Systematic Review and Meta-Analysis Medicine ®

OPEN

Effect of statins on cardiovascular complications

in chronic kidney disease patients
A network meta-analysis
∗ ∗
Seun Deuk Hwang, MD, PhDa, Kipyo Kima, Yoon Ji Kimb, Seoung Woo Leea, Jin Ho Leec, , Joon Ho Songa,

Abstract
Background: The rates of cardiovascular mortality and morbidity are increased in advanced chronic kidney disease (CKD). Mild to
moderate CKD is associated with an increase in cardiovascular events. This study aims to investigate the effects of statins on patient
mortality and cardiac events.
Study appraisal and synthesis methods: Studies on statins (atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin,
simvastatin, and simvastatin + ezetimibe) in Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and
Science Citation Index Expanded databases from 1970 to February 2019 were analyzed. Inclusion criteria were randomized control
trials and adult patients (>18 years old). Reviews, observational studies, and clinical trials that did not clearly define outcomes or that
did not have thrombosis as an outcome were excluded. We performed direct and indirect network meta-analysis using Bayesian
models and ranked different statins using generation mixed treatment comparison (GeMTC) and Stata version 13. The Grading of
Downloaded from http://journals.lww.com/md-journal by BhDMf5ePHKbH4TTImqenVKNoQAGGabrfhg7A2dKtc2cwV10hDCJ9wOmH0XCTqKyB on 06/02/2020

Recommendations Assessment, Development, and Evaluation (GRADE) of network meta-analysis approach specified 4 levels of
certainty for a given result: high, moderate, low, and very low. The outcomes were cardiac events, cardiac mortality, and all-cause
mortality.
Results: Nineteen studies (45,863 patients) were included. Compared with placebos, pravastatin 40 mg group showed a
significantly lower patient mortality (odds ratio 0.66 [95% credible interval, 0.46–0.91]).
Atorvastatin 80 mg, fluvastatin 40 mg, lovastatin 20 mg, pravastatin 40 mg, and simvastatin 40 mg showed significant results in
reducing cardiac events.
In rank probability, pravastatin showed the best effect at all-cause mortality rate. Lovastatin, fluvastatin, and pravastatin showed
good effects in the 1st, 2nd, and 3rd ranks in cardiac events.
Conclusions and implications of key findings: Pravastatin 40 mg demonstrated the best effect on all-cause mortality, and
was observed to be effective with high ranking in cardiac events. We anticipate that the data of this study will assist physicians in
making informed decisions when selecting statins, such as pravastatin, as a treatment option for CKD patients.
Abbreviations: AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study, ASCOT = Angle-
Scandinavian Cardiac Outcomes Trial, CARDS = Collaborative Atorvastatin Diabetes Study, CARE = Cholesterol and Recurrent
Events, CENTRAL = Cochrane Central Register of Controlled Trials, CI = confidence interval, CKD = chronic kidney disease, CVD =
cardiovascular disease, GeMTC = generation mixed treatment comparison, GRADE = Grading of Recommendations Assessment,
Development, and Evaluation, HDL-C = high density lipoprotein cholesterol, HMG CoA = hydroxymethylglutaryl coenzyme A, HPS =
Heart Protection Study, IDEAL = Incremental Decrease in End Points through Aggressive Lipid Lowering, LDL-C = low-density

Editor: Andre Durães.

SDH and KK contributed equally to this work.
JHL and JHS are co-corresponding authors for this work.
This meta-analysis was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the
Ministry of Education, Science, and Technology (SDH: NRF-2017R1D1A1B03030691 and the Bio & Medical Technology Development Program of the National
Research Foundation (NRF) and funded by the Korean government (MSIT) (SDH: NRF-2019M3E5D1A02069619).
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
The authors have no conflicts of interest to disclose.
Supplemental Digital Content is available for this article.
a
Division of Nephrology and Hypertension, Department of Internal Medicine, Inha University School of Medicine, Incheon, b Division of Endocrinology and Metabolism,
Department of Internal Medicine, Mediplex Sejong Hospital, Incheon, c Division of Nephrology, Department of Internal Medicine, Leesin Hemodialysis and Intervention
Clinic, Busan, South Korea.
∗
Correspondence: Joon Ho Song, Division of Nephrology and Hypertension, Department of Internal Medicine, Inha University, College of Medicine, Inha University
Hospital, 27 Inhang-Ro, Jung-gu, Incheon 22332, South Korea (e-mail: jhsong@inha.ac.kr).
Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
How to cite this article: Hwang SD, Kim K, Kim YJ, Lee SW, Lee JH, Song JH. Effect of statins on cardiovascular complications in chronic kidney disease patients: A
network meta-analysis. Medicine 2020;99:22(e20061).
Received: 10 October 2019 / Received in final form: 25 March 2020 / Accepted: 25 March 2020
http://dx.doi.org/10.1097/MD.0000000000020061

1
Hwang et al. Medicine (2020) 99:22 Medicine

lipoprotein cholesterol, LIPID = Long-term Intervention with Pravastatin in Ischemic Disease, MD = mean difference, NKF-K/DOQI =
National Kidney Foundation Kidney Disease Outcomes Quality Initiative, OR = odds ratio, PRISMA = Preferred Reporting Items for
Systematic Reviews and Network Meta-Analyses, PROSPER = Prospective Study of Pravastatin in the Elderly at Risk, RCTs =
randomized control trials, REAL-CAD = Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin
in Coronary Artery Disease, 4S = Scandinavian Simvastatin Survival Study, SUCRA = surface under the cumulative ranking, TAU =
treatment as usual, TNT = Treating to New Targets, WOSCOPS = West of Scotland Coronary Prevention Study.
Keywords: all-cause mortality, cardiac event, chronic kidney disease, network meta-analysis, statins

