Original Article

Angiology
1-10
Meta-Analysis Comparing Rosuvastatin ª The Author(s) 2015
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and Atorvastatin in Reducing DOI: 10.1177/0003319715599863
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Concentration of C-Reactive Protein
in Patients With Hyperlipidemia

Qian Ma, MD1, Yujie Zhou, PhD1, Guangyao Zhai, MD1,

Fei Gao, MD1, Linlin Zhang, MD1, Jianlong Wang, MD1,
Qing Yang, MD1, and Wanjun Cheng, MD1

Abstract
We conducted a meta-analysis of 13 randomized trials comparing the efficacy of rosuvastatin versus atorvastatin in reducing
concentrations of C-reactive protein (CRP). We searched PubMed, Ovid, and Elsevier databases until June 2014. Search terms
included C-reactive protein or CRP, rosuvastatin, atorvastatin, randomized, randomly, and randomization; 13 trials (3798
patients) were included. Funnel plots for CRP were inspected to assess publication bias. The pooled analysis demonstrated the
benefit of rosuvastatin over atorvastatin therapy for all 13 trials (mean difference [MD] ¼ 0.11, which is standardized mean with
no unit although the raw data before pooling is mg/L, 95% confidence interval 0.15 to 0.07, P < .0001) with no evidence of
significant publication bias (I2 ¼ 6.9%, P ¼ .377). Subgroup analysis indicated a significant benefit of rosuvastatin over atorvastatin
regarding the 1/1 dose ratio (MD ¼ 0.14, 95% CI 0.21 to 0.06) and 1/2 dose ratio (MD¼ 0.11, 95% CI 0.16 to 0.05).
Cumulative and influence analyses showed accuracy and stability for the estimation mentioned earlier. Our meta-analysis shows
that rosuvastatin produces better reduction in CRP concentrations than atorvastatin at a dose ratio of 1/1 and 1/2 (rosuvastatin/
atorvastatin), respectively.

Keywords
meta-analysis, C-reactive protein, rosuvastatin, atorvastatin, hyperlipidemia, inflammation

