Carotid artery stenting (CAS) is an effective method to treat carotid artery stenosis. Compared with carotid endarterectomy (CEA), the trauma is milder, and the hospital stays are shorter. Nevertheless, the risk of periprocedural ischemic brain damage after the operation is higher, with 85%–90% of the cases being asymptomatic and termed silent new ischemic cerebral lesions (sNICL; Bonati et al., 2010; Cho et al., 2017). This will increase the incidence of ischemic stroke or TIA events in the future and affect the cognitive dysfunction of patients (Capoccia et al., 2010; Gensicke et al., 2015). Hence, how to reduce the risk of periprocedural ischemic brain damage in patients with CAS and further improve the safety of CAS has become the focus of recent research.

The efficacy of statins in reducing severe cardiovascular events is mainly due to the reduction in low-density lipoprotein cholesterol (LDL-C), while the lipid-lowering effect of high-dose statins is more substantial (Baigent, 2010, 2). Studies have shown that high-dose atorvastatin can effectively reduce LDL-C concentrations below 70 mg/dl, effectively reducing the incidence of major adverse cardiac and cerebrovascular events (MACCEs) in patients with ischemic stroke or TIA (Amarenco et al., 2020). Therefore, we speculate that applying high-dose statins during the perioperative period of CAS may further reduce periprocedural ischemic brain damage. The Preventing Ischemic brain damage after Carotid Artery Stenting (PICAS) pilot randomized controlled trial (RCT) was to establish the feasibility of investigating whether perioperative treatment with high-dose atorvastatin could reduce the risk of ischemic brain injury and severe adverse cardiovascular events in CAS patients.

From August 2017 to April 2020, 150 patients underwent randomization; 20 did not undergo CAS after the DSA examination and were excluded from the PICAS study (Figure 1). Among the 130 patients, four patients’ DW-MRI did not meet the time requirements of the protocol, and three patients lacked postoperative DW-MRI; therefore, all 7 of those patients were excluded. Additionally, 2 patients took statins for less time than the protocol requirements.

Among the 123 patients, 98 were male, and 25 were female, with an average age of 70.5 ± 8.8 years. There were 61 patients in the elderly group (age > 70) and 62 in the nonelderly group. Fifty patients had symptomatic carotid stenosis, and 73 patients were asymptomatic. Sixty-three patients were enrolled in the high-dose group, and 60 were enrolled in the standard-dose group. All patients finished follow-up. The demographic characteristics, preoperative serological data, and baseline data of the surgical conditions of the two groups are shown in Table 1. The baseline data of the two groups were similar, but there was no significant difference (p > 0.05). All patients used open-loop stents and remote protection devices.

The primary endpoints mainly adopted the ITT principle. Three patients lacked major endpoint events and four patients failed to complete DW-MRI within the required time; therefore, those seven patients were excluded from the statistical total analysis set. Among 123 patients, the total incidence of major endpoint events was 73.2% (90/123). The incidence of major endpoint events in the high-dose group was 69.8% (44/63), among which 42 patients showed sNICL on DW-MRI after the operation; the incidence was 66.7% (42/63). In the high-dose group, 2 patients suffered from ischemic stroke during the perioperative period, 1 patient suffered from retinal embolism during the operation, and the other patient suffered from mild hemiplegia on the second day after the operation. In the standard-dose group, the incidence of major endpoint events was 78.3% (46/60), of which 45 patients showed sNICL on DW-MRI, and the incidence was 75% (45/60). One patient in the standard-dose group developed mild hemiplegia immediately after the operation. The absolute difference in the incidence of major endpoint events between the two groups was 8.5% (HR, 0.705; 95% CI, 0.315–1.576; p = 0.393). The p-values were not significant for the secondary endpoints (Table 2).

A subgroup analysis was performed according to the prestratification of the protocol (Figures 2, 3). In the patients with symptomatic carotid stenosis, the incidence of primary endpoint events was 74% (37/50), of which the incidence in the high-dose group was 63% (17/27) and that in the standard-dose group was 87% (20/23; HR, 0.255; 95% CI, 0.060–1.080; p = 0.054). In the patients with asymptomatic carotid stenosis, the incidence of primary endpoint events was 72.6% (53/73), 75% (27/36) in the high-dose group, and 70.3% (26/37) in the standard-dose group. There was no significant difference in the incidence of major endpoint events between the two groups (HR, 0.792; 95% CI, 0.452–3.564; p = 0.651). Among the elderly patients, the incidence of primary endpoint events was 77% (47/61), of which the incidence in the high-dose group was 44.7% (21/28) and that in the low-dose group was 55.3% (26/33). There was no significant difference between the two groups (HR, 0.808; 95% CI, 0.244, 2.668; p = 0.726). The incidence of primary endpoint events in the nonelderly patients was 69.4% (43/62), among which the incidence in the high-dose group was 62.9% (22/35) and that in the standard-dose group was 74.1% (20/27). There was no significant difference between the two groups (HR, 0.671; 95% CI, 0.221, 2.032; p = 0.479). Regarding the incidence of sNICL, the incidence of the high-dose group was 71.4% (20/28) and that of the standard-dose group was 75.8% (25/33). There was no significant difference between the two groups (HR, 0.800; 95% CI, 0.255, 2.509; p = 0.702). In the nonelderly group, there was an incidence of sNICL of 62.9% (22/35) in the high-dose group, it was 74.1% (20/27) in the low-dose group, and these were not significantly different (HR, 0.592; 95% CI, 0.197, 1.780; p = 0.349).