1. Introduction 2.2. Data sources, searches, and inclusion and exclusion

Patients with chronic kidney disease (CKD) have a high
prevalence of cardiovascular disease (CVD), leading to increased
mortality and morbidity.[1] Patients with CKD show elevated
levels of triglycerides in the blood, decreased levels of high density
lipoprotein cholesterol (HDL-C), and changes in low-density
lipoprotein cholesterol (LDL-C).[2] Dyslipidemia is considered a
major cause of CVD in patients with CKD; thus, its management
plays an important role in the treatment of these patients.[3]
Although atherosclerosis is a major cause of CVD in the general
population, vascular calcification due to hyperphosphatemia and
secondary hyperparathyroidism in patients with CKD further
increase the risk of CVD. Vascular calcification reduces blood
vessel elasticity, induces hypertension, and has antagonistic
effects on stenosis and thrombogenesis.[4] CKD is a risk factor for
CVD. Moreover, smoking and conditions such as diabetes,
hypertension, hyperlipidemia, and history of thrombosis are also
classified as risk factors for CVDs. Increased total cholesterol,
particularly LDL-C, is a risk factor for atherosclerosis, thus,
increasing the incidence of CVD.[5] For treatment and manage-
ment of these diseases, hydroxymethylglutaryl coenzyme A
(HMG CoA) reductase inhibitors or statins are recommended as
primary treatment agents besides lifestyle changes such as dietary
control and appropriate exercise. The mechanism of action of
statins involves blockage of the HMG CoA conversion to
mevalonate during cholesterol synthesis in hepatocytes and an
increase in the number of LDL receptors on the cell surface to
reduce serum LDL-C.[6] Compared with other drugs, statins are
known to have better lipid-lowering effects. According to the
National Kidney Foundation Kidney Disease Outcomes Quality
Initiative (NKF-K/DOQI) guidelines, the LDL-C level for patients
with diabetes mellitus and CKD should be less than 100 mg/dL.[7]
The guidelines recommend statin therapy for LDL-C levels >100
mg/dL. Although studies on individual statins have been
published and several statins have been used in clinical practice,
comparative studies on these drugs have been lacking. Herein, we
performed a network meta-analysis to compare the CVD
reduction effects of different statins administered to patients
with CKD. We anticipate that the findings of this study will assist
practitioners in selecting statins for patients with CKD.
2. Methods
2.1. Ethics statement
All results are shown in accordance with the guidelines of
Preferred Reporting Items for Systematic Reviews and Network
Meta-Analyses (PRISMA) statement (S1 Checklist).[8] All
analyses were based on previously published studies; therefore,
ethical approval and patient consent were not required.
criteria
We performed comprehensive searches of the following databases
from inception of the database until February 21, 2019: MED-
LINE (via PubMed), EMBASE, CINAHL, Web of Science, and the
Cochrane Central Register of Controlled Trials (CENTRAL) in the
Cochrane Library. Using a highly sensitive search strategy to
identify randomized control trials (RCTs), we searched for
important keywords according to patient group and intervention.
(Supplement 3, http://links.lww.com/MD/E143.) The criteria for
including studies in the review were as follows: RCTs and adult
patients (>18 years old). Reviews, observational studies, and
clinical trials that did not clearly define outcomes or that did not
have thrombosis as an outcome were excluded.[9] The search was
limited to human studies but was not restricted to any particular
language or publication date. Reference lists from all available
review articles and RCTs were searched manually (Fig. 1).
2.3. Study selection and data extraction
The abstracts and full texts identified were independently
evaluated by 2 researchers (SDH and JHL). Two reviewers
extracted and re-evaluated data extraction. Any disagreements
were resolved through discussions and consultations with
another researcher, (JHS). Inclusion criteria for the papers used
in the analysis were as follows:
(1) randomized controlled studies;
(2) studies referring to at least 2 of the following eligible statins:
placebo, lovastatin, atorvastatin, rosuvastatin, pitavastatin,
pravastatin, simvastatin + ezetimibe, simvastatin, atorvasta-
tin, and fluvastatin; and
(3) studies that reported one or more of the primary or secondary
outcomes (Fig. 2).
2.4. Risk of bias assessment
Two researchers (SDH and JHL) independently assessed the risk
of bias of each trial using the Cochrane Collaboration’s Risk of
Bias tool.[10] We assessed the risk of bias during random sequence
generation, allocation concealment, blinding of participants and
personnel, blinding of outcome assessment, analysis of incom-
plete outcome data, selective reporting, and in other areas. All
these judgments were categorized as “yes” (low risk of bias) or
“unclear” or “no” (high risk of bias).[10,11]
2.5. Quality of evidence assessment
We assessed the overall quality of the evidence for our primary
outcomes using an adapted Grading of Recommendations

2
Hwang et al. Medicine (2020) 99:22 www.md-journal.com

Figure 1. Flow diagram of the current systematic review (PRISMA flow diagram).

Assessment, Development, and Evaluation (GRADE) ap- 2.6. Outcome measures

proach.[12] The quality of the evidence for a specific outcome
was based on the performance versus the limitations of the study
design, inconsistency of results, indirectness of evidence,
imprecision of results, and publication bias among all studies
measuring a particular outcome. The overall quality of the
evidence for the outcome was produced by combining assess-
ments from all domains (Fig. 3).[13]pt
We aimed to determine the effectiveness of eligible statins
against patient mortality and the occurrence of cardiac events.
We also investigated the potential of adverse outcomes
associated with these medications and assessed the efficacy of
the medications on any heart failure, stroke, hospitalization,
peripheral artery disease, change in LDL-C and renal function,
and adverse events such as elevations in alanine aminotransfer-

Figure 2. Network flow among each intervention as all-cause mortality (A) and cardiac events (B).

