl J Med 2009;361:2019–2032
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:• 13–15 g/dL (group 1)• 10.5–11.5 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
1. Drüeke TB et al. N Engl J Med 2006;355:2071–2084; 2. Levin A. Nephrol Dial Transplant 2007;22:309–312
Higher Hb targets in pre-dialysis CKD patients are associated with significant improvements in quality of life (QoL) parameters
Group 1 Group 2
General Health
Ch
an
ge
fro
m b
as
eli
ne
in
q
ua
lity
of
life
sc
ore
-7-6-5-4-3-2-1012345
MentalHealth
Physical Function
Physical Role
Social Function
Vitality
p=0.003 p<0.001 p<0.001 p=0.01 p=0.006 p<0.001
Van Wyck D et al. Clin J Am Soc Nephrol 2007;2:13–14; Pisoni RL et al. Am J Kidney Dis 2004;44:94–111
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 1996–2001 and 12 countries 2001–2004
Mea
n H
b le
vel (
g/d
L)
49.5
10.0
10.5
11.0
11.5
12.0
12.5
6 8 10 12 14 16 18
Mean epoetin dose x 103 (units/patient/wk)
Spain
Germany
Japan
AUS/NZCanada Belgium
US
Italy
Sweden
FranceUK
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 (n=2012) or placebo (n=2026)
– Primary endpoint: composite outcomes of death, CV events or ESRD
Pfeffer MA et al. N Engl J Med 2009;361:2019–2032
ESA therapy effectively corrected Hb levels compared with placebo, however, no difference was observed in disease progression or mortality
Renal composite (ESRD or death)
ESRD
Months since randomization0
Mea
n H
b (
g/d
L)
0.06 12 18 24 30 36 42 48
9.5
10.0
10.5
11.0
11.5
12.0
12.5
13.0
13.5
Darbepoetin alfa
Placebo
Months since randomization0
Pat
ien
ts w
ith
eve
nt
(%)
06 12 18 24 30 36 42 48
10
20
30
40
50Darbepoetin alfa
PlaceboHazard ratio, 1.06 (95% CI, 0.95–1.19)p=0.29
Months since randomization0
Pat
ien
ts w
ith
eve
nt
(%)
06 12 18 24 30 36 42 48
10
20
30
40
50
Darbepoetin alfa
Placebo
Hazard ratio, 1.02 (95% CI, 0.87–1.18)p=0.83
The Efficacy of Iron Therapy
Numerous I.v. Iron Preparations are Available
Fishbane S. Curr Opin Nephrol Hypertens 2009;18:112–115Macdougall IC & Ashenden M. Adv Chron Kid Dis 2009;16:117–130
2000s1990s1950s
Ferric carboxymaltose150 kDa
t1/2 16 hours
Ferumoxytol308–750kDa
t1/2 9.3–14.5 hours
Low MW iron dextran72–90 kDa
t1/2 5–35 hours
Sodium ferric gluconate12 kDa
t1/2 1–2 hours
Iron sucrose45 kDa
t1/2 5 hours
2010
MW, molecular weight
20XXHematide
High MW iron dextran265 kDa
t1/2 60 hours
1970s
Darbepoetin t1/2 25–72 hours Epoetin Epoetin
t1/2 6–24 hours
Methoxy PEG-epoetin
(CERA)t1/2 130 hours
Epoetin t1/2 6–24 hours
Biosimilarepoetins
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
Eschbach JW et al. N Engl J Med 1987;316:73–78
1933–2007
‘One of the clinical features seen with this form of treatment was
a state of functional iron deficiency’
45
Re
tic
ulo
cy
tes
Co
rre
cte
d (
%)
Weeks-8 0 +8 +20 +24
25
15
6.0
2.0
0
Anephric
+16+12+4-12
35
4.0H
em
ato
cri
t(%
) 200 mLRBCs
1000 mgi.v. irondextran
rHuEPO 50 U/kg 3x/wk
% saturated 52 13 26 ferritin 885 578 1035
-4
Besarab A et al. J Am Soc Nephrol 1999;10:2029–2043
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
Ch
ang
e in
hem
og
lob
in (
%)
Pre Post
Ferritin (ng/mL)
209±40 447±50
TSAT (%)
22±2 35±4
0
0 10 20 30 40 50 60 70 80
10
20
30
40
50
60
70
Reduction in ESA dose (%)
r=0.56p<0.05
1. Kalantar-Zadeh K et al. J Am Soc Nephrol 2005;16:3070–3080
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
All
-ca
us
e m
ort
ali
ty
ha
zard
ra
tio
0.40 1–199
200–399 ≥400
0.8
1.0
1.5
2.0
0.6
UnadjustedCase mixCase mix and MICS
I.v. iron dose (mg/month)
CV
mo
rta
lity
ha
zard
ra
tio
0.40 1–199
200–399 ≥400
0.8
1.0
1.5
2.0
0.6
UnadjustedCase mixCase mix and MICS
I.v. iron dose (mg/month)MICS; malnutrition-inflammation complex syndrome
Greater Increase in Hb with I.v. Iron Sucrose Versus Oral Iron
• Randomized controlled multicenter trial– Pre-dialysis CKD patients Stage 3–5
– I.v. iron sucrose (n=79) versus oral ferrous sulfate (n=82)
*p<0.05; **p<0.01; ***p<0.001 from baseline +p<0.05 after 42 weeks between groups
Pat
ien
ts a
chie
vin
g
