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\begin{document}

\title{The efficacy and safety of fingolimod plus standardized treatment versus
standardized treatment alone for acute ischemic stroke: a systematic
review and meta-analysis}



\author[1]{Peng Bai}%
\author[1]{Runxiu Zhu}%
\author[1]{Ping Wang}%
\author[1]{Feng Jiang}%
\author[1]{Jin Zhen}%
\author[1]{Yuan Yao}%
\author[2]{Chenhui Zhao}%
\author[1]{Zihong Liang}%
\author[1]{Meiling Wang}%
\author[1]{Bin Liu}%
\author[1]{Min Li}%
\author[1]{Na Li}%
\author[1]{Jun Yuan}%
\affil[1]{Inner Mongolia People's Hospital}%
\affil[2]{The First Affiliated Hospital of Wannan Medical College}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Aims Acute ischemic stroke (AIS) is the most common type of stroke.
Fingolimod is a sphingosine analog that acts on sphingosine-1-phosphate
receptors(S1PR). Recently, the safety and efficacy of fingolimod in both
patients with intracerebral hemorrhage and patients with AIS have been
investigated in proof-of-concept trials. In this review, we performed a
meta-analysis to evaluate the efficacy and safety of fingolimod for AIS.
Methods This study was conducted according to the PRISMA (Preferred
Reporting Items for Systemic review and Meta-Analysis) statement. We
searched for publications on the PubMed, Embase, Cochrane Central
Register of Controlled Trials, Clinical trials, CNKI, Wanfang Data, VIP,
CBM up to August 2021. We compiled 5 studies; a main Meta-analysis
forest plots were conducted for the values of the proportion of patients
whose modified Rankin scale(MRS) score was 0-1 at day 90. A sensitivity
analysis was performed with a mean difference (MD) of the efficacy of
fingolimod plus standardized treatment versus standardized treatment
alone. Random effect karyotype is used for Meta-analysis regardless of
the I2 index. The methodological quality of each randomized controlled
trial (RCTs) was assessed according to the Cochrane Collaboration tool
to assess the risk of bias (ROB). Results A meta-analysis of 5 studies
with 228 participants was conducted. The risk ratio of patients whose
MRS score was 0-1 at day 90 between fingolimod plus standardized
treatment and standardized treatment alone was 2.59. Conclusions The
Fingolimod plus standard treatment group resulted in more ischemic
penumbra rescue and improved clinical function than the standard
treatment.%
\end{abstract}%



\sloppy


\textbf{The efficacy and} \textbf{safety offingolimodplus standardized
treatment versusstandardized treatment alone} \textbf{for acute ischemic
stroke: a systematic review and meta-analysis}

Peng Bai\textsuperscript{1}. baipeng0510@sina.cn

Runxiu Zhu\textsuperscript{1}. zhurunxiu@sina.com

Ping Wang\textsuperscript{1}. nmgwangping68@163.com

Feng Jiang\textsuperscript{1}. jiangwind@126.com

Jin Zhen\textsuperscript{1}. zhenjin2006106@126.com

Yuan Yao\textsuperscript{1}. zhjyq129@163.com

Chenhui Zhao\textsuperscript{2}. zhaochenhui0510@sina.com

Zihong Liang\textsuperscript{3}. liangzihong2011@163.com

Meiling Wang\textsuperscript{1}.wangmeiling4558204@163.com

Bin Liu\textsuperscript{1}.mianfei4865889@163.com

Min Li\textsuperscript{1}.2711382863@qq.com

Na Li\textsuperscript{4}.1416994341@qq.com

Jun Yuan\textsuperscript{1}.13947108585@139.com

Affiliations

1 Department of Neurology, Inner Mongolia People's Hospital No.20 of
Zhaowuda Road, Hohhot 010017, Inner Mongolia, People's Republic of
China.

2 Department of Neurosurgery, The First Affiliated Hospital of Wannan
Medical College, Wuhu, China.

3 Department of psychiatry, Inner Mongolia People's Hospital No.20 of
Zhaowuda Road, Hohhot 010017, Inner Mongolia, People's Republic of
China.

4 Medical Department, Inner Mongolia People's Hospital No.20 of Zhaowuda
Road, Hohhot 010017, Inner Mongolia, People's Republic of China.

