CLINICAL RESEARCH

European Heart Journal (2013) 34, 18071817

doi:10.1093/eurheartj/eht065

Prevention and epidemiology

Effect of statin therapy on cardiovascular and

renal outcomes in patients with chronic kidney
disease: a systematic review and meta-analysis
Wanyin Hou 1, Jicheng Lv1*, Vlado Perkovic 2, Lihong Yang 3, Na Zhao1, Meg J. Jardine 2,
Alan Cass 2, Hong Zhang 1, and Haiyan Wang 1
1

Received 27 August 2012; revised 17 December 2012; accepted 5 February 2013; online publish-ahead-of-print 6 March 2013

See page 1772 for the editorial comment on this article (doi:10.1093/eurheartj/eht136)

Aims

The effects of statin therapy in patients with chronic kidney disease (CKD) remain uncertain. We undertook a systematic review and meta-analysis to investigate the effects of statin on major clinical outcomes.
.....................................................................................................................................................................................
Methods
We systematically searched MEDLINE, Embase, and the Cochrane Library for trials published between 1970 and
and results
November 2011. We included prospective, randomized, controlled trials assessing the effects of statins on cardiovascular outcomes in people with kidney disease. Summary estimates of relative risk (RR) reductions were calculated
with a random effects model. Thirty-one trials that include at least one event were identified, providing data for
48 429 patients with CKD, including 6690 major cardiovascular events and 6653 deaths. Statin therapy produced
a 23% RR reduction (16 30) for major cardiovascular events (P,0.001), an 18% RR reduction (827) for coronary
events, and 9% (1 16) reduction in cardiovascular or all-cause deaths, but had no significantly effect on stroke (21%,
12 to 44) or no clear effect on kidney failure events (5%, 21 to 10). Adverse events were not significantly increased
by statins, including hepatic (RR 1.13, 95% CI 0.921.39) or muscular disorders (RR 1.02, 95% CI 0.95 1.09). Subgroup analysis demonstrated the relative effects of statin therapy in CKD were significantly reduced in people with
advanced CKD (P , 0.001) but that the absolute risk reductions were comparable.
.....................................................................................................................................................................................
Conclusion
Statin therapy reduces the risk of major cardiovascular events in patients with chronic kidney disease including those
receiving dialysis.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Cardiovascular events Statin Chronic kidney disease Meta-analysis

Introduction
Chronic kidney disease (CKD) is a major public health problem.1
Cardiovascular disease (CVD) continues to be the leading cause
of morbidity and mortality among people with CKD worldwide,
with rates of cardiovascular events and mortality consistently
increasing as kidney function declines.2,3 Dialysis patients have
mortality rates up to 40-fold higher than the general population,
with CVD being responsible for up to 50% of these deaths.4
Patients with CKD have higher prevalence of a number of risk
factors for CVD, including lipid abnormalities, hypertension,
obesity, and diabetes.

Kidney Disease Outcome Quality Initiative (K/DOQI) clinical

practice guidelines have recommended statin therapy for the prevention of CVD in patients with CKD and high-LDL cholesterol
(LDL-C) levels.5 However, the value of this approach continues
to be debated, particularly in those with the most advanced
kidney dysfunction. Levels of cholesterol in patients with kidney
disease do not always have the same log-linear relationship with
cardiovascular events observed in the general population.6
Indeed, a U-shaped or inverse relationship has been described
in cohort studies of dialysis patients where people with the
lowest levels of LDL-C have the worst outcomes. The burden of
CVD may not be predominantly due to atherosclerotic disease

* Corresponding author. Tel: +86 10 83572388, Fax: +86 10 66551055, Email: jichenglv75@gmail.com
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 10, 2015

Renal Division, Peking University First Hospital, Institute of Nephrology, Peking University and Key Laboratory of Renal Disease, Ministry of Health of China, No. 8, Xishiku Street,
Xicheng District, Beijing, China; 2The George Institute for Global Health, University of Sydney, New South Wales, Australia; and 3Guangdong Provincial Hospital of Chinese
Medicine, Guangzhou, Guangdong, China

1808

Methods
Data sources, search strategy, and selection
criteria
We performed a systematic review of the published literature
according to the approach recommended by the statement for the
conduct of meta-analyses of intervention studies. We included data
from randomized, controlled trials in which statin was given for at
least 6 months to patients with CKD. These data were extracted
either from studies conducted solely in people with kidney disease,
or from subsets of other trials where data on the CKD population
could be obtained.
Relevant studies were identified by searching the following data
sources: MEDLINE via Ovid (from 1950 to November 2011),
Embase (from 1966 to November 2011), and the Cochrane Library
database (Cochrane Central Register of Controlled Trials; no date restriction), with relevant text words and medical subject headings that
included all spellings of kidney disease, dyslipidemia, hypercholesterolemia, cardiovascular disease, myocardial infarction, revascularisation, stroke, simvastatin, atorvastatin, rosuvastatin, pravasatin
(see Supplementary material online). Trials were considered without
language restriction. Reference lists from identified trials and review
articles were manually scanned to identify any other relevant studies.
The ClinicalTrials.gov website was also searched for randomized
trials that were registered as completed but not yet published.
The literature search, data extraction, and quality assessment were
undertaken independently by two authors (W.H. and L.Y.) using a standardized approach. All completed randomized, controlled trials assessing the effects of statin compared with placebo and/or compared with
conventional therapy in CKD, and that reported one or more of the
primary or secondary outcomes, were eligible for inclusion. Trials
that recruited patients with kidney transplants were not included in
this study.

