Hemoglobin Targets for the Anemia of Chronic Kidney

J Am Soc Nephrol 15: 3154–3165, 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
Children’s 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 kidney 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 comprehensive 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, hypertension, 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
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 hypertension and death). There is insufficient data to guide decisions in patients without cardiovascular disease or in the
predialysis population.
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 (1–3). 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, neurocognitive 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-
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 (7–10).
Current treatment options for anemia include blood transfusion, recombinant human EPO (␣ or ␤) or darbepoetin ␣. The
latter are growth factors for the bone marrow erythroid precursors, 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 patient’s 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 thrombosis, hypertension, and an increased number of adverse cardiovascular events. Also, reaching and maintaining higher Hb
targets implies major costs (8,15–18). Very recently, a number
of trials in cancer patients were terminated prematurely because of unexpectedly higher mortality in the higher Hb
groups, mainly as a result of disease progression and thromboembolic 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
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 Children’s Hospital at Westmead and the University of
Sydney, Westmead, NSW 2145, Australia. Phone: 02-98453088; Fax: 02-98453038;
E-mail: [email protected] and [email protected]
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
J Am Soc Nephrol 15: 3154–3165, 2004
Hemoglobin Targets for the Anemia of Chronic Kidney Disease
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 sensitive 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 hemofiltration, 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 proceedings of the American Society of Nephrology and European Dialysis and Transplantation Association meetings of 1999 to 2003 were
searched for abstracts of relevant trials. Information about unpublished 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 characteristics of the study sample, doses and modalities of treatment,
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methodologic characteristics of the trials, and outcomes: all-cause
mortality, left ventricular hypertrophy, cardiovascular mortality (myocardial infarction, stroke), adverse events (patients with hypertension
requiring exclusion from study or administration of additional antihypertensive 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 completeness 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, difference 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 random-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 randomized trials that evaluated other interventions (e.g., subcutaneous versus intravenous EPO treatment for anemia of CKD)
or because only surrogate and hemorheologic outcomes were
Table 1. Published guidelines on Hb targets in patients with CKDa
Guidelines
Country
Year
Target Hb
Level (g/L)
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)
United States
United Kingdom
Canada
Europe
United States
Australia
2000
2002
1999
2004
2000
2003
110–120
ⱖ100
110–120
⬎110b
103–120
ⱕ120c
120–140d
a
Hb, hemoglobin; CKD, chronic kidney disease.
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).
b
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Journal of the American Society of Nephrology
reported (e.g., blood viscosity, hematopoietic progenitor cell
assays; Figure 1). Full-text assessment of 43 potentially eligible 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
J Am Soc Nephrol 15: 3154–3165, 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 cardiovascular 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 improved 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
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.
EPO versus EPO
EPO versus EPO
EPO versus EPO or no
treatment
g/L)
EPO versus EPO
EPO versus EPO
EPO versus EPO
Randomized
Intervention
24
Oral or IV Fe (target transferrin saturation ⬎20%/ferritin ⬎100 ␮g/L)
66
40
10
7
31
3
5
40
19
31
6
3
6
3
3
9
2
6
12
12
6
3
4
80
16
73
200
17
618
22
No. of
Patients
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
High Target Group
4
63
38
12
7
42
11
6
43
19
86
5
⬍100.0
⬍90.0
84.0–104.0b
94.0
84.3 ⫾ 6.3
80–93.0g
⬍100.0
89.3 ⫾ 12.0
⬍100.0
100.0
86.6 ⫾ 6.6
75
15
73
216
14
618
21
105.0–120.0g
116.0–120.0g
NA
123.0–133.0g
NA
100.0–116.0
95.0–110.0g
⬎100.0
126.0–133.0g
NA
NA
133.0
120.0–130.0g
140.0 ⫾ 10.0
130.0–140.0g
130.0–150.0d,g
140.0 ⫾ 10.0
140.0 ⫾ 10.0
140.0 ⫾ 10.0
b
115.0
120.0
100–116.6g
128.0–133.3d
116.6 ⫾ 6.6
100.0–116.6b
95.0–110.0g
106.0–117.0g
119.3
118.3 ⫾ 13.3
126.6
123.0 ⫾ 6.6
122.0 ⫾ 7.0g
136.0 ⫾ 17.0
119.0–125.0g
143 ⫾ 11.0h
140.0 ⫾ 3.6
140.0 ⫾ 10.0
140.0 ⫾ 10.0
No. of
Targeted
Achieved
Patients Hb Value (g/L) Hb Value (g/L)
96.0 ⫾ 10
110.0 ⫾ 10.0g
100 ⫾ 14.3
102.0–106.0g
113.0 ⫾ 13.0h
100.0 ⫾ 10.0
95.0–105.0g
90.0–120.0d,g
90.0–100.0g
101.0 ⫾ 3.3
100.0 ⫾ 10.0
100.0 ⫾ 10.0
Achieved
Hb Value (g/L)
100.0 ⫾ 10.0
100.0 ⫾ 10.0
100.0 ⫾ 10.0
Targeted
Hb Value (g/L)
Low Target Group
IV, intravenous; NA, not available.
