Contoh Jurnal Meta Analisis
Contoh Jurnal Meta Analisis
American
Journal of
Nephrology
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
Nephrology Department, Faculty of Medicine, University of Medicine and Pharmacy Gr. T. Popa, Iasi, Romania;
CNR-Institute of Clinical Physiology, Reggio Calabria, Italy; c Renal Unit, Guys and St. Thomas NHS Foundation
Hospital, Kings Health Partners, London, UK
Key Words
Chronic kidney disease Anemia
Erythropoiesis-stimulating agents ESA
CKD-progression Meta-analysis Systematic review
Abstract
Background: The effect of anemia correction on kidney
function in chronic kidney disease (CKD) patients remains
unclear. As 1940% of patients with CKD receive an erythropoiesis-stimulating agent (ESA), this is a potentially important consideration. Summary: We conducted a systematic
review and meta-analysis of randomized trials to January 1,
2014 in adult patients with CKD stages 1 to 4. Selection criteria for studies: randomized controlled trials of at least
2 months duration. Patients were allocated to ESA versus
placebo, no treatment, or different ESA doses with the purpose of achieving a higher versus a lower hemoglobin target. The analyzed outcomes were the need for renal replacement therapy, doubling of serum creatinine, change in GFR
(ml/min), mortality and withdrawal of treatment due to adverse events. A total of 19 trials (n = 8,129 participants with
CKD stage 14) were reviewed. There was no difference in
the risk of end-stage kidney disease (RR, 0.97 [CI 0.831.20],
17 trials, 8,104 participants), change in GFR (Mean Difference
[MD] 0.45 [2.21, 1.31], 9 trials, 1,848 participants) or with-
Introduction
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
Methods
The systematic review and meta-analysis was performed according to a previously published protocol (http://www.crd.york.
ac.uk/PROSPERO/display_record.asp?ID = CRD42014007162).
We searched MEDLINE (January 1966 to 1st of January 2014)
and the Cochrane Controlled Clinical Trials Register Database
(through Issue 1 of 12, January 2014); we also hand searched reference lists of textbooks, articles, and scientific proceedings for relevant articles (online suppl. table1; for all online suppl. material,
see www.karger.com/doi/10.1159/000366025).
We included all RCTs and quasi-RCTs with a study period of
at least 2 months duration and assessed the effects of different hemoglobin (Hb) targets in pre-dialysis patients with anemia of CKD
on the prevention of the progression of CKD. The first period of
randomized crossover studies was also considered for inclusion.
There was no language restriction. The higher Hb target could be
achieved by EPO ( or ) or darbepoetin; the lower target could be
achieved by lower doses of the same drugs or by a placebo or no
treatment or blood transfusion.
Studies enrolling any patient with CKD stages 14 (as defined
by the Kidney-Disease Outcomes and Quality Initiative [K-DOQI]
guidelines: stage 1 = GFR 90 ml/min/1.73 m2; stage 2 = GFR 60
89 ml/min/1.73 m2; stage 3 = GFR 3059 ml/min/1.73 m2; stage 4=
GFR 1529 ml/min/1.73 m2; stage 5 = GFR <15 ml/min/1.73 m2
not requiring dialysis) were included. We excluded studies enrolling patients with CKD stage 5 (GFR <15 ml/min/1.73 m2) and who
were receiving hemodialysis or other forms of dialysis including
peritoneal dialysis. We also included studies on kidney transplanted patients if participants had residual GFR >15 ml/min/1.73 m2.
264
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
Covic/Nistor/Donciu/Dumea/Bolignano/
Goldsmith
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
1 of additional records
identified through other
sources
Other population
Surrogate outcomes
Follow-up less than 2 months
19 studies included in
qualitative synthesis
Results
Search Results
The combined search of MEDLINE, CENTRAL databases, and hand search by experts identified 5,257 citations, of which 3,808 were excluded (non-RCTs or studies
evaluating other interventions not relevant to this review).
Full-text assessment of 319 potentially relevant articles resulted in the identification of 19 eligible trials enrolling a
total of 8,129 patients [10, 11, 1315, 2235] (fig.1).
