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. 2017 Aug 30;11:2517–2526. doi: 10.2147/DDDT.S135785

Secondary prevention of major cerebrovascular events with seven different statins: a multi-treatment meta-analysis

Ping Zhong 1,2,*, Danhong Wu 3,*, Xiaofei Ye 4, Ying Wu 2, Tuming Li 2, Shuwen Tong 2, Xueyuan Liu 1,5,✉
PMCID: PMC5587089  PMID: 28919704

Abstract

Background

Statins have been recommended for the use in atherosclerotic cardiovascular diseases, but different statins have distinct pharmacological characteristics. This multi-treatment meta-analysis aimed to evaluate the efficacy of seven statins in the secondary prevention of major cerebrovascular events (CVEs).

Methods and analyses

The PubMed, Embase, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials were searched to identify studies published between January 1, 2011, and June 30, 2016. The included randomized controlled trials investigated the efficacy of lovastatin, atorvastatin, fluvastatin, simvastatin, pitavastatin, pravastatin or rosuvastatin in the secondary prevention of CVEs. The primary outcomes were CVEs; the secondary outcomes were all-cause death, fatal stroke and nonfatal stroke. Meta-analysis and network meta-analysis were used for data synthesis.

Results

A total of 42 studies with 82,601 patients were included for analysis. In the secondary prevention of cardiovascular diseases, the major CVEs in pravastatin (risk ratio [RR] 0.87, 0.76–0.99)- and atorvastatin (RR 0.59, 0.49–0.72)-treated patients reduced significantly compared with controls. Indirect comparisons with network meta-analysis showed that RR was 0.60 (0.40–0.92) for atorvastatin compared with rosuvastatin. Compared to controls, the all-cause death was reduced by 12% in statins-treated patients (RR 0.88, 0.81–0.96). Indirect comparisons with network analysis showed a significant difference in the nonfatal stroke between fluvastatin-treated patients and lovastatin-treated patients (RR 0.28, 0.07–0.95).

Conclusion

Different statins have distinct pharmacological characteristics, and there are differences in statistical and clinical outcomes among several statins.

Keywords: atherosclerotic cardiovascular disease, cerebrovascular event, randomized, controlled trial, primary outcome

Introduction

In the past century, the disease profile changed significantly worldwide. Atherosclerotic cardiovascular disease (ASCVD) accounted for 1/10 of causes of death in early 1900s, but it has been the leading cause of death worldwide so far, accounting for one-third of causes of death. The prevalence of ASCVD increases with age. In addition, its prevalence further elevates in late life with the reduced mortality related to infection and malnutrition. Thus, ASCVD is affecting the decision making of world public health policy. Ischemic stroke is one of the most important clinical types of ASCVD and has a high recurrence rate. The ischemic stroke-related neurological impairment and subsequent emotional dysfunction and social dysfunction bring a great burden to the society and the families of these patients. Currently, controlling the serum lipid marker (low-density lipoprotein cholesterol [LDL-C]) is crucial to reduce the recurrence rate of transient ischemic attack (TIA) or ischemic stroke.1

To date, statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor) have been widely used in the lipid-lowering therapy. On the basis of findings from randomized controlled trials (RCTs), statins have been a major strategy in reducing the risk for ASCVD.2 Several clinical trials have shown that statins can significantly reduce serum LDL-C and effectively decrease the risk for stroke.3 Statins can reduce the incidence of major cardiovascular events, and thus, they have been recommended for the secondary prevention of ischemic stroke.1,4,5 In addition, there is evidence showing that high-dose statins are better to reduce the risk for stroke compared to standard-dose statins.6 However, there is still controversy on the clinical effects of different statins on the outcomes of ASCVD. A study indirectly compared influence of atorvastatin, pravastatin and simvastatin on the cerebrovascular events (CVEs), but it was a placebo-control study with a small sample size and there were active comparator trials in this study.7 The network meta-analysis was conducted to evaluate the RCT that investigated the effects of primary and secondary prevention with atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin in CVD patients, but it excluded head–head evaluation of different statins. Although another network meta-analysis used head–head evaluation, but pitavastatin was not investigated.8 Moreover, the incidence of cerebrovascular diseases was not a primary outcome in previous head–head network meta-analysis.9–12