3
Hwang et al. Medicine (2020) 99:22
Figure 3. Risk of bias graph and summary of our assessment of each risk of bias item for each included study. (+) green circle, good; yellow circle, moderate; ( )
red circle, bad.
ase, aspartate aminotransferase, hematuria, albuminuria, or
myopathy.
Cardiac events considered in this study included death from
coronary heart disease, non-fatal acute myocardial infarction,
resuscitation after cardiac arrest, cardiac revascularization, and
hospital admission for unstable angina.[14]
2.7. Statistical analyses
We compared statin effectiveness in terms of patient survival,
cardiac event, and adverse outcomes among 10 types of statin
therapy for CKD by Bayesian network meta-analysis. We
performed direct and indirect network meta-analysis using
Bayesian models and generated rankings of different statin
agents using generation mixed treatment comparison (GeMTC)
and Stata version 13 (StataCorp).[15–17] The relative ranking
probability of each treatment was estimated, and the treatment
hierarchy of competing interventions was obtained using
rankograms, surface under the cumulative ranking (SUCRA)
curves, and mean ranks. We performed network meta-analysis on
studies that were recorded on multiple treatments, which allows
estimation of the pooled effects within each treatment.[18] For
multi-arm trials, correlations among the treatment effects
between arms were included in the investigations. Studies with
j + 1 treatment arms are based on comparison of the treatment
effects with the reference treatment through multivariate normal
distribution, whereas the treatment as usual (TAU) studies are
based on the homogeneity between study variances across
treatments.[19,20] Inconsistency tests, homogeneity analysis, and
sensitivity analysis were performed using the node analysis
method in R software. The results of inconsistency tests were
assessed according to the Bayesian P-value, where P < .5 was
considered evidence for the existence of significant inconsisten-
cy.[21,22] An I2 test was performed (I2 > 50% is considered as the
existence of significant heterogeneity) to assess homogeneity.
Furthermore, sensitivity analysis was conducted by comparing
the differences found between fixed-effect and random-effect
models. The clinical outcome indicators were evaluated using the
mean difference (MD) or the odds ratio (OR) with a 95%
confidence interval (CI) (MD for continuous outcomes, OR for
binary outcomes).[19,23] When a loop connected 3 treatments, it
was possible to evaluate the inconsistency between direct and
4
Medicine
indirect evidence.[24] We also used the node-splitting method to
calculate the inconsistency of the model, which separated
evidence for a particular comparison into direct and indirect
evidence.[22] We then evaluated the agreement between the direct
and indirect evidence and reported its Bayesian P value.
Sensitivity analyses were carried out using the same methods,
after omission of data obtained from specific studies (studies with
a small number of patients and events in a specific treatment arm,
and studies with a large population that may dominate the data of
specific treatment arms).[25]
3. Results
A total of 9115 records were initially retrieved from the electronic
database search, from which we removed 1385 duplicate records.
Of the remaining records, 7663 were excluded based on a review
of either the title or abstract and 67 records were retrieved for
full-text review. Among these, 46 were excluded based on the
following criteria: studies involving drugs other than statins (n =
7), duplicated data (n = 8), patients who have undergone kidney
transplantation (n = 12), and hemodialysis and peritoneal dialysis
(n = 11), ADPKD (n = 2), an outcome that could not be included
in the statistics (n = 2); review articles (n = 3); or editorial
comments (n = 3).
Finally, 19 trials reporting outcomes for 45,863 patients
(24,373 women and 21,490 men) were included in the analysis
(Table 1). Six studies each were conducted in United States[26–31]
and the United Kingdom,[32–37] whereas 1 study was conducted
in each of the following countries: Norway,[38] Japan,[39]
Canada,[40] Scotland,[41] the Netherlands,[42] Sweden,[43] and
Greece.[44] The number of patients per study ranged from 91 to
9180, and the median follow-up period was 2.1 years (0.5–3.1
years).
3.1. Risk of bias in included studies
Although all the included studies were described as randomized,
few gave specific details of either the method of randomization or
concealment of allocation. For all studies, the blinding of study
subjects and investigators was considered adequate.
Risks of bias were frequently low (Figs. 3 and S1). There were
18 (94%) studies that reported low-risk methods for random
Hwang et al. Medicine (2020) 99:22 www.md-journal.com