ESA for Prevention of CKD-Progression
19 studies included in
quantitative synthesis
(meta-analysis)
265
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
266
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
Covic/Nistor/Donciu/Dumea/Bolignano/
Goldsmith
Watson
1990 [23]
Clyne
1992 [24]
Revicki
1995 [25]
Kleinman
1989 [22]
Study
No
Diabetic
nephropathy:
not reported
Diabetes
mellitus:
exclusion
criterion
Diabetic
nephropathy:
9%
Diabetic
nephropathy:
57%
Baseline
kidney
disease
12 months
Arm 1: no ESA
treatment
Arm 2: ESA 50 U/kg/
week 3 to achieve and
maintain HCT >35%
HCT (%)
Arm 1:
26.83.6
Arm 2:
26.84.5
Not
Arm 1:
reported n = 40
Arm 2:
n = 43
Creatinine
clearance:
Arm 1
(no ESA):
10.04.1
Arm 2
(ESA):
10.24.1
Number of patients
starting RRT during
study period, change in
quality of life,
Glomerular filtration
rate at end of study;
Serum creatinine level
at end of study; blood
pressure at end of study;
Number of patients with
new antihypertensive
treatment
3 months
Iron therapy was
available for all
patients is the ferritin
levels were within the
normal range
Arm 1: No ESA
injection, standard care;
Arm 2: Aiming HCT
level of >30% with EPO
intravenously injection
once a week
Not
Arm 1:
reported n = 12
Arm 2:
n = 10
Arm 1:
938
Arm 2:
868
Insulin
creatinine
clearance:
Arm 1
(no ESA):
8.03.0
Arm 2
(ESA):
10.04.0
Renal function
outcomes, serum
potassium levels,
adverse events and
blood pressure control
Renal function
outcomes, adverse
effects, quality of life
3 months
Not
Arm 1
reported (no ESA):
n=6
Arm 2
(ESA):
n=5
Not
reported
Cr-DTPA
clearance:
Arm 1:
12.43.5
Arm 2:
13.024.4
3 months
Study
duration,
months
Not
Arm 1:
reported n = 7
Arm 2:
n=7
Co-intervention in
treatment arm (n),
type of ESA, notes
Intervention
Use of
No. of
ACE
patients
inhibitor
or ARB
HCT (%)
Arm 1
(placebo):
28.2
Arm 2
(ESA): 28.1
Baseline Hb
level, g/l
(mean SD)
Creatinine
values from
3 to 11 mg/dl
Baseline renal
function, ml/
min/1.73 m2
(mean SD)
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
267
Furuland
2003 [27]
Gouva
2004 [10]
Kuriyama
1997 [26]
Study
No
Table 1. (continued)
Diabetes
mellitus was
an exclusion
criterion
Diabetic
nephropathy
(type 2):
2415%
Diabetes
mellitus:
Arm 1
(no ESA):
58%
Arm 2
(ESA):
55%
Baseline
kidney
disease
Cockcroft
Gault equation:
Arm 1:
25.79.1
Arm 2:
22.36.0
Arm 1
(means SD):
101.05
Arm 2
(means SD):
101.06
Not
Arm 1:
reported n = 45
Arm 2:
n = 43
Protocol:
until all
patients had
completed
2years of
follow-up.