Different statins have distinct pharmacological characteristics. As the number of patients in need for statin therapy continues to increase, information regarding the relative efficacy of statins is needed for better decision making. Meta-analysis with a large amount of updated data may provide true and strict clinical evaluation and accurately assess the therapeutic efficacy. This meta-analysis aimed to systemically evaluate the efficacy of statins in clinical studies that were conducted between statins-treated patients and routine controls or placebo controls and different statin-treated patients. In addition, the role of different statins in the secondary prevention of major CVEs was evaluated in patients with cardiovascular diseases.

Methods and analyses

Systematic review methods

We searched PubMed, Embase, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials to identify studies published between January 1, 2011, and June 30, 2016. We identified the studies prior to January 2011 from the bibliography of previously published systematic literature reviews and meta-analyses. We used the search terms “lovastatin”, “atorvastatin”, “fluvastatin”, “simvastatin”, “pitavastatin”, “pravastatin”, “rosuvastatin”, “cardiovascular disease” and “HMG-CoA reductase inhibitors/therapeutic use”. Two reviewers (PZ and DW) independently performed abstract, title and full-text screening and entered data into a data extraction form. A third reviewer (YW) approved the study selection.

The inclusion criteria were as follows: 1) open and double-blind RCTs were included; 2) head–head studies or those with placebo, diet or routine therapy as a control were included; 3) patients had cardiovascular diseases; 4) the number of patients was >60; 5) atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin was used for >4 weeks and 6) the primary outcomes were major CVEs, and the secondary outcomes were all-cause death, fatal stroke and nonfatal stroke. The major CVEs in this study included fatal stroke, nonfatal stroke and TIA; the nonfatal stroke did not include TIA. In addition, clinical studies in which there were patients with renal dysfunction were excluded. The study characteristics, including methods, participants, interventions and outcomes, were extracted from each study (Supplementary material).

Statistical analysis

To summarize all available evidence, we conducted both direct and network meta-analyses. First, we did traditional pairwise meta-analysis for direct comparisons between two treatment arms by Review Manager 5.1. In the conventional direct meta-analysis, two or more studies that compared two interventions of interest were statistically combined. We calculated the pooled risk ratio (RR) with a 95% CI. Heterogeneity was assessed using the Cochran’s Q and I2 statistics. For the Q statistic, a P-value >0.10 and for the χ2 test and for the I2 statistic, an I2 value <25% were interpreted as low-level heterogeneity. A pooled effect was calculated with a fixed-effect model when there was no statistically significant heterogeneity; otherwise, a random-effect model was used.

A network meta-analysis was conducted using a Bayesian Markov Chain Monte Carlo method and fitted in R package. Analytical results are presented as RR with 95% credible intervals (CrIs). The RR was estimated using the median of the posterior distribution, and 95% CrIs were obtained based on the 2.5th and 97.5th percentiles of the posterior distribution, which can be interpreted in the same way as conventional 95% CIs. Rankings for the treatment efficacy of the interventions were originally derived from Monte Carlo simulations and presented as the probability of possessing a specific ranking; the probabilities of different rankings of the same treatment were summed to 100%. Pooled results were considered as statistically significant for P<0.05 or if the 95% CI (CrI) did not contain the value 1. In this study, the patient samples from different statins were weighted in both pairwise meta-analysis and network meta-analysis.

