Study selection and quality assessment
As shown in Fig 1, 4020 potentially relevant articles were identifed in the initial analysis. Among them, a total of 3391 articles were identified after removal of duplicate studies. Only 27 articles were retained after screening the title and abstract. Finally, 12 studies involving 3183 patients were included in the present meta‑analysis[7-18]. Among them, 1545 patients belonged to intensive statin treatment group and 1638 patients belonged to non-intensive statin treatment group. Further more, non-intensive statin treatment group involved moderate-intensity statin, placebo and no statin pretreatment group which included 738, 244 and 656 patients, respectively. All patients were female in one study[16]. The characteristics of the included studies were shown in Table 1. The baseline clinical, angiographic and procedural characteristics of patients are listed in Table 2. Quality assessment results were described in Table 3.
Table 1 Characteristics of the included studies
Study, years
|
Sample size(intensive/non-intensive statin)
|
Clinical Presentation
|
Statin medication history
|
Primary/Elective PCI
|
Statin Regimen
Before PCI
|
Statin Regimen After PCI
|
Follow‑up
(days)
|
Outcome indicators
|
|
|
|
|
|
|
|
|
Effectiveness
|
Safety
|
Liu et al,
2016[7]
|
616(307/309)
|
Stable
Angina, ACS
|
statin-naive or atorvastatin≤20 mg/day,
or equivalent dose statin
|
Elective PCI
|
atorvastatin 80mg 12h before PCI vs no statin pretreatment
|
40mg/d vs20mg/d
|
30
|
MACE, nonfatal MI
|
myalgia/myasthenia*
|
182(93/89)
|
STEMI
|
statin-naive or atorvastatin≤20 mg/day,
or equivalent dose statin
|
Primary PCI
|
atorvastatin 80mg just before primary PCI vsno statin pretreatment
|
40mg/d vs20mg/d
|
90
|
|
ALT
|
Jiao et al,
2015[8]
|
72(33/39)
|
NSTE-ACS
|
Not mentioned
|
Elective PCI
|
rosuvastatin 20mg 12h before PCI + 20mg just before PCI vs no statin pretreatment
|
10mg/d
|
30
|
MACE, cardiac death, nonfatal MI, TVR
|
|
Jiao et al,
2015[9]
|
126(62/64)
|
NSTE-ACS
|
Not mentioned
|
Elective PCI
|
rosuvastatin 20mg 12h before PCI + 20mg just before PCI vs no statin pretreatment
|
10mg/d
|
30
|
|
myalgia/myasthenia
|
Zheng et al,
2015[10]
|
1202(573/629)
|
Stable
Angina ,NSTE-ACS
|
statin-naive or atorvastatin≤20 mg/day,
or equivalent dose statin
|
Elective PCI
|
atorvastatin 80mg at night before PCI for 2-Day vsatorvastatin≤20mg or equivalent dose statin at night before PCI
|
40mg/d vs ≤20mg/d or equivalent dose statin
|
30
|
MACE, cardiac death, nonfatal MI, TVR
|
|
Xie et al,2014[11]
|
159(79/80)
|
NSTE-ACS
|
statin-naive
|
Elective PCI
|
rosuvastatin 20mg 12h before PCI + 20mg 2h before PCI vs no statin pretreatment
|
10mg/d
|
30
|
MACE, cardiac death, nonfatal MI, TVR
|
|
Yong et al,2014[12]
|
60(20/40)
|
STEMI
|
statin-naive
|
Primary PCI
|
atorvastatin 80mg 1.2h before PCI vs 20mg 1.2h before PCI
atorvastatin 80mg 1.2h before PCI vs no statin pretreatment**
|
20mg/d
|
30
|
MACE, cardiac death, nonfatal MI, TVR
|
myalgia/myasthenia, ALT
|
Luo et al,
2013[13]
|
67(31/36)
|
NSTE-ACS
|
statin-naive
|
Elective PCI
|
rosuvastatin 20mg 12h before PCI + 20mg 2h before PCI vs no statin pretreatment
|
10mg/d
|
30
|
MACE, cardiac death, nonfatal MI, TVR
|
|
Wang et al,2013[14]
|
125(62/63)
|
NSTE-ACS
|
statin-naive
|
Elective PCI
|
rosuvastatin 20mg 2~4h before PCI vsplacebo 2~4h before PCI
|
10mg/d
|
30
|
MACE, cardiac death, nonfatal MI, TVR
|
|
Li et al,
2013[15]
|
215(106/109)
|
Stable
Angina
|
regular statin for at least 3 months
|
Elective PCI
|
atorvastatin 80mg 12h before PCI vs 20mg 12h before PCI
|
20mg/d
|
30
|
MACE, cardiac death, nonfatal MI, TVR
|
|
Gao et al,2012[16]
|
117(59/58)
|
NSTE-ACS
|
statin-naive
|
Elective PCI
|
rosuvastatin 20mg 12h before PCI + 10mg 2h before PCI vs placebo 12h before PCI + 2h before PCI
|
10mg/d
|
90
|
MACE, cardiac death, nonfatal MI, TVR
|
|
Li et al,
2012[17]
|
161(78/83)
|
STEMI
|
statin-naive
|