Because
of EPO alpha
withdraw,
patients
were followed
for a median
of 22.5
months
(interquartile
range 16 to
24months)
IV iron to keep
transferrin saturation
>20% and serum
ferritin between
400800 mg/dl;
Epoetin alfa
administered
subcutaneously; In
the low Hb group,
the target level was
obtained with or
without ESA
treatment
Arm 1: Aiming Hb
level 135150 g/l in
females and 145160
g/l in males
Arm 2: Aiming Hb
level 90120 g/l
Not
Arm 1:
reported n = 36
Arm 2:
n = 36
Arm 1:
10610
Arm 2:
1097
Doubling of serum
creatinine, mortality
rates, adverse events,
need for dialysis,
proteinuria level,
diabetes control
9 months
24-h urine
collection,
iohexol
clearance or
Cr-EDTA
clearance:
Arm 1: 169
Arm 2: 176
Arm 1:
n = 31
Arm 2:
n = 42
Arm 1:
68.0%
Arm 2:
59.0%
HCT (%)
Arm 1:
27.91.8
Arm 2:
272.3
Creatinine
clearance:
Arm 1:
17.17.2
Arm 2:
19.17.2
Study
duration,
months
Co-intervention in
treatment arm (n),
type of ESA, notes
Intervention
Use of
No. of
ACE
patients
inhibitor
or ARB
Baseline Hb
level, g/l
(mean SD)
Baseline renal
function, ml/
min/1.73 m2
(mean SD)
268
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
Covic/Nistor/Donciu/Dumea/Bolignano/
Goldsmith
Levin
2005 [29]
CHOIR
2006 [31]
10
ECAP
2006 [30]
Roger
2004 [28]
11
Study
No
Table 1. (continued)
Diabetic
nephropathy:
2627%
Diabetic
nephropathy:
46.850.8%
Diabetes
mellitus:
Arm 1: 41%
Arm 2: 35.1%
Diabetes
mellitus:
Arm 1: 24%
Arm 2: 33%
Baseline
kidney
disease
MDRD Arm 1:
30.310.5
MDRD Arm 2:
28.38.9
MDRD Arm 1:
36.717.0
MDRD Arm 2:
37.117.9
Arm 1:
115.010.0
Arm 2:
116.09.0
Arm 1:
101.09.0
Arm 2:
101.09.0
Arm 1:
91.0%
Arm 2:
87.0%
Arm 1:
73.7%
Arm 2:
74.2%
Arm 1:
n = 192
Arm 2:
n = 193
Arm 1:
n = 715
Arm 2:
n = 717
16 months
Both groups of
patients initially
received epoetin alfa
subcutaneously
weekly; Iron
Arm 1: % = 31.2
Arm 2: % = 29.9
Changes in LVMI,
renal function,
functional cardiac
status, QoL from
baseline to 24 months
24 months
Subcutaneous epoetin
alpha; iron
supplementation as
necessary
Arm 1:
n = 78
Arm 2:
n = 74
Arm 1:
37.2%
Arm 2:
29.7%
Arm 1:
117.67.6
Arm 2:
117.38.0
Cockcroft
Gault equation:
Arm 1:
37.413.6
Arm 2:
35.113.0
MDRD Arm 1:
29.711.1
MDRD Arm 2:
27.89.3
Changes in LVMi in
2years, renal function,
cardiac performance,
and quality of life,
renal deterioration
was assessed on the
basis of the time to the
onset of renal
replacement therapy,
the calculated
creatinine clearance,
and nuclear estimations
of GFR
24 months
Subcutaneous epoetin
alpha
Arm 1:
n = 75
Arm 2:
n = 80
Arm 1:
74.0%
Arm 2:
74.0%
Arm 1
(means SD):
1129
Arm 2
(means SD):
1128
Cockcroft
Gault equation:
Arm 1:
2611
Arm 2:
2511
Study
duration,
months
Co-intervention in
treatment arm (n),
type of ESA, notes
Intervention
Use of
No. of
ACE
patients
inhibitor
or ARB
Baseline Hb
level, g/l
(mean SD)
Baseline renal
function, ml/
min/1.73 m2
(mean SD)
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
269
Study
CREATE
2006 [11]
Macdougall
2007 [32]
ACORD
2007 [33]
No
12
13
14
Table 1. (continued)
Diabetes
mellitus
type 1 or 2:
100%
Diabetic
nephropathy:
22.023.4%
Diabetes
mellitus:
Arm 1: 27%
Arm 2: 25%
Baseline
kidney
disease
Not
Arm 1:
reported n = 65
Arm 2:
n = 132
Arm 1:
108.96.0
Arm 2:
107.66.6
Not
Arm 1
reported
(median
(IQR)): 11.9
(11.312.2)
Arm 2 (median
(IQR)): 11.7
(11.312.0)
Cockcroft
Gault equation:
Arm 1:
25.7512.23
Arm 2:
23.2610.15
Cockcroft
Gault equation
(median
(IQR)):
Arm1:
51 (3967)
Arm 2:
46 (3555)
Arm 1:
n = 301
Arm 2:
n = 302
Arm 1:
70.0%
Arm 2:
69.0%
Arm 1
(means SD):
116.06.0
Arm 2
(means SD):
