J Am Soc Nephrol 15: 31543165, 2004
Hemoglobin Targets for the Anemia of Chronic Kidney
Disease: A Meta-analysis of Randomized, Controlled Trials
GIOVANNI F.M. STRIPPOLI,* JONATHAN C. CRAIG,* CARLO MANNO, and
FRANCESCO P. SCHENA
*Cochrane Renal Group, NHMRC Centre for Clinical Research Excellence in Renal Medicine, The
Childrens Hospital at Westmead, University of Sydney, Australia; Department of Emergency and Organ
Transplantation, Section of Nephrology, University of Bari, Bari, Italy; and School of Public Health,
University of Sydney, Australia
Abstract. Anemia affects almost all patients with chronic kid-
ney disease (CKD), reduces quality of life, and is a risk factor
for early death. Higher hemoglobin (Hb) targets have been
widely advocated because of data from observational studies
showing that higher Hb is associated with improved survival
and quality of life, but higher Hb targets may cause access
thrombosis and hypertension and are costly. This study aimed
to evaluate the benefits and harms of different Hb targets in
CKD on the basis of randomized trial evidence. A comprehen-
sive search of the Cochrane Trials Registry, Medline, Embase,
and reference lists was performed. Two independent reviewers
assessed studies for inclusion criteria and extracted data on
all-cause mortality, cardiovascular disease, strokes, hyperten-
sion, seizures, hyperkalemia, access thrombosis, and quality of
life. Analysis was by a random-effects model, and results are
expressed as relative risk (RR) or weighted mean difference
Anemia is a common complication of chronic kidney disease
(CKD). The prevalence of anemia varies with the degree of
renal impairment in predialysis patients with CKD, but once
end-stage kidney failure occurs, all patients are eventually
affected (13). Anemia develops once renal function decreases
to 50% because of a deficiency in endogenous erythropoietin
(EPO) production by the kidney, decreased red cell survival,
blood losses, and increased red blood cell destruction once the
patient begins dialysis treatment, particularly hemodialysis (4).
Anemia reduces physical capacity, well-being, neurocogni-
tive function, and energy level and worsens quality of life both
in predialysis and dialysis patients (5). Anemia also induces
adaptive cardiovascular mechanisms to maintain tissue oxygen
supply. This leads to left ventricular hypertrophy, left ventric-
Received April 14, 2004. Accepted August 31, 2004.
Correspondence to Dr. Giovanni F.M. Strippoli, Centre for Kidney Research,
NHMRC Centre for Clinical Research Excellence in renal medicine, Cochrane
Renal Group, Locked Bag 4001, The Childrens Hospital at Westmead and the
University of Sydney, Westmead, NSW 2145, Australia. Phone: 02-98453088; Fax:
02-98453038; E-mail: gfmstrippoli@katamail.com and GiovannS@chw.edu.au
1046-6673/1512-3154
Journal of the American Society of
Nephrology
Copyright 2004 by the American Society of
Nephrology
DOI:
10.1097/01.ASN.0000145436.09176.A7
with 95% confidence intervals (CI). Nineteen relevant trials
were identified. Twelve trials (638 patients) compared use of
erythropoietin versus no erythropoietin treatment, and seven
trials (2058 patients) compared higher versus lower Hb targets.
Compared with Hb values of 130 g/L or more in the CKD
population with cardiovascular disease, Hb values of 120 g/L
were associated with lower all-cause mortality (RR, 0.84; 95%
CI ,0.71 to 1.00). Hb values of 100 g/L or less reduced the risk
of hypertension (RR, 0.50; 95% CI, 0.33 to 0.76) but increased
the risk of seizures (RR, 5.25; 95% CI, 1.13 to 24.34). From
the available trial evidence, in CKD patients with
cardiovascular disease, the benefits associated with higher Hb
targets (reduced seizures) are outweighed by the harms
(increased risk of hy- pertension and death). There is
insufficient data to guide de- cisions in patients without
cardiovascular disease or in the predialysis population.
ular dilation, and myocardial ischemia, which are risk factors
for cardiovascular disease and death (5,6). It is plausible that
reversing anemia may reduce this risk (710).
Current treatment options for anemia include blood transfu-
sion, recombinant human EPO ( or ) or darbepoetin . The
latter are growth factors for the bone marrow erythroid precur-
sors, which stimulate production of erythrocytes (11,12).
Treatment of anemia improves muscle strength and function,
cardiac function, and cognitive and brain electrophysiologic
function because of improved peripheral oxygen supply
(10,13). Aspects of the patients quality of life such as fatigue,
depression, and relationships with others are better at higher
hemoglobin (Hb) levels (5,10,14), but higher Hb levels may
also lead to an increased risk of arteriovenous fistula throm-
bosis, hypertension, and an increased number of adverse car-
diovascular events. Also, reaching and maintaining higher Hb
targets implies major costs (8,1518). Very recently, a number
of trials in cancer patients were terminated prematurely be-
cause of unexpectedly higher mortality in the higher Hb
groups, mainly as a result of disease progression and throm-
boembolic events (19).
There has been a consistent trend toward higher Hb levels in
dialysis patients of all ages, genders, and race categories
during the past decade (2). Guidelines have been developed for
Hb targets, but there remains considerable debate regarding
the
J Am Soc Nephrol 15: 31543165, 2004
appropriate Hb levels as shown by the wide variation that still
exists in anemia management practices between and within
countries (Table 1). The aim of this systematic review is to
summarize the benefits and harms of lower versus higher Hb
targets in the treatment of the anemia of CKD using existing
randomized, controlled trial data.
Materials and Methods
Inclusion Criteria
We included any randomized, controlled trial that was of at least 2
mo duration and assessed the effects of different Hb targets in pre- or
postdialysis patients with anemia of CKD. The higher Hb target could
be achieved by EPO ( or ) or darbepoetin or blood transfusion;
the lower target could be achieved by lower doses of the same drugs
or by a placebo or no treatment or blood transfusion.
Search Strategy
Electronic searches were performed in Medline (1966 through May
2003) and Embase (1988 through May 2003) using optimally sensi-
tive search strategies for identification of randomized, controlled
trials developed by the Cochrane Collaboration (20). The Cochrane
Renal Group Specialized Register was also searched. The following
medical subject heading terms and text words were used: anemia,
hemoglobin, hematocrit, CKD, renal replacement therapy, renal
dialysis and he- mofiltration, end stage renal disease, uremia, EPO,
and darbepoetin. Trials were considered without language restriction.
The results of these searches were analyzed in title and abstract form
by one of the authors according to the inclusion criteria (G.F.M.S.).
Reference lists from all identified articles were also searched. The
conference pro- ceedings of the American Society of Nephrology and
European Di- alysis and Transplantation Association meetings of
1999 to 2003 were searched for abstracts of relevant trials.
Information about unpub- lished trials were sought from experts in the
field, and pharmaceutical companies involved in the production of
EPO and darbepoetin (Janssen-Cilag, Amgen, Roche) were
approached for information about relevant trials.
Data Extraction and Quality Assessment
Each trial was assessed by two independent reviewers (G.F.M.S.
and C.M.). From all included trials, data were extracted on charac-
teristics of the study sample, doses and modalities of treatment,
Table 1. Published guidelines on Hb targets in patients with CKD
Guidelines
National Kidney Foundation-Dialysis Outcome Quality Initiative (NKF-DOQI)
British Renal Association (BRA)
Canadian Society of Nephrology (CSN)
European Best Practice Guidelines (EBPG)
Health Care and Financing Administration (HCFA)
Caring for Australians with Renal Impairment (CARI)
a
Hb, hemoglobin; CKD, chronic kidney disease.
b
Hb concentrations 120 g/L are not recommended for patients with severe cardiovascular disease unless continuing severe symptoms
dictate otherwise.
c
In patients with proven or likely significant cardiovascular disease (level I evidence).
d
In patients without cardiovascular disease (suggestion for clinical care).
Hemoglobin Targets for the Anemia of Chronic Kidney Disease 3155
methodologic characteristics of the trials, and outcomes: all-cause
mortality, left ventricular hypertrophy, cardiovascular mortality (myo-
cardial infarction, stroke), adverse events (patients with hypertension
requiring exclusion from study or administration of additional anti-
hypertensive medication, seizures, access thrombosis, hyperkalemia),
hospitalization rates and days of hospitalizations, renal function, BP,
and quality of life.
Quality of the trials was assessed using standard criteria (allocation
concealment, blinding, analysis by intention to treat, and complete-
ness of follow-up) (21). Any differences in data extraction were
resolved by discussion among authors. When data were missing or
incomplete, the authors of the trial were contacted for clarification.
Statistical Analyses
Dichotomous outcome data from individual trials were analyzed
using the relative risk (RR) measure and its 95% confidence intervals
(CI). The analysis was based on published event rates and took no
account of the risk estimates provided by the trials, which in some
cases could be adjusted for having performed interim analyses and
other factors. When continuous outcome data were analyzed, differ-
ence in means and 95% CI at the end of treatment or difference in
mean change between baseline and end of treatment value were
calculated for individual trials. Subgroup analysis was planned to
explore potential sources of variability in observed treatment effect
when possible (overt or nonovert cardiovascular disease, time on
dialysis, time on predialysis treatment). Heterogeneity of treatment
effects between studies was formally tested using the Q
(heterogeneity
2
) and the I2 statistics. When appropriate, summary estimators of
treatment effects were calculated using the Der Simonian-Laird ran-
dom-effects model with RR and its 95% CI for dichotomous
outcomes and weighted mean difference with 95% CI for continuous
outcomes (22).
Results
The combined search of Medline, Embase, and the specialist
registry of the Cochrane Renal Group identified 1365 articles,
1322 of which were excluded. The major reasons for exclusion
were that selected studies were not randomized or were ran-
domized trials that evaluated other interventions (e.g., subcu-
taneous versus intravenous EPO treatment for anemia of CKD)
or because only surrogate and hemorheologic outcomes were
a
Target Hb
Country Year Level (g/L)
United States 2000 110120
United Kingdom 2002 100
Canada 1999 110120
Europe 2004 110b
United States 2000 103120
Australia 2003 120c
120140d
3156 Journal of the American Society of Nephrology
reported (e.g., blood viscosity, hematopoietic progenitor cell
assays; Figure 1). Full-text assessment of 43 potentially eligi-
ble papers identified 19 eligible trials (2696 patients) reported
in 25 publications (13,15,16,23 43). Authors of 12 trials were
contacted for clarification about study methods and/or request
for additional unpublished information; four responded.
Trial Characteristics
Two groups of studies were identified. In seven trials (2058
patients), the hypothesis of whether a higher and normal Hb
target was better than a lower Hb target was tested. Patients
were randomized to reach the two pre-established Hb targets.
Generally a low EPO dose was administered to achieve a
lower Hb target and a higher dose was administered to achieve
a higher Hb target. However, in two of these trials, some
patients in the low Hb target group received lower doses of
EPO or no EPO at all (42,43). Overall, the achieved Hb values
of the experimental arms in this group of trials were in the
range of
119 to 150 g/L and the achieved Hb values of the control arm
were in the range of 90 to 120 g/L. Of the seven studies in this
group, the Besarab et al. (16), Berns et al. (26), and Conlon et
al. (28) trials enrolled patients with severe cardiovascular
disease (congestive heart failure or ischemic heart disease).
The Besarab et al. (16) trial was terminated at the third interim
analysis when differences in mortality between the groups
were recognized as sufficient to make it very unlikely that
continuation of the study would reveal a benefit for the higher
Hb target group. There was also a significantly higher rate of
vascular access loss in the higher Hb target group, indicating
Figure 1. Flowchart indicating the number of citations retrieved by individual searches and the final number and grouping of included trials;
reasons for exclusions are provided.
J Am Soc Nephrol 15: 31543165, 2004
that patients in this group were experiencing harmful effects.
The publication of this trial resulted in a change in the methods
of the Furuland et al. (42) trial, with 33 enrolled patients with
cardiovascular impairment excluded from this study, and the
inclusion criteria were changed to avoid further enrollment of
patients with cardiovascular impairment. No patients with car-
diovascular disease were enrolled in the Brandt et al. (26) and
Roger et al. (43) trials; left ventricular hypertrophy or dilation
was one of the inclusion criteria of the Foley et al. (29) trial
(Table 2).
In the other 12 trials (638 patients), the tested hypothesis
was a pharmacologic one; that is, whether EPO treatment
compared with no EPO treatment was associated with im-
proved outcomes. Patients who were randomized to placebo
ended up having a lower Hb target of 95 g/L, whereas those
who were randomized to EPO treatment achieved higher Hb
levels of 100 g/L (15,23,24,27,30 37). Overall, the achieved
Hb targets of the experimental arms in this group of trials were
in the range of 95 to 133.3 g/L and the achieved Hb targets of
the control arm were in the range of 75 to 104 g/L. The
patients who were enrolled in this second group of trials had
no overt cardiovascular comorbidity. The Canadian
Erythropoietin Study Group trial had three arms: one of
placebo, one of low-dose EPO, and one of high dose EPO.
The Lim et al. (32) trial included four arms: one of placebo
and three of different EPO doses.
In summary, the first group contained studies in which the
intervention was to achieve different Hb targets, and trials
included individuals with clinical cardiovascular disease. The
 J
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So
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ph
rol
Table 2. Characteristics of patients and interventions in trials of EPO or randomized Hb targets for the anemia of CKDa 15:
Low Target Group High Target Group
31
Randomized 54
Treatment

