Stroke is a common devastating neurological condition and one of the top causes of disability and mortality worldwide (1, 2). There are two major types: ischemic stroke and hemorrhagic stroke. Of note, acute ischemic stroke (AIS) accounts for ~80% of total strokes (3). In terms of treatment strategy of AIS, timely reperfusion of ischemic tissue to save the ischemic penumbra is the key to avoid severe disability and premature death (4). Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator, which is the only thrombolytic drug approved by the US Food and Drug Administration for AIS (5, 6), is considered to be most effective when administered within the first few hours of stroke onset (7).

For many years, researchers and medical doctors have been looking for a combination therapy to reduce the risk of mortality and improve functional outcomes for AIS patients treated with IVT. Statins, one of the most commonly prescribed medications for treatment of dyslipidemia, have gained attention recently as promising therapeutic agents for neurological conditions (8). Studies in animal models have shown that statins have pleiotropic effects on neuronal survival, angiogenesis, neurogenesis, and brain remodeling in ischemic stroke brain injury (9–12). Thereby, statins have potential neuroprotective and neurorestorative effects for AIS. Previous meta-analyses driven mostly by observational studies showed that statin use in AIS patients may be associated with improved functional outcome and short-term survival (13, 14). Accordingly, a recent guideline from the American Heart Association/American Stroke Association (15) recommends that AIS patients qualified for statin treatment should receive statin therapy as soon as possible. However, this recommendation is mainly based on observational studies of AIS patients with heterogeneous treatments. The existing observational studies on whether the use of statin is associated with any clinical benefit in AIS patients after IVT have reported fragmentary and conflicting results. Thus, a relatively homogeneous set of participants (AIS patients receiving IVT) was enrolled in this meta-analysis.

We hypothesize that statin use is likely to be associated with improved mortality and functional outcomes in AIS patients treated with IVT. Given that there is no randomized clinical trial (RCT) to date evaluating the safety and efficacy of statin therapy in patients with AIS treated with IVT, we performed a comprehensive systematic review and meta-analysis of post-hoc analyses of RCTs and observational studies to investigate its comparative safety and efficacy.

This meta-analysis was conducted strictly in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (16). It was prospectively registered in the PROSPERO (International Prospective Register of Systematic Reviews) registry, with registration number of CRD42021254919. The PRISMA checklist is available in Supplementary Table 1.

There were two major findings in this comprehensive systematic review and meta-analysis with 22 studies involving more than 15,000 participants. The primary finding was that pre-stroke statin use was associated with a potentially higher risk of systematic ICH in AIS patients treated with IVT whereas in-hospital statin use was related with a lower likelihood of symptomatic ICH. The secondary finding was that in-hospital statin use was associated with improved outcome in AIS patients treated with IVT, a finding not observed in patients using statin prior to hospital admission.

According to the American Heart Association/American Stroke Association guidelines updated in 2019 (15), it is reasonable to initiate statin therapy in eligible AIS patients. This is supported by previously published meta-analyses (13, 14), which have shown that the use of statins was associated with improved outcome. However, conflicting data were observed in a subgroup restricted to thrombolysis-treated patients (13, 14, 45). The heterogeneity in the previous studies may be due to several reasons. Firstly, a heterogeneous population undergoing different treatment modalities, including mechanical recanalization, IVT, and intra-arterial thrombolysis, was included. Secondly, the starting time of statin administration, including pre-stroke statin use and in-hospital statin use, was not considered separately. A large multicenter RCT should be the best way to address the question whether the use of statin is associated with any clinical benefit in AIS patients after IVT. Such a trial may be challenging in determining the duration and frequency of statin. However, to date, there is only one small RCT with 310 patients that has investigated the safety and efficacy of intensive statin in the acute phase of ischemic stroke after IVT therapy (46). In this trial, because of the recommendation from the American Heart Association/American Stroke Association guidelines (15), the ethics committee did not approve the no-statin group based on the principles of non-maleficence and beneficence. Therefore, we performed a comprehensive systematic review and meta-analysis of observational studies and post-hoc RCT analyses. Our findings may provide a good basis for determining the use of statin in combination with IVT for patients with AIS.