1166.0
Cockcroft
Gault equation:
Arm 1:
24.96.3
Arm 2:
24.26.0
Arm 1:
n = 88
Arm 2:
n = 82
Intervention
Use of
No. of
ACE
patients
inhibitor
or ARB
Baseline Hb
level, g/l
(mean SD)
Baseline renal
function, ml/
min/1.73 m2
(mean SD)
subcutaneous
erythropoietinepoetin beta;
Subcutaneous
erythropoietinepoetin beta; Iron
supplementation
(intravenous or oral)
was recommended at
the discretion of the
investigators
Co-intervention in
treatment arm (n),
type of ESA, notes
15 months of
follow-up
Study
duration,
months
270
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
Covic/Nistor/Donciu/Dumea/Bolignano/
Goldsmith
Akizawa 2011
[37]
NEPHRODIAB2 Diabetic
2011 [14]
nephropathy
(type 2):
5062.8%
17
18
TREAT
2009 [35]
16
Diabetes
mellitus:
Arm 1: 21.1%
Arm 2: 22.5%
Type 2
diabetes
100%
Diabetes
mellitus:
Arm 1: 23.9%
Arm 2: 12.2%
Cianciaruso
2008 [34]
15
Baseline
kidney
disease
Study
No
Table 1. (continued)
Arm 1:
82.6%
Arm 2:
83.8%
Arm 1:
97.7%
Arm 2:
89.1%
Arm 1:
114.78.10
Arm 2:
114.210.6
Cockcroft and
Gault Arm 1:
37.09.1
Cockcroft and
Gault
Arm 2:
36.69.4
MDRD Arm 1:
29.612.8
MDRD Arm 2:
31.814.3
Arm 1:
91.57.9
Arm 2:
91.88.6
Arm 1:
n = 2,012
Arm 2:
n = 2,026
Arm 1:
79.7%
Arm 2:
80.0%
Arm 1:
median 105.0
Arm 2:
median 104.0
MDRD Arm 1:
median 34
MDRD Arm 2:
median 33
MDRD Arm 1:
19.046.96
MDRD Arm2:
18.576.32
Arm 1:
n = 46
Arm 2:
n = 49
Arm 1:
78.2%
Arm 2:
73.4%
Arm 1:
116.07.0
Arm 2:
117.08.0
Cockcroft
Gault equation:
Arm 1:
28.515.6
Arm 2:
29.414.0
MDRD Arm 1:
26.217.4
MDRD Arm 2:
26.714.0
Arm 1:
n = 161
Arm 2:
n = 160
Arm 1:
n = 43
Arm 2:
n = 46
Use of
No. of
ACE
patients
inhibitor
or ARB
Baseline Hb
level, g/l
(mean SD)
Baseline renal
function, ml/
min/1.73 m2
(mean SD)
The number of
patients with and the
occurrence rate of
adverse events, changes
in LVMI, functional
cardiac status, QoL
from baseline to
week 12
The study
lasted 12
months for
both groups
High Hb group
(11.013.0 g/dl)
received darbepoetin
alfa (DA) and the low
Hb group (9.011.0
g/dl) received
recombinant human
erythropoietin
(rHuEPO)
Arm 1: Aiming Hb level
range between 110 and
130 g/l
Arm 2: Aiming Hb level
range 90110 g/l
24 months
Iron and ESA therapy
modality was under
the responsibility of
each investigator (type
of iron and ESA was
free). ESA therapy
wasnot started unless
serum ferritin was
<200 g/l
Patients in the
placebo group were
assigned
To receive
darbepoetin alfa as a
rescue agent if the Hb
level fell below 9.0 g
per deciliter, with a
return to placebo once
the hemoglobin level
was 9.0 g per deciliter
or higher
Changes in LVMI,
renal function,
functional cardiac
status, QoL from
baseline to 24 months
24 monthsintended;
12-month
analysis
carried out
subcutaneous epoetin
alpha
Study
duration,
months
Co-intervention in
treatment arm (n),
type of ESA, notes
Intervention
Trial Quality
Trial quality was sub-optimal on overall. Allocation
concealment was adequate in three of 19 trials (16%) [29,
32, 34] and unclear in the remaining 10 out of 19 trials
(85%). A consistent high risk of bias concerning the blinding of participants and personnel was found for the majority of included studies, with exception of one, in which
the investigators stated the double-blinded design of the
trial, but without providing any additional information
[23] and two studies with low risk of bias [22, 35]. Only
three of the 19 trials (16%) were analyzed on an intentionto-treat basis [11, 35, 37]. The dropout rate ranged from
0 to 15% and did not differ between the treatment and
control groups (fig.2).