Study ID Cointerventions
Modality Intervention Follow-up No. of Targeted Achieved No. of Targeted Achieved 31
(Months) 65,
Patients Hb Value (g/L) Hb Value (g/L) Patients Hb Value (g/L) Hb Value (g/L) 20
Berns et al. (25) Hemodialysise EPO versus EPO None indicated 12 17 100.0 10.0 101.0 3.3 14 140.0 10.0 140.0 3.6 04
Low Hb target
Besarab et al.( (16)
100 g/L) versus high hemoglobin target ( e 140
Hemodialysis g/L)
EPO versus EPO IV Fe 29 618 100.0 10.0 100.0 10.0 618 140.0 10.0 140.0 10.0
Brandt et al.b (26) Predialysis EPO versus EPO Oral (3 mg/kg per d) or IV 2 mg/kg 3/wk Fe (target ferritin 100 20 22 100.0 10.0 100.0 10.0 21 140.0 10.0 140.0 10.0
Peritoneal dialysis ng/mL/transferrin saturation 20%)
Hemodialysis
c
Conlon et al. (28) Hemodialysise EPO versus EPO None indicated 6 16 100.0 10.0 100 14.3 15 140.0 10.0 136.0 17.0
Foley et al. (29) Hemodialysise EPO versus EPO None indicated 12 73 95.0105.0g 102.0106.0g 73 130.0140.0g 119.0125.0g
Furuland et al. (42) Predialysis EPO versus EPO or no Oral or IV Fe (target transferrin saturation 20%/ferritin 250 g/L) 1219 200 90.0120.0d,g 113.0 13.0h 216 130.0150.0d,g 143 11.0h
Hemodialysis treatment
Peritoneal dialysis
Roger et al. (43) Predialysis EPO versus EPO or no Oral or IV Fe (target transferrin saturation 20%/ferritin 100 g/L) 24 80 90.0100.0g 110.0 10.0g 75 120.0130.0g 122.0 7.0g

