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Francesco LocatelliDipartimento di Nefrologia, Dialisi e Trapianto di Rene
Ospedale “Alessandro Manzoni” di Lecco
Bari, 19-20 Marzo 2010
XV Convegno del gruppo di studio di Dialisi Peritoneale
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EPO receptor EPO receptor
Elliott S, et al. Blood 89: 493-502, 1997Syed RS, et al. Nature 395: 511-516, 1998
Erythropoietin has two erythropoietin receptor binding sites
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EPO receptor
Erythropoietin has two erythropoietin receptor binding sites
EPO receptorrHuEPO
Elliott S, et al. Blood 89: 493-502, 1997Syed RS, et al. Nature 395: 511-516, 1998
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The ideal ESA
Effective
Safe
Flexible administration route
Less frequent administration schedule
Cheap
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Currently available ESAs Recombinant human erythropoietin (rHuEPO)
– Epoetin alfa– Epoetin beta
Long-acting ESAs– Darbepoetin alfa
• Different molecular structure
• Increased biological activity
- CERA• Different mechanism of action
• Different molecular structure
• Increased biological activity
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rHuEPO3 N-linked carbohydrate chains
Up to 14 sialic acids 30,400 daltons ~40% carbohydrate
Egrie JC, Browne JK. Nephrol Dial Transplant. 2001;16(suppl 3):3-13
4 N-linked carbohydrate chains Up to 18 sialic acids 33,750 daltons ~46% carbohydrate
NESP 5 N-linked carbohydrate chains
Up to 22 sialic acids 37,100 daltons ~51% carbohydrate
Bio
log
ical
act
ivit
y
Ser
um
hal
f-li
fe
Rec
epto
r b
ind
ing
Biochemical and biological properties of rHuEPO and glycosylation analogs
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Hb concentrations at 4-week intervals
7
8
9
10
11
12
13
14
15
Study week
251 5 9 13 17 21 37 49
Hb
(g
/dL
)
37
129
35
128
35
127
33
127
34
123
33
121
31
106 77 51
rHuEPO
NESP
rHuEPO
NESP
Patientnumbers:
Locatelli F et al. Kidney Int 2001; 60: 741-747
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- 3 - 2 - 1 0 1 2 3
- 0.54 [ -1.27, 0.19 ]
- 0.56 [ - 1.22, 0.11 ]
PPITT
Group ratio
Once week epoetin beta in HDMean time-adjusted AUC for haematocrit
• Mean [ 90% CI ]
Locatelli et al. Am J Kidney Dis 2002, 40: 119-125
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Weeks since withheld dose
9
10
11
12
13
14
15
16
–5 –4 –3 –2 –1 0 1 2 3 4 5 6 7 8 9 10 11–6
Hb
(g
/dL
)Time for Hb to return to 12 g/dL
after dose withheld due to Hb >14 g/dL
rHuEPO (n = 13)
NESP (n = 31)
Locatelli F et al. Kidney Int 2001; 60: 741-747
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DA administration Q2W was not associated with an increased frequency of Hb >14 g/dL
Percentage of Hb values >14 g/dL
5
4
3
2
1
0Q2W
(n=153)QW
(n=153)
Mea
n %
of
Hb
val
ues
>
14
g/d
L
1.3
2.6
Locatelli F et al. Nephrol Dial Transplant 2005;20 S.5:MP181
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16 (10) 2007
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Serum half life of ESAs
3. Dougherty et al. ASCO 20044. Macdougall et al. ASN 2005
Agent Population Mean (± SE)half-life (h)
IV SCEpoetin alfa Healthy volunteers1 6.8 ± 0.6 19.4 ± 2.5
Epoetin beta Healthy volunteers1 8.8 ± 0.5 24.2 ± 2.6
Darbepoetin alfa
Peritoneal dialysis patients2
25.3 ± 2.2 48.8 ± 5.2
C.E.R.A. Healthy volunteers3 133 ± 9.8 137 ± 21.9
Peritoneal dialysis patients4
134 ± 19 139 ± 20
1. Halstenson et al. Clin Pharmacol Ther. 1991:50:702-7122. Macdougall et al. J Am Soc Nephrol. 1999;10:2392-2395
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Understanding how C.E.R.A. is different
Receptor bindingproperties
Pharmacokineticproperties
Different pharmacologic profile
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C.E.R.A: Dose independent of scheduleCore study, PP population, n=124 (BA16286)
Mean (SE) change in Hb (g/dL) at 6 wk
Locatelli et al. Curr Med Res Opin 2007;23:969–979
n.s.