These authors contributed equally to this work.

Corresponding author: Peng Bai

Department of Neurology, Inner Mongolia People's Hospital No.20 of
Zhaowuda Road, Hohhot 010017, Inner Mongolia, People's Republic of
China.

E-mail address: baipeng0510@sina.cn

\textbf{Abstract}

\textbf{Aims}

Acute ischemic stroke (AIS) is the most common type of stroke.
Fingolimod is a sphingosine analog that acts on sphingosine-1-phosphate
receptors(S1PR). Recently, the safety and efficacy of fingolimod in both
patients with intracerebral hemorrhage and patients with AIS have been
investigated in proof-of-concept trials. In this review, we performed a
meta-analysis to evaluate the efficacy and safety of fingolimod for AIS.

\textbf{Methods}

This study was conducted according to the PRISMA (Preferred Reporting
Items for Systemic review and Meta-Analysis) statement. We searched for
publications on the PubMed, Embase, Cochrane Central Register of
Controlled Trials, Clinical trials, CNKI, Wanfang Data, VIP, CBM up to
August 2021. We compiled 5 studies; a main Meta-analysis forest plots
were conducted for the values of the proportion of patients whose
modified Rankin scale(MRS) score was 0-1 at day 90. A sensitivity
analysis was performed with a mean difference (MD) of the efficacy of
fingolimod plus standardized treatment versus standardized treatment
alone. Random effect karyotype is used for Meta-analysis regardless of
the I2 index. The methodological quality of each randomized controlled
trial (RCTs) was assessed according to the Cochrane Collaboration tool
to assess the risk of bias (ROB).

\textbf{Results}

A meta-analysis of 5 studies with 228 participants was conducted. The
risk ratio of patients whose MRS score was 0-1 at day 90 between
fingolimod plus standardized treatment and standardized treatment alone
was 2.59.

\textbf{Conclusions}

The Fingolimod plus standard treatment group resulted in more ischemic
penumbra rescue and improved clinical function than the standard
treatment.

\textbf{Key Words} Acute ischemic stroke, Fingolimod, Meta-analysis,
Modified Rankin Scale

\textbf{1.Introduction}

Acute ischemic stroke (AIS) is the most common type of stroke. It has
the characteristics of high morbidity, high mortality, and high
disability, which seriously endangers the health and life of patients.
(1) Effective treatment after AIS will directly affect the prognosis of
patients. (1)

The devastating, often crippling aftermath of stroke makes it second
only to cardiac ischemia as a cause of death worldwide. Therapy for AIS
centers first on rapid revascularization of arterial territories, with
additional focus on managing blood pressure and cerebral
edema.(2)Revascularization is currently achieved by the intravenous
administration of tissue plasminogen activator (tPA) and intravascular
therapy. However, the benefit of tPA is highly time-dependent,
considering that pooled analysis has documented loss of benefit beyond
4.5 h from onset of symptoms.(2-4). Despite numerous clinical trials
conducted to salvage cells from death, no significant breakthrough has
been made to improve the outcome of stroke patients.(2, 5, 6)

Cerebral ischemia-induced cell death swiftly activates the immune system
and initiates inflammation within the brain.(7-11)In an early phase,
these immune responses appear to exacerbate neurovascular dysfunction by
promoting thrombus formation, and accumulation of blood components in
the cerebral microvasculature.(11-13)These changes subsequently
exacerbate the ischemic cascade catalyzing neural cell death in the
penumbra, resulting in the extension of infarction, which potentially
limits the efficacy of pharmacologic or mechanical reperfusion. (11,
14-16)

Fingolimod is a sphingosine analog that acts on sphingosine-1-phosphate
receptors(S1PR). It was approved by the US. Food and Drug Administration
in 2010 as the first oral disease-modifying therapy for the
relapsing-remitting form of multiple sclerosis (MS). (17, 18) Fingolimod
inhibits the egress of lymphocytes from lymph nodes and limits their
recirculation.(18, 19) Additional effects on the integrity of the
blood-brain barrier(BBB) and direct action on neurons and glia that bear
sphingosine-1-phosphate receptor may also contribute to its beneficial
attributes in MS.(18, 20-22) Recently, the safety and efficacy of
fingolimod in both patients with intracerebral hemorrhage and patients
with AIS have been investigated in proof-of-concept trials.(2, 18)
Fingolimod limited the expansion of infarct volume and ameliorated
hemorrhagic transformation in patients with acute ischemic stroke who
received intravenous alteplase within 4.5 hours after stroke onset(11,
18), Meanwhile, in patients with acute anterior circulation occlusion
who are \textgreater{}4.5 hours after disease onset, fingolimod
significantly improved the clinical outcome, reduced secondary lesion
growth, and decreased microvascular permeability. (18) In this
systematic review, we performed a meta-analysis to evaluate the efficacy
and safety of fingolimod for acute ischemic stroke.