Sensitivity analyses were performed based on per-protocol (PP) analysis for the primary outcome, and patients who did not receive a loading dose as protocol request were excluded. In our study, one of the patients in each group did not meet the requirements of the PICAS protocol. The PP analysis showed that the incidence of primary endpoint events in the high-dose group was 69.4% (43/62), while that in the standard-dose group was 76.3% (45/59; HR, 0.704; 95% CI, 0.314–1.578; p = 0.393). The incidence of sNICL in the high-dose and standard-dose groups was 66.1% (41/62) and 74.6% (44/59), respectively. Overall, the results of the sensitivity analyses were consistent with the study’s main findings.

We also performed an exploratory analysis of the influence of the different subgroups on the primary endpoint events (Figure 4). The results showed that different sexes might have opposite trends in high-dose statin treatment (p-value for the interaction = 0.047).

None of the patients complained of adverse reactions related to statins during follow-up. Before and after the operation, the serological examination showed that total cholesterol, low-density lipoprotein, alanine transaminase, blood urea, blood urea, and blood uric acid decreased, creatine kinase and lactate dehydrogenase had no apparent changes, and serum creatinine and total bilirubin increased slightly. Nevertheless, they were all within the normal reference value range.

Statins are the cornerstone of drug treatment for patients with atherosclerotic diseases (ASCVDs) and can prevent cardiovascular events. It has been reported that the main mechanism of action for statins is to reduce low-density lipoprotein cholesterol, and the early pleiotropic effect of statins after initiation also has a protective effect on cardiovascular events (Patti et al., 2013). At present, the effect of statins on ischemic brain injury during the CAS perioperative period needs to be proven by higher-level research.

The PICAS pilot RCT explored the effect of perioperative high-dose atorvastatin on new ischemic lesions in the CAS perioperative period, and, due to the study’s experimental nature, the research conclusion is more credible than that of previous observational studies. To the best of our knowledge, this study is mainly aimed at the Asian population and is the first RCT study on the Chinese people. The ARMYDA-9 CAROTID study shows that (Patti et al., 2013) preoperative high-dose atorvastatin (120 mg) can reduce the occurrence of early cerebral ischemia events in European and American countries. Due to ethnic differences in the polymorphisms of the genes of statin-dependent metabolic enzymes and transporters, there are differences in the drug response and safety between Chinese, European, and American populations. Several guidelines indicate that Asian patients may need careful monitoring when using high-intensity statins, which affects their dosing intensity when starting statins (Stone et al., 2014). However, the 2016 Guidelines for the Prevention and Treatment of Dyslipidemia in Adults in China pointed out that the potential increase in benefit and the safety of the maximum allowable dose of statins in the Chinese population have not yet been determined (Lloyd-Jones et al., 2016).

A retrospective cohort study in Japan showed that the oral administration of 20 mg rosuvastatin or 40 mg atorvastatin before surgery can reduce the positive rate of ischemic lesions on DW-MRI after the procedure (Shinozaki et al., 2020). Another prospective cohort showed that taking pitavastatin for 4 weeks before surgery can reduce perioperative ischemic complications (Takayama et al., 2014). However, there were significant differences in total cholesterol and LDL-C baseline values between the treatment and control groups in both studies, with the high-dose group having values that were significantly lower than the control group. In the retrospective cohort study, the usage and dosage of statins in the control group were not mentioned. Therefore, the evidence level of these studies is not high, and the difference in the baseline data reduces the applicability of their research results, which has certain limitations.

The results of this study showed that perioperative high-dose atorvastatin did not reduce the incidence of the primary component outcome within 30 days. However, in patients with symptomatic carotid stenosis receiving CAS, the perioperative administration of high-dose atorvastatin can reduce sNICL on DW-MRI and may reduce the cumulative incidence of sNICL on post-CAS cerebral DW-MRI, TIA or ischemic stroke within 30 days after CAS, since the results show a strong tendency toward statistical significance (p = 0.054).

