Intensive versus non-intensive statin pretreatment before percutaneous coronary intervention in Chinese patients: a meta-analysis of randomized controlled trials

Background: Studies of intensive statin pretreatment before percutaneous coronary intervention (PCI) was very limited in Chinese and there were no corresponding meta-analysis involving hard clinical endpoints has been published so far. Therefore, the guidelines did not give a positive recommendation, which was inconsistent with Western people. The aim of this study was to evaluate the efficacy and safety of high-dose statin loading before PCI in Chinese patients through meta-analysis. Method: Relevant studies were identified via search of electronic databases of PubMed, Embase, and Cochrane’s Library to December 2019. The outcomes included major adverse cardiovascular event (MACE), nonfatal myocardial infarction(MI), cardiac death, target vessel revascularization (TVR), myalgia/myasthenia and abnormal alanine aminotransferase (ALT) in all enrolled patients were assessed. Results: 12 studies involving 3183 individuals were included in this reviewThe results showed different from cardiac death and TVR, the incidence of MACE ( RR =0.49, 95% CI : 0.30 to 0.80, P =0.004, I 2 =63%) and nonfatal MI ( RR =0.54, 95% CI : 0.33~ 0.88, P = 0.01, I 2 =62%) between intensive statin and non-intensive statin treatment group were statistically significant. The subgroup analysis further suggested the benefits of different treatment were not consistent. 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 : 0.340.65, P <0.00001, I 2 =0%; RR =0.49, 95% CI : 0.350.70, P <0.0001, I 2 =0%. 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, I 2 =11%; RR =1.10, 95% CI : 0.861.39,


Introduction
As the cornerstone of primary and secondary prevention of arteriosclerotic cardiovascular disease (ASCVD), statin have been widely used in clinical practice. In recent years, several studies have suggested that intensive statin before percutaneous coronary intervention (PCI) can significantly reduce the level of postoperative myocardial damage markers, the incidence of perioperative myocardial infarction and short-term cardiovascular events [1][2][3] . Current clinical practice guidelines recommend high-dose statin loading before PCI in Europe and the United States [4][5] . However, the research on this field was very limited in Chinese population and no corresponding meta-analysis involving hard clinical endpoints has been published so far. In addition, there were significant differences in statin metabolism between Chinese and Western people [6] . It was unknown whether this would affect the outcome of intensive statin treatment. This paper intended to evaluate the efficacy and safety of intensive statin compared with non-intensive statin pretreatment before PCI in Chinese population through meta-analysis.

Search strategy
A comprehensive search of electronic databases including PubMed, EMBASE, and Cochrane Library was performed. The search was limited from the inception up to December 2019, and of English language. Search terms included "intensive", "intensity", "high", "load", "loading", "statin", "atorvastatin", "rosuvastatin", "percutaneous coronary intervention", "PCI" and connected using the logical word "AND" or "OR". It was worth mentioning that in order to avoid missing important literatures, retrieval type was not included some terms such as "China" or "Chinese". We checked the location of the research center and the specific inclusion criteria in the article to comprehensively determine the patient was Chinese. The references of the identifed articles and relevant reviews were screened to include other potentially suitable trials.

Inclusion and exclusion criteria
Studies satisfying the following criteria were eligible: (1) randomized controlled trials (RCTs); (2) the patient was Chinese; (3) the patient with emergency or elective PCI; (4) preoperative interventions for intensive and non-intensive statin therapy which included moderate-intensity statin, placebo and no statin pretreatment; (5) high-intensity statin therapy referred to atorvastatin≥40mg/d or rosuvastatin≥20mg/d and moderate-intensity statin therapy referred to atorvastatin 40mg/d or rosuvastatin 20mg/d or equivalent dose statin; (6) outcome indicators included effectiveness and safety. The former referred to major adverse cardiovascular event (MACE) and the latter referred to myalgia/myasthenia and abnormal alanine aminotransferase (ALT). MACE is defined as cardiac death, nonfatal myocardial infarction and target vessel revascularization. Abnormal ALT is defined as ALT levels that rised more than 3 times the upper limit of normal; (7) follow-up lasted for 1~3 months after PCI; (8) literature language was English. Exclusion criteria included any of the following: chronic high-intensity statin therapy before PCI, abnormal liver enzymes (ALT or aspartate aminotransferase [AST] more than 40 U/L); blood creatinine >2 mg/dL, or history of muscle disease. The studies were reviewed by two independent investigators to determine whether they met the inclusion criteria and any disagreement was resolved by consensus.

Data extraction
The baseline data involving study characteristics(first author, year of publication, sample size, intervention, follow-up time), patient characteristics(clinical presentation, statin medication history) and outcome indicators were extracted directly from the articles.
Differences in assessments were resolved by discussing with a third investigator.

Quality assessment
The RCTs were evaluated according to the following methodological criteria recommended by the Cochrane Collaboration: sequence generation, concealment of allocation, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias.

