108 Journal of Atherosclerosis and Thrombosis　Vol.20, No.1

Original Article

Effect of Statin Therapy on the Progression of Common Carotid Artery Intima-Media Thickness: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials

Yubei Huang1, Weiqin Li2, Lili Dong3, Ruilai Li4 and Yangfeng Wu4, 5

1Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China2Tianjin Women’s and Children’s Health Center, Tianjin, China3Tianjin University of Traditional Chinese Medicine, Tianjin, China4The George Institute for Global Health, Beijing, China5Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China

Aim: To evaluate the effect of statin therapy on the decrease of common carotid artery intima-media thickness (CCA-IMT) compared to placebo or usual care.Methods: A systematic search of electronic databases (MEDLINE, EMBASE, and Cochrane Center Register) up to December 2011 was performed. Two reviewers independently determined the eligi-bility of randomized controlled trials (RCTs) comparing statin therapy with a placebo or usual care with a minimum follow-up of 6 months.Results: Twenty-one RCTs involving 6317 individuals were included in this review. The pooled weighted mean difference (WMD) between statin therapy and placebo or usual care on CCA-IMT was −0.029 mm (95%CI: −0.045, −0.013). Subgroup analyses showed significant effects of lovas-tatin (WMD: −0.077; 95%CI: −0.082, −0.073) and simvastatin (WMD: −0.069; 95%CI: −0.094, −0.045), followed by pravastatin and rosuvastatin, but no significant benefits of atorvastatin, fluvas-tatin, or cerivastatin. A greater decrease in mean CCA-IMT was observed in the setting of secondary prevention versus primary prevention (WMD: −0.045 vs. −0.004), in younger patients versus older patients (WMD: −0.057 vs. −0.041), and in studies where the patient proportion was males ≥ females (−0.044 vs. −0.008). Meta-regression analysis showed a significant association between changes in mean CCA-IMT with decreasing triglyceride levels. A similar, but not statistically significant trend was also found between CCA-IMT decrease and the decrease in LDL-C levels or increase in HDL-C levels.Conclusion: Statin therapy is associated with a favorable decrease in CCA-IMT, an effect that seems to be mainly driven by the CCA-IMT at baseline and the extent of lipid decrease, specifically triglyc-erides.

J Atheroscler Thromb, 2013; 20:108-121.

Key words; Statin, IMT, Systematic review, Meta-analysis, Trials

Introduction

The PLAC Ⅱ (Pravastatin, Lipids, and Atheroscle-

Address for correspondence: Yangfeng Wu, Room 334, Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, No. 38, Xueyuan Road, Haidian District, Beijing, 100191 ChinaE-mail: ywu@george.org.cn.Received: March 28, 2012Accepted for publication: July 24, 2012

rosis in the Carotids) study in 1995 was the first trial to demonstrate pravastatin’s role in reducing common carotid artery intima-media thickness (CCA-IMT) in hypercholesterolemic patients with coronary heart dis-ease1). Several other randomized controlled trials that followed further demonstrated statins’ beneficial effect on progression of CCA-IMT in a wide range of indi-viduals2-6). However, other trials soon emerged show-ing conflicting results7-12), including the Regression Growth Evaluation Statin Study (REGRESS), which

Yubei Huang and Weiqin Li contributed equally to this work.

109Statin Therapy and the Common Carotid Artery Intima-Media Thickness

at the end of the trial; and (3) follow-up was at least 6 months.

Data Sources and Searching StrategyTo identify relevant trials, searches in the follow-

ing 3 databases (from inception to October 25, 2011), MEDLINE (OVID), EMBASE, and Cochrane Cen-tral Register of Controlled Trials, were performed by two reviewers working independently and in parallel. References of related published major systematic reviews on the subject were also obtained and reviewed. Finally, the authors of possibly relevant trials were contacted when more information or clarification was needed.

Searches were not limited by language. Studies were obtained using the two groups of key terms as Medical Subject Headings in the searching strategies: 1) HMG-COA reductase inhibitor, hydroxymethylgl-utaryl-CoA reductase inhibitors, atorvastatin, fluvas-tatin, lovastatin, pravastatin, rosuvastatin and simvas-tatin; 2) carotid artery plaque, carotid artery diseases, carotid artery injuries, and carotid stenosis. (for details refer to Appendix 1).

Study SelectionTwo review authors (Huang and Li) working inde-

pendently and in parallel, scanned related abstracts and obtained the full text reports of studies when the abstract indicated or suggested the study was a RCT evaluating statin therapy based on the outcome of interest. After obtaining full reports of the candidate trials (either in full peer-reviewed publications or press articles), the same review authors independently assessed the eligibility of the studies for inclusion in the review. Any disagreement in study selection was adjudicated by a third reviewer (Wu).