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
271
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
On patients
with posttransplant
anemia only;
nodata about
the incidence
ofdiabetes
mellitus
Arm 1:
n = 63
Arm 2:
n = 62
Arm 1:
69.8%
Arm 2:
71.0%
Arm 1
(means SD):
104.09
Arm 2
(means SD):
106.07
Cockcroft
Gault equation:
Arm 1:
38.910.6
Arm 2:
37.811.0
MDRD Arm 1:
34.410.0
MDRD Arm 2:
33.710.8
Subcutaneous
erythropoietinepoetin beta
Table 1. (continued)
Table 2. Baseline, target and achieved hemoglobin concentrations for the included studies
Baseline Hgb
concentration, g/dl
high/active group
low/no treatment
high/active group
low/no treatment
HCT of 28.2%
HCT of 3840%
HCT of 3840%
HCT of 35.8%
HCT of 28.3%
HCT of 282%
HCT of 38%
No target
HCT of 352%
HCT of 262%
8.60.8
HCT of >30%
No target
11.71.1
9. 41.0
HCT of 26.83.6%
HCT of 35%
No target
Not reported
8.91.2
HCT of 27.91.8%
HCT of 3335%
HCT <30%
11.831.33
8.430.63
10.61
13.015.0
9.012.0
14.31.1
11.31.3
9.011.6
13.0
Unless Hb <9.0
12.5
12.5
Unless Hb <9.0 at 2
consecutive clinic visits
or Hb <8.0 at any visit
12.20.7
11.01.0
11.013.5
Not reported
11.41.2
<11.0
13.5
11.3
Not reported
Not reported
Men: <13.0
Women: <12.5
13.015.0
11.012.0
16.2
16.1
11.012.5
13.015.0
10.511.5
Not reported
Not reported
11.01
Not reported
Not reported
13.015.0
10.511.5
13.015.0
>10.511.5
12.014.00.5
Unless Hb <9.0
<11.0
>13.0
Unless Hb 9.0
10.012.9
13.014.9
11.012.9
<12.0
>13.0
<10.0
11.013.0
9.011.0
10.50.8
13.015.0
10.511.5
13.11.7
Not reported
11.41.0
Study
25%
50%
75%
100%
272
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
Covic/Nistor/Donciu/Dumea/Bolignano/
Goldsmith
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
273
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
Quantitative Analysis
Number of Patients Starting RRT during the Study
Period
With regard to the number of patients that required
the initiation of RRT during the study, there were no data
that would favor either of the two groups (low versus high
Hb target) (17 trials, 8,104 participants, RR 0.97; 95% CI
0.831.15). The heterogeneity for this outcome was moderate: (2 = 28.59, I2 = 44%) (fig.3, table3).
For the composite outcome all-cause mortality or
RRT, there was no statistically significant difference between the high Hb and the low Hb arm (17 trials, 8,104
participants, RR = 0.95; 95% CI 0.811.12); heterogeneity
was again moderate (2 = 38.23, I2 = 58%) (fig.3).
