Supplementary Material
Title:
Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney
disease: a systematic review and meta-analysis.
Authors:
Wanyin Hou, Jicheng Lv , Vlado Perkovic, Lihong Yang, Na Zhao, Meg J Jardine, Alan Cass, Hong Zhang, Haiyan
Wang
Supplementary Figure S1: Publication bias Funnel plots for cardiovascular disease.
Supplementary Figure S2: Effects for statin therapy on major cardiovascular events among
non-dialysis patient and dialysis patients. Risk ratio adjusted by LDL reduction.
Supplementary Figure S3: Effect of more versus less statin regimen on cardiovascular events
among chronic kidney disease population
Supplementary Table S1 : JADAD SCALE of individual trial
Supplementary Table S2 :Cardiovascular event defined by each trial
Supplementary Table S3.1-3.3 : Absolute risk reduction (ARR) and number needed to treat
(NNT)of statin in patients with chronic kidney disease
Supplementary material: Search strategy
- 34 -
Supplementary material Figure S1. Publication bias Funnel plots for cardiovascular disease.
No evidence of statistically significant publication bias for trials reporting cardiovascular
events(Begg’s test p=0.726,Egger’s test p=0.062)
- 35 -
Supplementary material Figure S2: Effects for statin therapy on major cardiovascular events among non-dialysis patient and dialysis patients.
Risk ratio adjusted by LDL reduction.
36
Supplementary material Figure S3: Effect of more versus less statin regimen on cardiovascular events among chronic kidney disease population
37
Randomization
Double
blinding
Withdraws
and
dropouts
JADAD
Score
PREVEND IT
2
2
1
5
Seung Hyeok Han-2011
2
0
0
2
ATTEMP
1
0
0
1
SHARP
1
2
1
4
Air Force/Texas
1
2
1
4
JUPITER
2
2
1
5
LORD
2
2
1
5
PANDA
2
2
1
5
MEGA
2
0
1
3
AURORA
1
2
1
4
CARDS
2
2
1
5
ALLIANCE
1
0
1
2
4S
1
2
1
4
ALLHAT
2
0
1
3
TNT
1
2
1
4
Melanie S Joy ,2008
4D
1
2
0
2
0
1
1
5
Stegmayr2005
1
0
1
2
LIPS
0
2
1
3
Vincenzo Panichi,2005
1
2
0
3
38
Dornbrook,2005
Anil Verma,2005
1
1
0
0
1
1
2
2
UK-HARP-I,2005
1
0
1
2
Verglione2004
0
0
1
1
Lins2004
1
1
1
3
CARE
2
2
1
5
MRC/BHF-HPS
1
2
1
4
Saltissi 2002
1
1
1
3
PERFECT 1997
1
0
1
2
Rayner 1996
0
0
1
1
Supplementary material Table S1 :
JADAD SCALE of individual trial
39
Study with
cardiovascular
event
ATTEMP
SHARP
Air Force/Texas
JUPITER
LORD
PANDA
MEGA
Drug
Intevention
Experiment
atodvastatin
simvastatin
+ ezetimibe
lovastatin
rosuvastatin
atodvastatin
atorvastatin
pravastatin
Endpoint
Control
LDL-C target
<100mg/dl
LDL-C target
<130mg/dl
20mg/d+10mg/d
matching
placebo
20mg
20mg/d
matching
matching
placebo
placebo
20mg/d
placebo
10mg/d
placebo
80mg/d
10mg/d
10-20mg/d
Diet therapy
unstable angina (UA), myocardial
infarction MI), percutaneous coronary
intervention (PCI) or coronary artery
bypass drafting (CABG), stroke,
transient
ischemic attack (TIA), and CVD death
major atherosclerotic events(non-fatal
myocardial infarction or coronary
death, non-haemorrhagic stroke, or
any
arterial revascularisation procedure)
Fatal and non-fatal cardiovascular
events(myocardial
infarction, coronary death, coronary
revascularization)
nonfatal
myocardial infarction, nonfatal stroke,
hospitalization
for
unstable
angiography, arterial revascularization
procedure, or confirmed death from
cardiovascular causes
Acute myocardial infarction, stroke,
transient ischemic attack, angiography
and /or vascular intervention
non-fatal AI ,acute coronary sydrome
Coronary heart disease, stroke
40
AURORA
rosuvastatin
10 mg/d
matching
placebo
CARDS
atorvastatin
10 mg/d
placebo
ALLIANCE
atodvastatin
10-80mg/d
usual
care(statin
included)
4S-60
simvastatin
20 - 40mg
matching
placebo
TNT
Atorvastatin
80mg/d
10mg/d
Melanie S
Joy ,2008
atorvastin
10-20mg
no
treatment
4D
atorvastatin
20 mg /d
matching
placebo
major cardiovascular event(non-fatal
MI , stroke , death from cardiovascular
causes)
acute coronary heart disease event
(myocardial infarction including silent
infarction, unstable angina,
acute coronary heart disease death,
resuscitated cardiac arrest),coronary
revascularization
procedures,
or
stroke.