Data CollectionThe same two review authors extracted data from

the eligible trials independently using standardized forms. Information about the statin, the type of inter-vention being tested, the baseline characteristics of the population being studied [age, sex, body mass index (BMI), current smoking, hypertension, history of myocardial infarction (MI), history of diabetes melli-tus (DM)], the baseline lipid levels [total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG)], the measurement and mean CCA-IMT in each arm, and the length of follow-up were collected.

When studies did not report baseline characteris-tics for the whole population, we re-calculated the

concluded that pravastatin had no effect on the far wall of CCA-IMT in male patients with coronary artery disease13).

Although previous systematic reviews have explored the effects of statin therapy on the progres-sion of CCA-IMT to make sense of the existing evi-dence, several critical concerns in the study designs of these reviews likely biased the pooled results. Ama-renco (2004) and Kang (2004) identified only 9 and 10 trials, respectively14, 15). The latest review (2010) included 11 trials16), but a few large-scale trials, such as the FAST (Fukuoka Atherosclerosis Trial)6), HYRIM (Hypertension High Risk Management trial)17), LiSA (Lescol in Severe Atherosclerosis trial)18), and PRE-VEND IT (Prevention of REnal and Vascular ENd-stage Disease Intervention Trial), were not included8). Each of these three reviews also included at least 2 of the following 4 trials, ARBITER (ARterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol), ASAP (Atorvastatin versus Simvastatin on Atherosclerosis Progression), Van and VYCTOR (The VYtorin on Carotid intima-media Thickness and Overall arterial Rigidity), which compared the effects of different statins but not statins with a placebo and/or usual care19-22). These selection choices undoubtedly caused heterogeneity among the included trials and biased the pooled results. Furthermore, none of the three reviews explored the effect of statin therapy on the progression of CCA-IMT in different subgroups with respect to the demographic characteristics of the participants, the duration of follow-up, and the type and dose of statin used.

In order to update the current evidence on statin therapy and its effect on CCA-IMT progression, we undertook this systematic review and meta-analysis to help resolve these uncertainties and further define statins’ effect on CCA-IMT.

Method

We conducted this systematic review according to the PRISMA statement23).

Eligibility CriteriaAll potential randomized controlled trials (RCTs)

and cluster-RCTs were considered for review, exclud-ing quasi-RCTs (trials with little or no randomiza-tion), and trials comparing different statins or differ-ent doses of the same statin on CCA-IMT. Only eligi-ble RCTs fulfilling the following criteria were included in this systematic review: (1) the RCT compares a statin with either a placebo or usual care (including diet control); (2) the RCT provides mean CCA-IMT

110 Huang et al.

plots of the WMD versus its standard error25, 26). The I2 statistic was calculated as a measure of the propor-tion of the overall variation that is attributable to between-study heterogeneity27, 28). Because cerivastatin was withdrawn from the market in 2001 due to reports of fatal rhabdomyolysis29), sensitivity analysis excluding the trials evaluating the effect of cerivastatin was conducted.

Pre-specified subgroup meta-analysis was used to explore potential sources of between-study heteroge-neity according to the type of statin, patient’s condi-tion (primary prevention or secondary prevention), study quality (JADAD scored as low or high), dura-tion of follow-up (≥2 years or ＜2 years), mean age of participants (≥60 years or ＜60 years) and gender pro-portion (male ≥ female or male ＜ female). Univariate meta-regression analysis was used to explore the dose response relationship between the change in CCA-IMT and baseline level of CCA-IMT, as well as the change in CCA-IMT and between-group differences in lipid level decrease30, 31).

All statistical analyses were performed with STATA (version 12.0).

arithmetical means. Any disagreement in data collec-tion was adjudicated by the same third reviewer (Wu).

Jadad scoring was used to assess the methodolog-ical quality of the studies24). Based on this system, studies are scored according to the presence of three key methodological features: randomization, blinding, and withdrawals/dropouts, with scores ranging from 0-5. Studies with a Jadad score of 4 or 5 are consid-ered high quality, while those receiving a score of 3 or less, low quality.

Data AnalysisWe calculated the weighted mean difference

(WMD) and appropriate 95% confidence intervals [CIs] using a random-effect model according to the number of patients based on intention-to-treat analy-sis when possible. The weight given to each study was equal to the inverse of the variance. In cases where studies did not report results based on intention-to-treat, we analyzed outcomes based on the randomized population.