Results

General data

A total of 20,770 studies potentially related to the topic were identified, of which 607 studies were included for final analysis and 20,163 unrelated studies that did not meet the inclusion criteria were excluded (Figure 1). In addition, 42 clinical trials published between 1994 and 2016 were included for network meta-analysis. The general information of these studies is presented in Table 1. In the studies included for network meta-analysis, 82,601 subjects received treatment with one of seven statins and 24.1% subjects were female. Of these studies, treatment with one statin was compared with control (placebo treatment, routine treatment or diet treatment) in 32 studies. Of these 32 studies, pravastatin was evaluated in 13 studies,13–25 atorvastatin in seven,26–32 lovastatin in three,33–35 simvastatin in three,36–38 fluvastatin in three,39–41 rosuvastatin in two42,43 and pitavastatin in one.44 In 10 studies, the treatment with one statin was compared with therapy of another statin.45–54 In these 10 studies, a statin was used at two doses in one study,54 the head–head study of atorvastatin and pravastatin was found in four studies,45,46,48,51 head–head study of atorvastatin and rosuvastatin was found in three studies49,50,54 (rosuvastatin at two doses was used in one study), head–head study of atorvastatin and simvastatin was found in two studies52,53 and head–head study of rosuvastatin and simvastatin was found in one study.47 The follow-up period ranged from 143 weeks to 317 weeks. In five studies, the follow-up period was <24 weeks. Figure 2 shows the meta-analysis of seven statins in the prevention of major CVEs.

Figure 1.

Figure 1

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Flowchart of study inclusion.

Table 1.