There was no significant difference in the baseline data among the patients in this study, and no statin-related adverse reactions occurred during the 30-day follow-up. Before and after the operation, the serological examinations showed no abnormal changes in the liver and kidney function indexes, which proved the safety of perioperative atorvastatin and verified our research design. In this study, the total incidence of ischemic events within 30 days was 73.2%, and the incidence of sNICL was 66.7%, which is consistent with previous studies (Müller et al., 2019; Volkers et al., 2019). Nevertheless, compared with recent literature reports, the incidence of sNICL in this study was higher. We consider the following reasons. First, it may be related to our detailed cerebral angiography. Diagnostic angiography can make the incidence of new ischemic lesions in DWI-MRI as high as 24.65% (Al-Hussain et al., 2021). In our study, each subject underwent bilateral internal carotid, vertebral and subclavian arteriography and selective internal carotid angiography. Repeated attempts to push the catheter and guidewire may increase the shedding of thrombus fragments and cause an embolism at the distal end. However, foreign studies usually do not perform cerebral angiography and selective internal carotid angiography. Second, this study’s proportion of male patients was as high as 80%. Some studies have reported that male patients may have an increased incidence of new ischemic lesions after CAS (Pini et al., 2013). In addition, the average age of the subjects in this study (70.54 ± 8.757) was older than that of other studies. Many studies have shown that new ischemic lesions after CAS increase with age. Third, all patients in this study received MRI with a 3.0 T field strength. There are differences in the detection rate of DWI ischemic lesions by MRI with different field strengths. In other studies, the accuracy of detecting new ischemic foci by high-field magnetic resonance is higher than that of 1.5 T field magnetic resonance. It is easier to find new ischemic foci (Bijuklic et al., 2013a,b). Fourth, the subjects in this study underwent MRI within 1–5 days after CAS, while in most other studies, MRIs were completed within 12 to 48 h after CAS. There is evidence that microemboli fragments may still be produced within a few weeks after stent placement, leading to new ischemic foci (Jiang et al., 2011). Therefore, the reexamination of MRI 1–5 days after the operation, as designed in this study, can identify the incidence of NICL after the operation more accurately. Fifth, in all the patients in this study, open-loop stents and distal protective devices were used, and it has been reported that open-loop stents (Wodarg et al., 2018; de Vries et al., 2019) and distal embolization protective devices (Schmidt et al., 2004; Bijuklic et al., 2012) may be risk factors leading to asymptomatic new ischemic brain injury during the perioperative period. Therefore, these factors may lead to a higher incidence of new ischemic focus events in our study than in other studies.

According to the subgroup analysis specified in the PICAS protocol, perioperative high-dose atorvastatin can reduce early sNICL after CAS in patients with symptomatic carotid stenosis, which provides a reliable basis for the application of high-dose atorvastatin in the perioperative period. The exploratory analysis of this study found that high-dose atorvastatin has different influence trends on major endpoint events in different sexes (p = 0.047). We consider that this subgroup has certain limitations, including that it does not meet the principle of randomness and that the sample size is small. Therefore, such results need to be carefully interpreted, and a further clinical trial basis is required to support clinical evidence.

Compared with the ARMYDA-9 CAROTID randomized controlled study [8], the PICAS study did not conclude that intensive lipid-lowering therapy can reduce the risk of NICL after surgery in all patients, which is inconsistent with its results. In addition to the influence of MRI examination time and the operation factors mentioned above, the higher proportion of symptomatic carotid stenosis patients, ulcer plaque, and intraoperative predilation included in the PICAS study is also an important reason. Comparing the proportion of those three variables in the ARMYDA-9 CAROTID study to the PICAS study, the data were 14.1% vs. 40.6%, 29.5% vs. 55.3%, and 19.9% vs. 91.1%, respectively. Previous studies have shown that symptomatic carotid stenosis, ulcer plaque, and predilation are independent risk factors for new ischemic foci during the perioperative period (Rots et al., 2019).

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.

The studies involving human participants were reviewed and approved by Beijing Hospital Ethics Committee. The patients/participants provided their written informed consent to participate in this study.

HW, JL, DW, and JW contributed to the design and conception of the study. HW, JW, PQ, XY, KC, SH, SZ, EL, RL, QG, JL, GD, and DW contributed to the acquisition of data and analysis interpretation of the results. HW, JL, and DW drafted the first version of the manuscript. All authors contributed to the article and approved the submitted version.

The trial was funded by National High Level Hospital Clinical Research Funding with grant numbers (121-2016006 and 121-2018086), the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (no. 2019TX320002), and CAMS Innovation Fund for Medical Sciences (CIFMS; grant number 2021-2M-C&T-B-092).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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