\textbf{2.Methods}

\textbf{Protocol and registration}

Our protocol was registered prospectively with the Prospero
website(CRD42021272343), the prospective international register of
systematic reviews available at https://
www.crd.york.ac.uk/prospero/display\_record.php?ID=CRD42021272343.

\textbf{Literature search}

This search was restricted only to articles published in English and
Chinese language. We searched for publications on the PubMed, Embase,
Cochrane Central Register of Controlled Trials, Clinical trials, CNKI,
Wanfang Data, VIP, CBM up to August 2021. We did keyword, and Medical
Subject Heading (MeSH) searches for our theme, and MeSH terms, keywords,
and their synonyms related to ''Fingolimod hydrochloride'' and
''Cerebrovascular Disorders.'' A flowchart of the search strategy is
shown in Fig. 1. One of us used a standardized form of data extraction
to extract data; another person checked it, and revisited the data that
did not match, and resolved the differences through discussion and
consensus.

\textbf{Inclusion and exclusion criteria for the literature}

Studies were included if they fulfilled the following criteria:
Published English and Chinese randomized controlled trial in various
journals regardless of whether the blind method was used or not;
\textgreater{}18 years of age; acute onset of focal neurological
deficit consistent with acute ischemic stroke; fingolimod was given 0.5
mg of the drug orally once daily, for 3 consecutive days plus
standardized treatment in the test group, standardized treatment was
given in control group (standard treatment adhered to current American
Heart Association guidelines including the intravenous administration of
tPA, intravascular therapy, antiplatelet drugs and so on). Exclusion
criterion: Case reports and studies that included fewer than 2
patients, review, meta-analysis; (2)studies from which no data are
provided or data are otherwise not extractable; (3)preexisting
neurologic disability (a score greater than 2 on the MRS); (4)for
studies published in more than one report, the most comprehensive and
up-to-date version will be used.

\textbf{Main variables}

Among the 5 articles selected, we extracted the values of the proportion
of patients whose MRS score was 0-1 at day 90, the change in National
Institutes of Health Stroke Scale (NIHSS) score at 24 hours, the change
in NIHSS score at day 7, the change in NIHSS score at day 90, relative
infarct lesion growth at 24 hours, relative infarct lesion growth at day
7, the incidence of complications/adverse events.

\textbf{Data abstraction}

The titles and abstracts of studies retrieved during the searches were
screened for duplicates by two independent reviewers (PB and PW).
Potentially relevant full-texts were then screened according to our
inclusion and exclusion criteria. The final included studies were then
collated, and the two reviewers used standardized data extraction
formats to extract the data. After extraction, both reviewers matched
their data with each other and revisited papers where disagreements
arose. Any discrepancies were resolved through discussion with other
team members. The extracted data included the following: first author,
study design, site of study, year of publication, language, number of
patients receiving fingolimod, the values of variables If required data
was missing, not reported in the paper, or reported in an unusual form,
the corresponding authors of the respective papers were contacted for
clarification. Supplementary material associated with the main paper was
also explored in such cases.

\textbf{Risk of Bias Assessment and Quality of Evidence}

Two authors (PB and PW)individually assessed the methodological quality
of RCTs using the Cochrane Collaboration tool for assessing the risk of
bias. (23) (24)The criteria were selected a priori and included: (1)
random sequence generation, (2) allocation concealment, (3) blinding of
participants, (4) blinding of outcome assessment, (5) incomplete outcome
data, (6) selective reporting(including reporting of all outcomes and
specifying a primary outcome), and (7) other bias. The evaluated domains
were judged as low risk, high risk, or unclear bias per established
criteria. In the case of evaluation discrepancies, the authors discussed
and came to an agreement.