baseline patient characteristics (age, sex, history of diabetes, history of

CVD, mean systolic and diastolic blood pressure values, lipid concentrations), statin used, dose of drug, follow-up duration, change in
LDL-C concentrations, outcome events, and adverse events. Study
quality was judged by the proper conduct of randomization, concealment of treatment allocation, similarity of treatment groups at baseline,
the provision of a description of the eligibility criteria, completeness of
follow-up, and the use of an intention-to-treat analysis, and was quantified with the Jadad scale.13 Any disagreement in the abstracted data
was adjudicated by a third reviewer (J.L.).
We collected data for major cardiovascular events (defined as a
composite including fatal or non-fatal myocardial infarction, fatal or
non-fatal stroke, revascularization procedures, cardiovascular death,
and heart failure, or comparable definitions used by individual
authors), cardiovascular mortality, all-cause death, new onset cancer,
and other drug-related adverse events. We listed all cardiovascular
events for each included studies in Supplementary material online,
Table S2. Trials that compare high- vs. low-dose statin therapy met
the inclusion criteria but in a separate analysis. Kidney failure events
were defined as a 25% decrease in the estimated GFR, doubling of
serum creatinine, or end stage renal disease (ESRD) as defined by
the authors of each study.
When required quantitative data were not provided in the relevant
article from the text, we use the g3 data software (http://www.frantz.fi/
software/g3data.php) to extract exact numbers from published figures.

Statistical analysis
Individual patient data were not available from the studies in this analysis, so tabular data were used. Individual study relative risks (RRs) and
95% CIs were calculated from event numbers and total population at
risk extracted from each trial, using a standard method14 before data
pooling. In the calculation of risk ratios, the total number of patients
randomly assigned in each group was used as the denominator.
Summary estimates of risk ratios were obtained with a random

Data extraction, quality assessment,

and outcome estimation
Published reports were obtained for each eligible trial, and relevant information was extracted into a spreadsheet. The data sought included

Figure 1 Identification process for eligible studies.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 10, 2015

in people with severely decreased GFR when compared with

people with normal renal function. Emerging data suggest the
pattern of cardiovascular pathology may be different in advanced
CKD, with vascular stiffness and calcification, structural heart
disease, and sympathetic overactivity contributing to an increasing
risk of cardiac arrhythmia and heart failure.7 Thus, the effect of
statin therapy may be less compared with the general population.
In the past few years, several large-scale trials of statin therapy in
people with CKD have been completed, including the recent
large SHARP (Study of Heart and Renal Protection) trial.8
Although some of these trials have shown benefit,8 others
have shown no effect,9,10 leading to uncertainty about the presence and magnitude of cardiovascular protective effects and therefore difficulties for clinicians in the interpretation of the results.
Two recent overviews have investigated the effect of statin in
patients with CKD. However, both have not evaluated the effect
of kidney function on the statin therapy.11,12 In this systematic
review, we sought to synthesize all the available clinical trial data
and define better the balance of risks and benefits of statin in patients
with CKD and also the effect of kidney function on statin use.

W. Hou et al.

Study

Year

Inclusion criteria

Definition of CKD

Duration
of time,
year

Treatment group

Control group

Mean
age,
years

Baseline

...........................

LDL- C,
mmol/L

eGFR,
mL/min/
1.73 m2

Number
of
patients

History
of CVD
(%)

.............................................................................................................................................................................................................................................
Han, 2011

2011

PD . 3 months

Dialysis

0.5

Rosuvastatin 10 mg/
day + ARB 80 mg/day

Placebo + ARB
80 mg/day

49

4.83

ATTEMP

2011

CKD stage 3 patients with

metabolic syndrome, no
CVD or DM

3.5

Atorvastatin LDL-C
target on 100 mg/L

Atorvastatin
LDL-C target
on 130 mg/dL

57

4.37

SHARP

2011

History of CKD, age . 40, Scr:

men .150 mmol/L, women
.130 mmol/L

Simvastatin + ezetimibe

Placebo

62

Air Force/
Texas
JUPITER

2009

5.2

Lovastatin

Placebo

1.9

Rosuvastatin

LORD

2008

Hyperlipidaemia, no CVD or
DM
No history of CVD,
LDL-C , 130 mg/dL
History of CKD,
Scr . 120 mmol/L

CKD stage 3,
eGFR 30
59 mL/min/
1.73 m2
Increased Scr: men
.150 mmol/L,
women
.130 mmol/L
eGFR , 60 mL/min/
1.73 m2
eGFR , 60 mL/min/
1.73 m2
Increased Scr
120 mmol/L

2.5

PANDA

2010

Type 2 DM

Urinary albumin
creatinine . 5 mg
/mmol

MEGA

2009

No history of CHD and/or

stroke

AURORA

2009

CARDS

2009

ALLIANCE

47.60

349

2.70

26.60

9438

15

62

3.90

53.00

304

Placebo

70

2.82

56.00

3267

Atorvastatin

Placebo

60

3.22

31.90

123

17

2.1

Atorvastatin

Atorvastatin

64

3.06

71.70

119

28

eGFR , 60 mL/
min/1.73 m2

5.3

Pravastatin

Diet therapy

NA

4.00

52.60

2978

ESRD patients, regular

haemodialysis for at least 3
months
Type 2 DM or with risk factors
such as hypertension,
proteinuria, no CVD history

Dialysis

3.2

Rosuvastatin

Placebo

64

2.59

2776

40

eGFR , 60 mL/min/
1.73 m2

3.9

Atorvastatin

Placebo

65

3.10

53.30

970

2009

With known CHD patients

eGFR , 60 mL/min/
1.73 m2

4.53

Atordvastatin

Usual care
(atorvastatin
will not be
excluded from
the usual-care
group)