Low-hemoglobin group
Events
Total
26
10
11
47
0
0
3
1
3
10
8
6
5
7
43
Risk ratio
MH, Random, 95% CI
Year
0.5%
5.5%
7.0%
0.3%
5.9%
4.8%
3.1%
15.6%
0.8%
15.9%
0.5%
11.6%
1.4%
18.1%
1.0%
6.4%
1.7%
100.0%
1992
1994
1997
2003
2004
2004
2005
2006
2006
2006
2007
2007
2008
2009
2011
2011
2012
0.8%
7.5%
9.1%
0.5%
8.0%
6.7%
4.5%
16.3%
16.5%
1.3%
0.8%
13.4%
2.2%
1.6%
8.5%
2.6%
100.0%
1992
1994
1997
2003
2004
2004
2005
2006
2006
2006
2007
2007
2008
2011
2011
2012
10
40
31
36
43
80
74
717
302
82
195
132
49
2,026
43
160
62
4,082
0.5%
5.4%
7.1%
0.6%
5.8%
5.5%
3.6%
14.6%
14.8%
0.8%
1.6%
10.8%
1.5%
16.9%
2.3%
6.1%
2.1%
100.0%
1992
1994
1997
2003
2004
2004
2005
2006
2006
2006
2007
2007
2008
2009
2011
2011
2012
31
62
43
136
65.1%
10.8%
24.1%
100.0%
1997
2004
2012
7
6
40
36
87
302
132
195
49
160
1,014
2.0%
2.3%
3.7%
4.1%
3.6%
31.2%
7.9%
14.7%
13.3%
17.4%
100.0%
1989
1989
1994
2003
2005
2006
2007
2007
2008
2011
10
40
31
36
80
43
74
717
82
302
195
132
49
2,026
43
160
62
4,082
1.2.2 Number of patients starting RRT during study period_Treat trial excluded
Clyne 1992
1
2
10
12
Revicki 1995
16
13
40
43
Kuriyama 1997
14
20
31
42
Furuland 2003
2
0
36
36
Roger 2004
24
15
80
75
Gouva 2004
10
18
43
45
Levin 2005
11
8
74
78
CHOIR 2006
155
134
717
715
CREATE 2006
127
111
302
301
ACORD 2007
2
3
82
88
ECAP 2006
3
1
195
195
Macdougall 2007
30
63
132
64
Cianciaruso 2008
4
4
49
46
NEPHRODIAB2 2011
2
5
43
46
Akizawa 2011
21
26
160
161
CAPRIT 2012
3
13
62
63
Subtotal (95% CI)
2,056
2,010
425
436
Total events
Heterogeneity: Tau2 = 0.06; Chi2 = 28.59; df = 15 (p = 0.02); I2 = 48%
Test for overall effect: Z = 0.57 (p = 0.57)
1.2.3 Starting RRT and all cause mortality: composite outcome
Clyne 1992
1
2
12
Revicki 1995
16
14
43
Kuriyama 1997
15
22
42
Furuland 2003
6
1
36
Gouva 2004
13
22
45
Roger 2004
24
15
75
Levin 2005
12
11
78
CHOIR 2006
207
170
715
CREATE 2006
158
132
301
ACORD 2007
2
3
88
ECAP 2006
4
7
195
Macdougall 2007
31
68
64
Cianciaruso 2008
5
4
46
TREAT 2009
750
725
2,012
NEPHRODIAB2 2011
6
10
46
Akizawa 2011
22
26
161
CAPRIT 2012
4
16
63
Subtotal (95% CI)
4,022
1,276
1,248
Total events
Heterogeneity: Tau2 = 0.04; Chi2 = 38.23; df = 16 (p = 0.001); I2 = 58%
Test for overall effect: Z = 0.59 (p = 0.56)
Weight
Risk ratio
MH, Random, 95% CI
Study or Subgroup
0.5 0.7
1
1.5 2.0
Favours high-Hb group Favours low-Hb group
274
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
Covic/Nistor/Donciu/Dumea/Bolignano/
Goldsmith
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
Fig. 3. Effect of high Hb target versus low Hb target on dichotomous outcomes: 1.2.1 number of patients starting RRT during study period. 1.2.2 number of patients starting RRT during study period_TREAT trial excluded. 1.2.3 number of patients starting RRT and allcause mortality: composite outcome. 1.2.4 doubling of serum creatinine. 1.2.5 number discontinued due to adverse events.