Administration schedule
QW Q3W Q4W
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
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-1.00 -0.75 -0.50 -0.25 0.00 0.25 0.50 0.75 1.00
Difference in adjusted group mean Hb (g/dL) change between baseline and evaluation (97.5% CI)
P<0.0001 for all comparisons
PP
0.004
-0.215 0.223C.E.R.A. Q2W
-0.173 0.275
0.051C.E.R.A. Q4W
Non-inferiority limit:C.E.R.A. groups vs epoetin
Primary efficacy analysisC.E.R.A. up to once-monthly as effective as epoetin TIW-QW
Levin NW et al. Lancet 2007, 370 (9596): 1415-1421
ITT-0.213
0.031
0.276
0.025
0.270-0.220
C.E.R.A. Q2W
C.E.R.A. Q4W
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IV C.E.R.A. once- and twice-monthly maintains stable Hb over one year
BL 1 2 3 4 5 6 7 8 9 10 11 127
8
9
10
11
12
13
14
15
16
Final visit
4 8 12 16 20 24 28 32 36 40 44 48 52
C.E.R.A. Q2W IV
C.E.R.A. Q4W IV
Epoetin TIW-QW IV
Mean (SD) Hb (g/dL)
Months
Weeks
Levin NW et al. Lancet 2007, 370 (9596): 1415-1421
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- 1.00 - 0.75 - 0.50 - 0.25 0.00 0.25 0.50 0.75 1.00
Non-inferiority lower 97.5% CI limit
Difference in mean adjusted Hb versus epoetin (g/dL)
SC C.E.R.A. once-monthly and twice-monthly as effective as epoetin 3x/wk
PROTOS: primary efficacy analysis (PP population)
P < 0.0001 for all comparisons
0.141
- 0.098 0.380C.E.R.A. 1x/2wk
- 0.262 0.217
- 0.022 C.E.R.A. 1x/4wk
Sulowicz, Locatelli Clin J Am Soc Nephrol. 2007 Jul;2(4):637-46
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BL 1 2 3 4 5 6 7 8 9 10 11 127
8
9
10
11
12
13
14
15
16
Final visit
Mean (SD) Hb (g/dL)
4 8 12 16 20 24 28 32 36 40 44 48 52
Months
Weeks
C.E.R.A. 1x/2wk
C.E.R.A. 1x/4wk
Epoetin 1-3x/wk
Stable Hb maintenance with once-monthly SC C.E.R.A.
PROTOS: ITT population
Sulowicz, Locatelli Clin J Am Soc Nephrol. 2007 Jul;2(4):637-46
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0.180
-0.049 0.408
0.180
- 0.049 0.408
- 1.00 - 0.75 - 0.50 - 0.25 0.00 0.25 0.50 0.75 1.00
Non-inferiority lower 95.0% CI limit
Difference in mean adjusted Hb (g/dL)
P < 0.0001
IV C.E.R.A. twice-monthly as effective as darbepoetin 1x/wk
STRIATA: primary efficacy analysis (PP population)
Canaud….Locatelli et al. ERA - EDTA 2006Canaud….Locatelli et al. Advance Access Published Nephrol Dial Transplant. 2008 Jul
31
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BL 1 2 3 4 5 6 7 8 9 10 11 127
8
9
10
11
12
13
14
15
16
Final visit
Mean (SD) Hb (g/dL)
4 8 12 16 20 24 28 32 36 40 44 48 52
Months
Weeks
C.E.R.A. 1x/2wk
Darbepoetin 1x/wk
Stable Hb maintenance with twice-monthly IV C.E.R.A.