66

3.83

51.30

579

100

4S

2008

With a history of MI and/or

stable angina

eGFR , 60 mL/min/
1.73 m2

5.5

Simvastatin

Placebo

63

4.97

54.80

409

100

ALLHAT

2008

Stage 1 or 2 hypertension with

at least one additional CHD
risk factor

eGFR , 60 mL/min/
1.73 m2

4.8

Pravastatin

Usual care

71

3.79

50.80

1557

18

NA

Continued

1809

124

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 10, 2015

2010

NA

Effects of statin therapy in patients with CKD

Table 1 Characteristics of studies reporting the effects of statin in patients with chronic kidney disease

1810

Table 1 Continued
Study

Year

Inclusion criteria

Definition of CKD

Duration
of time,
year

Treatment group

Control group

Mean
age,
years

Baseline

...........................

LDL- C,
mmol/L

eGFR,
mL/min/
1.73 m2

Number
of
patients

History
of CVD
(%)

.............................................................................................................................................................................................................................................
TNT

2008

With clinically evident CHD

Melanie
S. Joy,
2008

2008

Hyperlipidaemia and CKD

patients

4D

2005

Stegmayr,
2005

2005

LIPS

2004

Type 2 DM receiving
maintenance haemodialysis
for ,2 years
GFR , 30 measured by
clearance of either
creatinine, Cr51-EDTA, or
iohexol.
Successfully undergone their
first PCI, mild renal
impairment

Vincenzo
Panichi,
2005
Dornbrook,
2005

2005

Verma, 2005

2005

2005

eGFR , 60 mL/min/
1.73 m2
Dialysis

Atorvastatin 80 mg/day

0.69

Dialysis

66

2.49

Atorvastatin

Atodvastatin
10 mg/day
No treatment

65

2.92

Atorvastatin

Matching placebo

66

eGFR , 30 mL/min/
1.73 m2

2.58

Atorvastatin

Placebo

Renal impairment,
creatinine
clearance
, 55.9 mL/min

3.8

Fluvastatin

CRF with
hypercholesterolaemia
(LDL-C . 100 mg/dL)
Hyperlipidaemia and
undergoing long-term
dialysis

Mean creatinine
clearance 45 mL/
min
Dialysis

0.5

GFR , 60; no clinical evidence

of acute renal failure

53.00

3107

100

NA

45

51

3.23

NA

1255

29

68

3.56

NA

143

37

Placebo

69

3.39

NA

310

100

Simvastatin

Placebo

58

3.59

55

NA

1.67

Atorvastatin

No treatment

66

3.05

19

NA

eGFR , 60 mL/min/
1.73 m2

0.38

Rosuvastatin

No treatment

73

3.62

91

45.00

NA

42.30

2005

Scr 150 mmol/L

Scr 150 mmol/L

Simvastatin

Placebo

54

3.21

NA

448

2004

No antihypertension therapy
and Tchol , 8 mmol/L or
Tchol , 5 previous MI

Microalbuminuria
with 15300 mg/
24 h

3.83

Pravastatin

Placebo

52

4.10

NA

864

Verglione,
2004

2004

C-reactive protein 3 mg/L;

undergo HD treatment for
at least 6 months

Dialysis

0.5

Atorvastatin

Placebo

65

NA

NA

33

NA

Tonelli, 2004
(PPP)

2004

CKD subgroup of trials in

WOSCOPS, LIPID, CARE

eGFR , 60 mL/min/
1.73 m2

Pravastatin

Placebo

NA

NA

NA

16 824

NA

Lins, 2004

2004

CRF treated with

haemodialysis . 3months
and hyperlipidaemia

Dialysis

0.23

Atordvastatin

Placebo

64

3.39

NA

42

NA

CARE

2003

GFR , 60, with AMI and

hyperlipidaemia

eGFR , 60 mL/min/
1.73 m2

Pravastatin

Placebo

63

3.61

690

11

53.20

W. Hou et al.

UK-HARP-I
PREVEND IT

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 10, 2015

1811

1996
Rayner, 1996

CKD, chronic kidney disease; CVD, cardiovascular event; MI, myocardial infarction; AMI, acute myocardial infarction; CHD, coronary heart disease; CRF, chronic renal failure; DM, diabetes mellitus; PD, peritoneal dialysis; HD, haematodialysis
dialysis; CAPD, continuous ambulatory peritoneal dialysis; IMN, idiopathic membranous nephropathy; Scr, serum creatinine; ESRD, end stage renal disease.

12
17
84.30
8.00
42
Low cholesterol
diet or
diet alone
Simvastatin
1.61
IMN patients with
Scr , 150 mmol/
L, urine
protein 3.5 g/
24 h

NA

NA
107

57
NA

NA
4.10

NA
59

NA
Placebo

Placebo + diet

Simvastatin

Simvastatin + diet
0.5

0.5
Dialysis
1997
PERFECT

HD or CAPD patients
2002
Saltissi, 2002

Age 1875 receiving

haemodialysis or CAPD, no
cardiovascular history
IMN patients with an
Scr , 150 mmol/L, urine
protein 3.5/24 h,
cholesterol . 6.1 mmol/L
were eligible the trial