Primary PCI
|
atorvastatin 80mg 1.5h before PCI vs placebo 1.5h before PCI
|
40mg/d
|
30
|
|
ALT
|
Yu et al,
2011[18]
|
81(41/40)
|
NSTE-ACS
|
statin-naive
|
Elective PCI
|
atorvastatin 80mg 12h before PCI + 40mg 2h before PCI vs placebo 12h before PCI + 2h before PCI
|
20mg/d
|
30
|
MACE, cardiac death, nonfatal MI, TVR
|
|
* Follow-up for 1 year; **Moderate-intensity group and no statin pretreatment group included 20 patients separately
NSTE-ACS non-ST segment elevation acute coronary syndrome, STEMI ST segment elevation myocardial infarction, PCI percutaneous coronary intervention, MI myocardial infarction, TVR target vessel revascularization
Table 2 Baseline clinical, angiographic and procedural characteristics in the overall population
Variable
|
High-intensity statin
n/population (%)
|
Moderate-intensity statin
n/population (%)
|
Placebo or no statin pretreatment
n/population (%)
|
Number of patients
|
1544/3183(48.5%)
|
758/3183(23.8%)
|
881/3183(27.7%)
|
Male
|
1070/1544(69.3%)
|
536/758(70.7%)
|
582/881(66.1%)
|
Hypertension
|
956/1544(61.9%)
|
501/758(66.1%)
|
544/881(61.7%)
|
Diabetes Mellitus
|
443/1449(30.6%)
|
234/758(30.9%)
|
251/778(32.3%)
|
Dyslipidaemia
|
201/771(26.1%)
|
152/649(23.4%)
|
78/201(38.8%)
|
Smokers
|
552/1544(35.8%)
|
293/758(38.7%)
|
297/881(33.7%)
|
Previous MI
|
99/630(15.7%)
|
9/20(45.0%)
|
96/632(%)
|
Previous PCI
|
159/1183(%)
|
51/629(%)
|
103/612(15.2%)
|
Previous CABG
|
6/500(1.2%)
|
0/0(0%)
|
6/496(1.2%)
|
Stable angina
|
230/506(45.5%)
|
109/109(100%)
|
118/398(29.6%)
|
NSTE-ACS
|
518/767(67.5%)
|
0/0(0%)
|
539/778(69.3%)
|
STEMI
|
223/498(44.8%)
|
20/20(100%)
|
224/501(44.7%)
|
Single vessel
|
84/266(31.6%)
|
6/20(30.0%)
|
80/279(28.7%)
|
Double vessel
|
106/266(39.8%)
|
4/20(20.0%)
|
111/279(39.8%)
|
More than three and triple vessel
|
81/266(30.5%)
|
10/20(50.0%)
|
95/279(34.1%)
|
Target vessel LM
|
36/877(4.1%)
|
25/629(4.0%)
|
7/320(2.2%)
|
Target vessel LAD
|
634/1038(61.1%)
|
427/649(65.8%)
|
261/483(54.0%)
|
Target vessel LCX
|
330/1038(31.8%)
|
201/649(31.0%)
|
159/483(32.9%)
|
Target vessel RCA
|
352/1038(33.9%)
|
243/649(37.4%)
|
168/483(34.8%)
|
B2/C lesions
|
346/609(56.8%)
|
0/0(0%)
|
333/615(54.1%)
|
Multivessel lesions
|
33/78(42.3%)
|
0/0(0%)
|
39/83(47.0%)
|
Multivessel intervention
|
244/773(31.6%)
|
215/629(34.2%)
|
62/201(30.8%)
|
Aspirin
|
1375/1491(92.2%)
|
622/738(84.3%)
|
802/822(97.6%)
|
Clopidogrel/Ticlopidine
|
1300/1385(93.9%)
|
541/629(86.0%)
|
807/822(98.2%)
|
β-blockers
|
1104/1491(74.0%)
|
495/738(67.1%)
|
630/822(76.6%)
|
ACEI/ARB
|
1045/1491(70.1%)
|
404/738(54.7%)
|
667/822(81.1%)
|
Glycoprotein IIb/IIIa inhibitors
|
95/370(25.7%)
|
9/20(45.0%)
|
113/380(29.7%)
|
DES
|
822/851(96.6%)
|
701/738(95.0%)
|
176/179(98.3%)
|
Previous MI previous myocardial infarction, Previous PCI previous percutaneous coronary intervention, Previous CABG Previous Coronary artery bypass grafting, NSTE-ACS non-ST segment elevation acute coronary syndrome, STEMI ST segment elevation myocardial infarction, LM left main, LAD left anterior descending, LCX left circumflex, RCA right coronary artery, DES drug-eluting stent
Table 3 Assessment of randomized controlled trials
|
Study, year
|
Randomization
sequence generation
|
Allocation
concealment
|
Blinding of participants,
personnel and outcome
assessors
|
Incomplete outcome
data
|
Selective
reporting
|
Other
sources
of bias
|
Liu et al, 2016[7]
|
Low risk
|
Low risk
|
High risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Jiao et al, 2015[8]
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Jiao et al, 2015[9]
|
Low risk
|
Low risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Zheng et al, 2015[10]
|
Unclear risk
|
Unclear risk
|
High risk
|
Low risk
|
Low risk
|
Unclear risk
|
Xie et al, 2014[11]
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Yong et al, 2014[12]
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Luo et al, 2013[13]