Introduction of Coronary Atheroma by Intravascular Ultrasound: Effect of

Statins reduce adverse cardiovascular (CV) events and limit
the development of coronary atherosclerosis.1-3 Atorvastatin
and rosuvastatin are widely prescribed and are the most effec-
tive statins for reducing low-density lipoprotein cholesterol
(LDL-C) levels.4 Rosuvastatin is more efficacious for lowering
LDL-C level than atorvastatin at equal doses.5 According to the
2014 National Institute for Health and Clinical Excellence
(NICE) guidelines, atorvastatin 20 mg and rosuvastatin 10 mg
daily can decrease LDL-C by 43%.5 Direct comparison of
long-term clinical outcomes between these 2 statins therapy is
still unclear.6
C-reactive protein (CRP) is an inflammatory factor asso-
ciated with the initiation, progression, and instability of
atherosclerotic plaques as well as the risk of CV events.7-8
A meta-analysis of randomized trials compared the effect of
atorvastatin and rosuvastatin on CRP levels by searching
through June 2011 using Internet-based search Web sites
(PubMed and OVID) and found no significant difference in
CRP levels between the 2 statins.9 However, several clinical
trials have been completed since then, including the The Study
Rosuvastatin versus Atorvastatin (SATURN) trial.10 To deter-
mine whether rosuvastatin or atorvastatin reduces CRP levels
to a greater extent, we conducted an updated meta-analysis
in patients with hyperlipidemia.
Methods
The study was performed in line with the recommendations of
the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) statement.11
1
Department of Cardiology, Beijing An Zhen Hospital, Capital Medical
University and Beijing Institute of Heart Lung and Blood Vessel Disease,
Anzhenli Avenue, Chao Yang District, Beijing, China
Corresponding Author:
Yujie Zhou, Department of Cardiology, Beijing An Zhen Hospital, Capital
Medical University and Beijing Institute of Heart Lung and Blood Vessel
Disease, Anzhenli Avenue, Chao Yang District, Beijing, 100029, China.
Email: azzyj12@163.com
2 Angiology
Figure 1. Quality of reporting of meta-analyses flow diagram for meta-analysis. RCT indicates randomized controlled trial; ACS, acute coronary
syndrome.
Inclusion Criteria, Data Sources, and Search Protocol
Two investigators (Q Ma and G Zhai) independently extracted
data and 1 investigator (Y Zhou) resolved disputes. We
searched PubMed, Ovid, and Elsevier databases for all clinical
trials till June 2014. The search key words included C-reactive
protein or CRP, rosuvastatin, atorvastatin, randomized, ran-
domly, and randomization. Studies that were considered for
inclusion had to meet the following criteria: a prospective ran-
domized controlled clinical trial (RCT) design, fixed dosage
of rosuvastatin versus atorvastatin therapy randomly
assigned, a study population of patients with dyslipidemia,
and confirmation that these RCTs were completed. The RCTs
were excluded if irrelevant titles/abstracts, duplicate publica-
tion, populations with acute coronary syndromes (ACSs)/HIV
infection/metabolic syndrome. The flow diagram of Quality
of Reporting of Meta-analyses of the study selection process
is illustrated in Figure 1.
Selection and Quality Assessment
Trials were assessed for eligibility and risk of bias based on
allocation concealment, sequence generation, incomplete out-
come data, blinding of participants, personnel and outcome
assessors, selective outcome reporting, and other sources of
bias from the Cochrane Collaboration.11
Outcome Measures, Data Collected, and Statistical
Analyses
Two investigators independently recorded and calculated
the data regarding CRP concentrations. To report the mean dif-
ference (MD) between the 2 therapies, we extracted the number
of participants, arithmetic means, and standard deviations
(SDs) or standard errors (SEs) from the included RCTs. The
pooled mean is the standardized mean with no unit although the
raw data before pooling is mg/L. Given the potential abnormal
distribution of CRP data and hence arithmetic means or SDs
indirectly provided, the mean and variance were estimated
using the median, range, and size of a sample. In cases with
only baseline and follow-up CRP levels, the SDs with regard
to changes in CRP concentrations from baseline were derived
with imputed correlation coefficients of .8 according to the
Cochrane Handbook.12
We used fixed-effects and random-effects models to evalu-
ate the overall pooled MD, yielding equivalent findings. In the
random-effects model, we added the prediction interval to
illustrate the degree of heterogeneity in forests plots, which
also provided a predicted range for the treatment effect in indi-
vidual studies. The Q test and I-square (I2) statistic method
were used to determine heterogeneity between the studies.13,14
These indices were used to assess the percentage of variability
across studies, which is due to heterogeneity rather than chance.
Ma et al 3

Table 1. Eligible Trials and Characteristics.a

Patients, n Mean Age, y Intervention, mg/d

Trial Indication R A R A R A Follow-Up, m

Stein et al (2003)15 Dyslipidemia 435 187 48 + 14 47 + 13 20-6 w, 20-6 w, 4.5

40-6 w, 40-6 w,
80-6 w 80-6 w
Ferdinand et al (2006)16 Dyslipidemia 186 179 55.0 + 11.2 54.9 + 10.3 10 10 1.5
Ferdinand et al (2006)16 Dyslipidemia 189 178 55.4 + 12.8 54.9 + 11.9 20 20 1.5
ATOROS (2006)17 Dyslipidemia 60 60 53.5 + 7.9 53.3 + 7.7 10-6 w, 20-6 w, 6
20-6 w 40-6 w
Betteridge et al (2007)18 Dyslipidemia þ DM 227 229 61 + 11 62 + 11 10 10 2
Brunetti et al (2007)19 Dyslipidemia þ DM 11 11 60.3 + 7.2 60.2 + 10.0 10 20 3
Karalis et al (2010)20 Dyslipidemia 39 41 65.8 + 7.7 64.0 + 9.8 10 20 4.5
Hong et al (2011)21 Diameter stenosis 30%-70% þ 65 63 59 + 10 58 + 10 20 40 11
dyslipidemia
Thongtang et al (2011)22 Dyslipidemia 137 135 55.9 + 13.5 59.6 + 10.1 40 80 1.5
PATROL (2011)23 Dyslipidemia 96 96 61.7 + 10.3 61.5 + 9.5 2.5 10 4
Anagnostis et al (2011)24 Dyslipidemia 18 18 54.7 + 11.3 59.8 + 10.3 10 20 3
Tsutamoto et al (2011)25 Dyslipidaemia þ DM 31 32 59.8 + 8.8 60.6 + 10.9 2.5 5 6
Nicholls et al (2011)26 Dyslipidemia 520 519 57.4 + 8.6 57.9 + 8.5 40 80 26
Liu et al (2011)27 Stable atherosclerosis þ 18 18 58.3 + 9.2 56.8 + 10.1 10 20 1
dyslipidemia
Abbreviations: R, rosuvastatin; A, atorvastatin; Comets, comparative study with rosuvastatin in patients having metabolic syndrome; ATOROS, comparison of the
effects of ATOrvastatin and ROSuvastatin; PATROL, randomized head-to-head comparison of Pitavastatin, Atorvastatin, and Rosuvastatin for Safety and Efficacy
(Quantity and Quality of LDL); DM, diabetes mellitus.
a
In the RCT from Ferdinand et al 2006, eligible patients were randomized (1:1:1:1) to receive once daily 10- or 20-mg doses of rosuvastatin or atorvastatin.