treatment
No EPO treatment (Hb 95 g/L) versus EPO treatment (Hb 100 g/L)
Abraham and Macres (23) Predialysis EPO versus standardf
Fe (dose/route NA) (target transferrin saturation 20%); folic acid 1 3 4 NA 96.0 10 4 133.0 123.0 6.6
mg/d He
f
Bahlmann et al. (24) Hemodialysis EPO versus standard None indicated 3 66 NA 100.0 63 100.0116.0 100.0116.6b mo
Canadian Erythropoietin Study Group (40) Hemodialysis EPO versus placebo Oral or IV Fe (dose NA) (target ferritin 250 g/L) 6 40 NA 90.0 38 95.0110.0g 95.0110.0g glo
Clyne and Jogestrand (27) Predialysis EPO versus standardf Oral (200300 mg/d) or IV (100 mg/wk) Fe for all patients 3 10 NA 84.0104.0b 12 100.0 106.0117.0g bin
Kleinman et al. (30) Predialysis EPO versus placebo Fe (dose/route NA) 3 7 NA 94.0 7 126.0133.0g 119.3 Ta
Kuriyama et al. (31) Predialysis EPO versus no treatment Fe at investigators discretion 9 31 NA 84.3 6.3 42 NA 118.3 13.3
8093.0g
rge
Lim et al. (32) Predialysis EPO versus placebo Oral (300 mg 3/d) Fe and oral folic acid 1 mg/d to all patients 2 3 NA 11 NA 126.6
except those with excess iron stores ts
d
Morris et al. (33) Peritoneal dialysis EPO versus placebo None indicated 6 5 NA 100.0 6 105.0120.0g 115.0 for
Revicki et al. (34) Predialysis EPO versus no treatment Iron 200 mg/d (route not indicated) if transferrin saturation 12 40 NA 89.3 12.0 43 116.0120.0g 120.0 the
Sikole et al. (35) Hemodialysis EPO versus no treatment None indicated 12 19 NA 100.0 19 NA 100116.6g An
Techan et al. (36) Predialysis EPO versus placebo None indicated 6 31 NA 100.0 86 123.0133.0g 128.0133.3d em
Watson et al. (37) Predialysis EPO versus placebo None indicated 3 6 NA 86.6 6.6 5 NA 116.6 6.6 ia
a
of
IV, intravenous; NA, not available. Ch
b
Trial enrolling children. ro
c
Substudy of the Besarab et al. trial. nic
d
Hb target was 135 to 150 g/L in females and 145160 g/L in males. Ki
e
Known cardiovascular abnormality. dn
f
No treatment or blood transfusion. ey
g Di
Range. sea
h
The highest achieved targets are reported independent of specific subgroup (in this trial, target Hb values were presented separately for the three groups of predialysis, se
hemodialysis, and peritoneal dialysis patients).