NA
Placebo
4.8

Scr . 110 mmol/L

for women,
.130 mol/L for
men, but
, 200 mmol/L for
both
Dialysis
Without CVD in previous 6
months
2003
MRC/
BHF-HPS

effects model. The percentage of variability across studies attributable

to heterogeneity beyond chance was estimated with the I2 statistic. For
each trial, we calculated not only the average risk reduction, but also
the average risk reduction per 1.0 mmol/L LDL-C reduction at the
end of each trial where data were available (1 divided by the observed
LDL reduction, for example, if the RR was 0.7 and the reduction in
systolic blood pressure was 0.8 mmol/L, the standardized RR estimate
was 0.71/0.8.15
Potential publication bias was assessed with the Egger test and
represented graphically with Begg funnel plots of the natural log of
the RR vs. its standard error.
We explored potential heterogeneity in the estimates of treatment
effect with univariate meta-regression (for end-of-trial parameters
such as achieved LDL-C concentrations) and by comparing summary
results obtained from the subsets of studies grouped by number of
patients, number of mortality events, publication year, statin used,
diabetic status, stage of CKD, baseline morbidity, and study quality.
A two-sided P-value ,0.05 was regarded as significant for all analyses.
All statistical analyses were done with STATA (version 12.0).

Results
The literature search yielded 2310 articles, of which 134 were
reviewed in full text (Figure 1). Of these, 31 randomized, controlled
trials met the inclusion criteria. These trials included a total of
48 429 patients with CKD, in whom 6690 major cardiovascular
events were reported from 22 studies, and 6653 deaths from
23 studies. Study follow-up duration ranged from 6 months to 4.9
years. Thirteen trials were placebo-controlled and 18 trials used
open-label designs. Ten trials reported post hoc analyses of the subgroup with CKD, four compared intensive lipid-lowering therapy to
conventional or low-dose therapy. Formal statistical testing
suggested the possibility of publication bias for the outcome of
major cardiovascular outcomes with a borderline Egger test result
(P 0.062, see Supplementary material online, Figure S1).
Table 1 summarizes the characteristics of the included studies.
Ten trials with 4503 participants were exclusively undertaken in
dialysis patients,9,10,16 18 18 trials (n 33 252) were in non-dialysis
patients, and another 3 trials (n 10 029) had a mixed population
that included both dialysis and non-dialysis patients. Baseline estimated GFR levels for the participants in the trials were reported
in the published paper or could be calculated or estimated from
the inclusion criteria (Figure 2). Two trials were undertaken in
people with diabetes and CKD.
The mean age of the study participants ranged between 42
and 73 years. Included studies were undertaken in Europe,
North America, and in some part of Asia and Africa. The agents
used in the studies varied: 12 studies assessed the effects of atorvastatin, 8 assessed simvastatin, 5 assessed pravastatin, 4 assessed
rosuvastatin, where 1 assessed fluvastatin and 1 lovastatin.
We also recorded key indicators of trial quality, in particular the
process of randomization, concealment of allocation, and the use
of intention-to-treat analysis techniques, blinding, withdraws and
dropouts (see Supplementary material online, Table S1). Overall,
13 trials had a Jadad scale of 4, others scored 3.
Data regarding the effects of statin on major cardiovascular
events were available from 22 trials, including 44 096 participants
and 6695 events. Overall, statin therapy produced a 23% reduction

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 10, 2015

Simvastatin

NA

NA

1329

NA

Effects of statin therapy in patients with CKD

1812

kidney disease (CKD) 2 stage with few endpoints (4 cardiovascular events and 105 patients), and we combined chronic kidney disease stage 3 and chronic kidney disease stage 2 into one subgroup.

W. Hou et al.

Figure 2 Summary of the effects of statin therapy on major cardiovascular events stratified by kidney function. Only one trial and one subgroup (SHARP .60 and Rayner, 1996) were in chronic

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 10, 2015

1813

Effects of statin therapy in patients with CKD

Table 2

Absolute risk reduction and number needed to treat of statin in patients with chronic kidney disease

CKD stagea

Statin, number
of patients

Placebo, number Experiment

of patients
CVE

Control
CVE

ARR (95% CI) (per study NNT (95% CI) (per study
duration on average)
duration on average)

4283

4237

933

1015

0.022 (0.004 0.040)

46 (25257)

CKD stage 4
1263
CKD stages 3, 2 6194

1335
6211

134
504

179
764

0.028 (0.003 0.053)

0.042 (0.031 0.052)

36 (19330)
24 (1932)

...............................................................................................................................................................................
CKD stage 5

CVE, cardiovascular event.

a
CKD stage 5: estimated GFR (eGFR) ,15 mL/min/1.73 m2; CKD stage 4: eGFR 15 30 mL/min/1.73 m2; CKD stage 3: eGFR 30 60 mL/min/1.73 m2; CKD stage 2: eGFR
60 90 mL/min/1.73 m2.

in the risk of cardiovascular events (RR 0.77, 95% CI 0.700.85,

P,0.001) (Figure 2A) or an 18% per 1 mmol/L LDL (RR 0.82,
95% CI 0.74 0.91, P,0.001, see Supplementary material online,
Figure S2) with evidence of heterogeneity in the results of individual
trials. Subgroup analysis showed that statin effect was significantly
modified by kidney function (Figure 2B). Four trials with 4154 participants that compared more vs. less intensive statin regimens
showed that intensive statin therapy reduced cardiovascular
events by 28% in people with CKD (see Supplementary material
online, Figure S3).
Data for coronary events were available from 15 trials8 10,19 29
including 26 262 patients in whom 2516 events were recorded.
Statin therapy reduced the risk of coronary events by 22%
(RR 0.78, 95% CI 0.69 0.88) without evidence of heterogeneity
(I 2 29.6%, P 0.134) (Figure 3). Eight trials reported stroke,