Heterogeneity was considered significant when P < .10 for the Table 2. Clinical and Procedural Features in the Overall Population.
Q test or I2 >50%.
Variables Rosuvastatin Atorvastatin P Value
The funnel plots for CRP were visually inspected, and we
used Egger regression test to evaluate publication bias statisti- Population size 2032 1766
cally. We performed subgroup analysis based on drug dosage Men 1326 (65) 1209 (68) NA
levels (rosuvastatin/atorvastatin: 1/1, 1/2, and 1/4) to explore Family history of CAD 310 (15) 307 (17) NA
possible heterogeneity in each specific subpopulation. In addi- Hypertension 1201 (59) 1101 (62) NA
Diabetes mellitus 600 (29) 559 (32) NA
tion, we conducted an influence analysis by removing individual
Smoking 621 (30) 545 (31) NA
trials from the meta-analysis. We included CRP outcome data from Previous myocardial infarction 165 (8) 108 (6) NA
all available trials sequentially in the cumulative meta-analysis Previous PCI 248 (12) 270 (15) NA
based on the initial publication date to determine the development Previous CABG 2 (0) 3 (0) NA
of the observed effects with time. Metaregression at study level was Medical therapy 1991 (98) 1747 (99) NA
implemented to explore the effects of study treatments and LDL-C b-blocker 620 (30) 487 (28) NA
reduction on CRP reduction. ACEI/ARB 870 (43) 866 (49) NA
CCB 725 (36) 577 (33) NA
R 3.0.3 (R Foundation for Statistical Computing, Vienna,
Antithrombotic therapy 1822 (90) 1622 (92) NA
Austria. URL http://www.R-project.org/) with package ‘‘meta’’
was used for statistical analyses. Abbreviations: CAD, coronary artery disease; PCI, percutaneous coronary syn-
drome; CABG, coronary artery bypass graft; ACEI, angiotensin-converting
enzyme inhibitor; ARB, angiotensin II receptor antagonist; CCB, calcium channel
Results blocker; NA, not available.

Study Selection and Characteristics of Included Trials

We identified 53 potentially relevant studies. Of these, 13 RCTs
in 3798 patients treated with rosuvastatin or atorvastatin were
included (Figure 1). Follow-up varied from 1 to 26 months. The
designs employed in each trial are summarized in Table 1.15-27
We excluded study populations with ACS/HIV infection/meta-
bolic syndrome. The clinical and procedural characteristics of
the entire population are shown in Table 2. The quality of the
included RCTs is shown in Table 3.
Efficacy of Rosuvastatin Compared With Atorvastatin
in Reducing CRP
The differences (mg/L) in CRP concentrations from baseline
to follow-up were analyzed using the fixed-effect models
(Figure 2) and demonstrated significant benefits of rosuvasta-
tin compared with atorvastatin in all trials (MD ¼ 0.11,
which is standardized mean with no unit although the raw data
4 Angiology

Table 3. Quality of included RCTs.