Table 1
Important characteristics of the included studies and proportions of patients with using statin treatment.
Prior Current LDL Total eGFR
Using statin Compare Number of Age mean, Male, diabetes, smoker, cholesterol cholesterol (mL min/
Refs. Country/yr treatment drug patients n yr n (%) n (%) n (%) (mg/dL) (mg/dL) 1.73 m2) BMI
Shepherd UK/2007 Atorvastatin 80 mg Atorvastatin 1602/1505 65.5 ± 7.0 2102 (67.7) 546 (17.6) 280 (9.0) 96 ± 17.5 175.9 ± 24.4 52.9 ± 6.5 28.5 ± 4.5
10 mg
Koren US/2009 Atorvastatin 80 mg Placebo 286/293 65.2 ± 7.2 445 (76.9) 162 (28.0) 87 (15.0) 147.1 ± 27.4 22.7. ± 33.5 51.2 ± 8.1 29.2 ± 5.2
Holme Norway/2010 Atorvastatin 80 mg Simvastatin 1162/1159 67.0 ± 7.9 1875 (80.8) 335 (14.4) 355 (15.3) 123.6 ± 36.7 199.9 ± 41.3 52.0 ± 6.6 27.2 ± 3.9
20 mg
Ridker US/2010 Rosuvastatin 20 mg Placebo 1638/1629 70 ± 5 1138 (34.8) 264 (8.1) 109 189 56 ± 5 29.0 ± 3.6
Rutter UK/2010 Atorvastatin 80 mg Atorvastatin 60/59 63.5 ± 9.5 51 (42.8) 60 (51) 13 (23) 62 ± 18 34 ± 6
10 mg
Amarenco US/2014 Atorvastatin 80 mg Placebo 789/811 68.0 ± 9.3 673 (42.1) 263 (16.4) 197 (12.3) 134.4 ± 24 216.0 ± 28.7 52.3 ± 7.0 27.6 ± 4.6
Nakamura Japan/2009 Pravastatin 10 mg Placebo 1507/1471 60 366 (24.3) 283 (18.8) 188 (12.5) 52.6 ± 5.7 –
Lemos Netherlands/2005 Fluvastatin 80 mg Placebo 150/160 69 ± 7 208 (77) 38 (12) 53 (17) 131 ± 31 200 ± 33 47 ± 7 –
Tonelli Canada/2004 Pravastatin 40 mg Placebo 2217/2274 65.6 ± 5.6 3671 (81.7) 445 (9.9) 461 (10.3) 151.5 ± 28.6 221.3 ± 32.8 51.8 ± 6.3 25.5 ± 3.4
Colhoun Scotland/2009 Atorvastatin 10 mg Placebo 482/488 65.0 ± 6.7 233 (48.3) 482 (49.3) – 117 ± 28 207 ± 32 53.5 ± 5.3 –
Baigent UK/2011 Simvastatin 20 mg + Placebo 4193/4191 62 ± 12 5281 (63) 1054 (23) 626 (13) 26.6 ± 12.9 27.1 ± 5.7
ezetimibe 10 mg
Stegmayr Sweden/2005 Atorvastatin 10 mg Placebo 70/73 67.8 ± 12.4 98 (68.6) 22 (31.9) 44 (30.7) <30 26.4 ± 5.1
Verma US/2005 Rosuvastatin 10 mg Placebo 48/43 73 ± 10 36 (40.1) 22 (46) 9 (9.8) 140 ± 47 224 ± 61 42.3 ± 11.1 –
Baigent UK/2005 Simvastatin 20 mg Placebo 112/111 52 ± 15 157 (70.5) 12 (10.7) – 124 ± 30 202 ± 22 <30 27.5 ± 4.4
Katsiki Greece/2011 Atorvastatin 80 mg Placebo 172/177 57 ± 9 – – 55 (32) 47.6 ± 6.7 32 ± 5
Kendrick US/2010 Lovastatin 20 mg Placebo 145/159 62 ± 8 119 (39.6) 121 (40.3) 15 (10) 151 ± 19 224 ± 23 53 ± 6 27 ± 3
Rahman US/2008 Pravastatin 40 mg Placebo 779/778 70.7 ± 7.9 703 (45.2) 249 (32) 134 (17.2) 146.5 ± 21.2 226.2 ± 26.3 50.8 ± 8.2 29.1 ± 5.7
Shepherd UK/2002 Pravastatin 40 mg Placebo 2888/2912 75.4 ± 3.4 2801 (48.3) 303 (10.5) 753 (26) 49.8 ± 6.3 26.8 ± 4.1
Mihaylova UK/2016 Simvastatin 20 mg + Placebo 4650/4620 62 ± 12 5800 (63) 2091 (23) 1243 (13) 61.3 ± 10. 27.1 ± 5.6
ezetimibe 10 mg

BMI, body mass index; eGFR, estimated glomerular filtration rate; UK, United Kingdom; USA, United States of America.

sequence generation and adequately concealed allocation; while
16 (84%) studies showed low-risk for blinding of outcome
assessment (detection bias). However, only 3 studies (15%)
reported low risk in selective reporting among studies. The grades
of all-cause mortality and cardiac events started with high quality
and well-made RCT, which then decreased by 1 point owing to
the possibility of reporting bias. Thus, scientific evidence showed
moderate quality results. The findings were added to the results in
the manuscript.
3.2. Effect of interventions
The data obtained from all 19 studies (n = 45,863) contributed to
the network analysis. The primary endpoint was patient survival.
Compared with a placebo as the reference, pravastatin 40 mg
significantly reduced patient mortality (OR 0.75, 95% CrL 0.53–
0.98) (Table 2). However, atorvastatin 10 mg (0.91, 0.58–1.40),
atorvastatin 80 mg (0.92, 0.27–3.1), fluvastatin 40 mg (1.00,
0.57–1.80), rosuvastatin 10 mg (0.80, 0.47–1.10), and simva-
statin 40 mg (0.98, 0.48–1.90) were not associated with higher
benefits than the placebo. No differences were found among the
different interventions on the results for secondary outcome,
which included myocardial infarction, heart failure, stroke,
hospitalization, peripheral artery disease, a change in LDL-C and
renal function, and adverse events. A placebo was used as the
reference point in cases of any cardiac event. Atorvastatin 80 mg
(OR 0.72, 95% CrL 0.52–0.98); fluvastatin 40 mg (0.67, 0.43–
0.99); lovastatin 20 mg (0.37, 0.13–0.92); pravastatin 40 mg
(0.67, 0.51–0.85); and simvastatin 40 mg (0.72, 0.55–0.92) were
associated with lower ORs than the placebo in reducing cardiac
events. Atorvastatin 10 mg (0.88, 0.62–1.2); rosuvastatin 10 mg
(0.78, 0.52–1.1); and simvastatin 20 mg + ezetimibe 10 mg (0.88,
0.68–1.10) showed no significant difference (Fig. 4).
The side effects observed subsequent to statin therapy showed
no differences among the medications in terms of persistent
elevations in alanine aminotransferase and/or aspartate amino-
transferase, persistent elevation in creatine phosphokinase,
hematuria, albuminuria, or myopathy.
3.3. Rank probabilities
Pravastatin 40 mg ranked first and second with probabilities of
0.292 and 0.345, respectively, for all-cause mortality; the model-
fit statistic of DIC was 43.0, and the residual deviance was 22.8.
The rank probabilities of cardiac events showed that lovastatin
20 mg had the highest ranking (0.824). Second in the rank
probabilities was fluvastatin 40 mg with a probability of 0.309,
whereas pravastatin 40 mg ranked third with a probability of