\textbf{Statistical analysis}

Data analysis of efficacy was performed using statistical software
provided by Revman5.3. Data analysis of safety was performed using
statistical software provided by Stata16.0. For continuous variables,
mean difference (MD) is adopted as the effective index, and the point
estimated value and 95\% confidence interval(CI) of each effect quantity
are given. For the data of median, maximum, and minimum values mentioned
in the included study, combined analysis is carried out after
transformation according to the formula. (25) The analysis was carried
out for categorical variables using the risk ratio (RR), LogRR, and its
95\% CI. The heterogeneity included in the study was analyzed by the
X\textsuperscript{2} test (the test level was axiom 0.1) and evaluated
with the I\textsuperscript{2} index. Random effect karyotype is used for
Meta-analysis regardless of the I\textsuperscript{2} index.

The sensitivity analysis was to remove the individual studies in turn,
then reconduct the Meta-analysis and evaluate the difference between the
results after the exclusion and the original combined results. A p-value
of \textless{}0.05 was considered statistically significant. (24)

\textbf{3.Results}

\textbf{Study identification and selection}

By searching PubMed, Embase, Cochrane Central Register of Controlled
Trials, Clinical trials, CNKI, Wanfang Data, VIP, CBM database dated
until August 2021. The database search identified 731 records. After
removing duplicates, 692 titles were initially screened, and 9
theme-related abstracts were selected for further screening. 4 studies
were excluded because data were not available. Finally, 5 studies were
included in this systematic review(Fig. 1).(1, 2, 11, 18, 26) 4 used the
values of the proportion of patients whose MRS score was 0-1 at day 90
in total,3 used the change in NIHSS score at 24 hours, 2 used the change
in NIHSS score at day 7, 2 used the change in NIHSS score at day 90, 2
used the relative infarct lesion growth at 24 hours, 2 used the relative
infarct lesion growth at day 7.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Fig. 1 Flow chart presenting the process of the study selection for
fingolimod meta-analysis

\textbf{Study characteristics and quality assessment}

Table 1 lists detailed information from the 5 included studies. The
included studies were published between 2014 and 2019. The number of
participants per study ranged from 22 to 90, with a total number of 228.
Patients have received fingolimod were recorded in 114 of 228 (50\%).
All studies were randomized controlled trials.

\textbf{Table 1} Clinical and demographic characteristics of 228
patients from 5 studies included in the systematic review\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
Reference (study) & Research type & Patient No & Country & Language &
Interventions & Outcome measures\tabularnewline
\midrule
\endhead
& & & & & T C &\tabularnewline
Zhang Liantao2019 & RCTs & 90 & China & English & FTY720 ST &
\tabularnewline
De-Cai Tian 2018 & RCTs & 46 & China & English & FTY720 ST &
\tabularnewline
Zilong Zhu 2015 & RCTs & 47 & China & English & FTY720 ST &
\tabularnewline
Ying Fu 2014 & RCTs & 22 & China & English & FTY720 ST &
\tabularnewline
De-Cai Tian 2017 & RCTs & 23 & China & Chinese & FTY720 ST &
\tabularnewline
\bottomrule
\end{longtable}

RCTs: randomized clinical trials, FTY720:fingolimod, ST: standardized
treatment, the proportion of patients whose MRS score was 0,1 at day
90, the change of NIHSS scores over 24 hours,the change of NIHSS
scores at day 7,  the change of NIHSS scores at day 90, relative
infarct lesion growth over 24 hours, relative infarct lesion growth at
day 7

Figure 2 shows the risk of bias assessment of the five randomized
trials; two trials described adequate methods of random sequence
generation, one trial described allocation concealment. In four trials,
the participants were blinded. The rate of the dropout was low in all
trials. None of these studies had incomplete outcome data or selective
outcome reporting. All five studies had no other bias.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Fig. 2 Risk of bias summary for included studies.

Note: A ''+'' stands for low risk, ''-'' for high risk, and ''?'' for
unclear risk.