Characteristics of studies included

Year Trial name Mean age, years % woman Treatment Number randomized Major cerebrovascular events, n All-cause death, n Fatal stroke, n Nonfatal stroke, n TIA, n
1993 MARS33 58 9 Lovastatin 123 NR 2 NR NR NR
58 9 Placebo 124 NR 1 NR NR NR
1994 4S36 58.6 19 Simvastatin 2,221 124 182 14 95 19
58.6 18 Placebo 2,223 102 256 12 61 29
1994 MAAS37 54.9 12 Simvastatin 193 NR 4 NR NR NR
55.6 11 Placebo 188 NR 11 NR NR NR
1994 CCAIT34 53 18 Lovastatin 165 0 2 0 NR NR
53 19 Placebo 166 0 2 0 NR NR
1994 LRTS35 62 28 Lovastatin 203 0 3 NR 0 NR
62 29 Placebo 201 1 1 NR 1 NR
1995 PLAC-II16 63 15 Pravastatin 75 NR 3 NR NR NR
63 15 Placebo 76 NR 5 NR NR NR
1995 REGRESS17 56.5 0 Pravastatin 450 NR 5 0 NR NR
55.9 0 Placebo 434 NR 7 0 NR NR
1995 PLAC-I20 57 62 Pravastatin 206 0 4 0 0 NR
57 62 Placebo 202 2 6 0 2 NR
1996 CARE21 59 14 Pravastatin 2,081 54 NR NR 54 NR
59 14 Placebo 2,078 78 NR NR 78 NR
1997 PREDICT15 58.5 17 Pravastatin 347 1 4 1 NR NR
58.2 15.6 Placebo 348 0 1 0 NR NR
1998 LIPID13 62 17 Pravastatin 4,512 169 498 NR NR NR
62 17 Placebo 4,502 204 633 NR NR NR
2000 GISSP-P14 59.7 13.3 Pravastatin 2,138 20 72 4 16 NR
60 14.2 Placebo 2,133 19 88 4 15 NR
2000 SCAT38 61 13 Simvastatin 230 4 13 NR 4 NR
61 9 Placebo 230 2 6 NR 2 NR
2001 MIRACL31 65 35.5 Atorvastatin 1,538 12 64 3 9 NR
65 34.1 Placebo 1,548 24 68 2 22 NR
2002 GREACE27 58 22 Atorvastatin 800 9 23 NR 9 NR
59 21 Usual care 800 17 40 NR 17 NR
2002 FLORIDA39 61 19 Fluvastatin 265 2 7 2 NR NR
60 15 Placebo 275 1 11 1 NR NR
2002 LIPS41 60 15.8 Fluvastatin 844 2 36 2 NR NR
60 16.6 Placebo 833 1 49 1 NR NR
2002 PROSPER – secondary23 75.3 51.7 Pravastatin 2,891 135 298 22 116 77
75.4 51.7 Placebo 2,913 131 306 14 119 102
2003 TREAT TO 63 24.3 Atorvastatin 556 0 0 0 NR NR
TARGET52 62.5 24.8 Simvastatin 537 0 0 0 NR NR
2004 PROVE 58.1 22.2 Atorvastatin 2,099 21 46 NR 21 NR
IT-TIMI45 58.3 21.6 Pravastatin 2,063 21 66 NR 21 NR
2004 PACT24 NR 23.5 Pravastatin 1,710 NR 24 NR NR NR
NR 24.3 Placebo 1,698 NR 37 NR NR NR
2004 Bae et al28 60 37 Atorvastatin 105 1 0 0 1 NR
60 27 Usual care 100 1 0 0 1 NR
2004 ALLIANCE30 61.1 17.8 Atorvastatin 1,217 35 121 35 NR NR
61.3 17.7 Usual care 1,225 39 127 39 NR NR
2004 PCS19 59.2 91 Pravastatin 54 3 5 0 3 NR
59.9 92 Diet 66 4 3 0 4 NR
2004 REVERSAL51 NA NA Atorvastatin 327 1 1 NR 1 NR
NA NA Pravastatin 327 1 1 NR 1 NR
2005 PCABG18 59.6 19.7 Pravastatin 152 1 6 0 1 0
58.2 11.9 Placebo 151 6 11 1 5 1
2005 IDEAL53 61.6 19.2 Atorvastatin 4,439 NR 366 NR NR NR
61.8 19.1 Simvastatin 4,449 NR 374 NR NR NR
2005 Stone et al32 NR 14 Atorvastatin 96 1 1 NR 1 NR
NR 12 Placebo 103 0 0 NR 0 NR
2005 ATHEROMA25 NA NA Pravastatin 186 5 1 NR 5 NR
NA NA Diet 187 4 2 NR 4 NR
2006 SPARCL26 63 39.7 Atorvastatin 2,365 165 216 24 247 153
62.5 41 Placebo 2,366 311 211 41 280 208
2006 ASPEN – secondary29 60.5 38 Atorvastatin 252 7 26 NR NR NR
60.4 37 Placebo 253 9 27 NR NR NR
2007 SAGE46 72.4 31.2 Atorvastatin 446 NR 6 NR NR NR
72.6 29.9 Pravastatin 445 NR 18 NR NR NR
2007 CORONA42 73 24 Rosuvastatin 2,514 103 728 14 89 NR
73 24 Placebo 2,497 115 759 11 104 NR
2008 GISSI-HF43 68 23.8 Rosuvastatin 2,285 82 657 38 44 NR
68 21.4 Placebo 2,289 66 644 29 37 NR
2008 OACIS-LIPID22 63.6 26.7 Pravastatin 176 0 3 NR 0 NR
62.9 19.8 Usual care 177 2 2 NR 2 NR
2009 SPACE 62.1 20.7 Rosuvastatin 633 2 11 NR 2 1
ROCKET47 62.5 20.5 Simvastatin 630 0 16 NR 0 2
2010 FACS40 60.9 29.5 Fluvastatin 78 1 1 NR 1 NR
63.2 34.6 Placebo 78 3 4 NR 3 NR
2010 CENTAURUS49 NA NA Rosuvastatin 406 3 2 0 3 NR
NA NA Atorvastatin 423 0 4 NR 0 NR
2011 SATURN50 57.4 27.1 Rosuvastatin 520 3 NR NR 3 NR
57.9 25.6 Atorvastatin 519 2 NR NR 2 NR
2012 LUNAR54 52.9 11.2 Atorvastatin 278 NR 1 NR NR NR
53 15.3 20 rosuvastatin 277 NR 0 NR NR NR
52.8 15.9 40 rosuvastatin 270 NR 2 NR NR NR
2013 PEARL44 62.9 19.1 Pitavastatin 289 8 27 NR 8 NR
62.2 17.8 Control 288 9 37 NR 9 NR
2015 ALPS-AMI48 65.7 19 Pravastatin 261 10 14 5 5 NR
66.3 19.6 Atorvastatin 264 5 9 4 1 NR
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Abbreviations: TIA, transient ischemic attack; NR, not reported; NA, not applicable.

Figure 2.

Figure 2

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Meta-analysis of seven statins in the prevention of major CVEs.