Low-hemoglobin group
Events
Total
Weight
Risk ratio
MH, Random, 95% CI
1.2.6 Number of patients with at least one adverse event during the intervention period
CHOIR 2006
607
589
688
10.8%
686
CREATE 2006
279
273
302
7.8%
300
ECAP 2006
144
140
195
1.2%
195
Macdougall 2007
62
126
132
4.3%
65
TREAT 2009
1,880
1,878
2,019
67.2%
2,004
Akizawa 2011
154
153
160
8.3%
161
NEPHRODIAB2 2011
22
27
43
0.1%
46
CAPRIT 2012
41
33
49
0.3%
63
Subtotal (95% CI)
3,588 100.0%
3,520
3,189
3,219
Total events
Heterogeneity: Tau2 = 0.00; Chi2 = 4.38; df = 7 (p = 0.74); I2 = 0%
Test for overall effect: Z = 1.67 (p= 1.10)
1.2.7 Number of patients with at least one hospitalisation during the intervention period
369
715
334
717
94.6%
Gouva 2004
CHOIR 2006
4
45
6
43
0.7%
ECAP 2006
32
195
26
195
4.6%
Subtotal (95% CI)
955 100.0%
955
405
366
Total events
Heterogeneity: Tau2 = 0.00; Chi2 = 1.01; df = 2 (p = 0.60); I2 = 0%
Test for overall effect: Z = 1.97 (p = 0.05)
Risk ratio
MH, Random, 95% CI
Year
2006
2006
2007
2007
2009
2011
2011
2012
2004
2006
2007
Study or Subgroup
0.5 0.7
1
1.5 2.0
Favours high-Hb group Favours low-Hb group
Fig. 3. Effect of high Hb target versus low Hb target on dichotomous outcomes: 1.2.6 number of patients with at least one adverse event
during the intervention period. 1.2.7 number of patients with at least one hospitalization during the intervention period.
Trials reporting
more than one
event/total number
of trials included in
the outcome
Number of
patients
included in
the outcome
Relative
effect
95% CI
Median
treatment
duration,
months
Quality of
evidence*
17/17
3/3
9/10
9/9
8,104
286
1,958
1,828
0.97
0.53
1.18
0.45
(0.83, 1.15)
(0.31, 0.89)
(0.77, 1.81)
(2.21, 1.31)
18.41
18.5
15.25
21.67
Moderate
Very low
Low
Very low
*Definition of quality of evidence: High quality = additional research is very unlikely to change our confidence in the estimates of
effect; Moderate quality = additional research is likely to have an important impact on our confidence in the estimate of effect; Low quality = additional research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the
estimate; Very low quality = any estimate of the effect is very uncertain.
non-US participants. There were no significant effect estimates or heterogeneity differences found (online suppl.
fig.4).
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
Discussion
275
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
Key Findings
Our analysis included 19 studies, enrolling 8,129 participants with CKD stages 14. There was no difference
in risks for end-stage kidney disease, reduction in GFR,
serum creatinine or GFR (ml/min) values, or in protein-
High-hemoglobin group
Mean
SD
Total
Low-hemoglobin group
Mean
SD
Total
Mean difference
Weight IV, Random, 95% CI
Mean difference
IV, Random, 95% CI
13.8
3
19
7
6.3
12.2
10
7.1
62 12.2%
8 13.2%
293 15.5%
21 11.2%
43 14.4%
43 12.9%
61 14.4%
6
6.2%
537 100.0%
12
9
12
11
11
62 20.6%
8
9.4%
302 31.8%
31 18.1%
61 20.1%
464 100.0%
ACORD 2007
5.5
8.29
85
3.4
9.92
Akizawa 2011
2.3
3.18
160
2.4
3.06
CAPRIT 2012
2.4
1.1
63
6
1.1
Cianciaruso 2008
2
0.9
37
1.3
0.5
CREATE 2006
3.6
6.7
287
3.1
5.3
Levin 2005
7.4
11.1
78
9.1
10
Macdougall 2007
6.96
8.28
65
7.82
7.5
NEPHRODIAB2 2011
5.1
7.8
46
8.7
12.2
Roger 2004
8
9
66
6
8
Subtotal (95% CI)
887
2
2
2
Heterogeneity: Tau = 5.99; Chi = 302.41; df = 8 (p < 0.00001); I = 97%
Test for overall effect: Z = 0.50 (p = 0.62)
Study or Subgroup
20
10
0
10
20
Favours high-hemoglobin
Favours low-hemoglobin
Fig. 4. Effect of high Hb target versus low Hb target on continuous outcomes: 1.3.1 reduction in GFR at the end of the study (ml/min).
1.3.2 GFR at end of study (ml/min). 1.3.3 diastolic blood pressure at end of the study (mm Hg).
276
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
overall quality of the investigational and trial design approaches used to address this key end-point was suboptimal. Finally, data on proteinuria were reported only by
three studies.