Similarity Blinding
JADAD Allocation of Baseline Eligibility Outcome Care Intention Completeness
Trial score Concealment Characteristics Criteria Assessor Provider Patient to Treat Follow-Up

Stein et al (2003)15 5 NA Yes Yes No Yes Yes Yes Yes

Ferdinand et al (2006)16 5 NA Yes Yes Yes Yes Yes Yes Yes
ATOROS (2006)17 4 NA Yes Yes No Yes Yes Yes Yes
Betteridge et al (2007)18 5 Yes Yes Yes No Yes Yes Yes Yes
Brunetti et al (2007)19 3 NA Yes Yes No Yes Yes Yes Yes
Karalis et al (2010)20 5 Yes Yes Yes No Yes Yes Yes Yes
Hong et al (2011)21 4 NA Yes Yes No Yes Yes Yes Yes
Thongtang et al (2011)22 3 Yes Yes Yes No No No Yes Yes
PATROL (2011)23 4 NA Yes Yes No Yes Yes Yes Yes
Anagnostis et al (2011)24 3 NA Yes Yes No No No Yes Yes
Tsutamoto et al (2011)25 6 Yes Yes Yes Yes Yes Yes Yes Yes
Nicholls et al (2011)26 6 Yes Yes Yes Yes Yes Yes Yes Yes
Liu et al (2011)27 4 NA Yes Yes No Yes Yes Yes Yes
Abbreviation: NA, not available.

Figure 2. Forest plots of the meta-analysis. Forest plot of mean difference (mg/L) between rosuvastatin and atorvastatin with regard to changes
in C-reactive protein (CRP) concentration from baseline through follow-up.

before pooling is mg/L, 95% CI: 0.15 to 0.07, P < .0001).
No differences in the pooled data from random-effects models
were noted. However, minimal trial heterogeneity was detected
(I2 ¼ 6.9%, P ¼ .377).
We generated a funnel plot of the CRP mean differences
(mg/L) versus inverse of standard error for each trial (Figure 3)
to determine publication bias. Significant publication bias was
not detected (along with Egger linear regression test: P ¼ .382).
Subgroup analysis was performed according to the drug
dosage (rosuvastatin/atorvastatin: 1/1, 1/2, and 1/4). Statisti-
cally significant benefits of rosuvastatin compared with
atorvastatin were found for the 1/1 dose ratio (3 RCTs,
MD ¼ 0.14, 95% CI: 0.21 to 0.06) and 1/2 dose ratio
(9 RCTs, MD ¼ 0.11, 95% CI: 0.16 to 0.05). In terms
of anti-inflammatory effects, the 2 statins function equiva-
lently at 1/4 dose ratio (1 RCT, MD ¼ 0.05, 95% CI:
0.19 to 0.29; Figure 4).
To explore the evolution of the summary effect estimation
over time and the robustness when removing individual studies
one by one, cumulative and influence analyses were conducted,
respectively (Figures 5 and 6). Cumulative meta-analysis
showed significant mean difference (mg/L) between rosuvasta-
tin and atorvastatin (fixed-effect model) since Ferdinand KC
2006 (eg, 3 included studies with 810 participants then;
MD ¼ 0.21, 95% CI: 0.38 to 0.03. and the trend in favor
of rosuvastatin was maintained later on; Figure 5).
Ma et al 5

Figure 3. Funnel plot of the meta-analysis. Funnel plot of CRP mean difference (mg/L) vs inverse of standard error (along with Egger linear
regression test: P ¼ .382).

Figure 4. Subgroup meta-analysis of CRP mean difference (mg/L) between rosuvastatin and atorvastatin. Subgroup analysis was performed
according to drug dosage levels (rosuvastatin/atorvastatin: 1/1, 1/2, and 1/4).
6 Angiology

Figure 5. Cumulative meta-analysis. Cumulative meta-analysis of CRP mean difference (mg/L) between rosuvastatin and atorvastatin (fixed-
effect model).

Figure 6. Influence meta-analysis. Influence analysis of individual study using meta-analysis of CRP mean difference (mg/L) between rosuvastatin
and atorvastatin (fixed-effect model).