31
57
3158 Journal of the American Society of Nephrology
second group compared EPO treatment with no EPO
treatment. Overall, trials that were pooled in this second group
resulted in lower Hb levels achieved in both the intensive and
control arms than the Hb levels in the corresponding arms in
the first group of trials. On the basis of these considerations,
the results of these two groups of studies were analyzed
separately. Of note, follow-up duration was higher and
publication date was more recent in the first group of trials.
These trials seemed more generalizable to current practice,
whereas those done earlier seemed to be conducted mainly to
demonstrate dose-response relationships and safety of EPO
treatment.
Trial Quality
Trial quality was variable. Allocation concealment was un-
clear in all 19 trials. Outcome assessors were not stated as
blinded in any of the trials, and only three studies were ana-
lyzed on an intention-to-treat basis. The dropout rate ranged
from 0.0 to 57.8%.
Trial Results
All-Cause Mortality. In the high Hb target versus low Hb
target trials, there was a lower risk of death with the lower Hb
target compared with the high Hb target (four trials, 1949
patients; RR, 0.84; 95% CI, 0.71 to 1.00; P 0.05). This
analysis was dominated by the Besarab et al. (16) study,
contributing 86.2% of the weight. There was no heterogeneity
across these trials (heterogeneity 2 0.59, P 0.8, I2 0%;
Figure 2).
In the trials of EPO treatment versus no EPO treatment,
there was no statistically significant difference in the risk of
all-cause mortality between the two arms (three trials, 255
patients; RR, 1.83; 95% CI, 0.48 to 7.06). Heterogeneity across
these trials was also not significant (heterogeneity 2 0.45,
P 0.8, I2 0%).
Seizures. This outcome was reported only in the trials of
EPO treatment versus no EPO treatment, and we obtained
additional data of the Besarab et al. (16) trial by personal
Figure 2. Effect of high versus low hemoglobin (Hb) targets on all-cause mortality.
J Am Soc Nephrol 15: 31543165, 2004
communication. In the Besarab et al. study, there was no
significant difference in the risk of seizures across the two
groups (1233 patients; RR, 1.14; 95% CI, 0.66 to 1.97). For
the trials of EPO treatment versus no EPO treatment, there was
a higher risk of seizures in the no EPO treatment (lower Hb)
group (four trials, 219 patients; RR, 5.25; 95% CI, 1.13 to
24.34; P 0.03) compared with the group that was treated
with EPO. No heterogeneity was demonstrated between trials
(heterogeneity 2 0.74, P 0.86, I2 0%; Figure 3).
Hypertension. Eight studies provided data on the number
of patients who had hypertensive episodes and required addi-
tional antihypertensive medication or exclusion of patients
from the trial because of hypertension. Two of these were from
the group of trials that compared high versus low Hb targets,
and six were from the group of trials of EPO treatment versus
no EPO treatment. No significant difference for hypertension
was demonstrated between the two Hb targets in the first group
of trials (two trials, 1277 patients; RR, 0.92; 95% CI, 0.59 to
1.45). Heterogeneity was not significant across these trials
(heterogeneity 2 1.41, P 0.24, I2 29.0%). There was
a significantly lower risk of hypertension in the EPO treatment
arm compared with no EPO treatment in the second group of
trials (six trials, 387 patients; RR, 0.50; 95% CI, 0.33 to 0.76;
P 0.001). Heterogeneity in this group of studies was not
significant (heterogeneity 2 2.88, P 0.72, I2 0%;
Figure 4).
Quality of Life. Many problems were evident in the eval-
uation of these data. Five of 10 trials in which quality of life or
exercise capacity was analyzed did not use validated scales for
the assessment of quality of life (i.e., codified scales for the
assessment of quality of life or exercise capacity such as the
Short Form-36 or the Kidney Disease Quality of Life ques-
tionnaires, which have been validated using standard methods
and in relevant populations) (24,27,30,32,36). Also, dimen-
sion-specific and composite quality-of-life outcomes reported
were not prespecified, and only positive results were
presented. When codified scales were used, overall scores
presented were
J Am Soc Nephrol 15: 31543165, 2004
Figure 3. Effect of high versus low Hb targets on the reported number of patients with seizures.
Figure 4. Effect of high versus low Hb targets on the reported number of patients with hypertensive events that required exclusion from the
study or administration of additional antihypertensive medication.
not described in detail. Commonly, individual items of quality
of life that had improved with the higher Hb target were
reported as an indication of an overall positive effect of the
higher target, or else a positive effect of EPO treatment on
quality of life. It was not possible to perform a pooled analysis
given the wide variability of the assessment of these outcomes
and uncertainties regarding the validity of the instruments used
(Table 3).
Summary data for all other patient-relevant outcomes (myo-
cardial infarction, serious cardiovascular events [including an-
gina, atrial fibrillation, and severe arrhythmia], stroke, hyper-
kalemia, access thrombosis, hospitalization rates and days of
hospitalization, left ventricular hypertrophy, systolic BP, dia-
stolic BP, and mean arterial pressure) were also analyzed,
although minimal data were available. These analyses showed
no significant difference between lower and higher Hb targets
or EPO treatment and no EPO treatment in relation to any of
Hemoglobin Targets for the Anemia of Chronic Kidney Disease 3159
the outcomes (Table 4). Of note, data on the effect of EPO on
serum creatinine were available in only four trials of EPO
treatment versus no EPO treatment, and there was no signifi-
cant effect (four studies, 77 patients; weighted mean differ-
ence, 0.01; 95% CI, 1.21 to 1.22). Two trials of the high
versus low Hb target group indicated a significantly better
creatinine clearance at the end of the trials in the lower Hb
target arms (two trials, 167 patients; weighted mean difference,
1.07; 95% CI, 2.10 to 0.05).
Discussion
Key Findings
We find that on the basis of available randomized, controlled
trials, Hb targets of 120 g/L are associated with a lower risk
of death in the population with cardiovascular disease and
CKD compared with Hb targets of 130 g/L (RR, 0.84; 95%
CI, 0.71 to 1.00). In absolute terms, the risk of death is 3.0%
Table 3. Quality of life and physical capacity assessment of patients enrolled in trials of EPO or randomized
3160 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 31543165, 2004