Potential publication bias was assessed with the Begg test and represented graphically with funnel

229 reports identified using Medline,

EMBASE and Cochrane Center

181 reports excluded

- not randomized controlled trials (RCT)

- RCT with non-statin intervention

- RCT did not use intima-media thickness

(IMT) as outcome

46 reports identified from 35 potentially

relevant trials 14 trials excluded

- PLAS-II, KAPS, PHYLLIS, CAIUS did not

have enough data for meta-analysis

- Watanabe, OSACA-2, Yamada used

integrated backscatter values or plaque

thickness rather than IMT as outcome

- ARBITER, ASAP, Van, and VYCTOR

compared different statins

- Yu’s trial compared different doses of the

same statin

- Nakamura’s trial had a follow-up of less than

6 months

- Lorenzo’s trial was still ongoing

21 studies fulfilled the criteria and were

included

Fig.1. Flow chart of study selection.

111Statin Therapy and the Common Carotid Artery Intima-Media ThicknessTa

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250

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164

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522

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365

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162

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24 (1

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112 Huang et al.Ta

ble

2.M

ean

CC

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1.02

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1.07

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0.49

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1.05

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1.05

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0.87

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760

0.87

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890

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158

0.88

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890

0.90

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945

0.76

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1.09

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586

0.85

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864

0.79

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831

0.72

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690

0.66

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740

0.76

1/0.

778

0.80

0/1.

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0.81

0/0.

810

0.83

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1.37

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470

0.73

0/0.

770

1.04

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1.09

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0.48

7/0.

487

1.04

0/1.

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1.04

0/1.

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0.91

0/0.

810

0.88

0/0.

900

1.11

0/0.

900

0.86

0/0.

920

0.19

0/0.

190

0.29

0/0.

150

0.20

5/0.

216

0.11

6/0.

124

0.64

2/0.

501

0.17

7/0.

190

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9/0.

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0.13

0/0.

110

0.01

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0.12

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120

0.18

0/0.

150

0.16

0/0.

170

0.05

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0.19

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310

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100

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167

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0.12

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0.30

0/0.

240

0.22

0/0.

240

0.38

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240

0.27

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270

236.

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6.2

194.

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9.0

237.

6/23

6.1

212.

5/21

6.7

251.

5/25

5.2

229.

5/23

1.0

217.

9/22

1.0

289.

0/28

4.0

230.

3/23

4.1

229.

0/23

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236.

1/23

6.1

224.

5/22

4.5

239.

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6.8

198.

9/20

8.6

181.

9/17

4.2

255.

9/19

1.7

256.

1/19

1.7

302.

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0.0

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232.

2/19

3.5

251.

0/24

3.0

257.

0/24

3.0

247.

0/25

0.0

−

153.

0/18

3.0

−

173.

8/22

2.1

193.

7/24

0.0

−

177.

6/21

6.7

238.

7/27

0.1

155.

2/23

1.4

151.

0/23

0.0

193.

5/24

7.7

−

190.

4/23

7.6

162.

9/19

9.7

149.

0/17

4.2

− −

246.

0/29

8.0

− −

193.

5/19

3.5

201.

0/24

2.0

205.

0/24

2.0

202.

0/24

3.0

318.

6/32

7.5

193.

0/18

3.0

99.1

/105

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161.

1/16

6.4

168.

7/13

5.8

154.

0/16

2.0

157.

5/14

6.0

189.

0/18

3.0

157.

5/15

8.4

126.

0/13

4.0

203.

6/19

4.7

−

163.

7/16

1.1

−

147.

8/16

6.4

150.

4/12

9.1

184.

5/12

9.1

70.0

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0

− −

150.

5/11

5.1

− −

189.

0/17

6.0

−

174.

0/19

0.0

−

141.

6/15

2.2

− −

140.

7/14

8.7

−

119.

5/16

1.1

98.0

/139

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132.

8/22

1.3

−

147.

8/17

2.6

−

126.

6/17

7.9

− −

58.0

/65.

0

− −

141.

6/11

5.1

− −

154.

0/16

7.0

157.

1/15

5.6

122.

0/11

3.0

162.

5/16

2.5

133.

1/13

7.4

160.

7/17

1.6

149.

8/15

0.2

149.

8/15

5.6

198.

0/19

3.0

156.

0/15

8.7

155.

0/15

4.0

127.

7/12

3.8

−

168.

7/16

7.6

−

97.9

/92.

1

− −

239.

0/23

7.0

138.

5/13

1.6

140.

5/13

1.6

135.

5/13

1.6

150.

0/16

0.0

148.

0/16

0.0

154.

0/15

6.0

−

86.0

/109

.0

−

99.8

/146

.3

103.

0/15

7.0

130.

8/15

4.4

108.

0/14

7.8

144.

7/17

7.6

85.1

/154

.8

78.0

/152

.0

81.3

/127

.7

−

120.

4/16

6.4

−

72.0

/90.

2

− −

182.

0/23

7.0

97.1

/133

.5

84.0

/133

.5

123.

8/12

7.7

103.