STRIATA: ITT Population
Canaud….Locatelli et al. ERA - EDTA 2006Canaud….Locatelli et al. Advance Access Published Nephrol Dial Transplant. 2008 Jul
31
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SC C.E.R.A.: Smooth and steady Hb increase with a high response rate
ARCTOS: ITT population
Response rate (%)
95% CI
C.E.R.A. 1x/2wk 97.5 93.8-99.3
Darbepoetin alfa 1x/wk
96.3 92.1-98.6
Mean (SD) Hb (g/dL)
C.E.R.A. 1x/2wk
Darbepoetin alfa 1x/wk
Macdougall, … Locatelli et al. Clin J Am Soc Nephrol. 2008 Mar;3(2):337-47
BL 1 2 3 4 5 67
8
9
10
11
12
13
14
15
16
Final visitMonthsWeeks 4 8 12 16 20 24
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Mean (SD) Hb (g/dL)
BL 1 2 3 4 5 6
7
8
9
10
11
12
13
14
15
16
Final visitMonthsWeeks 4 8 12 16 20 24
C.E.R.A. 1x/2wk
Darbepoetin alfa 1x/wkrHuEPO
Locatelli F et al. Kidney Int 2001; 60: 741-
747
Hb concentrations during 24-week intervals
Macdougall, … Locatelli et al. Clin J Am Soc Nephrol. 2008 Mar;3(2):337-47
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P < 0.0001
Pat
ien
ts (
%)*
Fewer patients exceed Hb 13 g/dL with C.E.R.A. than with darbepoetin alfaARCTOS: ITT population
*Patients with ≥1 Hb value >13 g/dL during first 8 weeks
C.E.R.A. 1x/2wk Darbepoetin alfa 1x/wk0
10
20
30
40
Macdougall, … Locatelli et al. Clin J Am Soc Nephrol. 2008 Mar;3(2):337-47
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Decline in Hb after withholding treatment Long C.E.R.A. half-life does not affect Hb decline
following dose interruption – pooled analysis of maintenance studies
Mean (SD) Hb (g/dL)
Safety populations
Epoetin (QW to TIW) or darbepoetin alfa (QW or Q2W) (n=126)
C.E.R.A. Q4W (n=59)
Weeks since treatment interruption (time 0)
Locatelli F. et al Kidney Intern. S. 2008 : Heifets & Dougherty. WCN 2007
-3 -2 -1 0 1 2 3 4 5 610
11
12
13
14
15
16
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alfa beta alfa
020
40
60
80
100
120
140
Ho
urs
Epoetin Epoetin Darbepoetin
SCIV
Half life comparison
Halstenson. Clin Pharmacol Ther. 1991;50:702Macdougall. J Am Soc Nephrol. 1999;10:23925
Reigner. Nephrol Dial Transplant. 2003;18(suppl 4):167 Abstract M527
Methoxy polyethylene glycol-epoetin beta’s half-life is much longer than that of darbepoetin alfa
137 h vs 38 h when given SC
133 h vs 25 h when given IV
Methoxy polyethlene glycol-epoetin beta
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Half life of epoetins
Halstenson. Clin Pharmacol Ther. 1991;50:702 Macdougall. J Am Soc Nephrol. 1999;10:2392
Reigner. Nephrol Dial Transplant. 2003;18(suppl 4):167. Abstract M527Woodburn. Blood. 2004;104:2904
*Healthy volunteers†Peritoneal dialysis patients
t½ (hours)
Intravenous
Subcutaneous
Epoetin alfa 6.8* 19.4*
Epoetin beta 8.8* 24.2*
Darbepoetin alfa† 25.3 48.8
3:1
3:1
2:1
Methoxy polyethylene glycol-epoetin beta
130 1331:1
Hematide 75 ~801:1
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Nissenson AR et al. J Am Soc Nephrol 5:1517-1529, 1995
Ht response to EPO or placebo in PD patients
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* ERI: EPO resistance index
Wei M, et al. Int Urol Nephrol. 2007;39(3):935-40.
Cosa può influenzare la scarsa risposta agli ESAs in DP?