including 21 505 and 647 events. Overall, there was no effect of

statin therapy on the risk of stroke (RR 0.79, 95% CI 0.561.12)
with evidence of heterogeneity between trials (P-value for heterogeneity 0.001).
Cardiovascular death was reported in 11 trials including 31 859
patients among whom 2123 events were observed. Nineteen trials
reported all-cause death, including 39 722 patients and 6653
events. Statin therapy reduced all-cause death (RR 0.92, 95% CI
0.85 0.99) and also cardiovascular death (RR 0.91, 95% CI
0.84 0.99) without clear evidence of heterogeneity (Figure 3).
Kidney failure events defined as a 25% decrease in the estimated
GFR, doubling of serum creatinine, or ESRD were reported in six
trials8,20,23,26,30,31 including 11 924 participants and 2824 events.
There was no clear evidence that statins reduced the risk of
kidney failure (RR 0.95, 95% CI 0.901.01) (Figure 3).

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 10, 2015

Figure 3 Summary of the relative risks of all outcomes. aKidney failure events defined as a 25% decrease in the estimated GFR, doubling of
serum creatinine, or ESRD.

1814

W. Hou et al.

The heterogeneity in the effect across the included studies was

assessed by subgroup analysis and meta-regression. This revealed
that the effect of statin therapy on major cardiovascular events
was modified by the average baseline kidney function of the participants in the included trials (P-value for heterogeneity , 0.001),
with a progressively smaller relative risk reduction (RRR) with a
lower estimated GFR. The RRR for cardiovascular event in
trials with CKD stage 5 including patients with dialysis (8
trials8 10,27,29,32 with 7987 participants) was 8% (95% CI 114,
I 2 0%) and 22% (95% CI 437, I 2 0%) in stage 4 (2 trials or
subgroups,8,27 2598 patients) and 31% (95% CI 437, I 2 0%)
in stage 3 or 2 (11 trials or subgroups with 12 330 participants).
Only two small trials or subgroups included 107 participants
with CKD stage 2, so meta-analysis was not separately done in
this group. The benefits of statin in patients not on dialysis (RR
0.70, 95% CI 0.630.88) was larger (P-value for heterogeneity ,
0.001) than those in patients on dialysis (RR 0.92, 95% CI 0.85
0.99). Adjusting the risk ratio for cardiovascular events by weighted
average LDL-C reduction did not substantially modify these
findings. Reductions in the risk of cardiovascular events per
1 mmol/L LDL-C reduction at the end of each trial were 27%
(RR 0.73, 95% CI 0.650.83, P , 0.001) in patients with CKD

not requiring dialysis compared with 10% (RR 0.90, 95% CI

0.830.97, P 0.01) in patients requiring dialysis (P-value for heterogeneity 0.007) (see Supplementary material online, Figure
S2). Similar findings were observed for coronary events (RR
0.69, 95% CI 0.580.83 in the non-dialysis population and RR
0.91, 95% CI 0.811.02 in the dialysis population, P-value for
heterogeneity 0.042) and stroke (RR 0.61, 95% CI 0.390.95
in non-dialysis patients and RR 1.16, 95% CI 0.91 1.47 in dialysis
patients, P-value for heterogeneity 0.001) (Figure 3).
As the risk of CVD increased as the kidney function deteriorated, but with the risk ratio lower, we calculated the absolute
risk reduction among patients with different CKD stages
[Table 2; we also provide three models for the number needed
to treat (NNT), see Supplementary material online, Tables S3.1
3.3]. The NNT to reduce one major cardiovascular event was
46 in CKD stage 5 (25 257), 36 in CKD stage 4 (19 330), and
24 in CKD stages 23 (19 32).
Subgroup analysis was done for major cardiovascular events
according to other baseline characteristics (Figure 4). The effect
sizes were greater in trials that recorded a higher mean baseline
LDL-C concentration (P-value for heterogeneity 0.012). On
univariate meta-regression, there was a trend for statin therapy

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 10, 2015

Figure 4 Subgroup analyses for the effects of statin on major cardiovascular events. aTrials that recruited only patients with chronic kidney
disease. bTrials that were conducted in the general population where subgroups of patients with kidney disease were available.

Effects of statin therapy in patients with CKD

to produce the greatest benefit when LDL-C concentrations were

improved most (Figure 5, P 0.062) in non-dialysis patients. In
contrast, no clear relationship between LDL-C reduction and
cardiovascular benefit was observed in patients receiving dialysis.
Key adverse outcomes were reported by few trials. For hepatic
impairment6,8,9,25,26,32,33 (RR 1.13, 95% CI 0.921.39), muscle
pain6,26 28,34 36 (RR 1.02, 95% CI 0.951.09), increased creatinine
kinase level6,8,16,22,24,26,28,30,31,37,38 (RR 1.18, 95% CI 0.891.55),
cancer morbidity6,8,24,39 (RR 0.95, 95% CI 0.871.05), and severe
adverse event8,9,25,26,30,32,36 (RR 0.95, 95% CI 0.891.03) in the
analysis (Figure 6), no significant difference in risk was observed
in the statin-treated participants.
The conclusions were not changed after adjustment for publication bias with the trim-and-fill method (data not shown).