cardiac
death,
nonfatal
MI,
resuscitated cardiac arrest, cardiac
revascularization, and unstable angina
requiring hospitalization
major coronary events( coronary
deaths,
definite
or
probable
hospital-verified nonfatal acute MI,
resuscitated cardiac arrest, and
definite silent MI verified by using
electrocardiogram. )
death from
CHD, nonfatal non–procedure-related
myocardial infarction, resuscitation
after cardiac arrest, or fatal or
nonfatal stroke
non-Q MI
a composite of death from cardiac
causes, nonfatal myocardial infarction,
intervention to treat coronary heart
disease(PTCA ,CABG etc.)
41
Death due to heart disease, non-fatal
MI,PTCA or CABG, stroke,death for
acute MI, congestive heart failure or
other
cardiac
death,
cerebral
infarction or bleeding
Adverse
corory
atherosclerotic
events(Cardiac
death,
nonfatal
myocardial
infarction,
and
re-interventions not related to
restenosis）
nonfatal myocardial infarction or
myocardial ischemia, heart failure,
peripheral vascular disease, and/or
cerebrovascular accident.
Stegmayr2005
atorvastatin
10 mg/d
placebo
LIPS
fluvastatin
40mg twice per
day
placebo
PREVEND IT
pravastatin
40 mg
placebo
Verglione2004
atorvastatin
10 mg/d
placebo
Fatal and non-fatal
infarction, stroke
Tonelli2004(PPP)
______
_______
_______
Cardiovascular events*
myocardial
CARE
pravastatin
40mg /d
placebo
Major coronary event(fatal coronary
disease,
nonfatal
myocardial
infarction, coronary artery bypass
surgery, or coronary angioplasty)
MRC/BHF-HPS
simvastatin
40 mg/d
matching
placebo
major vascular event(major coronary
event, stroke or revascularization )
Saltissi 2002
simvastatin
5mg/d
placebo
cardiovascular adverse event
Rayner 1996
simvastatin
10-40mg/d
fatal and non-fatal MI
*reported on a previous meta- analysis1
Supplementary material Table S2 : Cardiovascular event defined by each trial
42
CKD
stage
Statin Placebo
Experiment Control
No. of
No. of
CVE
CVE
patients patients
ARR(95%CI)
NNT(95%CI)
CKD
stage 5
4283
4237
933
1015
0.022(0.004-0.040)
46(25-257)
CKD
stage 4
1263
1335
134
179
0.028(0.003-0.053)
36(19-330)
CKD
stage3,2
6194
6211
504
764
0.042(0.031-0.052)
24(19-32)
Supplementary material Table S3.1 Absolute risk reduction (ARR) and number needed to treat (NNT)of statin in patients with chronic kidney
disease
Model 1, Equal weight to each trials, NNT=1/ (CER-EER), CER=control event/control total, EER=experiment event/experiment total,
43
CKD
stage
CKD
stage 5
CKD
stage 4
CKD
stage3,2
Statin Placebo
Experiment Control
No. of
No. of
CVE
CVE
patients patients
ARR(95%CI)
NNT(95%CI)
4283
4237
933
1015
0.038(0.023-0.063)
26(16-43)
1263
1335
134
179
0.083(0.008-1.000)
12(1-125)
6194
6211
504
764
0.050(0.038-0.059)
20(17-26)
Supplementary material Table S3.2 Absolute risk reduction (ARR) and number needed to treat (NNT)of statin in patients with chronic kidney
disease
Model 2, Random effect to perform a meta-analysis of ARR and then calculate NNT value.