Trial enrolling children.
c
Substudy of the Besarab et al. trial.
d
Hb target was 135 to 150 g/L in females and 145–160 g/L in males.
e
Known cardiovascular abnormality.
f
No treatment or blood transfusion.
g
Range.
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,
hemodialysis, and peritoneal dialysis patients).
a
f
3
6
12
12–19
12
29
20
Follow-up
(Months)
None indicated
None indicated
Oral or IV Fe (target transferrin saturation ⬎20%/ferritin 250 ␮g/L)
None indicated
IV Fe
Oral (3 mg/kg per d) or IV 2 mg/kg ⫻ 3/wk Fe (target ferritin ⬎100
ng/mL/transferrin saturation ⬎20%)
Cointerventions
Fe (dose/route NA) (target transferrin saturation ⬍20%); folic acid 1
mg/d
None indicated
Bahlmann et al. (24)
Hemodialysis
EPO versus standard
Canadian Erythropoietin Study Group (40) Hemodialysis
EPO versus placebo
Oral or IV Fe (dose NA) (target ferritin ⬍250 ␮g/L)
Clyne and Jogestrand (27)
Predialysis
EPO versus standardf
Oral (200–300 mg/d) or IV (100 mg/wk) Fe for all patients
Kleinman et al. (30)
Predialysis
EPO versus placebo
Fe (dose/route NA)
Kuriyama et al. (31)
Predialysis
EPO versus no treatment Fe “at investigator’s discretion”
Lim et al. (32)
Predialysis
EPO versus placebo
Oral (300 mg ⫻ 3/d) Fe and oral folic acid 1 mg/d “to all patients
except those with excess iron stores”
d
Peritoneal dialysis EPO versus placebo
None indicated
Morris et al. (33)
Revicki et al. (34)
Predialysis
EPO versus no treatment Iron ⬍200 mg/d (route not indicated) if transferrin saturation
Sikole et al. (35)
Hemodialysis
EPO versus no treatment None indicated
Techan et al. (36)
Predialysis
EPO versus placebo
None indicated
Watson et al. (37)
Predialysis
EPO versus placebo
None indicated
EPO versus EPO or no
treatment
No EPO treatment (Hb ⬍95 g/L) versus EPO treatment (Hb ⬎100 g/L)
Abraham and Macres (23)
Predialysis
EPO versus standardf
Low Hb target (⬃100 g/L) versus high hemoglobin target (⬃140
Berns et al. (25)
Hemodialysise
Besarab et al. (16)
Hemodialysise
Brandt et al.b (26)
Predialysis
Peritoneal dialysis
Hemodialysis
c
Conlon et al. (28)
Hemodialysise
Foley et al. (29)
Hemodialysise
Furuland et al. (42)
Predialysis
Hemodialysis
Peritoneal dialysis
Roger et al. (43)
Predialysis
Study ID
Treatment
Modality
Table 2. Characteristics of patients and interventions in trials of EPO or randomized Hb targets for the anemia of CKDa
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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 unclear in all 19 trials. Outcome assessors were not stated as
blinded in any of the trials, and only three studies were analyzed 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
J Am Soc Nephrol 15: 3154–3165, 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 additional 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 evaluation 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 questionnaires, which have been validated using standard methods
and in relevant populations) (24,27,30,32,36). Also, dimension-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
Figure 2. Effect of high versus low hemoglobin (Hb) targets on all-cause mortality.
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Hemoglobin Targets for the Anemia of Chronic Kidney Disease
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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 (myocardial infarction, serious cardiovascular events [including angina, atrial fibrillation, and severe arrhythmia], stroke, hyperkalemia, access thrombosis, hospitalization rates and days of
hospitalization, left ventricular hypertrophy, systolic BP, diastolic 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
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 significant effect (four studies, 77 patients; weighted mean difference, 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%
A codified scale for the standard assessment of quality of life or exercise capacity whose validity has been tested in patients with kidney disease.