0/15

3.0

108.

0/15

3.0

118.

0/15

6.0

52.2

/52.

0

37.6

/37.

3

53.4

/53.

4

47.6

/46.

8

56.7

/56.

5

49.1

/49.

5

36.8

/36.

4

53.0

/56.

0

43.0

/43.

3

50.0

/49.

0

52.2

/51.

1

−

38.3

/37.

5

−

48.4

/46.

1

51.5

/48.

3

49.0

/48.

3

47.0

/48.

0

− −

46.4

/50.

3

54.0

/60.

0

54.0

/60.

0

52.0

/57.

0

−

39.1

/36.

7

−

46.4

/47.

2

60.3

/59.

6

−

37.2

/35.

2

−

46.4

/44.

5

53.0

/50.

0

62.7

/50.

7

−

40.6

/36.

8

−

48.4

/47.

6

− −

50.0

/49.

0

− −

46.4

/46.

4

61.0

/62.

0

57.0

/62.

0

57.0

/55.

0

Not

e: B

: bas

elin

e; F

: end

of f

ollo

w-u

p; I

: int

erve

ntio

n; C

: con

trol

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113Statin Therapy and the Common Carotid Artery Intima-Media Thickness

IMT as the outcome measure35-37); (3) ARBITER, ASAP, Van, and VYCTOR compared different statins19-22); (4) Yu’s trial compared different doses of the same statin38); (5) Nakamura’s trial had a follow-up of less than 6 months39); and (6) Lorenzo’s trial was still ongoing at the time of our analysis40). Twenty-one studies met the inclusion criteria and were thus included in this systematic review (Fig.1).

Study CharacteristicsThe 21 trials (investigating 7 different statins) had

a sample size ranging from 36 to 984, and involved 6317 individuals2-13, 17, 18, 41-47). Twelve of the studies recruited participants with a previous history of car-diovascular disease or subclinical carotid atherosclero-sis (AS). The remaining 9 studies recruited partici-pants without an obvious diagnosis of carotid AS. The reported mean age of the participants ranged from 51 to 71 years old with the exception of Wiegman’s study

Role of the Funding SourceNo funding sources had a role in the study

design, data collection, analysis, interpretation or writ-ing of the report. The writing group had full access to all the data contained in the study and take final responsibility for the explanation of the results.

Results

Study SelectionA search of Medline, EMbase and Cochrane

Central provided 229 citations. Of these, 181 trials did not meet all the inclusion criteria based on a review of the abstracts and were discarded. Another 14 trials were excluded after reviewing the full papers: (1) PLAS-Ⅱ, KAPS, PHYLLIS, and CAIUS did not pro-vide enough data for meta-analysis1, 32-34); (2) Wata-nabe, OSACA-2, and Yamada used integrated back-scatter values or plaque thickness rather than CCA-

NOTE: Weights are from random effects analysis

Overall (I-squared = 95.7%, p = 0.000)

ID

Wu 2007-2

Ito 2004-2

METEOR 2007

ACAPS, 1994

Ito 2004-1

Wu 2007-1

LiSA, 1999

Wiegman 2004

BCAPS, 2001

REGRESS, 1998 PREVEND IT 2005

Reid 2005

Takahashi 2005-1

Beishuizen 2004

Peng 2006

Takahashi 2005-2

MARS, 1993

LIPID, 1998

Zhang 2004

FAST, 2002 HYRIM, 2004

Yokoyama 2005

Bae, 2004

Spring 2008

Study

-0.03 (-0.05, -0.01)

WMD (95% CI)

0.02 (-0.03, 0.07)

0.21 (-0.05, 0.47)

-0.02 (-0.03, -0.00)

-0.04 (-0.07, -0.00)

-0.02 (-0.21, 0.17)

0.02 (-0.03, 0.07)

0.03 (0.01, 0.05)

0.00 (-0.01, 0.01)

-0.04 (-0.07, -0.01)

-0.01 (-0.02, 0.00) 0.00 (-0.03, 0.03)

-0.10 (-0.24, 0.04)

-0.00 (-0.11, 0.10)

-0.01 (-0.04, 0.02)

-0.28 (-0.33, -0.23)

0.05 (-0.06, 0.17)

-0.08 (-0.08, -0.07)

-0.04 (-0.04, -0.04)

0.10 (-0.05, 0.25)

-0.50 (-0.67, -0.32) -0.01 (-0.04, 0.02)

-0.06 (-0.23, 0.11)

-0.01 (-0.07, 0.05)

-0.04 (-0.08, -0.00)

Statin

61, 1.040 (0.120)

12, 1.110 (0.380)

702, 0.761 (0.120)

230, 1.123 (0.190)

13, 0.880 (0.220)

50, 1.040 (0.110)