≥1 g
/dL
incr
ease
in H
b (
%)
Ch
ang
e in
Hb
(g
/dL
)
Time after start of treatment (days)Time after start of treatment (days)
0
20
40
60
0 14 28 42 56 0 14 28 42 56
0.0
1.0
0.8
0.6
0.4
0.2
****
***
*
*** ***
*
I.v. iron Oral iron I.v. iron Oral iron
++
+ +
Adapted from Van Wyck DB et al. Kidney Int 2005;68:2846–2856
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 (n=48) versus oral ferrous sulfate (n=48)
Adapted from Charytan C et al. Nephron Clin Pract 2005;100:c55-62
Pat
ien
t re
spo
nse
* (%
)
Mea
n H
b c
han
ge
fro
m
bas
elin
e (g
/dL
)
p=0.0281.2
1.0
0.8
0.6
0.4
0.2
0Baseline 15 36 43
Study day
p<0.0001
p<0.0001
p<0.0001
p<0.0001
p=0.002
p=0.017
I.v. iron Oral iron
I.v. iron Oral iron
31.3
54.2
0
10
20
30
40
50
60
*Achieving Hb >11.0 g/dLp values are versus baseline values
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 1–5) with anemia
– I.v. ferumoxytol (n=228) versus oral ferrous fumerate (n=76)
Spinowitz BS et al. J Am Soc Nephrol 2008;19:1599–1605
Mea
n c
han
ge
in H
b f
rom
b
asel
ine
(g/d
L)
Pat
ien
t re
spo
nse
* (%
)
p=0.001
I.v. iron(n=83)
Oral iron(n=33)
I.v. iron(n=83)
Oral iron(n=33)
1.16
0.19
0.0
0.2
0.4
0.6
0.8
1.0
1.2 55.4
24.2
0
10
20
30
40
50
60
*Achieving ≥1g/dL increase from baseline
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 (n=152) versus oral ferrous sulfate (n=103)
p<0.001
I.v. iron(n=144)
60.4
Oral iron(n=101)
34.7
0
25
50
75
100
Pat
ien
t re
spo
nse
* (%
)
*Achieving ≥1g/dL increase from baseline at any time during the study
Benjamin J & Qunibi W. 42nd ASN Renal Week, 27 October–1 November 2009, San Diego, USA. Poster SA−PO2422
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
Benjamin J & Qunibi W. 42nd ASN Renal Week, 27 October–1 November 2009, San Diego, USA. Poster SA−PO2422
†p<0.008; ‡p<0.002*Achieving ≥1g/dL increase from baseline at any time during the study
0
20
40
60
80
100
84.8†
I.v. iron + ESA(n=33)
50.0†
Oral Iron + ESA(n=24)
53.2‡
I.v. iron only(n=11)
29.9‡
Oral iron only(n=77)
Pat
ien
t re
spo
nse
* ra
te (
%)
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
*p<0.05 versus baseline
Baseline 12 months*
Pat
ien
ts a
chie
vin
g t
arg
ets
(%)
Hb >10 g/dL
Serum ferritin >100 ng/mL and TSAT >20%
Mircescu G et al. Nephrol Dial Transplant 2006;21:120–124
44
80
49
76
0
25
50
75
100
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 500–1200 ng/mL, TSAT <25%– I.v. sodium ferric gluconate (n=68) versus no iron (n=66)– Primary endpoint: Hb change from baseline
Coyne DW et al. J Am Soc Nephrol 2007;18:975–984
10.0Week 0
Study week
Hb
leve
l (g
/dL
)
10.210.410.610.811.011.211.411.611.812.012.2
Week 1 Week 2 Week 3 Week 4 Week 5 Week 6(LOCF)
10.4
10.710.8
11.3
11.7
**11.9 11.9
11.311.2
11.1
10.9
10.7
10.5
10.2
I.v. ironControl
*p = 0.028
LOCF, last observation carried forward
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 3–4 populations
• Patients with comorbidity excluded– Most anemia therapy studies in patients with CKD exclude
individuals with comorbidities such as inflammatory disease and heart failure
Where Do We Go From Here?
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
FIND-CKD
Visits: every 2 weeks (weeks 0–8), then every 4 weeks (weeks 8–52), dosing every 4 weeks
Screening (up to 4 weeks)
ND-CKD ESA-naïveHb 9–10.5 g/dLFerritin <100 µg/L
Anemia management per standard practice
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 anemiaSecondary 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
Rescreening permitted
R
Ferric carboxymaltose: high dose (ferritin target= 400–600 µg/L) 254 patients
Ferric carboxymaltose: low dose (ferritin target= 100–200 µg/L) 254 patients
Oral iron, daily ferrous sulphate508 patients
No ESA (weeks 0–8)
Macdougall IC et al. 42nd ASN Renal Week, 27 October–1 November 2009, San Diego, USA. Poster SA–PO2402
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 (10–12 g/dL) is associated with positive effects on QoL and physical function
• A restrictive transfusion policy is recommended