(95% CI, 1.0 to 6.0%) lower in the group of patients with Hb

every 6 moincrease of physical function score; no significant changes in other scores of the scale with higher targets

Improvement of main physical symptoms in the normal compared with the lower Hb group.
target of 120 g/L compared with the group of patients with

Baseline and end of treatmentImprovement in level of energy, ability to do work, and overall quality of life with higher targets
Angina, dyspnea, other cardiovascular symptoms, and sexuality improved with higher targets
Hb target 130 g/L. For every 30 patients treated to an Hb
target of 120 g/L compared with an Hb target of 130 g/L,
approximately one death is avoided.
The present findings are applicable mainly to hemodialysis
patients with clinical cardiovascular disease because the ma-
jority of patients included in these trials had these attributes
(44 46). Higher Hb targets have been recommended in
other CKD populations (e.g., CKD stages 3 to 4 or individuals
Result

without overt cardiovascular disease) despite the absence of

A codified scale for the standard assessment of quality of life or exercise capacity whose validity has been tested in patients with kidney disease.
randomized trial data. If higher Hb targets really reduced
mortality, then this should be even more evident in studies that
include high-risk patients, as those enrolled in the Besarab et
al. (16) trial. However, the most favorable interpretation of the
Besarab et al. study can be only that there was no survival
benefit demonstrated. To find a survival benefit in lower risk
patients would be more difficult because a larger number of
individuals would have to be studied to have adequate power,
and empiric evidence of qualitative effect modification (i.e.,
Change in KDQ score for main physical symptoms, fatigue, depression, and frustration favored the normal compared with the lower hematocrit group.