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• Sono stati condotti pochi trials sull'uso degli ESA's nei pazienti in dialisi peritoneale
• La via di somministrazione di ESAs in dialisi peritoneale deve, per ragioni pratiche, essere SC
• Le dosi di ESAs necessarie per mantenere livelli di Hb nel range suggerito dalle linee guida in dialisi peritoneale sono ridotte rispetto ai pazienti in emodialisi
ESAs in dialisi peritoneale
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1Ling B et al. Clin Nephrol 2005;63:327-34; 2Agarwal AK et al. J Intern Med 2006;260:577-85; 3Disney A et al. Nephrology (Carlton) 2007;12:95-101; 4Sousa American Society of Nephrology 2006; Abstract SA-PO218; 5Hoggard J et al. Curr Med Res Opin 2006;22:2023-30.
Once monthly (QM) dosing of darbepoetin alfa was effective in CKD patients not on dialysis
Reference Open-label study description*
Treatment + evaluation
period
Hb study target range
Primaryendpoint
Ling1 n=98Q2W DA → QM DA
29 weeks 10-12 g/dl % of patients withinHb study target range
Agarwal2 n=152Q2W DA → QM DA
33 weeks 11-13 g/dl % of patientswith Hb ≥11 g/dl
Disney3 n=66Q2W DA → QM DA
33 weeks 10-13 g/dl Maintaining mean Hb ≥10 g/dl
Sousa4 n=71Q2W DA → QM DA
18 months 11-13 g/dl Effectiveness and safetyof DA QM
Hoggard5
n=442QW/Q2W rHuEPO →
QM DA28 weeks 10-12 g/dl
% of patients convertingfrom EA QW who
preferred DA QM at week 21
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Limited evidence with once-monthly dosing
DrugAdministration
interval (route of administration)
Target Hb(g/dL)
Population (no. patients
enrolled)Trial design Reference
Epoetin alfa QW, Q2WQ3W, Q4W (SC)
≥11 CKD not on dialysis (n=519)
Randomised Provenzano et al 2005
Darbepoetin alfa
Q4W (SC) 10-12 CKD not on dialysis (n=97)
Single arm, non-randomised
Ling et al 2005
Darbepoetin alfa
Q4W (SC) ≥10 CKD not on dialysis (n=66)
Single arm, non-randomised
Disney et al 2007
Darbepoetin alfa
Q4W (SC) ≥11 CKD not on dialysis (n=152)
Single arm, non-randomised
Agarwal et al 2006
Darbepoetin alfa
Q3W, Q4Wa (IV and SC)
10-13 Dialysis patients (n=54)
Single arm, non-randomised
Jadoul et al 2004
aDosing once a month is not indicated for darbepoetin alfa in dialysis, except in Switzerland
ESAs, erythropoiesis-stimulating agents; Hb, haemoglobin; IV, intravenous; SC, subcutaneous
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Limited evidence of efficacy in HD patients for once-monthly darbepoetin alfaa
Patients on darbepoetin alfa Q2W converted to Q3W dosing and, if Hb stable (10-13 g/dL), to Q4W dosinga
522 patients originally recruited
Limited conversion to Q4W dosinga:Of 54 patients entering the study, 36 patients were converted to Q4W dosing
Limited maintenance on Q4W dosinga:Of 36 patients converting to Q4W dosing, 30 patients maintained Hb >10 g/dL over 20 weeks
Jadoul et al. Nephrol Dial Transplant 2004;19:898-903
13.0
12.5
12.0
11.5
11.0
10.5
10.0
9.5
9.0
100
80
60
40
20
0–2 0 4 8 12 16 20 26 30 34 4238
Hb (g/dL) Dose (g/wk)
Study week
Q3W dosing (n=44) Q4W dosinga (n=30)
HbDose
aDosing once a month is not indicated for darbepoetin alfa in dialysis, except in Switzerland
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Labelled dosing information on maintenance therapy dosing interval
MIRCERA– Once-monthly maintenance dosing in CKD patients on
dialysis and not on dialysis
Darbepoetin alfa– In HD patients
Once weekly or once every 2 weeks maintenance dosing
In Switzerland in selected HD patients, also once monthly
– In CKD patients not on dialysisStepwise expansion from QW over Q2W to QM for those patients stable on previous dose interval and by doubling the dose
ARANESP, Summary of Product Characteristics, 2006; MIRCERA, Summary of Product Characteristics, 2007
CKD, chronic kidney disease; HD, haemodialysis; QW, weekly; Q2W, every 2 weeks; QM, once monthly
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The PATRONUS study: a randomised comparison of the
efficacy and safety of MIRCERA® with darbepoetin alfa using once-monthly dosing in haemodialysis
patients