Our findings have important implications for both policymakers and clinicians. Firstly, previously published systematic reviews have raised concerns that statin therapy could increase the risk of ICH (47, 48). We found that in-hospital statin use probably decreased the risk of systematic ICH. Our findings provide evidence against the theoretical concerns of increased ICH risk with statin treatment. Additionally, previously published systematic reviews found that statin therapy at stroke onset was associated with improved outcome; however, inconclusive results were observed in studies restricted to thrombolysis-treated patients (13, 14, 33, 45). Our meta-analysis found that, in AIS patients receiving IVT, statin use during hospitalization was associated with improved outcome. We consider that our findings further support current international recommendations that AIS patients qualified for statin treatment should receive statin therapy as soon as possible (class of recommendation = II, level of evidence = C) (15). In addition, we believe that pretreatment with statins is not recommended as it does not improve outcomes of AIS patient treated with IVT but increases the risk of ICH.

Our findings might be attributed to the cholesterol-independent (pleiotropic) protective effects of statins. Among these, the pleiotropic effects can inhibit the differentiation of microglia to M1 cells and the release of inflammatory factors after tissue plasminogen activator treatment, thereby protecting neurovascular function. Reducing blood–brain barrier destruction may explain the positive effect of in-hospital statin treatment on the incidence of hemorrhagic transformation and clinical outcomes (49, 50). In a rat model of embolic stroke, combination treatment with atorvastatin and tissue plasminogen activator at 4 h after stroke significantly reduced the infarct volume, improved the neurologic function, and decreased the incidence of hemorrhagic transformation by decreasing neutrophil infiltration and metalloproteinase-9 expression (49). In addition, Lu et al. also found that rosuvastatin combined with tissue plasminogen activator after stroke onset prevented the activation of astrocytes and microglia and reduced the release of inflammatory factors, thereby alleviating blood–brain barrier disruption and hemorrhagic transformation severity (50). However, in stroke patients receiving IVT, the beneficial effects have not been observed consistently in prior statin users, because the beneficial effects of statins may diminish after withdrawal (51, 52), which is in agreement with one previous study (44). In addition, compared with statin treatment after thrombolysis, statin use before stroke significantly increased the fibrinolytic effect and disrupted homeostasis between coagulation and fibrinolysis (25). Hence, it might be possible that pre-stroke statin use associates with a potential higher risk of systematic ICH in AIS patients treated with IVT.

Certain limitations of the present study warrant further consideration. Firstly, this is a meta-analysis of observational studies. Our findings were exclusively based on data of observational studies that predispose to inherent biases, especially selection bias. Secondly, despite the use of adjusted ORs whenever applicable, unmeasured confounders cannot be eliminated due to a lack of individual study patient data. It is possible that differences in cardiovascular risk factors might account for observed associations, while the confounding role of pharmacologic differences in statins cannot be excluded. Thirdly, specific data for statin, including dosage, duration, compliance, pharmacokinetics, and statin type, were not assessed. These parameters could have introduced unmeasured biases in our analysis.

Our study also has several strengths. Firstly, to our knowledge, this is the first systematic review and meta-analysis to explore the effects of starting time of statin administration (pre-stroke or in-hospital) in patients with AIS treated with IVT. Secondly, the majority of the included studies were prospective cohort studies or post-hoc analysis of RCTs with high quality and had adequately adjusted for confounders. This might reduce the influences of other cardiovascular risk factors on the association of pre-stroke statin use with clinical outcomes. Thirdly, the number of available studies and the sample size were large, which allowed us to explore the association of pre-stroke and in-hospital statin administration with clinical outcomes.

In AIS patients treated with IVT, pre-stroke statin use was probably associated with increased risk of ICH, but had no effect on good functional outcome or mortality at 3 months. On the contrary, in-hospital statin use probably decreased the risk of ICH and 3-month mortality and was associated with good functional outcome at 3 months.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

YG: study concept and design, acquisition of data, analysis and interpretation, and critical revision of the manuscript for important intellectual content. XG: acquisition of data, analysis and interpretation, and critical revision of the manuscript for important intellectual content. KZ: critical revision of the manuscript for important intellectual content. QB and JY: acquisition of data. MY: study supervision and critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.

This research was funded by the Science and Technology Department of Qinghai Province (Grant No. 2019-ZJ-7040) and the National Key R&D Program of China (Grant Nos. 2018YFC1312600 and 2018YFC1312601).

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.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.