Influence analysis of individual studies using meta-analysis contributing most to the comprehensive result but not to a cru-
of CRP mean difference (mg/L) between rosuvastatin and ator- cial degree. The comprehensive result was not reversed omit-
vastatin (fixed-effect model) was shown in Figure 6. In this ting each study from the analysis. Meta-regression showed
‘‘leave-one out’’ sensitivity analysis, we identified a study as that the LDL-C change from baseline did not affect the fall
Ma et al
in CRP levels (estimated regression coefficient ¼ .003 and
P ¼ .358).
Discussion
Our study is an updated meta-analysis comparing the effects of
atorvastatin and rosuvastatin on CRP levels. The pooled anal-
ysis revealed a significant advantage (P < .0001) of rosuvasta-
tin compared with atorvastatin therapy in all 13 trials with no
evidence of significant publication bias. Subgroup analysis sta-
tistically indicated a significant benefit of using rosuvastatin
over atorvastatin found in 1/1 dose ratio and 1/2 dose ratio.
Cumulative and influence analyses reflected the accuracy and
stability of the estimate mentioned earlier. The study is under-
powered for the 1/4 comparison. Thus, no conclusion can be
derived on this issue.
Inflammation is now recognized as having comprehensive
ties with risk factors for atherosclerosis.28,29 Among the vari-
ous studied inflammatory biomarkers, CRP has received the
most attention because of its ability to predict the clinical
response to anti-inflammatory therapy.30,31 The CRP has been
used as an adjunct to risk prediction and reclassification of
CVD because of its involvement in the immunologic process
leading to vascular remodeling and plaque deposition, thereby
resulting in increased CV disease risk.32-35 The Justification for
the Use of Statins in Prevention: An Intervention Trial Evalu-
ating Rosuvastatin (JUPITER) trial randomized 17 802
intermediate-risk patients with LDL-C <130 mg/dL and hsCRP
>2 mg/L that were given rosuvastatin 20 mg or placebo.36 As
rosuvastatin resulted in 50% reductions in LDL-C and 37%
reduction in hsCRP levels, the trial was stopped early because
of a 44% relative risk reduction (RRR) (P < .00001) regarding
the primary end points myocardial infarction (MI), stroke,
revascularization, and hospitalization.36 Based on the JUPI-
TER trial, the US Food and Drug Administration included
asymptomatic JUPITER-eligible individuals with only 1 addi-
tional risk factor in the indications for rosuvastatin use.37,38 The
CRP was considered the most powerful inflammatory marker
predicting CV events but also triggered considerable contro-
versy. According to some subgroup analyses, some experts
thought that the CV protective effect of statins was affected by
the baseline CRP level. For patients with elevated CRP levels,
the effect of statins was greater, and for patients with lower CRP
and LDL-C levels, statin therapy may not be effective.39 The
CRP levels vary widely among different ages, sexes, and ethni-
cities.40 The Heart Protection Study trial, involving 20 536 high-
risk individuals, reported a correlation between baseline CRP
levels and CV events. It was shown that simvastatin treatment
resulted in reduction in the number of CV events, independent
of baseline CRP levels.41 After further statistical analysis, the
JUPITER trial also showed that the CV protective function of
rosuvastatin was not affected by the baseline CRP levels.42
Although epidemiological studies and large clinical trials
have failed to produce conclusive evidence for routine CRP
testing in risk prediction and for initiating statin therapy,
CRP can be used as a biological marker to evaluate the
7
anti-inflammatory effect of statins.43 Statin therapy reduces
LDL-C levels, CRP levels, slows down progression, and even
induces regression of atherosclerotic coronary lesions.44,45 The
Cholesterol and Recurrent Events (CARE), Pravastatin or
Atorvastatin Evaluation and Infection Therapy-Thrombolysis
In Myocardial Infarction 22 (PROVE IT–TIMI 22), and
Reversing Atherosclerosis with Aggressive Lipid Lowering
(REVERSAL) trials showed that intensive statins therapy
achieved a greater reduction in LDL-C and hsCRP levels and
reduced clinical events and reversed the progression of athero-
sclerosis.46-48 In the meta-analysis, the clinical benefit of pre-
treatment with high-dose statin in reducing periprocedural MI
after PCI compared to no statin therapy or therapy with low-