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PATRONUS study objectives
• Primary– To compare the efficacy of once-monthly IV MIRCERA®
with that of darbepoetin alfa* in the maintenance of Hb levels in HD patients with chronic renal anaemia previously receiving IV darbepoetin alfa maintenance therapy
• Secondary– To assess the safety and tolerability of IV MIRCERA® in HD
patients with chronic renal anaemia previously receiving IV darbepoetin alfa maintenance treatment
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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Evaluation (wk 50-53)
4 weeks 26 weeks 26 weeks
Screening period
Darbepoetin alfa1x/2 weeks
(n=245)
Darbepoetin alfa1x/week
Darbepoetin alfa*1x/month
Primary end point
MIRCERA®
1x/month(n=245)
MIRCERA®
1x/month
R
PATRONUS compared once-monthly MIRCERA® and darbepoetin alfa maintenance treatment
R, randomisation
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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• Primary end point: superiority assessment of the difference in the proportion of responders between groups– Responders are patients with an average Hb decrease
from baseline of <1.0 g/dL and an average Hb >10.5 g/dL during evaluation
• Study was powered to detect an absolute difference of 15% in the primary end point between the 2 treatment groups– Assumed 60% of patients would respond to MIRCERA®
vs 45% to darbepoetin alfa
• Target Hb range: 11–13 g/dL
PATRONUS primary end point
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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Analysis population
• Primary efficacy analysis used the intent-to-treat population, defined as all randomised patients– In case of withdrawals, the last Hb value in the second treatment
period was used for the Hb assessment (last value carried forward)
– To correct for any increase in Hb caused by RBC transfusion, the Hb values measured within 3 weeks after a transfusion were replaced by the Hb value measured immediately before the transfusion
• Safety population included all patients who received >1 dose of MIRCERA® or darbepoetin alfa
RBC, red blood cell
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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Darbepoetin alfa to MIRCERA® dose conversion schedule
Weekly darbepoetin alfa dose
(g/week)
MIRCERA® starting dose(g/month)
<40 120
40–80 200
>80 360
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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Darbepoetin alfa starting doses
4 weekbaseline period
Two changes needed:
Week 1 Week 27
26 weeks 26 weeks
Double Week 25 dose
Double Week – 1 dose
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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PATRONUS: A multicentre, multinational trial Country Patients enrolled
France 95
Italy 86
Spain 80
Canada 65
Germany 33
Belgium 31
UK 22
Portugal 21
Australia 15
Austria 15
Switzerland 11
Finland 9
Denmark 7
Total 490
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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Baseline patient characteristicsMIRCERA®
n=245
Darbepoetin alfa
n=245 Male, n (%) 148 (60) 156 (64)
Race, n (%)Caucasian 233 (95) 225 (92) Black 5 (2) 12 (5)Other 7 (3) 8 (3)
Mean age, years (SD) 66.2 (13.6) 65.5 (13.9)
Mean weight, kg (SD) 72.3 (15.1) 73.8 (16.9)
Mean baseline Hb, g/dL (SD) 12.09 (0.56) 12.07 (0.55)
Mean time since first dialysis, years (SD) 4.20 (5.92) 4.15 (5.55)
Dosing
Median darbepoetin alfa dose at weekbefore randomisation, g (IQR) 30.0 (20-40) 20.0 (15-40)
Median study drug dose in month 1, g/month (IQR) 120.0 (120-200) 100 (60-160)
SD = standard deviation; IQR = Interquartile Range
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Once-monthly MIRCERA® exhibited a superior response rate compared with once-monthly
darbepoetin alfa*
CI, confidence interval
Res
pons
e ra
te (
%)
64.1%
40.4%
*
Primary end point
*P<0.0001
®
64.1%
40.4%
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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Once-monthly MIRCERA® shows a 59% higher likelihood of response compared with once-monthly darbepoetin alfa*