Table 2
Comparison of the included statins for all-cause mortality: odds ratio (95% CI). Each cell indicates the effect of the column-defining
intervention relative to the row-defining intervention.
Atorvastatin 10 1.022 (0.316, 3.154) 1.145 (0.535, 2.437) 1.102 (0.693, 1.726) 0.830 (0.455, 1.359) 0.879 (0.432, 1.519) 1.067 (0.448, 2.543)
Atorvastatin 80 1.114 (0.286, 4.607) 1.062 (0.311, 3.801) 0.797 (0.218, 2.837) 0.841 (0.223, 3.096) 1.041 (0.256, 4.427)
Fluvastatin 40 0.958 (0.523, 1.732) 0.723 (0.349, 1.350) 0.763 (0.325, 1.503) 0.936 (0.365, 2.347)
Placebo 0.756 (0.527, 0.972) 0.799 (0.471, 1.142) 0.966 (0.471, 2.024)
Pravastatin 40 1.058 (0.610, 1.733) 1.292 (0.617, 2.944)
Rosuvastatin 10 1.221 (0.569, 3.039)
Simvastatin 40

5
Hwang et al. Medicine (2020) 99:22
Figure 4. All-cause mortality (A) and cardiac events (B) associated with
different types of statins and doses compared with placebos used as
references.
0.265. Model-fit statistic of DIC of any cardiac event was 84.8,
and the residual deviance was 45.3. The network heterogeneity
was estimated by comparing a common heterogeneity variance
(tau [t]) within each network with an empirical distribution of
heterogeneity variances. The network for all-cause mortality
indicated the presence of substantial heterogeneity with t = 0.86,
whereas t = 0.74 for networks for cardiac event.
4. Discussion
In this study, statistically significant reduction in mortality was
only observed in the groups receiving pravastatin 40 mg.
Lovastatin 20 mg, fluvastatin 40 mg, and pravastatin 40 mg were
ranked first, second, and third in terms of cardiac events,
respectively.
This study evaluated and confirmed the potency and
effectiveness of individual statins, through network meta-
analysis, to reduce patient mortality and cardiac events in
patients with CKD. Previous studies, however, focused only on a
few representative statins, while this study identified the benefits
and effects of almost all commercially available statins and their
ability to reduce LDL. In these studies, statistically significant
reduction in mortality was only observed in the groups receiving
pravastatin 40 mg. Lovastatin 20 mg, fluvastatin 40 mg, and
pravastatin 40 mg, were ranked first, second, and third, in terms
of cardiac events, respectively.
Lovastatin is metabolized in the CYP3A4 pathway and has a
short half-life. It was found to be advantageous in primary
prevention in Air Force/Texas Coronary Atherosclerosis Preven-
tion Study (AFCAPS/TexCAPS) clinical trials.[7,45] Fluvastatin
also has a short half-life. It is metabolized by CYP2C9, and has a
low drug-interaction potential, except with fluconazole (CYP2C9
inhibitor) and warfarin. In the ALER trial, fluvastatin reduced the
incidence of cardiovascular events in patients after kidney
transplantation; none of the patients developed rhabdomyoly-
sis.[46,47] Pravastatin, a hydrophilic statin, has a short half-life,
which is unaffected by food intake. It has shown cardiovascular
6
Medicine
benefits in patients with coronary artery disease in the
Cholesterol and Recurrent Events (CARE) and Long-term
Intervention with Pravastatin in Ischemic Disease (LIPID) trial,
high-risk primary prevention West of Scotland Coronary
Prevention Study (WOSCOPS), and Prospective Study of
Pravastatin in the Elderly at Risk (PROSPER) trial.[36,48–50]
Simvastatin has a short half-life and is metabolized by CYP3A4
and can be administered without food. It was reported to reduce
total mortality in both the Scandinavian Simvastatin Survival
Study (4S) and HPS (Heart Protection Study).[51,52] Simvastatin
and ezetimibe are often administered in combination; when co-
administered with simvastatin, ezetimibe prevents intestinal
absorption of cholesterol and reduces LDL by 15%. Atorvastatin
has a long half-life and is metabolized by CYP3A4. It has been
shown to be both safe and effective in many trials, such as the
TNT (Treating to New Targets), Incremental Decrease in End
Points through Aggressive Lipid Lowering (IDEAL), Angle-
Scandinavian Cardiac Outcomes Trial (ASCOT), and Collabo-
rative Atorvastatin Diabetes Study (CARDS).[53–56] Rosuvasta-
tin, a hydrophilic statin with similar structure to other synthetic
statins, has a long half-life (20–24 h). It has no significant CYP
drug interactions and is metabolized to a minimum. In the
JUPITER clinical trial, rosuvastatin significantly reduced the
frequency of cardiovascular events compared with the placebo
group.[57] Pitavastatin, a newly synthesized statin, is almost
completely metabolized by CYP2C9, resulting in very low drug
interactions. It showed a good lipid-lowering effect in the
Randomized Evaluation of Aggressive or Moderate Lipid
Lowering Therapy with Pitavastatin in Coronary Artery Disease
(REAL-CAD) study.[58]
Among statins, pravastatin, lovastatin, fluvastatin, and
simvastatin have shorter half-lives than rosuvastatin and
atorvastatin. The half-lives of rosuvastatin and atorvastatin
range from 10 to 20 h, whereas the half-lives of statins that
reduced cardiovascular events were 1 to 3 h. We hypothesized
that these outcomes could occur in patients with CKD (and not in
general population), because they have delayed metabolism and
excretion, which may interfere with other medications, particu-
larly antiplatelet agents, thus, reducing the drug effects. Most of
the statins are metabolized via CYP3A4 and CYP2C9 in the liver,
except pravastatin. This could be beneficial in reducing all-cause
mortality and cardiovascular events because pravastatin has low
level of interaction with other medications administered
simultaneously, even at high doses.
A meta-analysis of randomized clinical trials in a healthy
population (without CKD) revealed that statin therapy signifi-
cantly reduced the risk of death, ischemic stroke, and coronary
artery revascularization due to myocardial infarction or coronary
heart disease.[46,59] When CKD progresses to stage 4, other
cardiovascular pathologies (including vascular stiffness and