Figure 3, including four articles, shows a forest plot of the risk ratio
of patients whose MRS score was 0-1 at day 90 between fingolimod plus
standardized treatment and standardized treatment alone. This finding
suggested that the risk ratio of the proportion of patients whose MRS
score was 0-1 at day 90 between fingolimod plus standardized treatment
and standardized treatment alone was 2.59 (95\%CI, 1.48 to 4.56). A
random-effect model was used. Sensitivity analyses were performed by
removing each study in turn and re-analyzed it. No studies were found to
significantly affect heterogeneity.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Fig. 3 Forest plot of the risk ratio of the proportion of patients whose
MRS score was 0-1 at day 90 between fingolimod plus standardized
treatment and standardized treatment alone.

Figure 4(A), including three articles, shows a forest plot of the mean
difference in the change in NIHSS score at 24 hours between fingolimod
plus standardized treatment and standardized treatment alone. This
finding suggested that the mean difference in NIHSS score change at 24
hours of fingolimod plus standardized treatment versus standardized
treatment alone was 2.78 (95\%CI, 1.46 to 4.10). A random-effect model
was used. Sensitivity analyses were performed by removing each study in
turn and re-analyzed it. The application of sensitivity analysis showed
that the study by De-Cai Tian et al. 2017 significantly affected
heterogeneity. Figure 4(B), including two articles, shows a forest plot
of the mean difference in the change in NIHSS score at day 7 between
fingolimod plus standardized treatment and standardized treatment alone.
This finding suggested that the mean difference in NIHSS score change at
day 7 of fingolimod plus standardized treatment versus standardized
treatment alone was 2.59 (95\%CI, -0.27 to 7.26). A random-effect model
was used. Figure 4(C), including two articles, shows a forest plot of
the mean difference in the change in NIHSS score at day 90 between
fingolimod plus standardized treatment and standardized treatment alone.
This finding suggested that the mean difference in NIHSS score change at
day 90 of fingolimod plus standardized treatment versus standardized
treatment alone was 3.98(95\%CI, 1.15 to 6.80). A random-effect model
was used. Figure 4(D), including two articles, shows a forest plot of
the mean difference in the change in relative infarct lesion growth at
24 hours between fingolimod plus standardized treatment and standardized
treatment alone. This finding suggested that the mean difference in
relative infarct lesion growth change at 24 hours of fingolimod plus
standardized treatment versus standardized treatment alone was
-26.46(95\%CI, -43.64 to -9.28). A random-effect model was used. Figure
4(E), including two articles, shows a forest plot of the mean difference
in the change in relative infarct lesion growth at day 7 between
fingolimod plus standardized treatment and standardized treatment alone.
This finding suggested that the mean difference in relative infarct
lesion growth change at day 7 of fingolimod plus standardized treatment
versus standardized treatment alone was -17.42(95\%CI, -32.67 to -2.18).
A random-effect model was used.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Fig. 4 Forest plot of the mean difference in the change in NIHSS score
at 24 hours, NIHSS score at day 7, NIHSS score at day 90, relative
infarct lesion growth at 24 hours, relative infarct lesion growth at day
7 between fingolimod plus standardized treatment and standardized
treatment alone.

\textbf{Safety Outcomes:}

We combined the data retrieved from the five trials for serious adverse
events (SAEs) and adverse events (AEs) such as deaths, myocardial
infarctions, recurrent strokes, hernia, hemorrhage of the digestive
tract, fever (\textgreater{}38 \selectlanguage{ngerman}°C), hemorrhagic transformation at 24
hours, lung infection, urinary tract infection, herpes virus infection,
abnormal laboratory liver-function test, gastrointestinal disorders,
arrhythmia, and macular edema. The collected data of common AEs are
displayed in Table 2. Data analysis was performed using statistical
software provided by Stata16.0.We did not find any significant
difference between the fingolimod and standardized treatment groups in
terms of SAEs and AEs.