Discussion
The management of lipids in people with CKD has been an area of
intense debate over recent years, particularly in those with more
advanced kidney dysfunction. This large quantitative review, including 31 trials with more than 48 000 individuals, suggests that
therapy with statin reduces the risk of cardiovascular events

across different levels of kidney function. Major cardiovascular

events are reduced by 23%, including a 22% reduction in coronary
events, and 9% reduction in cardiovascular or all-cause death. No
significant effect was observed on the risk of kidney failure, or on
the risk of adverse events including cancer mortality.
The most important new finding of this study is the clear result
that the effect of statin therapy is significantly modified by kidney
function. The observed beneficial effects appear to be smaller in
people with stage 5 kidney disease and those requiring dialysis.
Similar findings were observed for coronary heart disease and
stroke. Importantly, the absolute risk reductions and NNT were
only slightly less in people with advanced kidney disease, suggesting
that statin therapy still confers important benefits in these individuals. In this analysis, we did not find that the adverse events of
statin were increased in the patients with CKD, which suggested
the safety of using statin in this population. However, this is still
needed to be cautious given many trials included in this
meta-analysis are post hoc analysis, and adverse events are reported
by only a few trials. For the effect on stroke risk in patients with
dialysis, the risk ratio even goes in the opposite direction
(RR 1.16, 95% CI 0.901.47), and more data are still needed to
evaluate the safety of statin in dialysis patients.
The effects of LDL-lowering with statin therapy in patients
without CKD have been described by the Cholesterol Treatment
Trialists (CTT) Collaboration, and shown that statin therapy can
safely reduce the 5-year incidence of major coronary events, coronary revascularization, and stroke by about one-fifth per mmol/L
reduction in LDL-C.40 In this study, LDL-C-lowering with statin in
CKD could yield 18% reduction per 1.0 mmol/L reduction in major
cardiovascular events, which is close consistent with the effects
seen in the CTT study. Our study is also consistent with the
results from the SHARP study and supports statin use in patients
with CKD, including dialysis patients. However, SHARP did not
have sufficient power to assess the effects separately in dialysis
and non-dialysis patients. This large meta-analysis with more than
four times of participants strongly supports larger benefits in
patients with less severe renal impairment. Further support
comes from the meta-regression analysis that a linear association
trend exists in patients with non-dialysis although not obvious in
patients with dialysis.
The reason for the lesser RRR in patients with ESRD than those
achieved in patients with less severe kidney disease may reflect
differences in the distribution of CVD among these groups of
patients. Cardiovascular disease may have different aetiological
pathways in people with ESRD compared with those with better
renal function, and indeed may have a different pathophysiology.39,41,42 Cardiovascular risk factors specific to ESRD include
calcium and phosphorus dysregulation, anaemia, hyperhomocysteinaemia, increased levels of oxidant stress, and chronic inflammation.33,37 39,43 45 In addition, the burden of cardiovascular
dysfunction may be further accelerated by haemodynamic instability in dialysis patients. It is postulated that statins may not impact
the substantial proportion of cardiovascular events in ESRD populations resulting from non-ischaemic myocardial abnormalities, left
ventricular hypertrophy, and fluctuations in electrolytes and fluid
volumes.43 These may explain the more modest relative effect of
statins than that seen in an earlier stage of kidney disease.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 10, 2015

Figure 5 Univariate meta-regression exploring the role of

achieved lipid concentrations on the effectiveness of statin
therapy on cardiovascular events. Meta-regression of cardiovascular events and LDL cholesterol reduction difference between
statin and placebo or conventional therapy groups. Black circle
were trials exclusively in dialysis patients (PREVEND IT,
ATTEMP, Air Force, JUPITER, PANDER, ALLIANCE, LIPS,
Rayner 1996). White circle were trials exclusively in non-dialysis
patients(AURORA; 4D; Melanie S. Joy, 2008; Saltissi, 2002). Grey
Circles were trials of mixed population, respectively indicated
Stegmayr 2005 and SHARP. They were included in both non-dialysis and dialysis trials in the regression analysis. P-value for nondialysis patients 0.062, coefficient 20.503; P-value for dialysis patients 0.625, coefficient 20.234.

1815

1816

W. Hou et al.

Trials including individuals with high average baseline LDL-C

concentrations reported significantly greater proportional risk
reductions, a finding that accords with the results in the general
population. Importantly, we noted a significant relationship
between the magnitude of LDL-C-lowering achieved with
therapy and the reported risk reductions in patients with nondialysis patients, although this phenomenon was not observed in
patients with ESRD. This further supports the hypothesis that
the excess of cardiovascular events observed in people with
advanced kidney disease may not be atherosclerotic in nature,
and therefore not able to be reduced with statins.7 However, in
this analysis, given that the rates of cardiovascular events and mortality consistently increase as kidney function deteriorates, clinically
meaningful absolute risk reductions can still be achieved in patients
with severe kidney dysfunction. In the subgroup analysis, we also
noted significant heterogeneity between trials only involving
patients with kidney disease and trials in the general population
where the subgroup with CKD was available. This difference may
be due to different kidney functions among these trials. The
trials with CKD are mostly studies involving patients with dialysis,
whereas in the post hoc analysis, participants were mainly nondialysis patients.
This meta-analysis benefits from a large volume of data available,
and the resultant precision in the observed benefits across a broad
range of kidney function. Our study does, however, have limitations
mainly as a result of it being based on published data, which limits
the capacity to fully explore effects in subgroups. The different definitions used by the contributing trials cannot be fully integrated, and

the outcome definitions, in particular, required some grouping of

event types. Also in the meta-regression assessing kidney function
and the effect of statins, we were only able to use the mean baseline
GFR of the included trials rather than individual patient kidney
function.
In conclusion, this study has provided strong evidence that statin
therapy reduces the risk of major vascular events, as well as cardiovascular and all-cause death in patients with CKD, across a broad
range of kidney functions including patients with dialysis. Although
the relative vascular protection of statins is significantly modified
by kidney function, meaningful reductions in absolute risk would
be expected to be achieved in every stage of CKD. Additional
protective strategies are required to address the large excess of
cardiovascular events in the population with ESRD.