Statistical analysis
We used the RevMan (Version 5.3; Cochrane Collaboration, Oxford, UK) and Stata software (version 12.0; Stata Corporation, College Station, TX, USA) for the meta-analysis and statistical analysis. Dichotomous data were presented as risk ratios (RR) with 95% confdence intervals (CI).The heterogeneity was evaluated using I 2 and p value based on Chi-square test. I 2 ≤50% or p≥0.1 did not demonstrate a signifcant heterogeneity and a fixed-effects model was used. I 2 50% or p 0.1 indicated a signifcant heterogeneity, and therefore, a random-effects model was applied. Subgroup analysis was carried out to explore the sources of heterogeneity. Sensitivity analyses were performed by excluding sequentially one study at a time to test the robustness of the results. Potential publication bias was assessed with a funnel plot and Egger's regression asymmetry test. All p values were two-sided, and results were considered statistically signifcant when the value of p 0.05.

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][8][9][10][11][12][13][14][15][16][17][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.

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] 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][12][13][14]16,18] Figure S1a; RR=0.49, 95%CI: 0.35~0.70, p<0.0001, I 2 =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] .

Discussion
Some studies have been completed on intensive statin therapy before PCI. In 2013, the ALPACS study took the lead in exploration in Asia [20] . In terms of safety, no significant differences were found in liver enzymes, creatine kinase and other indicators.
In addition to multi-center clinical studies, many scholars tried to find further answers with meta-analysis. In 2013, Guo et al.conducted a meta-analysis on the impact of sequential statin therapy on the prognosis of Chinese patients with PCI [21] . 10 studies involving 1015 patients were included in this article. The results suggested a significant reduction in the incidence of MACE within 6 months. Since some patients in experimental group just received intensive statin treatment after PCI, the subjects were not entirely consistent with the characteristics discussed in this paper. In 2017, a systematic review and meta-analysis involving 11 RCTs with 802 patients was performed by Ye et al [22] .
Compared with preoperative rosuvastatin 10mg/d, using loading dose of 20 mg/d before PCI could significantly reduce cTnT and hs-CRP levels 24 hours and LDL-C, TC, and TG levels 30 days after PCI. However, the clinical indicators analyzed and evaluated in this article were surrogate indicators, which did not involve cardiovascular end point events, nor did they examine the safety. In 2018, Cao et al. discussed the effectiveness of highdose statin before PCI in reducing cardiovascular events in Asian populations [23] . The systematic review included 7 RCTs involving 1381 patients, all of whom were Chinese or Korean. The analysis results indicated that the incidence of MACE and perioperative myocardial infarction in the intensive statin group were significantly lower than those in the control group. This article did not discuss the benefits of the Chinese population through subgroup analysis.
Compared with the previously published meta-analysis, this article was improved in the following aspects. First of all, four new studies published after 2014 were included in this paper [7][8][9][10] . The full paper included 12 RCTs with 3183 patients. It meant the total number of studies as well as patients exceeded any previously published meta-analysis. Secondly, the population involved in this paper was all Chinese, so the interference of other Asian populations such as Korean population was removed. Thirdly, new outcome indicators such as cardiac death and target vessel revascularization were established to make the data more complete.
An important finding of this study was that the subgroup analysis could eliminate the heterogeneity of the overall population, which suggested the benefits of different treatment were not consistent. On the one hand, people received high-intensity statin could benefit from patients received placebo or no statin treatment before PCI. This conclusion was consistent with the results of previous studies involving Western populations. On the other hand, there were no statistically differences in MACE and other outcome indicators between patients received high-intensity and patients received moderate-intensity statin preoperatively, which suggested two regimens had a consistent effect on short-term outcomes. We further searched the database and found the lack of RCTs of two regimens in Western populations at present. In fact, there have been reports of racial differences in the pharmacokinetics of statin. With a single dose of 20 mg or 40 mg rosuvastatin, the area under the curve and peak blood concentration of Chinese were 1.79, 1.89, 2.31, and 2.36 times that of Caucasians, respectively [24][25] . Differences in race sensitivity to statin may be related to genetic factors. Genetic differences in metabolic enzymes and drug transporters between Chinese and white may partially explain this phenomenon [6] . However, based on the results of this paper and previous studies, we did not find any racial differences on the efficacy and safety of preoperative intensive statin therapy.
The sensitivity analysis of this study suggested that the results of the ISCAP was the source of heterogeneity which was the largest clinical study to date targeting Chinese patients. Although negative results were obtained, we also noticed there might be some confounding factors that affected the final conclusions. Firstly, about 60% patients enrolled had previously taken low-intensity even moderate-intensity statin and only 40% were statin-naive patients. It was unclear whether statin history could reduce the benefits from intensive treatment in Chinese patients. Secondly, the time of drug administration in the ISCAP was at night before the operation and it was not exactly fixed. Different from it, the time were 2~4 hours or 12 hours before elective PCI and relatively fixed in other trials [7][8][9]11,[13][14][15][16]18] [27][28] . The results of this meta-analysis were consistent with the recommendations of the guidelines and further strengthen the foundation of evidencebased medicine.

Study limitations
This article has the following limitations and deficiencies: (1) The quality of included studies were generally not high. The remaining 11 RCTs were single-center and lacked rigorous trial design except ISCAP. The randomization, blinding and data analysis of these       Additional file 1.docx