dose statin was prevalent in patients with elevated baseline
CRP levels.2 More and more evidence showed that achieving
lower levels of hsCRP was independently associated with bet-
ter long-term outcome.49
A number of studies reported that rosuvastatin compared
with atorvastatin at the same dose lower LDL-C levels to a
greater extent.5 We compared the anti-inflammatory ability
of these 2 statins. Our meta-analysis showed that rosuvastatin
provides a greater reduction in CRP levels compared with
atorvastatin at a dose ratio of 1/1 and 1/2 (rosuvastatin/atorvas-
tatin). Independent of different ‘‘potency’’ of pleiotropic
effects, statin therapy inducing LDL-C reduction may be asso-
ciated with greater CRP decrease. Thus, we corrected and
adjusted the results for LDL-C reduction during the 2 treat-
ments (atorvastatin vs rosuvastatin). Meta-regression showed
that the LDL-C change from baseline did not affect the fall
in CRP levels.
Anti-inflammation is one of the important pleiotropic
effects of statins. Takagi has conducted a meta-analysis of ran-
domized head-to-head trials of atorvastatin and rosuvastatin in
reduction of CRP. The RCTs through June 2011 were searched
using Internet-based Web sites (PubMed and OVID) with
unrestricted study populations. In our study, 13 RCTs enrolling
3798 patients (dyslipidemia without HIV/ACS/metabolic syn-
drome) were screened out from 2000 to June 2014, including
the SATURN study.10 The SATURN investigators performed
a series of CRP tests in 1039 patients at baseline and 104 weeks
after treatment with either atorvastatin (80 mg daily) or rosu-
vastatin (40 mg daily) to determine the effects of these 2 statin
regimens, with results favoring rosuvastatin to achieve lower
level of CRP and LDL-C and higher level of HDL-C. However,
these differences failed to show a significant incremental effect
in clinical benefits in preventing CV events. The Comparison
of high reloading ROsuvastatin and Atorvastatin pretreatment
in patients undergoing elective PCI to reduce the incidence
of MyocArdial periprocedural necrosis (ROMA II) trial com-
pared a reloading dose of rosuvastatin (40 mg, n ¼ 175) and
atorvastatin (80 mg, n ¼ 175) administered within 24 hours
before coronary angioplasty in reducing the rate of major car-
diac events in patients undergoing elective PCI. There was no
difference in terms of major adverse cardiovascular events
(MACEs) between the atorvastatin and the rosuvastatin groups
at 30 days, 6-, and 12-month follow-up.50 The 2 studies
8 Angiology
mentioned earlier showed that despite the fact rosuvastatin
lowers CRP more than atorvastatin, this did not result in more
clinical benefit probably because the absolute CRP reduction
with rosuvastatin versus atorvastatin was very low. This degree
of CRP decrease with rosuvastatin is unlikely to cause an addi-
tive clinical benefit compared with atorvastatin. Randomized
head-to-head trials of atorvastatin and rosuvastatin regarding
reduction in adverse CV events and decrease in the progression
of coronary atherosclerosis are rather limited, leading inevita-
bly to a requirement for prospective confirmation in a large-
scale trial focused on long-term clinical outcome.
Our analysis has several limitations. When SDs were una-
vailable, missing SDs were obtained according to the baseline
and follow-up CRP levels according to the Cochrane Hand-
book.12 We only included study populations with hyperlipide-
mia without ACS/HIV/metabolic syndrome which would have
increased heterogeneity.
In conclusion, rosuvastatin seems more effective than ator-
vastatin at lowering hsCRP levels but the clinical relevance of
this finding remains to be established. Any clinical benefit may
be masked by the small magnitude of the difference in hsCRP
lowering.
Authors’ Note
The corresponding author had full access to all the data in the study
and decided to submit the manuscript for publication. Y Zhou and
Q Ma contributed to substantial conception and design. Q Ma and G
Zhai contributed to acquisition of data. Y Zhou, F Gao and L Zhang
contributed to analysis and interpretation of data. Q Ma and J Wang
contributed to drafting the article. Q Yang and W Cheng contributed
to revising the article. Y Zhou gave final approval of the version to be
published.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article: supported
by the National Nature Science Foundation of China (#81400324).
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