Two rather different studies included in our metaanalysis seemed to show protective outcomes for the deployment of ESAs in CKD. These were the studies by
Gouva et al. (2004) [10] and the more recent CAPRIT
study from 2012 [15].
The Gouva study was one of the smallest ones (n = 88)
of the 19 included in the meta-analysis, and was focused
on non-diabetic patients with a wide range of serum creatinine concentrations (26 mg/dl) and mild-to-moderate anemia (Hb 911 g/dl), from 14 clinical centers in
Covic/Nistor/Donciu/Dumea/Bolignano/
Goldsmith
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
uria, at the end of the study periods when aiming at higher hemoglobin (Hb) targets. Furthermore, no statistically
significant differences in a composite outcome need for
RRT plus mortality (Risk Ratio [RR] 0.95 [CI 0.811.12],
17 trials, n = 8,104 patients) were observed. Withdrawal
of treatment due to adverse events was similar, as well as
the general control of BP, between high and low Hb targets cohorts of patients.
Some important shortcomings in the manner of reporting outcomes deserve mentioning. Only four studies
out of 19 had renal endpoints as primary outcomes; the
remaining studies only described these events as secondary outcomes. The studies did not generally feature or
recruit from rapidly-progressing CKD cohorts. The
published in 2004, although the evidence was quite limited, 4 trials including 77 patients in one meta-analysis
and 5 trials with 207 patients in the second. Nevertheless,
both meta-analyses showed no difference between Hb
groups regarding the renal progression outcome.
The most meaningful comparison should probably
be made with a 2010 meta-analysis by Palmer et al. [12]
that evaluated the effects of ESA in CKD patients. Our
work has in addition three subsequent published studies
included. Most importantly, our main aim was to focus
on assessing different renal outcomes, which were not
the main output focus of the Palmer paper, whose principal objective was a cardiovascular event/mortality
analysis.
Strengths and Limitations
Our review has a number of strengths and limitations.
Strengths include a systematic search of medical databases, data extraction and analysis, and trial quality assessment by two independent reviewers. We also carefully
analyzed the most important potential renal end-points
including loss of renal function, and dialysis initiation.
This has not been done before. Another strength of our
review was a detailed examination of trials quality and
heterogeneity. The major limitation is the lack of longterm studies analyzing the efficacy of ESA on mortality,
progression of CKD, and entry onto dialysis. Another
limitation is the populations included in the 19 studies,
and how many of them were truly demonstrating progressive loss of GFR prior to enrollment. The majority of
the included studies enrolled a relatively small number of
patients; they were powered to observe differences in surrogate end-points rather than patient-focused outcomes,
and used nonoptimal measures of renal function change
over time. Also, in our aim to study ESA role in CKD progression, our search found limited data for all proposed
outcomes. The absence of data for some relevant outcomes (e.g., doubling of serum creatinine) might represent an open pathway for future research. In addition, the
preponderance of high risk of bias regarding the lack of
blinding could be considered a possible limitation.
Implications for Practice
In CKD patients with anemia, the current KDIGO
[42] and ERBP guidelines [43] suggest that a careful exploration of the risk-benefit relationship between Hb,
ESAs, and outcomes, should be undertaken for all patients. In some cases, it is expected that clinically relevant benefits of using ESAs to raise Hb will be seen, but
not in all cases, while there are definite risks associated
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
277
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
with active therapy. However, in the quest for nephroprotection to prevent progressive loss of renal function
and the eventual need for dialysis, adjusting the patients Hb concentration using ESAs does not seem,
from our evidence, to have a compelling logic to support it.
Disclosure Statements
Adrian Covic received speaker honoraria from Amgen, Roche,
Fresenius Medical Care and Abbott, and is a member of the
European Renal Best Practices Board.
David Goldsmith received speaker honoraria from Roche,
Amgen, Vifor, Takeda, Sandoz.
Acknowledgements
None to declare.
References
278
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
Covic/Nistor/Donciu/Dumea/Bolignano/
Goldsmith
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM
Am J Nephrol 2014;40:263279
DOI: 10.1159/000366025
279
Downloaded by:
198.143.33.33 - 4/6/2016 6:15:54 PM