Notes: Rosuvastatin vs atorvastatin: K=2, n=3,561, I2=0%; RR =0.68 (0.15–3.13); atorvastatin vs simvastatin: K=1, n=1,093, I2=0%; RR = not estimated; rosuvastatin vs control: K=2, n=9,585, I2=61%; RR =1.04 (0.75–1.44); atorvastatin vs pravastatin: K=3, n=5,341, I2=0%; RR =1.20 (0.71–2.00) and atorvastatin vs control: K=7, n=12,768, I2=7%; RR =0.59 (0.49–0.72).

Abbreviations: CVE, cerebrovascular event; RR, risk ratio.

Comparative benefits of statins on major CVEs: findings of the multiple-treatment meta-analyses

In 32 studies comparing statins treatment and control treatment, major CVEs were reported in 27 studies13–15,18–23,25–32,34–36,38–44 in which there were 66,007 patients and a total of 2,057 major CVEs. In the secondary prevention of cardiovascular diseases, results showed that pravastatin and atorvastatin could reduce the incidence of major CVEs by 13% and 41%, respectively, compared with the control group, but there was no significant difference between other statins and control (Table 2). In 10 head–head studies,45–54 the influence of statins on the major CVEs was reported in seven studies,45,47–52 in which there were 9,565 patients and a total of 69 major CVEs. Paired comparison in network meta-analysis showed a significant difference only between atorvastatin and rosuvastatin (RR 1.7,1.10–2.50).

Table 2.

Network meta-analysis of prevention of major CVEs: direction comparisons between statin treatment and control treatment as well as different statin treatments

Treatment comparison RR (95% CI)
Stain treatment vs control treatment
 Pravastatin vs control 0.87 (0.76–0.99)
 Atorvastatin vs control 0.59 (0.49–0.72)
 Fluvastatin vs control 1.01 (0.29–3.45)
 Simvastatin vs control 1.23 (0.96–1.59)
 Lovastatin vs control 0.33 (0.01–8.05)
 Rosuvastatin vs control 1.04 (0.75–1.44)
 Pitavastatin vs control 0.89 (0.35–2.26)
 All statins vs control 0.88 (0.71–1.10)
Two different statin treatments
 Pravastatin vs atorvastatin 1.20 (0.71–2.00)
 Atorvastatin vs rosuvastatin 0.68 (0.15–3.13)
 Rosuvastatin vs simvastatin 4.98 (0.24–103.45)
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Abbreviations: CVEs, cerebrovascular events; RR, risk ratio.

Comparative benefits of statins on all-cause mortality: findings of the multiple-treatment meta-analyses

The all-cause death was investigated in 40 studies,13–20,22–49,51–54 in which there were 76,483 patients and 7,328 deaths. Of included studies, statin treatment was compared with control treatment in 31 studies, in which there were 6,391 deaths occurring in 57,354 patients; comparison between two statin treatments was found in 10 studies,42,45–49,51–54 in which there were 937 deaths occurring in 19,133 patients. Direct meta-analysis showed that the mortality of any cause in statin-treated patients was reduced by 12% compared to the control group (RR 0.88, 0.81–0.96), and a significant difference was only noted between the pravastatin group and the control group (RR 0.84, 0.76–0.94). Comparison between two treatments showed significant difference between pravastatin and atorvastatin (RR 1.60, 1.17–2.19), but network meta-analysis showed a marked difference only between fluvastatin and lovastatin (RR 3.60, 1.10–14.00; Table 3).

Table 3.

Network meta-analysis of prevention of major CVEs and death of any cause with seven different statins