a
No
No
Study specific
Study specific
Lim et al. (32)
Teehan et al. (36)
Baseline and end of treatment
Baseline and end of treatment
Baseline and end of treatment
No
Kleinman et al. (30)
Baseline and end of treatment
No
Standardized symptom-limited exercise test and electrically braked
bicycle ergometer
Model developed for patients with advanced cancer
Clyne and Jogestrand (27)
Yes
Yes
Improvement in level of energy, ability to do work, and overall quality of life with higher
targets
Improvement in exercise capacity with higher targets
Improvement in energy level and work capacity with higher targets
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Kidney Disease Quality of Life tool
Sickness Impact Profile
Canadian Erythropoietin Study Group (40)
Baseline and end of treatment
No
Angina, dyspnea, “other” cardiovascular symptoms, and sexuality improved with higher
targets
Improvement in fatigue, physical symptoms, depression, and relationship with others
measures with higher targets
Overall improvement with Short Form 36 with higher targets
Significant increase in exercise capacity with higher targets
Baseline and 12 and 24 mo
Roger et al. (43)
Short Form 36
Renal Quality of Life Profile (Hb ⬎100 g/L)
No EPO treatment (Hb ⬍ 95 g/L) versus EPO treatment
Bahlmann et al. (24)
Study specific
Yes
Improvement of main physical symptoms in the normal compared with the lower Hb group.
Change in KDQ score for main physical symptoms, fatigue, depression, and frustration
favored the normal compared with the lower hematocrit group.
No significant difference in any score between the two groups
Baseline and 12 mo
Yes
Yes
Furuland et al. (42)
Kidney Disease Questionnaire (KDQ) part 1 and part 2
Baseline and 3, 6, and 7 mo
Foley et al. (29)
Kidney Disease Quality of Life tool
Short Form 36
Yes
Significant increase of physical function score; no significant changes in other scores of the
scale with higher targets
Improvement in fatigue, depression, and relationship with others measures with higher targets
No changes with Short Form 36
Baseline and every 6 mo
Yes
Low Hb target (⬃100 g/L) versus high Hb target (⬃140 g/L)
Besarab et al. (16)
Short Form 36
Scale or Tool
Validateda
Time of Assessment
Result
Journal of the American Society of Nephrology
Study ID
Table 3. Quality of life and physical capacity assessment of patients enrolled in trials of EPO or randomized Hb targets for anemia of CKD
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(95% CI, 1.0 to 6.0%) lower in the group of patients with Hb
target of ⬍120 g/L compared with the group of patients with
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 majority 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
without overt cardiovascular disease) despite the absence of
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.,
harm in one group and benefit in another using the same
intervention) is very rare (47). The finding of higher mortality
in higher Hb target groups from very recent cancer trials would
also make a survival benefit of higher Hb values in the CKD
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
this trial are in fact generalizable.
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
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%)
lower with Hb values of ⬎100 compared with the group of
patients with Hb ⬍95 g/L. This means that for every 25
patients treated to an Hb level of ⬎100 g/L, one fewer will
develop seizures.
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
absolute terms, the risk of developing hypertensive episodes is
16% lower (95% CI, 8 to 24%) with Hb values ⬍95 g/L
compared with Hb ⬎100 g/L. For every seven patients treated
to obtain an Hb ⬎100 g/L, one patient will require additional
antihypertensive medication.
Comparison with Other Studies
This systematic review is influenced mainly by the finding
of Besarab et al. (16) of an association of higher mortality in
individuals who have cardiovascular disease and are treated to
Hb targets ⬎130 g/L. The other small trials are inadequately
powered to show any evidence of benefit or harm, both separately and combined (RR, 0.98; 95% CI, 0.61 to 1.55). They
show no difference between the arms that treated to higher
No. of Studies
No. of Patients
b
a
41
22
19
4
14
5
296
445
150.70
77.30
105.60
—
16.00–24.00b
105.00
4.80
1
0
1
5
0
1
12
143.40–151.10b
84.50–93.90b
67.30–113.30b
5.70–10.83b
12.90–18.00b
87.60–171.80b
2
2
0
11
2
0
5
139.90–151.00b
81.40–92.90b
67.30–112.30b
4.00–10.50b
10.30–20.00b
101.20–133.80b
No. of Patients with Events or
Meansa in High Target Group
42
28
14
3
9
3
242
425
151.50
75.90
104.80
—
13.00–23.00b
102.00
3.80
No. of Patients with Events or
Meansa in Low Target Group
1.56
1.36
0.71
1.56
0.79
0.56
0.94
—
—
—
—
—
—
1.03
1.28
0.74
0.75
0.65
0.62
1.05
0.96
—
—
—
—
—
—
—
Relative Risk
CI, confidence interval.
Means are provided for continuous variables; lower and higher mean is provided for analyses including more than one trial.