Table 2. Safety outcomes in the meta-analysis\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
No.of studies\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
LogRR\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
95\%CI\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
P value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Complications}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Deaths\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-1.08\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-2.59-0.43\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.16\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Myocardial infarctions\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.28\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-1.37-1.92\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.74\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Recurrent strokes\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.26\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-1.39-1.91\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.75\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Hernia\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-0.97\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-2.02-0.07\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.07\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Hemorrhage of the digestive tract\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-0.72\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-2.00-0.56\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.27\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Hemorrhagic transformation at 24 hours\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.94\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-0.20-2.08\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.11\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Fever (\textgreater{}38 \selectlanguage{ngerman}°C)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-0.09\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-0.89-0.71\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.82\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Event}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{All events}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
At least 1 adverse event\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-0.12\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-0.85-0.61\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.75\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Any serious adverse event\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-0.06\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-1.99-1.87\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.95\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Frequent or special interest adverse events}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Lung infection\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.06\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-0.58-0.69\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.86\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Urinary tract infection\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.02\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-0.95-0.99\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.97\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Abnormal laboratory liver-function test\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-0.04\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-2.26-2.18\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.97\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Gastrointestinal disorders\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-0.04\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-2.26-2.18\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.97\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Herpes virus infection\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-0.03\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-1.96-1.90\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.98\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Arrhythmia\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.67\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-1.33-2.66\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.51\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Macular edema\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-0.04\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
-2.26-2.18\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.97\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

RR, relative risk; CI, confidence interval

\textbf{4.Discussion}

This meta-analysis included 5 trials to assess the efficacy and safety
of fingolimod in patients with AIS. Recently, the effectiveness and
safety of fingolimod in patients with AIS have been investigated in some
RCTs.(1, 2, 11, 18, 26). This systematic review and meta-analysis
provide data to support the efficacy and safety of fingolimod for AIS.

\textbf{Theefficacy of Fingolimod}

Our meta-analysis presented that fingolimod resulted in more ischemic
penumbra rescue and improved clinical function. Our primary endpoint
here is based on a proportion of patients with MRS 0--1 at 90 days,
decrease in NIHSS score at 24 hours, decrease in NIHSS score at day 7,
decrease in NIHSS score at 90 days, relative infarct lesion growth at 24
hours, and relative infarct lesion growth at 7 days. The sensitivity
analysis with analyses of the decrease in NIHSS score at 24 hours and at
day 7 showed that the study by De-Cai Tian et al. 2017 significantly
affected heterogeneity. It showed no statistically significant
differences between fingolimod and standardized treatment in NIHSS score
at day 7.

Studies have shown critical linkages between various immunomodulatory
mechanisms in ischemic stroke.(18, 27) Ischemic stroke involves neuronal
dysfunction and complex interactions between other cells, including
vascular endothelial cells, BBB, extracellular matrix, and immune
system.(28-30) Early clinical observations suggest a link between
inflammation and ischemic stroke. Inflammation predisposes people to
ischemic stroke and directly leads to many pathological changes.(29,
31-34) Further understanding of the relationship between immunity and
brain tissue in ischemic stroke is helpful to develop new
immunomodulatory therapy.

Fingolimod significantly reduced infarct expansion at 24h. Fingolimod
not only inhibits lymphocyte infiltration into the brain parenchyma and
protects brain tissue from secondary injury but also, at an earlier
stage, by reducing the number of cells accumulating in the brain
microvasculature. Inhibit the formation of capillary-inflammatory
thrombosis and protect the function of the CNS.(35-38)In addition,
fingolimod also targets intrinsic cells of the CNS, including vascular
endothelial cells. It produces non-immune effects, thereby protecting
brain tissue to some extent. The effect of fingolimod on vascular
endothelial cells can inhibit the proinflammatory and thrombotic states
of endothelial cells and improve the integrity of BBB.(35, 39)

\textbf{The safety of Fingolimod}

Our meta-analysis showed no significant difference in the incidence of
complications and adverse events between fingolimod and the standard
treatment. Because of the brief fingolimod treatment, this drug does not
necessarily produce an immune-deficient state.

\textbf{Strengths and limitations}

Our meta-analysis aimed to present efficacy and safety data. To date, no
meta-analysis has been published about the effects and safety of
fingolimod for AIS. Limitations of this study:1) Although the search
strategy is relatively complete, it does not rule out that eligible
articles are not included 2) A large sample of studies lacked in the
included studies 3) the fact that it only includes randomized controlled
trials 4) It is not distinguished patients who receive different
standard treatments such as the intravenous administration of tPA,
intravascular therapy, antiplatelet drugs and so on. 5) Four of the
included trials came from the same group of investigators 6) Four of the
excluded studies' data are not extractable. The records with
unobtainable data may cause bias in the results. 7) None of the included
trials were double-blinded(most had a PROBE design). 8) High
heterogeneity across studies should not be neglected, though a
random-effects model was used for adjustment. Nonetheless, results were
broadly similar even if sensitivity analysis which decreased the
heterogeneity, were performed. Inherent limitations in the majority of
meta-analyses, such as lack of access to raw data and the variety in
definitions of outcomes in the included studies, are unavoidable. None
of the included studies was adequately sized to evaluate the proposed
primary endpoint. 9) The entire data were derived from patients in
China. More studies are needed that include other ethnic groups. 10)
Different inclusion/exclusion criteria and follow-up periods in the
included studies led to high heterogeneity. 10) The treatment of five
included studies did not cover intravascular therapy. RCTs with greater
patient numbers will be needed for future studies.