harm in one group and benefit in another using the same

intervention) is very rare (47). The finding of higher mortality
Baseline and end of treatment

Baseline and end of treatment

Notreatment Baseline and end of treatment

Baseline and 3, 6, and 7 mo

Baseline and 12 and 24 mo

Time of Assessment

in higher Hb target groups from very recent cancer trials would

Baseline andSignificant

also make a survival benefit of higher Hb values in the CKD

Baseline and 12 mo

population very unlikely (19). The annualized mortality rate in

the 1233 patients of the Besarab et al. study was 24%, which
is very similar to the annualized mortality rate for every 1000
patients (20.4%) reported by the United States Renal Data
System (http://www.usrds.org), suggesting that results from
Validateda

Yes

Yes

Yes Yes

Yes

Yes Yes

this trial are in fact generalizable.

No

No

No

No of
Baseline and end

Lower Hb targets of 95 g/L in individuals who are not

treated with EPO are associated with a significantly increased
risk of seizures (RR, 5.25; 95% CI, 1.13 to 24.34) compared
Standardized symptom-limited exercise test and electrically braked bicycle ergometer

with treatment with EPO and Hb values of 100 g/L. In

absolute terms, the risk of seizures is 4% (95% CI, 3 to 10%)
Kidney Disease Questionnaire (KDQ) part 1 and part 2

lower with Hb values of 100 compared with the group of

patients with Hb 95 g/L. This means that for every 25
100 g/L) Short Form 36

patients treated to an Hb level of 100 g/L, one fewer will

Scale or Tool

develop seizures.
Profile Kidney Disease Quality of Life tool
Short Form 36 Kidney Disease Quality of Life tool

Finally, lower Hb levels of 95 g/L with no EPO treatment

are associated with a reduced risk of patients who present with
hypertensive episodes (RR, 0.62; 95% CI, 0.42 to 0.92). In
Renal Quality of Life Profile (Hb

absolute terms, the risk of developing hypertensive episodes is

Short Form 36

Study specific

Study specific Study specific

16% lower (95% CI, 8 to 24%) with Hb values 95 g/L

Low Hb target ( 100 g/L) versus high Hb target ( 140 g/L)

compared with Hb 100 g/L. For every seven patients treated

95 g/L) versus EPO treatment

to obtain an Hb 100 g/L, one patient will require additional

antihypertensive medication.
Study Group
Canadian Erythropoietin Sickness (40)
Impact

Comparison with Other Studies

This systematic review is influenced mainly by the finding
Clyne and Jogestrand (27)
Study ID

of Besarab et al. (16) of an association of higher mortality in

Bahlmann et al. (24)

Kleinman et al. (30)

No EPO treatment (Hb
Furuland et al. (42)
Besarab et al. (16)

Lim et al. (32) Teehan et al. (36)

individuals who have cardiovascular disease and are treated to

Roger et al. (43)
Foley et al. (29)

Hb targets 130 g/L. The other small trials are inadequately

powered to show any evidence of benefit or harm, both sepa-
rately and combined (RR, 0.98; 95% CI, 0.61 to 1.55). They
a

show no difference between the arms that treated to higher

 J
A
m
So
c
Ne
ph
rol
15:
31
a 54
Table 4. Other outcomes analyzed in trials of EPO or randomized Hb targets in patients with anemia of CKD
Results
31
No. of Patients with Events or No. of Patients with Events or Heterogeneity 65,
Meansa in Low Target Group Meansa in High Target Group Weighted Mean
2
P Value
Outcome Analyzed No. of Studies No. of Patients Relative Risk 95% CI
Difference 95% CI 20
04

Low Hb target ( 100 g/L) versus high Hb target ( 140 g/L)