Pravastatin 0.73 (0.55–1.0) 1.1 (0.38–3.3) 1.2 (0.82–1.90) 1.3 (0.75–2.10) 2.8 (0.22–93.00) 1.8 (0.55–6.30) 1.1 (0.88–1.40)
1.10 (0.91–1.50) Atorvastatin 1.5 (0.51–4.5) 1.7 (1.10–2.50) 1.8 (0.97–2.80) 3.8 (0.29–1.3×102) 2.4 (0.73–8.50) 1.5 (1.10–1.90)
1.30 (0.70–2.50) 1.1 (0.61–2.10) Pitavastatin 1.1 (0.36–3.30) 1.2 (0.36–3.70) 2.5 (0.17–95.0) 1.6 (0.33–7.8) 1.0 (0.35–2.90)
1.00 (0.79–1.60) 0.92 (0.70–1.30) 0.81 (0.43–1.60) Rosuvastatin 1.10 (0.57–1.80) 2.3 (0.18–7.7) 1.5 (0.44–5.3) 0.92 (0.63–1.3)
1.10 (0.84–1.60) 1.00 (0.75–1.30) 0.88 (0.45–1.70) 1.10 (0.73–1.50) Simvastatin 2.2 (0.16–72.0) 1.4 (0.40–5.0) 0.85 (0.56–1.4)
0.37 (0.098–1.20) 0.33 (0.09–1.00) 0.29 (0.07–1.10) 0.35 (0.09–1.20) 0.33 (0.09–1.10) Lovastatin 0.62 (0.02–11.0) 0.39 (0.01–5.0)
1.30 (0.82–2.30) 1.20 (0.72–2.00) 1.00 (0.49–2.20) 1.30 (0.74–2.10) 1.20 (0.70–2.00) 3.60 (1.10–14.00) Fluvastatin 0.62 (0.18–2.0)
0.96 (0.82–1.20) 0.86 (0.71–1.00) 0.75 (0.41–1.40) 0.93 (0.68–1.20) 0.84 (0.66–1.10) 2.60 (0.83–9.80) 0.72 (0.45–1.10) Control
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Notes: RR is from the comparison of drugs in the rows and lines. The upper data refer to the influence of statins on major CVEs; the lower data refer to the influence of statins on the death of any cause. The underline indicates RR of comparison between drugs in the row and the line has statistical significance.

Abbreviations: CVEs, cerebrovascular events; RR, risk ratio.

Comparative benefits of statins on nonfatal and fatal strokes: findings of the multiple-treatment meta-analyses

Of the studies on pitavastatin, fatal stroke had never been reported. In 19 studies with 41,144 patients,14,15,17–20,23,26,28,30,31,34,36,39,41–43,48,52 the fatal stroke was reported in 323 patients. In 26 studies,14,18–23,25–28,31,32,35,36,38,40,42–45,47–51 nonfatal stroke was reported as an outcome, and it was found in 1,529 patients among 49,710 patients included in these studies. Direct meta-analysis showed no significant difference between statin treatment and control treatment as well as between two statin treatments. Table 4 summarizes the results of network meta-analysis of fatal stroke and nonfatal stroke. Our results showed that significant difference was observed in the nonfatal stroke only between atorvastatin and simvastatin (RR 1.9, 1.1–3.7).

Table 4.

Network meta-analysis of prevention of fatal stroke and nonfatal stroke with seven different statins

Pravastatin 0.50 (0.24–1.10) – 0.76 (0.28–1.70) 0.63 (0.16–1.90) 9.3×103 (0.20–2.5×1018) 1.9 (0.32–14.0) 0.57 (0.27–1.0)
0.84 (0.53–1.2) Atorvastatin – 1.5 (0.57–3.10) 1.3 (0.33–3.40) 1.9×104 (0.36–5.2×1018) 3.8 (0.66–26.0) 1.1 (0.57–1.7)
1.1 (0.36–3.3) 1.3 (0.43–4.0) Pitavastatin – – – – –
1.2 (0.73–2.0) 1.4 (1.10–3.70) 1.0 (0.35–3.4) Rosuvastatin 0.83 (0.23–2.5) 1.3×104 (0.21–3.4×1018) 2.5 (0.45–19.0) 0.73 (0.39–1.4)
1.6 (0.85–2.9) 1.9 (1.10–3.7) 1.5 (0.45–4.9) 1.4 (0.67–2.5) Simvastatin 1.5×104 (0.27–4.3×1018) 3.1 (0.46–29.0) 0.90 (0.35–2.6)
1.0 (0.02–58.0) 1.2 (0.02–65.0) 0.95 (0.02–48.0) 0.86 (0.02–51.0) 0.62 (0.01–35.0) Lovastatin 0.0002 (−1.0×1018–13) −5.9×105 (−2.1×1019–3.2)
0.65 (0.08–4.5) 0.79 (0.09–5.5) 0.59 (0.06–5.4) 0.56 (0.07–3.9) 0.40 (0.05–3.0) 0.61 (0.006–43.0) Fluvastatin 3.4 (0.67–24.0)
1.1 (0.81–1.5) 1.3 (0.98–1.9) 0.99 (0.35–2.9) 0.96 (0.60–1.4) 0.67 (0.41–1.2) 1.1 (0.02–58.0) 1.7 (0.25–14.0) Control
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Notes: RR is from the comparison of drugs in the rows and lines. The upper data refer to the influence of statins on fatal stroke; the lower data refer to the influence of statins on the nonfatal stroke. The underline indicates RR of comparison between drugs in the row and the line has statistical significance.