44
CKD
stage
Incidence of
Statin Placebo
Experiment Control
CVE in
No. of
No. of
CVE
CVE
CKD(100-person
patients patients
year)
ARR(95%CI)
NNT(95%CI)
CKD
stage 5
4283
4237
933
1015
36.60
0.029(0.004-0.051)
34(20-273)
CKD
stage 4
1263
1335
134
179
21.80
0.048(0.009-0.081)
21(12-115)
CKD
stage3,2
6194
6211
504
764
11.29
0.035(0.026-0.042)
29(24-39)
Supplental TableS 3.3 Absolute risk reduction(ARR) and number needed to treat (NNT)of statin in patients with chronic kidney disease
Model 3 , a pooled RR(transform) from meta-analysis was used to calculate NNT as describes as (RR-1)/RR= incidence of CVE in CKD/NNT, and the
incidence of CVE in CKD was from a previous report2. CVE, cardiovascular event
45
Search strategy
Medline
1
2
3
4
exp kidney disease
chronic kidney disease.tw.
exp Renal Dialysis/
(hemodialysis or hemodialysis).tw.
5
dialysis.tw.
6
(PD or CAPD or CCPD).tw.
7
or/1-6
8
9
exp hyperlipidemia/
hyperlipid?emia.tw.
10
dyslipid?emia.tw
11
dislipid?emia.tw.
12
13
hypercholesterol?emia.tw.
(LDL or HDL).tw
14
15
exp cardiovascular disease
exp myocardial infarction
16
exp stroke
17
exp heart failure
18
19
or/8-17
exp Hydroxymethylglutaryl-CoA Reductase
Inhibitors
"hydroxymethylglutaryl-CoA reductase
inhibitor$".tw.
20
21
"HMG CoA reductase inhibitor$".tw.
22
statin$.tw.
(fluvastatin$ or simvastatin$ or pravastatin$ or
lovastatin$ or lovastatin$ or meglutol or
cerivastatin$ or atorvastatin$ or mevastatin$ or
pitavastatin$ or rosuvastatin$ or ezetimibe).tw.
23
24
25
(cholesterol lowering or lipid lowering).tw.
or/19-23
exp Clinical Trial
26
exp Random Allocation
27
exp Single Blind Method
28
exp Double Blind Method
29
30
(random$ adj5 trial$).tw.
(random$ adj5 allocation$).tw.
31
(Blind$ adj5 method$).tw.
32
or/25-31
33
7 and 18 and 24 and 32
46
Embase
1
2
kidney disease
(chronic kidney disease)
3
(hemodialysis or hemodialysis)
4
dialysis
Re
5 renal dysfunction
6 renal impairment
7
8
9
10
11
12
13
14
15
16
17
18
renal insufficient
kidney failure
peritoneal dialysis
or/1-9
hyperlipidaemia or hyperlipidemia
dyslipidaemia or dyslipidemia
dislipidemia or dislipidaemia
hypercholesterolemia or hypercholesterolaemia
19
20
21
Or/16-18
clinical and trial or 'clinical trial'
controlled and clinical and trial or' controlled clinical trial'
randomised and controlled and trial or 'randomised clinical
trial '
22
23
24
25
26
27
or/11-14
hydroxymethylglutaryl coenzyme a reductase inhibitor
statin or statins
(fluvastatin or simvastatin or pravastatin or lovastatin or
lovastatin or meglutol or cerivastatin or atorvastatin or
mevastatin or pitavastatin or rosuvastatin or ezetimibe)
random and allocation
single blind and method
double blind and method
or/20-25
10 and 15 and 19 and 26
47
CENTRAL
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
kidney disease explode all trees
RENAL DIALYSIS explode all trees\
(hemodialysis or hemodialysis)
dialysis
(pd or capd or ccpd)
(#1 or #2 or #3 or #4or#5 )
HYPERLIPIDEMIA explode all trees
hyperlipidaemia or hyperlipidemia
dyslipidaemia or dyslipidemia
dislipidaemia or dislipidaemia
hypercholesterolemia or hypercholesterolaemia
(#7 or #8 or # 9 or #10 or #11 )
HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS explode all
trees
(hydroxymethylglutaryl-coa next reductase next inhibitors)
(((hmg next coa) or hmg-coa or (hmg next co-a)) and (reductase next
inhibitor*))
((cholesterol next lowering) or (lipid next lowering))
statin*
fluvastatin
simvastatin
pravastatin
lovastatin
meglutol
cerivastatin
atorvastatin
ezetimibe
（ #13or#14or#15or#16or#17or#18or#19or#20or#21or#22or#23or#24
or#25）
（#6 and #12 and #26）
Reference
1. Strippoli GF, Navaneethan SD, Johnson DW, Perkovic V, Pellegrini F, Nicolucci A, Craig JC. Effects of statins in
patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials. BMJ
2008;336(7645):645-51.
2. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular
events, and hospitalization. N Engl J Med 2004;351(13):1296-305.
48