myocardial infarction (all) 1 1389 42 41 1.03 0.681.56 NA
myocardial infarction (fatal) 1 1233 28 22 1.28 0.742.21 NA
myocardial infarction (nonfatal) 1 1233 14 19 0.74 0.371.46 NA
serious cardiovascular events 1 146 3 4 0.75 0.173.23 NA
stroke 1 1233 9 14 0.65 0.281.48 NA
hyperkalemia 2 1277 3 5 0.62 0.152.56 0.89
access thrombosis 3 1795 242 296 1.05 0.631.75 0.01
hospitalization for all causes 1 1233 425 445 0.96 0.891.03 NA
systolic BP 1 246 151.50 150.70 0.80 4.786.38 NA
diastolic BP 1 246 75.90 77.30 1.40 4.371.57 NA
mean arterial pressure 1 16 104.80 105.60 0.80 12.3910.79 NA
serum creatinine NA
creatinine clearance 2 167 13.0023.00b 16.0024.00b 1.07 2.10 0.05 0.48 He
left ventricular mass index (g/m2) 1 127 102.00 105.00 3.00 10.664.66 0.0005
mo
days of hospitalization 1 416 3.80 4.80 1.00 2.750.75 NA
No EPO treatment (Hb 95 g/L) versus EPO treatment (Hb 100 g/L)
glo
myocardial infarction (all) 3 170 2 1 1.56 0.269.50 0.60 bin
myocardial infarction (fatal) 2 156 2 0 1.36 0.802.31 0.40 Ta
myocardial infarction (nonfatal) 1 14 0 1 0.71 0.371.39 0.30 rge
serious cardiovascular events 1 245 11 5 1.56 0.495.03 0.10 ts
stroke 2 1412 2 0 0.79 0.361.72 0.60
hyperkalemia 1 14 0 1 0.56 0.152.01 0.86
for
access thrombosis 2 1972 5 12 0.94 0.591.51 0.20 the
systolic BP 3 123 139.90151.00b 143.40151.10b 0.66 7.506.19 0.78 An
diastolic BP 3 369 81.4092.90b 84.5093.90b 2.11 6.440.12 0.75 em
mean arterial pressure 4 60 67.30112.30b 67.30113.30b 0.35 5.636.33 0.89 ia
serum creatinine 4 77 4.0010.50b 5.7010.83b 0.01 1.211.22 0.16 of
creatinine clearance 2 19 10.3020.00b 12.9018.00b 2.15 6.141.84 0.50 Ch
left ventricular mass index (g/m2) 2 45 101.20133.80b 87.60171.80b 16.64 66.4533.17 0.04 ro
nic
a
CI, confidence interval. Ki
b
Means are provided for continuous variables; lower and higher mean is provided for analyses including more than one trial. dn
ey
Di
sea
se

