Breaking the Vicious Cycle – Efficacy of Anemia Therapies Peter Bárány Division of Renal Medicine Department of Clinical Science, Intervention and Technology.

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