187, 0.720 (0.130)

106, 0.487 (0.048)

395, 0.905 (0.205)

131, 0.831 (0.051) 317, 0.810 (0.160)

28, 1.370 (0.190)

15, 1.041 (0.136)

125, 0.765 (0.116)

82, 0.800 (0.180)

15, 1.099 (0.153)

99, 0.662 (0.012)

273, 0.790 (0.009)

24, 0.910 (0.300)

83, 1.091 (0.642) 283, 0.855 (0.177)

20, 0.860 (0.270)

105, 0.880 (0.290)

48, 0.730 (0.090)

N, mean (SD);

2913

Control

40, 1.020 (0.120)

11, 0.900 (0.240)

282, 0.778 (0.120)

231, 1.158 (0.190)

11, 0.900 (0.240)

40, 1.020 (0.120)

178, 0.690 (0.110)

108, 0.487 (0.044)

398, 0.945 (0.216)

124, 0.842 (0.050) 325, 0.810 (0.170)

26, 1.470 (0.310)

15, 1.045 (0.167)

125, 0.774 (0.124)

80, 1.080 (0.150)

15, 1.045 (0.167)

89, 0.740 (0.017)

249, 0.831 (0.009)

28, 0.810 (0.240)

81, 1.586 (0.501) 285, 0.864 (0.190)

20, 0.920 (0.270)

100, 0.890 (0.150)

52, 0.770 (0.100)

N, mean (SD);

100.00

Weight

4.42

0.37

6.74

5.43

0.68

4.40

6.20

6.96

5.85

6.96 6.14

1.14

1.67

5.81

4.20

1.55

7.22

7.26

1.00

0.75 5.78

0.82

3.45

5.22

% WMD (95% CI)

3404

Statin reduces IMT Statin increases IMT 0 WMD (95% CI)

Fig.2. Meta-analysis of statin therapy on the progression of mean CCA-IMT.

114 Huang et al.

This was consistent across both the low and high qual-ity studies as identified by JADAD scoring. A signifi-cant decrease in mean CCA-IMT was observed in studies using statins for secondary prevention (WMD: −0.045; 95%CI: −0.046, −0.043), but not primary prevention (WMD: −0.004; 95%CI: −0.013, 0.006). The effect was also significant only after a duration of at least 2 or more years on statin therapy (WMD: −0.044; 95%CI: −0.045, −0.043). The effect was observed to be greater among a younger patient pop-ulation than an older patient population (WMD: −0.057 vs. −0.041), and in trials where males out-numbered females (−0.044 vs. −0.008) (Table 3).

In an attempt to identify other sources of resid-ual difference between trials, we performed meta-regression analysis of baseline mean CCA-IMT and the net decrease (difference between decrease of inter-vention and control group) in lipid levels (TC, TG, LDL-C and HDL-C) (Fig.4). Of these variables, we found a significant association between decreases of mean CCA-IMT with net decrease in TG levels. A similar, but not statistically significant trend was also seen in mean CCA-IMT decrease and decrease in LDL-C levels and increase in HDL-C levels. No such association was found in regard to changes in TC levels.

Discussion

Summary of EvidenceOverall, statins can significantly reduce CCA-

IMT compared to a placebo or usual care; however,

(mean age 13 years old)47), and the proportion of males in the included studies ranged from 32% to 100% (Table 1). CCA-IMT was measured with B- mode ultrasound in all included cases (for details refer to Appendix 2) and the mean CCA-IMT at baseline ranged from 0.495 mm to 1.525 mm (Table 2).

Syntheses of ResultsWe detected a significant weighted mean differ-

ence (WMD) in the decrease in mean CCA-IMT between statin therapy and placebo or usual care (WMD: −0.029; 95%CI: −0.045, −0.013). Strong evidence of heterogeneity (I2=95.7%, p＜0.001) was observed (Fig.2). Sensitivity analyses excluding the trial evaluating the effect of cerivastatin resulted in a minor increase in the I2 from 95.7% to 95.9%, but no change in the pooled WMD46). Another sensitivity analysis excluding Wiegman’s trial resulted in a slight improvement in heterogeneity, but again no change in the pooled WMD47); however, both the Begg test (p=0.005) and funnel plots (Fig.3) demonstrated a significant publication bias when looking at all 21 tri-als.

Additional AnalysesSubgroup analyses showed significant effects of

lovastatin (WMD: −0.077; 95%CI: −0.082, −0.073) and simvastatin (WMD: −0.069; 95%CI: −0.094, −0.045) on the decrease of mean CCA-IMT, followed by pravastatin and rosuvastatin, but no significant benefits of atorvastatin, fluvastatin, or cerivastatin.