Supplementary material
Supplementary material is available at European Heart Journal
online.

Funding
This study was supported by grants from the Major State Basic
Research Development Program of China (973 program,
No. 2012CB517700), National Natural Science Foundation of China
(No. 81270795, 30825021), Natural Science Fund of China to the Innovation Research Group (81021004) and Program for New Century
Excellent Talents in University from the Ministry of Education of China
(NCET-12-0011).

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 10, 2015

Figure 6 Adverse events of statin reported in the trials with chronic kidney disease. Drug-related adverse events (hepatic disorder defined as
ALT or AST . normal 3 times; muscle pain; creatinine kinase . normal 3 times; cancer new onset; severe adverse event) were involved in
the meta-analysis.

Effects of statin therapy in patients with CKD

Conflict of interest: none declared.

References

21. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ,
Charlton-Menys V, DeMicco DA, Fuller JH. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the
Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis 2009;54:
810 819.
22. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study
of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005 2016.
23. Kendrick J, Shlipak MG, Targher G, Cook T, Lindenfeld J, Chonchol M. Effect of
lovastatin on primary prevention of cardiovascular events in mild CKD and
kidney function loss: a post hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study. Am J Kidney Dis 2010;55:42 49.
24. Lemos PA, Serruys PW, de Feyter P, Mercado NF, Goedhart D, Saia F,
Arampatzis CA, Soares PR, Ciccone M, Arquati M, Cortellaro M, Rutsch W,
Legrand V. Long-term fluvastatin reduces the hazardous effect of renal impairment on four-year atherosclerotic outcomes (a LIPS substudy). Am J Cardiol
2005;95:445 451.
25. Nakamura H, Mizuno K, Ohashi Y, Yoshida T, Hirao K, Uchida Y. Pravastatin and
cardiovascular risk in moderate chronic kidney disease. Atherosclerosis 2009;206:
512 517.
26. Ridker PM, MacFadyen J, Cressman M, Glynn RJ. Efficacy of rosuvastatin among
men and women with moderate chronic kidney disease and elevated highsensitivity C-reactive protein: a secondary analysis from the JUPITER (Justification
for the Use of Statins in Prevention-an Intervention Trial Evaluating Rosuvastatin)
trial. J Am Coll Cardiol 2010;55:1266 1273.
27. Stegmayr BG, Brannstrom M, Bucht S, Crougneau V, Dimeny E, Ekspong A,
Eriksson M, Granroth B, Grontoft KC, Hadimeri H, Holmberg B, Ingman B,
Isaksson B, Johansson G, Lindberger K, Lundberg L, Mikaelsson L, Olausson E,
Persson B, Stenlund H, Wikdahl AM. Low-dose atorvastatin in severe chronic
kidney disease patients: a randomized, controlled endpoint study. Scand J Urol
Nephrol 2005;39:489 497.
28. Tonelli M, Moye L, Sacks FM, Cole T, Curhan GC. Effect of pravastatin on loss of
renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 2003;14:1605 1613.
29. Vernaglione L, Cristofano C, Muscogiuri P, Chimienti S. Does atorvastatin influence serum C-reactive protein levels in patients on long-term hemodialysis? Am
J Kidney Dis 2004;43:471 478.
30. Fassett RG, Robertson IK, Ball MJ, Geraghty DP, Coombes JS. Effect of atorvastatin on kidney function in chronic kidney disease: a randomised double-blind
placebo-controlled trial. Atherosclerosis 2010;213:218 224.
31. Rayner BL, Byrne MJ, van Zyl Smit R. A prospective clinical trial comparing
the treatment of idiopathic membranous nephropathy and nephrotic
syndrome with simvastatin and diet, versus diet alone. Clin Nephrol 1996;46:
219 224.
32. Saltissi D, Morgan C, Rigby RJ, Westhuyzen J. Safety and efficacy of simvastatin in
hypercholesterolemic patients undergoing chronic renal dialysis. Am J Kidney Dis
2002;39:283 290.
33. Luciak M, Trznadel K. Free oxygen species metabolism during haemodialysis with
different membranes. Nephrol Dial Transplant 1991;6(Suppl. 3):66 70.
34. Verma A, Ranganna KM, Reddy RS, Verma M, Gordon NF. Effect of rosuvastatin
on C-reactive protein and renal function in patients with chronic kidney disease.
Am J Cardiol 2005;96:1290 1292.
35. Baigent C, Landray M, Leaper C, Altmann P, Armitage J, Baxter A, Cairns HS,
Collins R, Foley RN, Frighi V, Kourellias K, Ratcliffe PJ, Rogerson M, Scoble JE,
Tomson CR, Warwick G, Wheeler DC. First United Kingdom Heart and Renal
Protection (UK-HARP-I) study: biochemical efficacy and safety of simvastatin
and safety of low-dose aspirin in chronic kidney disease. Am J Kidney Dis 2005;
45:473484.
36. Lins RL, Matthys KE, Billiouw JM, Dratwa M, Dupont P, Lameire NH, Peeters PC,
Stolear JC, Tielemans C, Maes B, Verpooten GA, Ducobu J, Carpentier YA. Lipid
and apoprotein changes during atorvastatin up-titration in hemodialysis patients
with hypercholesterolemia: a placebo-controlled study. Clin Nephrol 2004;62:
287294.
37. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey
(1988 1994). Arch Intern Med 2002;162:1401 1408.
38. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Arterial
media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003;18:1731 1740.
39. Francis ME, Eggers PW, Hostetter TH, Briggs JP. Association between serum
homocysteine and markers of impaired kidney function in adults in the United
States. Kidney Int 2004;66:303 312.
40. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A,
Sourjina T, Peto R, Collins R, Simes R. Efficacy and safety of cholesterol-lowering