Primary end point
−0.75 1.00 1.25 1.50 1.75 2.0
Relative risk of response at evaluation for MIRCERA® vs darbepoetin alfa
1.59*
1.901.33
Superiority limit:MIRCERA® vs darbepoetin alfa
*P<0.0001
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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Med
ian
Hb
valu
e (g
/dL)
14.0
12.0
10.0
8.0
7.0
MIRCERA® (median, IQR)Darbepoetin alfa (median, IQR)
Baseline 4 8 12 16 20 24 28 32 36 40 44 48 52
Weeks (of trial treatment)
16.0
Evaluation (wk 50-53)
15.0
9.0
13.0
11.0
Only once-monthly MIRCERA® maintained Hb levels during the second 26-week treatment period
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Darbepoetin alfa dose increased by >30% during the second 26-week treatment
period
• The median MIRCERA® dose was virtually unchanged during the second 26-week treatment period whereas darbepoetin alfa substantially increased by 35%
Median (IQR) treatment dose, g/month
MIRCERA®
n=211 Darbepoetin alfa
n=219
Week 27 200 (120-313) 150 (80-280)
Months 11 and 12 196 (120-351) 225 (106-400)
Secondary end point
0% +35%
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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150
125
100
75
50
25
0
−25
−50
Tri
al tr
ea
tme
nt d
ose
ch
ang
e (%
)
7 8 9 10 11 12
MIRCERA (median, IQR)Darbepoetin alfa (median, IQR)
Months (of trial treatment)
MIRCERA® dose was unchanged during the second 26-week treatment period
Secondary end point
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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Most safety parameters were similar between the two PATRONUS study groups
• Similar incidence of AEs in both study arms– higher rate of constipation with MIRCERA®
• Most common AEs in both arms were hypertension (14.7 vs 10.7%), procedural hypotension (8.6 vs 11.1%) and nasopharyngitis (10.2 vs 8.2%)
• Fewer withdrawals with MIRCERA® than with darbepoetin alfa
MIRCERA®, n (%)n=245
Darbepoetin alfa, n (%)n=244
AEs 222 (90.6) 217 (88.9)
SAEs 99 (40.4) 94 (38.5)
AEs leading to withdrawals 3 (1.2) 7 (2.9)
Withdrawals 58 (23.7) 96 (39.3)
Withdrawals due to insufficient response 10 (4.1) 48 (19.7)
Deaths* 14 (5.7) 14 (5.7)
AEs, adverse event; SAEs, serious adverse events *includes 3 patients who died after withdrawal due to other events
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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SAEs (>5% in either group) were comparable between study groups in PATRONUS
MIRCERA®
n=245n (%)
Darbepoetin alfa
n=244 n (%)
All body systems 99 (40.4) 94 (38.5)
Infections and infestations 29 (11.8) 27 (11.1)
Injury, poisoning and procedural complications
26 (10.6) 18 (7.4)
Cardiac 16 (6.5) 16 (6.6)
Vascular 14 (5.7) 16 (6.6)
Gastrointestinal 11 (4.5) 16 (6.6)
Nervous system 7 (2.9) 13 (5.3)
Neoplasms 10 (4.1) 5 (2.0)
Metabolism and nutrition 10 (4.1) 4 (1.6)
Respiratory, thoracic and mediastinal 4 (1.6) 7 (2.9)
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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Clinical Nephrology, Vol 73 – n 2/2010 (94-103)
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ConclusionsMIRCERA® was shown to be superior to darbepoetin alfa as once-monthly treatment in the dialysis setting
– Significantly more patients responded with MIRCERA® compared with darbepoetin alfa
– MIRCERA® maintained Hb levels within a tight target range during the second 26-week treatment period
– Mean Hb levels for patients receiving darbepoetin alfa fell to below the lower target (11 g/dL) over the same 26-week period, despite substantial dose increases
This is the first large, randomised, prospective head-to-head study that has shown one ESA to offer superior efficacy compared with another
Carrera F et al. WCN 2009 Milano, poster M558
* Darbepoetin alfa is not licensed for once monthly treatment in dialysis in the UK.
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Hb (or at least high levels) vs ESA (or at least high levels)
ESA
Hb