0

.05

.1

.15

S

E(W

MD

)

-0.6 -0.4 -0.2 0 0.2

Weighted mean difference (WMD)

Fig.3. Funnel plot of the weighted mean difference versus its SE.

115Statin Therapy and the Common Carotid Artery Intima-Media Thickness

showed that lowering serum cholesterol is effective in controlling the progression of CCA-IMT in a preven-tative setting and/or in patients whose presentation of atherosclerosis is still at an asymptomatic stage32, 33).

Thirdly, we found a significant relationship between CCA-IMT decrease and the net decrease in TG (Fig.5). We also found a strong, although not sta-tistically significant relationship between the magni-tude of CCA-IMT decrease and the net decrease in LDL-C levels. The role of hypertriglyceridemia in the pathogenesis of atherosclerotic disease has been con-troversial for many years48, 49), despite extensive inves-tigation by basic scientists, clinicians, and epidemiolo-gists. Because triglycerides do not accumulate in the vessel wall, its atherogenicity is thought to be based on the association between triglycerides and cholesterol50). Because of the multiple links between elevated triglyc-eride levels and risk for atherosclerotic cardiovascular disease, it seems prudent to screen for the presence of hypertriglyceridemia when determining a patient’s risk for atherosclerotic cardiovascular disease. A therapeu-tic program targeting a decrease of triglycerides is even more important in patients with hypertriglyceridemia than in persons with isolated hypercholesterolemia50).

Fourthly, findings from CAIUS and ACAPS sug-

this beneficial effect is not consistently seen in all statins, as insufficient evidence was found in the cases of atorvastatin, fluvastatin and cerivastatin. This is the first difference drawn from our systematic review compared with previous systematic reviews; however, further studies are needed to clarify the differential effects of statins on CCA-IMT.

Secondly, we found that the effect of lipid lower-ing on decreases in CCA-IMT was significant only in the setting of statin’s use in secondary prevention, namely in the presence of carotid AS or more advanced arterial diseases such as coronary artery dis-ease, but not in the setting of primary prevention. A possible explanation for this observation may be due to the larger IMT seen in more serious diseases, thus providing greater potential for decrease; however, this does not mean that statin therapy is unnecessary in the primary prevention of subclinical carotid AS. The lack of statin’s beneficial effect in a primary prevention setting may be due to the small sample size, because the pooled WMD was still negative at −0.004, although statistically insignificant. An included trial that looked at statin therapy in the setting of primary prevention, FAST6), showed it to be effective in reduc-ing CCA-IMT. Similar findings in CAIUS and KAPS

Table 3. Pre-specified subgroup analysis of statin therapy on the progression of mean CCA-IMT

Subgroup analysis Number of study Weighted mean difference (95%CI) p for test of WMD=0 I2

Type of statinLovastatinAtorvastatinFluvastatinSimvastatinPravastatinRosuvastatinCerivastatin

Patient conditionSecondary preventionPrimary prevention

Study qualityLowHigh

Duration of follow-upFollow up ≥2 yrsFollow up ＜2 yrs

Mean ageAge ≥60Age ＜60

GenderMale ≥FemaleMale ＜Female

2444811

1113

186

1311

1311

146

−0.077 (−0.082, −0.073)−0.008 (−0.031, 0.016)−0.002 (−0.018, 0.014)−0.069 (−0.094, −0.045)−0.040 (−0.041, −0.038)−0.017 (−0.034, 0.000)−0.020 (−0.206, 0.166)

−0.045 (−0.046, −0.043)−0.004 (−0.013, 0.006)

−0.067 (−0.070, −0.063)−0.040 (−0.041, −0.038)

−0.044 (−0.045, −0.043)0.009 (−0.007, 0.025)

−0.041 (−0.043, −0.040)−0.057 (−0.060, −0.053)

−0.044 (−0.046, −0.043)−0.008 (−0.019, 0.002)

＜0.0010.5230.772

＜0.001＜0.001

0.0440.833

＜0.0010.443

＜0.001＜0.001

＜0.0010.274

＜0.001＜0.001

＜0.0010.118

82.80%45.00%77.90%96.60%93.30%−

−

97.60%70.20%

94.10%94.10%

97.50%38.70%

90.60%97.10%

97.10%86.10%

116 Huang et al.

Fig.4. The association between the effect of statin therapy and baseline mean CCA-IMT and between-group differ-ences in lipid reduction.