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 10, 2015

1. James MT, Hemmelgarn BR, Tonelli M. Early recognition and prevention of

chronic kidney disease. Lancet 2010;375:1296 1309.
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;
351:1296 1305.
3. Yach D, Leeder SR, Bell J, Kistnasamy B. Global chronic diseases. Science 2005;
307:317.
4. Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal disease: a new
paradigm. Am J Kidney Dis 2000;35(4 Suppl. 1):S117 S131.
5. Snyder JJ, Collins AJ. KDOQI hypertension, dyslipidemia, and diabetes care guidelines and current care patterns in the United States CKD population: National
Health and Nutrition Examination Survey 19992004. Am J Nephrol 2009;30:
44 54.
6. Liu Y, Coresh J, Eustace JA, Longenecker JC, Jaar B, Fink NE, Tracy RP, Powe NR,
Klag MJ. Association between cholesterol level and mortality in dialysis patients:
role of inflammation and malnutrition. JAMA 2004;291:451459.
7. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in
chronic renal disease. Am J Kidney Dis 1998;32(5 Suppl. 3):S112 S119.
8. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C,
Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M,
Kasiske B, Walker R, Massy ZA, Feldt-Rasmussen B, Krairittichai U,
Ophascharoensuk V, Fellstrom B, Holdaas H, Tesar V, Wiecek A, Grobbee D,
de Zeeuw D, Gronhagen-Riska C, Dasgupta T, Lewis D, Herrington W,
Mafham M, Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J,
Armitage J, Baxter A, Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S,
Simpson D, Sleight P, Young A, Collins R. The effects of lowering LDL cholesterol
with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of
Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;
377:2181 2192.
9. Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J,
Chae DW, Chevaile A, Cobbe SM, Gronhagen-Riska C, De Lima JJ, Lins R,
Mayer G, McMahon AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S,
Sci D, Suleymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wuthrich RP,
Gottlow M, Johnsson E, Zannad F. Rosuvastatin and cardiovascular events in
patients undergoing hemodialysis. N Engl J Med 2009;360:1395 1407.
10. Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, Ritz E. Atorvastatin
in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med
2005;353:238 248.
11. Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2012;157:263 275.
12. Upadhyay A, Earley A, Lamont JL, Haynes S, Wanner C, Balk EM. Lipid-lowering
therapy in persons with chronic kidney disease: a systematic review and
meta-analysis. Ann Intern Med 2012;157:251 262.
13. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ,
McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:112.
14. Woodward M. Epidemiology: Study design and data analysis. 2nd edition. Boca
Raton, FL, USA: Chapman and Hall/CRC; 2005.
15. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the
context of expectations from prospective epidemiological studies. BMJ 2009;
338:b1665.
16. Han SH, Kang EW, Yoon SJ, Yoon HS, Lee HC, Yoo TH, Choi KH, Han DS,
Kang SW. Combined vascular effects of HMG-CoA reductase inhibitor and angiotensin receptor blocker in non-diabetic patients undergoing peritoneal dialysis.
Nephrol Dial Transplant 2011;26:3722 3728.
17. Joy MS, Dornbrook-Lavender KA, Chin H, Hogan SL, Denu-Ciocca C. Effects of
atorvastatin on Lp(a) and lipoprotein profiles in hemodialysis patients. Ann Pharmacother 2008;42:915.
18. Dornbrook-Lavender KA, Joy MS, Denu-Ciocca CJ, Chin H, Hogan SL, Pieper JA.
Effects of atorvastatin on low-density lipoprotein cholesterol phenotype and
C-reactive protein levels in patients undergoing long-term dialysis. Pharmacotherapy 2005;25:335 344.
19. Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA, de
Zeeuw D, de Jong PE, van Veldhuisen DJ, van Gilst WH. Effects of fosinopril and
pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation
2004;110:2809 2816.
20. Chonchol M, Cook T, Kjekshus J, Pedersen TR, Lindenfeld J. Simvastatin for secondary prevention of all-cause mortality and major coronary events in patients
with mild chronic renal insufficiency. Am J Kidney Dis 2007;49:373382.

1817

1817a
treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267 1278.
41. Lindner A, Charra B, Sherrard DJ, Scribner BH. Accelerated atherosclerosis in
prolonged maintenance hemodialysis. N Engl J Med 1974;290:697 701.
42. Ribeiro S, Ramos A, Brandao A, Rebelo JR, Guerra A, Resina C, Vila-Lobos A,
Carvalho F, Remedio F, Ribeiro F. Cardiac valve calcification in haemodialysis
patients: role of calcium-phosphate metabolism. Nephrol Dial Transplant 1998;
13:2037 2040.

W. Hou et al.

43. Herzog CA, Mangrum JM, Passman R. Sudden cardiac death and dialysis patients.
Semin Dial 2008;21:300 307.
44. Roselaar SE, Nazhat NB, Winyard PG, Jones P, Cunningham J, Blake DR. Detection of oxidants in uremic plasma by electron spin resonance spectroscopy.
Kidney Int 1995;48:199 206.
45. Stenvinkel P, Heimburger O, Paultre F, Diczfalusy U, Wang T, Berglund L,
Jogestrand T. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999;55:1899 1911.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 10, 2015