Abbreviation: RR, risk ratio.

Discussion

This meta-analysis was based on 42 studies in which a total of 82,601 subjects randomly received treatment with seven different statins. Statistical and clinical differences were found in several statins. Our results showed that, in the secondary prevention of cardiovascular diseases, the mortality of any cause was reduced by 12% after statin treatment compared to the control treatment; the incidence of major CVEs was reduced by 13% and 41% after treatment with pravastatin and atorvastatin, respectively, compared with the control treatment. Indirect comparison with network meta-analysis showed that rosuvastatin was better than atorvastatin in the prevention of major CVEs and fluvastatin was better than lovastatin in the prevention of nonfatal stroke when statins were used in the secondary prevention of cardiovascular diseases.

Statins have pleiotropic effects, including the lipid- lowering, vasodilation, anti-thrombotic, anti-inflammatory and anti-oxidative effects.55–62 Animal experiments and clinical studies have shown that statins may exert neuroprotective effects after acute cerebral infarction.63–65 Our results further confirmed and expanded previous results from meta-analysis. Clinical guideline recommends the use of statins in the secondary prevention of noncardiac stroke.66 To reduce LDL-C has been one of important strategies in the clinical prevention of cardiovascular events, and undoubtedly statins, are the most effective drugs used to reduce LDL-C. Statins may competitively inhibit hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, which is a rate-limiting enzyme in the endogenous cholesterol synthesis, and then block the metabolism of intracellular hydroxymaleic acid and reduce the endogenous production of cholesterol, exerting lipid-lowering effect. Although different statins have the identical mechanism in their lipid-lowering effect, the difference in the chemical structure among these statins makes their physical characteristics and internal pharmacokinetics different. SPARCL was the only one study that investigated the influence of statins used for secondary prevention on the TIA and stroke,26 but we could not expand their results to the use of other statins. In this study, meta-analysis was conducted in the population with cardiovascular diseases who were medicated with statins for the secondary prevention, and results showed difference among several statins. Probably, the actual difference among other statins might not be identified by this meta-analysis.

In this study, the majority of clinical trials included did not fully report the information about the randomization and allocation concealment, which may compromise the overall validity. Of note, the studies on different statins had similarities on the study design and implementation, and the lack of information about the quality assessment might be ascribed to the manuscript drafting but not to the actual defect in study design as shown in other systemic reviews.67 In our study, new network meta-analysis was used, and placebo-controlled and active comparator trials were merged to investigate the head–head studies of statins. Our study was different from previous network analysis: 1) not only placebo-controlled trials but also active comparator trials were included for analysis; 2) our study was an update of previous studies, and studies investigating seven commercially available statins (cerivastatin is not commercially available due to adverse effects) were included for analysis, which was not found in previous meta-analysis of stroke and 3) in this study, the major CVEs served as the main outcomes, but cardiovascular events were used as main outcomes in previous meta-analyses.

There were limitations in this study. First, this was a meta-analysis based on previous studies, and the number of studies included was limited. Only a few prospective, head–head clinical trials with clinical outcome were identified in the available studies. Second, the meta-analysis based on the data from published studies was limited by the quality of these studies. For example, the included studies that reported major CVEs might not report the fatal stroke. Third, there was a difference in the results of direct and indirect analyses, but direct comparison would make the results be more likely to be true. This difference might be related to the small sample size and the conservative nature of the Bayesian hierarchical random-effects model.

Conclusion

Different statins have distinct pharmacological characteristics and there are differences of statistical and clinical outcome among several statins.

Footnotes

Disclosure

The authors report no conflicts of interest in this work.

References

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