NO Trial

1 ACAPS, 1994

2 Bae, 2004

3 BCAPS, 2001

4 Beishuizen 2004

5 FAST, 2002

6 HYRIM, 2004

7 LIPID, 1998

8 LiSA, 1999

9 MARS, 1993

10 METEOR 2007

11 Peng 2006

12 PREVEND IT 2005

13 REGRESS, 1998

14 Reid 2005

15 Spring 2008

16 Takahashi 2005-1

17 Takahashi 2005-2

18 Wiegman 2004

19 Wu 2007-1

20 Wu 2007-2

21 Zhang 2004

22 Ito 2004-1

23 Ito 2004-2

24 Yokoyama 2005

NOTE: (1) Between-group lipid

reduction (mg/dl) =

reduction in intervention group –

reduction in control group;

Reduction in intervention group =

mean lipid value at baseline (I) –

mean lipid value at follow up (I);

Reduction in control group =

mean lipid value at baseline (C) –

mean lipid value at follow up (C);

I, intervention; C, control.

(2) Negative weighted mean

difference (WMD) indicates

regression of CCA-IMT. By contrast,

positive WMD indicates progression.95%CI of WMD WMD prediction valueWMD for each trial

1898 1012154 76

2113222243

23

11

161920171

5

14

-0.6

-0.4

-0.2

00

.20

.4

0.5 1 1.5 CCA-IMT (mm) at baseline

WMD

21615 2

23

7 248

224

5

19 13

11

18209

10

-0.6

-0.4

-0.2

00

.20

.4

0 20 40 60 80Between-group LDL-C reduction, mg/dl

1415 27

824

21

5

4 2213

23

18

11

910

-0.6

-0.4

-0.2

00

.20

.4

30 40 50 60 70 80Between-group TC reduction, mg/dl

11

24 22

2113

9218107

23

5

154

-0.6

-0.4

-0.2

00

.20

.4

-10 -5 0 5Between-group HDC reduction, mg/dl

421

18 7 24213 1510

9

11

-0.6

-0.4

-0.2

0.0

20

.4

0 20 40 60 80 100 Between-group TG reduction, mg/dl

117Statin Therapy and the Common Carotid Artery Intima-Media Thickness

ues could not be calculated. Although we can still use the data from the remaining studies with complete baseline and follow-up lipid values, the results may lead to lower power for the conclusion.

Conclusions

Statins can significantly reduce the common carotid intima-media thickness when compared with a placebo or usual care, and this effect is mainly driven by baseline CCA-IMT and the extent of between-group lipid decrease.

Conflict of Interest

None.

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118 Huang et al.

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120 Huang et al.

Appendix 1. Searching strategies

MEDLINE (OVID)(up to 10-25-2011)

1. exp Clinical Trial/2. exp Random Allocation/3. exp Single Blind Method/4. exp Double Blind Method/5. (random$ adj5 trial$).tw.6. (random$ adj5 allocation$).tw.7. (Blind$ adj5 method$).tw.8. 1 or 2 or 3 or 4 or 5 or 6 or 79. exp statin/

10. exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/11. exp HMG-COA reductase inhibitor/12. exp lovastatin/13. exp pravastatin/14. exp simvastatin/15. 9 or 10 or 11 or 12 or 13 or 1416. exp carotid artery plaque/17. exp Carotid Artery Diseases/18. exp Carotid Artery Injuries/19. exp Carotid Stenosis/20. 16 or 17 or 18 or 1921. 8 and 15 and 20

COCHRANE CONTROLLED TRIALS(MeSH descriptor explode all trees)(up to 2011-10-25)

#1. MeSH descriptor Hydroxymethylglutaryl-CoA Reductase Inhibitors explode all trees#2. MeSH descriptor Simvastatin explode all trees#3. MeSH descriptor Lovastatin explode all trees#4. MeSH descriptor Pravastatin explode all trees#5. MeSH descriptor Carotid Artery Diseases explode all trees#6. MeSH descriptor Carotid Artery Injuries explode all trees#7. MeSH descriptor Carotid Stenosis explode all trees#8. (#1 OR #2 OR #3 OR #4)#9. (#5 OR #6 OR #7)

#10. (#8 AND #9)

EMBASE (up to 2011-10-25)(‘controlled clinical trial’ or ‘randomizedcontrolled trial’)

#1. ‘statin’/exp#2. ‘hydroxymethylglutaryl coa’ AND ‘reductase’/exp AND ‘inhibitors’/exp#3. ‘hmg coa’/exp AND ‘reductase’/exp AND ‘inhibitor’/exp#4. ‘lovastatin’/exp#5. ‘pravastatin’/exp#6. ‘simvastatin’/exp#7. ‘atorvastatin’/exp#8. ‘rosuvastatin’/exp#9. ‘pitavastatin’/exp

#10. ‘fluvastatin’/exp#11. ‘carotid’/exp AND ‘artery’/exp AND ‘plaque’/exp#12. ‘carotid’/exp AND ‘stenosis’/exp#13. ‘carotid’/exp AND ‘artery’/exp AND ‘diseases’/exp#14. ‘carotid’/exp AND ‘artery’/exp AND ‘ injuries’/exp#15. #11 OR #12 OR #13 OR #14#16. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10#17. #15 AND #16

121Statin Therapy and the Common Carotid Artery Intima-Media Thickness

Appendix 2. Measurement of common carotid artery IMT in included trials

Trial, Year of Publication

Measurement of common carotid artery IMT

ACAPS, 1994

B-mode ultrasound with a 10-MHz transducer was used to measure mean IMT, proximal and distal, to the common carotid, the bifurcation, and the internal carotid arteries on both sides of the neck.