31
61
3162 Journal of the American Society of Nephrology
versus lower Hb targets, although the CI do not exclude benefit
or harm.
Seizures are reported to be a complication of EPO in the
product information. However, this systematic review indicates
that treating with EPO may be protective against seizures.
There is some uncertainty with this finding as a result of the
small number of trials reporting this outcome; a small number
of patients were present in each Hb target group, and very
small number of events were reported. The physiologic ratio-
nale underlying the protective role of EPO against seizures
could be the increased peripheral cerebral oxygenation of neu-
rons and the observation that neurons develop EPO receptors
during ischemia, with a neuroprotective effect of EPO inde-
pendent of its effects on Hb (48).
Hypertension is a widely known adverse effect of EPO
treatment, and our review confirms this finding (9). Access
thrombosis is another recognized complication of EPO treat-
ment, although the results in the available studies are conflict-
ing. In our review, we found that the Besarab et al. (16) study
showed a significantly higher risk of access thrombosis with
the higher Hb target, whereas the remaining trials did not
confirm this finding.
Reports of stroke episodes in the available trials in individ-
uals with CKD are few. This aspect mandates further investi-
gation, in light of available data suggesting that EPO promotes
thrombosis by interaction with platelet function (49). A recent
trial of EPO versus placebo in breast cancer patients was
terminated prematurely because of significantly higher mortal-
ity in the group that was treated with EPO, as a result of an
increase in the incidence of thrombotic and vascular events and
breast cancer progression in the EPO-treated patients (50).
Another placebo-controlled trial of EPO in patients with head
and neck cancer found that EPO corrects anemia, but there
was a significantly higher number of deaths in patients in the
EPO arm (51). A recent editorial in Lancet Oncology reported
similar findings from other still unpublished studies (19). The
applicability of these results to CKD patients is unclear but a
cause of concern.
EPO is widely reported to improve quality of life. We could
not pool results on quality of life; nonvalidated scales were
often used, and authors reported individual domains of a qual-
ity-of-life scale, which were significantly different, without
prespecification, rather than report the summary measure of
effect, suggesting outcome reporting bias (52).
Many narrative reviews and some meta-analyses have been
published on this debated topic. Two Cochrane systematic
reviews of randomized trials of EPO use or Hb targets for
anemia of CKD are consistent with the present larger analysis
that includes the most recently published trials (53,54). Our
studys findings are also consistent with the results of an
Agency for Healthcare Research and Quality report on EPO
use for anemia of CKD (55). This report, which was also based
on randomized, controlled trials, concluded that there is not
strong evidence showing that maintaining Hb 120 g/L is
more beneficial to CKD patients than Hb 120 g/L. Compared
with ours, the Agency for Healthcare Research and Quality
report did not include some recently published trials and did
J Am Soc Nephrol 15: 31543165, 2004
not consider seizures as an outcome, and there was no standard
quality assessment of the included trials. The most recently
published is a systematic review of the impact of epoetin
on clinical end points in patients with CKD (50), which sug-
gested that epoetin therapy provides important clinical and
quality-of-life benefits while substantially reducing hospital-
izations and transfusions. This study had the following limita-
tions: It did not fulfill standard requirements for systematic
reviews, as it lacked clear inclusion criteria and an explicit and
comprehensive search strategy; it included both randomized
and cohort studies; and there was no quality assessment of
included studies. We conclude that on the basis of available
data from randomized trials, it is not possible to draw evidence
of improvement in quality of life, hospitalizations, and
transfusions.
Strengths and Weaknesses
Although there are many studies and reviews on this debated
topic, this is the most updated systematic review of
randomized trials reported. Our findings contrast with data
from large observational studies that have shown a consistent
association between higher Hb values and improved outcomes,
including increased survival (56). This discrepancy between
observa- tional and trial data are well recognized.
Observational studies are not the best study design to answer
intervention questions, because of bias and confounding, the
effects of which are unpredictable and may result in an
overestimate, an underes- timate, or true estimate of effect
(57). In this setting, observa- tional studies may well be flawed
as a result of residual confounding such that the higher Hb
values may reflect under- lying better survival potential as a
result of an inability to adjust completely for all known and
unknown predictors of survival. In short, healthier patients
(with higher Hb values) live longer. Only randomized trials
can show whether changing Hb values improves survival,
because any baseline predictors of survival should be balanced
between treatment arms as a result of the randomization.
Recent examples of the unpredict- able biased nature of
observational studies include the findings of the ADEMEX and
the HEMO Study (randomized trials), which contrast with the
results of the CANUSA (observational) study (58,59).
It is important to point out the potential reasons for hetero-
geneity in the studies included in these analyses to understand
the limitations of the conclusions that can be derived from
them. These differences, which include variable sample size,
treatment protocols (treatment targets or EPO interventions),
populations studied, follow-up times (16,42), deficiencies in
design, and reporting of the published trials, all were made
explicit in this study but did not result in statistically
significant heterogeneity of any analysis.
Applicability to Clinical Practice
From the available trial evidence, the benefits associated
with EPO treatment achieving higher Hb targets (reduced
seizures) are outweighed by the harms (increased risk of hy-
pertension and mortality), and data for patients with CKD and
cardiovascular disease clearly indicate that the preferred Hb
J Am Soc Nephrol 15: 31543165, 2004
target should be 120 g/L. Data relating to other populations
(predialysis patients with CKD with and without cardiovascu-
lar impairment) are unclear. Higher Hb targets have long been
known to be associated with improvement in the quality of life,
but available evidence from randomized, clinical trials is prob-
lematic. Until additional, well-designed trials that adequately
assess safety and quality of life are available, clinicians always
need to consider the potential harms and costs whenever pre-
scribing interventions of unproved efficacy.
Future Research
Our study highlights the need for randomized, controlled
trials in the area of anemia management in CKD. The concern-
ing results about higher risk of all-cause mortality in patients
who have cardiovascular comorbidities and are treated with
higher EPO doses in the pursuit of higher Hb targets arise
mainly from the most recent trials that had the longest fol-
low-up duration and seem to be more generalizable to current
practice than the remaining ones. Adequately powered, well-
designed and reported long-term, randomized, controlled trials
comparing the benefits and harms of different Hb levels are
necessary. Given the findings of Besarab et al. (16) of in-
creased all-cause mortality with a higher Hb target (Hb 140
g/L) and the uncertainties of trials in which an average (Hb
100 to 110 g/L) target was tested, future studies should com-
pare the effect of treatment targets for Hb in the range of 120
to 140 with lower targets, with adequate power, and in
different populations (e.g., predialysis CKD patients). Trials of
Hb tar- gets could be done with EPO but also the newer agent
darbe- poetin. Seizures should be reported, and quality of life
should be assessed using validated tools. The trials should be
ade- quately powered to detect relevant patient outcomes,
including mortality and thrombovascular accidents. With a
power of
80%, ~1500 patients would be needed in a population with a
baseline mortality risk of 15% if we expected the intervention
(high Hb target) to reduce mortality to 10%. Approximately
2000 would be needed with a baseline mortality of 20% and an
expected reduction to a value of 15%, a 2-yr accrual time and
3-yr follow-up, and an expected noncompliance of ~10%.
Insights for the management of the anemia of CKD may also
derive from the three ongoing randomized trials on the topic
(CREATE, CHOIR, and TREAT). Their results are particu-
larly expected to elucidate the potential impact of different Hb
targets in predialysis patients with CKD. Additional informa-
tion on the relationship between Hb values achieved and clin-
ical outcomes could be gleaned from an individual patient data
meta-analysis.
Acknowledgments
This study was partly funded by the Cochrane Renal Group, the
NHMRC Centre for Clinical Research Excellence in Renal Medicine,
and a young investigator award granted to G.F.M.S. by the Italian
Society of Nephrology.
We acknowledge collaboration of Drs. J. Berns, A. Besarab, and R.
Foley and Ms. Cindy Wong, and Dr. A. Laupacis for providing data
relating to their trials that were not reported or were unclear in the
publications. Drs. J. Berns, A. Besarab, J. Conlon, A. Laupacis, A.
Hemoglobin Targets for the Anemia of Chronic Kidney Disease 3163
Nissenson, and V. Montinaro kindly agreed to review the manuscript.
We are indebted to Premala Sureshkumar for collaboration in some of
the data analysis, Friederike Bachmann for translating one of the trials
and assisting in data extraction, Narelle Willis for assistance as
coordinator of the Cochrane Renal Group, Ruth Mitchell and Gail
Higgins for assistance in the development of search strategies, and
Sandra Puckeridge for excellent administrative support. We also ac-
knowledge the anonymous reviewers who provided useful comments
to previous versions of this analysis.
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