\textbf{5.Conclusion}

The Fingolimod plus standard treatment group resulted in more ischemic
penumbra rescue and improved clinical function than the standard
treatment. A higher proportion of patients with MRS 0--1 at 90 days in
the fingolimod plus standard group than the standard treatment group.
Fingolimod plus standard treatment showed a decrease in NIHSS score at
24 hours compared with standard treatment. However, the trend did not
persist through 7 days, and there was no statistically significant
decrease in NIHSS scores at 7 days compared to the standard treatment
group. Still, there was a statistically significant decrease at 90 days.
The fingolimod plus standard treatment group showed less lesion
enlargement at 24 hours than the standard treatment group. The trend
continued for 7 days. There was no significant difference in the
incidence of complications and adverse events between the standard
treatment group and fingolimod plus standard treatment group. Our study
shows that it is feasible to use fingolimod to treat AIS.

\textbf{Abbreviations:} AIS: Acute ischemic stroke, PRISMA: Preferred
Reporting Items for Systemic Reviews and Meta-Analysis, MRS: Modified
Rankin Scale, MD: mean difference, RCTs: Randomized controlled
trials,tPA: tissue plasminogen activator, BBB: blood-brain barrier,
MeSH: Medical Subject Heading, NIHSS: National Institutes of Health
Stroke Scale, CI: confidence interval, RR: risk ratio, SAEs: serious
adverse events, AEs: adverse events, S1PR: sphingosine-1-phosphate
receptors, MS: multiple sclerosis.CNS: Central nervous system, PB: Peng
Bai, NL: Na Li, JY: Jun Yuan, RZ: Runxiu Zhu, PW: Ping Wang, FJ: Feng
Jiang, JZ: Jin Zhen, YY: Yuan Yao, CZ: Chenhui Zhao, ZL: Zihong Liang,
MW: Meiling Wang, BL: Bin Liu, ML: Min Li.

\textbf{Acknowledgments}

This work was supported in part by the Doctoral Research start-up fund
of Inner Mongolia Autonomous Region People's Hospital(Grant No.
2021BS04),the Natural Science Foundation of Inner Mongolia Autonomous
Region of China (Grant No. 2020MS03063), the Natural Science Foundation
of Inner Mongolia Autonomous Region of China(Grant No.2018MS8009), and
the Natural Science Foundation of Inner Mongolia Autonomous Region of
China(Grant No.2019MS08077). The authors thank Chenhui Zhao of the First
Affiliated Hospital of Wannan Medical College for their excellent
technical support. We are thankful to Zihong Liang and Meiling Wang from
Inner Mongolia People's Hospital for her assistance in figure
composition.

\textbf{Conflict of interest statement}

The authors declare no conflict of interest.

\textbf{Funding information}

This work was also funded by the Doctoral Research start-up fund of
Inner Mongolia Autonomous Region People's Hospital(Grant No.
2021BS04),the Natural Science Foundation of Inner Mongolia Autonomous
Region of China (Grant No. 2020MS03063), the Natural Science Foundation
of Inner Mongolia Autonomous Region of China(Grant No.2018MS8009), and
the Natural Science Foundation of Inner Mongolia Autonomous Region of
China(Grant No.2019MS08077).

\textbf{Data availability statement}

All data analyzed during this study are included in this article.

\textbf{Contributors:}

PB, PW, FJ, BL, ML: designed the study, search and screen the
literature, extract and analyzed the data, drafting the
manuscript.PB,JZ,YY,NL:collate the data,guide manuscript writing. JY,
CZ, ZL, MW: revising the manuscript.

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