Bae, 2004

B-mode ultrasound (Hewlett-Packard Sonos 5500) with a 7.5 MHz probe was used to measure left common carotid artery IMT using M’ATH software.

BCAPS, 2001

B-mode ultrasound (Acuson 128) with a 7-MHz transducer was used to measure mean IMT in the common carotid artery (10-mm-long section) and maximum IMT in the carotid bulb.

Beishuizen, 2004

B-mode ultrasound (Acuson Aspen) with a linear array 7.5-MHz probe was used to measure IMT 1.0 cm distal to the common carotid artery, the carotid bifurcation, and 1.0 cm proximal to the internal carotid artery.

FAST, 2002

B-mode ultrasound (Aloka SSD-2000) with a 7.5-MHz transducer was used to measure IMT 2, 2.5 and 3 cm proximal to the carotid bifurcation in each of the right and left common carotid arteries.

HYRIM, 2004

B-mode ultrasound (Acuson 128) with a 7-MHz transducer was used to measure mean IMT at the right carotid artery from 30mm proximal to 10mm distal to the bifurcation, including the common carotid artery (CCA), the bifurcation, and interna and externa

LIPID, 1998

B-mode ultrasound (ATL UM-8) with a 10-MHz transducer was used to measure IMT; three views of the right distal common carotid artery were collected.

LiSA, 1999

B-mode ultrasound (7.5 MHz) was used to measure IMT located in the common 10 mm distal to the bifurcation, and in the interna and externa 10 mm proximal to the bifurcation, both left and right sides.

MARS, 1993

B-mode ultrasound (Diasonics CV400) with a 7.5-MHz probe (Diasonics, Milpitas, California) was used to measure IMT at the proximal and distal walls of the right distal common carotid artery.

METEOR, 2007

B-mode ultrasound was used to measure common carotid artery IMT in the segment extending from 10 to 20 mm proximal to the tip of the flow divider.

Peng, 2006

B-mode ultrasound (Acuson Aspen) with a linear array 7.5-MHz probe was used to measure IMT at the carotid bifurcation, and the proximal 1.0-1.5 cm of the internal carotid artery.

PREVEND IT, 2005

B-mode ultrasound (Pie Medical Scanner 200) with a linear array 7.5-MHz transducer was used to measure IMT at the posterior wall of the left common carotid artery 1 cm proximal to the bulbus at 3 different positions.

REGRESS, 1998

B-mode ultrasound (Acuson 128) with a linear array 7.0-MHz transducer was used to measure IMT at the carotid bulb (carotid dilation and carotid flow divider) and internal carotid artery (1 cm proximal to the carotid dilation), right and left.

Reid, 2005

B-mode ultrasound (ATL5000) with a linear array 7.0-MHz transducer was used to measure IMT at the carotid artery bifurcation, 2 cm lengths of the distal common carotid artery, right and left.

Spring, 2008 B-mode ultrasound with a linear array 7.5-MHz transducer was used to measure IMT at the right brachial artery.

Takahashi, 2005-1

B-mode ultrasound (Powerversion SSA-370A) with a 7.5-MHz transducer was used to measure IMT at the bifurcation far wall of both common carotid arteries.

Wiegman, 2004

B-mode ultrasound (Acuson 128) with a 5-10-MHz transducer was used to measure IMT at left and right far walls of the common carotid arteries.

Wu, 2007-1

B-mode ultrasound (EUB-6500) with a 10-MHz transducer was used to measure IMT 3 cm proximal to the carotid bifurcation 6 times.

Zhang, 2004

B-mode ultrasound (SONOS-5500) with a 4-10-MHz transducer was used to measure IMT at the common carotid, internal carotid arteries, the bifurcation, and 2 cm proximal to the carotid bifurcation.

Ito, 2004-1

B-mode ultrasound (SONOS-5500) with a 5-12-MHz transducer was used to measure IMT in the middle of the bilateral common carotid arteries and the bifurcation of the external carotid artery and internal carotid artery.

Yokoyama, 2005

B-mode ultrasound (SONOS-5500) with a 5-12-MHz transducer was used to measure IMT in the middle of the right common carotid arteries and bifurcation of the external carotid artery and the internal carotid artery.