calcification, structural heart disease, and sympathetic hyperpla-
sia) may develop, which contribute to an increased risk of cardiac
arrhythmia and heart failure.[48] Patients with CKD have a
significantly higher prevalence of CVD than the general
population.[1] Their plasma lipid profile is characterized by
increased levels of triglycerides, decreased levels of HDL-C, and
inconsistent change in LDL-C.[3] Statins may alleviate cardiovas-
cular diseases through their lipid-lowering potential or via their
pleiotropic effects, which alter expression of endothelial nitric
oxide synthase, stability of atherosclerotic plaques, production of
inflammatory cytokines and reactive oxygen species, reactivity of
platelets, and development of cardiac hypertrophy and fibro-
Hwang et al. Medicine (2020) 99:22
sis.[60,61] Recently, it was reported that statins reduced the
incidence of CVD by reducing oxidant stress and inflammation at
an early stage of CKD.[62] Moreover, animal studies have shown
that statins reduce the incidence of CVD indirectly by reducing
the rate of CKD progression. Two meta-analysis studies showed
that statins lower the rate of estimated glomerular filtration rate
(eGFR) decline.[63,64] However, in a recent systematic review,
statins were shown to have no significant effect on the reduction
of GFR in patients with diabetes, hypertension, or glomerulone-
phritis; this was only observed in patients with known CVDs.[64]
Several recent studies have described the effect of statins on serum
C-reactive protein levels in patients with CKD. Panichi et al
reported that a commonly used dose of simvastatin showed anti-
inflammatory effects in patients with CKD.[65] Similarly,
Goicoechea et al demonstrated that atorvastatin treatment
improved inflammatory status in patients besides showing
beneficial effects on the lipid profile.[66] Previous statin trials
have shown that reduction in LDL-C results in a proportional
decrease in the risk.[46,59] Thus, increasing the statin dose is an
effective strategy to increase the benefit to high-risk patients,
although it is not always desirable because of drug toxicity
concerns, especially when the dose is already high or CKD has
progressed. The response to statin therapy in dialysis patients is
different from that in the normal population or patients with pre-
dialysis CKD. Recent large-scale SHARP, 4D, and AURORA
studies have shown that statin therapy had no benefit in dialysis
patients in terms of improving primary outcomes (non-fatal
myocardial infarction, non-fatal hemorrhagic stroke, non-fatal
non-hemorrhagic stroke, and coronary revasculariza-
tion).[34,67,68] Therefore, the KDOQI guidelines recommended
that statin therapy should not be initiated in adult dialysis
patients, although it does not need to be stopped if already
initiated.[7]
This study has some limitations. First, data for certain
medications, such as pitavastatin, which have been used recently
and for which not many RCTs were available, were not included.
Owing to the lack of RCTs for these drugs, information is lacking
on the effectiveness of the drugs used for patients with CKD.
Second, the effects of drugs on the progression of CKD need to be
analyzed. There is a paucity of information on the effects of
statins and lipid profiles on the progress of CKD, and further
research is needed in this respect. In addition, there is a possibility
of a difference between actual conditions and those assessed using
estimation formulae without directly examining CKD progres-
sion in a patient. Third, there is a lack of information regarding
other medications that a patient might be taking simultaneously
with statin therapy. Other drugs may affect outcomes if they
affect the serum concentration or action of statins. There is
currently insufficient evidence that comorbidity of the genetic
profile of a patient or underlying disease can cause CVD more
frequently.
In conclusion, administration of statins to reduce patient
mortality and cardiac events in patients with CKD is an effective
and proven therapy. Among the statins currently prescribed,
atorvastatin 80 mg, fluvastatin 40 mg, lovastatin 20 mg, prava-
statin 40 mg, and simvastatin 40 mg effectively reduced the risk of
cardiac events compared with the corresponding placebos. In our
network meta-analysis, pravastatin 40 mg showed the highest
rank probability for all-cause mortality, whereas for cardiac
events, lovastatin 20 mg, fluvastatin 40 mg, and pravastatin 40
mg ranked first, second, and third, respectively. Although there
are a variety of statins available for the treatment of patients with
7
www.md-journal.com
CKD, the availability and usage of these agents are often country-
or hospital-dependent. Given these circumstances, primary care
physicians tend to select medicines based on their previous
experience with medication or advice from a senior physician.
The findings of this study may prove beneficial for selection of
statins to lower the risk of CVD in patients with CKD. Although
we cannot provide guidelines for selecting statins that will be the
most effective, we anticipate that the data in this study will assist
physicians in making informed decisions when selecting statins.
Author contributions
Conceptualization: HSD, LJH, YJK, and SJH; methodology &
data acquisition: HSD, LJH, LSW, YJK, KK, and SJH; data
analysis and interpretation: HSD, LJH, YJK, KK, and SJH;
statistical analysis: HSD, LJH, and SJH; writing – original draft
preparation: HSD, LJH, and SJH; writing – review and editing:
HSD, LJH, and SJH; funding acquisition: HSD and SJH.
References
[1] Levey AS, Coresh J. Chronic kidney disease. Lancet 2012;379:
165–80.
[2] Tonelli M, Bohm C, Pandeya S, et al. Cardiac risk factors and the use of
cardioprotective medications in patients with chronic renal insufficiency.
Am J Kidney Dis 2001;37:484–9.
[3] Weiner DE, Tabatabai S, Tighiouart H, et al. Cardiovascular outcomes
and all-cause mortality: exploring the interaction between CKD and
cardiovascular disease. Am J Kidney Dis 2006;48:392–401.