Low Hb target (⬃100 g/L) versus high Hb target (⬃140 g/L)
myocardial infarction (all)
1
1389
myocardial infarction (fatal)
1
1233
myocardial infarction (nonfatal)
1
1233
serious cardiovascular events
1
146
stroke
1
1233
hyperkalemia
2
1277
access thrombosis
3
1795
hospitalization for all causes
1
1233
systolic BP
1
246
diastolic BP
1
246
mean arterial pressure
1
16
serum creatinine
—
—
creatinine clearance
2
167
left ventricular mass index (g/m2)
1
127
days of hospitalization
1
416
No EPO treatment (Hb ⬍95 g/L) versus EPO treatment (Hb ⬎100 g/L)
myocardial infarction (all)
3
170
myocardial infarction (fatal)
2
156
myocardial infarction (nonfatal)
1
14
serious cardiovascular events
1
245
stroke
2
1412
hyperkalemia
1
14
access thrombosis
2
1972
systolic BP
3
123
diastolic BP
3
369
mean arterial pressure
4
60
serum creatinine
4
77
creatinine clearance
2
19
left ventricular mass index (g/m2)
2
45
Outcome Analyzed
Table 4. Other outcomes analyzed in trials of EPO or randomized Hb targets in patients with anemia of CKDa
0.26–9.50
0.80–2.31
0.37–1.39
0.49–5.03
0.36–1.72
0.15–2.01
0.59–1.51
—
—
—
—
—
—
0.68–1.56
0.74–2.21
0.37–1.46
0.17–3.23
0.28–1.48
0.15–2.56
0.63–1.75
0.89–1.03
—
—
—
—
—
—
—
95% CI
—
—
—
—
—
—
—
⫺0.66
⫺2.11
0.35
0.01
⫺2.15
⫺16.64
—
—
—
—
—
—
—
—
0.80
⫺1.40
⫺0.80
—
⫺1.07
⫺3.00
⫺1.00
Weighted Mean
Difference
Results
—
—
—
—
—
—
—
⫺7.50–6.19
⫺6.44–0.12
⫺5.63–6.33
⫺1.21–1.22
⫺6.14–1.84
⫺66.45–33.17
—
—
—
—
—
—
—
—
⫺4.78–6.38
⫺4.37–1.57
⫺12.39–10.79
—
⫺2.10–⫺0.05
⫺10.66–4.66
⫺2.75–0.75
95% CI
0.60
0.40
0.30
0.10
0.60
0.86
0.20
0.78
0.75
0.89
0.16
0.50
0.04
NA
NA
NA
NA
NA
0.89
⬍0.01
NA
NA
NA
NA
NA
0.48
0.0005
NA
Heterogeneity
␹2 P Value
J Am Soc Nephrol 15: 3154–3165, 2004
Hemoglobin Targets for the Anemia of Chronic Kidney Disease
3161
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 rationale underlying the protective role of EPO against seizures
could be the increased peripheral cerebral oxygenation of neurons and the observation that neurons develop EPO receptors
during ischemia, with a neuroprotective effect of EPO independent 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 treatment, although the results in the available studies are conflicting. 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 individuals with CKD are few. This aspect mandates further investigation, 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 mortality 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 quality-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
study’s 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: 3154–3165, 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 suggested that epoetin ␣ therapy provides important clinical and
quality-of-life benefits while substantially reducing hospitalizations and transfusions. This study had the following limitations: 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 observational 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 underestimate, or true estimate of effect (57). In this setting, observational studies may well be flawed as a result of residual
confounding such that the higher Hb values may reflect underlying 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 unpredictable 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 heterogeneity 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 hypertension and mortality), and data for patients with CKD and
cardiovascular disease clearly indicate that the preferred Hb
J Am Soc Nephrol 15: 3154–3165, 2004
target should be ⬍120 g/L. Data relating to other populations
(predialysis patients with CKD with and without cardiovascular 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 problematic. 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 prescribing interventions of unproved efficacy.
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 acknowledge the anonymous reviewers who provided useful comments
to previous versions of this analysis.
References
Future Research
Our study highlights the need for randomized, controlled
trials in the area of anemia management in CKD. The concerning 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 follow-up duration and seem to be more generalizable to current
practice than the remaining ones. Adequately powered, welldesigned 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 increased 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 compare the effect of treatment targets for Hb in the range of 120
to 140 with lower targets, with adequate power, and in different
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be assessed using validated tools. The trials should be adequately powered to detect relevant patient outcomes, including
mortality and thrombovascular accidents. With a power of
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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 particularly expected to elucidate the potential impact of different Hb
targets in predialysis patients with CKD. Additional information on the relationship between Hb values achieved and clinical outcomes could be gleaned from an individual patient data
meta-analysis.
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NHMRC Centre for Clinical Research Excellence in Renal Medicine,
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