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Wang et al, 2013[14]
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Li et al, 2013[15]
|
Low risk
|
Low risk
|
Low risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Gao et al, 2012[16]
|
Unclear risk
|
Unclear risk
|
High risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Li et al, 2012[17]
|
Unclear risk
|
Unclear risk
|
Low risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Yu et al, 2011[18]
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Unclear risk
|
Effectiveness analysis
There were 10 studies that compared the effects of preoperative intensive statin therapy and non-intensive statin therapy on the incidence of MACE and nonfatal MI respectively[7-8,10-16,18]. Due to the heterogeneity between different results, a random effects model was used. The results showed the incidence of MACE (RR=0.49, 95%CI: 0.30~0.80, p=0.004, I2=63%, Fig. 2a) and nonfatal MI (RR=0.54, 95%CI: 0.33~0.88, p=0.01, I2=62%, Fig. 2b) between two groups were statistically significant. There were 9 studies that compared the effects of preoperative intensive statin therapy and non-intensive statin therapy on the incidence of cardiac death and target vessel revascularization[8,10-16,18]. Considering the homogeneity between the results, a fixed effect model was used and both indicators were not statistically significant(RR=0.37, 95%CI:0.01~8.96, p=0.54, Fig. 2c; RR=0.43, 95%CI:0.18~1.02, p =0.06, I2=0%, Fig. 2d).
Safety analysis
There were 3 studies that compared the effects of preoperative intensive statin therapy and non-intensive statin therapy on the incidence of myalgia/myasthenia[7,9,12] and abnormal ALT[7,12,17] respectively. No significant difference was observed between two groups(RR=1.35, 95%CI:0.30~5.95, p=0.69, I2=0%, Fig. 3a; RR=1.47, 95%CI:0.54~4.02, p=0.45, I2=0%, Fig. 3b).
Subgroup analysis according to intensive statin therapy
Due to the heterogeneity in MACE and nonfatal MI for the overall results, a subgroup analysis was attempted to find a source of heterogeneity. It was performed by dividing the non-intensive statin treatment group into moderate-intensity[10,12,15] and placebo/no statin treatment group[7,8,11-14,16,18] involving 10 studies. The results showed that the heterogeneity has disappeared in both two subgroup. Compared with the preoperative intensive statin therapy, the incidence of MACE and nonfatal MI were significantly elevated in patients receiving placebo or no statin treatment before surgery(RR=0.47, 95%CI: 0.34~0.65, p<0.00001, I2=0%, Fig. 2a; RR=0.49, 95%CI: 0.35~0.70, p<0.0001, I2=0%, Fig. 2b). These findings were consistent with the general population. However, the incidence of MACE and nonfatal MI were not statistically significant compared preoperative high-intensity statin therapy with moderate-intensity statin therapy(RR=0.96, 95%CI: 0.44~2.08, p=0.91, I2=11%, Fig. 2a; RR=1.10, 95%CI: 0.86~1.39, p=0.44, Fig. 2b). The results for this subgroup were inconsistent with overall results and could explain the cause of heterogeneity.
Sensitivity analysis
Considering the results of the subgroup were inconsistent with overall population, sensitivity analysis conducted further through the removal of any single trial. The heterogeneity of general population in MACE and nonfatal MI no longer existed when excluding the study by Zheng et al(RR=0.46, 95%CI: 0.33~0.65, p<0.00001, I2=0%, Additional file 1: Figure S1a; RR=0.49, 95%CI: 0.35~0.70, p<0.0001, I2=0%, Additional file 1: Figure S1b)and it did not essentially affect the results of pooled general population and subgroup[10].
Publication bias
The plots were symmetrical on visual inspection, indicating risk of publication bias (Fig.4). Egger’s regression test also demonstrated risk of publication bias (p=0.001, Fig.5). The small number of studies included in the overall population and subgroup may be one of the reasons for publication bias [19].