[4] Sarnak MJ. Cardiovascular complications in chronic kidney disease. Am
J Kidney Dis 2003;41(Suppl):11–7.
[5] Parikh NI, Hwang S-J, Larson MG, et al. Cardiovascular disease risk
factors in chronic kidney disease: overall burden and rates of treatment
and control. Arch Intern Med 2006;166:1884–91.
[6] Grundy SM. HMG-CoA reductase inhibitors for treatment of hyper-
cholesterolemia. N Engl J Med 1988;319:24–33.
[7] Slinin Y., Ishani A, Rector T, et al. Management of hyperglycemia,
dyslipidemia, and albuminuria in patients with diabetes and CKD: a
systematic review for a KDOQI clinical practice guideline. Am J Kidney
Dis 2012;60:747–69.
[8] Hutton B, Salanti G, Caldwell DM, et al. The PRISMA extension
statement for reporting of systematic reviews incorporating network
meta-analyses of health care interventions: checklist and explanations.
Ann Intern Med 2015;162:777–84.
[9] Muchayi T, Salman L, Tamariz LJ, et al. A meta-analysis of randomized
clinical trials assessing hemodialysis access thrombosis based on access
flow monitoring: where do we stand? Semin Dial 2015;28:E23–9.
[10] Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane
Collaboration’s tool for assessing risk of bias in randomised trials.
BMJ 2011;343:d5928–30.
[11] Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength
of recommendations. BMJ 2004;328:1490.
[12] Puhan MA, Schünemann HJ, Murad MH, et al. A GRADE Working
Group approach for rating the quality of treatment effect estimates from
network meta-analysis. BMJ 2014;349:g5630.
[13] Bae JM, Choi YY, Park CO, et al. Efficacy of allergen-specific
immunotherapy for atopic dermatitis: a systematic review and meta-
analysis of randomized controlled trials. J Allergy Clin Immunol
2013;132:110–7.
[14] McManus DD, Aslam F, Goyal P, et al. Incidence, prognosis, and factors
associated with cardiac arrest in patients hospitalized with acute
coronary syndromes (the Global Registry of Acute Coronary Events
Registry). Coron Artery Dis 2012;23:105–12.
[15] Chaimani A, Higgins JPT, Mavridis D, et al. Graphical tools for network
meta-analysis in STATA. PLoS One 2013;8:e76654.
[16] Liu Y, Wang W, Zhang A-B, et al. Epley and Semont maneuvers for
posterior canal benign paroxysmal positional vertigo: a network meta-
analysis. Laryngoscope 2016;126:951–5.
[17] van Valkenhoef G, Dias S, Ades AE, et al. Automated generation of node-
splitting models for assessment of inconsistency in network meta-
analysis. Res Synth Methods 2016;7:80–93.
Hwang et al. Medicine (2020) 99:22
[18] Caldwell DM, Ades AE, Higgins JPT. Simultaneous comparison of
multiple treatments: combining direct and indirect evidence. BMJ 2005;
331:897–900.
[19] Lu G, Ades AE. Combination of direct and indirect evidence in mixed
treatment comparisons. Stat Med 2004;23:3105–24.
[20] Higgins JP, Whitehead A. Borrowing strength from external trials in a
meta-analysis. Stat Med 1996;15:2733–49.
[21] Du S, Ye J, Chen H, et al. Interventions for treating 3- or 4-part proximal
humeral fractures in elderly patient: a network meta-analysis of
randomized controlled trials. Int J Surg 2017;48:240–6.
[22] Dias S, Welton NJ, Caldwell DM, et al. Checking consistency in mixed
treatment comparison meta-analysis. Stat Med 2010;29:932–44.
[23] Salanti G, Ades AE, Ioannidis JPA. Graphical methods and numerical
summaries for presenting results from multiple-treatment meta-analysis:
an overview and tutorial. J Clin Epidemiol 2011;64:163–71.
[24] Bucher HC, Guyatt GH, Griffith LE, et al. The results of direct and
indirect treatment comparisons in meta-analysis of randomized
controlled trials. J Clin Epidemiol 1997;50:683–91.
[25] Hwang SD, Lee JH, Lee SW, et al. Efficacy and safety of induction
therapy in kidney transplantation: a network meta-analysis. Transplant
Proc 2018;50:987–92.
[26] Koren MJ, Davidson MH, Wilson DJ, et al. Focused atorvastatin therapy
in managed-care patients with coronary heart disease and CKD. Am J
Kidney Dis 2009;53:741–50.
[27] Ridker PM, MacFadyen J, Cressman M, et al. Efficacy of rosuvastatin
among men and women with moderate chronic kidney disease and
elevated high-sensitivity 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;55:1266–73.
[28] Amarenco P, Callahan A3rd, Campese VM, et al. Effect of high-dose
atorvastatin on renal function in subjects with stroke or transient
ischemic attack in the SPARCL trial. Stroke 2014;45:2974–82.
[29] Verma A, Ranganna KM, Reddy RS, et al. Effect of rosuvastatin on C-
reactive protein and renal function in patients with chronic kidney
disease. Am J Cardiol 2005;96:1290–2.
[30] Kendrick J, Shlipak MG, Targher G, et al. 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;55:42–9.
[31] Rahman M, Baimbridge C, Davis BR, et al. Progression of kidney disease
in moderately hypercholesterolemic, hypertensive patients randomized
to pravastatin versus usual care: a report from the Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
Am J Kidney Dis 2008;52:412–24.
[32] Shepherd J, Kastelein JJP, Bittner V, et al. Intensive lipid lowering with
atorvastatin in patients with coronary heart disease and chronic kidney
disease: the TNT (Treating to New Targets) study. J Am Coll Cardiol
2008;51:1448–54.
[33] Rutter MK, Prais HR, Charlton-Menys V, et al. Protection Against
Nephropathy in Diabetes with Atorvastatin (PANDA): a randomized
double-blind placebo-controlled trial of high- vs. low-dose atorvastatin
(1). Diabet Med 2011;28:100–8.
[34] Baigent C, Landray MJ, Reith C, et al. 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;377:2181–92.
[35] Baigent C, Landray M, Leaper C, et al. 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;45:473–84.
[36] Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly
individuals at risk of vascular disease (PROSPER): a randomised
controlled trial. Lancet 2002;360:1623–30.
[37] Mihaylova B, Schlackow I, Herrington W, et al. Cost-effectiveness of
Simvastatin plus Ezetimibe for Cardiovascular Prevention in CKD:
results of the Study of Heart and Renal Protection (SHARP). Am J
Kidney Dis 2016;67:576–84.
[38] Holme I, Fayyad R, Faergeman O, et al. Cardiovascular outcomes and
their relationships to lipoprotein components in patients with and
without chronic kidney disease: results from the IDEAL trial. J Intern
Med 2010;267:567–75.
[39] Nakamura H, Mizuno K, Ohashi Y, et al. Pravastatin and cardiovascular
risk in moderate chronic kidney disease. Atherosclerosis 2009;206:
512–7.
8
Medicine
[40] Tonelli M, Keech A, Shepherd J, et al. Effect of pravastatin in people with
diabetes and chronic kidney disease. J Am Soc Nephrol 2005;16:
3748–54.
[41] Colhoun HM, Betteridge DJ, Durrington PN, et al. 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;54:810–9.
[42] Lemos PA, Serruys PW, de Feyter P, et al. Long-term fluvastatin reduces
the hazardous effect of renal impairment on four-year atherosclerotic
outcomes (a LIPS substudy). Am J Cardiol 2005;95:445–51.
[43] Stegmayr BG, Brännström M, Bucht S, et al. Low-dose atorvastatin in
severe chronic kidney disease patients: a randomized, controlled
endpoint study. Scand J Urol Nephrol 2005;39:489–97.
[44] Katsiki N, Elisaf M. Multifactorial treatment for improvement of renal
function and cardiovascular risk: an ATTEMPT for patients with
metabolic syndrome and chronic kidney disease. Curr Med Res Opin
2011;27:1669–72.
[45] Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute
coronary events with lovastatin in men and women with average
cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas
Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615–22.
[46] Cholesterol Treatment Trialists’ C, Baigent C, Blackwell L, et al. Efficacy
and safety of more intensive lowering of LDL cholesterol: a meta-analysis
of data from 170,000 participants in 26 randomised trials. Lancet
2010;376:1670–81.
[47] Holdaas H, Fellström B, Jardine AG, et al. Effect of fluvastatin on cardiac
outcomes in renal transplant recipients: a multicentre, randomised,
placebo-controlled trial. Lancet 2003;361:2024–31.
[48] Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovas-
cular disease in chronic renal disease. Am J Kidney Dis 1998;32(Suppl 3):
S112–9.
[49] Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on
coronary events after myocardial infarction in patients with average
cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
N Engl J Med 1996;335:1001–9.
[50] Long-Term Intervention with Pravastatin in Ischaemic Disease Study G.
Prevention of cardiovascular events and death with pravastatin in
patients with coronary heart disease and a broad range of initial
cholesterol levels. N Engl J Med 1998;339:1349–57.
[51] ScandinavianSimvastatinSurvivalStudyGroup . Randomised trial of
cholesterol lowering in 4444 patients with coronary heart disease: the
Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–9.
[52] Heart Protection Study Collaborative G. MRC/BHF Heart Protection
Study of cholesterol lowering with simvastatin in 20,536 high-risk
individuals: a randomised placebo-controlled trial. Lancet 2002;360:
7–22.
[53] LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with
atorvastatin in patients with stable coronary disease. N Engl J Med
2005;352:1425–35.
[54] Pedersen TR, Faergeman O, Kastelein JJP, et al. High-dose atorvastatin
vs usual-dose simvastatin for secondary prevention after myocardial
infarction: the IDEAL study: a randomized controlled trial. JAMA
2005;294:2437–45.
[55] Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary and stroke
events with atorvastatin in hypertensive patients who have average or
lower-than-average cholesterol concentrations, in the Anglo-Scandina-
vian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): a
multicentre randomised controlled trial. Lancet 2003;361:1149–58.
[56] Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of
cardiovascular disease with atorvastatin in type 2 diabetes in the
Collaborative Atorvastatin Diabetes Study (CARDS): multicentre
randomised placebo-controlled trial. Lancet 2004;364:685–96.
[57] Ridker PM, Group JS. Rosuvastatin in the primary prevention of
cardiovascular disease among patients with low levels of low-density
lipoprotein cholesterol and elevated high-sensitivity C-reactive protein:
rationale and design of the JUPITER trial. Circulation 2003;108:
2292–7.
[58] Taguchi I, Iimuro S, Iwata H, et al. High-dose versus low-dose
pitavastatin in Japanese patients with stable coronary artery disease
(REAL-CAD): a randomized superiority trial. Circulation 2018;137:
1997–2009.
[59] Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-
lowering treatment: prospective meta-analysis of data from 90,056
participants in 14 randomised trials of statins. Lancet 2005;366:
1267–78.
Hwang et al. Medicine (2020) 99:22
[60] Liao JK. Clinical implications for statin pleiotropy. Curr Opin Lipidol
2005;16:624–9.
[61] Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the
cardiovascular system. Circ Res 2017;120:229–43.
[62] Chan DT, Irish AB, Dogra GK, et al. Dyslipidaemia and cardiorenal
disease: mechanisms, therapeutic opportunities and clinical trials.
Atherosclerosis 2008;196:823–34.
[63] Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the
progression of renal disease: a meta-analysis. Kidney Int 2001;59:
260–9.
[64] Sandhu S, Wiebe N, Fried LF, et al. Statins for improving renal outcomes:
a meta-analysis. J Am Soc Nephrol 2006;17:2006–16.
www.md-journal.com
[65] Panichi V, Paoletti S, Mantuano E, et al. In vivo and in vitro effects of
simvastatin on inflammatory markers in pre-dialysis patients. Nephrol
Dial Transplant 2006;21:337–44.
[66] Goicoechea M, de Vinuesa SG, Lahera V, et al. Effects of atorvastatin on
inflammatory and fibrinolytic parameters in patients with chronic kidney
disease. J Am Soc Nephrol 2006;17(Suppl 3):S231–5.
[67] Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2
diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:
238–48.
[68] Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and
cardiovascular events in patients undergoing hemodialysis. N Engl J Med
2009;360:1395–407.